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Cohen MM Jz, Kreiborg S: A clinical study of the craniofacial  features in Apert syndrome, Int J Oral Maxillofac Surg 25:45-53,  1996.   Hennekam RCM, Krantz ID, Allanson JE: Apert syndrome (acro-  cephalosyndactyly). In Gorlin’s syndromes of the head and neck, ed  5, New York, 2010, Oxford University Press, pp 732-736.   Ibrahimi OA, Chiu ES, McCarthy JG, et al: Understanding the  molecular basis of Apert syndrome, Plast Reconstr Surg 115:264—  270, 2005.   Katzen JT, McCarthy JG: Syndromes involving craniosynostosis and  midface hypoplasia, Otolaryngol Clin North Am 33:1257-1284,  2000.    Kreiborg S, Cohen MM Jr: The oral manifestations of Apert syn-  drome, J Craniofac Genet Dev Biol 12:41-48, 1992.   Marsh JL, Galic M, Vannier MW: Surgical correction of the cranio-  facial dysmorphology of Apert syndrome, Clin Plast Surg 18:251-  275, 1991.   Stavropoulos D, Bartzela T, Bronkhorst E, et al: Dental agenesis pat-  terns of permanent teeth in Apert syndrome, Eur J Oral Sci  119:198—203, 2011.   Hennekam RCM, Krantz ID, Allanson JE: Mandibulofacial dysosto-  sis (Treacher Collins syndrome, Franceschetti-Zwahlen-Klein syn-  drome). In Gorlins syndromes of the head and neck, ed 5, New York,  2010, Oxford University Press, pp 889-892.    Marszalek B, Wéjcicki P, Kobus K, et al: Clinical features, treatment  and genetic background of Treacher Collins syndrome, J App/  Genet 43:223-233, 2002.   Posnick JC: Treacher Collins syndrome: perspectives in evaluation  and treatment, J Oral Maxillofac Surg 55:1120-1133, 1997.   Posnick JC, Ruiz RL: Treacher Collins syndrome: current evaluation,  treatment, and future directions, Cleft Palate Craniofac J 37:434,  2000.   Thompson JT, Anderson PJ, David DJ: Treacher Collins syndrome:  protocol management from birth to maturity, J Craniofac Surg  20:2028—2035, 2009.   Trainor PA, Dixon J, Dixon MJ: Treacher Collins syndrome: etiology,  pathogenesis and prevention, Eur J Hum Genet 17:275—283,  2009.    The abnormalities of the teeth can be divided into those  that are influenced by environmental forces and those that  are idiopathic and appear hereditary in nature. Later parts  of this chapter delineate the idiopathic and hereditary alter-  ations of teeth. Box 2-1 lists the major categories of tooth  alteration that can be affected by environmental influences.  In many cases the cause and effect are obvious; in others  the primary nature of the problem is less distinct.    ‘The ameloblasts in the developing tooth germ are extremely  sensitive to external stimuli, and many factors can result  in abnormalities in the enamel (Box 2-2). When multiple  factors are active simultaneously, the severity of the enamel  defects is worse. The primary hereditary abnormalities of  the enamel that are unrelated to other disorders are termed  amelogenesis imperfecta (see page 92).   Dental enamel is unique in that remodeling does not  occur after initial formation. Therefore, abnormalities in  enamel formation are etched permanently on the tooth  surface. The enamel develops in three major stages:  1) matrix formation, 2) mineralization, and 3) matura-  tion. During matrix formation, the enamel proteins are laid  down. In the next phase, minerals are deposited and the  majority of the original proteins are removed. During the  final maturation period, the enamel undergoes final miner-  alization and the remnants of the original proteins are  removed. In the early stage of mineralization, the enamel is  dull, white, and relatively soft. During the late stage of  maturation, the final hard translucent enamel replaces this  diffuse opaque enamel.   The timing of the ameloblastic damage has a great effect  on the location and appearance of the defect in the enamel.  The cause of the damage does not appear to be of major  importance, because many different local and systemic  stimuli can result in defects that have similar clinical appear-  ances. The final enamel represents a record of all significant  insults received during tooth development. Deciduous    enamel contains a neonatal ring, and the rate of enamel  apposition is estimated to be 0.023 mm/day. Using this  knowledge, the clinician can accurately estimate the timing  of an insult to the deciduous teeth to within 1 week. In the  permanent dentition, the position of the enamel defects  provides a rough estimate of the time of damage; however,  available data on the chronology of tooth development are  derived from a relatively small sample size, and the ranges  of normal values are wide. In addition, gender and racial  variations are not established thoroughly.    Almost all visible environmental enamel defects can be clas-  sified into one of three patterns:   Subtle enamel defects can be masked by saliva, plaque,  or poor illumination. When attempting to detect areas of  altered enamel, the dentition should be cleaned thoroughly;  then it should be dried with gauze. Dental operatory lights  are an ideal light source (direct sunlight should be avoided).  Plaque-disclosing solution can be used to highlight small  defects. The altered enamel may be localized or present on  numerous teeth, and all or part of the surfaces of each  affected tooth may be involved. Enamel hypoplasia is a  quantitative defect and occurs in the form of pits, grooves,  or larger areas of missing enamel. Enamel opacities are a  qualitative defect that may be diffuse or demarcated and  appear as variations in the translucency of the enamel. The  affected enamel is of normal thickness. When diffuse, the  affected teeth demonstrate an increased white opacity with  no clear boundary with the adjacent normal enamel.  Demarcated opacities of enamel show areas of decreased  translucence, increased opacity, and a sharp boundary with  the adjacent enamel. The opacity may be white, cream,  yellow, or brown. Yellow or brown opacities typically are  more porous than white opacities and are more strongly  associated with posteruptive loss of enamel.   ‘The crowns of the deciduous dentition begin to develop  at approximately the fourteenth week of gestation and con-  tinue until the child is 12 months of age. Development of  the crowns of the permanent dentition occurs from approxi-  mately 6 months to 15 years of age. The site of coronal    e Birth-related trauma: Breech presentations, hypoxia, multiple  births, premature birth, prolonged labor   e Chemicals: Amoxicillin, antineoplastic chemotherapy, cigarette  smoke, fluoride, lead, tetracycline, thalidomide, vitamin D   e Infections: Chicken pox, cytomegalovirus (CMV),  gastrointestinal infections, measles, pneumonia, otitis media,  respiratory infections, rubella, syphilis, tetanus, urinary tract  infections   e Inherited diseases: Amelo-cerebro-hypohidrotic syndrome,  amelo-onycho-hypohidrotic syndrome, epidermolysis bullosa,  galactosemia, mucopolysaccharidosis IV, Nance-Horan  syndrome, oculo-dento-osseous dysplasia, phenylketonuria,  pseudohypoparathyroidism, tricho-dento-osseous syndrome,  tuberous sclerosis, vitamin D-dependent rickets   e Medical conditions: Asthma, cardiac disease, celiac disease,  gastrointestinal malabsorption, gastrointestinal  lymphangiectasia, hepatobiliary disease, hyperbilirubinemia,  hypocalcemia, hypothyroidism, hypoparathyroidism, maternal  diabetes, renal disease, toxemia of pregnancy    e Local acute mechanical trauma: Falls, gunshots, neonatal  mechanical ventilation, ritual mutilation, surgery, vehicular  accidents    damage correlates with the area of ameloblastic activity at  the time of the injury; the affected enamel is restricted to  the areas in which secretory activity or active maturation  of the enamel matrix was occurring.   Environmental enamel abnormalities are extremely  common. In a review of more than 1500 children from 12  to 15 years of age in an industrialized nation, the prevalence  of enamel defects in the permanent dentition was 68.4%.  Within this group, 67.2% demonstrated opacities, 14.6%  revealed hypoplasia, and both patterns were seen in 13.4%  of the children. The average number of affected teeth per  individual was 3.6, with greater than 10% of the children  having 10 or more teeth involved.   A common pattern is seen as a result of systemic influ-  ences, such as exanthematous fevers, that occur during the    e Fig. 2-1 Environmental Enamel Hypoplasia. Bilaterally sym-  metrical pattern of horizontal enamel! hypoplasia of the anterior denti-  tion. Maxillary central incisors have been restored previously. (From  Neville BW, Damm DD, White DK: Color atlas of clinical oral pathology,  ed 2, Hamilton, 1999, BC Decker.)    @ Fig. 2-2 Environmental Enamel Hypoplasia. Same patient as  depicted in Fig. 2-1. Note the lack of enamel damage on bicuspids.  (From Neville BW, Damm DD, White DK: Color atlas of clinical oral  pathology, ed 2, Hamilton, 1999, BC Decker.)    first 2 years of life. Horizontal rows of pits or diminished  enamel are present on the anterior teeth and first molars  (Figs. 2-1 and 2-2). The enamel loss is bilaterally symmetric,  and the location of the defects correlates well with the  developmental stage of the affected teeth. A similar pattern  of enamel defects can be seen in the cuspids, bicuspids, and  second molars when the inciting event occurs around the  age of 4 to 5 years (Fig. 2-3).    Another frequent pattern of enamel defects seen in perma-  nent teeth is caused by periapical inflammatory disease of  the overlying deciduous tooth. The altered tooth is called a  Turner tooth (after the clinician whose publications allowed  this problem to be widely recognized). The appearance of  the affected area varies according to the timing and severity  of the insult. The enamel defects vary from focal areas of  white, yellow, or brown discoloration to extensive hypopla-  sia, which can involve the entire crown. The process is noted    @ Fig. 2-3 Environmental Enamel Hypoplasia. Horizontal enamel  hypoplasia of the bicuspids and second molars. Note sparing of the  first molars. (From Neville BW, Damm DD, White DK: Color atlas of  clinical oral pathology, ed 2, Hamilton, 1999, BC Decker.)    ° Fig. 2-4 Turner Hypoplasia. Extensive enamel hypoplasia of man-  dibular first bicuspid secondary to previous inflammatory process  associated with overlying first deciduous molar. (From Halstead CL,  Blozis GG, Drinnan Au, et al: Physical evaluation of the dental patient,  St Louis, 1982, Mosby.)    most frequently in the permanent bicuspids because of their  relationship to the overlying deciduous molars (Figs. 2-4  and 2-5). Anterior teeth are involved less frequently because  crown formation is usually complete before the develop-  ment of any apical inflammatory disease in the relatively  caries-resistant anterior deciduous dentition. Factors that  determine the degree of damage to the permanent tooth by  the overlying infection include the stage of tooth develop-  ment, length of time the infection remains untreated, the  virulence of the infective organisms, and the host resistance  to the infection.   In addition to classic Turner teeth, an increased preva-  lence of demarcated opacities has been reported in the per-  manent successors of carious primary teeth. In one report,  if the primary tooth developed caries, the successor was  twice as likely to demonstrate a circumscribed enamel  defect. In addition, if the primary tooth was extracted for  any reason other than trauma, then the prevalence of a  demarcated enamel defect increased fivefold.    e Fig. 2-5 Turner Hypoplasia. Radiograph of the same tooth  depicted in Fig. 2-4. Note the lack of significant enamel and irregularity  of the dentin surface. (From Halstead CL, Blozis GG, Drinnan Au, et al:  Physical evaluation of the dental patient, St Louis, 1982, Mosby.)    ° Fig. 2-6 Turner Hypoplasia. Extensive coronal hypoplasia of per-  manent maxillary left central incisor secondary to previous trauma to  deciduous central incisor.    Traumatic injury to deciduous teeth also can cause sig-  nificant alterations of the underlying dentition and the for-  mation of Turner teeth. This is not a rare occurrence; up to  45% of all children sustain injuries to their primary teeth.  In a prospective study of 114 children with 255 traumatized  primary teeth, 23% of the corresponding permanent teeth  demonstrated developmental disturbances. The maxillary  central incisors are affected in the majority of the cases; the  maxillary lateral incisors are altered less frequently (Fig.  2-6). In several large reviews, the prevalence of involvement  of the posterior teeth or mandibular incisors was less than  10% of all cases.   ‘The frequency of traumatic damage of the anterior max-  illary dentition is not surprising, considering the common    occurrence of trauma to the deciduous dentition of the  prominent anterior maxilla and the close anatomic relation-  ship between the developing tooth bud and the apices of  the overlying primary incisors. As would be expected, the  clinical appearance of the alteration varies according to the  timing and severity of the damage.   Because of the position of the primary apices relative to  the tooth bud, the facial surface of the maxillary incisors is  the location most frequently affected. Typically, the affected  area appears as a zone of white or yellowish-brown discol-  oration with or without an area of horizontal enamel hypo-  plasia. The trauma also can cause displacement of the  already formed hard-tooth substance in relation to the soft  tissue of the remaining developing tooth. This results in a  bend of the tooth known as dilaceration and can affect  either the crown or the root of a tooth (see page 89). Severe  trauma early in the development of the tooth can result in  such disorganization of the bud that the resultant product  may resemble a complex odontoma (see page 674). Similar  levels of damage late in the formative process can lead to  partial or total arrest in root formation.    In the 1970s, studies from Scandinavia described a pattern  of hypomineralization that predominantly affected the per-  manent first molars, and eventually this was designated as  molar-incisor hypomineralization (MIH) in 2001. The  process is defined as a hypomineralization of one to four  permanent first molars, although the incisors also are  affected frequently. Since this original description, preva-  lence studies have identified MIH not only in Europe but  also in New Zealand, Australia, Brazil, Libya, Kenya, and  Hong Kong. The reported prevalence varies widely from a  low of 2.4% in Germany to a high of 40.2% in Brazil.  Similar prevalence studies from North America are lacking.   Patients affected with MIH have enamel defects of one  or more first permanent molars. The altered enamel may be  white, yellow, or brown, with a sharp demarcation between  the defective and surrounding normal enamel (Fig. 2-7).    re ‘A . ae eS .  ® Fig. 2-7 Molar-Incisor Hypomineralization (MIH). First perma-  nent mandibular molars demonstrating brown hypomaturation with  areas of coronal breakdown.    Yellow or brown opacities appear to be more porous and  often are associated with posteruptive enamel loss. With loss  of enamel, the teeth become more sensitive leading to  avoidance of proper oral hygiene with rapid caries develop-  ment. During attempts at dental therapy, these teeth often  are highly sensitive and very difficult to anesthetize. There  appears to be spectrum of the disease in which only the  molars may be affected or the incisors also may be involved.  The extent of incisor involvement appears to correlate with  the number of affected molars. Affected incisors demon-  strate only white opacities that primarily create aesthetic  problems.   The etiology of MIH remains unclear. It may be multi-  factorial, and suggested influences include the nutritional  status, birth and neonatal factors, previous childhood ill-  nesses, high fever, antibiotics such as tetracycline or amoxi-  cillin, environmental toxins, long duration of breast feeding  (thought to transmit pollutants such as dioxin), and  fluoride.    As modern medicine increases the prevalence of successful  therapy against childhood cancer, it has become evident  that a number of developmental alterations arise secondary  to use of therapeutic radiation or chemotherapy. As would  be expected, developing teeth are affected most severely,  with these therapies producing clinically obvious alterations  most commonly in patients younger than 12 years and most  extensively in those younger than 5 years. The degree and  severity of the developmental alterations are related to the  patient’s age at treatment, the form of therapy, and the dose  and field of radiation, if used.   Although both chemotherapeutic agents and radiation  therapy can be responsible for developmental abnormalities,  the most severe alterations are associated with radiation.  Doses as low as 0.72 Gy are associated with mild develop-  mental defects in both enamel and dentin. As the dose  escalates, so does the effect on the developing dentition and  jaws. Frequently noted alterations include hypodontia,  microdontia, radicular hypoplasia, and enamel hypoplasia  (Fig. 2-8). In addition, mandibular hypoplasia and a reduc-  tion of the vertical development of the lower third of the  face are not rare. The mandibular hypoplasia may be the  direct effect of the radiation, reduced alveolar bone growth  secondary to impaired root development, or (possibly)  growth failure related to altered pituitary function caused  by cranial radiation. Chemotherapy alone results in much  less dramatic alterations but can produce an increased  number of enamel hypoplasias and discolorations, slightly  smaller tooth size, and occasional radicular hypoplasia that  is less severe than that secondary to radiation.    The ingestion of excess amounts of fluoride also can result  in significant enamel defects known as dental fluorosis.  Fluoride appears to create enamel defects through retention  of the amelogenin proteins in the enamel structure. This    @ Fig. 2-8 Hypoplasia Caused by Antineoplastic Therapy. Multiple teeth demonstrating radicular  hypoplasia secondary to radiation and chemotherapy for cancer. (Courtesy of Dr. Bret Johnson.)    @ Fig. 2-9 Dental Fluorosis. Dentition exhibiting lusterless, white,  and opaque enamel with areas of chipping. Notice that the deciduous  teeth are spared.    leads to the formation of hypomineralized enamel that  alters light reflection and creates the appearance of white,  chalky areas. Most of the problems associated with dental  fluorosis are aesthetic, particularly when the anterior teeth  are affected.   ‘The severity of dental fluorosis is dose dependent, with  greater ingestion of fluoride during critical periods of tooth  development causing more severe fluorosis. Interestingly,  individuals who consume similar levels of fluoride may  demonstrate varying degrees of dental fluorosis, suggesting  a genetic influence. The affected teeth are caries resistant,  and the altered tooth structure appears as areas of lusterless  white opaque enamel that may have zones of yellow to  dark-brown discoloration (Figs. 2-9 and 2-10). In the past,  areas of moderate-to-severe enamel fluorosis were termed  mottled enamel. True enamel hypoplasia is uncommon but  can occur as deep, irregular, and brownish pits. Because  other factors can result in a similar pattern of enamel    ® Fig. 2-10 Dental Fluorosis. Diffuse white opaque alteration of the  dentition with areas of brown enamel mottling. Patient spent his child-  hood in Kenya.    damage, a definitive diagnosis requires that the defects be  present in a bilaterally symmetric distribution, plus evi-  dence of prior excessive fluoride intake or elevated levels of  fluoride in the enamel or other tissues should be found.  Initially, fluoride’s ability to reduce caries was thought to  be secondary to its incorporation into developing enamel,  resulting in a stronger and more acid-resistant fluorapatite  crystal. Most investigators now agree that the posteruptive  effects of fluoride are predominant and control caries by  altering the demineralization and remineralization process  that occurs at the tooth/bacterial biofilm interface. Never-  theless, fluoridated water remains an important topical  source of application. Even though fluoride is present in  numerous dental products, foods, and beverages, studies  have shown that cessation of water fluoridation has been  associated with an approximately 18% increase in dental  caries. Consumption of optimally fluoridated water has  been associated with a low frequency of altered enamel,    which usually is mild in degree. However, an increased  prevalence of dental fluorosis has been noted in recent years.  The US Centers for Disease Control and Prevention  reported that from 1986 to 1987, 22.6% of adolescents  demonstrated some degree of fluorosis, whereas a similar  group from 1999 to 2004 revealed a prevalence of 40.7%.  Water fluoridation typically aims for a concentration  between 0.7 to 1.2 ppm. In warm climates, the recom-  mended concentration is 0.7 ppm due to higher consump-  tion of water, whereas regions with more temperate climates  use a concentration of 1 ppm. In 2011, the US Department  of Health and Human Services recommended a nationwide  standardized level of 0.7 ppm of fluoride.   The crowns of the maxillary central incisors are the most  cosmetically important and demonstrate completion of  their development by age 3. Therefore, close monitoring of  all sources of fluoride intake during the first 3 years of life  is recommended strongly. A significant reduction in dental  fluorosis can be seen if brushing with fluoride toothpaste  does not start until after 12 months of age. In addition,  reconstitution of infant formula with fluoridated water  should be avoided. Because of the dissemination of fluoride  through the food supply, the need for supplements in non-  fluoridated areas is declining. Fluoride supplements are rec-  ommended only in non-fluoridated areas for children who  are at high risk for rampant caries.   Congenital syphilis (see page 172) results in a pattern of  enamel hypoplasia that is well known but currently so rare  that lengthy discussion is not warranted. Anterior teeth  altered by syphilis are termed Hutchinson incisors and  exhibit crowns that are shaped like straight-edge screwdriv-  ers, with the greatest circumference present in the middle  one-third of the crown and a constricted incisal edge. The  middle portion of the incisal edge often demonstrates a  central hypoplastic notch. Altered posterior teeth are termed  mulberry molars and demonstrate constricted occlusal  tables with a disorganized surface anatomy that resembles  the bumpy surface of a mulberry.    Most defects in the enamel are cosmetic rather than func-  tional dental problems. Those affected by dental fluorosis  often benefit from surface microabrasion, which produces  a dramatic and permanent improvement in the surface  brown or yellow discoloration. Improvement in the white  surface markings usually requires further restorative den-  tistry. Other types of environmental enamel hypoplasia have  been associated with an increased prevalence of caries, with  one study reporting more than twice the level in patients  with such enamel defects. The decreased caries resistance is  thought to be secondary to focal loss of enamel or because  of imperfect enamel. The areas most frequently associated  with an increased prevalence of caries demonstrate full-  thickness enamel defects. Aesthetically or functionally    defective teeth can be restored through a variety of cosmeti-  cally pleasing techniques, such as the following:    Tooth structure can be lost after its formation by a variety  of influences beyond the obvious cases related to caries or  traumatic fractures. Destruction can begin on the enamel  surface of the crown through abrasion, attrition, erosion, or  abfraction. In addition, loss of tooth structure can begin on  the dentin or cemental surfaces of the teeth by external or  internal resorption.    Tooth wear, also termed tooth surface loss, is a normal physi-  ologic process that occurs with aging but must be consid-  ered pathologic when the degree of destruction creates  functional, aesthetic, or dental sensitivity problems.  Although the four causes of tooth wear (i.e., attrition, abra-  sion, erosion, and abfraction), often are discussed as inde-  pendent pathoses, most of these types of tooth loss are  the result of a combination of influences. Many cases of  attrition are accelerated by the presence of abrasive materials  in the mouth. Erosion or abrasion often further damages  areas of dentin exposed by attrition or abfraction. Areas  softened by erosion are more susceptible to attrition, abra-  sion, and abfraction. The clinician should appreciate that  acquired environmental loss of tooth structure often is  multifactorial.   Most researchers agree that the reported prevalence of  tooth wear is increasing. This is explained partly by a greater  awareness among clinicians and by the adult population  retaining more natural teeth as they age. In addition,  younger individuals appear to exhibit an increased tooth  surface loss that many believe may be caused by a more  acidic diet (e.g., acidic soft drinks, diet foods, and fresh  fruits). This belief is supported by the knowledge that con-  sumption of acidic soft drinks in the United States has  increased 300% over the past 20 years.   Attrition is the loss of tooth structure caused by tooth-  to-tooth contact during occlusion and mastication. The  term comes from the Latin verb attritum, which refers to  the action of rubbing against another surface. Some degree  of attrition is physiologic, and the process becomes more  noticeable with age. When the amount of tooth loss is  extensive and begins to affect aesthetic appearance and  function, the process must be considered pathologic.   The following factors can accelerate tooth destruction:  ¢ Poor-quality or absent enamel (e.g., fluorosis, environ-   Abrasion is the pathologic wearing away of tooth struc-  ture or restoration secondary to the mechanical action of an  external agent. The term arises from the Latin verb abrasum,  which literally means to scrape off'and implies wear or partial  removal through a mechanical process. The most common  cause of abrasion is toothbrushing that combines abrasive  toothpaste with heavy pressure and a horizontal brushing  stroke. Other items frequently associated with dental abra-  sion include pencils, toothpicks, pipe stems, and bobby  pins. Chewing tobacco, cracking nuts and seeds, biting  fingernails or thread, and using dental floss inappropriately  also can cause clinically significant abrasion. When tooth  wear is accelerated by chewing an abrasive substance between  opposing teeth, the process has been termed demastication  and exhibits features of both attrition and abrasion.   Erosion is the loss of tooth structure caused by a non-  bacterial chemical process. The term is derived from the  Latin verb erosum, which literally means to corrode and  implies gradual destruction of a surface by a chemical or  electrolytic process. Some investigators have suggested that  the term dental corrosion would be a more appropriate des-  ignation for this process, but both terms are acceptable,  with little need for a disruption in the long-held nomencla-  ture of tooth wear. Typically, the exposure to an acid is to  blame, but chelating agents are occasionally the primary  cause. Although saliva aids remineralization and contains  bicarbonate with a significant buffering ability, the bicar-  bonate level of saliva is directly correlated to salivary flow,  with the buffering capability reduced in situations with  low flow rates. Causes for salivary gland hypofunction  include salivary gland aplasia, dehydration, therapeutic  radiation, medications, and systemic conditions such as  Sjégren syndrome, bulimia nervosa, and diabetes. The  acidic source often is foods or drinks, but other causes  include some medications (e.g., chewable vitamin C and  aspirin tablets), swimming pools with poorly monitored  pH, chronic involuntary regurgitation (e.g., hiatal hernia,  esophagitis, chronic alcoholism, and pregnancy), voluntary  regurgitation (e.g., psychologic problems, bulimia, and  occupations that require low body weight), and industrial  environmental exposure. Erosion from dental exposure to  gastric secretions is termed perimolysis. Because saliva has  the ability to remineralize tooth surfaces exposed to acid, it  appears that areas of erosive damage must have some abra-  sive component that removes the softened enamel before  remineralization.   Agreement on the prevalence of dental erosion does not  exist. Some investigators believe erosion rarely is responsible  solely for loss of tooth structure. Others support the idea  that there is an epidemic of erosion associated with increased  numbers of young women with eating disorders, teenage  males who ingest large quantities of sports drinks and  soft drinks, middle-aged males with gastroesophageal reflux,  and elderly individuals with age- and medication-related  xerostomia.    Abfraction refers to the loss of tooth structure from  occlusal stresses that create repeated tooth flexure with  failure of enamel and dentin at a location away from the  point of loading. The term is derived from the Latin words  ab and fractio, which respectively translate into away and  breaking. Dentin is able to withstand greater tensile stress  than enamel. When occlusal forces are applied eccentrically  to a tooth, the tensile stress is concentrated at the cervical  fulcrum, leading to flexure that may produce disruption in  the chemical bonds of the enamel crystals in the cervical  areas. Once damaged, the cracked enamel can be lost or  more easily removed by erosion or abrasion.   Like erosion, agreement on the prevalence of abfraction  does not exist. Some propose that abfraction causes most  cervical tooth loss; others believe that little evidence exists  to indicate that this sequence of events actually occurs in  the mouth. Some investigators have suggested that the engi-  neering models used to justify abfraction have not taken  into consideration the cushioning provided by the sur-  rounding bone and periodontium, which may dissipate  occlusal forces acting on a tooth. The pattern of cervical  tooth loss tends to occur at sites with diminished serous  salivary flow and could be explained by the initial loss of  salivary protection rather than excess occlusal forces.  Involvement by abfraction of the facial cervical areas of the  anterior maxillary dentition is very puzzling, because the  flexure during function would occur on the palatal surface  of the tooth, not the facial surface. During function, inves-  tigators have found little evidence that strains in lingual  enamel and dentin are any different from those that occur  in facial sites; however, areas of focal cervical tooth loss  occur almost exclusively on the facial surfaces. Others  contend that the bone on the facial surface of the alveolar  ridge is thinner and more flexible allowing lingual to facial  forces to dissipate tensile loads on the lingual surfaces.  Review of skulls from ancient Australian aborigines has  revealed advanced tooth wear both occlusally and inter-  proximally; and despite evidence of heavy occlusal forces  that one would expect to be associated with abfraction, no  lesions were found. Finally, studies of patients demonstrat-  ing high levels of bruxism failed to demonstrate an associa-  tion between heavy occlusal loads and cervical tooth wear.  Due to the uncertain causes for this pattern of enamel loss,  investigators have warned against destructive, irreversible  treatment such as extensive occlusal adjustments.    Attrition can occur in both the deciduous and the perma-  nent dentitions. As would be expected, the surfaces pre-  dominantly affected are those that contact the opposing  dentition. Most frequently, the incisal and occlusal surfaces  are involved, in addition to the lingual of the anterior maxil-  lary teeth and the labial of the anterior mandibular teeth.  Large, flat, smooth, and shiny wear facets are found in a  relationship that corresponds to the pattern of occlusion.  The interproximal contact points also are affected from the    ® Fig. 2-11 Attrition. Extensive loss of coronal tooth height without  pulp exposure in patient with anterior edge-to-edge occlusion.    ® Fig. 2-12 Abrasion. Horizontal cervical notches on the anterior  mandibular dentition. Note visible pulp canals that have been filled with  tertiary dentin.    vertical movement of the teeth during function. Over time,  this interproximal loss can result in a shortening of the  arch length. Pulp exposure and dentin sensitivity are rare  because of the slow loss of tooth structure and the apposi-  tion of reparative secondary dentin within the pulp chamber  (Fig. 2-11).    Abrasion has a variety of patterns, depending on the cause.  Toothbrush abrasion typically appears as horizontal cervical  notches on the buccal surface of exposed radicular cemen-  tum and dentin (Fig. 2-12). The defects usually have sharply  defined margins and a hard, smooth surface. If acid also is  present, then the lesions are more rounded and shallower.  The degree of loss is greatest on prominent teeth (i.e.,  cuspids, bicuspids, and teeth adjacent to edentulous areas)  and occasionally is more advanced on the side of the arch  opposite the dominant hand. Thread biting or the use of  pipes or bobby pins usually produces rounded or V-shaped  notches in the incisal edges of anterior teeth (Fig. 2-13).  ‘The inappropriate use of dental floss or toothpicks results  in the loss of interproximal radicular cementum and dentin.    @ Fig. 2-13 Abrasion. Notching of the anterior dentition on the right  side caused by long-term use of tobacco pipe.    In patients with erosion, the tooth loss does not correlate  with functional wear patterns or with those typically associ-  ated with known abrasives. The predominant sites of tooth  loss appear to correlate closely with those areas not pro-  tected by the serous secretions of the parotid and subman-  dibular glands. The facial and palatal surfaces of the maxillary  anterior teeth and the facial and occlusal surfaces of the  mandibular posterior teeth are affected most frequently.  Involvement of the lingual surfaces of the entire mandibular  dentition is uncommon, possibly because of the protective  buffering capacity of the submandibular serous saliva.   ‘The classic pattern of dental erosion is the cupped lesion  in which a central depression of dentin is surrounded by  elevated enamel. Cupped areas are seen on the occlusal cusp  tips, incisal edges, and marginal ridges (Fig. 2-14). In con-  trast to abrasion, erosion commonly affects the facial sur-  faces of the maxillary anteriors and appears as shallow  spoon-shaped depressions in the cervical portion of the  crown. The posterior teeth frequently exhibit extensive loss  of the occlusal surface, and the edges of metallic restorations  subsequently may be above the level of the tooth structure    depressions of dentin surrounded by elevated rims of enamel. Note  the amalgam in the first bicuspid that is raised above the surface of  the surrounding depressed dentin.    @ Fig. 2-16 Erosion. Extensive loss of enamel and dentin on the  buccal surface of the maxillary bicuspids. The patient had sucked  chronically on tamarinds (an acidic fruit).    (Fig. 2-15). After a portion of the cuspal enamel has been  lost, the dentin is destroyed more rapidly than the remain-  ing enamel, often resulting in a concave depression of the  dentin surrounded by an elevated rim of enamel (see Fig.  2-15). The more rapid dissolution of the dentin can lead to  undermined enamel that often is lost easily by chipping.  Occasionally, entire buccal cusps are lost and replaced  by ski slope—like depressions that extend from the lingual  cusp to the buccal cementoenamel junction (Fig. 2-16).  When palatal surfaces are affected, the exposed dentin has  a concave surface and shows a peripheral white line of  enamel (Fig. 2-17). Active erosion typically reveals a clean,  unstained surface, whereas inactive sites become stained and  discolored.   Erosion limited to the facial surfaces of the maxillary  anterior dentition often is associated with dietary sources of  acid. When the tooth loss is confined to the incisal portions  of the anterior dentition of both arches, an external envi-  ronmental source is suggested. When erosion is located on  the palatal surfaces of the maxillary anterior teeth and the    @ Fig. 2-17 Erosion. Palatal surfaces of the maxillary dentition in  which the exposed dentin exhibits a concave surface and a peripheral  white line of enamel. The patient had bulimia.    @ Fig. 2-18 Abfraction. Deep and narrow enamel cervical defects  on the facial surface of the mandibular dentition. (From Neville BW,  Damm DD, White DK: Color atlas of clinical oral pathology, ed 2,  Hamilton, 1999, BC Decker.)    occlusal surfaces of the posterior teeth of both dentitions,  regurgitation of gastric secretions is a probable cause. The  location of the tooth structure loss may suggest the cause  of the damage but is not completely reliable.    Abfraction appears as wedge-shaped defects limited to the  cervical area of the teeth and may closely resemble cervical  abrasion or erosion. Clues to the diagnosis include defects  that are deep, narrow, and V-shaped (which do not allow  the toothbrush to contact the base of the defect) and often  affect a single tooth with adjacent unaffected teeth (Fig.  2-18). In addition, occasional lesions are subgingival, a site  typically protected from abrasion and erosion. The lesions  predominantly affect the facial surfaces of the bicuspids and  molars.   In all forms of tooth wear, the process typically proceeds  at a slow rate that allows deposition of tertiary dentin and  prevents pulp exposure, even when extensive loss of tooth  structure is present (see Fig. 2-12). In some cases, especially  in the deciduous dentition, the tooth loss can proceed at a    more accelerated rate, which results in a near or frank expo-  sure of the pulp.    Normal levels of attrition require no therapy, with interven-  tion reserved for those cases that create a pathologic degree  of tooth loss. Early diagnosis and intervention may assist in  preserving the permanent dentition. Before any definitive  action, the clinician must remember that tooth wear almost  invariably has a multifactorial cause. Failure to recognize the  interrelationships of these pathoses can lead to inappropri-  ate therapy and failure of any attempted repair. Intervention  should emphasize detailed diagnosis, preventive measures,  and long-term monitoring. Immediate therapy should be  directed toward resolution of tooth sensitivity and pain, but  identifying the causes of tooth structure loss and protecting  the remaining dentition also are important goals.   In patients affected by dental erosion, preventive inter-  ventions should attempt not only to reduce acid exposure  but also to improve the oral cavity’s ability to resist the effects  of acid. Upon exposure to an acid, the saliva has the ability  to achieve remineralization with time, but teeth are vulner-  able to abrasion before completion of this action. Although  some investigators have recommended a minimum 1-hour  interval between acid exposure and toothbrushing in an  attempt to minimize abrasion of the weakened enamel, other  studies have shown that a 6-hour remineralization time is  necessary to completely reharden enamel softened by acid  exposure. Patients with erosion should limit toothbrushing  to once a day in the morning because of the increased vulner-  ability of acid-etched enamel to abrasion and attrition. Low-  abrasive toothpaste and professional guidance to prevent  inappropriate, overzealous, or too frequent toothbrushing  may assist in reducing associated abrasion. Consumption of  buffering substances such as milk, cheese, and sugar-free  antacids also is thought to be beneficial. Rinsing the mouth  with water after acid exposure and proper hydration have  been suggested to reduce the severity of demineralization and  maintain sufficient salivary flow with appropriate buffering  capability. A suspected common cause of tooth loss is  decreased salivary flow secondary to dehydration, often asso-  ciated with strenuous work or athletic activities and possibly  complicated by use of acidic soft drinks or sports beverages  in the place of water. Chewing xylitol gum has been sug-  gested as a method for decreasing dental erosion by increas-  ing salivary flow after acid exposure, but others have  demonstrated that enamel softened by acid can be damaged  by the adjacent soft tissues during the movements of chewing  in this time of vulnerability. Patients should be informed of  the potential for loss of tooth structure associated with the  overuse of acidic foods and drinks (e.g., wine, carbonated  beverages, foods pickled in acetic acid, and citrate-containing  fruits, fruit juices, and candies), chronic regurgitation, and  improper oral hygiene techniques. Mouth guards and occlu-  sal adjustment can be used to slow nocturnal attrition and  to protect the teeth from frequent exposure to acid from    regurgitation or industrial sources. Dental sensitivity can be  reduced through the use of varnishes, mouthwashes, or  toothpastes containing strontium chloride, stannous fluo-  ride, or monofluorophosphate. If initially unsuccessful, these  agents can be combined with iontophoresis.   Active restorative therapy is premature in the presence of  ongoing tooth wear and should be postponed until the  patient expresses strong aesthetic concerns, exhibits dental  sensitivity that is nonresponsive to conservative interven-  tions, or demonstrates progressive and uncontrollable wear.  Once indicated, the minimum treatment necessary to solve  the problem should be implemented. In lesions thought to  represent abfraction, glass ionomer materials are recom-  mended because of their greater resilience that allows  the material to flex with the tooth. In areas of abrasion, a  material with optimum resistance to the abrasive process  should be chosen. Replacement of lost posterior teeth and  avoidance of edge-to-edge occlusion limit the effects of  attrition. Lost tooth structure can be restored with compos-  ite resins, veneers, onlays, or full crowns. Restorative proce-  dures that do not involve significant removal of remaining  tooth structure are preferable in patients demonstrating  extensive tooth wear.    In addition to loss of tooth structure that begins on the  exposed coronal surfaces, destruction of teeth also can occur  through resorption, which is accomplished by cells located  in the dental pulp (i.e., internal resorption) or in the peri-  odontal ligament (PDL) (i.e., external resorption). Inter-  nal resorption is a relatively rare occurrence, and most cases  develop after injury to pulpal tissues, such as physical  trauma or caries-related pulpitis. The resorption can con-  tinue as long as vital pulp tissue remains and may result in  communication of the pulp with the PDL.   By contrast, external resorption is extremely common;  with close examination, all patients are most likely to have  root resorption on one or more teeth. In one radiographic  review of 13,263 teeth, all patients showed evidence of root  resorption, and 86.4% of the examined teeth demonstrated  external resorption, with an average of 16 affected teeth per  patient. Most areas of resorption are mild and of no clinical  significance, but 10% of patients exhibit unusual amounts  of external resorption.   The potential for resorption is inherent within the peri-  odontal tissue of each patient, and this individual suscepti-  bility to resorption is the most important factor in the  degree of resorption that will occur after a stimulus. The  factors reported to increase the severity of external resorp-  tion are delineated in Box 2-3. Many cases have been termed  idiopathic because no factor could be found to explain the  accelerated resorption. Although local factors may exert a  strong influence, many researchers believe genetic predispo-  sition plays a strong role. One investigation demonstrated  a 5.6-fold increase in root resorption during orthodontics  in patients demonstrating homozygosity for the interleukin-1   Intracoronal bleaching of pulpless teeth  Local involvement by herpes zoster  Paget disease of bone    beta (IL-1B) allele. In addition, examples of families with  generalized idiopathic root resorption and monozygotic  twins presenting with identical patterns of root resorption  have been reported. Genetics appears to be a modifying  factor that can increase the severity of external resorption  when triggered by a secondary influence. When pretreat-  ment radiographs of a given patient exhibit a degree of  resorption beyond that which is normally seen, the clinician  should realize the potential risks involved in initiating pro-  cedures (e.g., orthodontics) that are known to be associated  with an increased risk of external resorption.    Resorption of dentin or cementum can occur at any site  that contacts vital soft tissue. Internal resorption usually is  asymptomatic and discovered through routine radiographs.  Pain may be reported if the process is associated with sig-  nificant pulpal inflammation. Two main patterns are seen:  1) inflammatory resorption and 2) replacement or meta-  plastic resorption (Fig. 2-19). In inflammatory resorption,  the resorbed dentin is replaced by inflamed granulation  tissue. Although this pattern may involve any portion of the  canal, the cervical zone is affected most frequently (and the  pulpal inflammation is usually caused by bacterial invasion).  ‘The resorption continues as long as vital pulp remains; typi-  cally, the coronal pulp is necrotic with the apical portion  remaining vital. The results of pulp testing are variable. In  this pattern, the area of destruction usually appears as a  uniform, well-circumscribed symmetric radiolucent enlarge-  ment of the pulp chamber or canal. When it affects the  coronal pulp, the crown can display a pink discoloration  (pink tooth of Mummery) as the vascular resorptive  process approaches the surface (Fig. 2-20). When it occurs  in the root, the original outline of the canal is lost and a  balloonlike radiographic dilation of the canal is seen (Fig.  2-21). If the process continues, the destruction eventually  can perforate the lateral root surface, which may be difficult  to distinguish from external root resorption. Internal    @ Fig. 2-19 Tooth Resorption. Illustration contrasting the common  patterns of internal and external tooth resorption. Internal resorption  will result in a radiolucent enlargement of the pulp chamber or canal.  In external resorption, the radiolucency is superimposed on the pulp  canal, which should not be enlarged.    resorption secondary to infectious pulpitis may cease upon  necrosis of the responsible cells within the pulp. Although  many cases are progressive, some cases are self-limiting and  usually arise in traumatized teeth or those that have recently  undergone orthodontic or periodontal therapy.   The remaining pattern of internal resorption is termed  replacement or metaplastic resorption. In this form, portions  of the pulpal dentinal walls are resorbed and replaced with  bone or cementum-like bone (see Fig. 2-19). Radiographi-  cally, replacement resorption appears as an enlargement of  the canal, which is filled with a material that is less radiodense  than the surrounding dentin. Because a central zone of the  pulp is replaced with bone, the radiographic appearance  often demonstrates partial obliteration of the canal. The  outline of destruction is less defined than that seen in  inflammatory resorption.   By contrast, external resorption typically appears as a  “moth-eaten” loss of tooth structure in which the radiolu-  cency is less well defined and demonstrates variations in  density (Figs. 2-22 to 2-25). If the lesion overlies the pulp  canal, then close examination demonstrates the retention of  the unaltered canal through the area of the defect. Most  cases involve the apical or midportions of the root. External  resorption can create significant defects in the crowns of  teeth before eruption (see Fig. 2-24). This pattern frequently  is misdiagnosed as preeruptive caries and is thought by some  investigators to be caused by defects in the enamel epithe-  lium that allow connective tissue to come into direct contact  with the enamel.   In reimplanted avulsed teeth, extensive external resorp-  tion of the root is extremely common without rapid and  appropriate intervention (see Fig. 2-23). Ifthe tooth remains  outside of the socket without being placed in a proper  storage medium, then the PDL cells undergo necrosis.    @ Fig. 2-20 Internal Resorption (Pink Tooth of Mummery). A,  Pink discoloration of the maxillary central incisor. B, Radiograph of  same patient showing extensive resorption of both maxillary central  incisors.    Without vital PDL cells, the surrounding bone views the  tooth as a foreign object and initiates resorption and replace-  ment by bone.   External resorption occurring during orthodontics  appears to be influenced most strongly by the patient's  individual susceptibility. However, heavy forces have been  shown to induce a greater degree of resorption, and com-  pressive forces appear more strongly related than tensile  forces. The single most important local factor is the distance  a tooth is moved during therapy. The maxillary anterior  teeth typically are the most severely affected, particularly in    patients who have been treated with premolar extractions.  Movement of teeth with an abnormal root shape (such as,  dilaceration) also has been associated with an increased  severity of external resorption. In patients who have dem-  onstrated significant resorption during therapy, a 2 to 3  month treatment pause has been shown to reduce the final  amount of treatment-associated external resorption.  Occasionally, external resorption may begin in the cervi-  cal area and extend from a small opening to involve a large  area of the dentin between the cementum and the pulp. The  resorption can extend apically into the pulp or coronally  under the enamel and simulate the pink tooth seen in  internal resorption. The cervical pattern of external resorp-  tion often is rapid and has been termed invasive cervical  resorption. In some instances, several teeth may be involved,  and an underlying cause for the accelerated destruction may  not be obvious (multiple idiopathic root resorption)    @ Fig. 2-23 External Resorption. “Moth-eaten” radiolucent altera-  tion of the maxillary left central incisor. The tooth had been reimplanted  after traumatic avulsion. (Courtesy of Dr. Harry Meyers.)    @ Fig. 2-24 External Resorption. Extensive external resorption of  the crown of the impacted right maxillary cuspid. Histopathologic  examination revealed resorption without bacterial contamination or  caries.    (Fig. 2-26). The exact cause of this pattern of resorption has  been elusive, and it may result from a variety of inflamma-  tory, traumatic, or bacterial stimuli affecting the clastic cells  within the PDL. The process has been noted after orth-  odontic therapy, orthognathic surgery, other dentoalveolar  surgery, root scaling or planing, internal bleaching of end-  odontically treated teeth, local trauma, bruxism, and tooth  fracture. Other investigators believe this pattern of    e Fig. 2-25 External Resorption. Diffuse external resorption of  radicular dentin of maxillary dentition. This process arose after initiation  of orthodontics.    ® Fig. 2-26 Multiple Idiopathic Root Resorption. Extensive inva-  sive cervical resorption of several anterior mandibular teeth. (Courtesy  of Dr. Keith Lemmerman.)    resorption can be triggered by periodontal pathogens and  have seen good response to local mechanical débridement  combined with systemic antibiotics.   In addition to invasive cervical resorption, generalized  and progressive external resorption also can affect the apical  portion of the roots. Although this pattern can occur    secondary to an endocrine disturbance or one of a small  number of systemic conditions, many of these cases are  idiopathic and difficult to arrest. On occasion, the idio-  pathic apical resorption demonstrates a bilaterally sym-  metrical pattern that suggests the possibility of occlusal  interferences triggering resorption in a genetically predis-  posed patient (Fig. 2-27).   If difficulty arises in distinguishing external from internal  resorption, then the mesial-buccal-distal rule can be used  through two radiographic exposures: one perpendicular and  one mesial (objects closer to the source of radiation shift  distally). With this technique, the sites of external resorption  appear to shift away from the pulp canal when the radio-  graphs are compared. In addition, the radiographs can reveal  which side of the root is affected in cases of external resorp-  tion. Although these plain film techniques remain valid, the  diagnostic accuracy of cone beam computed tomography  (CT) has been shown to be superior and should be consid-  ered if standard views provide insufficient information.    In patients with internal inflammatory resorption, the pulp  tissue in the area of destruction is vascular and exhibits  increased cellularity and collagenization. Immediately    adjacent to the dentinal wall are numerous multinucleated  dentinoclasts, which are histologically and functionally  identical to osteoclasts (Fig. 2-28). An inflammatory  infiltrate characterized by lymphocytes, histiocytes, and  polymorphonuclear leukocytes is not uncommon. In  replacement resorption, the normal pulp tissue is replaced  by woven bone that fuses with the adjacent dentin. External    resorption is similar in appearance, with numerous multi-  nucleated dentinoclasts located in the areas of structure loss.  Areas of resorption often are repaired through deposition of  osteodentin. In large defects, external inflammatory resorp-  tion results in deposition of inflamed granulation tissue,  and areas of replacement with woven bone may also be seen.  Extensive bony replacement in areas of external resorption  can lead to ankylosis.    The treatment of internal and external resorption centers on  the removal of all soft tissue from the sites of dental destruc-  tion. Internal resorption can be stopped consistently if end-  odontic therapy successfully removes all vital pulp tissue  before the process perforates into the PDL. Once perfora-  tion occurs, therapy becomes more difficult and the prog-  nosis is poor. In such cases, initial placement of calcium  hydroxide paste occasionally may result in remineralization  of the site of perforation and stop the resorptive process. If  remineralization of cervical sites of perforation is not suc-  cessful, then surgical exposure and restoration of the defect  may halt the process. Extraction often is necessary for radic-  ular perforations that do not respond to therapy.   The first step in treating external resorption is the iden-  tification and elimination of any accelerating factor. Api-  cally located sites cannot be approached without significant  damage created by attempts at access. Those cases located  in the cervical areas can be treated by surgical exposure,  removal of all soft tissue from the defects, and restoration  of the lost structure of the tooth. Because the cells respon-  sible for the resorption are located within the PDL, end-  odontic therapy is not effective in stopping the process. In  one report of generalized cervical resorption, therapy  directed against local periodontal pathogens (débridement  combined with systemic metronidazole and amoxicillin)  stopped the resorption and was associated with an increased  density of the adjacent crestal bone. In patients with idio-  pathic root resorption, evaluation and elimination of  obvious occlusal interferences appear appropriate.   For avulsed teeth, the best way to prevent resorption is  to maintain PDL vitality by immediate reimplantation or  short-term use of a physiologic storage solution. Teeth reim-  planted with an open apex should be monitored monthly;  for teeth with a closed apex, endodontic therapy is neces-  sary. Avulsed teeth with an open apex and nonvital PDL  cells should not be implanted.    The color of normal teeth varies and depends on the shade,  translucency, and thickness of the enamel. In primary teeth,  the normal color is bluish white, whereas permanent teeth  tend to be grayish white or yellowish white. With aging, the  enamel thins and the dentin thickens, leading to teeth that    are more yellow or grayish yellow. Abnormal colorations  may be extrinsic or intrinsic. Extrinsic stains occur from  surface accumulation of an exogenous pigment and typi-  cally can be removed with a surface treatment, whereas  intrinsic discolorations arise from an endogenous material  that is incorporated into the enamel or dentin and cannot  be removed by prophylaxis with toothpaste or pumice. Box  2-4 lists the most frequently documented causes of tooth  discolorations.   Dental fluorosis is discussed in the section on environ-  mental effects on the structural development of the teeth  (see page 52). The alterations associated with amelogenesis  imperfecta (see page 92) and dentinogenesis imperfecta  (DGI) (see page 98) are presented later in this chapter in  the text devoted to primary developmental alterations of the  teeth.    Bacterial stains are a common cause of surface staining of  exposed enamel, dentin, and cementum. Chromogenic bac-  teria can produce colorations that vary from green or black-  brown to orange. The discoloration occurs most frequently  in children and usually is seen initially on the labial surface  of the maxillary anterior teeth in the gingival one-third. In  contrast to most plaque-related discolorations, the black-  brown stains most likely are not primarily of bacterial origin  but are secondary to the formation of ferric sulfide from an  interaction between bacterial hydrogen sulfide and iron in  the saliva or gingival crevicular fluid.   Extensive use of tobacco products, tea, or coffee often  results in significant brown discoloration of the surface  enamel (Fig. 2-29). The tar within the tobacco dissolves in  the saliva and easily penetrates the pits and fissures of the  enamel. Smokers (of tobacco or marijuana) most frequently  exhibit involvement of the lingual surface of the mandibular    ® Fig. 2-29 Tobacco Discoloration. Extrinsic brown stains of the  enamel on the lingual surfaces of the anterior mandibular dentition  secondary to long-term tobacco abuse.    incisors; users of smokeless tobacco often demonstrate  involvement of the enamel in the area of tobacco placement.  Stains from beverages also often involve the lingual surface  of the anterior teeth, but the stains are usually more wide-  spread and less intense. In addition, foods that contain  abundant chlorophyll can produce a green discoloration of  the enamel surface.   The green discoloration associated with chromogenic  bacteria or the frequent consumption of chlorophyll-  containing foods can resemble the pattern of green staining  seen secondary to gingival hemorrhage. As would be  expected, this pattern of discoloration occurs most fre-  quently in patients with poor oral hygiene and erythema-  tous, hemorrhagic, and enlarged gingiva. The color results  from the breakdown of hemoglobin into green biliverdin.   A large number of medications may result in surface  staining of the teeth. In the past, use of products containing  high amounts of iron or iodine was associated with signifi-  cant black pigmentation of the teeth. Exposure to sulfides,  silver nitrate, or manganese can cause stains that vary from  gray to yellow to brown to black. Copper, nickel, or cipro-  floxacin may produce a green stain; cadmium, essential oils,  doxycycline, linezolid, glibenclamide, and amoxicillin-  clavulanic acid may be associated with a yellow to brown  discoloration.   More recently, the most frequently reported culprits  include stannous fluoride and chlorhexidine. Fluoride  staining may be associated with the use of 8% stannous  fluoride and is thought to be secondary to the combination  of the stannous (tin) ion with bacterial sulfides. This black  stain occurs predominantly in people with poor oral hygiene  in areas of a tooth previously affected by early carious  involvement. The labial surfaces of anterior teeth and the  occlusal surfaces of posterior teeth are the most frequently  affected. Chlorhexidine is associated with a yellow-brown  stain that predominantly involves the interproximal surfaces  near the gingival margins. The degree of staining varies with  the concentration of the medication and the patient’s sus-  ceptibility. Although an increased frequency has been asso-  ciated with the use of tannin-containing beverages, such as    e Fig. 2-30 Erythropoietic Porphyria-related Discoloration.  Red-brown discoloration of the maxillary dentition.    tea and wine, effective brushing and flossing or frequent  gum chewing can minimize staining. Chlorhexidine is not  alone in its association with tooth staining; many oral anti-  septics, such as Listerine and sanguinarine, also may produce  similar changes.   Congenital erythropoietic porphyria (Giinther disease)  is an autosomal recessive disorder of porphyrin metabolism  that results in the increased synthesis and excretion of por-  phyrins and their related precursors. Significant diffuse dis-  coloration of the dentition is noted as a result of the  deposition of porphyrin in the teeth (Fig. 2-30). Affected  teeth demonstrate a marked red-brown coloration that  exhibits a red fluorescence when exposed to a Wood’s ultra-  violet (UV) light. The deciduous teeth demonstrate a more  intense coloration because porphyrin is present in the  enamel and the dentin; in the permanent teeth, only the  dentin is affected. Excess porphyrins also are present in  the urine, which may reveal a similar fluorescence when  exposed to a Wood’s light.   Another autosomal recessive metabolic disorder, alkap-  tonuria, is associated with a blue-black discoloration termed  ochronosis that occurs in connective tissue, tendons, and  cartilage. On rare occasions, a blue discoloration of the  dentition may be seen in patients who also are affected with  Parkinson disease.   Bilirubin is a breakdown product of red blood cells, and  excess levels can be released into the blood in a number of  conditions. The increased amount of bilirubin can accumu-  late in the interstitial fluid, mucosa, serosa, and skin, result-  ing in a yellow-green discoloration known as jaundice (see  page 765). During periods of hyperbilirubinemia, develop-  ing teeth also may accumulate the pigment and become  stained intrinsically. In most cases the deciduous teeth are  affected as a result of hyperbilirubinemia during the neonatal  period. The two most common causes are erythroblastosis  fetalis and biliary atresia. Other diseases that less frequently  display intrinsic staining of this type include the following:  e Premature birth  e ABO incompatibility    @ Fig. 2-31 Hyperbilirubinemia-Related Discoloration. Diffuse  grayish-blue discoloration of the dentition. Cervical portions are stained  most intensely. (Courtesy of Dr. John Giunta.)   The extent of the dental changes correlates with the  period of hyperbilirubinemia, and most patients exhibit  involvement limited to the primary dentition. Occasionally,  the cusps of the permanent first molars may be affected. In  addition to enamel hypoplasia, the affected teeth frequently  demonstrate a green discoloration (chlorodontia). The  color is the result of the deposition of biliverdin (the break-  down product of bilirubin that causes jaundice) and may  vary from yellow to deep shades of green (Fig. 2-31). The  color of tooth structure formed after the resolution of the  hyperbilirubinemia appears normal. The teeth often dem-  onstrate a sharp dividing line, separating green portions  (formed during hyperbilirubinemia) from normal-colored  portions (formed after normal levels of bilirubin were  restored).   Coronal discoloration is a frequent finding after trauma,  especially in the deciduous dentition. Posttraumatic injuries  may create pink, yellow, or dark-gray discoloration. Tempo-  rary pink discoloration that arises 1 to 3 weeks after trauma  may represent localized vascular damage and often returns  to normal in 1 to 3 weeks. In these instances, periapical  radiographs are warranted to rule out internal resorption  that may produce a similar clinical presentation. A yellow  discoloration is indicative of pulpal obliteration, termed  calcific metamorphosis, and is discussed more fully in  Chapter 3 (see page 114). Occasionally, during a postmor-  tem examination, a pink discoloration of teeth is found. The  crowns and necks of the teeth are affected most frequently,  and the process is thought to arise from hemoglobin break-  down within the necrotic pulp tissue in patients in whom  blood has accumulated in the head.   A similar pink or red discoloration of the maxillary  incisors has been reported in living patients with leproma-    @ Fig. 2-32 Amalgam Discoloration. Green-gray discoloration of  mandibular central incisor, which had endodontic access preparation  restored with amalgam.    tous leprosy (see page 179). Although controversial, some  investigators believe these teeth are involved selectively  because of the decreased temperature preferred by the caus-  ative organism. This process is thought to be secondary to  infection-related necrosis and the rupture of numerous  small blood vessels within the pulp, with a secondary release  of hemoglobin into the adjacent dentinal tubules.   Dental restorative materials, especially amalgam, can  result in black-gray discolorations of teeth. This most fre-  quently arises in younger patients who presumably have  more open dentinal tubules. Large Class I proximal restora-  tions of posterior teeth can produce discoloration of the  overlying facial surface. In addition, deep lingual metallic  restorations on anterior incisors can significantly stain  underlying dentin and produce visible grayish discoloration  on the labial surface. To help reduce the possibility of dis-  coloration, the clinician should not restore endodontically  treated anterior teeth with amalgam (Fig. 2-32).   Several different medications can become incorporated  into the developing tooth and result in clinically evident  discoloration. The severity of the alterations is dependent  on the time of administration, the dose, and the duration  of the drug’s use. The most infamous is tetracycline, with  the affected teeth varying from bright yellow to dark brown  and, in UV light, showing a bright yellow fluorescence (Fig.  2-33). After chronic exposure to ambient light, the fluores-  cent yellow discoloration fades over months to years into a  nonfluorescent brown discoloration. Often the facial sur-  faces of the anterior teeth will darken while the posterior  dentition and lingual surfaces remain a fluorescent yellow.  ‘The drug and its homologues can cross the placental barrier;  therefore, administration should, if possible, be avoided  during pregnancy and in children up to 8 years of age. All  homologues of tetracycline are associated with discoloration  and include chlortetracycline (gray-brown discoloration)  and demethylchlortetracycline and oxytetracycline (yellow).   One semisynthetic derivative of tetracycline, minocy-  cline hydrochloride, has been shown to produce significant  discoloration of the dentition and also may affect teeth that  are fully developed. Minocycline is a widely used    ° Fig. 2-33 Tetracycline-Related Discoloration. Diffuse brownish  discoloration of the permanent dentition.    medication for the treatment of acne and also is occasionally  prescribed to treat rheumatoid arthritis. Its prevalence of  use is increasing (and, presumably, so will the number of  patients affected with discolored teeth and bone).   Although the mechanism is unknown, minocycline  appears to bind preferentially to certain types of collagenous  tissues (e.g., dental pulp, dentin, bone, and dermis). Once  in these tissues, oxidation occurs and may produce the  distinctive discoloration. Some investigators believe supple-  mentation with ascorbic acid (an antioxidant) can block  formation of the discoloration. No matter the cause, once  the pulp tissues are stained, the coloration can be seen  through the overlying translucent dentin and enamel. The  staining is not universal; only 3% to 6% of long-term users  become affected. In those affected, the period of time before  discoloration becomes evident can range from just 1 month  to several years.   In susceptible individuals, minocycline creates discolor-  ation in the skin, oral mucosa (see page 290), nails, sclera,  conjunctiva, thyroid, bone, and teeth. Coloration of the  bone occasionally results in a distinctive blue-gray appear-  ance of the palate, mandibular tori, or anterior alveolar  mucosa, which represents the black bone showing through  the thin, translucent oral mucosa (Fig. 2-34). Several pat-  terns of staining are noted in the dentition. Fully erupted  teeth typically reveal a blue-gray discoloration of the incisal  three-fourths, with the middle one-third being maximally  involved (see Fig. 2-34). The exposed roots of erupted teeth  demonstrate a dark-green discoloration, although the roots  of developing teeth are stained dark black.   Another antibiotic, ciprofloxacin, is given intravenously  to infants for Klebsiella spp. infections. Although less  notable than tetracycline, this medication also has been  associated with intrinsic tooth staining—usually a greenish  discoloration.    Careful polishing with fine pumice can remove most extrin-  sic stains on the teeth; typically, normal prophylaxis paste    ® Fig. 2-34 Minocycline-Related Discoloration. Dentition demon-  strating grayish discoloration predominantly noted on the incisal half  of the teeth. Note the horizontal bands of bluish alteration of the maxil-  lary and mandibular alveolar ridges. (Courtesy of Dr. Roger Miller.)    is insufficient. Stubborn stains often are resolved by mixing  3% hydrogen peroxide with the pumice or by using bicar-  bonate spray solutions. The use of jet prophylactic devices  with a mild abrasive is the most effective. Recurrence of the  stains is not uncommon unless the cause is reduced or  eliminated. Improving the level of oral hygiene often mini-  mizes the chance of recurrence.   Intrinsic discoloration is much more difficult to resolve  because of the frequent extensive involvement of the dentin.  Suggested aesthetic remedies include external bleaching of  vital teeth, internal bleaching of nonvital teeth, bonded  restorations, composite buildups, laminate veneer crowns,  and full crowns. The treatment must be individualized to  fulfill the unique needs of each patient and his or her spe-  cific pattern of discoloration.    Eruption is the movement of a tooth from its position of  development within the bone to its functional location in  the mouth. After the tooth is in full occlusion, slight erup-  tion continues in order to compensate for normal attrition  and continued vertical growth of the face. Although delayed  eruption is not a rare problem, few well-written reviews  have been published on the subject.   Emergence is the moment of eruption when the first part  of the cusp or crown is visible through the gingiva. This  process normally occurs when the dental root is approxi-  mately two-thirds its final length. Emergence occurs over a  broad chronologic age range and differs according to a  number of influences, such as racial and gender variations.  Eruption is considered delayed if emergence has not  occurred within 12 months of the normal range or by the  time 75% root formation is complete. Box 2-5 lists local  conditions reported in the literature that can be associated    with delayed eruption; Box 2-6 highlights systemic disor-  ders associated with delayed eruption.    The failure of eruption may be localized or diffuse. In many  localized examples, the cause is readily apparent upon radio-  graphic examination when objects are discovered in the  path of eruption. In other cases, the cause is not obvious   Failure of resorption of deciduous tooth  Gingival fibromatosis or hyperplasia  Impaction of deciduous tooth    and may be discovered after surgical exploration (such  as a small intramural odontogenic hamartoma within the  follicular sac). Diffuse delayed eruption often is more  problematic and frequently is associated with a systemic  disorder (Fig. 2-35). An excellent example is presented  during the discussion of hypothyroidism in Chapter 17 (see  page 777).    @ Fig. 2-35 Delayed Eruption. Adult patient presenting with multiple unerupted permanent teeth  without obvious causation. (Courtesy of Dr. Mark Lingen.)    For localized delayed emergence, removal of any pathosis in  the path of eruption may be sufficient to allow eruption to  occur. If eruption does not proceed, surgical exposure  accompanied by orthodontic traction has been shown to be  successful. When the delayed eruption is generalized, the  patient should be evaluated for systemic diseases known to  be associated with the process. Successful resolution of the  underlying disorder often is followed by completion of  eruption.    Teeth that cease to erupt before emergence are impacted.  Some authors subdivide these non-erupted teeth into those  that are obstructed by a physical barrier (impacted) and  those that appear to exhibit a lack of eruptive force (embed-  ded). In many cases a tooth may appear to be embedded;  however, on removal a previously undetected overlying  odontogenic hamartoma or neoplasm is discovered. There-  fore, it appears appropriate to classify all these teeth as  impacted.    Impaction of deciduous teeth is extremely rare; when seen,  it most commonly involves second molars. Analysis of cases  suggests that ankylosis plays a major role in the pathogen-  esis. In the permanent dentition, the most frequently  impacted teeth are the mandibular third molar, followed by  maxillary third molars and maxillary cuspids. In decreasing  order of frequency, impaction also may occur with man-  dibular premolars, mandibular canines, maxillary premo-  lars, maxillary central incisors, maxillary lateral incisors, and  mandibular second molars. First molars and maxillary  second molars are rarely affected.   Lack of eruption most frequently is caused by crowding  and insufficient maxillofacial development. Procedures that  create more space, such as removal of bicuspids for orth-  odontic purposes, are associated with a decreased prevalence  of third molar impaction. Impacted teeth are frequently  diverted or angulated and eventually lose their potential to  erupt (on completion of root development). Other factors  known to be associated with impaction include the  following:  ¢ Overlying cysts or tumors  ¢ Trauma  ¢ Reconstructive surgery  e Thickened overlying bone or soft tissue  ¢ A host of systemic disorders, diseases, and syndromes   Impacted teeth may be partially erupted or completely  encased within the bone (i.e., full bony impaction). In addi-  tion, the impaction may be classified according to the angu-  lation of the tooth in relationship to the remaining dentition:  mesioangular, distoangular, vertical, horizontal, or inverted.  On occasion, a small spicule of nonvital bone may be seen    e Fig. 2-36 Eruption Sequestrum. A radiopaque fragment of  sequestrating bone can be seen overlying an impacted third molar.    radiographically or clinically overlying the crown of par-  tially erupted permanent posterior tooth (Fig. 2-36). The  process is termed an eruption sequestrum and occurs when  the osseous fragment becomes separated from the contigu-  ous bone during eruption of the associated tooth. On occa-  sion, mild sensitivity is noted in the area, especially during  eating.    The choices of treatment for impacted teeth include the  following:  ¢ Long-term observation  ¢ Orthodontically assisted eruption  e Transplantation  ¢ Surgical removal  ‘The presence of infection, nonrestorable carious lesions,  cysts, tumors, or destruction of adjacent tooth and bone  mandates extraction. Surgical removal of impacted teeth is  the procedure performed most frequently by oral and maxil-  lofacial surgeons. The choice of therapy in asymptomatic  cases is an area of hot debate, and no immediate resolution  is obvious. The risks associated with nonintervention  include the following:  ¢ Crowding of dentition  e Resorption, caries, and worsening of the periodontal  status of adjacent teeth (Fig. 2-37)  ¢ Development of pathologic conditions, such as infec-  tions, cysts, and tumors  The risks of intervention include the following:  e Transient or permanent sensory loss  ¢ Alveolitis  ¢ Trismus  e Infection  ¢ Fracture  ¢ Temporomandibular joint (TMJ) injury  ¢ Periodontal injury  ¢ Injury to adjacent teeth  Dental referral patterns provide a variety of perspectives  of different dental practitioners. Many specialists (e.g., oral    ® Fig. 2-37 Impaction-Related Tooth Resorption. Mesioangular  impaction of the right mandibular third molar associated with signifi-  cant resorption of the distal root of the second molar. (Courtesy of Dr.  Richard Brock.)    and maxillofacial surgeons, oral and maxillofacial patholo-  gists) see a large percentage of significant pathologic condi-  tions associated with impacted teeth compared with the  experience of other clinicians. Although pathology rarely is  associated with impacted teeth in children and young adults,  numerous reports have documented an increased prevalence  of problems in the later decades; therefore, any meaningful  prospective studies must be lifelong rather than confined to  just a few years. One review of 2646 pericoronal lesions  submitted to an active oral pathology service revealed that  32.9% of cases had pathologically significant lesions, with  strong relationship between increasing age and the preva-  lence of pericoronal pathosis. In this 6-year review were six  primary squamous cell carcinomas arising from dentigerous  cysts in addition to numerous odontogenic keratocysts and  odontogenic tumors. Because of the frequent occurrence of  significant pericoronal pathology, specialists often recom-  mend extraction over close observation of impacted teeth.  The eruption sequestrum requires no therapy and usually  undergoes spontaneous resorption or exfoliation.    Eruption continues after the emergence of the teeth to  compensate for masticatory wear and the growth of the  jaws. The cessation of eruption after emergence is termed  ankylosis and occurs from an anatomic fusion of tooth  cementum or dentin with the alveolar bone. Although the  areas of union may be too subtle to be detected clinically  and radiographically, histopathologic examination demon-  strates fusion between the affected tooth and the adjacent  bone in almost all cases. Other terms for this process within  the literature include infraocclusion, secondary retention,  submergence, reimpaction, and reinclusion. Secondary  retention is an acceptable term but may be confused with  retained primary teeth, which maintain their emergence.  Submergence, reimpaction, and reinclusion connote an active  depression, and this is not the case.    @ Fig. 2-38 Ankylosis. Deciduous molar well below the occlusal  plane of the adjacent teeth.    The pathogenesis of ankylosis is unknown and may be  secondary to one of many factors. Disturbances from  changes in local metabolism, trauma, injury, chemical or  thermal irritation, local failure of bone growth, and abnor-  mal pressure from the tongue have been suggested. The  periodontal ligament (PDL) might act as a barrier that  prevents osteoblasts from applying bone directly onto  cementum. Ankylosis could arise from a variety of factors  that result in a deficiency of this natural barrier. Such loss  could arise from trauma or a genetically decreased PDL gap.  Other theories point to a disturbance between normal root  resorption and hard tissue repair. Several investigators  believe genetic predisposition has a significant influence and  point to monozygotic twins who demonstrate strikingly  similar patterns of ankylosis to support this hypothesis.    Ankylosis may occur at any age; however, clinically the  condition is most obvious if the fusion develops during the  first two decades of life. Most patients reported in the lit-  erature with obvious alterations in occlusion are between  the ages of 7 and 18 years, with a peak prevalence occurring  in 8- to 9-year-old children. The reported prevalence of  clinically detectable ankylosis in children varies from 1.3%  to 8.9% and has been reported to be as high as 44% in  siblings of those affected.   Although any tooth may be affected, the most com-  monly involved teeth in order of frequency are the man-  dibular primary first molar, the mandibular primary second  molar, the maxillary primary first molar, and the maxillary  primary second molar. Ankylosis of permanent teeth is  uncommon. In the deciduous dentition, mandibular teeth  are affected ten times as often as the maxillary dentition.  The occlusal plane of the involved tooth is below that of  the adjacent dentition (infraocclusion) in a patient with a  history of previous full occlusion (Fig. 2-38). A sharp, solid  sound may be noted on percussion of the involved tooth  but can be detected only when more than 20% of the root  is fused to the bone. Radiographically, absence of the PDL    @ Fig. 2-39 Ankylosis. Radiograph of an ankylosed deciduous  molar. Note the lack of periodontal ligament (PDL) space.    space may be noted; however, the area of fusion is often in  the bifurcation and interradicular root surface, making  radiographic detection most difficult (Fig. 2-39).   Ankylosed teeth that are allowed to remain in position  can lead to a number of dental problems. The adjacent teeth  often incline toward the affected tooth, frequently with the  development of subsequent occlusal and periodontal prob-  lems. In addition, the opposing teeth often exhibit over-  eruption. Occasionally, the ankylosed tooth leads to a  localized deficiency of the alveolar ridge or impaction of the  underlying permanent tooth. An increased frequency of  lateral open bite and crossbite is seen.    Because they are fused to the adjacent bone, ankylosed  teeth fail to respond to normal orthodontic forces, with  attempts to move the ankylosed tooth occasionally result-  ing in intrusion of the anchor teeth. Recommended  therapy for ankylosis of primary molars is variable and  often is determined by the severity and timing of the  process. When an underlying permanent successor is  present, extraction of the ankylosed primary molar should  not be performed until it becomes obvious that exfoliation  is not proceeding normally or adverse occlusal changes are  developing. After extraction of an ankylosed molar, the  permanent tooth will erupt spontaneously in the majority  of cases. In permanent teeth or primary teeth without  underlying successors, prosthetic buildup can be placed to  augment the occlusal height. Severe cases in primary teeth  are treated best with extraction and space maintenance.  Luxation of affected permanent teeth may be attempted  with extraction forceps in an effort to break the ankylosis.  It is hoped that the subsequent inflammatory reaction  results in the formation of a new fibrous ligament in the  area of previous fusion. In these cases, reevaluation in 6  months is mandatory. Finally, several reports have docu-  mented successful repositioning of an ankylosed perma-  nent tooth with a combination of orthodontics, segmental  osteotomy, and distraction osteogenesis.    Gemination  Fusion  Concrescence  Accessory cusps  Dens invaginatus  Ectopic enamel  Taurodontism  Hypercementosis  Accessory roots  Dilaceration    Amelogenesis imperfecta (Al)  Dentinogenesis imperfecta (DGI)  Dentin dysplasia type | (DD-|)  Dentin dysplasia type II (DD-II)  Regional odontodysplasia    Numerous developmental alterations of teeth can occur.  Box 2-7 delineates the major reported alterations, and the  following text pertains to these entities. These alterations  may be primary or arise secondary to environmental influ-  ences (e.g., concrescence, hypercementosis, and dilacera-  tion). For the sake of convenience, both the primary and  the environmental forms will be discussed together.    Variations in the number of teeth that develop are common.  Several terms are useful in the discussion of the numeric  variations of teeth. Anodontia refers to a total lack of tooth  development. Hypodontia denotes the lack of development  of one or more teeth; oligodontia (a subdivision of  hypodontia) indicates the lack of development of six or  more teeth excluding third molars. Hyperdontia is the  development of an increased number of teeth, and the  additional teeth are termed supernumerary. Terms such as  partial anodontia are oxymorons and should be avoided. In  addition, these terms pertain to teeth that failed to develop  and should not be applied to teeth that developed but are  impacted or have been removed.   Ectodermal dysplasia  Ectodermal dysplasia, cleft lip (CL), cleft palate (CP)  Ehlers-Danlos   Hurler  Hypoglossia-hypodactylia  Incontinentia pigmenti  Johanson-Blizzard  Lacrimo-auriculo-dento-digital (LADD)  Lipoid proteinosis  Marshall-White  Melanoleukoderma  Monilethrix-anodontia  Oral-facial-digital type |  Otodental dysplasia  Palmoplantar keratosis, hypotrichosis, cysts of eyelid  Progeria    Genetic control appears to exert a strong influence on  the development of teeth. Hypodontia and hyperdontia  have been noted in patients with a variety of syndromes  (Boxes 2-8 and 2-9). In all of these syndromes, an increased  prevalence of hypodontia or hyperdontia exists, but the  strength of the association varies. Furthermore, the actual  genetic contribution to the increased or decreased number  of teeth may be unclear in some of these conditions. In  addition to these syndromes, an increased prevalence of  hypodontia is noted in patients with nonsyndromic cleft lip  (CL) or cleft palate (CP).   Genetic influences still may affect nonsyndromic numeric  alterations of teeth, because more than 200 genes are known  to play a role in odontogenesis. Because of the complexity of  the system, variations in tooth number arise in a wide variety  of patterns. A large percentage of primary hypodontia cases  appear to be inherited in an autosomal dominant fashion,  with incomplete penetrance and variable expressivity,    whereas a minority of examples presents an autosomal reces-  sive or sex-linked pattern. The environment is not without  its influence, with occasional examples suggesting multifac-  torial inheritance. Several investigators have reported vari-  able expression of hypodontia in monozygotic twins  (confirmed by DNA fingerprinting). This discordance con-  firms the occasional multifactorial nature of the process.  Overall, hypodontia most likely represents a variety of dis-  orders caused by variable genetic and epigenetic factors.   Research has identified a gene mutation in only a small  percentage of nonsyndromic hypodontia cases. Although  this list will continue to lengthen over time, the most fre-  quently implicated genes include the PAX9 gene, the MSX1  gene, and the AX7N2 gene. Other mutations mentioned less  frequently include the He-Zhao deficiency and the EDA,  WNT1OA, and the LTBP3 genes. Although variable expres-  sivity is common, most of these examples represent oligo-  dontia and exhibit numerous missing teeth. Interestingly,  the affected gene tends to correlate to the pattern of missing  teeth. It must be stressed that these genes are involved in  only a very small number of affected patients with hypodon-  tia, and the genetic basis for the vast majority of hypodontia  cases remains elusive.   Less information is available on the genetics of hyper-  dontia; however, like hypodontia, almost every possible  pattern of inheritance has been suggested. In all likelihood,  many cases are multifactorial and arise from a combination  of genetics and environmental influences. In spite of this,  studies on certain kindreds have suggested an autosomal  dominant pattern of inheritance with incomplete pene-  trance, autosomal recessive inheritance with lesser pene-  trance in females, and X-linked inheritance.   Some investigators have implied that hypodontia is a  normal variant, suggesting that humans are in an    intermediate stage of dentitional evolution. A proposed  future dentition would contain one incisor, one canine, one  premolar, and two molars per quadrant. Conversely, others  have suggested that hyperdontia represents atavism—the  reappearance of an ancestral condition. The latter hypoth-  esis is difficult to accept because some patients have had as  many as four premolars in one quadrant, a situation that  has never been reported in other mammals. The most widely  accepted theory is that hyperdontia is the result of a local-  ized and independent hyperactivity of dental lamina.   In contrast, hypodontia correlates with the absence of  appropriate dental lamina. As discussed, the loss of the  developing tooth buds in most instances appears to be  genetically controlled. In spite of this, the environment  most likely influences the final result or, in some cases, may  be responsible completely for the lack of tooth formation.  The dental lamina is extremely sensitive to external stimuli,  and damage before tooth formation can result in hypodon-  tia. Trauma, infection, radiation, chemotherapeutic medica-  tions, endocrine disturbances, and severe intrauterine  disturbances have been associated with missing teeth.    Failure of teeth to form is one of the most common dental  developmental abnormalities, with a reported prevalence of  3% to 10% in permanent teeth when absence of third  molars is excluded. The prevalence increases to 20% if third  molars are considered. A female predominance of approxi-  mately 1.5:1 is reported. Anodontia is rare, and most cases  occur in the presence of hereditary hypohidrotic ectodermal  dysplasia (see page 690). Indeed, when the number of  missing teeth is high or involves the most stable teeth (i.e.,  maxillary central incisors or first molars), the patient should  be evaluated for ectodermal dysplasia. Hypodontia is  uncommon in the deciduous dentition with a prevalence of  less than 1%. Absence of a deciduous tooth is associated  strongly with an increased prevalence of a missing successor.  Missing teeth in the permanent dentition are not rare, with  third molars being the most commonly affected. After the  molars, the second premolars and lateral incisors are absent  most frequently (Fig. 2-40). The teeth least likely to be  missing are the maxillary central incisors and mandibular  first molars and canines. In Caucasians with missing teeth,  approximately 80% demonstrate loss of only one or two  teeth. Ethnic differences have been documented, with Japa-  nese and Chinese populations more frequently having  absent mandibular central incisors when compared to Cau-  casians. In contrast, when compared to Caucasians, Ameri-  can blacks demonstrate a significantly decreased prevalence  of hypodontia and a reduced average number of missing  teeth per individual. In the deciduous dentition, 90% of  missing teeth involve the maxillary lateral incisors and man-  dibular incisors. Hypodontia is associated positively with  microdontia (see page 76), reduced alveolar development,  increased freeway space, anterior malocclusion, and retained  primary teeth (Fig. 2-41).    @ Fig. 2-40 Hypodontia. Developmentally missing maxillary lateral  incisors. Radiographs revealed no underlying teeth, and there was no  history of trauma or extraction.    @ Fig. 2-41 Hypodontia. A, Multiple developmentally missing per-  manent teeth and several retained deciduous teeth in a female adult.  B, The panoramic radiograph shows no unerupted teeth in either jaw.    Mutation of the PAX9 gene creates an autosomal domi-  nant pattern of oligodontia that can involve various teeth  but most commonly affects most of the permanent molars.  In severe cases, loss of the primary molars, second premo-  lars, and permanent mandibular central incisors also may  be seen. Mutation of the M/SXJ gene also is inherited as an  autosomal dominant trait. Those affected with this muta-  tion tend to demonstrate loss of the distal tooth of each  type, with more severely affected individuals also revealing  anterior progression of the agenesis. In these patients, the  most commonly missing teeth are the second premolars and  third molars. In more severe cases, often the maxillary first    premolars and maxillary lateral incisors also are missing.  With the MSXJ mutation, the degree of oligodontia is  severe with an average of approximately 12 missing teeth  per patient. The He-Zhao deficiency arose in a large kindred  from northwest China, whereas the L7BP3 gene was dis-  covered in a Pakistani. Both of these genes are associated  with a highly variable pattern of missing teeth. The EDA  gene is associated with a nonsyndromic X-linked pattern of  hypodontia, which primarily affects the maxillary and man-  dibular central incisors, lateral incisors, cuspids, and premo-  lars. Hypodontia associated with nonsyndromic mutation  of the WNTIOA gene appears limited to maxillary and  mandibular lateral incisors and second premolars.   For dentists and their patients, the most critical discovery  related to hypodontia revolves around the mutation of the  AXIN2 gene. This pattern of oligodontia is inherited as an  autosomal dominant disorder, with the most commonly  missing teeth being the permanent second and third molars,  second premolars, lower incisors, and maxillary lateral inci-  sors. The maxillary central incisors always are present and  usually accompanied by the canines, first premolars, and  first molars. However, the number and type of missing teeth  are highly variable, a typical finding of inheritable oligodon-  tia. Although the missing teeth can produce a significant  oral problem, the presence of the AXZN2 mutation in these  kindreds also has been associated with development of ade-  nomatous polyps of the colon and colorectal carcinoma.  This suggests that patients with similar examples of oligo-  dontia should be questioned closely for a family history of  colon cancer, with further medical evaluation recommended  for those possibly at risk.   Even in kindreds with an obviously inherited pattern of  hypodontia or oligodontia, it must be stressed that, in the  majority of the cases, the genes are yet to be discovered.    ‘The prevalence of supernumerary permanent teeth in whites  is between 0.1% and 3.8%, with a slightly higher rate seen  in Asian populations. Although limited data is available, the  prevalence in American blacks appears significantly higher  with reports documenting an increased frequency up to  nine times that seen in whites. The frequency in the decidu-  ous dentition is much lower and varies from 0.3% to 0.8%.  Approximately 76% to 86% of cases represent single-tooth  hyperdontia, with two supernumerary teeth noted in 12%  to 23%, and three or more extra teeth noted in less than  1% of cases. Single-tooth hyperdontia occurs more fre-  quently in the permanent dentition, and approximately  95% present in the maxilla, with a strong predilection for  the anterior region. However, these widely-accepted data  appear to be associated with a strong racial bias. Limited  prevalence studies in American blacks reveal that fourth  molars are the most common extra teeth, with a compara-  tively low frequency of supernumerary incisors. When all  prevalence studies are combined, the most common site is  the maxillary incisor region, followed by maxillary fourth  molars and mandibular fourth molars, premolars, canines,    ® Fig. 2-42 Hyperdontia (Mesiodens). Erupted supernumerary,  rudimentary tooth of the anterior maxilla.    ® Fig. 2-43 Hyperdontia (Mesiodens). Bilateral inverted supernu-  merary teeth of the anterior maxilla.    © Fig. 2-44 Hyperdontia. Right mandibular dentition exhibiting four  erupted bicuspids.    and lateral incisors (Fig. 2-42). Supernumerary mandibular  incisors are very rare. Although supernumerary teeth may  be bilateral, most occur unilaterally (Fig. 2-43). In contrast  to single-tooth hyperdontia, nonsyndromic multiple super-  numerary teeth occur most frequently in the mandible.  These multiple supernumerary teeth occur most often in the  premolar region, followed by the molar and anterior regions,  respectively (Fig. 2-44).    Although most supernumerary teeth occur in the jaws,  examples have been reported in the gingiva, maxillary tuber-  osity, soft palate, maxillary sinus, sphenomaxillary fissure,  nasal cavity, and between the orbit and the brain. The erup-  tion of accessory teeth is variable and dependent on the  degree of space available; 75% of supernumerary teeth in  the anterior maxilla fail to erupt. Unlike hypodontia, hyper-  dontia is positively correlated with macrodontia (see page  76) and exhibits a 2: 1 male predominance. Although exam-  ples may be identified in older adults, most supernumerary  teeth develop during the first two decades of life.   Several terms have been used to describe supernumerary  teeth, depending on their location. A supernumerary tooth  in the maxillary anterior incisor region is termed a  mesiodens (see Fig. 2-42); an accessory fourth molar is  often called a distomolar or distodens (Fig. 2-45). A pos-  terior supernumerary tooth situated lingually or buccally to  a molar tooth is termed a paramolar (Fig. 2-46).   Supernumerary teeth are divided into supplemental  (normal size and shape) or rudimentary (abnormal shape  and smaller size) types. Rudimentary supernumerary teeth    @ Fig. 2-46 Paramolar. A, Rudimentary tooth situated palatal to a maxillary molar in a patient who also  exhibits hypodontia. B, Radiograph of the same patient showing a fully formed tooth overlying the crown  of the adjacent molar.    are classified further into conical (small, peg-shaped),  tuberculate (barrel-shaped anterior with more than one  cusp), and molariform (small premolar-like or molar-  like). Although odontomas are considered hamartomas and  could be placed within this classification, these lesions  traditionally are included in the list of odontogenic neo-  plasms and are discussed in Chapter 15 (page 674). The  conical mesiodens represents one of the more common  supernumerary teeth and can erupt spontaneously, whereas  tuberculate examples are less frequent and rarely erupt.   On rare occasions, an affected patient can present with  both hypodontia and hyperdontia, which has been termed  hypohyperdontia. The process most commonly involves  missing mandibular incisors followed by second premolars;  in contrast, supernumerary teeth are seen most frequently  in the anterior maxilla followed by supplemental canines or  maxillary premolars.   Occasionally, normal teeth may erupt into an inappro-  priate position (e.g., a canine present between two premo-  lars). This pattern of abnormal eruption is called dental  transposition. Such misplaced teeth have been confused  with supernumerary teeth; but in reality, patients exhibiting  dental transposition have been reported to exhibit an  increased prevalence of hypodontia, not hyperdontia. The  teeth involved most frequently in transposition are the max-  illary canines and first premolars (Fig. 2-47). Crowding or  malocclusion of these normal teeth may dictate reshaping,  orthodontics, or extraction.   Accessory teeth may be present at or shortly after birth.  Historically, teeth present in newborns have been called  natal teeth; those arising within the first 30 days of life are  designated neonatal teeth. This is an artificial distinction,  and it appears appropriate to call all of these teeth natal  teeth (Fig. 2-48). Although some authors have suggested  that these teeth may represent predeciduous supernumerary  teeth, most are prematurely erupted deciduous teeth (not  supernumerary teeth). Approximately 85% of natal teeth  are mandibular incisors, 11% are maxillary incisors, and 4%  are posterior teeth.    e Fig. 2-47 Dental Transposition. Maxillary dentition exhibiting  cuspids and first bicuspids in inappropriate positions bilaterally. (Cour-  tesy of Dr. Wendy Humphrey.)    e Fig. 2-48 Natal Teeth. Mandibular central incisors that were  erupted at birth.    Sequelae associated with hypodontia include abnormal  spacing of teeth, delayed tooth formation, delayed decidu-  ous tooth exfoliation, late permanent tooth eruption, and  altered dimension of the associated gnathic regions. The  management of the patient with hypodontia depends on  the severity of the case. No treatment may be required for  a single missing tooth; prosthetic replacement often is  needed when multiple teeth are absent. Therapeutic options  include removable partial dentures, traditional fixed prosth-  odontics, resin-bonded bridges, or osseointegrated implants  with associated prosthetic crowns. Use of fixed prosthodon-  tics typically is not recommended for children because of  the risk of pulp exposure during abutment preparation and  because further growth can lead to infraocclusion and anky-  losis of teeth held together by the prosthesis. Likewise,  because implants act more like ankylosed teeth than erupt-  ing teeth, their use is not recommended before completion  of skeletal growth except for patients with anodontia. For  these reasons, a removable appliance or resin-bonded bridge  often is appropriate in children and young adults while  waiting for full dental and skeletal maturation.    In some cases of hypodontia, orthodontic therapy may  improve the restorative treatment or even negate its need in  selected patients. Patients with oligodontia exhibit an  increased prevalence of orthodontics-associated external  root resorption. This may be due to the altered root anatomy  or to the extensive tooth movement that is required in some  patients. Follow-up radiographs are recommended after 6  to 9 months of therapy to evaluate the root morphology for  evidence of excessive resorption.   ‘The presence of supernumerary teeth should be suspected  ifa significant delay is observed in the eruption of a localized  portion of the dentition. Because of the decreased clarity in  the anterior portion of a panoramic radiograph, this image  should be combined with occlusal and periapical radiographs  to fully visualize the area. Supernumerary teeth may develop  long after eruption of the permanent dentition. Several pub-  lications have documented supernumerary bicuspids arising  up to 11 years after completion of normal teeth develop-  ment. In patients previously diagnosed with supernumerary  teeth, or in those genetically predisposed, long-term moni-  toring for additional tooth development is warranted.   Early diagnosis and treatment often are crucial in mini-  mizing the aesthetic and functional problems of the adja-  cent teeth. Because only 7% to 20% of supernumerary teeth  exist without clinical complications, the standard of care is  removal of the accessory tooth during the time of the early  mixed dentition. Complications created by anterior super-  numerary teeth tend to be more significant than those asso-  ciated with extra teeth in the posterior regions. Reports have  documented spontaneous eruption of the adjacent denti-  tion in 75% of the cases if the supernumerary tooth is  removed early. After removal of the supernumerary tooth,  full eruption typically occurs within 18 months to 3 years.  Impacted permanent teeth having closed apices or those  associated with a tuberculate mesiodens may show a reduced  tendency for spontaneous eruption. Permanent teeth that  fail to erupt are treated best by surgical exposure with orth-  odontic eruption. Removal of unerupted deciduous teeth is  not recommended, because most will erupt spontaneously.   A consequence of late therapy may include the delayed  eruption, resorption of the adjacent teeth, displacement of  the teeth with associated crowding, dilaceration, malocclu-  sion, diastema formation, or eruption into the nasal cavity.  Supernumerary teeth also predispose the area to subacute  pericoronitis, gingivitis, periodontitis, abscess formation,  and the development of any one of a large number of odon-  togenic cysts and tumors. In selected cases, clinical judg-  ment may not dictate surgical removal, or patient resistance  to therapy may be present. In these instances, regular moni-  toring is appropriate.   A study attempting to determine the optimum time for  removal of mesiodentes in a pediatric population suggested  that removal after age 10 was associated with a higher  prevalence of developmental defects of the adjacent perma-  nent teeth such as dilaceration and root resorption. Although  a cautious surgical approach is necessary to avoid damage  to the adjacent developing incisor, removal of mesiodentes    prior to 6 to 7 years of age appears advantageous in decreas-  ing local developmental complications.   Natal teeth must be approached individually with sound  clinical judgment guiding appropriate therapy. Radiographs  may be difficult to obtain but could be helpful in distin-  guishing premature eruption of a deciduous tooth from a  supernumerary tooth. As stated, the erupted teeth in most  cases represent the deciduous dentition, and removal should  not be performed hastily. If the teeth are mobile and at risk  for aspiration, removal is indicated. The surgical procedure  must ensure complete removal of the associated dental  papillae and epithelial root sheath to prevent formation of  residual root fragments. If mobility is not a problem and  the teeth are stable, then they should be retained. Traumatic  ulcerations of the adjacent soft tissue (Riga-Fede disease)  (see page 260) may occur during breast feeding but often  can be resolved with appropriate measures.    Tooth size is variable among different races and between the  sexes. The presence of unusually small teeth is termed  microdontia; the presence of teeth larger than average is  termed macrodontia. Although heredity is the major factor,  both genetic and environmental influences affect the size of  developing teeth. The deciduous dentition appears to be  affected more by maternal intrauterine influences; the per-  manent teeth seem to be more affected by environment.    Although the size of teeth is variable, the two sides of the  jaws are usually symmetrical. Despite this, when significant  size variation is present, the entire dentition rarely is affected.  Typically, only a few teeth are altered significantly in size.  Differences in tooth sizes cannot be considered in isolation.  Microdontia is associated strongly with hypodontia (see  page 72); macrodontia often is seen in association with  hyperdontia (see page 73). Females demonstrate a higher  frequency of microdontia and hypodontia; males have a  greater prevalence of macrodontia and hyperdontia.    The term microdontia should be applied only when the  teeth are physically smaller than usual. Normal-sized teeth  may appear small when widely spaced within jaws that are  larger than normal. This appearance has been historically  termed relative microdontia, but it represents macrogna-  thia (not microdontia). Diffuse true microdontia is uncom-  mon but may occur as an isolated finding in Down  syndrome, in pituitary dwarfism, and in association with a  small number of rare hereditary disorders that exhibit mul-  tiple abnormalities of the dentition (Fig. 2-49).   Isolated microdontia within an otherwise normal denti-  tion is not uncommon. The maxillary lateral incisor is    @ Fig. 2-49 Diffuse Microdontia. Dentition in which the teeth are  smaller than normal and widely spaced within the arch.    ® Fig. 2-50 Isolated Microdontia (Peg Lateral). Small, cone-  shaped right maxillary lateral incisor.    affected most frequently and typically appears as a peg-  shaped crown overlying a root that often is of normal length  (Fig. 2-50). The mesiodistal diameter is reduced, and the  proximal surfaces converge toward the incisal edge. The  reported prevalence varies from 0.8% to 8.4% of the popu-  lation, and the alteration appears to be autosomal dominant  with incomplete penetrance. In addition, isolated micro-  dontia often affects third molars. Interestingly, the maxillary  lateral incisors and the third molars are among the most  frequent teeth to be congenitally missing. When a peg-  shaped tooth is present, the remaining permanent teeth  often exhibit a slightly smaller mesiodistal size.    Analogous to microdontia, the term macrodontia (mega-  lodontia, megadontia) should be applied only when teeth  are physically larger than usual and should not include  normal-sized teeth crowded within a small jaw (previously  termed relative macrodontia). In addition, the term mac-  rodontia should not be used to describe teeth that have been  altered by fusion or gemination. Diffuse involvement is rare,  and typically only a few teeth are abnormally large. Diffuse  macrodontia has been noted in association with pituitary  gigantism (see page 775), otodental syndrome, XYY males,    @ Fig. 2-51 Macrodontia. The patient’s left maxillary central incisor  is abnormally large. (Courtesy of Dr. Peter Fam.)    and pineal hyperplasia with hyperinsulinism. Macrodontia  with unilateral premature eruption is not rare in hemifacial  hyperplasia (see page 35). Authors have postulated that the  unilateral bone growth resulting from this condition may  also affect developing teeth on the altered side. Isolated  macrodontia is reported to occur most frequently in incisors  or canines but also has been seen in second premolars and  third molars (Fig. 2-51). In such situations, the alteration  often occurs bilaterally.    Treatment of the dentition is not necessary unless desired  for aesthetic considerations. Maxillary peg laterals often are  restored to full size by porcelain crowns.    Double teeth (connate teeth, conjoined teeth) are two sepa-  rate teeth exhibiting union by dentin and (perhaps) their  pulps. The union may be the result of fusion of two adjacent  tooth buds or the partial splitting of one into two. The  development of isolated large or joined (i.e., double) teeth  is not rare, but the literature is confusing when the appro-  priate terminology is presented. Historically, gemination was  defined as an attempt of a single tooth bud to divide, with  the resultant formation of a tooth with a bifid crown and,  usually, a common root and root canal. Conversely, fusion  was considered the union of two normally separated tooth  buds with the resultant formation of a joined tooth with  confluence of dentin. Finally, concrescence was the union of  two teeth by cementum without confluence of the dentin.   Many investigators have found these definitions confus-  ing and open to debate. A double tooth found in the place  of a maxillary permanent central incisor is a good example  of the controversy. If the joined tooth is counted as one and  the tooth number is correct, then the anomaly could result    from the division of a single tooth bud or the fusion of the  permanent tooth bud with the bud of an adjacent mesiodens.  Some have suggested that the terms gemination, fusion, and  concrescence should be discontinued, and all of these anoma-  lies should be termed twinning. This also is confusing  because other investigators use twinning to refer to the  development of two separate teeth that arose from the com-  plete separation of one tooth bud (this also is arguable).   Because of this confusion in terminology, the use of the  term f¢winning cannot be recommended. Extra teeth are  termed supernumerary, and another name is not necessary.  Even though the exact pathogenesis may be questionable in  some cases (whether caused by fusion of adjacent buds or  partial split of one bud), the terms gemination, fusion, and  concrescence serve a useful purpose because they are the most  descriptive of the clinical presentation. Gemination is  defined as a single enlarged tooth or joined (i.e., double)  tooth in which the tooth count is normal when the anoma-  lous tooth is counted as one. Fusion is defined as a single  enlarged tooth or joined (i.e., double) tooth in which the  tooth count reveals a missing tooth when the anomalous  tooth is counted as one. Concrescence is union of two  adjacent teeth by cementum alone, without confluence of  the underlying dentin. Unlike fusion and gemination,  concrescence may be developmental or postinflammatory.  When two teeth develop in close proximity, developmental  union by cementum is possible. In addition, areas of inflam-  matory damage to the roots of teeth are repaired by cemen-  tum once the inciting process resolves. Concrescence of  adjacent teeth may arise in initially separated teeth in which  cementum deposition extends between two closely approxi-  mated roots in a previous area of damage.    Double teeth (gemination and fusion) occur in both the  primary and the permanent dentitions, with a higher fre-  quency in the anterior and maxillary regions (Figs. 2-52 to  2-56). In the permanent dentition, the prevalence of double  teeth in whites is approximately 0.3% to 0.5%, whereas the  frequency in deciduous teeth is greater, with a reported  prevalence from 0.5% to 2.5%. Asian populations tend to  demonstrate a higher occurrence that exceeds 5% in some  studies. In both dentitions, incisors and canines are the  most commonly affected teeth. Involvement of posterior  primary teeth, premolars, and permanent molars also can  occur. Gemination is more common in the maxilla, whereas  fusion tends to occur more frequently in the mandible.  Bilateral cases are uncommon (Fig. 2-57).   Gemination and fusion appear similar and may be dif-  ferentiated by assessing the number of teeth in the denti-  tion. Some authors have suggested that gemination  demonstrates a single root canal. Separate canals are present  in fusion, but this does not hold true in all cases (Fig. 2-58).  A variety of appearances are noted with both fusion and  gemination. The processes may result in an otherwise ana-  tomically correct tooth that is greatly enlarged. A bifid    @ Fig. 2-52 Bilateral Gemination. Two double teeth. The tooth  count was normal when each anomalous tooth was counted as one.    @ Fig. 2-54 Gemination. Same patient as depicted in Fig. 2-53. Note  the bifid crown and shared root canal.    @ Fig. 2-55 Fusion. Double tooth in the place of the mandibular right  lateral incisor and cuspid.    @ Fig. 2-56 Fusion. Radiographic view of double tooth in the place  of the mandibular central and lateral incisors. Note separate root  canals.    @ Fig. 2-57 Fusion. Bilateral double teeth in the place of the man-  dibular lateral incisors and cuspids.    @ Fig. 2-58 Fusion. Radiograph of the same patient depicted in Fig.  2-57. Note the bifid crown overlying the single root canal; the contra-  lateral radiograph revealed a similar pattern.    crown may be seen overlying two completely separated  roots, or the joined crowns may blend into one enlarged  root with a single canal.    Concrescence is two fully formed teeth, joined along the  root surfaces by cementum. The process is noted more  frequently in the posterior and maxillary regions. The devel-  opmental pattern often involves a second molar tooth in  which its roots closely approximate the adjacent impacted  third molar (Fig. 2-59). The postinflammatory pattern fre-  quently involves carious molars in which the apices overlie  the roots of horizontally or distally angulated third molars.  This latter pattern most frequently arises in a carious tooth  that exhibits large coronal tooth loss. The resultant large  pulpal exposure often permits pulpal drainage, leading to a    ® Fig. 2-60 Concrescence. Union by cementum of maxillary second  and third molars. Note the large carious defect of the second molar.    @ Fig. 2-61 Concrescence. Gross photograph of the same teeth  depicted in Fig. 2-60. Histopathologic examination revealed that union  occurred in the area of cemental repair previously damaged by a  periapical inflammatory lesion.    resolution of a portion of the intrabony pathosis. Cemental  repair then occurs (Figs. 2-60 and 2-61).    ‘The presence of double teeth (i-e., gemination or fusion) in  the deciduous dentition can result in crowding, abnormal  spacing, and delayed or ectopic eruption of the underlying  permanent teeth. When detected, the progression of erup-  tion of the permanent teeth should be monitored closely by  careful clinical and radiographic observation. When appro-  priate, extraction may be necessary to prevent an abnormal-  ity in eruption. Occasionally, fusion in the primary dentition  is associated with absence of the underlying permanent  successor.    Several approaches are available for the treatment of  joined teeth in the permanent dentition, and the treatment  of choice is determined by the patient’s particular needs. In  gemination, if the double teeth have separate pulps, hemi-  section may be successful without root canal therapy. The  separation may be done intraorally or require extraction  with extraoral sectioning if the union extends close to the  apex. If extraction is necessary, immediate (within 5  minutes) replantation of the desirable half may result in  preservation of vitality and long-term survival of the tooth.  In double teeth that share a common pulp, endodontic  therapy is necessary if sectioning is considered. Selected  shaping with or without placement of full crowns has been  used in many cases. Other patients exhibit pulpal or coronal  anatomic features that are resistant to reshaping and require  surgical removal with prosthetic replacement. Double teeth  often will demonstrate a pronounced labial or lingual groove  that may be prone to develop caries. In such cases, place-  ment of a fissure sealant or composite restoration is appro-  priate if the tooth is to be retained.   Patients with concrescence often require no therapy  unless the union interferes with eruption; then surgical  removal may be warranted. Postinflammatory concrescence  must be kept in mind whenever extraction is planned for  nonvital teeth with apices that overlie the roots of an adja-  cent tooth. Significant extraction difficulties can be experi-  enced on attempted removal of a tooth that is unexpectedly  joined to its neighbor. Surgical separation often is required  to complete the procedure without loss of a significant  portion of the surrounding bone.    The cuspal morphology of teeth exhibits minor variations  among different populations; of these, three distinctive pat-  terns deserve further discussion: 1) cusp of Carabelli,  2) talon cusp, and 3) dens evaginatus. When an accessory  cusp is present, the other permanent teeth often exhibit a  slightly increased tooth size.    The cusp of Carabelli is an accessory cusp located on the  palatal surface of the mesiolingual cusp of a maxillary molar  (Fig. 2-62). The cusp may be seen in the permanent or  deciduous dentitions and varies from a definite cusp to a  small indented pit or fissure. When present, the cusp is most  pronounced on the first molar and is increasingly less  obvious on the second and third molars. When a cusp of  Carabelli is present, the remaining permanent teeth often  are larger than normal mesiodistally, but a similar associa-  tion in deciduous tooth size is typically not noted. A sig-  nificant variation exists among different populations, with  the prevalence reported to be as high as 90% in whites and  rare in Asians. An analogous accessory cusp is seen occasion-  ally on the mesiobuccal cusp of a mandibular permanent or  deciduous molar and is termed a protostylid.    ® Fig. 2-62 Cusp of Carabelli. Accessory cusp on the mesiolingual  surface of the maxillary first molar.    © Fig. 2-63 Talon Cusp. Accessory cusp present on the lingual  surface of a mandibular lateral incisor.    A talon cusp is a well-delineated additional cusp that is  located on the surface of an anterior tooth and extends at  least half the distance from the cementoenamel junction to  the incisal edge. A talon cusp is thought to represent the  end of a continuum that extends from a normal cingulum,  to an enlarged cingulum, to a small accessory cusp, and,  finally, to a full-formed talon cusp. Investigators have  muddied the literature associated with this spectrum by  categorizing all enlarged cingula as talon cusps and develop-  ing a classification system for the degree of enlargement.  These classification systems make prevalence data difficult  to evaluate and should be discouraged.   Three-fourths of all reported talon cusps are located in  the permanent dentition. The cusps predominantly occur  on permanent maxillary lateral (55%) or central (33%)  incisors but have been seen less frequently on mandibular  incisors (6%) and maxillary canines (4%) (Fig. 2-63). Their  occurrence in the deciduous dentition is very rare, with the  vast majority noted on maxillary central incisors. In almost  all cases, the accessory cusp projects from the lingual surface  of the affected tooth and forms a three-pronged pattern that  resembles an eagle’s talon. On rare occasions, the cusp may    ® Fig. 2-64 Talon Cusp. Radiograph of same patient shown in Fig.  2-63. Note the enamel and dentin layers within the accessory cusp.    project from the facial surface or from both surfaces of a  single tooth. A deep developmental groove may be present  where the cusp fuses with the underlying surface of the  affected tooth. Most, but not all, talon cusps contain a  pulpal extension. Radiographically, the cusp is seen over-  lying the central portion of the crown and includes enamel  and dentin (Fig. 2-64). Only a few cases demonstrate visible  pulpal extensions on dental radiographs.   Talon cusps appear to occur more frequently in Asians,  Native Americans, the Inuit, and those of Arab descent.  Both sexes may be affected, and the occurrence may be  unilateral or bilateral. In isolated cases, genetic influences  appear to have an effect, because identical talon cusps occa-  sionally have been documented in twins. Talon cusps also  have been seen in patients with Rubinstein-Taybi syndrome,  Mohr syndrome, Ellis-van Creveld syndrome, incontinentia  pigmenti achromians, Berardinelli-Seip syndrome, and  Sturge-Weber angiomatosis. Although the strength of asso-  ciation between the presence of talon cusps and these syn-  dromes generally is not clear, Rubinstein-Taybi syndrome  is strongly correlated as demonstrated by a study of 45  affected patients in which 92% demonstrated talon cusps.    Dens evaginatus (central tubercle, tuberculated cusp,  accessory tubercle, occlusal pearl, evaginated odontome,  Leong premolar, tuberculated premolar) is a cusplike eleva-  tion of enamel located in the central groove or lingual ridge    ® Fig. 2-65 Dens Evaginatus. Cusplike elevation located in the  central groove of mandibular first bicuspid.    of the buccal cusp of premolar or molar teeth (Fig. 2-65).  Although this pattern of accessory cusps has been reported  on molars, dens evaginatus typically occurs on premolar  teeth, is usually bilateral, and demonstrates a marked man-  dibular predominance. Deciduous molars are affected infre-  quently. The accessory cusp normally consists of enamel and  dentin, with pulp present in about half of the cases. Although  the prevalence is variable, most reviews suggest a frequency  between 1% and 4%. The anomaly is encountered most  frequently in Asians, the Inuit, and Native Americans but  is rare in whites. Researchers expect an increased prevalence  of this anomaly in the United States secondary to immigra-  tion by Asians and by Hispanics of mestizo heritage (i.e.,  those of mixed European and Native American ancestry).  Radiographically, the occlusal surface exhibits a tubercu-  lated appearance, and often a pulpal extension is seen in the  cusp (Fig. 2-66). The accessory cusp frequently creates  occlusal interferences that are associated with significant  clinical problems. In one large study, more than 80% of  the tubercles were worn or fractured, with pulpal pathosis  noted in more than 25% of patients. Pulpal necrosis is  common and may occur through a direct exposure or inva-  sion of patent, immature dentinal tubules. In addition to  abnormal wear and pulpal pathosis, the accessory cusp also  may result in dilaceration, displacement, tilting, or rotation  of the tooth.   Frequently, dens evaginatus is seen in association with  another variation of coronal anatomy, shovel-shaped inci-  sors. This alteration also occurs predominantly in Asians,  with a prevalence of approximately 15% in whites but close  to 100% in Native Americans and the Inuit. Affected inci-  sors demonstrate prominent lateral margins, creating a hol-  lowed lingual surface that resembles the scoop of a shovel    2-65. Note the tuberculated occlusal anatomy. Attrition on the acces-  sory cusp led to pulpal necrosis and periapical inflammatory disease.    © Fig. 2-67 Shovel-Shaped Incisors. Chinese patient exhibiting  maxillary incisors with prominent lateral margins, which create a hol-  lowed lingual surface.    (Fig. 2-67). Typically, the thickened marginal ridges con-  verge at the cingulum; not uncommonly, a deep pit, fissure,  or dens invaginatus is found at this junction. Maxillary  lateral and central incisors most frequently are affected,  with mandibular incisors and canines less commonly  reported.    Patients with cusps of Carabelli require no therapy unless a  deep groove is present between the accessory cusp and the  surface of the mesiolingual cusp of the molar. These deep  grooves should be sealed to prevent carious involvement.  Patients with talon cusps on mandibular teeth often  require no therapy; talon cusps on maxillary teeth frequently    interfere with occlusion and should be removed. Other  complications include compromised aesthetics, displace-  ment of teeth, caries, periodontal problems, and irritation  of the adjacent soft tissue (e.g., tongue or labial mucosa).  Because many of these cusps contain pulp, rapid removal  often results in pulpal exposure. Removal without the loss  of vitality may be accomplished through periodic grinding  of the cusp, with time allowed for tertiary dentin deposition  and pulpal recession. At the end of each grinding session,  the exposed dentin should be coated with a desensitizing  agent such as fluoride varnish, which also may speed the  rate of pulpal recession. Even with slow reduction and no  direct pulp exposure, loss of vitality is possible when large  numbers of immature dentin tubules are exposed. After  successful removal of the cusp, the exposed dentin can be  covered with calcium hydroxide, the peripheral enamel  etched, and a composite resin placed.   On eruption, the affected tooth should be inspected for  the presence of a deep fissure at the junction between the  talon cusp and the surface of the tooth. Ifa fissure is present,  it should be restored to avoid early carious extension into  the nearby dental pulp. Reports also have documented the  continuation of this fissure down the surface of the root,  with subsequent development of lateral radicular inflamma-  tory lesions secondary to the access provided to oral flora  by the deep groove. In these latter cases, further surgery is  required to expose the groove for appropriate cleansing.   Dens evaginatus typically results in occlusal problems  and often leads to pulpal death. In affected teeth, removal  of the cusp often is indicated, but attempts to maintain  vitality have met with only partial success. Slow, periodic  grinding of the cusp exposes immature patent dentinal  tubules and may lead to irreversible pulpitis without direct  exposure. To reduce the chance of pulpal pathosis, elimina-  tion of opposing occlusal interferences combined with  removal of minimal dentin and treatment of the area with  stannous fluoride has been recommended. More rapid  cuspal removal with indirect or direct pulp capping also has  proven beneficial in some patients. Other investigators  support removal of occlusal interferences, protection of the  cusp from fracture by the placement of surrounding resin  reinforcement, and delaying cuspal removal until evidence  of significant dentinal maturation, pulpal recession, and  apical root closure are present.   Shovel-shaped incisors should be inspected for surface  defects at the point where the marginal ridges converge.  Any deep fissures or invaginations should be restored  shortly after eruption to prevent carious exposure of the  adjacent pulp.    Dens invaginatus is a deep surface invagination of the  crown or root that is lined by enamel. Oehlers described  this condition thoroughly in three classic articles published  from 1957 to 1958. Two forms, coronal and radicular, are  recognized.    ® Fig. 2-68 Dens Invaginatus. Illustration depicting the three types  of coronal dens invaginatus.    By a great margin, coronal dens invaginatus is seen more  frequently; the reported prevalence varies from 0.04% to  10% of all patients. In order of decreasing frequency, the  teeth affected most often include the permanent lateral  incisors, central incisors, premolars, canines, and molars.  Involvement of deciduous teeth has been reported but is  uncommon. A strong maxillary predominance is seen.  The depth of the invagination varies from a slight  enlargement of the cingulum pit to a deep infolding that  extends to the apex. As would be expected, before eruption,  the lumen of the invagination is filled with soft tissue similar  to the dental follicle (i.e., reduced enamel epithelium with  a fibrous connective tissue wall). On eruption, this soft  tissue loses its vascular supply and becomes necrotic.  Historically, coronal dens invaginatus has been classified  into three major types (Fig. 2-68). Type I exhibits an invagi-  nation that is confined to the crown. The invagination in  type IT extends below the cementoenamel junction and ends  in a blind sac (Figs. 2-69 and 2-70). Large invaginations  may become dilated and contain dystrophic enamel in the  base of the dilatation (Fig. 2-71). In some cases, the enamel  lining of the invagination is incomplete, and channels com-  municate between the invagination and the pulp. These  connections can result in pulpal necrosis long before the  apex has closed. Type II extends through the root and  perforates in the apical or lateral radicular area without any  immediate communication with the pulp. In this latter  type, the enamel that lines the invagination is often replaced  by cementum close to the radicular perforation. This per-  foration provides direct communication from the oral cavity  to the intraosseous periradicular tissues and often produces  inflammatory lesions in the presence of a vital pulp (Figs.  2-72 and 2-73). Type I is by far the most common pattern  (79%) followed by type II (15%) and type III (5%).  Occasionally, the invagination may be rather large and  resemble a tooth within a tooth; hence the term dens in  dente. In other cases the invagination may be dilated and    ® Fig. 2-69 Coronal Dens Invaginatus Type II. Maxillary lateral  incisor exhibiting invagination of the surface enamel that extends below  the cementoenamel junction.    @ Fig. 2-70 Coronal Dens Invaginatus Type II. Buloous maxillary  cuspid exhibiting a dilated invagination lined by enamel.    °® Fig. 2-71 Coronal Dens Invaginatus Type II. Gross photograph  of a sectioned tooth. Note the dilated invagination with apical accu-  mulation of dystrophic enamel.    @ Fig. 2-72 Coronal Dens Invaginatus Type Ill. Parulis overlying  vital maxillary cuspid and lateral incisor. The cuspid contained a dens  invaginatus that perforated the mesial surface of its root.    disturb the formation of the tooth, resulting in anomalous  tooth development termed dilated odontome. Involve-  ment may be singular, multiple, or bilateral.   Radicular dens invaginatus is rare and thought to arise  secondary to a proliferation of Hertwig root sheath, with  the formation of a strip of enamel that extends along the  surface of the root. This pattern of enamel deposition is  similar to that frequently seen in association with radicular  enamel pearls (see Ectopic Enamel). Rather than protrude  from the surface (as seen in an enamel pearl), the altered  enamel forms a surface invagination into the dental papilla  (Fig. 2-74). Cementum-lined invaginations of the root have  been reported, but these represent a simple variation of root  morphology and should not be included under the term  radicular dens invaginatus.    @ Fig. 2-73 Coronal Dens Invaginatus Type Ill. Maxillary cuspid  exhibiting an enamel invagination that parallels the pulp canal and  perforates the lateral root surface. (Courtesy of Dr. Brian Blocher.)    @ Fig. 2-74 Radicular Dens Invaginatus. Illustration depicting the  radicular form of dens invaginatus.    Radiographically, the affected tooth demonstrates an  enlargement of the root. Close examination often reveals a  dilated invagination lined by enamel, with the opening of  the invagination situated along the lateral aspect of the root.    In small type I invaginations, the opening of the invagina-  tion should be restored after eruption in an attempt to  prevent carious involvement and subsequent pulpal inflam-  mation. If the invagination is not detected quickly, then  pulpal necrosis frequently results. With larger invaginations,  the contents of the lumen and any carious dentin must be  removed; then a calcium hydroxide base may be placed to  help treat any possible microcommunications with the adja-  cent pulp. In cases with obvious pulpal communication or  signs of pulpal pathosis, both the invagination and the  adjacent pulp canal require endodontic therapy. In teeth  with open apices, apexification with calcium hydroxide or  mineral trioxide aggregate often is successful, followed by  final obturation.    Type II] invaginations associated with periradicular  inflammatory lesions require endodontic-like therapy of the  perforating invagination. Once again, before final obtura-  tion with gutta-percha, temporary placement of calcium  hydroxide helps to build dentinal bridges and maintain  vitality of the adjacent pulp. If vitality is lost, endodontic  therapy of the parallel root canal also becomes necessary.  Some cases do not respond to conservative endodontic  therapy and require periapical surgery and retrofill. Large  and extremely dilated invaginations often have abnormal  crowns and need to be extracted.   If the invagination does not significantly disrupt the  morphologic appearance of the tooth, then complications  of radicular dens invaginatus are rare unless the radicular  opening is exposed to the oral cavity. After exposure occurs,  carious involvement often leads to pulpal necrosis. Open-  ings close to the anatomic neck of the tooth should be  exposed and restored to minimize damage to the tooth and  surrounding structures.    Ectopic enamel refers to the presence of enamel in unusual  locations, mainly the tooth root. The most widely known  are enamel pearls. These are hemispheric structures that  may consist entirely of enamel or contain underlying dentin  and pulp tissue. Most enamel pearls project from the surface  of the root and are thought to arise from a localized bulging  of the odontoblastic layer. This bulge may provide pro-  longed contact between Hertwig root sheath and the devel-  oping dentin, triggering induction of enamel formation.  Similar internal projections of enamel into the underlying  dentin rarely have been reported in the crowns of teeth.   In addition to enamel pearls, cervical enamel exten-  sions also occur along the surface of dental roots. These  extensions represent a dipping of the enamel from the  cementoenamel junction toward the bifurcation of molar  teeth. This pattern of ectopic enamel forms a triangular  extension of the coronal enamel that develops on the buccal  surface of molar teeth directly overlying the bifurcation. The  base of the triangle is continuous with the inferior portion  of the coronal enamel; the leading point of the triangle  extends directly toward the bifurcation of the tooth. These  areas of ectopic enamel have been called cervical enamel  projections, but this terminology is confusing because no  significant exophytic projections are seen.    Enamel pearls usually develop on the roots of the maxillary  permanent molars followed in prevalence by the mandibu-  lar permanent molars. Premolars and incisors rarely are  affected. Involvement of deciduous molars has been  reported. The prevalence of enamel pearls varies (1.1% to  9.7% of all patients) according to the population studied  and is highest in Asians. In most cases, one pearl is found,  but as many as four pearls have been documented on a    © Fig. 2-75 Enamel Pearl. Mass of ectopic enamel located in the  furcation area of a molar tooth. (Courtesy of Dr. Joseph Beard.)    ® Fig. 2-76 Enamel Pearl. Radiopaque nodule on the mesial surface  of the root of the maxillary third molar. Another less distinct enamel  pearl is present on the distal root of the second molar.    single tooth. The majority occur on the roots at the furca-  tion area or near the cementoenamel junction (Fig. 2-75).  Radiographically, pearls appear as well-defined, radiopaque  nodules along the root’s surface (Fig. 2-76) and can be  discerned easily during volumetric CT. Mature internal  enamel pearls appear as well-defined circular areas of  radiodensity, extending from the dentinoenamel junction  (DEJ) into the underlying coronal dentin.   The enamel surface of pearls precludes normal periodon-  tal attachment with connective tissue, and a hemidesmo-  somal junction probably exists. This junction is less resistant  to breakdown; once separation occurs, rapid loss of  attachment is likely. In addition, the exophytic nature  of the pearl is conducive to plaque retention and inadequate  cleansing.    @ Fig. 2-77 Cervical Enamel Extension. Flat V-shaped extension  of enamel into the bifurcation of a maxillary molar. (Courtesy of Dr. Keith  Lemmerman.)    As mentioned previously, cervical enamel extensions are  located on the buccal surface of the root overlying the  bifurcation (Fig. 2-77). Mandibular molars are affected  slightly more frequently than maxillary molars. In reviews  of extracted teeth in the lower 48 United States, the preva-  lence is surprisingly high, with approximately 20% of molars  being affected. Similar studies demonstrate an even greater  prevalence in other locations, such as Japan, China, and  Alaska, with cervical enamel extensions discovered in 50%  to 78% of extracted molars. Cervical enamel extensions may  occur on any molar, but they are seen less frequently on  third molars. Because connective tissue cannot attach to  enamel, these extensions have been correlated positively  with localized loss of periodontal attachment with furcation  involvement. On review of a large number of dentitions  with periodontal furcation involvement, a significantly  higher frequency of cervical enamel extensions was found  compared with dentitions without furcation involvement.  In addition, the greater the degree of cervical extension, the  higher the frequency of furcation involvement.   In addition to periodontal furcation involvement, cervi-  cal enamel extensions (in some cases) have been associated  with the development of inflammatory cysts that are  histopathologically identical to inflammatory periapical  cysts. The cysts develop along the buccal surface over the  bifurcation and most appropriately are called buccal    increased pulpal apico-occlusal height with apically positioned pulpal  floor and bifurcation. (Courtesy of Dr. Michael Kahn.)    bifurcation cysts (see page 650). The association between  cervical enamel extensions and this unique inflammatory  cyst is controversial.    When enamel pearls are detected radiographically, most are  incidental findings that require no therapy. In spite of this,  the area should be viewed as a weak point of periodontal  attachment. Meticulous oral hygiene should be maintained  in an effort to prevent localized loss of periodontal support  and exposure of the enamel mass. Ifan enamel pearl becomes  exposed and removal is contemplated, then the clinician  must remember that lesion occasionally contains vital pulp  tissue.   For teeth with cervical enamel extensions and associated  periodontal furcation involvement, therapy is directed at  achieving a more durable attachment and providing access  to the area for appropriate cleaning. Reports have suggested  that flattening or removing the enamel in combination with  an excisional new attachment procedure and furcation  plasty may accomplish this.    Taurodontism is an enlargement of the body and pulp  chamber of a multirooted tooth, with apical displacement  of the pulpal floor and bifurcation of the roots. This pattern  of molar formation has been found in ancient Neanderthals,  and the overall shape of the taurodont resembles that of the  molar teeth of cud-chewing animals (¢auro = bull; dont =  tooth).    Affected teeth tend to be rectangular and exhibit pulp  chambers with a dramatically increased apico-occlusal  height and a bifurcation close to the apex (Fig. 2-78). The    © Fig. 2-79 Taurodontism. Illustration exhibiting the classification of taurodontism according to the    diagnosis usually is made subjectively from the radiographic  appearance. The degree of taurodontism has been classified  into mild (hypotaurodontism), moderate (mesotaur-  odontism), and severe (hypertaurodontism), according to  the degree of apical displacement of the pulpal floor (Fig.  2-79). Witkop and colleagues and Shifman and Chanannel  presented useful biometric criteria for the determination of  taurodontism. These reports contain information that is  useful in epidemiologic studies of the process.   Some investigators include examples of taurodontism  in premolar teeth; others argue that taurodontism is not  shown by premolars. This argument is academic because the  presence of taurodontism in premolars cannot be docu-  mented in situ. Investigations of taurodontism in premolar  teeth require the examination of extracted teeth, because the  necessary radiographs depict the tooth in a mesiodistal  orientation.   Taurodontism may be unilateral or bilateral and affects  permanent teeth more frequently than deciduous teeth.  There is no sex predilection. The reported prevalence is  highly variable (0.5% to 46%) and most likely is related to  different diagnostic criteria and racial variations. In the  United States most reports indicate a prevalence of 2.5% to  3.2% of the population. Some investigators believe the  alteration is more of a variation of normal rather than a  definitive pathologic anomaly. The process often demon-  strates a field effect with the involvement of all molars.  When this occurs, the first molar is usually affected least  with increasing severity noted in the second and third  molars, respectively.   Taurodontism may occur as an isolated trait or as a  component of various syndromes (Box 2-10). An increased  frequency of taurodontism has been reported in patients  with hypodontia, cleft lip, and cleft palate. Investigations  have shown that taurodontism may develop in the presence  of any one of a large number of different genetic alterations.  These findings suggest that chromosomal abnormalities  may disrupt the development of the tooth’ form and  that taurodontism is not the result of a specific genetic  abnormality.    Amelogenesis imperfecta, hypoplastic type IE  Amelogenesis imperfecta-taurodontism type IV  Cranioectodermal dysplasia   Sex chromosomal aberrations (e.g., XXX, XYY)  Tricho-dento-osseous types |, Il, and Ill  Tricho-onycho-dental    Patients with taurodontism require no specific therapy.  Coronal extension of the pulp is not seen; therefore, the  process does not interfere with routine restorative proce-  dures. Some investigators have suggested the taurodontic  shape may exhibit decreased stability and strength as an  abutment tooth in prosthetic procedures due to decreased  root surface area, but this hypothesis has not been verified.  If endodontic therapy is required, then the shape of the pulp  chamber frequently increases the difficulty of locating,  instrumenting, and obturating the pulp canals. In addition,  the presence of supernumerary roots and canals mandates  careful exploration of all orifices and chamber grooves, with  magnification being highly beneficial. One bit of good news  is that patients have to demonstrate significant periodontal  destruction before bifurcation involvement occurs.    © Fig. 2-80 Hypercementosis. Gross photograph of a maxillary  bicuspid that exhibits thickening and blunting of the apical portion of  the root. (Courtesy of Dr. David Hicklin.)    Hypercementosis (cemental hyperplasia) is a nonneoplas-  tic deposition of excessive cementum that is continuous  with the normal radicular cementum.    Radiographically, affected teeth demonstrate a thickening  or blunting of the root, but the exact amount of increased  cementum often is difficult to ascertain because cementum  and dentin demonstrate similar radiodensities (Figs. 2-80  and 2-81). The enlarged root is surrounded by the radiolu-  cent PDL space and the adjacent intact lamina dura. On  occasion, the enlargement may be significant enough to  suggest the possibility of a cementoblastoma (see page 610).  However, the cementoblastoma usually can be distinguished  on the basis of associated pain, cortical expansion, and  continued enlargement.   Hypercementosis may be isolated, involve multiple teeth,  or appear as a generalized process. In a study of more than  22,000 affected teeth, the mandibular molars were affected  most frequently, followed by the mandibular and maxillary  second premolars and mandibular first premolars. In this  study, a 2.5:1 mandibular predominance was noted.   Hypercementosis occurs predominantly in adulthood,  and the frequency increases with age, which is most likely    @ Fig. 2-81 Hypercementosis. Periapical radiograph of the tooth  depicted in Fig. 2-80. Note the radiopaque enlargement of the apical  portion of the tooth. (Courtesy of Dr. David Hicklin.)    secondary to cumulative exposure to causative influences.  Its occurrence has been reported in younger patients, and  many of these cases demonstrate a familial clustering, sug-  gesting hereditary influence.   Box 2-11 lists several local and systemic factors that have  been associated with an increased frequency of the cemental  deposition. All of the listed systemic factors exhibit a weak  association with hypercementosis except for Paget disease  of bone (see page 582). Numerous authors have reported  significant hypercementosis in patients with Paget disease,  and this disorder should be considered whenever general-  ized hypercementosis is discovered in a patient of the appro-  priate age. In spite of the association with a number of  disorders, most localized cases of hypercementosis are not  related to any systemic disturbance.    ‘The periphery of the root exhibits deposition of an excessive  amount of cementum over the original layer of primary    © Fig. 2-82 Hypercementosis. A, Dental root exhibiting excessive  deposition of cellular and acellular cementum. The dividing line  between dentin and cementum is indistinct. B, Polarized light demon-  strating the sharp dividing line between the tubular dentin and  osteocementum.    cementum. The excessive cementum may be hypocellular  or exhibit areas of cellular cementum that resemble bone  (osteocementum). Often the material is arranged in con-  centric layers and may be applied over the entire root or be  limited to the apical portion. On routine light microscopy,  distinguishing between dentin and cementum often is dif  ficult, but viewing the section with polarized light helps to  discriminate between the two different layers (Fig. 2-82).    Patients with hypercementosis require no treatment. Because  of a thickened root, occasional problems have been reported  during the extraction of an affected tooth. Sectioning of the  tooth may be necessary in certain cases to aid in removal.    Dilaceration is an abnormal angulation or bend in the root  or, less frequently, the crown of a tooth (Figs. 2-83 and  2-84). Although most examples are idiopathic, a number of  teeth with dilaceration appear to arise after an injury that  displaces the calcified portion of the tooth germ, and the  remainder of the tooth is formed at an abnormal angle. The  damage frequently follows avulsion or intrusion of the over-  lying primary predecessor, an event that usually occurs  before 4 years of age. Injury-related dilaceration more fre-  quently affects the anterior dentition and often creates both  a functional and a cosmetic dental problem. Less frequently  the bend develops secondary to the presence of an adjacent  anatomic structure, cyst, tumor, or odontogenic hamartoma  (e.g., odontoma, supernumerary tooth) (Fig. 2-85).    In one review of 1166 randomly selected patients, 176  dilacerated teeth were identified. Of these teeth, the most    ® Fig. 2-83 Dilaceration. Sharp curvature of the root of a maxillary  central incisor.    °@ Fig. 2-84 Dilaceration. Maxillary second bicuspid exhibiting mesial  inclination of the root. The patient reported no history of injury to this  area. (Courtesy of Dr. Lawrence Bean.)    commonly affected were the mandibular third molars, fol-  lowed by the maxillary second premolars and mandibular  second molars. The maxillary and mandibular incisors were  the least frequently affected, representing approximately 1%  of the series. This contrasts with other authors who have  reported a high frequency of dilaceration involving anterior  teeth. In reality, the molars most likely demonstrate the  highest prevalence of dilaceration but are not highlighted  because of a lack of associated clinical problems in most  instances. Occasionally, involvement of the deciduous teeth  is reported, and some have been associated with  prior trauma secondary to neonatal laryngoscopy and  endotracheal intubation. Several publications have men-  tioned an increased prevalence associated with several syn-  dromes, including Smith-Magenis syndrome, variants of    ® Fig. 2-85 Dilaceration. Root angulation of a mandibular cuspid.  Development has been altered by the presence of an adjacent com-  pound odontoma. (Courtesy of Dr. Brent Bernard.)   The bend may occur anywhere along the length of the  crown or root. One review stated that dilaceration occurs  most frequently in the apical third of anterior or premolar  teeth, whereas the middle third is most common in molars,  and the cervical third is involved most frequently in third  molars. The maxillary central incisors are the most common  teeth to demonstrate crown dilacerations, followed by the  mandibular incisors. Impaction of the affected tooth occurs  in approximately 50% of these cases.   Dilaceration usually is radiographically obvious if the  bend occurs in a mesial or distal direction. Roots that bend  facially or lingually may be more difficult to detect. Often,  the apical portion of these teeth will demonstrate a round  increased radiodensity with a central radiolucent dark spot  that correlates to the root canal of the bent tooth. The dilacer-  ated portion of the root often may demonstrate a radiolucent  halo that represents the associated periodontal ligament.    ‘The treatment and prognosis vary according to the severity  of the deformity. Altered deciduous teeth often demonstrate  inappropriate resorption and result in delayed eruption of  the permanent teeth. Extraction is indicated when necessary  for the normal eruption of the succedaneous teeth. Patients  with minor dilaceration of permanent teeth frequently  require no therapy. Those teeth that exhibit delayed or  abnormal eruption may be exposed and orthodontically  moved into position. The possibility that orthodontic move-  ment of severely dilacerated teeth may result in    @ Fig. 2-86 Supernumerary Root. A, Gross photograph showing a  mandibular molar with a supernumerary root. B, Periapical radiograph  of the extracted tooth.    severe external root resorption must be considered during  treatment planning. In some cases with extensive deforma-  tion of the affected tooth, perforation of the buccal alveolar  ridge by the malpositioned root may occur on reposition-  ing. In such cases, amputation of the root apex with subse-  quent endodontic therapy may be necessary. Grossly  deformed teeth require surgical removal. The extraction of  affected teeth may be difficult and result in root fracture on  removal. When attempting to perform endodontic proce-  dures, the clinician must use great care to avoid root perfo-  ration of teeth with significant dilaceration.   Root dilaceration concentrates stress if the affected tooth  is used as an abutment for a dental prosthetic appliance.  ‘This increased stress may affect the stability and longevity  of the abutment tooth. Splinting of the dilacerated tooth to  an adjacent tooth results in a multirooted abutment and  overcomes the stress-related problems.    The term supernumerary roots refers to the development  of an increased number of roots on a tooth compared with  that classically described in dental anatomy.    Any tooth may develop accessory roots, and involvement  has been reported in both the deciduous and the permanent  dentitions. Data on the frequency of supernumerary roots  are sparse, but the prevalence appears to vary significantly  among different races. The most frequently affected teeth  are the permanent molars (especially third molars) from  either arch and mandibular cuspids and premolars (Fig.  2-86). In some instances the supernumerary root is diver-  gent and seen easily on radiographs; in other cases the  additional root is small, superimposed over other roots, and  difficult to ascertain.    @ Fig. 2-87 Globodontia. Dentition demonstrating clinically normal  anterior teeth and posterior teeth with enlarged bulbous crowns.  Patient had undiagnosed hearing loss that was discovered following  identification of otodental syndrome by dentist. (Courtesy of Dr. John  Eric Yezerski.)    No treatment is required for supernumerary roots, but the  detection of the accessory root is of critical importance  when endodontic therapy or exodontia is undertaken.  Extracted teeth always should be examined closely to ensure  that all roots have been removed successfully, because acces-  sory roots may not be obvious on the presurgical radio-  graphs. Just as important is the search for accessory canals  during endodontic access procedures, because failure to dis-  cover these additional openings often results in a lack of  resolution of the associated inflammatory process.    frequency sensorineural hearing loss are the primary diag-  nostic features of otodental syndrome. This autosomal  dominant disorder has been localized to chromosome  11q13, and the clinical findings are thought to be due to  haploinsufficiency of the FGF3 gene.    Both the deciduous and permanent dentitions are affected  with the cuspids and molars demonstrating dramatically  enlarged and bulbous crowns (Figs. 2-87 and 2-88). The  normal cusp and groove anatomy of the molars is replaced  by numerous developmental grooves that radiate from a  central depression onto the facial, lingual, and proximal  surfaces, resulting in an occlusal surface that has been  described as resembling the tied end of a sausage. The canines  are distorted similarly, often with three large bulbous pro-  jections separated by shallow grooves. The premolars often  are missing or reduced in size; when present, they may  demonstrate normal anatomy or appear conical. The inci-  sors are unaffected. The globodont roots are short, and the    @ Fig. 2-88 Globodontia. Bite-wing radiographs demonstrating pos-  terior teeth with bulbous crowns and complex pulpal anatomy. (Cour-  tesy of Dr. John Eric Yezerski.)    pulp chambers often appear bisected with vertical septa and  occasional pulp stones. Focal areas of yellow coronal hypo-  maturation may occur, especially on the facial surfaces of  the canines.   ‘The onset of the hearing loss varies from early childhood  to middle age, but it often begins in infancy and progresses  to a plateau in the fourth decade. A loss of approximately  65db is noted at all frequencies but is more pronounced at  about 1000 Hz. Other less consistent findings include  ocular colobomas, odontomas, and numerous microdontic  teeth.    Due to the grossly distorted anatomy, misalignment of the  teeth and malocclusion are frequent problems. If an affected  tooth develops dental caries, routine dental restorative treat-  ment can be provided. Endodontic therapy can be very  challenging in the molar teeth due to the complexity of the  pulpal anatomy. Patients also have a propensity to develop  endodontic-periodontic lesions, possibly due to the abnor-  mal coronal and pulpal configuration. An excellent program  of oral hygiene with regular professional care should be  encouraged.    Lobodontia refers to a rare hereditary dental anomaly in  which numerous teeth resemble those noted in carnivores.  The term is derived from Jobo, the Spanish word for wolf  that arose from the Latin word /upus. The abnormality is  extremely rare and is inherited as an autosomal dominant  trait.    The most distinctive features are the cuspids and premolars,  which demonstrate pointed fang-like cusps (Fig. 2-89). The  middle lobes of the cuspid crowns are conical with the  lateral lobes being dramatically reduced. The premolars  demonstrate prominent cone-shaped buccal cusps, often  with diminutive lingual cusps. The occlusal anatomy of the  molars also is altered significantly and demonstrates a mul-  titubercular appearance (Fig. 2-90). Additionally, a general-  ized reduction in tooth size is common. Other less consistent  findings include shovel-shaped incisors with prominent    cingulum pits, hypodontia, dens invaginatus of premolars  or incisors, and single conical roots of the molar teeth.    Thorough radiographic examination is prudent to discover  and restore teeth with dens invaginatus prior to devitaliza-  tion. The occlusal cusps of the multitubercular molars are  similar to dens evaginatus with traumatic occlusion, attri-  tion, or fracture predisposing to loss of pulp vitality.  Although appropriate therapy has not been described, com-  posite reinforcement of the prominent cusps may reduce  cuspal damage and allow time for pulpal recession from the  coronal protuberances.    Amelogenesis imperfecta encompasses a complicated group  of conditions that demonstrate developmental alterations in  the structure of the enamel in the absence of a systemic dis-  order or syndrome. Box 2-2 (see page 50) lists several    systemic diseases associated with enamel disorders that are  not considered isolated amelogenesis imperfecta. Although  the definition of amelogenesis imperfecta excludes any asso-  ciation with a syndrome, a number of other dental anomalies  are accepted within the spectrum of the disease: pulpal cal-  cification, taurodontism, delayed eruption, gingival over-  growth, open-bite malocclusion, and rarely prognathism.   The formation of enamel is a multistep process, and  problems may arise in any one of the steps. In general, the  development of enamel can be divided into three major  stages:   1. Elaboration of the organic matrix  2. Mineralization of the matrix  3. Maturation of the enamel   Historically, the hereditary defects of the formation of  enamel are divided along these lines: hypoplastic, hypocalci-  fied, and hypomaturation. Numerous hereditary subtypes  of amelogenesis imperfecta exist, with a wide variety of  clinical manifestations and patterns of inheritance. An ideal  classification system for amelogenesis imperfecta has not  been established yet. Witkop’s classification (Table 2-1)  relies on the phenotype and pedigree (i-e., clinical appear-  ance and apparent pattern of inheritance). Classification by  clinical appearance is problematic, because different pheno-  types have been noted within a single affected family. In  addition, similar phenotypes may be seen in individuals  with very different molecular patterns of disease. One  example of the potential confusion occurs in kindreds  affected with certain variants of autosomal dominant ame-  logenesis imperfecta in which homozygotes exhibit general-  ized thin hypoplasia, whereas heterozygotes exhibit localized  enamel pitting. Using Witkop’s system, different individuals  within this kindred would be placed into multiple catego-  ries (e.g., types IB, ID, IF).   Although the molecular basis underlying many patterns  of amelogenesis imperfecta remains poorly defined, the  genetics associated with several variations of amelogenesis  imperfecta has been clarified. This has led investigators to  suggest a future classification system based primarily on the  mode of inheritance with secondary discriminators that  include the phenotype, molecular basis (site and type of  chromosomal mutation, when known), and the biochemical  result (protein affected, when known). Although much  remains to be discovered, the information necessary for this  new classification system is accumulating rapidly, with move-  ment to this new pattern of classification being inevitable. A  discussion of the mutation type, mutation result, and protein  affected is beyond the scope of this text, and interested parties  are referred to the references associated with this section.   Investigations into the genetics are ongoing and produc-  ing results that are not only interesting but also directly  applicable to patient care. To date, mutations in seven genes  have been associated with amelogenesis imperfecta. Each  gene can be mutated in a variety of ways, often creating  diverse and distinct phenotypic patterns.   The AMELX gene is associated with the enamel protein  amelogenin, which constitutes up to 90% of enamel    matrix. AMELX-associated variants of amelogenesis imper-  fecta are X-linked with 14 different mutations currently  known. Because of the effect of lyonization, the male and  female phenotypes are variable but often associated with the  genotype. The male phenotypes include both the diffuse  smooth hypoplastic and the hypomaturation variants.   The ENAM gene is associated with another enamel  protein, enamelin, which represents approximately 1% to  5% of enamel matrix. Mutations of the ENAM gene have  been correlated with some autosomal dominant and reces-  sive patterns of hypoplastic amelogenesis imperfecta, ranging  from minor pitting to diffuse generalized thin enamel.   The MMP-20 gene codes for a proteinase named enam-  elysin; mutation of this gene has been associated with the  autosomal recessive, pigmented hypomaturation variant of  amelogenesis imperfecta.   The protease, kallikrein-4, is associated with the KLK4  gene, the mutation of which has been shown to be involved  with some forms of hypomaturation amelogenesis imper-  fecta. Both enamelysin and kallikrein-4 are thought neces-  sary for the removal of enamel matrix proteins during the  maturation stage of enamel development.   Mutations in the FAM83H gene have been associated  with autosomal dominant hypocalcified amelogenesis  imperfecta. Of the currently discovered genes, FAM83H is  associated with the highest prevalence of disease and the  most severe enamel alterations. The majority of these    A Hypoplastic Generalized pitted Autosomal dominant  B Hypoplastic Localized pitted Autosomal dominant  C Hypoplastic Localized pitted Autosomal recessive  D Hypoplastic Diffuse smooth Autosomal dominant  E Hypoplastic Diffuse smooth X-linked dominant  IF Hypoplastic Diffuse rough Autosomal dominant  G Hypoplastic Enamel agenesis Autosomal recessive  IA Hypomaturation Diffuse pigmented Autosomal recessive  IB Hypomaturation Diffuse X-linked recessive  IC Hypomaturation Snow-capped X-linked  ID Hypomaturation Snow-capped Autosomal dominant?  IIA Hypocalcified Diffuse Autosomal dominant  IIB Hypocalcified Diffuse Autosomal recessive  VA Hypomaturation-hypoplastic Taurodontism present Autosomal dominant  VB Hypoplastic-hypomaturation Taurodontism present Autosomal dominant  lodified from Witkop CJ Jr: Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification, J Oral Pathol    mutations result in involvement over the entire crown,  whereas some examples create areas of hypocalcification that  localize in the cervical half of the crown.   The function of the WDR72 gene is unknown, but  it is thought to be a scaffold for protein-protein interac-  tions. Mutations in this gene have been associated with  autosomal recessive patterns of hypomaturation amelogen-  esis imperfecta.   The C4orf26 gene encodes an extracellular matrix  protein in the enamel organ and has been associated with  an autosomal recessive pattern of hypomineralized amelo-  genesis imperfecta. The mutation was discovered initially in  an Omani family and led investigators to sequence another  57 apparently unrelated individuals presenting with reces-  sive patterns of amelogenesis imperfecta from across the  world. This research confirmed the mutation in an addi-  tional eight families with previously undefined mutations.   The DLX3 gene belongs to a group of genes that  code for a number of proteins that are critical for craniofa-  cial, tooth, hair, brain, and neural development; mutation  of this gene has been associated with the hypoplastic-  hypomaturation variants of amelogenesis imperfecta with  taurodontism. Some investigators have removed the gene  from the list of those associated with amelogenesis imper-  fecta due to the belief this pattern is a variant of the tricho-  dento-osseous syndrome. Others have documented an  identical pattern of abnormal enamel in patients with the    DLX3 mutation, but with no other features of tricho-dento-  osseous syndrome (see page 97).   Although no one has compiled a complete list of amelo-  genesis imperfecta types using the proposed new classifica-  tion, Table 2-2 provides a rough idea of how this might  be organized. Despite these exciting molecular genetic dis-  coveries, it must be stressed how much remains to be  investigated.    Amelogenesis imperfecta may be inherited as an autosomal  dominant, autosomal recessive, or X-linked disorder, with  both the deciduous and the permanent dentitions diffusely  involved in the vast majority. Due to differing gene pools,  the rate of occurrence varies geographically with a preva-  lence of 1:700 in Sweden and a frequency in the United  States of 1: 14,000.    In patients with hypoplastic amelogenesis imperfecta, the  basic alteration centers on inadequate deposition of enamel  matrix. Any matrix present is mineralized appropriately and  radiographically contrasts well with the underlying dentin.  In the generalized pattern, pinpoint-to-pinhead-sized pits  are scattered across the surface of the teeth and do not cor-  relate with a pattern of environmental damage (Fig. 2-91).  The buccal surfaces of the teeth are affected more severely,  and the pits may be arranged in rows or columns. Staining  of the pits may occur. Variable expressivity is seen within  groups of affected patients. The enamel between the pits is  of normal thickness, hardness, and coloration.   In the localized pattern, the affected teeth demonstrate  horizontal rows of pits, a linear depression, or one large area    of hypoplastic enamel. Typically, the altered area is located  in the middle third of the buccal surfaces of the teeth. The    *Please refer to discussion of DLX3 gene in the text portion.    e Fig. 2-91 Hypoplastic Amelogenesis Imperfecta, Generalized Pitted Pattern. A, Note the  numerous pinpoint pits scattered across the surface of the teeth. The enamel between the pits is of  normal thickness, hardness, and coloration. B, Occlusal view of same patient showing diffuse involvement  of all maxillary teeth, which would be inconsistent with environmental damage. (A, From Stewart RE,  Prescott GH: Oral facial genetics, St Louis, 1976, Mosby. B, Courtesy of Dr. Joseph S. Giansanti.)    incisal edge or occlusal surface usually is not affected. Both  dentitions, or only the primary teeth, may be affected. All  of the teeth may be altered, or only scattered teeth may be  affected. When the involvement is not diffuse, the pattern  of affected teeth does not correlate with a specific time in  development. The autosomal recessive type is more severe  and typically demonstrates involvement of all teeth in both  dentitions.   In Witkop’s phenotypic classification, amelogenesis  imperfecta with diffusely reduced enamel thickness was sub-  classified as smooth, rough, and enamel agenesis. This system  has proved to be problematic due to significant intrafamily  phenotypic variability and poor correlation between the  phenotype and the molecular defect. As an example, certain  mutations of autosomal dominant ENAM create thin hypo-  plastic enamel, with different patients demonstrating varia-  tions of surface texture ranging from smooth with and  without shallow grooves to rough with numerous shallow  pits. In addition, in patients diagnosed with enamel agen-  esis, the presence of a thin band of enamel has been    confirmed in many affected individuals. As a result, these  previously separated phenotypic patterns have been merged  into one category, generalized thin hypoplastic amelo-  genesis imperfecta.   In the generalized thin variants, the enamel is extremely  thin with teeth that are shaped like crown preparations and  demonstrate open contact points. The surface texture varies  from smooth with or without shallow grooves to rough with  or without scattered pits (Figs. 2-92 and 2-93). The color  of the teeth varies from opaque white to yellow to brown.  Anterior open bite is not rare. Radiographically, a thin  peripheral outline of radiopaque enamel will be noted on  many teeth. Often, unerupted teeth exhibiting resorption  are seen.   The X-linked patterns of generalized thin amelogenesis  imperfecta are a lesson in the lyonization effect. On approx-  imately the sixteenth day of embryonic life in all individuals  with two X chromosomes, one member of the pair is inac-  tivated in each cell. As a result of this event, females are  mosaics, with a mixture of cells, some with active maternal    ® Fig. 2-92 Hypoplastic Amelogenesis Imperfecta, Autosomal Dominant Smooth Pattern (Gen-  eralized Thin Pattern). A, Small, yellowish teeth exhibiting hard, glossy enamel with numerous open  contact points and anterior open bite. B, Radiograph of the same patient demonstrating thin peripheral  outline of radiopaque enamel. (B, Courtesy of Dr. John G. Stephenson.)    © Fig. 2-93 Hypoplastic Amelogenesis Imperfecta, Rough Pattern (Generalized Thin Pattern).  A, Small, yellow teeth with rough enamel surface, open contact points, significant attrition, and anterior  open bite. B, Radiograph of the same patient. Note the impacted tooth and the thin peripheral outline of  radiodense enamel.    X chromosomes and others with active paternal X chromo-  somes. Usually the mix is of approximately equal propor-  tions. If one X were to direct the formation of defective  enamel and the other X were to form normal enamel, then  the teeth would exhibit alternating zones of normal and  abnormal enamel. Hemizygous males exhibit diffuse thin  enamel in both dentitions. On the other hand, heterozy-  gous females exhibit vertical furrows of thin hypoplastic  enamel, alternating between bands of normal thickness. The  banding often is detectable with dental radiographs.    Both of these variants demonstrate defects in mineraliza-  tion, with hypomature teeth containing residual enamel  protein and hypocalcified teeth demonstrating lack of  enamel protein with more severe enamel abnormalities.  Classically, the hypomaturation pattern is associated with  enamel that chips and fractures easily but does not demon-  strate massive loss upon eruption. In contrast, the hypocal-  cification pattern has been associated with “cheesy” enamel  that is lost rapidly and diffusely except for a residual band  in the cervical portion of the teeth. In reality, the distinction  is hazy with a spectrum of enamel quality encountered. At  the ends of the spectrum, the separation between hypo-  maturation and hypocalcification can be made easily;  however, the center of the spectrum contains numerous  patterns that are difficult to classify on a phenotypic basis.  For this reason, many investigators prefer the term hypo-  mineralization for both variants. When struggling to  choose between these two patterns, it should be remem-  bered that most hypocalcified types are autosomal domi-  nant, whereas the hypomaturation variants usually are  autosomal recessive or X-linked.   Prior to eruption, both forms of hypomineralization  radiographically demonstrate enamel of normal thickness  with a radiodensity that is similar to dentin. In a person  with hypomaturation amelogenesis imperfecta, the  affected teeth are normal in shape but exhibit white opaque  enamel that may reveal areas of mottling. Upon eruption,  variable degrees of brown discoloration and enamel chip-  ping are seen. The presentation may closely resemble dental  fluorosis, making definitive diagnosis difficult in many  patients. On occasion, fluorosis may demonstrate horizon-  tal white banding that corresponds to periods of increased  fluoride intake. If present, a chronological distribution also  is helpful in interpreting the clinical appearance (such as  sparing of the deciduous dentition or premolars and second  molars [see Fig. 2-9, page 53)).   In the pigmented hypomaturation pattern, the surface  enamel is mottled and agar-brown. The enamel often frac-  tures from the underlying dentin and is soft enough to be  punctured by a dental explorer. Anterior open bite and  unerupted teeth exhibiting resorption are uncommon.  Occasionally, the surface enamel may be affected severely  and be similar in softness to that of hypocalcified patterns    Imperfecta,  X-Linked. A, Male patient exhibiting diffuse yellow-white dentition. B,  The patient’s mother exhibits vertical bands of white, opaque enamel  and translucent enamel. (Courtesy of Dr. Carlos Salinas.)    with rapid enamel loss upon eruption. These cases often  demonstrate extensive calculus deposition. A combined  hypomaturation and hypoplastic phenotype can be seen,  but posteruption enamel loss can complicate classification.   The X-linked hypomaturation pattern is another lesson  in lyonization; however, the lyonization is not as obvious as  that seen in the X-linked hypoplastic pattern. Affected  males exhibit different patterns in the deciduous and per-  manent dentitions. The deciduous teeth are opaque white  with a translucent mottling, whereas the permanent teeth  are opaque yellow and may darken with age (Fig. 2-94, A).  Heterozygous females exhibit a similar pattern in both den-  titions. The teeth demonstrate vertical bands of white  opaque enamel and translucent enamel; the bands are  random and asymmetric (see Fig. 2-94, B). The banding  can be seen under regular lighting but is more obvious with  transillumination.   The snow-capped hypomaturation patterns exhibit a  zone of white opaque enamel on the incisal or occlusal one-  quarter to one-third of the crown (Fig. 2-95). The altered  areas do not exhibit a distribution that would support an  environmental origin, and the surface lacks the iridescent  sheen seen with mild fluorosis. The affected teeth often  demonstrate an anterior-to-posterior distribution and have  been compared with a denture dipped in white paint (only  affected anteriors, the anteriors back to the bicuspids, or the    anteriors back to the molars). Both the deciduous and the  permanent dentitions are affected.   In hypocalcified amelogenesis imperfecta, the teeth are  appropriately shaped on eruption, but the enamel is very  soft and easily lost. On eruption, the enamel is yellow-  brown or orange, but it often becomes stained brown to  black and exhibits rapid calculus apposition (Fig. 2-96).  With years of function much of the coronal enamel is  removed, except for the cervical portion that is occasionally  calcified better. Unerupted teeth and anterior open bite are  not rare.    ‘This type of amelogenesis imperfecta exhibits enamel hypo-  plasia in combination with hypomaturation. The deciduous  and the permanent dentitions are diffusely involved. His-  torically, two patterns have been recognized that are similar    © Fig. 2-95 Hypomaturation Amelogenesis Imperfecta, Snow-  Capped Pattern. Dentition exhibiting zone of white opaque enamel  in the incisal and occlusal one-fourth of the enamel surface. (Courtesy  of Dr. Heddie O. Sedano.)    © Fig. 2-96 Hypocalcified Amelogenesis Imperfecta. A, Dentition exhibiting diffuse yellow-brown    but differentiated by the thickness of the enamel and the  overall tooth size. When studying a single kindred, pheno-  typic variation is seen that would place members of the same  family in both divisions; therefore, many believe these divi-  sions should be joined into one phenotype termed merely  amelogenesis imperfecta with taurodontism.   In the presentation known as the hypomaturation-  hypoplastic pattern, the predominant defect is one of  enamel hypomaturation in which the enamel appears as  mottled yellow-white to yellow-brown. Pits are seen fre-  quently on the buccal surfaces of the teeth. Radiographi-  cally, the enamel appears similar to dentin in density, and  large pulp chambers may be seen in single-rooted teeth in  addition to varying degrees of taurodontism.   In the hypoplastic-hypomaturation pattern, the pre-  dominant defect is one of enamel hypoplasia in which the  enamel is thin but also hypomature. Except for the decrease  in the thickness of the enamel, this pattern is radiographi-  cally similar to the hypomaturation-hypoplastic variant.   A pattern of teeth alteration similar to amelogenesis  imperfecta with taurodontism is seen in the systemic disor-  der, tricho-dento-osseous syndrome. This autosomal  dominant disorder is mentioned here because the diagnosis  may not be readily apparent without a high index of suspi-  cion (Fig. 2-97). In addition to the dental findings, the  predominant systemic changes are present variably and  include kinky hair, osteosclerosis, and brittle nails. The  kinky hair is present at birth but may straighten with age.  The osteosclerosis primarily affects the base of the skull and  the mastoid process. The mandible often exhibits a short-  ened ramus and an obtuse angle.   Some authors have suggested that amelogenesis imper-  fecta with taurodontism may represent partial expression of  the tricho-dento-osseous syndrome. Studies have identified  distinctly different gene mutations that are responsible for  tricho-dento-osseous syndrome and amelogenesis imper-  fecta with taurodontism. However, other investigators  dispute this fact, showing evidence that some examples of    discoloration. Note numerous teeth with loss of coronal enamel except for the cervical portion. B, Radio-  graph of the same patient. Note the extensive loss of coronal enamel and the similar density of enamel    ® Fig. 2-97 Tricho-Dento-Osseous Syndrome. A, Dentition exhibiting diffuse enamel hypoplasia and    straightened. A high index of suspicion was required to arrive at the diagnosis. B, Radiograph of the same  patient showing significant taurodontism of the first molar and thin enamel, which is similar in density to    this pattern of amelogenesis imperfecta appear allelic (dif-  ferent mutation on the same gene) to the syndrome.    The histopathologic alterations present in amelogenesis  imperfecta are not evident in routine preparations. Because  decalcification of the teeth is necessary before processing to  allow sectioning of paraffin-embedded specimens, all of the  enamel is lost. To examine the enamel structure of altered  teeth, ground sections of nondecalcified specimens are pre-  pared. The alterations discovered are highly diverse and vary  with each clinical type of amelogenesis imperfecta. Detailed  descriptions of such alterations were provided by Witkop  and Sauk.    ‘The clinical implications of amelogenesis imperfecta vary  according to the subtype and its severity, but the main  problems are aesthetics, dental sensitivity, and loss of verti-  cal dimension. In addition, in some types of amelogenesis  imperfecta there is an increased prevalence of caries, anterior  open bite, delayed eruption, tooth impaction, or associated  gingival inflammation.   Patients with generalized thin enamel hypoplasia dem-  onstrate minimal normal enamel associated with rapid attri-  tion. These variants require full coverage as soon as is  practical; if the treatment is delayed, a loss of usable crown  length occurs. In those patients without sufficient crown  lengths, full dentures (overdentures in some cases) often  become the only satisfactory approach.   The other types of amelogenesis imperfecta demonstrate  less rapid tooth loss, and the aesthetic appearance often is  the prime consideration. Many less severe cases can be  improved by the placement of full crowns or facial veneers  on clinically objectionable teeth. In some cases, a lack of    good enamel bonding of veneers occurs and does not result  in a durable restoration. The use of glass ionomer cements  with dentinal adhesives often overcomes this weakness.   Generalized delayed eruption and impaction of teeth  affected by generalized thin hypoplastic amelogenesis  imperfecta has been identified as a component of a very rare  syndrome that includes nephrocalcinosis and sometimes  renal failure. The renal changes often are not clinically overt,  and mortality associated with renal failure has been reported  in affected patients. Such patients should be referred for  renal evaluation.    Hereditary disorders of dentin can occur in association with  a number of syndromes or arise as an isolated disorder of  teeth with no systemic manifestations. Osteogenesis imper-  fecta is the syndrome most frequently associated with dental  manifestations that mimic dentinogenesis imperfecta, but  Ehlers-Danlos syndrome, Goldblatt syndrome, and Schimke  immuno-osseous dysplasia also have been associated with  similar dental changes. In addition, sporadic reports of  patients with dentinogenesis imperfecta—like alterations as  part of an obviously systemic, but as yet undefined, syn-  drome have been noted. In addition to a dentinogenesis  imperfecta—like phenotype, a variety of other dentin abnor-  malities have been noted in vitamin-D resistant rickets,  vitamin-D dependent rickets, tumoral calcinosis, and calci-  nosis universalis. The following section concentrates on the  nonsyndromic disorders of dentin.   As mentioned previously, the classification of amelogen-  esis imperfecta is very complicated and is evolving as the  genetic profile of the numerous phenotypic variations is  being established. Although the variations in hereditary  dentin disorders are much less complicated, the classifica-  tion of these conditions currently is in disarray and needs  clarification.    Data from Shields ED: A new classification of heritable human enamel defects and a discussion of dentin defects. In Jorgenson RJ, Paul NW: Dentition: genetic  effects (birth defects original article series), vol 19, no 1, pp 107-127, New York, 1983, Alan R Liss; Witkop CJ Jr: Amelogenesis imperfecta, dentinogenesis  imperfecta and dentin dysplasia revisited: problems in classification, J Oral Pathol 17:547-553, 1988.    Mature dentin is about 70% mineral, 20% organic  matrix, and 10% water. About 85% to 90% of the organic  matrix is type I collagen, with two genes intimately involved  in its production: COLIAI and COLIA2. The most abun-  dant non-collagenous proteins in dentin are derived from  dentin sialophosphoprotein (DSPP) that is cleaved to form  three important dentin proteins: dentin sialoprotein (DSP),  dentin glycoprotein (DGP), and dentin phosphoprotein  (DPP). The primary gene guiding the formation of these  proteins is the DSPP gene.   Dentinogenesis imperfecta (DGI) is a hereditary devel-  opmental disturbance of the dentin in the absence of any  systemic disorder and has been shown to be associated with  any one of a number of mutations of the DSPP gene. In  about half of affected patients, similar dental changes are  seen in conjunction with the systemic hereditary disorder  of bone, osteogenesis imperfecta (see page 572); but  genetic studies have shown that the dental alterations are  related to mutations in the COLIAI and COLIA2 genes.  Extensive pedigrees of individuals with DSPP-related den-  tinogenesis imperfecta have been studied, and none have  exhibited other changes suggestive of osteogenesis imper-  fecta. This groundbreaking research has confirmed that  osteogenesis imperfecta with opalescent teeth is clearly a  separate disease from dentinogenesis imperfecta.   Two systems for classification of hereditary dentin disor-  ders, one by Witkop and the other by Shields, historically  were well accepted but not totally satisfactory (Table 2-3).  The Shields system has been the most widely utilized,  but the recent advances in genetics have made the nomen-  clature problematic. The Mendelian Inheritance of Man  (MIM) database is the most current classification system  for the molecular genetics of human pathoses. In the  MIM system, dentinogenesis imperfecta type I as defined  by the original Shield’s classification (DGI-I) has been  removed from the list of DGI and is classified appropriately  as osteogenesis imperfecta. DGI-II has become DGI-I,  whereas DGI-III and the dentin dysplasias (dentin dysplasia  type I [DD-I] and dentin dysplasia type II [DD-II]) have  retained their previous names. The Shields and MIM  systems currently are contradictory, resulting in confusion  with respect to the definition of dentinogenesis imperfecta    Dentinogenesis imperfecta formerly was divided into  DGL-II (hereditary opalescent dentin) and DGI-HI (Brandy-  wine isolate). The defining phenotypic feature of the Bran-  dywine isolate was the presence of unusual pulpal  enlargement known as shell teeth with multiple pulp expo-  sures seen primarily in the deciduous teeth. Current evi-  dence strongly suggests that DGI-HI simply represents  variable expression of dentinogenesis imperfecta. The origi-  nal review of the isolate identified only 8% of the kindred  with shell teeth. Investigators have documented enlarged  pulps in affected individuals whose parents and children  have classic dentinogenesis imperfecta. Identical patterns of  expression also have been seen in other large kindreds with  no connection to the Brandywine isolate. Finally, identical  mutations of the DSPP gene have been shown to manifest  as DGI-II and DGL-HI in different families. It seems very  clear that dentinogenesis imperfecta type II and dentinogenesis  imperfecta type III represent a single disease with variable  expressions.   The confusion does not end with DGI-II/HI controversy.  Dentin dysplasia type II (DD-II) also has been shown to  arise from similar or even identical mutations of the DSPP  gene. A number of authorities now believe that DD-H,  DGI-II, and DGI-HI represent a spectrum of the same  disease, with DD-II being the mild end of the continuum  and DGI-III representing the severe end. Any modern clas-  sification will remain problematic until DD-II is renamed  and the genetics of DD-I become clarified. In spite of this,  the classification system in Table 2-4 is an attempt to clarify  the nomenclature based on the current phenotypic and  genotypic findings.    As the nomenclature of DSPP-associated dentin defects  evolves, it is expected that the diseases will be listed in the  order of phenotypic severity from the mildest to most severe  (DD-H, DGI-I], and DGI-III). In spite of this, these dis-  orders are described most efficiently when DGI-II is pre-  sented first.    DSPP-associated dentin disorders Autosomal dominant DSPP  e Dentin dysplasia type II (DD-II)  e Dentinogenesis imperfecta (includes old  DGI-II and DGI-III)  Dentin dysplasia type | (DD-l) Autosomal dominant Ge    | 3 Pe: SS  @ Fig. 2-98 Dentinogenesis Imperfecta (DGI). Dentition exhibiting  diffuse brownish discoloration and slight translucence.    The prevalence of dentinogenesis imperfecta (heredi-  tary opalescent dentin, Capdepont’s teeth) is not randomly  distributed throughout the United States and Europe. Most  cases can be traced to whites (people of English or French  ancestry) from communities close to the English Channel.  The disorder is autosomal dominant and occurs in about  1:8000 whites in the United States.   Dentinogenesis imperfecta affects teeth in both denti-  tions with the severity of the dental alterations varying with  the age at which the tooth develops. Deciduous teeth are  affected most severely, followed by the permanent incisors  and first molars, with the second and third molars being  least altered.   The dentitions have a blue-to-brown discoloration, often  with a distinctive translucence (Fig. 2-98). The enamel  frequently separates easily from the underlying defective  dentin. Once exposed, the dentin often demonstrates sig-  nificantly accelerated attrition (Fig. 2-99). Radiographically,  the teeth have bulbous crowns, cervical constriction, thin  roots, and early obliteration of the root canals and pulp  chambers (Fig. 2-100).   The trait exhibits close to 100% penetrance but variable  expressivity. Clinically obvious enamel hypoplasia is noted in  some patients (Fig. 2-101). During the initial development  of the dentinoenamel junction (DEJ), there is a temporary  expression of enamel proteins by odontoblasts and a similar  expression of dentin proteins by pre-ameloblasts. Some    @ Fig. 2-99 Dentinogenesis Imperfecta (DGI). Dentition exhibiting  grayish discoloration with significant enamel loss and attrition.    ® Fig. 2-100 Dentinogenesis Imperfecta (DGI). Radiograph of  dentition exhibiting bulbous crowns, cervical constriction, and obliter-  ated pulp canals and chambers.    investigators have suggested that the enamel hypoplasia may  be secondary to expression of mutant DSPP protein by pre-  ameloblasts during the early formative stage of the DEJ.  Although the pulps usually are obliterated by excess  dentin production, some teeth may show normal-sized  pulps or significant pulpal enlargement. Those with  expanded pulps are termed shell teeth and demonstrate  normal-thickness enamel in association with extremely thin  dentin and dramatically enlarged pulps (Fig. 2-102). The    @ Fig. 2-101 Dentinogenesis Imperfecta (DGI). Radiograph of  dentition exhibiting bulbous crowns, early obliteration of the pulp, and  enamel hypoplasia. (From Levin LS, Leaf SH, Jelmine Ru, et al: Den-  tinogenesis imperfecta in the Brandywine isolate (DI type Ill): clinical,  radiologic, and scanning electron microscopic studies of the dentition,  Oral Surg Oral Med Oral Pathol 56:267-274, 1983.)    @ Fig. 2-102 Shell Teeth. Dentition exhibiting normal thickness  enamel, extremely thin dentin, and dramatically enlarged pulps.    thin dentin may involve the entire tooth or be isolated to  the root. This rare abnormality has been seen most fre-  quently in deciduous teeth in the presence of dentinogenesis  imperfecta and often is associated with pulp exposures. The  alteration may be unassociated with dentinogenesis imper-  fecta as an isolated finding in both dentitions and demon-  strate normal tooth shape and coloration, a negative family  history, and diffuse involvement. In the isolated variant,  slow but progressive root resorption occurs.   Several kindreds affected with dentinogenesis imperfecta  also have been shown to demonstrate progressive, sensori-  neural, high-frequency hearing loss. Jaw position has been  shown to affect the anatomy of the inner ear, and premature  tooth loss has been associated with hearing deficits. At this  time, it is unclear if the hearing loss is correlated with the  DSPP mutation or an alteration secondary to the primary  gnathic changes. Investigators wonder if dental restoration  may prevent the hearing loss or if the DSPP gene may directly  affect bone formation and the structure of the inner ear.   Dentin dysplasia type II (DD-II; coronal dentin dys-  plasia) has dramatically different appearances in the primary  and succedaneous dentitions. The primary teeth have a blue-  to-amber-to-brown translucence, similar to dentinogenesis  imperfecta (Fig. 2-103). Radiographically, the dental changes  include bulbous crowns, cervical constriction, thin roots,  and early obliteration of the pulp. The permanent teeth have  a normal color clinically; however, radiographically, the pulp    @ Fig. 2-103 Dentin Dysplasia Type II (DD-II). Dentition demon-  strating darkened and translucent deciduous molars in association  with permanent incisors and first molars that appear clinically normal.  (Courtesy of Dr. James Zettler.)    @ Fig. 2-104 Dentin Dysplasia Type II (DD-II). Radiographic  appearance of the permanent dentition exhibiting thistle tube-shaped  enlargements of the pulp chambers and numerous pulp stones.    chambers exhibit significant enlargement and apical exten-  sion. These enlarged pulp chambers have been described as  thistle tube-shaped or flame-shaped (Fig. 2-104). Pulp stones  develop in the enlarged pulp chambers.   A similar but unrelated disorder is pulpal dysplasia.  This process develops in teeth that are normal clinically.  Radiographically, both dentitions exhibit thistle tube—  shaped pulp chambers and multiple pulp stones.    In dentinogenesis imperfecta, the dentin adjacent to the  enamel junction appears similar to normal dentin, but the  remainder is distinctly abnormal. Short misshapen tubules  course through an atypical granular dentin matrix, which  often demonstrates interglobular calcification (Fig. 2-105).  Scanty atypical odontoblasts line the pulp surface, and cells  can be seen entrapped within the defective dentin. In  ground sections the enamel is normal in most patients;    @ Fig. 2-105 Dentinogenesis Imperfecta (DGI). Coronal dentin  exhibiting short misshapen tubules within atypical granular dentin  matrix.    @ Fig. 2-106 Dentin Dysplasia Type II (DD-II). Affected tooth  exhibiting large pulp stone within the pulp chamber.    however, about one-third of the patients have hypoplastic  or hypocalcified defects.   In patients with dentin dysplasia type H, the deciduous  teeth demonstrate the pattern noted in dentinogenesis  imperfecta. The permanent teeth exhibit normal enamel  and coronal dentin. Adjacent to the pulp, numerous areas  of interglobular dentin are seen. The radicular dentin is  atubular, amorphous, and hypertrophic. Pulp stones develop  in any portion of the chamber (Fig. 2-106).    In dentinogenesis imperfecta, the entire dentition is at risk  because of numerous problems. The root canals become  threadlike and may develop microexposures, resulting in  periapical inflammatory lesions. In spite of the risk of  enamel loss and significant attrition, the teeth often are not  good candidates for full crowns because of cervical fracture.  The success of full coverage is best in teeth with crowns  and roots that exhibit close to a normal shape and size.  Overlay dentures placed on teeth that are covered with  fluoride-releasing glass ionomer cement have been used  with success in some cases.   Rheumatoid arthritis and hypervitaminosis D  Sclerotic bone and skeletal anomalies  Tumoral calcinosis    The success of therapy varies with the severity of the  dental changes in individual patients. In those with exten-  sive attrition, the vertical dimension can be rebuilt by  placing nonprecious metal castings with adhesive luting  agents on teeth that have received no preparation and are  not subject to significant occlusal stress. The newer compos-  ites combined with a dentin-bonding agent have been used  in areas subject to occlusal wear. When large kindreds have  been followed over a long term, many of those affected are  candidates for full dentures or implants by 30 years of age  in spite of the numerous interventions. Newer materials and  techniques may alter this outlook.   The deciduous teeth in dentin dysplasia type II can be  approached in a manner similar to that described for den-  tinogenesis imperfecta. Although not frequent, periapical  inflammatory lesions have been seen in association with the  permanent teeth of some affected patients. Because the pulp  canals usually are not obliterated completely, endodontic  therapy is accomplished more readily.    Dentin dysplasia was initially categorized in 1939. Two  major patterns have been described: type I and type H.  However, type II currently is thought to be a variation of  dentinogenesis imperfecta, and the discussion of this condi-  tion is included in that section (see page 101). By definition,  dentin dysplasia should have no correlation with systemic  disease. Systemic diseases reported to be associated with  similar dentin changes are listed in Box 2-12.    Dentin dysplasia type I (DD-I; radicular dentin dyspla-  sia) has been referred to as rootless teeth, because the loss  of organization of the root dentin often leads to a shortened  root length. The process exhibits an autosomal dominant  pattern of inheritance and is one of the rarest forms of  human dentin disorders with an approximate prevalence of  1:100,000. The enamel and coronal dentin are normal  clinically and well formed (Fig. 2-107), but the radicular  dentin loses all organization and subsequently is shortened  dramatically (Fig. 2-108). Wide variation in root formation  is produced because dentinal disorganization may occur  during different stages of tooth development. If the dentin  organization is lost early in tooth development, markedly  deficient roots are formed; later disorganization results in    minimal root malformation. The variability is most pro-  nounced in permanent teeth and may vary not only from  patient to patient but also from tooth to tooth in a single  patient. Because of the shortened roots, the initial clinical  signs are extreme tooth mobility and premature exfoliation,  spontaneously or secondary to minor trauma. Less fre-  quently, delayed eruption is the presenting symptom. The  strength of the radicular dentin is reduced, with the teeth  being predisposed to fracture during extractions.   Radiographically, variations in radicular anatomy have  been described, and a subclassification of dentin dysplasia  type I has been proposed (Box 2-13; Fig. 2-109). The decid-  uous teeth often are affected severely, with little or no  detectable pulp, and roots that are markedly short or absent  (similar to type DDIa). In most patients, the permanent  teeth demonstrate short roots with no canals and a small  crescent-shaped pulpal remnant parallel of the cementoe-  namel junction (types DDIb and DDIc). Type DDId is  most unusual and should warn the clinician to rule out  systemic diseases, such as tumoral calcinosis, that can  produce identical changes.   In general, the teeth without root canals are those that  frequently develop periapical radiolucencies without obvious    ® Fig. 2-107 Dentin Dysplasia Type | (DD-I). Dentition exhibiting  attrition but otherwise normal coronal coloration and morphology.    cause (see Fig. 2-108). The radiolucencies represent periapi-  cal inflammatory disease and appear secondary to caries or  spontaneous coronal exposure of microscopic threads of  pulpal remnants present within the defective dentin.   A similar but unrelated disorder is fibrous dysplasia of  dentin. This autosomal dominant disorder exhibits teeth    e DDla: No pulp chambers, no root formation, and frequent  periapical radiolucencies   e DDlb: A single small horizontally oriented and crescent-  shaped pulp, roots only a few millimeters in length, and  frequent periapical radiolucencies   e DDic: Two horizontally oriented and crescent-shaped pulpal  remnants surrounding a central island of dentin, significant  but shortened root length, and variable periapical  radiolucencies   e DDid: Visible pulp chambers and canals, near normal root  length, enlarged pulp stones that are located in the coronal  portion of the canal and create a localized bulging of the  canal and root, constriction of the pulp canal apical to the  stone, and few periapical radiolucencies    ® Fig. 2-108 Dentin Dysplasia Type | (DD-l). Posterior dentition  exhibiting dramatically shortened roots, absence of pulp canals, and  small, crescent-shaped pulp chambers. Note radiolucency at apex of  mandibular bicuspid. (Courtesy of Dr. Michael Quinn.)    ® Fig. 2-109 Dentin Dysplasia Type | (DD-I). Illustration demonstrating the variability of the radio-  graphic appearance according to the degree of dentin disorganization within the root.    that are normal clinically. Radiographically the teeth are  normal in shape but demonstrate a radiodense product  filling the pulp chambers and canals. In contrast to dentino-  genesis imperfecta, small foci of radiolucency can be seen  in the pulp. Unlike dentin dysplasia type I, no crescent pulp  chambers or decrease in root length is seen. The radiodense  intrapulpal material consists of fibrotic dentin.    In patients with dentin dysplasia type I, the coronal enamel  and dentin are normal. Apical to the point of disorganiza-  tion, the central portion of the root forms whorls of tubular  dentin and atypical osteodentin. These whorls exhibit a  peripheral layer of normal dentin, giving the root the appear-  ance of a “stream flowing around boulders” (Fig. 2-110).    In patients with dentin dysplasia type I, preventive care is  of foremost importance. Perhaps as a result of shortened  roots, early loss from periodontitis is frequent. In addition,  pulp vascular channels extend close to the dentinoenamel  junction; therefore, even shallow occlusal restorations can  result in pulpal necrosis. Meticulous oral hygiene must be  established and maintained.   If periapical inflammatory lesions develop, the root  length guides the therapeutic choice. Conventional end-  odontic therapy requires mechanical creation of canal  paths and has been successful in teeth without extremely  short roots. Teeth with short roots demonstrate pulpal  ramifications that eliminate conventional endodontic    treatment as an appropriate therapeutic option. Periapical  curettage and retrograde amalgam seals have demonstrated  short-term success.    Regional odontodysplasia is a localized, nonhereditary  developmental abnormality of teeth with extensive adverse  effects on the formation of enamel, dentin, and pulp. Most  cases are idiopathic, but a number have been related to  various syndromes, growth abnormalities, neural disorders,  and vascular malformations (Box 2-14). A number of causes  have been proposed (Box 2-15), but the most popular  theory revolves around an alteration in the vascular supply.  Several cases have occurred in patients with vascular nevi of  the head and neck; in addition, similar changes have been  induced in animals by restricting the vascular flow to an  area of the jaws.    Regional odontodysplasia is an uncommon finding that  occurs in both dentitions and exhibits no racial predilection  and a slight female predominance. A review of the age at  the time of diagnosis reveals a bimodal peak that correlates  with the normal time of eruption of the deciduous (2 to 4  years) and permanent (7 to 11 years) dentitions. Typically,  the process affects a focal area of the dentition, with involve-  ment of several contiguous teeth. A maxillary predominance    mandibular dentition exhibiting enlarged pulps and extremely thin  enamel and dentin. (Courtesy of Dr. John B. Perry.)    exists with a predilection for the anterior teeth. Occasion-  ally, an unaffected tooth may be intermixed within a row  of altered teeth. Ipsilateral involvement of both arches and  bilateral changes in the same jaw have been reported.  Although rare generalized involvement has been docu-  mented, the presence of regional odontodysplasia in more  than two quadrants is rare. Involvement of the deciduous  dentition typically is followed by similarly affected perma-  nent teeth. In the area of altered teeth, the surrounding  bone often exhibits a lower density; in addition, hyperplasia  of the soft tissue may be noted overlying affected teeth that  are impacted.   Many of the affected teeth fail to erupt. Erupted teeth  demonstrate small irregular crowns that are yellow to brown,  often with a very rough surface. Caries and associated peri-  apical inflammatory lesions are fairly common. Because of  dentinal clefts and very long pulp horns, pulpal necrosis is  common (often in the absence of an obvious cause). Radio-  graphically, the altered teeth demonstrate extremely thin  enamel and dentin surrounding an enlarged radiolucent  pulp, resulting in a pale wispy image of a tooth; hence the  term ghost teeth (Fig. 2-111). A lack of contrast is seen  between the dentin and the enamel, with an indistinct or  “fuzzy” appearance of the coronal silhouette. Short roots  and open apices may be seen. The enlarged pulps frequently  demonstrate one or more prominent pulp stones. The most  common presenting signs and symptoms include delayed or  failure of eruption, early exfoliation, abscess formation, mal-  formed teeth, and noninflammatory gingival enlargement.    In ground sections the thickness of the enamel varies, result-  ing in an irregular surface. The prism structure of the enamel  is irregular or lacking, with a laminated appearance. The  dentin contains clefts scattered through a mixture of inter-  globular dentin and amorphous material. Globular areas of  poorly organized tubular dentin and scattered cellular inclu-  sions often are seen. The pulp tissue contains free or attached    stones that may exhibit tubules or consist of laminated  calcification. The follicular tissue surrounding the crown  may be enlarged and typically exhibits focal collections of  basophilic enamel-like calcifications called enameloid con-  glomerates (Fig. 2-112). 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Like the brain, the dental pulp is encased in hard tissue that   dentin provides rigid mechanical support and protection  from the bacteria-rich oral cavity. A focal breach in this  barrier can adversely affect the health of the dental pulp.   If the inflammatory process is not contained, the dental  pulp is uniquely hampered in its response because the only  source of vascularity enters through the apical foramen  without a collateral blood supply. Upon exposure, the con-  taminated pulp space acts as a conduit between the oral  cavity and the usually sterile alveolar bone. Spread of pulpal  infection into bone can lead to serious complications, such  as cavernous sinus thrombosis (see page 127), Ludwig  angina (see page 126), or systemic sepsis with life-threatening  complications. Pulpitis-related pain is an important defense  mechanism that can lead to therapeutic intervention prior  to serious complications.   Four main types of noxious stimuli are common causes  of pulpal inflammation (pulpitis):   1. Mechanical damage: Mechanical sources of injury  include traumatic accidents, iatrogenic damage from  dental procedures, attrition, abrasion, and barometric  changes.   2. Thermal injury: Severe thermal stimuli can be transmit-  ted through large uninsulated metallic restorations or  may occur from such dental procedures as cavity prepa-  ration, polishing, and exothermic chemical reactions of  dental materials.   3. Chemical irritation: Chemical-related damage can arise  from erosion or from the inappropriate use of acidic  dental materials.   4, Bacterial effects: Bacteria can damage the pulp through  toxins or directly after extension from caries or transpor-  tation via the vasculature.   The best classification system for pulpitis is one that  guides the appropriate treatment. Reversible pulpitis denotes  a level of pulpal inflammation in which the tissue is capable    of returning to a normal state of health if the noxious  stimuli are removed. Irreversible pulpitis implies that a  higher level of inflammation has developed in which the  dental pulp has been damaged beyond the point of recovery.  Often, frank invasion by bacteria is the crossover point from  reversible to irreversible pulpitis.    Evaluation of pulpal pain (pulpalgia) includes a combina-  tion of the clinical presentation and the response of the  tooth to a variety of vitality testing procedures. The predic-  tive value of these tests is sometimes less than optimal.  When the procedures demonstrate that the pulp is disease  free, the results are highly reliable. However, when a pulp  appears to test positively for irreversible pulpitis, histopath-  ologic examination may demonstrate no obvious evidence  of pulpal disease. The practitioner should use all available  tests, clinical information, and personal judgment in an  attempt to arrive at an appropriate diagnosis.    Clinically, a normal pulp exhibits no signs or symptoms that  suggest pulpitis. These teeth respond to cold with mild pain  that resolves in 1 to 2 seconds, whereas heat is not associated  with pulpal discomfort. Pain to percussion will not be  evident, and the radiographic examination of the perira-  dicular bone will be within normal limits.    A tooth with reversible pulpitis is acutely painful when a  stimulus (usually cold or sweet foods, but sometimes heat)  is applied, but the discomfort resolves within a few seconds  after elimination of the stimulus. Typically, the tooth  responds to electric pulp testing at lower levels of current  than an appropriate control tooth. Mobility and sensitivity  to percussion are absent. A cracked tooth or defective res-  toration often is present if this pattern of pulpal pain is  noted in association with discomfort upon biting. If the  pulpitis is allowed to progress, then the duration of the pain  on stimulation can become longer and the pulp may become  affected irreversibly.   A similar pattern of pulpal pain can occur when exposed  dentin receives a thermal, chemical, or physical stimulus.    Dentin sensitivity should be considered if exposed dentin  is present and triggers for reversible pulpitis such as caries,  tooth fractures, and defective or newly placed restorations  are not present.    Patients with early irreversible pulpitis generally have  sharp, severe pain on thermal stimulation, and the pain  continues for a longer period of time after the stimulus is  removed. Cold is especially uncomfortable, although heat  or sweet and acidic foods also can elicit pain. In addition,  the pain may be spontaneous or continuous and may be  exacerbated when the patient lies down. The tooth responds  to electric pulp testing at lower levels of current.   In the early stages of irreversible pulpitis, the pain often  can be localized easily to the individual offending tooth;  with increasing discomfort, however, the patient may be  unable to identify the offending tooth within a quadrant.  Although pulpal pain never crosses the midline, it can be  referred from arch to arch, making pulp testing of both  arches a necessity in difficult cases.   In the later stages of irreversible pulpitis, the pain  increases in intensity and is experienced as a throbbing pres-  sure that can keep patients awake at night. At this point,  heat increases the pain; however, cold may produce relief.  The tooth responds to electric pulp testing at higher levels  of current or demonstrates no response. Mobility and sen-  sitivity to percussion are usually absent because significant  inflammation has not spread yet to the apical area. If pulpal  drainage occurs (e.g., crown fracture, fistula formation),  then the symptoms may resolve—only to return if the  drainage ceases.    Pulpal necrosis should be suspected when the tooth fails to  respond to electric or thermal sensitivity testing. Partial  pulpal necrosis (pulpal necrobiosis) often occurs and may  be isolated to the coronal portion or one canal of a multi-  rooted tooth. Teeth with necrotic pulps present with symp-  toms that vary from none to acute pain with or without  bite sensitivity and hyperocclusion.    One unique pattern of pulpal inflammation is chronic  hyperplastic pulpitis (pulp polyp). This condition occurs  in children and young adults who have large exposures of  the pulp in which the entire dentinal roof often is missing.  The most frequently involved teeth are the deciduous or  succedaneous molars, which have large pulp chambers in  these age groups. Mechanical irritation and bacterial inva-  sion result in a level of chronic inflammation that produces  hyperplastic granulation tissue that extrudes from the  chamber and often fills the associated dentinal defect (Figs.  3-1 to 3-3). The apex may be open and reduces the chance  of pulpal necrosis secondary to venous compression. The  tooth is asymptomatic except for a possible feeling of pres-  sure when it is placed into masticatory function.    ® Fig. 3-1 Chronic Hyperplastic Pulpitis. Erythematous granula-  tion tissue extruding from the pulp chamber of the mandibular first  molar.    @ Fig. 3-2 Chronic Hyperplastic Pulpitis. Gross photograph dem-  onstrating hyperplastic pulp tissue filling a large coronal carious defect.  Arrows delineate the previous roof of the pulp chamber.    in Fig. 3-2. Chronically inflamed granulation tissue fills the coronal  defect. Note surface stratified squamous epithelium.    Basically, the histopathology is primarily of academic inter-  est and usually does not affect treatment significantly.  Numerous investigations have shown a surprising lack of  correlation between histopathologic findings and the clini-  cal symptoms in the majority of pulps examined.    ® Fig. 3-4 Reversible Pulpitis. Dental pulp exhibiting hyperemia and  edema. The adjacent dentin was cut recently during placement of a  dental restoration.    ° Fig. 3-5 Irreversible Pulpitis. Dental pulp exhibiting acute inflam-  matory infiltrate consisting predominantly of polymorphonuclear  leukocytes.    In patients with reversible pulpitis, the pulp usually  shows hyperemia, edema, and a few inflammatory cells  underlying the area of affected dentinal tubules (Fig. 3-4).  Tertiary dentin may be noted in the adjacent dentinal wall,  and scattered acute inflammatory cells are found  occasionally.   Irreversible pulpitis often demonstrates congestion of the  venules that results in focal necrosis. This necrotic zone  contains polymorphonuclear leukocytes and _ histiocytes  (Fig. 3-5). The surrounding pulp tissue usually exhibits  fibrosis and a mixture of plasma cells, lymphocytes, and  histiocytes (Fig. 3-6).   Chronic hyperplastic pulpitis demonstrates a cap of sub-  acutely inflamed granulation tissue that fills the entire space  of the original pulp chamber and histopathologically resem-  bles a pyogenic granuloma (see page 483). The surface of  the polyp may or may not be covered with stratified squa-  mous epithelium, which migrates from the adjacent gingiva  or arises from sloughed epithelium within the oral fluids  (see Fig. 3-3). The deeper pulp tissue within the canals typi-  cally demonstrates fibrosis and a chronic inflammatory infil-  trate. Pulpal calcifications are common in both the radicular    6 Irreversible Pulpitis. Same tooth as depicted in Fig. 3-5.  The dental pulp exhibits an area of fibrosis and chronic inflammation  peripheral to the zone of abscess formation.    and coronal portions. Often the apical portion of the pulp  tissue is normal with minimal inflammation or fibrosis.    Reversible pulpitis is treated by removal of the local irritant.  On occasion, analgesic medications sometimes are desir-  able. The prognosis of reversible pulpitis is good if action is  taken early enough. The pulp status should be evaluated  periodically over the next 3 months to ensure that healing  has occurred and the process has not progressed to irrevers-  ible pulpitis or necrosis.   Irreversible and chronic hyperplastic pulpitis are treated  by extraction of the tooth or by root canal therapy.    Formation of dentin proceeds throughout life. The dentin  formed before completion of the crown is called primary  dentin. This process is followed by the formation of sec-  ondary dentin. The same odontoblasts that formed the  primary dentin remain functional and produce secondary  dentin. With advancing age in functioning teeth, dentin is  deposited diffusely along the inner walls and leads to smaller  pulp chambers and canals. This type of dentin is termed  physiologic secondary dentin and exhibits slow and  gradual deposition that increases after the age of 35 to 40  years. A significantly decreased amount of secondary dentin  has been described in impacted teeth, suggesting that func-  tional forces of occlusion promote the deposition. Deposi-  tion within the pulp chamber often is not totally uniform.  In posterior teeth, the greatest deposition is seen on the  pulpal floor, to a lesser extent on the roof, and least on the  sidewalls. Therefore, with age, pulp chambers decrease sig-  nificantly in height but not extensively in width. Forensic  scientists have suggested that the formation of this second-  ary dentin occurs so consistently that the width ratio of the  dentin taken at three different root levels correlates very  closely with age. Other investigators dispute this finding    and believe the process does not occur in a linear manner,  making age estimation difficult, especially in young adults.   Physiologic secondary dentin is more advanced in males  and has been associated positively with calcification-related  diseases (e.g., arthritis, gout, kidney stones, gall stones, ath-  erosclerosis, and hypertension). Early widespread formation  of secondary dentin has been seen in association with pro-  geria, a condition characterized by accelerated aging. On  occasion, significant traumatic injury can lead to early oblit-  eration of the pulp chamber and canal (calcific metamor-  phosis) in the affected tooth.   Localized new dentin also is laid down in areas of focal  injury. This dentin is more haphazardly organized and is  termed tertiary (reactionary, reparative, irregular, or irri-  tation) dentin. This localized dentin formation may occur  in response to the following:  ¢ Attrition  ¢ Fracture  ¢ Erosion  e Abrasion  * Caries  ¢ Periodontal disease  ¢ Mechanical injury from dental procedures  ¢ Irritation from dental materials   Injury of the peripheral odontoblastic processes is all that  is required to initiate tertiary dentin formation. If the stim-  ulus is mild to moderate, then the tertiary dentin typically  is produced by surviving odontoblasts and is termed reac-  tionary dentin. This type of tertiary dentin is more regular  in appearance and continuous with the tubules of the  primary and secondary dentin. If the stimulus is more severe  and leads to the death of the primary odontoblasts, then a  new generation of odontoblasts may arise from undifferenti-  ated cells within the pulp and continue to form tertiary  dentin that is termed reparative dentin. Demineralization of  dentin during caries also releases significant amounts of  calcium and phosphates. These minerals often diffuse  toward the pulp and assist in sclerosis of the tubules as  calcium phosphate.   The initial layer of reparative dentin is atubular and  known as interface dentin (fibrodentin). This thin band may  be acellular or exhibit scattered nuclear inclusions. After  deposition of the interface dentin, the remainder of the  reparative dentin is tubular but not continuous with the  primary, secondary, or reactionary dentin. This lack of com-  munication further assists in protecting the pulp from the  external stimulus. When the primary odontoblasts die, their  dentinal tubules are filled with degenerated odontoblastic  processes and are termed dead tracts. These tubules usually  are sealed off from the pulp by the reparative dentin.    As noted on periapical radiographs, the deposition of sec-  ondary dentin results in diminishing size of pulp chambers  and canals. Secondary dentin appears to reduce sensitivity  of the affected teeth, susceptibility to dentinal caries, and    @ Fig. 3-7 Physiologic Secondary Dentin. Periapical abscess with  all four teeth nonresponsive to electric pulp testing. Decreased deposi-  tion of physiologic secondary dentin on the right central incisor (arrow)  delineated the origin of the infection; endodontic treatment of this tooth  resolved the lesion.    the trauma of dental procedures. Although production of  secondary dentin makes pulp exposure during operative  procedures less likely, it also increases the difficulty of locat-  ing the pulp chamber and canals during endodontic therapy.  On occasion, large inflammatory lesions may involve more  than one apex; the size of the canals can be used to help  determine the original focus of infection because the canal  may be larger in the tooth that became nonvital earlier (Fig.  3-7). Teeth affected by calcific metamorphosis often are  discovered clinically by a yellow discoloration of the crown;  radiographically, the affected teeth exhibit an accelerated  closure of the pulp chamber and canal when compared with  adjacent or contralateral teeth (Fig. 3-8). In such cases, the  pulpal space may appear to be obliterated completely or  reduced dramatically. This alteration usually follows trauma  to the tooth and may be seen as early as 3 months after the  traumatic episode; however, usually the condition is not  detected for about 1 year.    Physiologic secondary dentin consists of regular tubular  dentin that is applied onto the primary dentin. These two  layers of dentin can be separated by a line of demarcation,  often indicated by a bending of the tubules (Fig. 3-9). With  advancing age, as the odontoblasts undergo degenerative  changes, the physiologic secondary dentin becomes more  irregular with fewer tubules.   The quality and appearance of tertiary dentin depend on  the severity of the noxious stimulus that promoted its    @ Fig. 3-8 Calcific Metamorphosis. A, Left deciduous maxillary  central incisor exhibiting yellow discoloration. B, Radiograph of the  same patient showing total calcification of the pulp chambers and  canals of the deciduous maxillary incisors. (Courtesy of Dr. Jackie L.  Banahan.)    ® Fig. 3-9 Physiologic Secondary Dentin. A distinct line of demar-  cation (arrow) separates the primary dentin and physiologic secondary  dentin.    formation. Tertiary dentin is localized to the pulpal end of  the odontoblastic processes that were affected (Fig. 3-10).  With a mild stimulus, such as abrasion or attrition, reac-  tionary dentin exhibits slow deposition characterized by  tubules that are continuous with the secondary dentin and  only slightly irregular. With more severe damage (e.g., a  rapidly progressing carious lesion), reparative dentin is  formed, a process that occurs more rapidly and consists of    Bares ba Ze ss Z ua te  @ Fig. 3-10 Reparative Secondary Dentin. Localized deposition of  secondary dentin (bottom) at the pulpal end of the dentinal tubules  affected by the carious process.    a thin layer of interface dentin on which is deposited irregu-  lar dentin with widely scattered, disorganized tubules.    In studies of teeth exhibiting calcific metamorphosis, the  vast majority of affected teeth never develop clinical or  radiographic features suggestive of periapical inflammatory  disease; therefore, endodontic therapy should be performed  only if periapical pathosis or negative vitality testing is  present. Even if a canal space cannot be identified radio-  graphically, conventional root canal therapy usually can  locate and negotiate the pulp canal. Because of the dramati-  cally reduced canal space, location of the pulp canal can be  difficult, and care must be exercised during access prepara-  tion to prevent perforation. If endodontic therapy is unsuc-  cessful, then periapical surgery can be performed in those  cases with evidence of periapical inflammatory disease. If  vitality testing is positive, then periodic reevaluation appears  prudent. To improve dental aesthetics, full coverage is rec-  ommended for discolored anterior teeth with large restora-  tions. Otherwise, bleaching often effectively resolves the  discoloration.    Calcifications within the dental pulp are not rare, but the  frequency is difficult to determine. Reported rates vary from  8% to 90%, but several investigators have documented a  prevalence of approximately 20% in individual teeth  reviewed radiographically. Because radiographically detect-  able pulp stones typically exceed 200 Um in diameter, the  prevalence in a histopathologic review would be expected  to be much higher. An increased prevalence of pulp stones  has been reported in association with a variety of chronic  pulpal irritants, such as attrition, abrasion, erosion, caries,  periodontitis, dental restorative procedures, orthodontic  tooth movement, and tooth injury. Although many exam-  ples remain idiopathic, pulpal calcification also has been    associated with aging, fluoride supplementation, hypervita-  minosis D, and a few genetic disorders, such as dentin  dysplasia type II (see page 101).   The three types of pulpal calcifications are:  1. Denticles  2. Pulp stones  3. Diffuse linear calcifications   All pulpal calcifications start out as free bodies within  the pulp tissue, but many may become attached or embed-  ded in the dentinal walls of the pulp.   Denticles are believed to form as a result of an epithelio-  mesenchymal interaction within the developing pulp. Epi-  thelial strands originating from the root sheath, or cervical  extensions into the pulp chamber adjacent to furcations,  induce odontoblastic differentiation of the surrounding  mesenchyme of the dental papilla, forming the core of the  denticle. Odontoblasts deposit tubular dentin as they move  away from the central epithelium and produce thimble-  shaped structures surrounding the epithelium.   Pulp stones are believed to develop around a central  nidus of pulp tissue (e.g., collagen fibril, ground substance,  necrotic cell remnants). Initial calcification begins around  the central nidus and extends outward in a concentric or  radial pattern of regular calcified material. Pulp stones are  formed within the coronal portions of the pulp and may  arise as a part of age-related or local pathologic changes.   Diffuse linear calcifications do not demonstrate the  lamellar organization of pulp stones; they exhibit areas of  fine, fibrillar, irregular calcification that often parallel the  vasculature. These calcifications may be present in the pulp  chamber or canals, and the frequency increases with age.    Denticles and pulp stones can reach sufficient size to be  detected on intraoral radiographs as radiopaque enlarge-  ments within the pulp chamber or canal (Fig. 3-11). Diffuse  calcifications are not detectable radiographically.   Other than rare difficulties during endodontic proce-  dures, pulpal calcifications are typically of little clinical    ® Fig. 3-11 Pulp Stones. Multiple teeth demonstrating radiographi-  cally obvious calcifications within the pulp chambers.    significance. Some investigators associate the calcifications  with dental neuralgias, but the high frequency of these  lesions in the absence of clinical symptoms argues against  this relationship. Others have suggested a relationship  between pulpal calcification and carotid artery calcification,  which potentially could be a marker for cardiovascular  disease. In spite of this, studies of the association by mul-  tiple groups have not proven a strong correlation. Promi-  nent pulpal calcifications have been noted in association  with certain disease processes, such as the following:    Denticles consist of tubular dentin surrounding a central  nest of epithelium. With time, the central epithelium  degenerates and the tubules undergo sclerosis, making their  detection difficult. Most denticles are attached or embed-  ded. Those that remain free in the pulp occasionally develop  outer layers of irregular fibrillar calcification or lamellated  layers of calcification similar to those seen in pulp stones.   Pulp stones demonstrate a central amorphous mass of  irregular calcification surrounded by concentric lamellar  rings of regular calcified material (Fig. 3-12). Occasionally,  a peripheral layer of tubular dentin may be applied by  odontoblasts, which arise from the surrounding pulp tissue  in response to the presence of the pulp stone. In addition,  fibrillar irregular calcified material also may be evident on  the periphery of pulp stones.   Diffuse linear calcifications consist entirely of fine, fibril-  lar, and irregular calcifications that develop in the pulp  chambers and canals (Fig. 3-13). This material often is  deposited in a linear fashion along the course of a blood  vessel or nerve.    @ Fig. 3-12 Pulp Stones. Multiple stones within the pulp chamber.    No treatment is required. Most pulpal calcifications are not  associated with any significant clinical alterations.    ‘The term periapical granuloma refers to a mass of chroni-  cally or subacutely inflamed granulation tissue at the apex  of a nonvital tooth. This commonly used name is not totally  accurate because the lesion does not show true granuloma-  tous inflammation microscopically. Although the term  apical periodontitis may be more appropriate, it may prove  confusing to the clinician. Formation of apical inflamma-  tory lesions represents a defensive reaction secondary to the  presence of microbial infection in the root canal with spread  of related toxic products into the apical zone. Initially, the  defense reaction eliminates noxious substances that exit the  canals. With time, however, the host reaction becomes less  effective with microbial invasion or spread of toxins into the  apical area.   In the early stages of infection, neutrophils predominate  and radiographic alterations are not present; this phase of  periapical inflammatory disease is termed acute apical peri-  odontitis. The involved inflammatory cells are primarily  neutrophils and release prostaglandins, which activate  osteoclasts to resorb the surrounding bone, leading to a  detectable periapical radiolucency. With time, chronic  inflammatory cells begin to dominate the host response.  Chronic lesions often are asymptomatic and demonstrate  little additional change radiographically.   Periapical granulomas may arise after quiescence of a  periapical abscess or may develop as the initial periapical  pathosis. These lesions are not necessarily static. In addi-  tion to possible periapical cyst formation, a worsening of    the pulpal infection can lead to a reappearance of inflam-  mation, redevelopment of symptoms, and possible enlarge-  ment of the associated radiolucency. Secondary acute  inflammatory changes within a periapical granuloma have  been termed a phoenix abscess, after the mythical bird that  would die, only to arise again from its own ashes. In pro-  gressive periapical granulomas, the enlargement often is  not continuous but occurs in spurts associated with peri-  odic acute exacerbations.    The initial phase of periapical inflammatory disease—acute  periapical periodontitis—creates a constant dull, throbbing  pain. The associated tooth responds negatively to vitality  testing or reveals a delayed positive result. Typically, pain  on biting or percussion is present, and no obvious radio-  graphic alterations are noted. If the acute inflammatory  process evolves into a chronic pattern, then the associated  symptoms diminish. In many instances, chronic periapical  inflammatory disease is detected without any previous rec-  ollection of a prior acute phase.   Most periapical granulomas are asymptomatic, but pain  and sensitivity can develop if acute exacerbation occurs.  Typically, the involved tooth does not demonstrate mobility  or significant sensitivity to percussion. The soft tissue over-  lying the apex may or may not be tender. The tooth does  not respond to thermal or electric pulp tests unless  the pulpal necrosis is limited to a single canal in a multi-  rooted tooth.   Most lesions are discovered on routine radiographic  examination. The associated radiolucencies are variable,  ranging from small, barely perceptible lesions to lucencies  exceeding 2 cm in diameter (Figs. 3-14 to 3-16). Affected  teeth typically reveal loss of the apical lamina dura. The  lesion may be circumscribed or ill-defined and may or may  not demonstrate a surrounding radiopaque rim. Root  resorption is not uncommon (Fig. 3-17). Although lesions  greater than 200 mm” often represent periapical cysts,  numerous investigators have been unable to distinguish  periapical granulomas from periapical cysts simply on the  basis of size and radiographic appearance. Because periapi-  cal inflammatory disease is not static and granulomas can  transform into cysts or abscesses (and vice versa) without  significant radiographic change, it is not surprising that the  radiographic features are not diagnostic.   Cone-beam computed tomography (CT) has demon-  strated a greater accuracy for detection of periapical inflam-  matory disease when compared to periapical or panoramic  radiographs. This technique should be considered when  clinical tests suggest periapical pathology but standard  radiographs demonstrate no detectable lesions.    Periapical granulomas consist of inflamed granulation  tissue surrounded by a fibrous connective tissue wall. The    @ Fig. 3-14 Periapical Granulomas. Discrete periapical radiolucen-  cies associated with the apices of the mandibular first molar. (Courtesy  of Dr. Garth Bobrowski.)    ® Fig. 3-15 Periapical Granuloma. Well-defined radiolucency asso-  ciated with the apex of the maxillary first bicuspid. (Courtesy of Dr.  Frank Beylotte.)    @ Fig. 3-16 Periapical Granuloma. Large, well-defined radiolu-  cency associated with the apices of the mandibular first molar. (Cour-  tesy of Dr. Robert E. Loy.)    granulation tissue demonstrates a variably dense lympho-  cytic infiltrate that is intermixed frequently with neutro-  phils, plasma cells, histiocytes, and, less frequently, mast  cells and eosinophils (Fig. 3-18). When numerous plasma  cells are present, scattered eosinophilic globules of gamma    @ Fig. 3-17 Periapical Granuloma. Ill-defined radiolucency associ-  ated with the mandibular first molar, which exhibits significant root  resorption.    e Fig. 3-18 Periapical Granuloma. Granulation tissue exhibits  mixed inflammatory infiltrate consisting of lymphocytes, plasma cells,  and histiocytes.    globulin (Russell bodies) may be seen. In addition, clusters  of lightly basophilic particles (pyronine bodies) also may  be present in association with the plasmacytic infiltrate.  Both of these plasma cell products are not specific for the  periapical granuloma and may be found within any accu-  mulation of plasma cells. Epithelial rests of Malassez may  be identified within the granulation tissue. Collections of  cholesterol clefts, with associated multinucleated giant cells  and areas of red blood cell extravasation with hemosiderin  pigmentation, may be present. Small foci of acute inflam-  mation with focal abscess formation may be seen but do  not warrant the diagnosis of periapical abscess.    Apical inflammatory lesions result from the presence of  microorganisms or their toxic products in the root canal,  the apical tissues, or both. Successful treatment depends on  the reduction and control of the offending organisms.  Because of the anatomic complexity of the root canal  systems, some investigators believe absolute eradication of    all microorganisms is unlikely; the goal of endodontics is to  reduce the microbial load to a level that is insufficient to  maintain periapical inflammation. If the tooth can be main-  tained, then root canal therapy can be performed. Nonre-  storable teeth must be extracted, followed by curettage of  all apical soft tissue. In symptomatic cases, nonsteroidal  antiinflammatory drugs (NSAIDs) are beneficial; use of  systemic antibiotic medications is not recommended unless  associated swelling or systemic changes are present.   Teeth treated endodontically should be evaluated at 1-  and 2-year intervals (at a minimum) to rule out possible  lesional enlargement and to ensure appropriate healing. In  addition, many clinicians believe that evaluations at 1, 3,  and 6 months are appropriate. Strong emphasis should be  placed on the importance of the recall appointments.   Research has shown the most important factor for the  successful treatment of periapical inflammatory disease is the  quality of the endodontic treatment. In addition, the coronal  restoration is critical, and failure can occur in cases with  excellent endodontic therapy but poor coronal restoration.   If initial conventional therapy is unsuccessful, endodon-  tic retreatment represents the best approach for minimizing  the bacterial contamination and should be considered  before periapical surgery. Periapical surgery remains an  important tool for resolution of periapical inflammatory  disease, but often it is reserved for lesions larger than 2 cm  or those associated with teeth that are not appropriate for  conventional endodontic therapy. Periapical surgery should  include thorough curettage of all periradicular soft tissue,  amputation of the apical portion of the root, and sealing  the foramen of the canal. All soft tissue removed during  periapical surgical procedures should be submitted for his-  topathologic examination. These surgical sites represent  areas that have failed to respond to appropriate therapy; as  such, histopathologic examination and diagnostic confirma-  tion are mandatory.   On occasion, the defect created by periapical inflamma-  tory lesions may fill with dense collagenous tissue rather  than normal bone (Fig. 3-19). These fibrous (periapical)  scars occur most frequently when both the facial and lingual  cortical plates have been lost (Fig. 3-20); however, they  occasionally arise in areas with intact cortical plates. If  during surgery both plates are discovered to be missing,  then the patient should be informed of the possibility of  scar formation. The development of a periapical scar is not  an indication for future surgery.    Epithelium at the apex of a nonvital tooth presumably can  be stimulated by inflammation to form a true epithelium-  lined cyst, or periapical cyst. The source of the epithelium  is usually a rest of Malassez but also may be traced to cre-  vicular epithelium, sinus lining, or epithelial lining of sinus  tracts. Cyst development is common with a wide range of    © Fig. 3-19 Periapical Fibrous Scar. Dense, fibrous connective  tissue with vital bone and no significant inflammatory infiltrate.    e Fig. 3-20 Periapical Fibrous Scar. Periapical radiolucency of  maxilla at the previous site of extraction in which both cortical plates  were lost. The site was filled with dense collagenous tissue. (Courtesy  of Dr. James Tankersley.)    prevalence noted that most likely is related to the stringency  of the diagnostic criteria used in a particular study.   When the cyst and root are removed totally, two varia-  tions of periapical cyst have been described. Periapical  pocket cysts are characterized by an incomplete epithelial  lining because of extension of the apical portion of the tooth  into the cyst lumen. Periapical true cysts form a complete  epithelium-lined baglike structure that is adjacent to, but  separated from, the tooth apex. Studies have shown an  inability to separate a “pocket” cyst from a “true” cyst unless  the entire tooth and associated soft tissue are removed  in toto, which makes the separation most impractical.  Because distinguishing between an epithelialized periapical  granuloma, a “pocket” cyst, or a “true” cyst has little   Periapical cysts represent a fibrous connective tissue wall  lined by epithelium with a lumen containing fluid and cel-  lular debris. Theoretically, as the epithelium desquamates  into the lumen, the protein content is increased. Fluid  enters the lumen in an attempt to equalize the osmotic  pressure, and slow enlargement occurs. Most periapical  cysts grow slowly and do not attain a large size.   On occasion, a similar cyst, best termed a lateral radicu-  lar cyst, may appear along the lateral aspect of the root.  Like the periapical cyst, this lesion also usually arises from  rests of Malassez, and the source of inflammation may be  periodontal disease or pulpal necrosis with spread through  a lateral foramen. Radiographically, these cysts mimic devel-  opmental lateral periodontal cysts (see page 645). Histo-  pathologically, however, they are consistent with cysts of  inflammatory origin.   Periapical inflammatory tissue that is not curetted at the  time of tooth removal may give rise to an inflammatory cyst  called a residual periapical cyst. With time, many of these  cysts exhibit an overall reduction in size, and spontaneous  resolution can occur from a lack of continued inflammatory  stimulus.   Typically, patients with periapical cysts have no symptoms  unless there is an acute inflammatory exacerbation. In addi-  tion, if the cyst reaches a large size, then swelling and mild  sensitivity may be noted. Movement and mobility of adja-  cent teeth are possible as the cyst enlarges. The tooth from  which the cyst originated does not respond to thermal and  electric pulp testing.   The radiographic pattern is identical to that of a periapi-  cal granuloma. Cysts may develop even in small periapical  radiolucencies, and the radiographic size cannot be used for  the definitive diagnosis. A loss of the lamina dura is seen  along the adjacent root, and a rounded radiolucency encir-  cles the affected tooth apex (Fig. 3-21). Root resorption is  common (Fig. 3-22). With enlargement, the radiolucency  often flattens out as it approaches adjacent teeth. Significant  growth is possible, and lesions occupying an entire quadrant  have been noted (Fig. 3-23). Although periapical cysts more  frequently achieve greater size than periapical granulomas,  neither the size nor the shape of the lesion can be considered  a definitive diagnostic criterion. The inability to separate  these pathoses on a consistent basis holds true even with  newer radiographic techniques, such as cone-beam CT.  Periapical cysts also are known to involve deciduous teeth.  These are most frequently associated with molar teeth and  appear as a radiolucent zone that surrounds the roots and  fills the interradicular space at the bifurcation (Fig. 3-24).    Lateral radicular cysts appear as discrete radiolucencies  along the lateral aspect of the root (Fig. 3-25). Loss of    @ Fig. 3-21 Periapical Cyst. Well-circumscribed radiolucency inti-  mately associated with the apex of the mandibular central incisor. Note  the loss of lamina dura in the area of the lesion.    @ Fig. 3-22 Periapical Cyst. Radiolucency associated with the max-  illary central incisor, which exhibits significant root resorption.    lamina dura and an obvious source of inflammation may  not be detected without a high index of suspicion. Before  surgical exploration of laterally positioned radiolucencies, a  thorough evaluation of the periodontal status and vitality  of adjacent teeth should be performed. Many examples of  the so-called globulomaxillary cyst (see page 25) prove to  be of inflammatory origin and represent lateral radicular  cysts (Fig. 3-26).    ® Fig. 3-23 Periapical Cyst. Large unilocular radiolucency extending  from the mandibular first molar to the contralateral first molar. (Courtesy  of Dr. John R. Cramer.)    @ Fig. 3-24 Periapical Cyst. Radiolucency involving the bifurcation  and apices of the deciduous right mandibular second molar.    The residual periapical cyst appears as a round-to-oval  radiolucency of variable size within the alveolar ridge at the  site of a previous tooth extraction (Fig. 3-27). As the cyst  ages, degeneration of the cellular contents within the lumen  occasionally leads to dystrophic calcification and central  luminal radiopacity.    The histopathologic features of all three types of inflamma-  tory cysts are similar. The cyst is lined by stratified squa-  mous epithelium, which may demonstrate exocytosis,  spongiosis, or hyperplasia (Fig. 3-28). As seen in dentiger-  ous cysts, scattered mucous cells or areas of ciliated  pseudostratified columnar epithelium may be noted in  periapical cysts (Fig. 3-29). Although some maxillary peri-  apical cysts lined by pseudostratified columnar epithelium    a) aes  @ Fig. 3-26 Lateral Radicular Cyst. Inverted pear-shaped radiolu-  cency between the maxillary lateral incisor and cuspid (arrow). The  lateral incisor ultimately proved to be nonvital.    ® Fig. 3-25 Lateral Radicular Cyst. A, Periapical radiograph of the left side of the posterior mandible  taken at time of completion of endodontic therapy of the bicuspid and molars. B, Subsequent radiograph  taken 27 months later. Note radiolucency between bicuspid and first molar extending laterally from the  mesial root of the first molar. (Courtesy of Dr. Carroll Gallagher.)    ® Fig. 3-27 Residual Periapical Cyst. Well-circumscribed radiolu-  cency of the maxilla at the site of previous tooth extraction.    ® Fig. 3-28 Periapical Cyst. Cyst lined by stratified squamous epi-  thelium. Note connective tissue wall, which contains a chronic inflam-  matory infiltrate and numerous cholesterol clefts.    may have originated from the adjacent sinus lining, the  presence of mucous cells or respiratory-like epithelium also  can be observed in mandibular cysts. The ability of odon-  togenic epithelium to demonstrate such specialized differ-  entiation represents an example of prosoplasia (forward    metaplasia) and highlights the diverse potential of odonto-  genic epithelium. The cyst lumen may be filled with  fluid and cellular debris. On occasion, the lining epithe-  lium may demonstrate linear or arch-shaped calcifications  known as Rushton bodies (Fig. 3-30). The wall of the cyst  consists of dense fibrous connective tissue—often with an  inflammatory infiltrate containing lymphocytes variably  intermixed with neutrophils, plasma cells, histiocytes, and  (rarely) mast cells and eosinophils. Dystrophic calcifica-  tion, cholesterol clefts with multinucleated giant cells, red  blood cells, and areas of hemosiderin pigmentation may be  present in the lumen, wall, or both. Due to the inability of  macrophages and giant cells to remove cholesterol, its pres-  ence may be partially responsible for failure of healing of  cysts in which the original focus of infection was treated  appropriately.   Intramural islands of odontogenic epithelium that closely  resemble squamous odontogenic tumor (see page 668)  rarely have been noted, which could be misdiagnosed as a  neoplastic process. Studies have shown these proliferations  are not neoplastic and mandate no further treatment beyond  the usual standard of care for periapical cysts.   Occasionally, the walls of inflammatory cysts will contain  scattered hyaline bodies (pulse granuloma, giant-cell  hyaline angiopathy). These bodies appear as small circum-  scribed pools of eosinophilic material that exhibits a cor-  rugated periphery of condensed collagen often surrounded  by lymphocytes and multinucleated giant cells (Fig. 3-31).  Initially, these foci were thought to be a vascular degenera-  tive process or a foreign body reaction to machinery oil or  vegetable matter. Subsequently, these bodies have been  shown to represent pools of inflammatory exudate (i.e.,  extravasated serum) that ultimately undergoes fibrosis and  occasionally dystrophic calcification. The multinucleated  giant cells are drawn to the site for removal of insoluble  hemosiderin granules. Hyaline bodies may be found in any  area of chronic intraosseous inflammation, especially peri-  apical inflammatory disease.    ne bodies appearing as  corrugated collagenous rings surrounding lymphocytes and plasma  cells; note early hyaline body filled with serum. B, Multiple hyaline  bodies with numerous multinucleated giant cells within and around the  corrugated collagenous rings.    A periapical cyst is treated in the same manner as a periapi-  cal granuloma. When clinical and radiographic features  indicate a periapical inflammatory lesion, extraction or con-  servative nonsurgical endodontic therapy is performed.  Although some authors believe that large cystic lesions  cannot be resolved with conventional endodontics, experi-  enced clinicians have successfully used nonsurgical root  canal therapy for large areas of periapical inflammatory  disease that approach 2 cm in diameter. Larger lesions asso-  ciated with restorable teeth have been treated successfully  with conservative endodontic therapy when combined with  biopsy and marsupialization, decompression, or fenestra-  tion. As with any periapical inflammatory lesion, minimal  follow-up at 1 and 2 years is advised strongly.   If the radiolucency fails to resolve, then the lesion often  can be managed successfully by nonsurgical endodontic  retreatment. As previously mentioned, periapical surgery  typically is performed for lesions exceeding 2 cm and those  associated with teeth that are not suitable for conventional  endodontics. Biopsy is indicated to rule out other possible  pathologic processes.   Because any number of odontogenic and nonodontogenic  cysts and tumors can mimic the appearance of a residual  periapical cyst, all of these cysts should be excised surgically.  All inflammatory foci in the area of a lateral radicular cyst  should be eliminated and the patient observed in a manner  similar to that described for the periapical cyst. In some  instances, lateral radicular cysts are removed before tooth  vitality testing or periodontal evaluation for an adjacent focus  of infection. If this diagnosis is made, then a thorough evalu-  ation for an inflammatory source is mandatory.    The accumulation of acute inflammatory cells at the apex  of a nonvital tooth is termed a periapical abscess. Acute    inflammatory lesions with abscess formation may arise as  the initial periapical pathosis or from an acute exacerbation  of a chronic periapical inflammatory lesion (see discussion  of phoenix abscess, page 117). Frequently, the source of the  infection is obvious. On occasion, however, pulpal death  may be trauma related, and the tooth may contain neither  a cavity nor a restoration.   In the earliest stage of all forms of periapical inflamma-  tory disease, the periapical periodontal ligament (PDL)  fibers may exhibit acute inflammation but no frank abscess  formation. This localized alteration, best termed acute  apical periodontitis, may or may not proceed to abscess  formation. Although this process often occurs in association  with a nonvital tooth, acute apical periodontitis may be  found in vital teeth secondary to trauma, high occlusal  contacts, or wedging by a foreign object. The clinical pre-  sentation often closely resembles that of a periapical abscess  and must be considered in the differential diagnosis.    Many investigators subdivide periapical abscesses into acute  and chronic types. However, these are misnomers because  both types represent acute inflammatory reactions. Periapi-  cal abscesses should be designated as symptomatic or  asymptomatic on the basis of their clinical presentations.   Periapical abscesses become symptomatic as the purulent  material accumulates within the alveolus. The initial stages  produce tenderness of the affected tooth that often is  relieved by direct application of pressure. With progression,  the pain becomes more intense, often with extreme sensitiv-  ity to percussion, extrusion of the tooth, and swelling of the  tissues. The offending tooth does not respond to cold or  electric pulp testing. Headache, malaise, fever, and chills  may be present.   Radiographically, abscesses may demonstrate a thicken-  ing of the apical periodontal ligament, an ill-defined radio-  lucency, or both; however, often no appreciable alterations  can be detected because insufficient time has occurred for  significant bone destruction. Phoenix abscesses demonstrate  the outline of the original chronic lesion, with or without  an associated ill-defined bone loss.   With progression, the abscess spreads along the path of  least resistance. The purulence may extend through the  medullary spaces away from the apical area, resulting in  osteomyelitis, or it may perforate the cortex and spread  diffusely through the overlying soft tissue (as cellulitis).  Each of these occurrences is described later in the chapter.   Once an abscess is in soft tissue, it can cause cellulitis or  may channelize through the overlying soft tissue. The corti-  cal plate may be perforated in a location that permits  entrance into the oral cavity. The purulent material can  accumulate in the connective tissue overlying the bone and  can create a sessile swelling or perforate through the surface  epithelium and drain through an intraoral sinus (Figs. 3-32  and 3-33). At the intraoral opening of a sinus tract, a mass  of subacutely inflamed granulation tissue often is found,    ® Fig. 3-32 Periapical Abscess. Bilateral soft tissue swelling of the  anterior palate.    e Fig. 3-33 Periapical Abscess. Same patient as depicted in  Fig. 38-32. Multiple, overlapping radiolucencies of the anterior maxilla  are present. All four maxillary incisors exhibit pulpal necrosis.    known as a parulis (gum boil) (Figs. 3-34 and 3-35).  Occasionally, the nonvital tooth associated with the parulis  may be difficult to determine, and insertion of a gutta-  percha point into the tract can aid in detection of the  offending tooth during radiographic examination (Fig.  3-36). Dental abscesses also may channelize through the  overlying skin and drain via a cutaneous sinus (Fig. 3-37).   Most dental-related abscesses perforate buccally because  the bone is thinner on the buccal surface. However, infec-  tions associated with maxillary lateral incisors, the palatal  roots of maxillary molars, and mandibular second and third  molars typically drain through the lingual cortical plate.   If a chronic path of drainage is achieved, a periapical  abscess typically becomes asymptomatic because of a lack  of accumulation of purulent material within the alveolus.    @ Fig. 3-34 Parulis. Erythematous mass of granulation tissue overlying  the left maxillary central incisor. Note discoloration of the maxillary right  central incisor.    @ Fig. 3-35 Parulis. Normal connective tissue has been replaced by  acutely inflamed granulation tissue, which exhibits focal areas of neu-  trophilic abscess formation. Note the central sinus tract, which courses  from the base of the specimen toward the surface epithelium.    Occasionally, such infections are discovered during a routine  oral examination after detection of a parulis or drainage  through a large carious defect (Figs. 3-38 and 3-39). If the  drainage site becomes blocked, then signs and symptoms of  the abscess frequently become evident in a short time. On  occasion, periapical infections can spread through the  bloodstream and result in systemic symptoms, such as fever,  lymphadenopathy, and malaise. The risk of dissemination  appears to be less for periapical abscesses that drain freely.    Biopsy specimens from pure abscesses are uncommon  because the material is in liquid form. Abscesses consist of  a sea of polymorphonuclear leukocytes often intermixed  with inflammatory exudate, cellular debris, necrotic mate-  rial, bacterial colonies, or histiocytes (Fig. 3-40). Phoenix  abscesses can maintain a soft tissue component; they present  as subacutely inflamed periapical granulomas or cysts inter-  mixed with areas of significant abscess formation. In these    ® Fig. 3-36 Periapical Abscess. A, Same patient as depicted in Fig. 3-34. None of the incisors dem-  onstrates obvious periapical radiolucency. (The large radiolucency at the top is the anterior portion of the  maxillary sinus.) B, Gutta-percha point revealed that the right maxillary incisor was the source of the  infection.    ° Fig. 3-37 Cutaneous Sinus. Erythematous, sensitive, and exo-  phytic mass of granulation tissue of the skin inferior to the left body of  the mandible.    cases the pathologist typically diagnoses the primary lesion  but comments about the abscess formation.    Treatment of the patient with a periapical abscess consists  of drainage and elimination of the focus of infection. Those  abscesses associated with a patent sinus tract may be asymp-  tomatic but, nevertheless, should be treated. With localized  periapical abscesses, the signs and symptoms typically  diminish significantly within 48 hours of initiation of  appropriate drainage. When the abscess causes clinical  expansion of the bone or soft tissue adjacent to the apex of  the affected tooth, incisional drainage of the swelling should    @ Fig. 3-38 Parulis. Asymptomatic yellow-red nodule of the anterior  mandibular alveolar mucosa. The adjacent teeth were asymptomatic  and appeared clinically normal.    be considered because this technique appears to be associ-  ated with more rapid resolution of the inflammatory process  when compared with drainage through the root canal. If  the affected tooth is extruded, then reduction of the occlu-  sion is recommended because chronic occlusal trauma  has been shown to delay resolution of the inflammatory  process. Unless contraindicated, treatment with NSAIDs  usually is appropriate preoperatively, immediately postop-  eratively, and for subsequent pain control. Typically, use of  antibiotic medications for a well-localized and easily drained  periapical abscess in a healthy patient is unnecessary. Anti-  biotic coverage should be reserved for the medically com-  promised and patients with significant cellulitis (see next  section) or clinical evidence of dissemination (i.e., fever,    ® Fig. 3-39 Periapical Abscess. Same patient as depicted in Fig.  8-38. Periapical radiolucency associated with the nonvital mandibular  lateral incisor.    @ Fig. 3-40 Periapical Abscess. Sheet of polymorphonuclear leu-  kocytes intermixed with scattered histiocytes.    lymphadenopathy, malaise). Once the infection has been  resolved by extraction or appropriate endodontic therapy,  the affected bone typically heals.   Usually, a sinus tract resolves spontaneously after the  offending tooth is extracted or endodontically treated. Sinus  tracts that persist are thought to contain sufficient infectious  material along the fistulous tract to maintain the surface  granulation tissue, and surgical removal with curettage of  the tract is required for resolution.    If an abscess is not able to establish drainage through the  surface of the skin or into the oral cavity, it may spread  diffusely through fascial planes of the soft tissue. This acute    and edematous spread of an acute inflammatory process is  termed cellulitis. Although cellulitis may occur in other-  wise healthy individuals, there is an increased prevalence in  patients with variety of medical conditions, such as use of  corticosteroid or cytotoxic medications, malignancy, diabe-  tes mellitus, or immunosuppressive disorders including  neutropenia, aplastic anemia, and acquired immunodefi-  ciency syndrome (AIDS). Although numerous patterns of  cellulitis can be seen from the spread of dental infections,  two especially dangerous forms warrant further discussion:  (1) Ludwig angina and (2) cavernous sinus thrombosis.   Ludwig angina, named after the German physician who  described the seriousness of the disorder in 1836, refers to  cellulitis of the submandibular region. Angina comes from  the Latin word angere, which means to strangle (an apt term,  considering the clinical features described in the following  section). In approximately 70% of cases, Ludwig angina  develops from spread of an acute infection from the lower  molar teeth. Other situations associated with this clinical  presentation are peritonsillar or parapharyngeal abscesses,  tongue piercing, oral lacerations, fractures of the mandible,  or submandibular sialadenitis.   ‘The cavernous sinus is a group of thin-walled veins that  are located lateral to the sella turcica and medial to the tem-  poral bone. The trochlear and oculomotor nerves and the  maxillary and ophthalmic branches of the trigeminal nerve  course through the area. In addition, the internal carotid  artery and abducens nerve travel within the sinus. The sinus  receives venous drainage from the orbit via the superior and  inferior ophthalmic veins. Infection of the sinus can produce  a variety of clinical symptoms related to the numerous ana-  tomic structures that course through this site.   Cavernous sinus thrombosis can occur via an anterior or  posterior pathway. Infection from the maxillary anterior  teeth can perforate the facial maxillary bone and spread to  the canine space. A septic thrombus develops in the valveless  facial veins located in this space, and retrograde propagation  occurs from the angular vein to the inferior ophthalmic vein  through the inferior orbital fissure into the cavernous sinus.  ‘The posterior pathway is followed by infections originating  from maxillary premolar or molar teeth, which demonstrate  buccal or infratemporal space involvement that may spread  via the emissary veins from the pterygoid venous plexus to  the inferior petrosal sinus and into the cavernous sinus.  Overall, cavernous sinus thrombosis is relatively uncom-  mon, and dental infections are responsible in approximately  10% of the cases.   Ludwig angina is an aggressive and rapidly spreading cel-  lulitis that involves the sublingual, submandibular, and sub-  mental spaces bilaterally. Once the infection enters the  submandibular space, it may extend to the lateral pharyn-  geal space and then to the retropharyngeal space. This  extension may result in spread to the mediastinum with  several serious consequences.    @ Fig. 3-41 Ludwig Angina. Soft tissue swelling of the right sub-  mandibular region. (Courtesy of Dr. Brian Blocher.)    Ludwig angina creates massive swelling of the neck that  often extends close to the clavicles (Fig. 3-41). Involvement  of the sublingual space results in elevation, posterior enlarge-  ment, and protrusion of the tongue (woody tongue),  which can compromise the airway. Submandibular space  spread causes enlargement and tenderness of the neck above  the level of the hyoid bone (bull neck). Although initially  unilateral, spread to the contralateral neck typically occurs.  Pain in the neck and floor of mouth may be seen in addition  to restricted neck movement, dysphagia, dysphonia, dysar-  thria, drooling, and sore throat. Involvement of the lateral  pharyngeal space can cause respiratory obstruction second-  ary to laryngeal edema. Tachypnea, dyspnea, tachycardia,  stridor, restlessness, and the patient’s need to maintain an  erect position suggest airway obstruction. Fever, chills, leu-  kocytosis, and an elevated sedimentation rate may be seen.  Classically, obvious collections of pus are not present.    Cavernous sinus thrombosis appears as an edematous peri-  orbital enlargement with involvement of the eyelids and  conjunctiva. In cases involving the canine space, swelling is  also typically present along the lateral border of the nose  and may extend up to the medial aspect of the eye and  periorbital area (Fig. 3-42). Protrusion and fixation of the  eyeball often are evident, in addition to induration and  swelling of the adjacent forehead and nose. Pupil dilation,    @ Fig. 3-42 Cellulitis Involving Canine Space. Erythematous and  edematous enlargement of the left side of the face with involvement  of the eyelids and conjunctiva. Patients with odontogenic infections  involving the canine space are at risk for cavernous sinus thrombosis.  (Courtesy of Dr. Richard Ziegler.)    lacrimation, photophobia, and loss of vision may occur.  Pain over the eye and along the distribution of the ophthal-  mic and maxillary branches of the trigeminal nerve often is  present. Proptosis, chemosis, and ptosis are noted in greater  than 90% of affected patients. The cavernous sinuses freely  communicate via the intercavernous sinus. Although many  cases are initially unilateral, without appropriate therapy,  the infection may spread to the contralateral side.   Fever, chills, headache, sweating, tachycardia, nausea,  and vomiting can occur. With progression, signs of central  nervous system (CNS) involvement develop. Meningitis,  tachycardia, tachypnea, irregular breathing, stiffening of the  neck, and deepening stupor with or without delirium indi-  cate advanced toxemia and meningeal involvement. Occa-  sionally, brain abscesses may result.   Treatment of Ludwig angina centers around two major  priorities: maintenance of the airway and resolution of  the infection. The choice of airway maintenance varies  according to the severity of the obstruction. Choices  include observation, orotracheal intubation, fiber-optic  nasotracheal intubation, and tracheotomy. Orotracheal  intubation often is very difficult because of the presence    of trismus and swollen soft tissues. On occasion, cricothy-  roidotomy is performed instead of a tracheostomy because  of a perceived lower risk of spreading the infection to the  mediastinum.   Resolution of the infection involves elimination of  the original focus of infection and intravenous (IV) anti-  biotic therapy. Penicillin with or without clindamycin  or metronidazole frequently is the initial choice with  culture and sensitivity testing used to guide final therapy.  Although controversial, corticosteroids are prescribed by  some clinicians to reduce swelling and augment antibiotic  penetration.   Although once an essential component of the treatment,  surgical decompression of the cellulitis has been reserved by  many clinicians for those patients who are nonresponsive to  the antibiotics or demonstrate evidence of localized abscess  formation. In spite of this, others believe decompression  should be performed in all cases and is associated with a  reduced hospital stay. Although drainage frequently does  not produce significant pus, copious amounts of edema  fluid often drain from the surgical excisions.   Before the use of modern antibiotic medications, the  mortality from Ludwig angina often exceeded 50%.  Although this rate has been reduced to less than 10%,  deaths still occur as the result of complications such as  pericarditis, pneumonia, mediastinitis, sepsis, empyema,  and respiratory obstruction.    The therapeutic cornerstones for cavernous sinus thrombo-  sis secondary to dental infections are surgical drainage com-  bined with high-dose antibiotic medications similar to  those administered for patients with Ludwig angina. The  offending tooth should be extracted, and drainage is required  if fluctuance is present. Administration of systemic cortico-  steroid drugs is indicated only in patients who have devel-  oped pituitary insufficiency in advanced cases of cavernous  sinus thrombosis. Some investigators also prescribe antico-  agulant medications to prevent thrombosis and _ septic  emboli; conversely, others believe that thrombosis limits the  infection and that the use of anticoagulant drugs may  promote hemorrhagic lesions in the orbit and brain.   In older series the mortality rate approached 75%.  Even with current medical advances and modern antibiotic  medications, the mortality rate remains at approximately  30% with fewer than 40% of patients achieving full    Osteomyelitis is an acute or chronic inflammatory process  in the medullary spaces or cortical surfaces of bone that  extends away from the initial site of involvement. The term  osteomyelitis arose from the ancient Greek words osteon  (bone) and muelinos (marrow) and literally implies infection  of the medullary segments of bone. This section describes  the classic pattern of osteomyelitis.    The vast majority of osteomyelitis cases are caused by  bacterial infections and result in an expanding lytic destruc-  tion of the involved bone, with suppuration and sequestra  formation. Many believe that this condition is more appro-  priately termed suppurative osteomyelitis, bacterial osteomyeli-  tis, or secondary osteomyelitis. This pattern of osseous pathosis  is in contrast to an ill-defined group of idiopathic inflam-  matory disorders of bone that do not respond consistently  to antibacterial medications and typically demonstrate ulti-  mate sclerosis of bone without suppuration or sequestra  formation. This second pattern of inflammatory bone  disease is most appropriately termed primary chronic osteo-  myelitis but often is included under the term diffuse scleros-  ing osteomyelitis. This disorder and several other patterns of  inflammatory bone disease (e.g., focal sclerosing osteomy-  elitis, proliferative periostitis, and alveolar osteitis) are  unique and are covered separately later in the chapter.  Osteoradionecrosis is excluded from this discussion because  this is primarily a problem of hypoxia, hypocellularity,  and hypovascularity in which the presence of bacteria rep-  resents a secondary colonization of nonhealing bone rather  than a primary bacterial infection (see page 269). In addi-  tion, medication-related osteonecrosis represents another  unique pattern that is discussed in a later chapter and  appears more strongly related to altered bone metabolism  (see page 271).   Suppurative osteomyelitis of the jaws is uncommon in  developed countries, but it continues to be a source of  significant difficulty in developing nations. In Europe and  North America, most cases arise after odontogenic infec-  tions or traumatic fracture of the jaws. In addition, many  cases reported in Africa occur in the presence of necrotizing  ulcerative gingivitis (NUG) or noma.   Chronic systemic diseases, immunocompromised status,  and disorders associated with decreased vascularity of bone  appear to predispose people to osteomyelitis. Tobacco use,  alcohol abuse, IV drug abuse, diabetes mellitus, exanthema-  tous fevers, malaria, sickle cell anemia, malnutrition, malig-  nancy, collagen vascular diseases, and AIDS have been  associated with an increased frequency of osteomyelitis. In  addition to radiation, several diseases (e.g., osteopetrosis,  dysosteosclerosis, late Paget disease, end-stage cemento-  osseous dysplasia) may result in hypovascularized bone that  is predisposed to necrosis and inflammation.   Acute suppurative osteomyelitis exists when an acute  inflammatory process spreads through the medullary spaces  of the bone and insufficient time has passed for the body  to react to the presence of the inflammatory infiltrate.  Chronic suppurative osteomyelitis exists when the defen-  sive response leads to the production of granulation tissue,  which subsequently forms dense scar tissue in an attempt  to wall off the infected area. The encircled dead space acts  as a reservoir for bacteria, and antibiotic medications have  great difficulty reaching the site. This pattern begins to  evolve about 1 month after the spread of the initial acute  infection and results in a smoldering process that is difficult  to manage unless the problem is approached aggressively.    @ Fig. 3-43 Acute Osteomyelitis. |ll-defined area of radiolucency of  the right body of the mandible.    Patients of all ages can be affected by osteomyelitis. There  is a strong male predominance, approaching 75% in some  reviews. Most cases involve the mandible due to its relatively  poor vascular supply and dense cortical bone that is more  susceptible to infection when compared to the maxilla.  Maxillary disease becomes important primarily in pediatric  patients and in cases that arise from NUG or noma (in  African populations).    Patients with acute osteomyelitis have signs and symptoms  of an acute inflammatory process that has typically been less  than 1 month in duration. Fever, leukocytosis, lymphade-  nopathy, significant sensitivity, and soft tissue swelling of  the affected area may be present. Plain dental or panoramic  radiographs may demonstrate an ill-defined radiolucency  (Fig. 3-43), occasionally combined with widening of the  periodontal ligament, loss of lamina dura, or loss of circum-  scription of the inferior alveolar canal or mental foramen.  Periosteal new bone formation also may be seen in response  to subperiosteal spread of the infection. This proliferation  is more common in young patients and presents as a single-  layered linear radiopaque line separated from the normal  cortex by an intervening radiolucent band. Because plain  radiographs require loss of up to 50% of bone mineral  density to demonstrate an obvious pathosis, such films often  may be unremarkable early in the course of infection. Scin-  tigraphy and magnetic resonance imaging (MRI) demon-  strate high sensitivity but low specificity. Conventional CT  is a better choice due to its good combination of sensitivity  and specificity. Being specially designed for imaging the  gnathic hard tissues, cone-beam CT represents another  excellent alterative with shorter scanning times and lower  doses of radiation when compared to conventional CT. On  occasion, paresthesia of the lower lip, drainage, or exfolia-  tion of fragments of necrotic bone may be discovered. A  fragment of necrotic bone that has separated from the    Pde y Se oe  ® Fig. 3-44 Acute Osteomyelitis with Sequestrum. Radiolucency  of the right body of the mandible with central radiopaque mass of  necrotic bone. (Courtesy of Dr. Michael Meyrowitz.)    adjacent vital bone is termed a sequestrum. Sequestra often  exhibit spontaneous exfoliation (Fig. 3-44). On occasion,  fragments of necrotic bone may become surrounded by new  vital bone, and the dead bone in this situation is known as  an involucrum.    If acute osteomyelitis is not resolved expeditiously, the  entrenchment of chronic osteomyelitis occurs, or the  process may arise primarily without a previous acute episode.  Swelling, pain, sinus formation, purulent discharge, seques-  trum formation, tooth loss, or pathologic fracture may  occur. Patients may experience acute exacerbations or  periods of decreased pain associated with chronic smolder-  ing progression (Fig. 3-45).   Radiographs reveal a patchy, ragged, and ill-defined  radiolucency that may contain central radiopaque sequestra  and be intermixed with zones of radiodensity. Less fre-  quently, the infection may be predominantly osteosclerotic  or occasionally almost totally osteolytic. The osseous change  is continuous and may exhibit spread to the periosteum by  direct extension. This is in contrast to primary chronic  osteomyelitis, in which multifocal and separate areas of  osteolysis are present within zones of sclerosis.   Because of an anatomic peculiarity, large portions of each  jawbone receive their blood supply through multiple arterial  loops originating from a single vessel. Involvement of this  single feeder vessel can lead to necrosis of a large portion of  the affected bone. Sequestration that has involved an entire  quadrant of the jaw has been reported in long-standing  cases of chronic osteomyelitis.    Generation of biopsy material from patients with acute  osteomyelitis is not common because of the predominantly  liquid content and lack of a soft tissue component. When  submitted, the material consists predominantly of necrotic  bone. The bone shows a loss of the osteocytes from their    @ Fig. 3-45 Chronic Osteomyelitis. A, |ll-defined area of radiolucency of the right body of the mandible  adjacent to a recent extraction site. B, After the initial intervention, the patient failed to return for follow-up  because of lack of significant pain. An enlarged, ill-defined radiolucency of the right body of the mandible  was discovered 2 years after the initial surgery. (Courtesy of Dr. Charles Waldron.)    ® Fig. 3-46 Acute Osteomyelitis. Nonvital bone exhibits loss of the  osteocytes from the lacunae. Peripheral resorption, bacterial coloniza-  tion, and surrounding inflammatory response also can be seen.    lacunae, peripheral resorption, and bacterial colonization  (Fig. 3-46). The periphery of the bone and the haversian  canals contain necrotic debris and an acute inflammatory  infiltrate consisting of polymorphonuclear leukocytes. The  submitted material will be diagnosed as a sequestrum unless  a good clinicopathologic correlation points to the appropri-  ate diagnosis of acute osteomyelitis.    Biopsy material from patients with chronic osteomyelitis  demonstrates a significant soft tissue component that con-  sists of chronically or subacutely inflamed fibrous connec-  tive tissue filling the intertrabecular areas of the bone (Fig.  3-47). Scattered sequestra and pockets of abscess formation  are common.    Therapy centers around surgical intervention to 1) resolve  the source of infection, 2) establish drainage, 3) removal of    obviously infected bone, and 4) obtain bacteriologic samples  for culture and antibiotic sensitivity testing. While waiting  on the bacteriologic evaluation, antibiotics are administered  empirically, usually penicillin with metronidazole or clinda-  mycin. Multiple procedures over days to weeks may be  required for complete elimination of the infection and  reconstruction of the gnathic defect.    Chronic osteomyelitis is difficult to manage medically, pre-  sumably because pockets of dead bone and organisms are  protected from antibiotic drugs by the surrounding wall of  fibrous connective tissue. Surgical intervention is manda-  tory. The antibiotic medications are similar to those used in  the acute form but must be given intravenously in high  doses.   The extent of the surgical intervention depends on the  spread of the process; removal of all infected material down  to good bleeding bone is mandatory in all cases. For  small lesions, curettage, removal of necrotic bone, and    saucerization are sufficient. In patients with more extensive  osteomyelitis, decortication or saucerization often is com-  bined with transplantation of cancellous bone chips. In  cases of persisting osteomyelitis, resection of the diseased  bone followed by immediate reconstruction with an autolo-  gous graft is required. Weakened jawbones must be  immobilized.   The goal of surgery is removal of all infected tissue. Per-  sistence of chronic osteomyelitis is typically the result of  incomplete removal of diseased tissue. On successful elimi-  nation of all infected material, resolution is expected.  Adjunctive procedures (e.g., hyperbaric oxygen) are rarely  necessary if thorough surgical curettage and sequestrectomy  have been accomplished. In an attempt to remove all areas  of necrotic bone thoroughly, tetracycline has been admin-  istered 48 hours in advance of surgery and used as a fluo-  rescent marker of vital bone. At the time of surgery, necrotic  bone will not fluoresce under the ultraviolet (UV) light of  a Wood's lamp, indicating that it should be removed.   Management of persistent cases of chronic osteomyelitis  often requires use of more sophisticated techniques. Scinti-  graphic techniques with technetium-99m (”"Tc)-labeled  phosphorus compounds can be used to evaluate the thera-  peutic response and progress of treatment. Hyperbaric  oxygen is recommended primarily for the rare patient who  does not respond to standard therapy or for disease arising  in hypovascularized bone (e.g., osteoradionecrosis, osteope-  trosis, Paget disease, and cemento-osseous dysplasia).    Diffuse sclerosing osteomyelitis is an ill-defined, highly  controversial, evolving area of dental medicine. This diag-  nosis encompasses a group of presentations that are charac-  terized by pain, inflammation, and varying degrees of  gnathic periosteal hyperplasia, sclerosis, and lucency.  Included in this category are three different pathoses:   In the purist’s view, diffuse sclerosing osteomyelitis is  different from primary chronic osteomyelitis and chronic  tendoperiostitis. This term should be used only when an  obvious infectious process directly is responsible for sclerosis  of bone. In these cases, a chronic intraosseous bacterial  infection creates a smoldering mass of chronically inflamed  granulation tissue that incites sclerosis of the surrounding  bone.   Primary chronic osteomyelitis often is confused with,  but must be distinguished from, chronic suppurative osteo-  myelitis (secondary chronic osteomyelitis). In contrast to  suppurative osteomyelitis, an association with a bacterial  infection is not obvious, and suppuration and sequestration  characteristically are absent. A number of causes have been  proposed, such as an altered immune response to an  organism of low virulence, but no single theory has  received widespread acceptance. In contrast to suppurative    osteomyelitis, a primary infectious cause cannot be proven,  because many studies have been unable to culture organisms  and the condition does not respond to long-term antibiotic  therapy.   On occasion, gnathic lesions presenting as primary  chronic osteomyelitis occur in patients with other signifi-  cant systemic manifestations. Chronic recurrent multifo-  cal osteomyelitis (CRMO) demonstrates involvement of  multiple bones and is thought by many to represent a wide-  spread variant of primary chronic osteomyelitis. SAPHO  syndrome is closely related and an acronym for a complex  clinical presentation that includes Synovitis, Acne, Pustu-  losis, Hyperostosis, and Osteitis in which the osseous lesions  mirror those of primary chronic osteomyelitis and CRMO.  The cause of CRMO and SAPHO is unknown, but they  possibly may arise in genetically predisposed individuals  who develop an autoimmune disturbance secondary to  exposure to dermatologic bacteria. Researchers theorize that  an abnormal immune response to the microorganism cross-  reacts with normal bone or joint structures, leading to the  variety of clinical manifestations. The organism associated  with acne, Propionibacterium acnes, has been recovered in  bone biopsies of some affected patients.   Although initially thought to be an obscure infectious  process, the clinical presentation of chronic tendoperios-  titis is similar to that of primary chronic osteomyelitis;  today many clinicians believe it represents a reactive altera-  tion of bone that is initiated and exacerbated by chronic  overuse of the masticatory muscles, predominantly the mas-  seter and digastric. In a large series of patients, parafunc-  tional muscle habits (e.g., bruxism, clenching, nail biting,  co-contraction, and inability to relax jaw musculature) were  known or became evident during follow-up. In neurophysi-  ologic studies, masseter inhibitory reflexes were abnormal  in the vast majority of patients studied. The cause of chronic  tendoperiostitis is controversial, and some investigators  believe this disorder may represent a variation of primary  chronic osteomyelitis, in which parafunctional muscle  habits exacerbate the process but are not the initial cause.    Diffuse sclerosing osteomyelitis is similar to the localized  variant (condensing osteitis; see page 134); however, the  disorder is also very different. It arises almost exclusively in  adulthood, does not exhibit a sex predominance, and pri-  marily occurs in the mandible. An increased radiodensity  develops around sites of chronic infection (e.g., periodon-  titis, pericoronitis, and apical inflammatory disease) in a  manner very similar to the increased radiodensity that may  be seen surrounding areas of chronic suppurative osteomy-  elitis. Typically, the altered area is restricted to a single site  but may be multifocal or extend to fill an entire quadrant.   The sclerosis centers on the crestal portions of the tooth-  bearing alveolar ridge and does not appear to originate in  the areas of attachment of the masseter or digastric muscle  (Fig. 3-48). The radiodensities do not develop from    @ Fig. 3-48 Diffuse Sclerosing Osteomyelitis. Diffuse area of  increased radiodensity of the right body of the mandible in the tooth-  bearing area. No other quadrants were involved. (Courtesy of Dr. Louis  M. Beto.)    previously radiolucent fibro-osseous lesions and do not  exhibit the predilection for black females, as is found in  those patients with florid cemento-osseous dysplasia. Pain  and swelling are not typical.    Primary chronic osteomyelitis is most commonly discovered  as an isolated process that typically is localized to the man-  dible. Extragnathic evidence of SAPHO syndrome or  CRMO is seen much less frequently. The onset of symp-  toms tends to demonstrate two peaks, one in adolescence  and the other in adults after the fifth decade of life. Affected  patients have recurrent episodes of pain, swelling, local  induration, and limited mouth opening that is not associ-  ated with any obvious dental infection. During periods of  disease activity, regional lymphadenopathy and reduced  sensation in the distribution of the inferior alveolar nerve  may be present. Absence of fever, purulence, sequestration,  and sinus formation are characteristic. The lack of an  obvious association with an odontogenic infection and the  nonsuppurative presentation clearly separate this condition  from chronic suppurative osteomyelitis.   In the early stages of primary chronic osteomyelitis,  radiographs tend to demonstrate a mixed pattern, with areas  of radiolucent osteolysis intermingled with zones of sclero-  sis. In contrast to the pattern noted in CT images of sup-  purative osteomyelitis, the osteolytic areas are not continuous  and alternate with zones of sclerosis. The affected area of  the bone typically is thickened and demonstrates a perios-  teal proliferation that is more solid than the typical lami-  nated proliferative periostitis of inflammatory origin. Facial  asymmetry is not uncommon and often takes years to  resolve secondary to slow remodeling. Over time, the  affected area becomes predominantly sclerotic, but during  subsequent periods of disease activity, new foci of osteolysis  and cortical bone destruction appear. These newly affected  areas subsequently undergo sclerosis, awaiting the next cycle  of disease activity. With disease progression, the clinical    symptoms typically diminish and the affected bone demon-  strates progressive sclerosis and a reduction in the volume.  Radiolucent osteolytic areas may remain, but they tend to  be relatively small and widely scattered. Overall, the pre-  dominant radiographic alteration of primary chronic osteo-  myelitis is medullary sclerosis, a pattern that is noted  invariably in affected patients. Skeletal scintigraphy demon-  strates significant uptake in the affected areas and should be  performed in all patients in an effort to rule out extra-  gnathic involvement.    CRMO and SAPHO syndrome appear closely related, and  many believe that CRMO represents the pediatric variant  of SAPHO. CRMO presents in childhood with pain and  swelling of multiple bones, classically the extremities.  Affected bones typically demonstrate hyperostosis with  osteitis that is associated with negative microbiologic cul-  tures and lack of response to antibiotics. Many patients  demonstrate concurrent or future neutrophilic skin diseases,  such as palmoplantar pustulosis, severe acne, hidradenitis  suppurativa, psoriasis, Sweet syndrome, or pyoderma gan-  grenosum. The dermatologic involvement may be absent,  appear after some delay, or be so subtle as to escape detec-  tion. In contrast, SAPHO usually is noted in adults, classi-  cally affects the axial skeleton (anterior chest wall), and  more frequently demonstrates concurrent neutrophilic skin  lesions. Gnathic involvement has been reported in both  CRMO and SAPHO, mandating full bone scan in any  patient with an unexplained primary chronic osteomyelitis.  In contrast to bacterial osteomyelitis, the osteolytic areas are  scattered randomly within areas of sclerotic bone. Periosteal  new bone formation is common but not related to cortical  bone perforation. Investigation of the entire skeleton by  bone scintigraphy classically reveals involvement of multiple  sites.   In early gnathic lesions, diffuse osteolytic zones are more  prominent than sclerosis, and the affected bone is enlarged  because of significant production of periosteal new bone.  With time, the bone becomes more sclerotic and decreases  in size because of diminished periosteal apposition, while  the osteolytic zones become smaller and fewer. External  bone resorption and deformity of the mandible are charac-  teristic in older lesions.    Although the mean age of occurrence is 40 years, chronic  tendoperiostitis may occur in people of all ages. There is no  sex predilection. Recurrent pain, swelling of the cheek, and  trismus are classic symptoms. Suppuration and an associ-  ated infectious cause are not found. Microbiologic cultures  are typically negative, with the lesions failing to respond to  appropriate antibiotic medications. Uncommon spontane-  ous resolution with development of radiographic normalcy  has been noted.   In most instances, the sclerosis is limited to a single  quadrant and centers on the anterior region of the    mandibular angle and posterior portion of the mandibular  body (i.e., attachment of the masseter muscle). Occasion-  ally, the cuspid and premolar region and the anterior man-  dible (ie., attachment of the digastric muscle) may be  involved. Relatively radiolucent zones are apparent within  the areas of radiodensity, but histopathologic examination  reveals only dense bone, formation of reactive bone, and  relatively few signs of inflammation. The inferior border of  the mandibular body is typically affected, and significant  erosion of the inferior border appears just anterior to the  angle of the mandible.    Diffuse sclerosing osteomyelitis demonstrates sclerosis and  remodeling of bone. The haversian canals are scattered  widely and little marrow tissue can be found. Although the  sclerosis occurs adjacent to areas of inflammation, the bone  is not typically intermixed with a significant inflammatory  soft tissue component. If the adjacent inflammatory process  extends into the sclerotic bone, then necrosis often occurs.  The necrotic bone separates from the adjacent vital tissue  and becomes surrounded by subacutely inflamed granula-  tion tissue. Secondary bacterial colonization often is visible.    Similar histopathologic features are seen in primary chronic  osteomyelitis, SAPHO syndrome, and CRMO. In the areas  of sclerosis, numerous irregular trabeculae of pagetoid bone  are present and demonstrate extensive evidence of remodel-  ing with prominent reversal lines, osteoblastic rimming, and  focal areas of osteoclastic activity (Fig. 3-49). Intertrabecu-  lar fibrosis is present, with scattered lymphocytes and plasma  cells. Present in many, but not all examples, are foci of  microabscess formation, hyalinization around small blood  vessels, and subperiosteal bone formation. The microab-  scesses have been correlated with the osteolytic foci noted    @ Fig. 3-49 Primary Chronic Osteomyelitis. Trabeculae of scle-  rotic, pagetoid bone showing numerous resting and reversal lines.    during active phases of the disease. In obvious contrast to  chronic suppurative osteomyelitis, bone necrosis, bacterial  colonization, and frank purulence are absent.    Chronic tendoperiostitis demonstrates sclerosis and remod-  eling of the cortical and subcortical bone with a resultant  increase in bone volume. If chronic inflammatory cells are  present, then they are located in cortical resorption defects  and the subcortical bone adjacent to sites of muscle  insertion.    Diffuse sclerosing osteomyelitis is treated best through reso-  lution of the adjacent foci of chronic infection. After resolu-  tion of the infection, the sclerosis remodels in some patients  but remains in others. The persistent sclerotic bone is hypo-  vascular, does not exhibit typical remodeling, and is very  sensitive to inflammation. The patient and the clinician  should work together to avoid future problems with peri-  odontitis or apical inflammatory disease. With long-term  alveolar resorption after denture placement, the altered  bone does not exhibit typical resorption and exposure with  secondary osteomyelitis can develop. These secondary  lesions can be treated in the same way as a primary acute  or chronic osteomyelitis (see page 130).    Even with significant surgical and medical intervention, the  disease course is characterized by flares separated by partial  remissions. Most treatments directed toward elimination of  infection have been proven ineffective. Long-term antibi-  otic treatment with or without hyperbaric oxygen therapy  has not produced consistent long-term success. Surgical  decortication has decreased the intensity and frequency of  symptoms but has failed to resolve the process totally.  Because of inconsistent results from surgical intervention,  extensive surgery is contraindicated, especially in young,  growing patients. Corticosteroid medications, NSAIDs, cal-  citonin, and tumor necrosis factor-@ antagonists have been  reported to relieve symptoms but usually are associated with  incomplete resolution. In a number of publications, IV  administration of bisphosphonates has shown significant  therapeutic benefits with reduction of symptoms and radio-  graphic resolution of bony abnormalities. In spite of this,  recurrences have been noted, often leading to additional  therapeutic interventions.    Treatment of chronic tendoperiostitis as a form of osteomy-  elitis has been most unsatisfactory. Large series of patients  have been treated with antibiotic medications, explorations,  intraoral decortication, implantation of gentamicin beads,  hyperbaric oxygen, and corticosteroid drugs with no signifi-  cant effect. Treatment directed toward resolution of muscle    Localized areas of bone sclerosis associated with the apices  of teeth with pulpitis (from large carious lesions or deep  coronal restorations) or pulpal necrosis are termed con-  densing osteitis. The association with an area of inflamma-  tion is critical, because these lesions can resemble several  other intrabony processes that produce a somewhat similar  pattern.    This secondary sclerosis of bone is seen most frequently in  children and young adults but also can occur in older adults.  The classic alteration consists of a localized, usually uniform  zone of increased radiodensity adjacent to the apex of a  tooth that exhibits a thickened periodontal ligament (PDL)  space or an apical inflammatory lesion (Fig. 3-50). Clinical  expansion should not be present. Most cases occur in the  premolar and molar areas of the mandible, and the dental  pulp of the involved tooth demonstrates pulpitis or necrosis.  The lesion does not exhibit a radiolucent border, as is seen  in cases of focal cemento-osseous dysplasia (see page 597),  although an adjacent radiolucent inflammatory lesion may  be present. In addition, the radiopacity is not separated  from the apex as would be seen in idiopathic osteosclerosis    @ Fig. 3-50 Condensing Osteitis. Increased areas of radiodensity  surrounding the apices of the nonvital mandibular first molar.    Treatment of the patient with condensing osteitis consists  of resolution of the odontogenic focus of infection. After  extraction or appropriate endodontic therapy of the involved  tooth, approximately 85% of cases of condensing osteitis  will regress, either partially or totally. Typically, resolution  of the lesion is associated with normalization of the associ-  ated periodontal membrane. If the lesion persists and the  periodontal membrane remains wide, then reevaluation of  the endodontic therapy should be considered. A residual  area of condensing osteitis that remains after resolution of  the inflammatory focus is termed a bone scar (Fig. 3-51).  Root resorption has been noted during orthodontics if the  sclerotic bone is the path of tooth movement.    Bone formation within a periosteal reaction is a common  finding that occurs in a wide variety of intraosseous pathoses  and in all age groups. Causes of periosteal new bone forma-  tion include osteomyelitis, trauma, cysts, infantile cortical  hyperostosis, fluorosis, avitaminosis C, hypertrophic osteo-  arthropathy, congenital syphilis, and neoplasms (such as,  Ewing sarcoma, Langerhans cell histiocytosis, and osteo-  genic sarcoma). Of these, osteomyelitis and malignant neo-  plasms are associated most frequently with formation of  bone within a periosteal reaction.   In 1893 a Swiss physician, Carl Garré, reported in the  German literature on patterns of acute osteomyelitis. Since  that time, numerous articles have been written that associate  Garré’s report with a form of inflammatory periosteal hyper-  plasia demonstrating an onionskin-like reduplication of the  cortical plate. (In these subsequent articles, Garré’s name  was misspelled consistently as Garré, with an incorrect  accent designation.) However, Garré did not have any  pathologic specimens for microscopic examination, and    @ Fig. 3-51 Bone Scar. Residual area of increased radiodensity in  the area of extraction of the mandibular first molar. (Courtesy of Dr.  Walter Blevins.)    Roentgen did not discover x-rays until 2 years after Garré’s  publication. Nowhere in the original publication is there  any mention of periostitis, periosteal duplication, or “onion-  skinning.” Although the term Garré osteomyelitis often is  used synonymously for this condition, it is an improper  designation that should be disassociated with the entity  described in the text that follows.    Proliferative periostitis represents a periosteal reaction to  the presence of inflammation. The affected periosteum  forms several rows of reactive vital bone that parallel each  other and expand the surface of the altered bone. Affected  patients tend to be primarily children and young adults,  with a mean age of 13 years. No sex predominance is noted.   As expected, the most frequent cause is dental caries with  associated periapical inflammatory disease, although lesions    have been reported secondary to periodontal infections,  fractures, buccal bifurcation cysts, and nonodontogenic  infections. Most cases arise in the premolar and molar area  of the mandible. The hyperplasia is located most frequently  along the lower border of the mandible, but buccal cortical  involvement also is common. Isolated lingual cortical  enlargement is infrequent. Most cases are unifocal, although  multiple quadrants may be affected.   Appropriate radiographs demonstrate radiopaque lami-  nations of bone that roughly parallel each other and the  underlying cortical surface (Fig. 3-52). The laminations  vary from 1 to 12 in number, and radiolucent separations  often are present between the new bone and the original  cortex. Less frequently, the new bone formation exhibits  consolidation and contains numerous fine bony projections  that radiate perpendicular from the underlying and intact  periosteum. Within the new bone, areas of small sequestra  or osteolytic radiolucencies may be found.    @ Fig. 3-52 Proliferative Periostitis. A, Firm swelling of the lateral and inferior border of the right  mandible that arose after traumatic injury. B, Computed tomography (CT) image demonstrating new  periosteal bone growth with onionskin laminations. C, Panoramic radiograph exhibiting new periosteal  bone formation along the right inferior border of the mandible. (Courtesy of Drs. Sherif Mekhail and    @ Fig. 3-53 Proliferative Periostitis. Interconnecting trabeculae of  new bone formation (top left) extending from the original cortical  surface (delineated by arrows).    Because of difficulty in proper angulation and problems  related to superimposition of the underlying bone, CT  scanning has proved to be consistently superior to conven-  tional radiography in demonstrating proliferative periosti-  tis. On plain films, the alterations are typically seen best on  a panoramic or lateral oblique radiograph. If lateral oblique  radiographs fail to demonstrate the lesion, then occlusal  views and, less frequently, posteroanterior radiographs may  be successful.    Usually, biopsy is not required unless the clinical diagnosis  is in question. Specimens often reveal parallel rows of highly  cellular and reactive woven bone in which the individual  trabeculae are frequently oriented perpendicular to the  surface. The trabeculae sometimes form an interconnecting  meshwork of bone or are scattered more widely, resembling  the pattern seen in immature fibrous dysplasia (Fig. 3-53).  Between the cellular trabeculae, relatively uninflamed  fibrous connective tissue is evident. Sequestra, if included,  demonstrate the typical features of bone necrosis (see Osteo-  myelitis, page 129).    Most cases of proliferative periostitis of the jaws are associ-  ated with periapical inflammatory lesions, and treatment in  these cases (either extraction of the offending tooth or  appropriate endodontic therapy) is directed toward elimi-  nating the source of the infection. After the focus of infec-  tion has been eliminated and inflammation has resolved,  the layers of bone will consolidate in 6 to 12 months as the  overlying muscle action helps to remodel the bone to its  original state.   If a unifocal periosteal reaction similar to proliferative  periostitis appears in the absence of an obvious source of  inflammation, biopsy is recommended because several neo-  plastic conditions can result in a similar pattern.    After extraction of a tooth, a blood clot is formed at the  site, with eventual organization of the clot by granulation  tissue, gradual replacement by coarse fibrillar bone, and,  finally, replacement by mature bone. Premature fibrinolysis  of the initial clot is thought to be responsible for the clinical  condition known as alveolar osteitis. Factors deemed to be  associated with an increased prevalence include oral contra-  ceptive use, tobacco use, preoperative infection, difficult  extraction, inexperienced surgeons, surgical flap design  (envelope flap rather than modified triangular flap), use of  a local anesthetic with vasoconstrictor, and inadequate post-  operative irrigation.    The frequency of alveolar osteitis is higher in the mandible  and the posterior areas. After oral contraceptive use is taken  into account, there does not appear to be a significant sex  predilection. The prevalence is between 1% and 3% of all  extractions, but it increases to 25% to 30% for impacted  mandibular third molars. The frequency appears to be  decreased when impacted teeth are removed prophylacti-  cally rather than for pericoronitis. The overall prevalence is  highest between 20 and 40 years of age (when the majority  of teeth are extracted), although the likelihood of develop-  ing alveolar osteitis appears greatest for extractions in the  40- to 45-year-old age group.   The affected extraction site is filled initially with a dirty  gray clot that is lost and leaves a bare bony socket (dry  socket). The detection of the bare socket may be hindered  by partial retention of the clot or by overlying inflamed  tissue that covers the site. The diagnosis is confirmed by  probing of the socket, which reveals exposed and extremely  sensitive bone. Typically, severe pain, foul odor, and (less  frequently) swelling and lymphadenopathy develop 3 to 4  days after extraction of the tooth. On occasion, the pain  radiates from the socket to the ipsilateral ear, temporal  region, or eye. Rarely, trismus also may be noted. The signs  and symptoms may last from 10 to 40 days.    On evaluation of the patient complaining of postextraction  pain, a radiograph should be taken of the affected area to  rule out the possibility of a retained root tip or a foreign  body. All sutures should be removed. The socket is irrigated  with warm saline, followed by thorough clinical inspection  of the socket for any unexpected pathosis. Curettage of the  socket is not recommended, because this typically increases  the associated pain. Potent oral analgesics should be pre-  scribed, and the patient should be given a plastic syringe  with instructions to keep the socket clean via home irriga-  tion with a chlorhexidine or saline solution. This irrigation    should continue until debris no longer collects within the  healing socket (usually 3 to 4 weeks).   Use of an obtundent and antiseptic dressing, such as  iodoform gauze containing eugenol, is controversial.  Although the dressing may reduce the symptoms and help  keep out food debris, many believe the dressing acts as  foreign material and delays healing of the extraction socket.  If a dressing is used, then it should be changed every 24  hours for the first 3 days, then every 2 to 3 days until  granulation tissue covers the exposed bone. The dressing  should be discontinued as soon as the patient is pain free.  After that time, the patient should be given a plastic syringe  with instructions for home irrigation.   Many investigators have studied preventive measures for  alveolar osteitis including systemic and topical antibiotics,  cessation of smoking the day before and after surgery,  copious surgical irrigation, and antifibrinolytic agents. 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Houston JP, McCollum J, Pietz D, et al: Alveolar osteitis: a review of  its etiology, prevention, and treatment modalities, Gen Dent 50:  457-463, 2002.   Krakiwiak PA: Alveolar osteitis and osteomyelitis of the jaws, Oral  Maxillofac Surg Clin N Am 23:401-413, 2011.   Noroozi A-R, Philbert RF: Modern concepts in understanding and  management of the “dry socket” syndrome: comprehensive review  of the literature, Oral Surg Oral Med Oral Pathol Oral Radiol Endod  107:30-35, 2009.    In this textbook of oral and maxillofacial pathology, the  discussion of periodontal diseases is limited appropriately  in scope. However, several fine textbooks are available on  periodontology and can provide the reader with more infor-  mation on the background, microbiology, clinical presenta-  tions, diagnostic procedures, and current therapies used. to  treat these diseases.    Gingivitis refers to inflammation limited to the soft tissues  that surround the teeth. It does not include the inflamma-  tory processes that may extend into the underlying alveolar  ridge, periodontal ligament, or cementum. A similar pattern  of inflammation has noted in the mucosa surrounding  implants and has been termed peri-implant mucositis. The  primary types of gingivitis are listed in Box 4-1. This part of  the text concentrates on the plaque-related types. Necrotiz-  ing ulcerative gingivitis (NUG), medication-influenced  gingivitis, and a specific type of allergic gingivitis (plasma  cell gingivitis) are presented later in this chapter. Additional  forms of allergic gingivitis are discussed in Chapter 9. The  gingivitis associated with specific infections (e.g., herpes  simplex, and human immunodeficiency virus [HIV]) is dis-  cussed in Chapters 5 and 7. The gingiva is a frequent site of  involvement in several of the dermatologic vesiculoerosive  diseases; these are well described in Chapter 16.    Most cases of gingivitis occur from lack of proper oral  hygiene, which leads to the accumulation of dental plaque  and calculus; however, many other factors can affect the  gingiva’s susceptibility to the oral flora. The frequency of  gingivitis is high in all age groups. Clinically detectable  inflammatory changes of the gingiva begin in childhood  and increase with age. With similar amounts of dental  plaque, the severity of gingivitis is greater in adults than in  prepubertal children. Around the time of puberty, there is  a period of increased susceptibility to gingivitis (puberty  gingivitis), with the peak prevalence of involvement occur-  ring between the ages of 9 and 14 years. Between the ages  of 11 and 17 years, the frequency declines; then a slow    increase is seen until the prevalence approaches 100% in  the sixth decade of life.   In most age groups, females demonstrate a lower fre-  quency of gingivitis than do males (although females have  periods of increased susceptibility). This may be due more  to better oral hygiene in females than to a physiologic dif-  ference between the sexes. In addition to the years of puberty,  females exhibit a greater susceptibility to gingivitis when  they are exposed to the high levels of progesterone associated  with pregnancy or some forms of oral contraceptives.   A number of other systemic factors have been shown to  increase the frequency of gingivitis and are listed in Box 4-2.  In contrast, smoking and use of many antibiotic drugs,  corticosteroid medications, and nonsteroidal antiinflamma-  tory drugs (NSAIDs) have been correlated with a reduced  gingival response to plaque. Various local factors that can  be related to gingivitis are shown in Box 4-3.   Injury to the gingiva from mastication, oral hygiene  techniques, or other habits may result in a breach of the  oral mucosa, with secondary infection from the local flora.  Most such injuries result in transient areas of erythema.  However, if the trauma follows a chronic pattern, then areas  of persistently swollen, erythematous gingiva may result.  Patients who are mouth breathers or demonstrate incom-  plete lip closure can display a unique pattern of gingivitis  in which the anterior facial gingiva is smooth, swollen, and  red (Fig. 4-1).   Susceptibility to plaque-related gingivitis appears to vary  within the population, and the individual traits seem to  determine the severity of gingivitis, independent of the  degree of plaque accumulation. In addition, evidence sug-  gests that susceptibility to gingivitis appears linked to sus-  ceptibility to future development of periodontitis.   Inflammation of the gingiva may be localized or general-  ized. The involved area may be diffuse or confined to the  free gingival margins (marginal gingivitis) (Fig. 4-2) or the  interdental papillae (papillary gingivitis). The earliest signs  of gingivitis include a loss of stippling plus bleeding on  gentle probing. Healthy gingiva is coral pink; with inflam-  mation, the involved gingiva becomes light red. With pro-  gression, the area becomes redder and edematous. As the  process becomes entrenched, the involved gingiva becomes  brighter red or magenta; the gingiva often demonstrates    1. Hormonal changes  e Puberty  e Pregnancy  e Oral contraceptive use  Stress  Substance abuse  Poor nutrition  e Ascorbate (vitamin C) deficiency (See page 770)  5. Certain medications (see page 148)  e Phenytoin  e Calcium channel blockers  e Cyclosporine  6. Diabetes mellitus (See page 785)  7. Down syndrome  8. Immune dysfunction  9. Heavy-metal poisoning (see page 286)    Local trauma  . Tooth crowding with overlapping  Dental anomalies  e Enamel pearls (see page 85)  e Enamel and radicular grooves  Tooth fracture  Dental caries  Gingival recession  High frenum attachments  latrogenic factors  e Overhanging restorations  e Removable prostheses  e Orthodontic appliances  9. Inadequate lip closure  10. Mouth breathing    margins that may be blunted, receded, or hyperplastic (Fig.  4-3). When chronic inflammation causes significant enlarge-  ment because of edema or fibrosis, the process is termed  chronic hyperplastic gingivitis (Fig. 4-4). Bleeding occurs  easily, and exudate can be seen in the gingival sulcus. A  localized tumorlike proliferation of subacutely inflamed  granulation tissue, known as a pyogenic granuloma (see  page 483), can develop on the gingiva of patients with  severe gingivitis (Fig. 4-5).    @ Fig. 4-1 Mouth Breathing-Related Gingivitis. Slick, swollen, and  red gingivitis of the anterior facial gingiva secondary to chronic mouth  breathing.    @ Fig. 4-2 Marginal Gingivitis. Diffuse erythematous alteration of the  free gingival margins.    ® Fig. 4-3 Chronic Gingivitis. Bright-red gingiva is blunted, receded,  and hyperplastic secondary to a total lack of oral hygiene. Note the  extensive calculus buildup.    Incipient gingivitis demonstrates a light inflammatory infil-  trate consisting of polymorphonuclear leukocytes that accu-  mulate in the connective tissue adjacent to the sulcular    @ Fig. 4-4 Chronic Hyperplastic Gingivitis. Diffuse erythema and  enlargement of marginal and papillary gingiva.    e Fig. 4-5 Hyperplastic Gingivitis with Pyogenic Granuloma.  Diffuse erythematous enlargement of marginal and papillary gingiva  with hemorrhagic, tumorlike proliferation (which arose during preg-  nancy) between the maxillary bicuspid and first molar.    epithelium. With progression, the infiltrate becomes more  intense and demonstrates a mixture of lymphocytes, plasma  cells, and acute inflammatory cells (Fig. 4-6). Areas of fibro-  sis, hyperemia, edema, and hemorrhage may be present.    Although periodontitis always is preceded by gingivitis,  most areas of gingivitis remain stable for years, and the  number of affected sites that convert to periodontitis is  small. In spite of this, optimal gingival health should be the  goal of all clinicians and their patients. Even when attach-  ment loss is not evident and the alterations appear restricted  to the gingival soft tissues, proactive interventions are rec-  ommended to eliminate these areas of persistent pathosis  during the early stages of disease.   Treatment of gingivitis consists of elimination (if possi-  ble) of any known cause of increased susceptibility and  improvement in oral hygiene to decrease the dental plaque  responsible for the inflammatory alterations. A further dis-  cussion of dental plaque and its relationship to gingival  inflammation is presented in the discussion of periodontitis    overlying connective tissue that contains inflammatory infiltrate con-  sisting of lymphocytes, plasma cells, and polymorphonuclear  leukocytes.    (see page 153). Most self-administered plaque control pro-  grams are ineffective unless periodic professional reinforce-  ment also is provided. Research has shown that few  individuals have the physical skills and motivation necessary  to obtain and maintain ultimate oral hygiene. An analysis  of multiple clinical trials revealed that use of a mechanical  toothbrush was associated with plaque reduction of less  than 50%. Although rotation/oscillation-powered brushes  have demonstrated the ability to remove an increased per-  centage of plaque, the best toothbrush remains the one that  gets into the mouth. Brushing fails to clean the interdental  areas and should be supplemented by other cleaning aids,  such as specialized wood sticks (not toothpicks), dental  floss, or interdental brushes.   Mechanical removal of dental plaque can be aided by the  use of numerous chemical agents, such as mouth rinses with  chlorhexidine or essential oils, or dentifrices containing tri-  closan or stannous fluoride. On occasion, hyperplastic and  fibrotic gingiva may have to be recontoured surgically to  achieve total resolution of the altered anatomy after improve-  ments in hygiene have been made. If the gingivitis does not  resolve after improved plaque control and elimination of  obvious contributing factors, then the patient should be  evaluated for underlying systemic disorders that could be  contributing to the process.    Localized juvenile spongiotic gingival hyperplasia is a  clinically and histopathologically distinctive gingival patho-  sis that was initially described in 2007. Although the disor-  der is idiopathic, it has been suggested that the alteration  represents an isolated patch of exteriorized junctional or  sulcular epithelium that may be altered secondarily by local  factors, such as mouth breathing. The changes do not   Prior to the initial description, some of these cases were  designed as puberty gingivitis, but several features dispute  this contention. Numerous examples have been reported in  prepubescent children and, in contrast to puberty gingivitis,  the lesions do not respond to improved oral hygiene. Addi-  tionally, an absence of estrogen and progesterone receptors  has been documented in these lesions.    The most common presentation of localized juvenile spon-  giotic gingival hyperplasia is a small bright red velvety or  papillary alteration that often bleeds easily upon manipula-  tion (Fig. 4-7). The facial gingiva overlying the root is  affected most frequently, but involvement of the interproxi-  mal areas also may occur. Although the lesion typically is  sessile, some examples may be very pedunculated with occa-  sional extension into the gingival sulcus (Fig. 4-8). Although  the lesion has been diagnosed in adulthood, the vast major-  ity occurs under 20 with a median age of 12 years. The    @ Fig. 4-7 Localized Juvenile Spongiotic Gingival Hyperplasia.  Bright red velvety alteration of maxillary facial gingiva in 9-year-old  male. (Courtesy of Dr. Tom Ocheltree.)    @ Fig. 4-8 Localized Juvenile Spongiotic Gingival Hyperplasia.  Red, papillary, and pedunculated lesion with a stalk that extends into  the gingival sulcus in a 28-year-old female.    alteration demonstrates a strong predilection for the maxil-  lary anterior facial gingiva with a female predominance.  Although occasional multifocal involvement may be seen,  most examples are isolated. The natural history of the lesion  is difficult to ascertain due to therapeutic removal, but  several examples have been noted for 2 to 3 years prior to  excision.    Microscopically, the epithelium is variably hyperplastic and  demonstrates a pebbly to papillary surface. Prominent inter-  cellular edema (spongiosis) and exocytosis by neutrophils  are noted consistently. Histopathologically, the epithelium  is remarkably similar to junctional or sulcular areas. Upon  immunoperoxidase evaluation, the epithelium demonstrates  a reactivity pattern to CK19 that mimics sulcular epithe-  lium and is not typical of the facial gingiva. The associated  stroma reveals vasodilation with congestion and a mixed  inflammatory cellular infiltrate.    The vast majority of the reported examples have been  excised conservatively with a recurrence rate that varies from  6% to 16.7%. Although the lesion may persist for years,  the possibility of spontaneous resolution is likely because  the process is reported infrequently in adults.    Necrotizing ulcerative gingivitis (NUG) has a distinctive  pattern of gingival pathologic changes that have been rec-  ognized for hundreds of years. Until recently, the name of  this process has been preceded by the term acute (i.e.,  ANUG); however, several investigators have discontinued  the use of this word, because there is no chronic form of  the disease. In the 1890s the French physician Jean Hya-  cinthe Vincent identified a fusiform bacterium, Bacillus  Jusiformis (currently Fusobacterium nucleatum), and a spiro-  chete, Borrelia vincentii, after microscopic examination of  plaque samples from affected sites. Vincent believed that the  fusiform bacteria were principally responsible for the condi-  tion, and the spirochetes mainly were saprophytic oppor-  tunists. The spirochete and fusiform bacterium association  remains true today, but more sophisticated techniques have  implicated Fusobacterium nucleatum, Prevotella intermedia,  Porphyromonas gingivalis, Treponema spp., and Selenomonas  spp. Although the association with bacteria is strong, con-  troversial research has suggested that viruses, such as cyto-  megalovirus, Epstein-Barr virus, and herpes simplex, may  contribute to the onset and progression of the process.  The infection frequently occurs in the presence of psy-  chologic stress. People in military service exhibit an increased  frequency of NUG; the disorder was so common in the    battlefield trenches during World War I that the nickname  trench mouth became well known.   In addition to stress, other factors have been related to  an increased frequency of NUG:  ¢ Immunosuppression  ¢ Smoking  ¢ Local trauma  ¢ Poor nutritional status  ¢ Poor oral hygiene  e Inadequate sleep  ¢ Recent illness   A number of medications have been reported to cause  agranulocytosis, a condition that may clinically present ini-  tially as NUG. A thorough investigation of all currently  utilized medications appears prudent and may lead to dis-  covery of a significant associated immunosuppression. In  addition, the immunocompromised status associated with  acquired immunodeficiency syndrome (AIDS) (see page  239) or infectious mononucleosis (see page 229) has been  related to the development of NUG. The list of predisposing  factors clearly supports the association between a depressed  systemic immunity and the appearance of the disorder.    NUG may occur at any age; however, when encountered in  the United States or Europe, it is seen most frequently in  young and middle-aged adults. Several publications have  reported a higher frequency in whites. The prevalence in the  normal population is less than 0.1%; however, in stressed  populations (e.g., military recruits) the frequency increases  up to 7%. In developing countries, NUG typically occurs  in very young children suffering from malnutrition.   In a classic case of NUG, the interdental papillae are  highly inflamed, edematous, and hemorrhagic. Typically,  the affected papillae are blunted and demonstrate areas of  “punched-out,” craterlike necrosis that are covered with a  gray pseudomembrane (Fig. 4-9). Early cases may be missed  easily because the ulceration initially involves only the tip  of the interdental papilla. A fetid odor, exquisite pain, spon-  taneous hemorrhage, and accumulations of necrotic debris  usually are noted. Although a bad odor is not always noted,  its absence in a patient without predisposing factors should  raise concern for other pathoses, such as gonorrhea (see  page 174). Occasional ancillary clinical features include  lymphadenopathy, fever, and malaise. The process some-  times can lead to a loss of attachment and the development  of associated periodontitis (necrotizing ulcerative peri-  odontitis) or spread to adjacent soft tissue (necrotizing  ulcerative mucositis, necrotizing stomatitis) (Fig. 4-10).  If the necrotizing infection extends through the mucosa to  the skin of the face, then it is typically termed noma  (cancrum oris) (see page 181).   Several investigators have suggested that NUG, necro-  tizing ulcerative periodontitis (NUP), and necrotizing  stomatitis are one disease process termed necrotizing gin-  givostomatitis. Evidence presented by numerous authors    @ Fig. 4-9 Necrotizing Ulcerative Gingivitis (NUG). Gingiva is  friable and hemorrhagic with necrosis of the interdental papillae.    © Fig. 4-10 Necrotizing Ulcerative Mucositis. Gingiva exhibits  epithelial necrosis that has extended between the adjacent interdental  papillae and apically to the alveolar mucosa junction.    has shown the diseases to be similar clinically, histopatho-  logically, and bacteriologically, with the only differences  being underlying systemic factors and anatomic extension  of the necrosis.    The histopathologic features of NUG are not specific. Typi-  cally, affected gingival papillae demonstrate surface ulcer-  ation that is covered by a thickened fibrinopurulent  membrane. The underlying lamina propria demonstrates an  intense acute or mixed inflammatory infiltrate and extensive  hyperemia. In nonulcerated affected epithelium, often a loss  of the typical surface keratinization occurs. Necrotic mate-  rial and extensive bacterial colonization often are included  in the material submitted for microscopic examination.    In contrast to most forms of periodontal disease, NUG  typically demonstrates quick resolution after removal of the  bacterial challenge. Even with conservative therapy, regen-  eration of the affected gingiva is normally seen. The affected    area is treated best with débridement by scaling, curettage,  or ultrasonic instrumentation (except when contraindi-  cated, as in HIV-positive patients). Topical or local anes-  thetic often is required before the clinician can débride the  tissues adequately. Frequent rinses with chlorhexidine,  warm saltwater, or diluted hydrogen peroxide are beneficial  in increasing the therapeutic response. Antibiotic medica-  tions (metronidazole and penicillin have been suggested as  the drugs of choice) are a useful adjunct, especially in the  presence of fever or lymphadenopathy.   Treatment should include instructions on oral hygiene  and patient motivation; identification and resolution of any  predisposing factors also are advantageous. Supportive  therapy (e.g., rest, appropriate fluid intake, and soft nutri-  tious diet) and smoking cessation often improve the clinical  response. Follow-up appointments are necessary to rein-  force the home care instructions and to rule out a recurrence  of the process. In cases resistant to treatment, further evalu-  ation to rule out HIV infection or infectious mononucleosis  is prudent.   The clinician must be ever vigilant in the search for other  signs and symptoms of immunosuppression. Subtle palatal  candidiasis or HIV-related oral hairy leukoplakia (see page  242) can be overlooked easily in a patient with NUG.  Appropriate attention must be directed toward the oral soft  tissue examination, especially in patients with infections  such as NUG that are related to immunosuppression. In  addition, a thorough investigation of underlying causes of  immunosuppression should be performed on_ patients  whose conditions are resistant to normal therapy.    A distinctive pattern of gingival inflammation, plasma cell  gingivitis, was brought to the attention of health care prac-  titioners during the late 1960s and early 1970s. A rash of  cases occurred during that time, and most appear to have  been related to a hypersensitivity to a component of chewing    gum. Since that time, the number of cases has dwindled,  but similar gingival alterations are reported occasionally.   Although the association with chewing gum has  decreased, allergy still is responsible for many reported  cases. A brand of herbal toothpaste, a specific type of mint  candy, and peppers used for cooking have all been impli-  cated in more recent reports. The list of allergens appears  to be variable, and a thorough evaluation often is required  to rule out an allergic cause.    Patients with plasma cell gingivitis experience a rapid onset  of sore mouth, which often is intensified by dentifrices and  hot or spicy foods. The entire free and attached gingiva  demonstrates a diffuse enlargement with bright erythema  and loss of normal stippling (Fig. 4-11). Extension onto the  palate can occur, and edentulous areas typically exhibit less  intense changes. On occasion, a similar localized gingival  and vestibular alteration can occur from topical placement  of a material that elicits a similar plasmacytic inflammatory  reaction.   Additional sites of involvement may be seen, or the  changes may be localized to the gingiva. In the chewing  gum-telated cases of the early 1970s, involvement of the  lips and tongue was typical. The lips were dry, atrophic,  occasionally fissured, and angular cheilitis was frequent.  Tongue involvement resulted in erythematous enlargement  with furrows, mild crenation, and loss of the typical dorsal  coating.   More recent reports have described lesions often isolated  to the gingiva without the classic lip and tongue involve-  ment seen in the past. A larger percentage of these cases are  idiopathic, and occasional extraoral involvement of sites  such as the supraglottic region occurs.    The cases of classic plasma cell gingivitis of the 1970s dem-  onstrated psoriasiform hyperplasia and spongiosis of the    @ Fig. 4-11 Plasma Cell Gingivitis. A, Diffuse, bright-red enlargement of the free and attached gingiva.  B, Same patient as depicted in A after elimination of the inciting allergen.    @ Fig. 4-12 Plasma Cell Gingivitis. High-power photomicrograph  exhibiting a dense inflammatory infiltrate consisting predominantly of  plasma cells with scattered lymphocytes.    surface epithelium with intense exocytosis and neutrophilic  microabscesses. The underlying lamina propria contains  numerous dilated vascular channels and an extremely dense  chronic inflammatory infiltrate that is composed predomi-  nantly of plasma cells (Fig. 4-12). The more recent cases are  similar but often demonstrate less involvement of the  surface epithelium and a less dense underlying plasmacytic  infiltrate.   Investigation of the clonality of the plasma cell infiltrate  may be necessary to rule out the possibility of a mono-  clonal plasma cell neoplasm. All allergic and idiopathic  cases of plasma cell gingivitis demonstrate a polyclonal  mixture of plasma cells and a normal profile on plasma  immunoelectrophoresis.   It must be remembered that an identical dense infiltrate  of plasma cells can be seen in plaque-related gingival hyper-  plasia and chronic periodontitis. The diagnosis depends on  a strong clinical and histopathologic correlation in which  the changes are associated with a rapid onset of sore mouth  and do not resolve with improved oral hygiene. Reports of  this entity that do not fulfill the diagnostic criteria still can  be found in the dental and medical literature. Review of the  original 1971 publication may be helpful for those contem-  plating the diagnosis.    All patients with plasma cell gingivitis should be instructed  to keep a complete dietary history with records of every-  thing taken into the mouth (e.g., foods, dentifrice, mouth-  wash, tobacco, alcohol, chewing gum, candy, and  medications). Possible allergens should be eliminated in an  attempt to discover the underlying cause. If an easy answer  is not apparent, then extensive allergy testing and an elimi-  nation diet can be undertaken.   Many patients in whom no underlying cause could be  discovered have been treated with topical or systemic immu-  nosuppressive medications with variable results. Betametha-  sone rinses, fluocinonide gel, topical triamcinolone, and    topical fusidic acid are several of the reported choices. In  spite of all the evaluations and therapeutic interventions,  some patients do not respond to treatment, and no cause  for the disease can be identified.    The presence of oral soft tissue alterations in association  with histopathologic evidence of noncaseating granuloma-  tous inflammation is termed orofacial granulomatosis (see  page 312). Gingival involvement is noted in approximately  25% of affected patients and is designated granulomatous  gingivitis. After a thorough microscopic examination for  foreign material and special stains for fungal and mycobac-  terial infection have ruled out those entities, an extended  search for a possible trigger often follows.   Several investigators have reported granulomatous gingi-  val lesions caused by the introduction of dental materials into  the connective tissue deep to the sulcular epithelium. As  more cases have been reported, it has become evident that the  associated inflammatory reaction often is not granulomatous  and may mimic gingival lichen planus or create a nonspecific  pattern of chronic or subacute mucositis. These lesions have  been termed foreign body gingivitis and are thought to arise  when damage to the sulcular epithelium during restorative or  oral hygiene procedures allows the introduction of foreign  material into the gingival tissues. Although the foreign mate-  rial may be obvious, often it is smaller than 1 [um in diameter  and so fine that it could be overlooked.   In a review of 85 cases of foreign body gingivitis, energy-  dispersive radiographic microanalysis revealed 21 different  elements embedded with the gingival soft tissues. The most  common elements were silver, aluminum, silicon, tin,  sulfur, copper, calcium, phosphorus, and iron. Elements  compatible with fine particles of amalgam dust were identi-  fied most often. Particles consistent with corundum or silica  also were common (sandpaper disks, polishing paste, tooth-  paste, and possibly restorative filling material). Materials  implicated less frequently include dust from tungsten  carbide burs, composite material, endodontic sealer compo-  nents, and temporary cement. This investigation demon-  strates that the presumed causative agents are diverse and  can originate from a wide variety of dental materials.    Both foreign body gingivitis and nonspecific granulomatous  gingivitis may occur at any age; however, they are most  frequently encountered in adulthood. The lesions may be  solitary or multifocal, typically with a diameter less than  2 cm. The affected areas appear as red or red-and-white  macules, which most frequently involve the interdental  papillae but also may occur along the marginal gingiva  (Figs. 4-13 and 4-14). On occasion, significant gingival  hyperplasia may be present in a localized or generalized  pattern. Pain or sensitivity is a common finding, and the  lesions persist despite conventional therapy and rigorous    thematous gingiva associated with the maxillary left central incisor. The  alterations developed shortly after placement of a porcelain-fused-to-  metal (PFM) full crown and were not responsive to conservative local  therapy. (Courtesy of Dr. Timothy L. Gutierrez.)    ° Fig. 4-14 Foreign Body Gingivitis. Red, atrophic mucosa of the  left maxillary facial gingiva. The alterations arose following placement  of two porcelain-fused-to-metal (PFM) crowns. Biopsy revealed lichen-  oid mucositis with intermixed fragments of foreign material.    oral hygiene. The process can be seen adjacent to clinically  normal teeth or next to teeth with restorations.   Frequently, foreign body gingivitis creates areas of ery-  thematous and atrophic mucositis that closely resemble gin-  gival lichen planus. A good clinicopathologic correlation  often is beneficial in arriving at the correct diagnosis. A diag-  nosis of gingival lichen planus should be viewed with suspi-  cion ina patient who does not have extragingival involvement  or if the gingival changes are somewhat localized and nonmi-  grating. In such cases, a request to the pathologist for a thor-  ough search for foreign material is prudent.    A biopsy specimen of granulomatous gingivitis demon-  strates focal collections of histiocytes intermixed with an  intense lymphocytic infiltrate (Fig. 4-15). On occasion,  well-formed histiocytic granulomas with multinucleated  giant cells are seen. Special stains for organisms should be    cytes, lymphocytes, and multinucleated giant cells within the superfi-  cial lamina propria of the gingiva.    @ Fig. 4-16 Foreign Body Gingivitis. Particles of pigmented foreign  material (arrow) intermixed with lymphocytes and plasma cells.    negative. If foreign material is reported, then the clinician  should consider the possibility of foreign body gingivitis.  In the previously mentioned review of 85 cases of foreign  body gingivitis, granulomatous inflammation was present in  approximately 20%. In the remainder, the inflammatory  infiltrate was dominated by lymphocytes, intermixed with  plasma cells and macrophages (Fig. 4-16). In some cases,  neutrophils were noted along with the chronic inflamma-  tory cellular infiltrate. Not infrequently, the mucositis was  lichenoid with degeneration of the basal cell layer of the  epithelium and a superficial bandlike inflammatory cell  infiltrate in the superficial lamina propria. Because the  immune reaction in lichen planus tends to be composed  primarily of lymphocytes, the presence of significant  numbers of plasma cells, histiocytes, or neutrophils in the  absence of plaque-related gingivitis should suggest a    thorough search for subtle foreign material. In many cases,  the foreign material is subtle and discovered only with a high  index of suspicion and after a thorough search. To ensure  that any foreign material is not an artifact introduced during  processing, it should be present in multiple sections.    When all of the histopathologic and clinical investigations  have been performed, the final differential diagnosis of  granulomatous gingivitis usually is narrowed down to a  localized form of orofacial granulomatosis or a foreign body  reaction. Without definitive demonstration of foreign mate-  rial, a complete physical evaluation for disorders known to  be associated with orofacial granulomatosis is appropriate  (see page 312).   Surgical excision of the affected tissue is the therapy of  choice for those cases related to foreign material if the  process is sufficiently symptomatic. In persistently atrophic  or erosive areas of foreign body gingivitis, overlaying the  damaged area with a graft from a healthy gingival donor site  may be a better option than complete excision. In an attempt  to prevent future introduction of iatrogenic foreign material,  clinicians should use care during restorative and oral hygiene  procedures that might introduce foreign material into a  surgical wound. In addition, dental prophylaxis should be  delayed for 2 days after scaling, root planing, and curettage  procedures. Patients who do not respond to surgical removal  and have recurrences of granulomatous gingivitis despite  cautious dental care probably should be classified as having  orofacial granulomatosis and managed accordingly.    Desquamative gingivitis is a clinical term for gingiva that  demonstrates superficial peeling of the epithelium charac-  terized by formation and rupture of mucosal vesicles. The  process almost always represents a manifestation of one of  several different vesiculoerosive diseases, usually mucous  membrane pemphigoid. Some clinicians broaden the defi-  nition to include patients with atrophic and erosive gingi-  val lesions without true peeling of the epithelium. In such  cases, lichen planus is diagnosed most frequently. Other  diagnoses that are made less frequently include linear IgA  disease, pemphigus vulgaris, epidermolysis bullosa acquis-  ita, systemic lupus erythematosus (SLE), chronic ulcerative  stomatitis, and paraneoplastic pemphigus. The gingival  manifestations of these mucosal and dermatologic diseases  are described in greater detail in Chapter 16, so further  discussion here is not warranted.    Drug-related gingival hyperplasia refers to an abnormal  growth of the gingival tissues secondary to use of a systemic    ® Fig. 4-17 Cyclosporine-Related Gingival Hyperplasia. Diffuse,  erythematous, and fibrotic gingival hyperplasia.    medication. A list of medications reported to be associated  with gingival hyperplasia is provided in Box 4-4. Of these  medications, a strong association has been noted only with  cyclosporine (Fig. 4-17), phenytoin, and nifedipine (Fig.  4-18). In addition to nifedipine, a definitive but much  weaker association has been documented with other calcium  channel-blocking agents, such as diltiazem, amlodipine, and  verapamil. In the remainder of these agents, the prevalence  is much lower or the association is weak or anecdotal. A  number of calcium channel blockers exist that have not  been associated with gingival hyperplasia and may represent  safer alternatives. As new drugs are developed, the list of  offending medications may grow. Cyclosporine is known to  be associated with hypertension, often leading to utilization  of a calcium channel blocker. When cyclosporine and    ee >  © Fig. 4-18 Nifedipine-Related Gingival Hyperplasia. Diffuse,  fibrotic gingival hyperplasia after 1 month of intensive oral hygiene.  Significant erythema, edema, and increased enlargement were present  before intervention.    e Fig. 4-19 Cyclosporine- and Nifedipine-Related Gingival  Hyperplasia. Dramatic gingival hyperplasia in a patient using two  drugs associated with gingival enlargement.    nifedipine are used concurrently, the severity of the associ-  ated hyperplasia often is increased (Fig. 4-19).   The prevalence of these hyperplasias varies widely;  however, as reported in one critical review of the literature,  the prevalence related to use of phenytoin is approximately  50%. Cyclosporine and nifedipine each produce significant  changes in about 25% of patients treated. Whether there is  a relationship between the particular dose and the risk or  severity of the hyperplasia is a controversial issue. Investiga-  tors have suggested that susceptibility to cyclosporine gin-  gival hyperplasia is associated with certain histocompatibility  antigen (HLA) types, whereas other HLA types appear to  protect against hyperplasia. Whether similar correlations  exist for the other forms of medication-associated gingival  hyperplasia is unknown.   ‘The degree of gingival enlargement appears to be related  significantly to the patient’s susceptibility and the level of  oral hygiene. In observations of patients with excellent oral  hygiene, gingival overgrowth (as ascertained by pseudo-  pocket formation) is reduced dramatically or not present.  Even with good oral hygiene, however, some degree of    @ Fig. 4-20 Mild Phenytoin-Related Gingival Hyperplasia. Gingi-  val enlargement present predominantly in the interdental papillae.    gingival enlargement can be discovered in susceptible indi-  viduals, although in many cases the changes are difficult to  detect. Rigorous oral hygiene often can limit the severity to  clinically insignificant levels. Of the medications discussed,  cyclosporine appears to be the least responsive to the institu-  tion of a rigorous program of oral hygiene; even with this  medication, however, the elimination of gingival inflamma-  tion results in noticeable clinical improvement. In addition,  the degree of drug-associated gingival hyperplasia appears  to be markedly higher in smokers.    Because young patients use phenytoin most often, the gin-  gival hyperplasia it induces is primarily a problem in people  younger than age 25. Cases related to the calcium channel  blockers occur mainly in middle-aged or older adults.  Cyclosporine is used over a broad age range, and this cor-  relates with the age of reported hyperplasia. A greater risk  for gingival hyperplasia occurs when the drug is used in  children, especially adolescents. No sex or race predilection  is present.   After 1 to 3 months of drug use, the enlargements origi-  nate in the interdental papillae and spread across the tooth  surfaces (Fig. 4-20). The anterior and facial segments are  the most frequently involved areas. In extensive cases, the  hyperplastic gingiva can cover a portion (or all) of the  crowns of many of the involved teeth (Figs. 4-21 and 4-22).  Extension lingually and occlusally can interfere with speech  and mastication. Edentulous areas generally are not affected,  but significant hyperplasia under poorly maintained den-  tures and around implants has been noted (Fig. 4-23).   Nongingival soft tissue growths that resemble pyogenic  granulomas have been reported in allogeneic bone marrow  transplant recipients who are receiving cyclosporine for  graft-versus-host disease (GVHD) (Fig. 4-24). It is thought  that cyclosporine triggers the proliferations in areas chroni-  cally inflamed by GVHD.   In the absence of inflammation, the enlarged gingiva is  normal in color and firm, with a surface that may be  smooth, stippled, or granular. With inflammation, the   @ Fig. 4-21 Phenytoin-Related Gingival Hyperplasia. Significant  erythematous gingival hyperplasia is covering portions of the crowns  of numerous teeth.    ® Fig. 4-22 Phenytoin-Related Gingival Hyperplasia. Significant  gingival hyperplasia almost totally covers the crowns of the posterior  maxillary dentition. (Courtesy of Dr. Ann Drummond and Dr. Timothy  Johnson.)    @ Fig. 4-23 Phenytoin-Related Palatal Hyperplasia. Extensive  hyperplasia of palatal mucosa in an edentulous patient with poor  denture hygiene.   @ Fig. 4-24 Nongingival Cyclosporine Hyperplasia. Exophytic  and granulomatous-appearing mass of the dorsal surface of the  tongue that arose in a bone marrow transplant patient who was receiv-    affected gingiva often becomes dark red and edematous,  with a surface that is friable, bleeds easily, and occasionally  is ulcerated. Pyogenic granuloma-like enlargements occa-  sionally are seen in the presence of heavy inflammation.    Upon histopathologic examination, the overlying surface  epithelium may demonstrate elongation of the rete ridges,  with long extensions into the underlying stroma. The lamina  propria exhibits an increased amount of fibrous connective  tissue that demonstrates a normal density of fibroblasts. In  patients with secondary inflammation, there is increased  vascularity and a chronic inflammatory cellular infiltrate  that most frequently consists of lymphocytes and plasma  cells. In patients with pyogenic granuloma-like overgrowths,  the proliferations often demonstrate an increased vascularity  and significant subacute inflammation.    Discontinuation of the offending medication by the attend-  ing physician often results in cessation, and possibly some  regression, of the gingival enlargement; even substitution of  one medication for another in the same class may be benefi-  cial. Often the response to medication substitution is not  immediate. If the drug use is mandatory, then professional  cleaning, frequent reevaluations, and home plaque control  are important. Antiplaque agents, such as chlorhexidine,  have been beneficial in the prevention of plaque buildup  and the associated gingival hyperplasia.   Systemic or topical folic acid has been shown to amelio-  rate the gingival hyperplasia in some cases. In addition,  several authors have documented significant resolution  of cyclosporine-related gingival hyperplasia after a short  course of metronidazole, azithromycin, or roxithromycin.  Azithromycin also may be beneficial in resolving gingival  hyperplasia related to nifedipine and phenytoin.    Although gingival hyperplasia is associated with increased  probing depths, some investigators do not believe this nec-  essarily leads to exaggerated attachment loss or an increased  loss of teeth. Therefore, some clinicians exercise watchful  waiting and do not perform invasive therapy without evi-  dence of attachment loss, inappropriate aesthetics, or dis-  ruption of speech or mastication. When objectionable  alterations are noted and all other interventions fail to  achieve significant resolution, eradication of the excess gin-  gival tissues remains the treatment of choice. Recurrence is  not uncommon, however, especially in patients with inad-  equate oral hygiene.    Gingival fibromatosis is a slowly progressive gingival enlarge-  ment caused by a collagenous overgrowth of the gingival  fibrous connective tissue. In spite of the name, this disorder  bears no relationship to the hypercellular and neoplastic  fibromatoses that can occur in soft tissue and bone (see  pages 481 and 613). Gingival fibromatosis is a rare condi-  tion with an estimated prevalence of 1:750,000.   Gingival fibromatosis may be familial or idiopathic.  Other findings sometimes seen in conjunction with gingival  fibromatosis include hypertrichosis (Fig. 4-25), generalized  aggressive periodontitis, epilepsy, intellectual disability, sen-  sorineural deafness, hypothyroidism, chondrodystrophia,  and growth hormone deficiency. The familial variations may  occur as an isolated finding or in association with one of  several hereditary syndromes. Box 4-5 lists the syndromes  that often have been associated with gingival fibromatosis.   In most cases of isolated gingival fibromatosis, an auto-  somal dominant pattern of inheritance is seen; however,  autosomal recessive examples also have been noted. Incom-  plete penetrance and variable expressivity are seen. The phe-  notype of hereditary gingival fibromatosis demonstrates  significant genetic heterogeneity with the existence of at  least five genes that are responsible for similar patterns of  clinical presentation.    In most instances, the enlargement begins before age 20 and  often is correlated with the eruption of the deciduous or  permanent teeth (Fig. 4-26). Most investigators believe that  the presence of teeth probably is necessary for the condition  to occur. In spite of this, rare patterns can present in infancy  or even at birth. After the process has begun, it can over-  grow the associated teeth and even interfere with lip closure.  Failure or delay in eruption, or altered position of the  erupted teeth, may be evident (Fig. 4-27). In some instances,  a tooth may have erupted into a normal position, but the  fibrous connective tissue continues to cover the crown and  prevent visualization.    @ Fig. 4-25 Hypertrichosis in Association with Gingival Fibro-  matosis. Dramatically increased body hair of the back and buttocks  in a patient with gingival fibromatosis. (Courtesy of Dr. George Blozis.)    ‘The gingival changes may be generalized or localized to  one or more quadrants. Either jaw may be involved, but the  maxilla is affected more frequently and demonstrates a  greater degree of enlargement. Palatal surfaces are typically  increased in thickness more than the buccal side. Typically,  extension past the alveolar mucosal junction into the muco-  buccal fold is not seen, but palatal extensions can cause  significant distortion of the contour of the palate and, at  times, almost can meet in the midline.   In localized cases, the hyperplasia may involve a group  of teeth and remain stable or, at a later date, may extend to  other segments of one or both jaws. One distinctive and  not uncommon pattern involves the posterior maxillary  alveolar ridge. In this pattern, the hyperplastic tissue forms    @ Fig. 4-26 Gingival Fibromatosis. A young child with cheeks  retracted by the parent. Note erythematous gingival hyperplasia aris-  ing in association with erupting deciduous dentition. (Courtesy of  Dr. George Blozis.)    @ Fig. 4-27 Gingival Fibromatosis. A, Dense fibrotic enlargement  of the gingiva, which results in flaring of the dentition and open contact  points. B, Same patient following surgical reduction of the excess  fibrotic gingival tissue.    bilaterally symmetrical enlargements that extend posteriorly  and palatally from the posterior alveolar ridges (Fig. 4-28).  Less commonly, the overgrowth also may be isolated to the  facial gingiva of the lower molars.   ‘The gingiva is firm, normal in color, and covered by a  surface that is smooth or finely stippled. In older patients,    1, : 8 raved  @ Fig. 4-28 Localized Gingival Fibromatosis. Bilateral and sym-  metrical fibrotic enlargements of the palatal surfaces of the posterior  maxillary alveolar ridges.    @ Fig. 4-29 Gingival Fibromatosis. Surface stratified squamous  epithelium exhibiting long, thin rete ridges and underlying dense,  fibrous connective tissue.    the surface may develop numerous papillary projections.  The frenular attachments may appear to divide the gingival  tissues of the alveolar ridge into lobules. Associated clinical  problems include poor aesthetics, prolonged retention of  deciduous teeth, abnormal occlusion, inadequate lip closure,  and difficulty in eating and speaking.    The enlargements of gingival fibromatosis consist of  dense hypocellular, hypovascular collagenous tissue, which  forms numerous interlacing bundles that generally are  arranged mostly in a parallel pattern. The surface epithelium  often is acanthotic and exhibits long, thin rete ridges that  extend deeply into the underlying fibrous connective tissue  (Fig. 4-29). Inflammation is absent to mild. On occasion,  scattered islands of odontogenic epithelium, foci of dystro-  phic calcification, or areas of osseous metaplasia may  be seen.    Mild cases often respond to scaling and root planing fol-  lowed by close professional follow-up. For more advanced  gingival thickening, conservative surgical removal is indi-  cated. The rate of recurrence following excision is reduced  if the removal is delayed until full eruption of the perma-  nent dentition. In spite of this, local and psychological  benefits often exceed the downside of recurrence, warrant-  ing earlier removal. Although recurrence is common in  dentulous patients, a rigorous program of oral hygiene often  slows regrowth. In severe cases, selective extraction of teeth  and gingivectomy often are required to achieve a normal  gingival morphology.    Periodontitis refers to an inflammation of the gingival  tissues in association with some loss of both the attachment  of the periodontal ligament and bony support. With pro-  gressive loss of attachment, significant destruction of the  periodontal ligament and adjacent alveolar bone can occur.  Apical migration of the crevicular epithelium along the root  surface results in the formation of periodontal pockets.  Loosening and eventual loss of teeth are possible.   For more than a century, the presence of the disease has  been correlated with the accumulation of dental plaque on  the tooth and under the gingiva. In spite of this, some  patients demonstrate extensive dental plaque but do not  develop destructive lesions of the periodontium. Many  investigators now believe that periodontitis represents a  microbial-shift disease. Dramatic differences exist in the  content of dental plaque in areas of healthy and diseased  periodontium. Healthy sites are colonized primarily by fac-  ultative gram-positive organisms, whereas plaque within  areas of active periodontitis contains anaerobic and micro-  aerophilic gram-negative flora. Of the more than 500 types  of bacteria that may reside in the oral cavity, only a few have  been related to periodontitis, and the specific types often  correlate with the clinical patterns of periodontitis. Chronic  periodontitis is associated strongly with Treponema denticola,  Tannerella forsythensis, and Porphyromonas gingivalis. Addi-  tional organisms frequently thought to be involved include  Aggregatibacter actinomycetemcomitans (formerly Actinoba-  cillus actinomycetemcomitans), Prevotella intermedia, Campy-  lobacter rectus, and Fusobacterium nucleatum. Although  controversial, some investigators also have suggested that  human cytomegalovirus and other herpesviruses could play  a contributing role.   The pathogenic organisms exist in an organized com-  munity termed a biofilm. Bacteria growing in biofilms are  relatively protected from normal host defenses and exhibit  an increased resistance to locally or systemically adminis-  tered antibiotic medications. Lipopolysaccharides released  from the biofilms are thought to trigger release of catabolic  inflammatory mediators that lead to the loss of attachment.  Mechanical disruption of this organized bacterial biofilm    may be an important factor associated with successful treat-  ment of periodontitis.   ‘The presence of pathogenic bacteria is essential but insuf-  ficient to produce periodontitis. Although mild-to-moder-  ate periodontitis is present in the majority of adults, only  10% to 15% of the population develops severe, generalized  disease. The variation of susceptibility to periodontitis  appears related to genetic influences on host response, with  50% of the risk for chronic periodontitis attributed to  heredity, 20% to tobacco abuse, and another 20% to colo-  nization by specific pathogenic bacteria.   The classification of periodontitis, as delineated by the  American Academy of Periodontology, is listed in Box 4-6.  In 1999, this classification underwent significant revision  with consolidation of many previously distinct disorders.  The concept of “early-onset periodontitis” and all of its  subdivisions has been reclassified as aggressive periodonti-  tis. The following text concentrates on the chronic form of  periodontitis; a later section discusses the aggressive forms  of periodontitis. From this list it should be clear that peri-  odontitis represents a heterogeneous group of disorders.   Periodontitis associated with systemic disease is not  rare, and Box 4-7 lists many of the disorders that may be  associated with a premature loss of periodontal attachment.  Necrotizing ulcerative periodontitis (NUP) represents the  loss of attachment that often occurs in association with  necrotizing ulcerative gingivitis (NUG) (see page 143). This  form has been correlated with aggressive invasion by a  number of spirochetes and Prevotella intermedia.    With the decline in caries, chronic periodontitis has  become the primary cause of tooth loss in patients older  than 35 years of age. The disorder demonstrates an increased  prevalence in males, although researchers believe that much  of this effect is related to poorer oral hygiene and    1. Chronic periodontitis  e Localized  e Generalized  2. Aggressive periodontitis  e Localized  e Generalized  3. Periodontitis as a manifestation of systemic diseases  e Associated with hematologic disorders  e Associated with genetic disorders  e Not otherwise specified  4. Necrotizing periodontal diseases  e Necrotizing ulcerative gingivitis (NUG)  e Necrotizing ulcerative periodontitis (NUP)  5. Abscesses of the periodontium  e Gingival abscess  e Periodontal abscess  e Pericoronal abscess (in association with pericoronitis)  6. Periodontitis associated with endodontic lesions    . Acatalasia  . Acrodynia  . Acquired immunodeficiency syndrome (AIDS)  . Blood dyscrasias  e Leukemia  e Agranulocytosis  e Cyclic neutropenia  . Chédiak-Higashi syndrome  . Cohen syndrome  . Crohn disease  . Diabetes mellitus  . Dyskeratosis congenita  . Ehlers-Danlos syndrome, types IV and VIII  . Glycogen storage disease  . Haim-Munk syndrome  . Hemochromatosis  . Hypophosphatasia  . Kindler syndrome  . Langerhans cell disease  . Leukocyte dysfunctions with associated extraoral infections  . Oxalosis  . Papillon-Lefévre syndrome  . Sarcoidosis  . Trisomy 21    dental-visit behavior. In addition, an increased prevalence  of chronic periodontitis is associated with the following:   Local factors also may predispose patients to isolated  periodontal defects; these include tooth shape and align-  ment, presence and quality of dental restorations, poor  interdental contact, calculus formation, subgingival dental  caries, traumatic occlusion, and abnormal alveolar bone or  gingival anatomy.   Conversely, it appears that the presence of significant  periodontitis may place patients at risk for an increased  prevalence or greater severity of certain medical disorders.  Although controversial, periodontitis has been associated  with an elevated risk for coronary artery disease, stroke,  progressive diabetes mellitus, respiratory diseases, and deliv-  ery of low—birth weight babies. Although strong direct asso-  ciations have been documented, the epidemiology is difficult  to interpret because of the additional risk factors associated  with both conditions. For example, cardiovascular disease  has been related to periodontitis, but the nature of this  association is cloudy because both are strongly associated  with smoking.   In chronic periodontitis, no abnormalities of the immune  system typically are found. Periodontitis begins in youth  and early adulthood, takes years to decades to progress, and  includes cyclic patterns of exacerbation and remission. The    @ Fig. 4-30 Adult Periodontitis. Diffuse gingival erythema with  blunting and apical positioning of the gingival margins. (Courtesy of  Dr. Samuel Jasper.)    © Fig. 4-31 Advanced Adult Periodontitis. Generalized horizontal  bone loss with an isolated vertical defect involving the mesial root of  the first molar.    assumption that periodontitis is a disease of aging has been  challenged, and most believe the increased periodontal  destruction observed in older adults reflects a lifetime of  disease accumulation rather than an age-specific disease.  In patients with periodontitis, gingivitis is present and  precedes the development of significant periodontal lesions.  Although many sites may demonstrate gingivitis and do not  progress to attachment loss, lifelong local measures directed  against sites of gingivitis represent an effective approach for  prevention of chronic periodontitis. As loss of attachment  occurs, blunting and apical positioning of the gingival  margins typically are present (Fig. 4-30). Periodontal disease  is present when a loss of attachment can be demonstrated  through the use of a periodontal probe. In the absence of  significant gingival hyperplasia, a measurement of pocket  depths greater than 3 to 4 mm indicates destruction of the  periodontal ligament and resorption of adjacent alveolar  bone; however, clinical attachment loss is the best measure-  ment of accumulated periodontal destruction and represents  the diagnostic gold standard. High-quality dental radio-  graphs exhibit a decreased vertical height of the bone sur-  rounding the affected teeth (Fig. 4-31). With advanced bone    @ Fig. 4-32 Periodontal Abscess. Localized erythematous gingival  enlargement with central purulent drainage.    loss, tooth mobility is present. Although to date there are  no confirmed biomarkers for periodontal disease, ongoing  research is attempting to analyze saliva for genomic and  microbial markers for the early diagnosis of periodontitis.    NUP has symptoms similar to NUG (see page 143), but it  also demonstrates loss of clinical attachment and alveolar  bone. This destructive form of periodontitis may arise  within a zone of preexisting periodontitis, or it may repre-  sent a sequela of a single or multiple episodes of NUG.  Many believe that NUG and NUP represent different stages  of the same infection. Patients affected with this pattern  frequently are younger than most patients affected with  chronic periodontitis and often demonstrate immunosup-  pression or malnutrition.    A periodontal abscess (Figs. 4-32 and 4-33) is a localized  purulent infection of the gingiva with involvement of the  adjacent periodontal attachment and alveolar bone. On  occasion, an abscess may be localized to the marginal or  interdental gingiva without involvement of the adjacent  periodontal ligament or alveolar bone. This lesion is termed  a gingival abscess and often is secondary to plaque or  foreign material that has become entrapped in the gingival  sulcus.   A periodontal abscess often arises in a preexisting peri-  odontal lesion and usually is precipitated by alterations in  the subgingival flora, host resistance, or both. Factors fre-  quently associated with abscess formation are closure of the  entrance into a periodontal pocket, furcation involvement,  or diabetes. Many cases arise in patients actively undergoing  periodontal therapy, perhaps because of incomplete removal  of deep calculus with microbial penetration of the soft tissue  surrounding the pocket or premature sealing of the coronal  opening to the pocket. Other factors involved less frequently  are trauma and anatomic dental anomalies, such as enamel  pearls (see page 85) and dens invaginatus (see page 82).  Most cases arise in adults; periodontal abscesses in children    ® Fig. 4-33 Periodontal Abscess. Same patient as depicted in  Fig. 4-32. Note extensive loss of bone support associated with the  maxillary cuspid.    e Fig. 4-34 Periodontal Abscess. Dark-red and hemorrhagic  enlargement of the interdental papilla between the maxillary right lateral  incisor and cuspid.    are rare and most frequently the result of a foreign body  that has been introduced into previously healthy periodon-  tal tissues.   A periodontal abscess appears as a zone of gingival  enlargement along the lateral aspect of a tooth. The involved  gingiva may be erythematous and edematous with a slick,  red surface, or it may be hemorrhagic with a dark-red col-  oration (Fig. 4-34). Common symptoms include the  following:   e Extreme sensitivity to palpation of the affected gingiva  ¢ Sensitivity, mobility, or extrusion of the adjacent tooth  ¢ Foul taste    ® Fig. 4-35 Pericoronitis. Painful erythematous enlargement of the  soft tissues overlying the crown of the partially erupted right mandibular  third molar.    Probing or gentle pressure on the affected gingiva often  results in the expression of pus from the sulcus. The abscess  may drain through an overlying sinus tract. With drainage,  the abscess becomes asymptomatic but can demonstrate  acute exacerbations if the mucosa heals over and the pressure  builds again. Radiographs often demonstrate bone loss asso-  ciated with the previous periodontal defect or additional  radiolucency secondary to the current acute process. In some  cases, the infection can spread into the periapical region and  create a combined periodontal-endodontic lesion.    Pericoronitis is an inflammatory process that arises within  the tissues surrounding the crown of a partially erupted  tooth. The inflammatory reaction often arises when food  debris and bacteria are present beneath the gingival flap  overlying the crown. Other predisposing factors include  stress and upper respiratory infections, especially tonsillitis  or pharyngitis.   These gingival flaps can exhibit long periods of chronic  inflammation without symptoms. If the debris and bacteria  become entrapped deep within the gingival flap, then  abscess formation develops. Abscess development is seen  most frequently in association with the mandibular third  molars, and the predominant symptoms are extreme pain  in the area, a foul taste, and inability to close the jaws. The  pain may radiate to the throat, ear, or floor of the mouth.  The affected area is erythematous and edematous, and the  patient often has lymphadenopathy, fever, leukocytosis, and  malaise (Fig. 4-35). NUG-like necrosis may develop in areas  of persistent pericoronitis.    When soft tissue from areas of periodontitis is examined  microscopically, gingivitis is present and the crevicular epi-  thelium lining the pocket is hyperplastic with extensive  exocytosis of acute inflammatory cells. The adjacent con-  nective tissue exhibits an increased vascularity and contains    an inflammatory cellular infiltrate consisting predominantly  of lymphocytes and plasma cells, but with a variable number  of polymorphonuclear leukocytes. Frequently, large colo-  nies of microorganisms, representing plaque and calculus,  are noted.    Initial attention must be directed toward elimination of any  existing risk factors. Once these influences have been  managed, the treatment of periodontitis is directed toward  stopping the loss of attachment. The foremost goal of this  process is the elimination of the pathogenic bacterial plaque.  Scaling, root planing, and curettage can be used to treat  early periodontal lesions. In deeper pockets, a surgical flap  may be required to gain access to the tooth for necessary  débridement. At this time, the underlying bone may be  recontoured. (if necessary) to aid in the resolution of the  periodontal pocket.   In some bony defects, regeneration of the attachment  can be attempted through interdental denudation or the  placement of autogenous bone grafts, allografts, or alloplas-  tic materials. Often these grafts are used in conjunction  with materials, such as polytetrafluoroethylene, in an  attempt to achieve guided tissue regeneration in moderate-  to-advanced periodontal defects.   Because of the chronic nature of periodontitis, antibiotic  medications generally are not used except in patients who do  not respond to conventional therapy. When required, tetra-  cycline or metronidazole is used most frequently. Several  studies also suggest that NSAIDs may help slow the progres-  sion of bone loss in some cases of destructive periodontitis.   Several forms of local antibiotic delivery have been devel-  oped. The antibiotic drugs are placed directly into sites of  refractory periodontitis and consist of gels, ointments, non-  resorbable fibers, and resorbable polymers. These antibiotic  agents represent an adjunct to scaling and root planing and  should be limited to sites that are resistant to conventional  therapy alone.   In many cases, the prognosis for chronic periodontitis  correlates directly with the patient’s desire to maintain oral  health. Long-term studies show that periodontal health can  be maintained after appropriate periodontal therapy if a  program of rigorous oral hygiene and professional care is  established. Bacterial morphotypes return to pretreatment  levels 42 days after professional prophylaxis, but pathogenic  complexes capable of inducing attachment loss require  approximately 3 months to be reestablished functionally. In  patients with less-than-optimal oral hygiene or with isolated  defects that cannot be self-cleaned, a loss of attachment can  be prevented if professional scaling and root planing are  performed at 3-month intervals.   Destructive periodontal disease that is nonresponsive to  normal therapy in compliant patients is termed refractory  periodontitis. In such cases the patient should be reevalu-  ated closely for any predisposing risk factors (such as,  smoking) or systemic diseases known to be associated with    an increased prevalence of periodontitis (such as, diabetes).  Subgingival microbial cultures can be obtained to assist in  selection of an appropriate antibiotic intervention. Antimi-  crobial therapy may be combined with more frequent peri-  odontal maintenance therapy and stronger reinforcement of  the patient’s oral hygiene techniques.    Once any underlying influence (e.g., immunosuppression,  malnutrition) has been resolved, NUP often responds well  to irrigation, débridement of the necrotic areas, effective  oral hygiene measures, and administration of systemic anti-  biotic medications. Failure to respond to standard therapy  mandates a thorough physical evaluation to rule out the  possibility of an underlying disease.    A gingival or periodontal abscess is treated by drainage  through the sulcus or by an incision through the overlying  mucosa. Thorough cleansing of the area with removal of all  foreign material, plaque, and calculus should be performed.  Penicillin or other antibiotic drugs are prescribed when a  fever is present. Analgesic agents are prescribed, and the  patient receives a soft diet, is told to use warm saltwater  rinses, and is instructed to return each day until the symp-  toms have resolved. After the acute phase has passed, the  patient is treated for any underlying chronic pathologic  periodontal condition.    Acute pericoronitis is treated with gentle antiseptic lavage  under the gingival flap to remove gross food debris and  bacteria. Systemic antibiotic agents are used if a fever or  general symptoms are noted. The patient is instructed to  use warm saltwater rinses and to return in 24 hours. Once  the acute phase has subsided, the tooth can be extracted if  long-term maintenance is contraindicated. If tooth reten-  tion is desirable, then the overlying gingival flap is removed  surgically, which is followed by elimination of all food  debris and bacterial colonies by thorough curettage.    Although periodontitis is much more frequent in older  adults, it also can be a significant problem in children and  young adults. Before the 1999 reclassification by the Ameri-  can Academy of Periodontology, destructive periodontal  disease in younger patients was termed early-onset peri-  odontitis and subdivided into prepubertal, localized juve-  nile, generalized juvenile, and rapidly progressing forms  of periodontitis. The “early-onset” designation was discon-  tinued during the 1999 workshop because the term was  deemed too restrictive.   The 1999 workshop concluded that the most logical  classification system should not be age dependent or require  knowledge of rates of progression. In general, the new des-  ignation of localized aggressive periodontitis replaces the    older term, localized juvenile periodontitis, whereas gen-  eralized aggressive periodontitis supersedes generalized  juvenile periodontitis. The pattern previously designated  as prepubertal periodontitis has been associated with a  systemic leukocyte dysfunction termed leukocyte adhesion  deficiency syndrome. This disease currently is classified as one  of the forms of periodontitis presenting as a manifestation  of a systemic disease.   By definition, aggressive periodontitis occurs in other-  wise healthy people; there should be no association with a  systemic disease process. In keeping with this definition, the  diagnosis is one of exclusion, and all systemic disorders  known to be related to premature loss of attachment (see  Box 4-7) should be ruled out before the definitive diagnosis  is made.   Researchers believe that aggressive periodontitis repre-  sents a number of different pathoses that have been grouped  together because of similar clinical presentations. The major-  ity of patients with aggressive periodontitis have a demon-  strable neutrophil dysfunction but without systemic  manifestations. Although this is a controversial topic, several  investigators have suggested that aggressive periodontitis  requires specific bacterial flora and the presence of a selective  immune dysfunction that allows these pathogens to flourish.  This unique pattern of immune alteration may explain the  failure to defend appropriately against certain periodontal  pathogens without exhibiting systemic signs of immunode-  ficiency. Familial aggregation of patients with aggressive  periodontitis is noted and suggests an underlying genetic  foundation. In all likelihood, aggressive periodontitis is  genetically heterogeneous, meaning the mutation of any one  of several different gene loci can result in the disease.   typically begins around the ages of 11 to 13 years and has   e Attachment loss localized to the first molars and incisors,  with involvement of no more than two teeth other than  the first molars and incisors   This form may appear to localize around the first molars  and the incisors, possibly because these teeth have been  erupted for the longest duration (Fig. 4-36). In numerous  clinical studies, minimal supragingival plaque or calculus  has been documented; however, this finding has been dis-  puted. The rate of bone destruction is three to five times  faster than that seen in chronic periodontitis.   In the first molar regions, radiographs reveal vertical  bone resorption that often is bilateral and symmetrical. In  classic cases an arc-shaped zone of bone loss extends from  the distal aspect of the second bicuspid to the mesial aspect    ® Fig. 4-36 Localized Aggressive Periodontitis. Loss of bone support in the area of the first molars  and incisors of both maxillary and mandibular arches in a 14-year-old patient.    of the second molar. Similar involvement is apparent around  the anterior teeth. Tooth migration and mobility are  common. If untreated, then the process often continues  until the teeth are exfoliated. In about one-third of patients  affected with localized aggressive periodontitis, progression  to more generalized disease occurs.   Of all the pathogens in dental plaque, A. actinomycetem-  comitans appears to be predominant in localized aggressive  periodontitis. This bacterium is present in disease sites in  more than 90% of cases. Its ability to invade gingival tissue  has created difficulties in mechanical eradication. Knowl-  edge of its importance to the disease process has led to  remarkable advances in therapy.   e Usually diagnosed in patients younger than 30 years old  but may occur at any age   ¢ Generalized loss of attachment that must affect at least  three teeth other than the first molars and incisors  Most affected patients are between the ages of 12 and    may be present. Compared with the localized variant, more  teeth are affected and the bone loss is not restricted to spe-  cific areas of the jaws.   Although the localized pattern is associated primarily  with A. actinomycetemcomitans, the pathogens active in the  generalized variant are more complex, more closely aligned  to chronic periodontitis, and also involve such organisms as  Prevotella intermedia, Porphyromonas gingivalis, Tannerella  forsythensis, Fusobacterium nucleatum, Campylobacter rectus,  and. Treponema denticola. As mentioned in the discussion of  periodontitis (see page 153), an association with a number  of viruses has been suggested by some, but disputed by  others. In patients whose disease progresses from the local-  ized to generalized pattern, the associated periodontal  pathogens often become more diverse as the patient ages  and the disease becomes more widespread.    The microscopic examination of granulation tissue removed  from sites of aggressive periodontitis does not differ dra-  matically from that seen in chronic periodontitis. In spite  of this, initial histopathologic examination of the material  removed from active sites of disease is important to rule out  the possibility of other disease processes, such as Langerhans  cell histiocytosis (see page 550). The definitive diagnosis  centers on the clinical, radiographic, histopathologic, and  microbiologic findings combined with the family history  and leukocyte function tests.    Unlike the treatment used for patients with chronic peri-  odontitis, scaling and root planing alone do not    stop progression of aggressive periodontitis. The defects in  leukocyte function, in addition to the invasive capabilities  of the involved pathogenic organisms, mandate the use of  antibiotics in combination with mechanical removal of sub-  gingival plaque and inflamed periodontal tissues. Although  tetracycline, amoxicillin and clavulanate potassium, mino-  cycline, and erythromycin can be used in selected patients,  the combination of high-dose (500 mg three times per day)  amoxicillin and metronidazole has been shown to be most  effective in controlling the involved periodontal pathogens,  especially A. actinomycetemcomitans. The effectiveness of the  antibiotics appears to be improved if initiated immediately  after scaling and root planing. Continued therapy often is  predicated on microbiologic testing to ensure selection of  the most appropriate antimicrobial agent. Some investiga-  tors have claimed better results if the scaling and root  planing are completed within a 24-hour period, rather than  treating a quadrant at a time over an extended period.  Reinfection of previously cleaned areas by organisms from  untreated sites is thought to worsen the response to therapy.  Use of local anti-infective agents, such as chlorhexidine, for  2 weeks after the initial débridement has proven to be ben-  eficial in many individuals. Patients with active disease may  be at increased risk for adverse peri-implant gingival infec-  tion. Some clinicians delay implant placement in patients  with the localized type because the disease process often  stabilizes with age.   A reevaluation with professional prophylaxis is per-  formed once a month for 6 months and then every 3  months thereafter. Specimens for anaerobic cultures are  obtained at each 3-month recall. Patients with refractory  disease or significant colonization by pathogenic organisms  receive additional courses of appropriate antibiotics. Long-  term follow-up is mandatory because of the possibility of  reinfection or incomplete elimination of the organisms. The  presence of deep residual pockets is associated with disease  progression. In such circumstances, periodontal surgery  often is performed to eliminate these defects. This interven-  tion is directed at any pocket consistently deeper than  5 mm and typically is performed after 2 to 6 months of  nonsurgical therapy.   Dental practitioners should alert proband patients with  aggressive periodontitis of the possible genetic transmission  of the disease process. In general, patients diagnosed with  localized aggressive periodontitis typically exhibit relatively  stable disease, whereas those initially diagnosed with gener-  alized involvement often continue to lose periodontal  attachment and teeth. Patients who present for therapy with  advanced clinical attachment loss tend to demonstrate a  worse prognosis and respond less reliably to therapy.  Smoking and psychosocial stress are related to a worse prog-  nosis and are thought possibly to alter immune function  and the susceptibility to infections.    In 1924, Papillon and Lefevre initially described the syn-  drome that bears their names. This autosomal recessive    disorder predominantly demonstrates oral and dermato-  logic manifestations; similar dermatologic changes can be  seen in the absence of oral findings (Unna-Thost syn-  drome, Howell-Evans syndrome, Vohwinkel syndrome,  Gamborg Nielsen syndrome, and mal de Meleda).  Because of the autosomal recessive inheritance pattern, the  parents typically are not affected; consanguinity is noted in  approximately one-third of cases.   Genetic studies of patients with Papillon-Lefévre syn-  drome have mapped the major gene locus to chromosome  11q14-q21 and revealed mutation and loss of function of  the cathepsin C gene. This gene is important in the structural  growth and development of the skin and is critical for  appropriate immune response of myeloid and lymphoid  cells. Researchers believe that the loss of appropriate func-  tion of the cathepsin C gene results in an altered immune  response to infection. In addition, the altered gene may  affect the integrity of the junctional epithelium surrounding  the tooth.   A closely related disease, Haim-Munk syndrome, also  exhibits palmoplantar keratosis, progressive periodontal  disease, recurrent skin infections, and several skeletal mal-  formations. In this syndrome, the skin manifestations are  more severe and the periodontal disease is milder. Studies  have demonstrated that Haim-Munk syndrome and  many examples of prepubertal periodontitis also exhibit  mutation of the cathepsin C gene and represent allelic vari-  ants of the mutated gene responsible for Papillon-Lefévre  syndrome.    Papillon-Lefévre syndrome exhibits a prevalence of one to  four per million people in the population, and carriers are  thought to be present in two to four per thousand persons.  In most cases, the dermatologic manifestations become  clinically evident in the first 3 years of life. Diffuse trans-  gredient (first occurs on the palms and soles and then  spreads to the dorsa of the hands and feet) palmar-plantar  keratosis develops, with occasional reports of diffuse follicu-  lar hyperkeratosis, nail dystrophy, hyperhidrosis, and kera-  tosis on the elbows and knees (Fig. 4-37). Other less  common sites of involvement include the legs, thighs,  dorsal surface of the fingers and toes, and (rarely) the trunk.  Although the appearance of the dermatologic manifesta-  tions is variable, the lesions typically present as white, light-  yellow, brown, or red plaques and patches that develop  crusts, cracks, or deep fissures.   The oral manifestations consist of dramatically advanced  periodontitis that is seen in both the deciduous and the  permanent dentitions. Upon eruption of the deciduous  teeth, diffuse hemorrhagic and hyperplastic gingivitis devel-  ops in association with rapid loss of periodontal attachment  (Fig. 4-38). The extensive loss of osseous support often  results in teeth that radiographically appear to be floating  in soft tissue (Fig. 4-39). At 4 to 5 years of age, all primary  teeth typically have been lost or extracted. Once edentulous,  the gingiva returns to a normal state of health until eruption    ® Fig. 4-39 Papillon-Lefévre Syndrome. Multifocal sites of bone  loss in all four quadrants. (From Giansanti JS, Hrabak RP, Waldron CA:  Palmoplantar hyperkeratosis and concomitant periodontal destruction  [Papillon-Lefévre syndrome], Oral Surg Oral Med Oral Pathol 36:40,  1973.)    of the permanent dentition restarts the cycle of rapidly  progressive periodontal disease. By age 15, all of the perma-  nent teeth have been lost in most affected individuals.  Although other pathogenic bacteria have been isolated from  sites of active disease, A. actinomycetemcomitans has been  related directly to the periodontal destruction.   In addition to the dermatologic and oral manifestations,  numerous investigators have documented less frequent find-  ings. Impaired somatic development and ectopic calcifica-  tions of the falx cerebri and choroid plexus have been  reported, in addition to an increased susceptibility to infec-  tions beyond the oral cavity. Pyoderma, furunculosis, pneu-  monia, hepatic abscesses, and other infections have been  documented.    Once again, the histopathologic features of Papillon-Lefévre  syndrome are similar to those seen in chronic periodontitis  and are not specific. Submitted tissue often contains hyper-  plastic crevicular epithelium with exocytosis. The underly-  ing connective tissue exhibits increased vascularity and a  mixed inflammatory cellular infiltrate consisting predomi-  nantly of plasma cells intermixed with polymorphonuclear  leukocytes, lymphocytes, and histiocytes. Initially, histo-  pathologic examination is recommended to rule out other  pathologic causes of the periodontal destruction.    Skin lesions in these patients have been treated most success-  fully using systemic retinoids, such as etretinate, acitretin,  and isotretinoin. This approach has resulted in remarkable  improvement with complete clearance in the majority of  patients. Surprisingly, a few authors have reported improve-  ment of the associated periodontal disease during periods of  retinoid use, but others have disputed this claim. Possible  adverse reactions caused by retinoid administration include  angular cheilitis, dry lips, hair loss, arthralgia, tendinous and  ligamentous calcifications, and teratogenicity. In an attempt  to avoid these drug-related adverse reactions, patients with  mild dermatologic manifestations often are treated with  topical lubricants, keratolytic agents (salicylic or lactic acid),  corticosteroids, or antibiotics.   Attempts at resolution of the periodontal disease often  have been frustrating. In spite of extensive periodontal  therapy and antibiotic agents, in many patients the disease  progresses until all teeth are lost. However, several investiga-  tors have reported a cessation of attachment loss, and two  different treatment approaches have been used.   Despite the use of numerous antibiotic medications,  several reports document a difficulty in resolution of the  infection associated with teeth that already exhibit attach-  ment loss. Some clinicians recommend extraction of all  deciduous teeth to eliminate the periodontal pathogens and  reduce the risk of transmitting these organisms to the per-  manent dentition. Following eruption of the permanent    teeth, antibiotics are utilized in an attempt to prevent rede-  velopment of periodontitis.   The second approach revolves around a direct attack  against A. actinomycetemcomitans. Therapy with high-dose  amoxicillin and metronidazole has proven effective when  combined with extraction of severely affected teeth, high  patient compliance, and strong supportive periodontal  therapy. In clinical studies, the progression of attachment  loss of the erupted dentition and the periodontal destruc-  tion of the teeth that erupt after the initiation of therapy  were slowed dramatically. 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Gelmetti C, Nazzaro V, Cerri D, et al: Long-term preservation of  permanent teeth in a patient with Papillon-Lefévre syndrome  treated with etretinate, Pediatr Dermatol 6:222-225, 1989.   Gorlin RJ, Sedano H, Anderson VE: The syndrome of palmar-plantar  hyperkeratosis and premature destruction of the teeth: a clinical  and genetic analysis of the Papillon-Lefévre syndrome, J Pediatr  65:895—908, 1964.   Hart TC, Hart PS, Bowden DW, et al: Mutations of the cathepsin C  gene are responsible for Papillon-Lefévre syndrome, / Med Genet  36:881-887, 1999.   Hart TC, Hart PS, Michalec M, et al: Haim-Munk syndrome and  Papillon-Lefévre syndrome are allelic mutations in cathepsin C,  J Med Genet 37:88-94, 2000.   Hewitt C, McCormick D, Linden G: The role of cathepsin C in  Papillon-Lefévre syndrome, prepubertal periodontitis, and aggres-  sive periodontitis, Hum Mutat 23:222-228, 2004.    Lundgren T, Crossner C-G, Twetman S, et al: Systemic retinoid  medication and periodontal health in patients with Papillon-  Lefévre syndrome, J Clin Periodontol 23:176-179, 1996.   Nickles K, Schacher B, Schuster G, et al: Evaluation of two siblings  with Papillon-Lefévre syndrome 5 years after treatment of peri-  odontitis in primary and mixed dentition, J Periodontol 82:1536-  1547, 2011.   Noack B, Gorgens H, Hoffmann TH, et al: Novel mutations in the  cathepsin C gene in patients with pre-pubertal aggressive periodon-  titis and Papillon-Lefévre syndrome, J Dent Res 83:368-370,  2004.   Wiebe CB, Hakkinen L, Putnins EE, et al: Successful periodontal  maintenance of a case with Papillon-Lefévre syndrome: 12-year  follow-up and review of the literature, 7 Periodontol 72:824—830,  2001.    Impetigo is a superficial infection of the skin that is caused  by Staphylococcus aureus, alone or in combination with  Streptococcus pyogenes (group A, B-hemolytic). Two main  patterns are seen. Seventy percent of the cases are nonbul-  lous impetigo, which typically demonstrates a mixture of  S. aureus and S. pyogenes. Bullous impetigo is less common  and predominantly caused by S. aureus. The term impetigo  is derived from a Latin word meaning “attack” because of  its common presentation as a scabbing eruption. Intact  epithelium normally is protective against infection; there-  fore, many cases arise in damaged skin, such as preexisting  dermatitis, cuts, abrasions, or insect bites. Secondary  involvement of an area of dermatitis has been termed impe-  tiginized dermatitis. An increased prevalence is associated  with debilitating systemic conditions, such as human  immunodeficiency virus (HIV) infection, type 2 diabetes  mellitus, or dialysis.    Nonbullous impetigo (impetigo contagiosa) is the more  prevalent pattern and occurs most frequently on the legs,  with less common involvement noted on the trunk, scalp, or  face. The facial lesions usually develop around the nose and  mouth. In many patients with facial involvement, the patho-  genic bacteria are harbored in the nose and spread onto the  skin into previously damaged sites, such as scratches or abra-  sions. Often, facial lesions will have a linear pattern that  corresponds to previous fingernail scratches. The infection is  more prevalent in school-aged children but also may be seen  in adults. The peak occurrence is during the summer or early  fall in hot, moist climates. Impetigo is contagious and easily  spread in crowded or unsanitary living conditions.  Nonbullous impetigo initially appears as red macules or  papules, with the subsequent development of fragile vesi-  cles. These vesicles quickly rupture and become covered  with a thick, amber crust (Fig. 5-1). The crusts are adherent  and have been described as “cornflakes glued to the surface.”  Some cases may be confused with exfoliative cheilitis (see  page 278) or recurrent herpes simplex (see page 220). Pru-  ritus is common, and scratching often causes the lesions to  spread (Fig. 5-2). Lymphangitis, cellulitis, fever, anorexia,    and malaise are uncommon, although leukocytosis occurs  in about half of affected patients.   In an infrequent pattern of impetigo termed ecthyma,  the central area of the crust becomes necrotic and forms a  deep indurated ulceration. This lesion heals slowly and  often is associated with a permanent scar.   Due to its strong association with S. aureus, bullous  impetigo also has been termed staphylococcal impetigo.  Like the nonbullous form, it most frequently affects the  extremities, trunk, and face. Infants and newborns are  infected most commonly, but the disease also may occur in  children and adults. The lesions are characterized by super-  ficial vesicles that rapidly enlarge to form larger flaccid  bullae. Initially, the bullae are filled with clear serous fluid,  but the contents of the bullae quickly become more turbid  and eventually purulent. Although the bullae may remain  intact, they usually rupture and develop a thin brown crust  that some describe as “lacquer.” Weakness, fever, and diar-  thea may be seen. Lymphadenopathy and cellulitis are  unusual complications. Meningitis and pneumonia are very  rare but may lead to serious complications, even death.    A strong presumptive diagnosis normally can be made  from the clinical presentation. When the diagnosis is not  obvious clinically or the infection fails to respond to  standard therapy within 7 days, the definitive diagnosis  requires isolation of S. aureus or S. pyogenes from cultures  of involved skin.    For patients with nonbullous impetigo involving only  a small area with few lesions, topical mupirocin or fusidic  acid (available in Canada and Europe, not in the United  States) has been shown to be effective. Although uncommon,  increasing reports of resistance to these medications are  appearing, especially in infections associated with methicillin-  resistant S. aureus (MRSA). In such cases, utilization of  topical retapamulin has been proven effective in many  patients. Removal of the crusts with a clean cloth soaked in  warm soapy water is recommended before application of  topical therapy, rather than placing the medication on inert,    ® Fig. 5-1 Impetigo. Amber crusts of the skin and vermilion border  of the lips.    @ Fig. 5-2 Impetigo. Scaly and amber-colored crusts of the perioral  skin.    dried, exfoliating skin. For bullous or more extensive lesions,  topical antibiotic drugs often are insufficient; the treatment  of choice is a 1-week course of a systemic oral antibiotic. The  best antibiotic is one that is effective against both S. pyogenes  and penicillin-resistant S. aureus. Cephalexin, dicloxacillin,  flucloxacillin, and amoxicillin-clavulanic acid represent good  current choices. In communities frequented with MRSA,  therapy with agents such as trimethoprim/sulfamethoxazole,  clindamycin, tetracycline, or fluoroquinolones is recom-  mended. If left untreated, then the lesions often enlarge  slowly and spread. Serious complications, such as acute glo-  merulonephritis, are rare but possible in prolonged cases.  Inappropriate diagnosis and treatment with topical cortico-  steroids may produce resolution of the surface crusts, but  infectious, red, raw lesions remain.    Erysipelas is a superficial skin infection most commonly  associated with B-hemolytic streptococci (usually group A,  such as S. pyogenes, but occasionally other groups, such as  group C, B, or G). Other organisms, such as Staphylococcus  aureus, have been isolated from the lesions, but it is unclear  if these bacteria are causative or a contaminant. The    infection rapidly spreads through the lymphatic channels,  which become filled with fibrin, leukocytes, and strepto-  cocci. Although also associated with ergotism, the term  Saint Anthonys fire has been used to describe erysipelas.  Because the French House of St. Anthony, an eleventh-  century hospital, had fiery red walls similar to the color of  erysipelas, the term Saint Anthonys fire was used to describe  this disease. Today, classical facial erysipelas is a rare and  often forgotten diagnosis. At times, the appropriate diagno-  sis has been delayed because of confusion with facial cel-  lulitis from dental infections.    Erysipelas tends to occur primarily in young and older adult  patients or in those who are debilitated, diabetic, immuno-  suppressed, obese, or alcoholic. Patients who have areas of  chronic lymphedema or large surgical scars (such as, post-  mastectomy or saphenous venectomy) also are susceptible  to this disease. The infection may occur anywhere on the  skin, especially in areas of previous trauma. The most com-  monly affected site is the leg in areas affected by tinea pedis  (athlete's foot). The face, arm, and upper thigh also fre-  quently are infected. In facial erysipelas, an increased preva-  lence is noted in the winter and spring months, whereas  summer is the peak period of involvement of the lower  extremities.   When lesions occur on the face, they normally appear  on the cheeks, eyelids, and bridge of the nose, at times  producing a butterfly-shaped lesion that may resemble lupus  erythematosus (see page 740). If the eyelids are involved,  then they may become edematous and shut, thereby resem-  bling angioedema (see page 326). The affected area is painful,  bright red, well-circumscribed, swollen, indurated, and  warm to the touch (Fig. 5-3). Often the affected skin will  demonstrate a surface texture that resembles an orange peel  (peau d orange). High fever and lymphadenopathy often are  present. Lymphangitis, leukocytosis, nausea, and vomiting  occur infrequently. Diagnostic confirmation is difficult  because cultures usually are not beneficial.    The treatment of choice is penicillin. Alternative antibiotic  drugs include macrolides (such as, erythromycin), cephalo-  sporins (such as, cephalexin), and fluoroquinolones (such  as, ciprofloxacin). On initiation of therapy, the area of skin  involvement often enlarges, probably secondary to the  release of toxins from the dying streptococci. A rapid resolu-  tion is noted within 48 hours. Without appropriate therapy,  possible complications include abscess formation, gangrene,  necrotizing fasciitis, toxic shock syndrome with possible  multiple organ failure, thrombophlebitis, acute glomerulo-  nephritis, septicemia, endocarditis, and death. Recurrences  may develop in the same area, most likely in a previous  zone of damaged lymphatics or untreated athlete’s foot.  With repeated recurrences, permanent and disfiguring    @ Fig. 5-3 Erysipelas. Red, swollen area of the left cheek. (Courtesy  of Dr. Arthur Gonty.)    enlargements may result. In cases with multiple recurrences,  prophylaxis with oral penicillin has been used.    Tonsillitis and pharyngitis are extremely common and  may be caused by many different organisms. The most  common causes are group A, B-hemolytic streptococci,  adenoviruses, enteroviruses, influenza, parainfluenza, and  Epstein-Barr virus. Although a virus causes the majority of  pharyngitis cases, infection with group A streptococci is  responsible for 20% to 30% of acute pharyngitis cases in  children and 5% to 15% of cases in adults. Spread is typi-  cally by person-to-person contact through respiratory drop-  lets or oral secretions, with a short incubation period of 2  to 5 days.    Although the infection can occur at any age, the greatest  prevalence occurs in children 5 to 15 years old, with most  cases in temperate climates arising in the winter or early  spring. The signs and symptoms of tonsillitis and pharyn-  gitis vary from mild to intense. Common findings include  sudden onset of sore throat, temperature of 101° to 104° F,  dysphagia, tonsillar hyperplasia, redness of the oropharynx  and tonsils, palatal petechiae, cervical lymphadenopathy,    @ Fig. 5-4 Tonsillitis. A, Hyperplastic pharyngeal tonsils with yellow-  ish exudate of crypts. B, Same patient following successful therapy  with amoxicillin/clavulanic acid. (Courtesy of Dr. Molly Housley.)    and a yellowish tonsillar exudate that may be patchy or  confluent (Fig. 5-4). Other occasional findings include a  “beefy” red and swollen uvula, excoriated nares, and a scar-  latiniform rash (see next topic). Systemic symptoms, such  as headache, malaise, anorexia, abdominal pain, and vomit-  ing, may be noted, especially in younger children. Conjunc-  tivitis, coryza (rhinorrhea), cough, hoarseness, discrete  ulcerative lesions, anterior stomatitis, absence of fever, a  viral exanthem, and diarrhea typically are associated with  the viral infections and normally are not present in strepto-  coccal pharyngotonsillitis.    Although the vast majority of pharyngitis cases are caused  by a viral infection, reviews have shown that about 70% of  adults in the United States receive antibiotic therapy. In an  attempt to minimize overuse, antibiotics should not be  prescribed without confirmation of bacterial infection.  Except for very rare infections, such as Corynebacterium  diphtheriae (see page 168) and Neisseria gonorrhoeae (see  page 174), antibiotics are of no benefit for acute pharyngitis  except for those related to group A streptococci.   Patients exhibiting features strongly suggestive of a viral  infection (see previous section) should not receive antibiotic    therapy or microbiologic testing for streptococcal infection.  Because the clinical features of streptococcal pharyngitis  overlap those of viral origin, the diagnosis cannot be based  solely on clinical features; however, laboratory testing of all  patients with sore throat cannot be justified. Diagnostic  testing is recommended only for those patients with clinical  and epidemiologic findings that suggest streptococcal infec-  tion or for those in close contact with a well-documented  case. Although less sensitive than throat culture, rapid  antigen detection testing provides quick results and exhibits  good sensitivity and specificity. If negative results are  obtained in children, then confirmatory throat cultures    Streptococcal pharyngitis usually is self-limited and resolves  spontaneously within 3 to 4 days after onset of symptoms.  In addition to reducing the localized morbidity of the infec-  tion, including the possibility of peritonsillar abscess forma-  tion, the main goal of therapy is to prevent development of  systemic complications, such as acute rheumatic fever and  acute glomerulonephritis. Initiation of appropriate therapy  within the first 9 days after development of the pharyngitis  prevents rheumatic fever. Patients are considered nonconta-  gious 24 hours after initiation of appropriate antibiotic  therapy.   The oral antibiotic of choice for group A streptococci is  either penicillin V or amoxicillin. Other choices for  penicillin-allergic patients include azithromycin, clindamy-  cin, cephalosporins (such as, cefadroxil or cephalexin), and  macrolides (such as, erythromycin or clarithromycin).    Scarlet fever is a systemic infection produced by group A,  B-hemolytic streptococci. The disease begins as a streptococ-  cal tonsillitis with pharyngitis in which the organisms elabo-  rate an erythrogenic toxin that attacks the blood vessels and  produces the characteristic skin rash. The condition occurs  in susceptible patients who do not have antitoxin antibod-  ies. The incubation period ranges from 1 to 7 days, and the  significant clinical findings include fever, enanthem, and  exanthem.    Scarlet fever is most common in children from the ages of  3 to 12 years. The enanthem of the oral mucosa involves  the tonsils, pharynx, soft palate, and tongue (see discussion  of streptococcal pharyngotonsillitis in previous section). The  tonsils, soft palate, and pharynx become erythematous and  edematous, and the tonsillar crypts may be filled with a  yellowish exudate. In severe cases, the exudates may become  confluent and can resemble diphtheria (see page 168).  Scattered petechiae may be seen on the soft palate in up  to 10% of affected patients. During the first 2 days, the    @ Fig. 5-5 Scarlet Fever. Dorsal surface of the tongue exhibiting  white coating in association with numerous enlarged and erythema-  tous fungiform papillae (white strawberry tongue).    dorsal surface of the tongue demonstrates a white coating  through which only the fungiform papillae can be seen; this  has been called white strawberry tongue (Fig. 5-5). By the  fourth or fifth day, red strawberry tongue develops when  the white coating desquamates to reveal an erythematous  dorsal surface with hyperplastic fungiform papillae.   Classically, in untreated cases, fever develops abruptly  around the second day. The patient’s temperature peaks at  approximately 103° F and returns to normal within 6 days.  Abdominal pain, headache, malaise, nausea, and vomiting  frequently are present. The exanthematous rash develops  within the first 2 days and becomes widespread within 24  hours. The classic rash of scarlet fever is distinctive and often  is described as a “sunburn with goose pimples.” Pinhead  punctate areas that are normal in color project through the  erythema, giving the skin of the trunk and extremities a  sandpaper texture. The rash is more intense in areas of pres-  sure and skin folds. Often, transverse red streaks, known as  Pastia lines, occur in the skin folds secondary to the capil-  lary fragility in these zones of stress. In contrast, the skin of  the face usually is spared or may demonstrate erythematous  cheeks with circumoral pallor.   The rash usually clears within 1 week, and then a period  of desquamation of the skin occurs. This scaling begins on  the face at the end of the first week and spreads to the rest  of the skin by the third week, with the extremities being the  last affected. The desquamation of the face produces small  flakes; the skin of the trunk comes off in thicker, larger  flakes. This period of desquamation may last from 3 to 8  weeks.    Throat culture is the standard for the diagnosis of strepto-  coccal pharyngitis and scarlet fever. Although less sensitive  than throat culture, rapid antigen detection testing provides  quick results and exhibits good sensitivity and specificity. If  negative results are obtained in children, then confirmatory  throat cultures should be performed.    Treatment of scarlet fever and the associated streptococcal  pharyngitis is necessary to prevent the possibility of com-  plications, such as peritonsillar or retropharyngeal abscess,  sinusitis, or pneumonia. Late complications are rare and  include otitis media, acute rheumatic fever, glomerulone-  phritis, arthralgia, meningitis, and hepatitis. The oral anti-  biotic of choice for group A streptococci is either penicillin  V or amoxicillin. Other choices for penicillin-allergic  patients include azithromycin, clindamycin, cephalosporins  (such as, cefadroxil or cephalexin), and macrolides (such as,  erythromycin or clarithromycin). Ibuprofen can be used to  reduce the fever and relieve the associated discomfort. The  fever and symptoms show dramatic improvement within 48  hours after the initiation of treatment. With appropriate  therapy, the prognosis is excellent.    Anatomically, the pharyngeal tonsils demonstrate numerous  deep, twisted, and epithelial-lined invaginations. The tonsil-  lar crypts function to increase the surface area for interac-  tion between the immune cells within the lymphoid tissue  and the oral environment. These convoluted crypts com-  monly are filled with desquamated keratin and foreign  material with secondary bacterial colonization. The con-  tents of the invaginations often become compacted and  form a mass of foul-smelling material known as a tonsillar  concretion. Occasionally, the condensed necrotic debris  and bacteria undergo dystrophic calcification and form a  tonsillolith. These structures have been shown to contain  a living biofilm of densely packed bacteria demonstrating a  diversity of rods, cocci, and filamentous organisms embed-  ded within an extracellular matrix.    Tonsillar concretions and tonsilloliths are not uncommon.  The affected tonsil demonstrates one or more enlarged crypts  filled with yellow debris that varies in consistency from soft  to friable to fully calcified. In contrast to acute tonsillitis, the  surrounding tonsillar tissue is not acutely painful, dramati-  cally inflamed, or significantly edematous. Tonsilloliths can  develop over a wide age range, from childhood to old age,  with a mean patient age in the early 40s. Men are affected  twice as frequently as women. These calcifications vary from  small clinically insignificant lesions to massive calcifications  more than 14 cm in length. Tonsilloliths may be single or  multiple, and bilateral cases have been reported.   Although many tonsillar concretions and tonsilloliths are  asymptomatic, these calcifications can promote recurrent  tonsillar infections and may lead to pain, abscess formation,  ulceration, dysphagia, chronic sore throat, irritable cough,  or otalgia. Halitosis is a common complaint and    not surprising because several of the bacteria within the  associated biofilm are known to produce hydrogen sulfide  and methyl mercaptan, both of which are associated strongly  with oral malodor. Occasionally, patients report a dull ache  ora sensation of a foreign object in the throat that is relieved  on removal of the tonsillar plug. In patients with large  stones, clinical examination often reveals a hard, yellow  submucosal mass of the affected tonsil. In older adult  patients, large tonsilloliths can be aspirated and produce  significant pulmonary complications. Most frequently, ton-  silloliths are discovered on panoramic radiographs as radi-  opaque objects superimposed on the midportion of the  mandibular ramus (Fig. 5-6).    A strong presumptive diagnosis can be made through a  combination of the clinical and radiographic features. After  detection on a panoramic radiograph, if further diagnostic  confirmation of tonsilloliths is deemed necessary, then their  presence can be confirmed with computed tomography  (CT), magnetic resonance imaging (MRI), or the demon-  stration of the calculi on removal of the affected tonsil.    Tonsilloliths discovered incidentally during evaluation of a  panoramic radiograph often are not treated unless associ-  ated with significant tonsillar hyperplasia or clinical symp-  toms. Affected individuals occasionally try to remove  tonsillar concretions with instruments, such as straws,  toothpicks, and dental instruments. Such therapy has the  potential to damage the surrounding tonsillar tissue and  should be discouraged. Patients should be educated to  attempt removal by gargling warm salt water or using pul-  sating jets of water.   Superficial calculi can be enucleated or curetted; deeper  tonsilloliths require local excision. Redevelopment of  removed concretions is common. Laser or Coblation cryp-  tolysis has been utilized successfully to reduce the extent of  the tonsillar invaginations and stop the redevelopment of  the concretions. If evidence of associated chronic tonsillitis  is seen, then tonsillectomy provides definitive therapy.    Diphtheria is a life-threatening infection most commonly  produced by Corynebacterium diphtheriae. C. ulcerans and  C. pseudotuberculosis are less common causes and usually  discovered in individuals exhibiting contact with farm  animals or dairy products. The disease initially was described  in 1826, and C. diphtheriae (also termed Klebs-Léffler bacil-  lus) was discovered by Klebs in 1883 and isolated in pure  culture by Léffler in 1884. Humans are the sole reservoir,  and the infection is acquired through contact with an  infected person or carrier. The bacterium produces a lethal  exotoxin that causes tissue necrosis, thereby providing    ® Fig. 5-6 Tonsilloliths. Cluster of radiopacities noted bilaterally in the midportion of the ascending  ramus. (Courtesy of Dr. Kim Nichols.)    nutrients for further growth and leading to peripheral  spread. The first effective antitoxin was discovered by the  German physician, Emil von Behring, who was awarded the  first Nobel Prize in medicine for this work. The antitoxin  has been available since 1913, and immunization has been  widespread in North America since 1922.   Widespread vaccination led to a dramatically decreased  prevalence of the infection until the 1990s when collapse  of the Soviet Union produced inconsistent vaccination and  localized outbreaks. The epidemic began in Moscow and  spread to involve all of the newly independent states of the  former Soviet Union. During this outbreak, more than  150,000 cases were reported with approximately 4500  deaths. The process finally was controlled by administration  of vaccine to all children, adolescents, and adults (regardless  of immunization histories).   In addition to this epidemic, infections may occur in  people who are immunosuppressed or who have failed to  receive booster injections as required. Isolated outbreaks still  are reported in the urban poor and Native American popu-  lations of North America. Occasional reports from indus-  trialized nations continue to document individuals who  have returned home after contracting the infection while  visiting a developing country.    The signs and symptoms of diphtheria arise 1 to 5 days after  exposure to the organism. The initial systemic symptoms,  which include low-grade fever, headache, malaise, anorexia,  sore throat, and vomiting, arise gradually and may be mild.  Although skin wounds may be involved, the infection pre-  dominantly affects mucosal surfaces and may produce exu-  dates of the nasal, tonsillar, pharyngeal, laryngotracheal,  conjunctival, or genital areas. Involvement of the nasal    cavity often is accompanied with prolonged mucoid or  hemorrhagic discharge. The oropharyngeal exudate begins  on one or both tonsils as a patchy, yellow-white, thin film  that thickens to form an adherent gray covering. With time,  the membrane may develop patches of green or black necro-  sis. The superficial epithelium is an integral portion of this  exudate, and attempts at removal are difficult and may  result in bleeding. The covering may continue to involve  the entire soft palate, uvula, larynx, or trachea, resulting in  stridor and respiratory difficulties. Palatal perforation has  rarely been reported. Rarely, the lesions have been isolated  to the oral cavity.   The severity of the infection correlates with the spread  of the membrane. Local obstruction of the airway can be  lethal. Involvement of the tonsils leads to significant cervical  lymphadenopathy, which often is associated with an edema-  tous neck enlargement known as bull neck. Toxin-related  paralysis may affect oculomotor, facial, pharyngeal, dia-  phragmatic, and intercostal muscles. The soft palatal paraly-  sis can lead to nasal regurgitation during swallowing. Oral  or nasal involvement has been reported to spread to the  adjacent skin of the face and lips.   Cutaneous diphtheria can occur anywhere on the body  and is characterized by chronic skin ulcers that frequently are  associated with infected insect bites and also may harbor  other pathogens, such as S. aureus or S. pyogenes. These skin  lesions can arise even in vaccinated patients and typically are  not associated with systemic toxic manifestations. When  contracted by travelers from developed nations, the diagno-  sis often is delayed because of the nonspecific clinical presen-  tation and a low index of suspicion. The cutaneous lesions  represent an important reservoir of infection and can lead to  more typical and lethal diphtheria in unprotected contacts.   Although bacteremia is rare, circulating toxin can result  in systemic complications, such as myocarditis, neuropathy,    thrombocytopenia, proteinuria, and renal failure. Myocar-  ditis and neurologic difficulties are seen most frequently and  usually are discovered in patients with severe nasopharyn-  geal diphtheria. Myocarditis may exhibit as progressive  weakness and dyspnea or lead to acute congestive heart  failure. Neuropathy is not uncommon in patients with  severe diphtheria, and palatal paralysis is the most com-  monly seen manifestation. A peripheral polyneuritis resem-  bling Guillain-Barré syndrome also may occur.    Although the clinical presentation can be distinctive in  severe cases, laboratory confirmation should be sought in all  instances. Although culture remains the diagnostic gold  standard, a polymerase chain reaction (PCR) analysis has  become available and has reduced the time required to  confirm the diagnosis. Except in the midst of an epidemic,  the diagnosis can be difficult due to the rarity of the infection  and the inexperience of many physicians with the disease.    Treatment of the patient with diphtheria should be initiated  at the time of the clinical diagnosis and should not be  delayed until the results of the culture are received. Anti-  toxin should be administered in combination with antibiot-  ics to prevent further toxin production, to stop the local  infection, and to prevent transmission. Erythromycin, pro-  caine penicillin, or intravenous (IV) penicillin may be used.  Most patients are no longer infectious after 4 days of anti-  biotic therapy, but some may retain vital organisms. The  patient is not considered to be cured until three consecutive  negative culture specimens are obtained.   Because the antitoxin neutralizes only circulating toxin  that is not bound to tissue, prompt administration is criti-  cal. This factor stresses the need for maintaining local stocks  that have not reached their expiration date.   Before the development of the antitoxin, the mortality  rate approached 50%, usually from cardiac or neurologic  complications. The current mortality rate is less than 5%,  but the outcome is unpredictable. Development of myocar-  ditis is an important predictor of mortality.   Deaths still occur in the United States because of delays  in therapy secondary to lack of suspicion. With worldwide  travel and visitors from across the globe, prevention is para-  mount. Even in those vaccinated as children, it must be  remembered that a booster inoculation is required every 10  years. Currently, the inoculation has been combined into  the 7dap vaccine that includes tetanus, diphtheria, and  pertussis.    Syphilis is a worldwide chronic infection produced by  Treponema pallidum. The organism is extremely vulnerable  to drying; therefore, the primary modes of transmission are    sexual contact or from mother to fetus. Humans are the  only proven natural host for syphilis.   After the advent of penicillin therapy in the 1940s, the  prevalence of syphilis slowly decreased for many years but  often demonstrated peaks and troughs associated with  sexual activity during that era. A peak occurred during the  “sexual revolution” of the 1960s, but fear of acquired immu-  nodeficiency syndrome (AIDS) in 2000 led to the fewest  reported cases of primary and secondary syphilis since  reporting began in 1941. As more effective therapy for  AIDS has been developed, sexual activity has changed once  again with an increasing prevalence of sexually transmitted  diseases being reported, primarily as a result of increases  among men who have sex with men (MSM).   Oral sex is thought to have played an increasingly impor-  tant contribution to the recent surge in a number of sexually  transmitted diseases in MSM. Because the risk of HIV  transmission through oral sex is lower than the rate associ-  ated with vaginal or anal sex, many falsely believed that  unprotected oral sex was a safe or no-risk sexual practice  and represented a good replacement for other higher-risk  behaviors.   In patients with syphilis, the infection undergoes a char-  acteristic evolution that classically proceeds through three  stages. A syphilitic patient is highly infectious only during  the first two stages, but pregnant women also may transmit  the infection to the fetus during the latent stage. Maternal  transmission during the first two stages of infection almost  always results in miscarriage, stillbirth, or an infant with  congenital malformations. The longer the mother has had  the infection, the less the chance of fetal infection. Infection  of the fetus may occur at any time during pregnancy, but  the stigmata do not begin to develop until after the fourth  month of gestation. The clinical changes secondary to the  fetal infection are known as congenital syphilis. Oral syph-  ilitic lesions are uncommon but may occur in any stage.  Due to the rarity of oral lesions and the nonspecific micro-  scopic pattern, appropriate histopathologic diagnosis easily  can be missed by pathologists inexperienced with the  pathosis.   Primary syphilis is characterized by the chancre that devel-  ops at the site of inoculation, becoming clinically evident 3  to 90 days after the initial exposure. Most chancres are soli-  tary and begin as papular lesions that develop a central  ulceration. Approximately 85% arise in the genital areas,  whereas 10% are anal, 4% are oral, and the remaining 1%  is discovered in other extragenital locations. Oral lesions are  seen most commonly on the lip, but other sites include the  buccal mucosa, tongue, palate, gingiva, and tonsils (Fig.  5-7). The upper lip is affected more frequently in males,  whereas lower lip involvement is predominant in females.  Some believe this selective labial distribution may reflect the  surfaces most actively involved during fellatio and cunnilin-  gus. The oral lesion appears as a painless, clean-based    @ Fig. 5-7 Chancre of Primary Syphilis. Erythematous and ulcer-  ated mass of the right anterior buccal mucosa. (Courtesy of Dr. Ben-  jamin Martinez.)    ulceration or, rarely, as a vascular proliferation resembling a  pyogenic granuloma. Regional lymphadenopathy, which  may be bilateral, is seen in most patients. At this time, the  organism is spreading systemically through the lymphatic  channels, setting the stage for future progression. If  untreated, then the initial lesion heals within 3 to 8 weeks.    ‘The next stage is known as secondary (disseminated) syphilis  and is discovered clinically 4 to 10 weeks after the initial  infection. The lesions of secondary syphilis may arise before  the primary lesion has resolved completely. During second-  ary syphilis, systemic symptoms often arise. The most  common are painless lymphadenopathy, sore throat, malaise,  headache, weight loss, fever, and musculoskeletal pain. A  consistent sign is a diffuse, painless, maculopapular cutane-  ous rash, which is widespread and can even affect the palmar  and plantar areas. The rash also may involve the oral cavity  and appear as red, maculopapular areas. Although the skin  rash may result in areas of scarring and hyperpigmentation  or hypopigmentation, it heals without scarring in the vast  majority of patients.   In addition, roughly 30% of patients have focal areas of  intense exocytosis and spongiosis of the oral mucosa, leading  to zones of sensitive whitish mucosa known as mucous  patches (Figs. 5-8 and 5-9). Occasionally, several adjacent  patches can fuse and form a serpentine or snail-track pattern.  Subsequently, superficial epithelial necrosis may occur,  leading to sloughing and exposure of the underlying raw  connective tissue. These may appear on any mucosal surface  but are found commonly on the tongue, lip, buccal mucosa,  and palate. Elevated mucous patches also may be centered  over the crease of the oral commissure and have been termed  split papules. Occasionally, papillary lesions that may  resemble viral papillomas arise during this time and are  known as condylomata lata. Although these lesions typi-  cally occur in the genital or anal regions, rare oral examples  occur (Fig. 5-10). In contrast to the isolated chancre noted    @ Fig. 5-8 Mucous Patch of Secondary Syphilis. Circumscribed  white plaque on the lower labial mucosa. (Courtesy of Dr. Pete  Edmonds.)    ° Fig. 5-9 Mucous Patch of Secondary Syphilis. Irregular thick-  ened white plaque of the right soft palate.    @ Fig. 5-10 Condyloma Lata. Multiple indurated and slightly papil-  lary nodules on the dorsal tongue. (Courtesy of Dr. Karen Novak.)    in the primary stage, multiple lesions are typical of second-  ary syphilis. Spontaneous resolution usually occurs within  3 to 12 weeks; however, relapses may occur during the  next year.   After the second stage, patients enter a period in which they  are free of lesions and symptoms, known as latent syphilis.  This period of latency may last from 1 to 30 years; then the  third stage known as tertiary syphilis develops in approxi-  mately 30% of affected individuals. This stage includes the  most serious of all complications. The vascular system can  be affected significantly through the effects of the earlier  arteritis. Aneurysm of the ascending aorta, left ventricular  hypertrophy, aortic regurgitation, and congestive heart  failure may occur. Involvement of the central nervous  system (CNS) may result in tabes dorsalis, general paralysis,  psychosis, dementia, paresis, and death. Ocular lesions such  as iritis, choroidoretinitis, and Argyll Robertson pupil may  occur. Argyll Robertson pupils constrict upon focusing, but  they fail to respond to bright light (nicknamed “prostitute’s  pupil” because they accommodate but do not react). Less  significant, but more characteristic, are scattered foci of  granulomatous inflammation, which may affect the skin,  mucosa, soft tissue, bones, and internal organs. This active  site of granulomatous inflammation, known as a gumma,  appears as an indurated, nodular, or ulcerated lesion that  may produce extensive tissue destruction. Intraoral lesions  usually affect the palate or tongue. When the palate is  involved, the ulceration frequently perforates through to the  nasal cavity (Fig. 5-11). The tongue may be involved dif-  fusely with gummata and appear large, lobulated, and irreg-  ularly shaped. This lobulated pattern is termed interstitial  glossitis and is thought to be the result of contracture of  the lingual musculature after healing of gummas. Diffuse  atrophy and loss of the dorsal tongue papillae produce a  condition called luetic glossitis. In the past, this form of  atrophic glossitis was thought to be precancerous, but  several more recent publications dispute this concept.    ® Fig. 5-11 Tertiary Syphilis. Perforation of the hard palate. (Cour-  tesy of Dr. George Blozis.)    In 1858, Sir Jonathan Hutchinson described the changes  found in congenital syphilis and defined the following three  pathognomonic diagnostic features, known as Hutchinson  triad:   Like many diagnostic triads, few patients exhibit all three  features. In addition to Hutchinson triad, a number of other  alterations may be seen, such as saddle-nose deformity,  high-arched palate, frontal bossing, hydrocephalus, intel-  lectual disability, gummas, and neurosyphilis. Table 5-1  delineates the prevalence rates of the stigmata of congenital  syphilis in a cohort of affected patients.   Infants infected with syphilis can display signs within 2  to 3 weeks of birth. These early findings include growth  impairment, fever, jaundice, anemia, hepatosplenomegaly,  rhinitis, rhagades (circumoral radial skin fissures), and des-  quamative maculopapular, ulcerative, or vesiculobullous  skin eruptions. Untreated infants who survive often develop  tertiary syphilis with damage to the bones, teeth, eyes, ears,    Modified from Fiumara NJ, Lessel S: Manifestations of late congenital  syphilis: an analysis of 271 patients, Arch Dermatol 102:78-83, 1970.  *In a cohort of 271 patients    and brain. It is these findings that were described well by  Hutchinson.   The infection alters the formation of both the anterior  teeth (Hutchinson incisors) and the posterior dentition  (mulberry molars, Fournier molars, Moon molars).  Hutchinson incisors exhibit their greatest mesiodistal width  in the middle third of the crown. The incisal third tapers to  the incisal edge, and the resulting tooth resembles a straight-  edge screwdriver (Fig. 5-12). The incisal edge often exhibits  a central hypoplastic notch. Mulberry molars taper toward  the occlusal surface with a constricted grinding surface. The  occlusal anatomy is abnormal, with numerous disorganized  globular projections that resemble the surface of a mulberry  (Fig. 5-13).   Worldwide, the prevalence of congenital syphilis has  increased fourfold to fivefold over the last 10 years. The  World Health Organization (WHO) has stated that the  number of congenital syphilis cases worldwide now equals  the prevalence of neonatal AIDS, but this problem has  received very little attention globally.    @ Fig. 5-12 Hutchinson Incisors of Congenital Syphilis. Dentition  exhibiting crowns tapering toward the incisal edges. (From Halstead  CL, Blozis GG, Drinnan Au, et al: Physical evaluation of the dental  patient, St Louis, 1982, Mosby.)    @ Fig. 5-13 Mulberry Molar of Congenital Syphilis. Maxillary  molar demonstrating occlusal surface with numerous globular  projections.    The histopathologic picture of the oral lesions in the syphi-  litic patient is not specific. During the first two stages, the  pattern is similar. The surface epithelium is ulcerated in  primary lesions and may be ulcerated or hyperplastic in the  secondary stage. Extensive exocytosis typically is noted and  represents a major clue to the diagnosis (Fig. 5-14). The  underlying lamina propria exhibits an intense chronic  inflammatory cellular infiltrate composed predominantly of  lymphocytes and plasma cells, which is noted primarily in    @ Fig. 5-14 Secondary Syphilis, Condyloma Lata. A, Low-power  photomicrograph of biopsy from patient in Fig. 5-10, which shows  papillary epithelial hyperplasia and a heavy plasmacytic infiltrate in  the connective tissue. B, High-power view showing intense exocy-  tosis of neutrophils into the epithelium. C, Immunoperoxidase reaction  for Treponema pallidum demonstrating numerous spirochetes in the  epithelium.    @ Fig. 5-15 Primary Syphilis. A chronic perivascular inflammatory  infiltrate of plasma cells and lymphocytes. (Courtesy of Dr. John  Metcalf.)    the superficial stroma and around deeper vascular channels  (Fig. 5-15). Although the presence of plasma cells is com-  monplace within ulcerations and areas of oral mucositis, the  combination of heavy exocytosis and an underlying dense  lymphoplasmacytic infiltrate often raises the index of sus-  picion to a level that supports search for the organism. The  use of special silver impregnation techniques, such as  Warthin-Starry or Steiner stains, or immunoperoxidase  reactions directed against the organism often show scattered  corkscrew-like spirochetal organisms that frequently are  found most easily within the surface epithelium and at the  interface between the epithelium and the superficial stroma  (see Fig. 5-14, C). The organism also can be detected in  tissue through direct fluorescent antibody or nucleic acid  amplification testing.   Oral tertiary lesions typically exhibit surface ulceration,  with peripheral pseudoepitheliomatous hyperplasia. The  underlying inflammatory infiltrate usually demonstrates  foci of granulomatous inflammation with well-circumscribed  collections of histiocytes and multinucleated giant cells.  Even with special stains, the organisms are hard to demon-  strate in the third stage; researchers believe the inflamma-  tory response is an immune reaction, rather than a direct  response to T’ pallidum.    The diagnosis of syphilis can be confirmed by demonstrat-  ing the spiral organism by biopsy or dark-field examination  of a smear of an active lesion. False-positive results in  smears are possible in the oral cavity because of morpho-  logically similar oral inhabitants, such as Treponema micro-  dentium, T. macrodentium, and T! mucosum. Demonstration  of the organism on a smear or in biopsy material should  be confirmed through the use of specific immunofluores-  cent antibodies, nucleic acid amplification testing, or sero-  logic evaluation.   Several nonspecific and not highly sensitive serologic  screening tests for syphilis are available. These include the    Venereal Disease Research Laboratory (VDRL) and the  rapid plasma reagin (RPR). After the first 3 weeks of infec-  tion, the screening tests are strongly positive throughout the  first two stages. After the development of latency, the posi-  tivity generally subsides with time. As part of appropriate  prenatal care, all pregnant women should receive one of the  nonspecific screening tests. Because these tests typically are  negative in the early primary stage and also may be falsely  negative in immunosuppressed patients (such as, AIDS),  tissue identification of the organism is critical in many  patients.   Specific and highly sensitive serologic tests for syphilis  also are available. These include the fluorescent treponemal  antibody absorption (FTA-ABS), 7° pallidum hemaggluti-  nation assay (TPHA), 7 pallidum particle agglutination  assay (TPPA), and microhemagglutination assay for anti-  body to 7 pallidum (MHA-TP). These test results remain  positive for life. This lifelong persistence of positivity limits  their usefulness in the diagnosis of a second incidence of  infection. Therefore, in cases of possible reinfection, the  organisms should be demonstrated within the tissue or  exudates.    The treatment for syphilis necessitates an individual evalu-  ation and a customized therapeutic approach. The treat-  ment of choice is penicillin. The dose and administration  schedules vary according to the stage, neurologic involve-  ment, and immune status. For primary, secondary, or early  latent syphilis, a single dose of parenteral long-acting ben-  zathine penicillin G is given. For late latent or tertiary  syphilis, intramuscular penicillin is administered weekly  for 3 weeks. For the patient with a true penicillin allergy,  doxycycline is second-line therapy, although tetracycline,  erythromycin, and ceftriaxone also have demonstrated anti-  treponemal activity.   Even in patients who obtain a clinical and serologic  “cure” with penicillin, it must be remembered that 7) pal-  lidum can escape the lethal effects of the antibiotic when  the organism is located within the confines of lymph nodes  or the CNS. Therefore, antibiotic therapy may not always  result in a total cure in patients with neurologic involve-  ment but may arrest only the clinical presentations of the  infection. Patients with immunosuppression, such as those  with AIDS, may not respond appropriately to standard  antibiotic regimens, and numerous reports have docu-  mented a continuation to neurosyphilis despite seemingly  appropriate single-dose therapy.    Gonorrhea, a sexually transmitted disease that is produced  by Neisseria gonorrhoeae, represents the most common  reportable bacterial infection in the United States with  an estimated 700,000 to 800,000 persons infected each  year. The disease is epidemic, especially in urban areas;    worldwide, millions of people are infected each year. The  rate in the United States remains the highest of any indus-  trialized country, and certain segments of the population,  such as those with a low socioeconomic or education level,  injecting drug users, prostitutes, homosexual men, and  military personnel, remain at high risk. In contrast to many  other sexually transmitted diseases, women are affected  slightly more frequently than men.    The infection is spread through sexual contact, and most  lesions occur in the genital areas. Indirect infection is rare  because the organism is sensitive to drying and cannot  penetrate intact stratified squamous epithelium. The incu-  bation period is typically 2 to 5 days. Affected areas often  demonstrate significant purulent discharge, but approxi-  mately 10% of men and up to 80% of women who contract  gonorrhea are asymptomatic.   In men, the most frequent site of infection is the urethra,  resulting in purulent discharge and dysuria. Less common  primary sites include the anorectal and pharyngeal areas.  The cervix is the primary site of involvement in women,  and the chief complaints are increased vaginal discharge,  intermenstrual bleeding, genital itching, and dysuria. The  organism may ascend to involve the uterus and ovarian  tubes leading to pelvic inflammatory disease (PID) with  long-term complications that include ectopic pregnancies  or infertility from tubal obstruction.   Between 0.5% and 3.0% of untreated patients with gon-  orrhea will have disseminated gonococcal infections from  systemic bacteremia. The most common signs of dissemina-  tion are myalgia, arthralgia, polyarthritis, and dermatitis. In  75% of patients with disseminated disease, a characteristic  skin rash develops. The dermatologic lesions consist of dis-  crete papules and pustules that often exhibit a hemorrhagic  component and occur primarily on the extremities. Less  common alterations secondary to gonococcal septicemia  include fever, endocarditis, pericarditis, meningitis, and oral  mucosal lesions of the soft palate and oropharynx, which  are similar to aphthous ulcerations.   Most cases of oral gonorrhea appear to be a result of  fellatio, although oropharyngeal gonorrhea may be the  result of gonococcal septicemia, kissing, or cunnilingus. The  majority of cases are reported in women or homosexual  men, with the most common sites being the pharynx,  tonsils, and uvula. Although pharyngeal gonorrhea usually  is asymptomatic, a mild-to-moderate sore throat may occur  and be accompanied by nonspecific, diffuse oropharyngeal  erythema. Involved tonsils typically demonstrate edema and  erythema, often with scattered, small punctate pustules.   Although most cases of pharyngeal infection resolve  spontaneously without adverse sequelae, new findings  suggest the infection has important implications, which  strongly support the need for treatment to reduce the  potential for spreading the infection. Research also has sug-  gested that pharyngeal involvement may play an important    ® Fig. 5-16 Gonorrhea. Necrosis, purulence, and hemorrhage of the  anterior mandibular gingiva. (From Williams LN: The risks of oral-genital  contact: a case report, Gen Dent 50:282-284, 2002. Published with  permission by the Academy of General Dentistry. Copyright 2002 by  the American Academy of General Dentistry. All rights reserved.)    role in the development of antibiotic resistance. Several  studies have shown that NV. gonorrhoeae may undergo muta-  tion by acquiring genetic material from other Neisseria  species that frequent the throat. This has led many to rec-  ommend periodic pharyngeal screening for high-risk groups,  such as men who have sex with men (MSM) and commer-  cial sex workers.   Rarely, lesions have been reported in the anterior portion  of the oral cavity, with areas of infection appearing ery-  thematous, pustular, erosive, or ulcerated. Occasionally, the  infection may simulate necrotizing ulcerative gingivitis  (NUG), but some clinicians have reported that the typical  fetor oris is absent, providing an important clue to the  actual cause (Fig. 5-16). Submandibular or cervical lymph-  adenopathy may be present.   During birth, infection of an infant’s eyes can occur from  an infected mother who may be asymptomatic. This infec-  tion is called gonococcal ophthalmia neonatorum and  can rapidly cause perforation of the globe of the eye and  blindness. Common signs of infection include significant  conjunctivitis and a mucopurulent discharge from the eye.    In males with a urethral discharge, a Gram stain of the puru-  lent material can be used to demonstrate gram-negative  diplococci within the neutrophils; additional testing usually  is not indicated. Although Gram stains may be beneficial in  women, confirmation of the diagnosis is recommended by  culture of endocervical swabs if conditions are adequate to  maintain viability of the organisms. A number of other diag-  nostic studies have been available for many years. Nucleic  acid amplification tests (NAATs) amplify and detect UN.  gonorrhoeae—specific DNA or RNA sequences and are recom-  mended for the diagnosis when conditions are not adequate  to maintain the viability of the organisms. In spite of the    availability of NAATs, culture remains the preferred diagnos-  tic method for diagnosis of oropharyngeal infections.    Treatment has been complicated due to the development of  antibiotic resistance by N. gonorrhoeae. Only one class of  antibiotics, the cephalosporins, is thought sufficiently effica-  cious by the Centers for Disease Control and Prevention  (CDC). In addition, coinfection by Chlamydia trachomatis  is common, leading to a suggested therapy that is effective  against both organisms. The currently recommended  regimen is intramuscular ceftriaxone combined with oral  azithromycin or doxycycline. Rescreening is recommended  1 to 2 months after therapy. The most common cause for  treatment failure is reexposure to infected partners, who  often are asymptomatic; therefore, the treatment of all  recent sexual partners is recommended. Truly resistant  infections should be cultured with antimicrobial testing and  selection of an appropriate alternate antibiotic. Prophylactic  ophthalmic erythromycin, tetracycline, or silver nitrate is  applied to the newborn’s eyes to prevent the occurrence of  gonococcal ophthalmia neonatorum.    Tuberculosis (TB) is a chronic infectious disease caused by  Mycobacterium tuberculosis. Worldwide, it is estimated that  2 billion people (one-third of the population) are infected.  Each year approximately 8 million additional individuals  become infected, with 2 to 3 million deaths annually attrib-  uted to TB. Worldwide, the prevalence of the infection  declined with the introduction of effective antimicrobials,  but in recent years it has demonstrated an increased fre-  quency that appears to be associated with emergence of  AIDS and drug-resistant strains. However, in the United  States during 2012, the annual incidence declined 6.1%,  which was the 20th consecutive year of declining rates. The  rate of TB in foreign-born individuals in the US was 11.5  times higher than US-born persons.   Nontuberculous mycobacterial disease can occur from a  variety of organisms. Before the tuberculin testing of dairy  herds, many cases arose from the consumption of milk  infected with Mycobacterium bovis. Except for HIV-infected  individuals, most other cases of nontuberculous mycobacte-  rial disease appear as localized chronic cervical lymphadeni-  tis in otherwise healthy children. In patients with AIDS (see  page 239), Mycobacterium avium-intracellulare is a common  cause of opportunistic infections.   Infection must be distinguished from active disease.  Primary tuberculosis occurs in previously unexposed people  and almost always involves the lungs. Most infections are the  result of direct person-to-person spread through airborne  droplets from a patient with active disease. The organism  initially elicits a nonspecific, chronic inflammatory reaction.  In most individuals, the primary infection results only in a  localized, fibrocalcific nodule at the initial site of    involvement. However, viable organisms may be present in  these nodules and remain dormant for years to life.   Only about 5% to 10% of patients with TB progress  from infection to active disease, and an existing state of  immunosuppression often is responsible. In rare instances,  active TB may ensue directly from the primary infection.  However, active disease usually develops later in life from a  reactivation of organisms in a previously infected person.  This reactivation is typically associated with compromised  host defenses and is called secondary tuberculosis. Diffuse  dissemination through the vascular system may occur and  often produces multiple small foci of infection that grossly  and radiographically resemble millet seeds, resulting in the  nickname, miliary tuberculosis. Secondary TB often is  associated with immunosuppressive medications, diabetes,  old age, poverty, and crowded living conditions. AIDS rep-  resents one of the strongest known risk factors for progres-  sion from infection to disease.    Primary TB usually is asymptomatic. Occasionally, fever  and pleural effusion may occur.   Classically, the lesions of secondary TB are located in the  apex of the lungs but may spread to many different sites by  expectorated infected material or through the lymphatic or  vascular channels. Typically, patients have a low-grade fever,  malaise, anorexia, weight loss, and night sweats. With pul-  monaty progression, a productive cough develops, often  with hemoptysis or chest pain. Progressive TB may lead to  a wasting syndrome that, in the past, was termed consump-  tion, because it appeared that the patient’s body was being  consumed or destroyed.   Extrapulmonary TB is seen and represents an increasing  proportion of the currently diagnosed cases. In patients  with AIDS, more than 50% will have extrapulmonary  lesions. Any organ system may be involved, including the  lymphatic system, skin, skeletal system, CNS, kidneys, and  gastrointestinal tract. Involvement of the skin may develop  and has been called lupus vulgaris.   Head and neck involvement may occur. The most  common extrapulmonary sites in the head and neck are the  cervical lymph nodes followed by the larynx and middle ear.  Much less common sites include the nasal cavity, nasophar-  ynx, oral cavity, parotid gland, esophagus, and spine.   Oral lesions of TB are uncommon. The most common  presentations for oral involvement are chronic ulcerations  or swellings (Fig. 5-17). Less frequent findings include non-  healing extraction sockets, areas of mucosal granularity, or  diffuse zones of inflammation (Fig. 5-18). Chronic tongue  ulcerations are seen most frequently and followed closely in  prevalence by mandibular swellings associated with intra-  bony involvement. Other affected sites in order of decreas-  ing frequency include the gingiva, lips, buccal mucosa, soft  palate, and hard palate.   Often oral ulcerative lesions of TB coexist with palpable  lymph nodes. Although this combination most strongly    @ Fig. 5-17 Tuberculosis (TB). Chronic mucosal ulceration of the  ventral surface of the tongue on the right side. (Reprinted with permis-  sion from the American Dental Association.)    @ Fig. 5-18 Tuberculosis (TB). Area of granularity and ulceration of  the lower alveolar ridge and floor of mouth. (Courtesy of Dr. Brian  Blocher.)    suggests squamous cell carcinoma, the possibility of TB also  must be considered, especially in younger patients and those  who reside in geographic areas with a high prevalence of the  infection.   The majority of the oral lesions represent secondary  infection from the initial pulmonary foci, occurring most  frequently in middle-aged adults. It is unclear whether these  lesions develop from hematogenous spread or from expo-  sure to infected sputum. The reported prevalence of clini-  cally evident oral lesions varies from 0.5% to 5.0%. The  discovery of pulmonary TB as a result of the investigation  of oral lesions occurs but is unusual. Primary oral TB  without pulmonary involvement is rare and is more common  in children and adolescents.   Nontuberculous mycobacterial infections from contami-  nated milk currently are rare in the industrialized world  because of pasteurization of milk, as well as rapid identifica-  tion and elimination of infected cows. Drinking contami-  nated milk can result in a form of mycobacterial infection  known as scrofula. Scrofula is characterized by enlargement  of the oropharyngeal lymphoid tissues and cervical lymph  nodes (Fig. 5-19). On occasion, the involved nodes may    @ Fig. 5-19 Tuberculosis (TB). Enlargement of numerous cervical  lymph nodes. (Courtesy of Dr. George Blozis.)    @ Fig. 5-20 Tuberculosis (TB). Submandibular fistula secondary to  involvement of underlying cervical lymph nodes.    develop significant caseous necrosis and form numerous  sinus tracts through the overlying skin (Fig. 5-20). In addi-  tion, areas of nodal involvement may radiographically  appear as calcified lymph nodes that may be confused with  sialoliths (Fig. 5-21). Pulmonary involvement is unusual in  patients with scrofula.    The cell-mediated hypersensitivity reaction is responsible  for the classic histopathologic presentation of TB. Areas of  infection demonstrate the formation of granulomas, which    ® Fig. 5-22 Tuberculosis (TB). Histopathologic presentation of the  same lesion depicted in Fig. 5-18. Sheets of histiocytes are intermixed  with multinucleated giant cells and areas of necrosis.    are circumscribed collections of epithelioid histiocytes, lym-  phocytes, and multinucleated giant cells, often with central  caseous necrosis (Fig. 5-22). The nuclei of the giant cells  frequently are arranged along the periphery of the cell in a  horseshoe or ring shape (Langhans giant cells). In a person  with TB, one of these granulomas is called a tubercle.  Special stains, such as the Ziehl-Neelsen or other acid-fast  stains, are utilized to demonstrate the mycobacteria (Fig.  5-23). A newer technique, fluorescence microscopy of  auramine-rhodamine stains, is employed by many institu-  tions in an attempt to increase the ease of finding the organ-  isms. Because of the relative scarcity of the organisms within  tissue, the special stains successfully demonstrate the organ-  ism in only 27% to 60% of cases. Therefore, a negative  result does not completely rule out the possibility of TB.    Approximately 2 to 4 weeks after initial exposure, a cell-  mediated hypersensitivity reaction to tubercular antigens  develops. This reaction is the basis for the purified protein  derivative (PPD) skin test (i.e., tuberculin skin test), which  uses a filtered precipitate of heat-sterilized broth cultures of    M. tuberculosis. Positivity runs as high as 80% in developing  nations; only 5% to 10% of the population in the United  States is positive. A positive tuberculin skin test result indi-  cates exposure to the organism and does not distinguish  infection from active disease. A negative tuberculin skin test  result does not totally rule out the possibility of TB. False-  negative reactions have been documented in older adults;  the immunocompromised; patients with sarcoidosis,  measles, or Hodgkin lymphoma; and when the antigen was  placed intradermally. The false-negative rate may be as high  as 66% in patients with AIDS.   Special mycobacterial stains and culture of infected  sputum or tissue must be used to confirm the diagnosis of  active disease. Even if detected with special stains, identifi-  cation of the organism by culture is appropriate. This iden-  tification is important because some forms of nontuberculous  mycobacteria have a high level of resistance to traditional  antituberculous therapy and frequently require surgical  excision. Because 4 to 6 weeks may be required to identify  the organism in culture, antituberculous therapy often is  initiated before definitive classification. PCR also is used to  identify M. tuberculosis DNA and speeds the diagnosis  without the need to await culture results.    M. tuberculosis can mutate and develop resistance to single-  agent medications. To combat this ability, multiagent  therapy is the treatment of choice for an active infection,  and treatment usually involves two or more active drugs for  several months to years. A frequently used protocol consists  of an 8-week course of pyrazinamide, isoniazid, rifampin,  and ethambutol, followed by a 16-week course of isoniazid  and rifampin. With an alteration of doses and the admin-  istration schedule, the response to therapy in patients with  AIDS has been good, but relapses and progression of infec-  tion have been seen.    A different protocol termed chemoprophylaxis is used for  patients who have a positive PPD skin test but no signs or  symptoms of active disease. Although this situation does not  mandate therapy, several investigators have demonstrated  the value of therapy, especially in young individuals. Bacil-  lus Calmette-Guérin (BCG) vaccine for TB is available to  approximately 85% of the global population, but its use is  restricted in the United States because of a controversy  related to its effectiveness.    Leprosy is a chronic infectious disease produced by Myco-  bacterium leprae. Because of worldwide efforts coordinated  by the World Health Organization (WHO), a dramatic  decrease in the prevalence of leprosy has been seen over the  past 15 years. However, leprosy remains a public health  problem in many areas of the world. Approximately 80%  of all currently reported cases are noted in seven countries:  Brazil, India, Indonesia, Madagascar, Myanmar, Nepal, and  Nigeria.   The organism has a low infectivity, and exposure rarely  results in clinical disease. Small endemic areas of infection  are present in Louisiana and Texas, but most patients in the  United States have been infected abroad. Many believe that  the organism requires a cool host body temperature for  survival. Although the exact route of transmission is not  known, the high number of organisms in nasal secretions  suggests that in some cases the initial site of infection may  be the nasal or oropharyngeal mucosa. Although humans  are considered the major host, other animals (e.g., arma-  dillo, chimpanzee, and mangabey monkey) may be addi-  tional possible reservoirs of infection.   For decades, leprologists have believed the bacillus is  highly temperature dependent and produces lesions primar-  ily in cooler parts of the body, such as the skin, nasal cavity,  and palate. This concept has been questioned because the  organism may be seen in significant numbers at sites of core  body temperature, such as the liver and spleen. Recently,  one investigator mapped common sites of oral involvement  and compared this pattern to a map of the local tempera-  ture. This comparison demonstrated that the oral lesions  tend to occur more frequently in the areas of the mouth  with a lower surface temperature. The temperature-  dependent theory of leprosy infection remains an area of  interest and controversy.   A variety of disease severity is seen. Two main clinical  presentations are noted at opposite ends of the spectrum,  and these are related to the immune reaction to the organ-  ism. The first, called tuberculoid leprosy, develops in  patients with a high immune reaction. Typically, the organ-  isms are not found in skin biopsy specimens, skin test results  to heat-killed organisms (lepromin) are positive, and the  disease usually is localized. The second form, lepromatous  leprosy, is seen in patients who demonstrate a reduced cell-  mediated immune response. These patients exhibit numer-  ous organisms in the tissue, do not respond to lepromin    skin tests, and exhibit diffuse disease. Many patients present  with intermediate disease that can be divided into three  subgroups: borderline-tuberculoid, borderline-borderline,  and borderline-lepromatous. Active disease progresses  through stages of invasion, proliferation, ulceration, and  resolution with fibrosis. The incubation period is prolonged,  with an average of 2 to 5 years for the tuberculoid type and  8 to 12 years for the lepromatous variant.    Because laboratory services such as skin smears often are not  available, patients increasingly are being classified on clini-  cal grounds using the number of lesions (primarily skin)  and the number of body areas affected.   Tuberculoid leprosy exhibits a small number of well-  circumscribed, hypopigmented skin lesions. Nerve involve-  ment usually results in anesthesia of the affected skin, often  accompanied by a loss of sweating. Oral lesions are rare in  this variant.   Lepromatous leprosy begins slowly with numerous, ill-  defined, hypopigmented macules or papules on the skin  that, with time, become thickened (Fig. 5-24). The face is a  common site of involvement, and the skin enlargements can  lead to a distorted facial appearance (leonine facies). Hair,  including the eyebrows and lashes, often is lost (Fig. 5-25).  Nerve involvement leads to a loss of sweating and decreased  light touch, pain, and temperature sensors. This sensory loss  begins in the extremities and spreads to most of the body.  Nasal involvement results in nosebleeds, stuffiness, and a loss  of the sense of smell. The hard tissue of the floor, septum,  and bridge of the nose may be affected. Collapse of the  bridge of the nose is considered pathognomonic.   The reported prevalence of oral lesion varies from a com-  plete absence of lesions to 60%. A number of authors  believe many reports document an artificially high fre-  quency of oral lesions due to a failure to prove an association  with the infection. Well-documented oral lesions occur pre-  dominantly in lepromatous leprosy and are rare in the  tuberculoid and borderline variants.    @ Fig. 5-25 Multibacillary (Lepromatous) Leprosy. Loss of eye-  brows and eyelashes.    The WHO mapped the frequency and distribution of  oral lesions in leprosy patients. The sites that are cooled by  the passage of air appear to be affected most frequently. The  locations affected in order of frequency are the hard palate,  soft palate, facial maxillary gingiva, tongue, lips, palatal  gingiva, mandibular gingiva, and buccal mucosa. Affected  soft tissue initially appears as yellowish to red, sessile, firm,  enlarging papules that develop ulceration and necrosis, fol-  lowed by attempted healing by secondary intention. Con-  tinuous infection of an area can lead to significant scarring  and loss of tissue. Complete loss of the uvula and fixation  of the soft palate may occur. The lingual lesions appear  primarily in the anterior third and often begin as areas of  erosion, which may develop into large nodules. Infection of  the lip can result in significant macrocheilia, which can be  confused clinically and microscopically with cheilitis granu-  lomatosa (see page 313).   Direct infiltration of the inflammatory process associated  with lepromatous leprosy can destroy the bone underlying  the areas of soft tissue involvement. Often the infection  creates a unique pattern of facial destruction that has been  termed facies leprosa and demonstrates a triad of lesions  consisting of atrophy of the anterior nasal spine, atrophy of  the anterior maxillary alveolar ridge, and endonasal inflam-  matory changes. Involvement of the anterior maxilla can  result in significant bone erosion with loss of the teeth in  this area. Maxillary involvement in children can affect the  developing teeth and produce enamel hypoplasia and short  tapering roots. Dental pulp infection can lead to internal  resorption or pulpal necrosis. Teeth with pulpal involve-  ment may demonstrate a clinically obvious red discolor-  ation of the crown. The cause of the discoloration is  unknown but appears to be related to intrapulpal vascular  damage secondary to the infection. Granulomatous involve-  ment of the nasal cavity can erode through the palatal  tissues and result in perforation.   Involvement of peripheral nerves is common, with  leprosy considered one of the most common causes of treat-  able peripheral neuropathy in the world. The facial and  trigeminal nerves can be involved with the infectious    process. Facial paralysis may be unilateral or bilateral.  Sensory deficits may affect any branch of the trigeminal  nerve, but the maxillary division is the most commonly  affected. In addition to sensory deficits, reports of disease-  related orofacial pain may be confused with temporoman-  dibular joint discomfort or tooth-related pain.    Biopsy specimens of tuberculoid leprosy typically reveal  granulomatous inflammation with well-formed clusters of  epithelioid histiocytes, lymphocytes, and multinucleated  giant cells (Fig. 5-26). A paucity of organisms exists; when  present, they can be demonstrated only when stained with  acid-fast stains, such as the Fite method. Lepromatous  leprosy demonstrates no well-formed granulomas; the  typical finding is sheets of lymphocytes intermixed with  vacuolated histiocytes known as lepra cells (Fig. 5-27).  Unlike tuberculoid leprosy, an abundance of organisms can  be demonstrated with acid-fast stains in the lepromatous  variant (Fig. 5-28). It has been reported that the organism  can be found with special stains in 100% of lepromatous  leprosy cases, 75% of borderline cases, and only 5% of  tuberculoid cases.    The definitive diagnosis is based on the clinical presentation  and supported by the demonstration of acid-fast organisms  on a smear or in the tissue. The organism cannot be culti-  vated on artificial media, but . leprae can be identified by  using molecular biologic techniques. No reliable test is  available to determine whether a person has been exposed    @ Fig. 5-27 Multibacillary (Lepromatous) Leprosy. Sheets of lym-  phocytes and histiocytes exhibiting scattered vacuolated lepra cells.    to M. leprae without developing the disease; this creates  difficulties in establishing the diagnosis and determining the  prevalence of the infection.    For therapeutic purposes, the WHO has developed a  simple classification system based upon the bacterial index  noted upon biopsy. Those with an index less than 2+ are  termed paucibacillary, whereas those greater than 2+ are  designated multibacillary. Paucibacillary patients present  clinically as tuberculoid or borderline-tuberculoid vari-  ants; multibacillary patients include borderline-borderline,  borderline-lepromatous, and lepromatous variants. Patients  with multibacillary leprosy receive a combination of rifam-  picin, clofazimine, and dapsone, whereas those presenting  with paucibacillary leprosy receive rifampicin and dapsone.  Use of dapsone or rifampicin alone has resulted in develop-  ment of resistance to that respective drug. Since the intro-  duction of multidrug therapy in 1981, an estimated 15  million patients have been cured, and disabilities have been  prevented in another 2 to 3 million individuals. One of the  major reasons for the decreasing prevalence of leprosy is the    provision of an uninterrupted supply of free, high-quality  medications in calendar blister packs to all patients regard-  less of the living conditions or remoteness of the location.    The term noma is derived from the Greek word nomein,  meaning to devour. Noma is a rapidly progressive, polymi-  crobial, opportunistic infection caused by components of  the normal oral flora that become pathogenic during periods  of compromised immune status. Fusobacterium necropho-  rum and Prevotella intermedia are thought by many to be  key players in the process and interact with one or more  other bacterial organisms of which the most commonly  implicated are Actinomyces pyogenes, Bacillus cereus, Bacteroi-  des fragilis, Fusobacterium nucleatum, and Prevotella mela-  ninogenica. Culture is thought to underestimate the variety  of organisms involved due to the difficulties in growing  many of these fastidious bacteria. Studies utilizing PCR for  bacterial gene sequences have failed to identify a specific  causative organism because the plausible bacteria were  noted in both affected and healthy subjects.   The reported predisposing factors  following:  ¢ Poverty  e Malnutrition or dehydration  ¢ Poor oral hygiene  ¢ Poor sanitation  ¢ Unsafe drinking water  ¢ Proximity to unkempt livestock  ¢ Recent illness  e Malignancy  e An immunodeficiency disorder, including AIDS   In many cases a recent debilitating illness appears to  set the stage for the development of noma. Measles most  frequently precedes development of noma; other common  but less frequent predisposing illnesses include herpes  simplex, varicella, scarlet fever, malaria, tuberculosis, gastro-  enteritis, and bronchopneumonia. Cases associated with  malignancies (e.g., leukemia) are not rare. In many instances,  the infection begins as necrotizing ulcerative gingivitis  (NUG) (see page 143), and several investigators believe that  noma is merely an extension of the same process. Because  the disease usually is well advanced at the time of initial  presentation, descriptions of the initial stages of the disease  are sketchy.   In the developed world, noma has virtually disappeared  except for an occasional case related to immunosuppressive  conditions, such as HIV infection, severe combined immu-  nodeficiency syndrome, or intense immunosuppressive  therapy. The World Health Organization (WHO) estimates  the global yearly incidence to be approximately 140,000.  This number is thought by many to be a gross underestima-  tion because less than 15% of acute cases present for therapy.    ® Fig. 5-29 Necrotizing Ulcerative Mucositis. A, Large area of soft tissue necrosis of the posterior soft  palate on the left side. B, Healing site of necrotizing mucositis 6 days after initiation of tetracycline therapy.    @ Fig. 5-30 Noma. Extensive blackish orofacial necrosis of the right  cheek in an immunocompromised patient.    Noma usually arises in children from 1 to 10 years of age,  although it also can occur in adults with a major debilitating  disease (e.g., diabetes mellitus, leukemia, lymphoma, or  HIV infection). The infection often begins on the gingiva  as NUG, which may extend either facially or lingually to  involve the adjacent soft tissue and form areas called nec-  rotizing ulcerative mucositis. Zones of necrosis also may  develop in soft tissue not contiguous with the gingiva, par-  ticularly in areas of trauma (Fig. 5-29). The necrosis can  extend into deeper tissues; over the next few days, zones of  blue-black discoloration of the overlying skin surface may  develop (Fig. 5-30). Often the necrotic zone is cone shaped,  with a small point of cutaneous necrosis overlying a larger  zone of oral mucosal destruction. Unlike other infections,  the process does not follow tissue planes and tends to spread  through anatomic barriers, such as muscle. These discolored  zones break down into areas of yellowish necrosis that also  frequently spreads into adjacent bone, with large areas of  osteomyelitis possible. In most instances the necrotic area  is well defined and unilateral. Fetid odor, significant pain,  fever, malaise, tachycardia, increased respiratory rate,    anemia, leukocytosis, and regional lymphadenopathy are  typical. Additional lesions also may occur in distant sites,  such as the scalp, neck, ear, shoulders, chest, perineum, and  vulva.    In addition to using appropriate antibiotics to treat noma,  the clinician must direct therapeutic attention not only to  local wound care but also toward correcting the inadequate  nutrition, hydration, and electrolyte imbalances. Penicillin  and metronidazole are the first-line therapeutic antibiotics  for necrotizing stomatitis. Conservative débridement of  gross necrotic areas is recommended, but aggressive removal  is contraindicated because it does not stop the extension of  the process and compounds the reconstruction problems.   Without therapy, only 10% to 20% of affected patients  survive. With appropriate intervention, the survival is  greater than 90%. Common causes of death include infec-  tious complications, such as pneumonia, diarrhea, and sep-  ticemia. Noma infection can cause significant morbidity  when it is not fatal. Facial disfigurement that affects the  patient’s future growth and development is not rare. Recon-  struction often is extremely challenging and should be  delayed until healing is complete.    Although the term actinomycosis seems to imply a fungal  infection, it is an infection of filamentous, branching, gram-  positive anaerobic bacteria. Actinomycetes are normal sap-  rophytic components of the oral flora. Documented sites of  colonization in healthy patients include the tonsillar crypts,  dental plaque and calculus, carious dentin, bone sequestra,  salivary calculi, gingival sulci, and periodontal pockets. The  colonies within the tonsillar crypts may form concretions  and become large enough for the patient to feel the firm  plugs within the crypts (see page 168). In surveys of docu-  mented actinomycosis, Actinomyces israelii is the causative  organism in the majority, with A. viscosus being a close    second. Much less frequent causes of the infection are A.  naeslundii, A. odontolyticus, A. meyeri, A. pyogenes, A. visco-  sus, and A. bovis, along with Arachnia propionica and Bifi-  dobacterium dentium. In most such cases, the primary  organism is combined synergistically with streptococci and  staphylococci.    Actinomycosis may be either an acute, rapidly progressing  infection or a chronic, slowly spreading lesion that is associ-  ated with fibrosis. Approximately 55% of cases of actino-  mycosis are diagnosed in the cervicofacial region, with 25%  occurring in the abdominal and pelvic region and 15% in  the pulmonary system. The remaining 5% exhibits a variety  of patterns, such as superficial skin infections, or infections  of the genitourinary region (often linked to use of intrauter-  ine contraceptive devices).   ‘The suppurative reaction of the infection may discharge  large yellowish flecks that represent colonies of the bacteria  called sulfur granules. Although common, sulfur granules  are not present invariably. In addition, another infection  that also can produce sulfur granules and mimic actinomy-  cosis is botryomycosis, an unrelated process that represents  an unusual host reaction to S. aureus and other bacteria.   In the cervicofacial region, the organism typically enters  tissue through an area of prior trauma, such as a soft tissue  injury, periodontal pocket, nonvital tooth, extraction socket,  or infected tonsil. The infection does not spread along the  typical fascial planes and usually disregards the normal lym-  phatic and vascular routes. Direct extension through soft  tissue is seen, and lymph nodes become involved only if  they are in the path of the process. The classic description  is of a “wooden” indurated area of fibrosis, which ultimately  forms a central, softer area of abscess. The infection may  extend to the surface, forming a sinus tract (Fig. 5-31). Pain  often is minimal. The soft tissues of the submandibular,  submental, and cheek areas are common areas of involve-  ment, with the area overlying the angle of the mandible  being the most frequently affected site.    @ Fig. 5-31 Actinomycosis. Draining fistula of the right submandibu-  lar area.    Localized abscesses without the associated chronic fibros-  ing reaction have been reported in soft tissue that has  received minor trauma. The tongue is the most frequently  mentioned site, but any oral mucosal location is possible.  Involvement of the tonsillar crypts may produce infectious  symptoms; in most cases, however, the primary change is  one of variable hyperplasia. Tonsillar hyperplasia thought to  be secondary to actinomycotic infestation of the crypts does  not appear responsive to antibiotics, probably because of  the superficial location of the bacterial colonies. Tonsillec-  tomy is generally the most effective treatment for this  situation.   Salivary gland involvement also is not unusual. Intra-  ductal colonization by the organism may lead to infections  in both the submandibular and parotid glands, resulting in  abscess formation in the submandibular and masseter  spaces, respectively. In addition, more localized infections  occur in minor salivary gland ducts, which also may dem-  onstrate mucous plugs or sialoliths.   Actinomycotic osteomyelitis of the mandible and maxilla  has been reported. Trauma, periodontal infections, nonvital  teeth, and extraction sites have all provided access. Ill-  defined areas of radiolucency, often surrounded by radi-  opacity, may be found with or without involvement of the  overlying soft tissue.   Intrabony colonization of dentigerous cysts without  other significant clinical or radiographic spread has been  reported. Periapical inflammatory lesions involved by the  bacteria can result in lesions that are difficult to resolve with  standard endodontic treatment, but such lesions typically  remain localized and do not evolve into invasive cervicofa-  cial actinomycosis.    The tissue removed from areas of active infection demon-  strates a peripheral band of fibrosis encasing a zone of  chronically inflamed granulation tissue surrounding large  collections of polymorphonuclear leukocytes and, with  luck, colonies of organisms (Fig. 5-32). The colonies consist    @ Fig. 5-33 Actinomycosis. Actinomycotic colony exhibiting club-  shaped filaments arranged in a radiating rosette pattern.    of club-shaped filaments that form a radiating rosette  pattern (Fig. 5-33). With hematoxylin and eosin (H&E)  stains, the central core stains basophilic and the peripheral  portion is eosinophilic. Methenamine silver stains demon-  strate the organisms well. If the colonies of actinomycetes  become displaced from the exudate, then a rim of neutro-  phils typically clings to the periphery of the organisms.    ‘The diagnosis of actinomycosis is achieved ideally by culture,  but less than 50% of cases are positive because of the over-  growth of associated bacteria, prior antibiotic therapy, or  improper anaerobic media conditions. Lacking positive  culture results, a strong presumptive diagnosis can be  obtained through a demonstration of the typical colonies in  lesional biopsy material. The material for culture and histo-  pathologic examination typically is obtained during surgical  exploration, with fine-needle aspiration being a satisfactory  substitute in many cases. Sulfur granules in infections other  than actinomycosis are so rare that their demonstration  strongly supports the diagnosis. If desired, then fluorescein-  conjugated antiserum can be used on the granules to specifi-  cally identify the Actinomyces species.    The treatment of choice for actinomycosis in chronic fibros-  ing cases is prolonged high doses of antibiotics in associa-  tion with abscess drainage and excision of the sinus tracts.  A high antibiotic concentration is required to penetrate  larger areas of suppuration and fibrosis. Although penicillin  remains the standard of care with no documented in vivo  resistance, some clinicians believe amoxicillin represents a  better first-choice antibiotic. Other investigators have dem-  onstrated in vitro resistance to penicillin and recommend  tetracycline, which is as effective as penicillin and is the drug  of choice for patients with a known allergy to penicillin.  Early cervicofacial actinomycosis typically responds to a    5- to 6-week course of penicillin; patients with deep-seated  infections may require up to 12 months.   In cases of osteomyelitis caused by actinomycetes, anti-  biotic therapy alone often is associated with persistent  disease. Adequate débridement appears to be the corner-  stone of therapy and ultimately determines the success of  the subsequent antibiotic treatment. When combined with  appropriate surgery, a 3-month course of penicillin usually  is curative. In resistant cases, repeated débridement should  be combined with cultures to direct future antibiotic  therapy. Care should be taken to ensure that colonization  of bony sequestra by actinomycotic colonies is not mistaken  for invasive actinomycotic osteomyelitis.   Several authors have indicated that localized acute acti-  nomycotic infections may be treated more conservatively  than the deep, chronic cases of actinomycosis. Localized  periapical and pericoronal actinomycosis, tongue abscesses,  and focal subacute sialadenitis with intraductal involvement  frequently respond well to surgical removal of infected  tissue. It appears best to reserve antibiotics for patients in  whom the microorganisms invade the surrounding struc-  tures and spread through the soft tissues.    Cat-scratch disease is an infectious disorder that begins in  the skin but classically spreads to the adjacent lymph nodes.  This infection is the most common cause of chronic regional  lymphadenopathy in children, with an estimated 22,000  cases occurring annually in the United States. This disease  has been recognized since 1931, but the definitive cause was  not determined until the 1980s. Isolation and culture of the  organism were finally achieved in 1988. The causative  organism was initially named Rochalimaea henselae but was  reclassified as Bartonella henselae when the genera Bartonella  and Rochalimaea were combined.   Almost all cases arise after contact with a cat. The spread  of the infection between cats appears to occur through cat  fleas. The organism becomes an intraerythrocytic parasite  and may be transmitted to humans via saliva or from a  scratch. Infection from other sources is highly unlikely, but  the disease rarely has been described via dogs, monkeys,  porcupine quills, and thorns. Person-to-person transmission  has not been documented.    Eighty percent of the cases occur in patients younger than  21 years of age. Cat-scratch disease begins as a papule that  develops in 3 to 14 days along the initial scratch line (Fig.  5-34). The lesion typically progresses through erythema-  tous, vesicular, and papular-crusted stages with resolution  usually occurring within 1 to 3 weeks. About the time the  skin lesion heals, lymph node changes arise and may be  accompanied by fever or malaise (Fig. 5-35). In about half  of the cases, a single node is involved. Multiple regional  nodes are affected in about 20%, and nodal enlargement is    @ Fig. 5-34 Cat-Scratch Disease. Papule that developed at initial  site of injury.    discovered in multiple sites in about 33%. Suppuration is  noted in approximately 10% of affected patients. The most  frequently affected nodes are those in the head and neck,  axillary, epitrochlear, and groin regions.   Although the vast majority of affected patients present  with typical cat-scratch disease as described above, a variety  of systemic manifestations may be seen. Of these, prolonged  fever of unknown origin and hepatosplenic disease are the  most common. Less common problems include cardiac,  hematologic, neurologic, ocular, orthopedic, and pulmo-  nary manifestations. Although necrotizing granulomas    @ Fig. 5-36 Cat-Scratch Disease. Intranodal area of necrosis sur-  rounded by a band of epithelioid histiocytes and lymphocytes.    usually are noted in immunocompetent patients, vasopro-  liferative disorders, such as bacillary angiomatosis or bac-  illary peliosis hepatis (a specific form of hepatosplenic  Bartonella disease) may be seen in immunocompromised  patients. Bacillary angiomatosis is an unusual subcutaneous  vascular proliferation that has been recognized in patients  with AIDS. The affected areas often resemble Kaposi  sarcoma (see page 244) and appear as variable numbers of  red-to-purple skin lesions. These may be macular, papular,  or pedunculated and exhibit a widespread distribution on  the skin. Pain and tenderness are common. ‘The larger  lesions are friable and bleed easily.    ‘The involved lymph nodes are enlarged as a result of signifi-  cant cortical hyperplasia, which classically contains areas of  stellate suppurative necrosis surrounded by a band of his-  tiocytes and neutrophils (Fig. 5-36). Upon Warthin-Starry  stains or the Brown-Hopps method of Gram staining, cat-  scratch bacilli usually are found in areas without significant  necrosis. As the disease progresses and necrosis increases, the  organisms become more difficult to identify. A commer-  cially available monoclonal antibody against B. henselae has  been used to demonstrate the organisms via immunoper-  oxidase techniques on paraffin-embedded material. Upon  immunostaining, the organisms are highlighted dramati-  cally, an important advance over the previous special stains.  Bacillary angiomatosis reveals lobular proliferations of  small blood vessels in an edematous to fibrotic stroma. The  supporting connective tissue typically demonstrates a sig-  nificant number of neutrophils and leukocytoclasis, impor-  tant clues to the diagnosis. Also present are variably sized  amphophilic and granular aggregates that upon Warthin-  Starry staining prove to be masses of the causative bacteria.    Today the diagnosis of cat-scratch disease usually is estab-  lished by a combination of clinical and serologic criteria.    Histopathology can confirm the clinical diagnosis but  involves an invasive procedure. In patients with a suggestive  clinical presentation, the diagnosis usually is confirmed by  negative evaluations for other common causes of adenopa-  thy, combined with positive serology. The most widely used  tests are an indirect fluorescent assay (IFA) or enzyme-  linked immunosorbent assay (ELISA) for detecting anti-  bodies to B. henselae. PCR techniques also are available but  are not widely used due to low sensitivity.    Cat-scratch disease is a self-limiting condition and normally  resolves within 4 months. The use of local heat, analgesics,  and aspiration of the node on suppuration is the typical  pattern of therapy. If persistent discomfort makes nodal  aspiration necessary, then drainage should be achieved with  a needle that is tunneled into the node laterally through  normal skin 1 to 2 cm away from the lesion. Incision directly  into the node could result in a chronic draining sinus.  Although the organism has demonstrated sensitivity to  a number of antibiotics in culture, the results in immuno-  competent patients have been inconsistent and difficult to  evaluate because the disease is self-limited in most cases.  Antibiotics typically are reserved for those cases that dem-  onstrate a prolonged course or severe involvement. Use of  antibiotic drugs in patients with AIDS and bacillary angio-  matosis has produced dramatic resolution within 2 days.  Although a number of medications have been used success-  fully, the primary antibiotics used for cat-scratch disease or  bacillary angiomatosis are azithromycin, erythromycin,  doxycycline, rifampin, ciprofloxacin, and gentamicin.    Sinusitis is one of the most common health complaints in  the United States with an associated annual incidence of 20  million doctor visits. To understand the problem, the clini-  cian must first have some knowledge of sinus anatomy.  Adults have bilateral maxillary, frontal, sphenoid, ethmoid,  and mastoid sinuses. Except for the mastoid sinuses, these  cavities drain into the nose through openings called ostia.  The frontal, sphenoid, and maxillary sinuses must drain  through the middle meatus. In addition, the ethmoids are  located bilaterally in this area of the nose and present as a  labyrinth of 3 to 15 small sinuses, which drain through  smaller ostia. The ostiomeatal complex, with its numerous  narrow openings (Fig. 5-37), is the key to sinus disease,  because it is the primary nasal site for the deposition of  foreign matter from inspired air.   Normal sinuses are lined by pseudostratified columnar  epithelium with cilia. The cilia are necessary to move the  sinus secretions toward the ostia. Gravity also is beneficial  in removing the secretions, except in the maxillary sinus  where there is a superior location of the ostial opening  and, therefore, the ciliary apparatus becomes even more  important.    @ Fig. 5-37 The Paranasal Sinuses. Illustration demonstrating the  ostiomeatal complex and its importance to appropriate sinus drainage.  The left side demonstrates the typical narrow middle meatus through  which all sinus drainage must pass. The right side reveals enlargement  of the middle meatus, such as that achieved through corrective endo-  scopic surgery. VM, Maxillary sinus; F frontal sinus; E, ethmoid sinuses;  MM, middle meatus.    For a long time, researchers believed that primary inflam-  mation of the lining of the maxillary antrum was the major  cause of sinusitis; however, advances have demonstrated  that most sinus disease begins from a blockage of the ostio-  meatal complex that disrupts normal drainage, decreases  ventilation, and precipitates disease. Less common localized  sinus infections can occur from focal areas of inflammation  within a single sinus, such as a dental infection affecting the  maxillary sinus.   Most acute sinusitis cases are viral in origin and arise  shortly after an upper respiratory tract infection. In con-  trast, most examples of chronic sinusitis are bacterial. All of  the sinuses contain bacteria. With bacteria already present  in the sinuses, changes as minor as a slight mucosal thicken-  ing in the ostiomeatal complex can lead to improper sinus  drainage and infection. The most common predisposing  factors for chronic sinusitis are a recent upper respiratory  viral infection, allergic rhinitis, or an adjacent odontogenic  infection.   Historically, 10% to 12% of maxillary sinusitis cases  were thought to arise from an odontogenic source, but  many current investigators believe the prevalence is closer  to 30%. Common causes include periapical or periodontal  infection from the maxillary teeth, dental trauma, or iatro-  genic causes, such as dental extractions, maxillary osteoto-  mies, or placement of dental implants. In such cases, therapy  requires resolution of the odontogenic pathosis in addition  to management of the sinus infection.   In otherwise healthy patients, the most common bacte-  rial organisms cultured from acute sinusitis are Streptococcus  pneumoniae, Haemophilus influenzae, and Moraxella catarrh-  alis. Chronic sinusitis is defined as recurring episodes of acute  sinusitis or symptomatic sinus disease lasting longer than 3    months. In these cases, the bacteria tend to be anaerobes  and are most frequently Streptococcus, Bacteroides, or Veil-  lonella spp. When sinusitis arises secondary to an odonto-  genic infection, the causative organisms are usually those  that predominate in periodontal or endodontic infections  and include bacteria, such as Peptostreptococcus spp., Fuso-  bacterium spp., Prevotella spp., Bacteroides spp., and Porphy-  romonas spp.   Infrequently, in an environment of chronic sinusitis, an  area of dystrophic calcification (antrolith) may develop and  be detected radiographically. The nidus for this calcification  may be endogenous from materials, such as inflamed mucus,  pus, or clots. In other cases the source may be exogenous  from tooth roots or foreign bodies, such as dental materials,  vegetable matter, paper, glass, and stone. Focal antral calci-  fication also has been seen in sinuses filled with a fungal ball  of Aspergillus fumigatus (noninvasive mycetoma) (see page  210). A sinus that is unresponsive to therapy and exhibits  focal antrolith formation within a diffuse soft tissue opaci-  fication is highly suggestive of noninvasive aspergillosis.    Presenting symptoms of acute sinusitis in adults include  headache, fever, and facial pain over the affected sinus.  Anorexia, photophobia, and malaise also may be seen. Ante-  rior nasal or posterior pharyngeal discharge is present; it  may be thick or thin in consistency and appear clear,  mucoid, or purulent. Children, with their less complex  sinuses, typically have only persistent cough, fever, and  purulent rhinorrhea. Localized involvement of the maxillary  sinus can occur as pain over the cheekbone, toothache,    periorbital pain, or temporal headache. Maxillary sinusitis  is associated with increased pain when the head is held  upright and less discomfort when the patient is supine.   Chronic sinusitis is less diagnostic, and radiographic  imaging becomes more important. Frequent complaints  include facial pressure, pain, or a sensation of obstruction.  In some cases, nonspecific symptoms, such as headache,  sore throat, lightheadedness, or generalized fatigue, also  may be present or even dominate. Radiographically, the  involved sinus has a cloudy, increased density (Fig. 5-38).   At times, sinusitis can be confused with an odontogenic  infection. In such cases, close examination of periapical  radiographs, a thorough periodontal examination, and  assessment of tooth vitality often may point to an odonto-  genic infection. A sinus infection should be strongly con-  sidered when patients complain of pain from several teeth,  demonstrate tenderness over one or both of the maxillary  sinuses, exhibit nasal congestion, or have a nasal discharge  accompanied by a foul odor, fever, and headache.   In addition to the patient’s symptoms, the diagnosis in  the past often was made by procedures (such as, transillu-  mination) and by plain radiographs (such as, the Waters,  Caldwell-Luc, lateral, and submental vertex views). Today,  when the diagnosis is in question, many clinicians use nasal  endoscopy, CT, or cone beam CT. Areas of infection and  sites of improper drainage will be found. These techniques  not only confirm the diagnosis but also pinpoint the primary  pathologic alteration that led to the obstructive sinusitis.   An antrolith appears radiographically as a radiodense  focus within the sinus. The calcification often is seen in  association with a thickening of the antral lining or diffuse  clouding of the affected sinus.    Treatment options for acute sinusitis include moisturizing  sprays, decongestants, mucolytics, corticosteroids, antibiot-  ics, or mechanical intervention, such as sinus puncture or  lavage. Although acute sinusitis is usually a self-limiting  disease, antibiotics frequently are prescribed. Most cases are  viral in origin and resolve within 2 weeks, with or without  antibiotic therapy. A Cochrane meta-analysis demonstrated  a small benefit associated with antibiotic therapy, but this  appeared to be overshadowed by adverse effects, such as  diarrhea, abdominal pain, and vomiting.   If antibiotics are used, the first-line therapy for acute  sinusitis in otherwise healthy patients is amoxicillin. Doxy-  cycline or clarithromycin are alternatives for patients allergic  to penicillin. If amoxicillin is associated with a poor clinical  response, other choices include azithromycin, cefoxitin, cef-  triaxone, cephalexin, clindamycin, and moxifloxacin. The  choice of antibiotics should be guided by local resistance  patterns and by appropriately collected cultures.   In otherwise healthy adult patients, chronic sinusitis that  is not responsive to typical medical management often is  corrected surgically. When located in the maxillary sinus,  such invasive therapy should be performed only after a  thorough examination to rule out an association with an  adjacent odontogenic infection. On occasion, a clinical  dental evaluation with plain films will fail to discover the  origin. If a high index of suspicion exists, CT often proves  beneficial in highlighting the associated focus of infection.   Nasal endoscopy has shown that sinusitis is a disease of  obstruction and that mucosal inflammation is usually a  secondary development. 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Longhini AB, Ferguson BJ: Clinical aspects of odontogenic maxillary  sinusitis: a case series, Int Forum Allergy Rhinol 1:409-415,  2011.   Mehra P, Jeong D: Maxillary sinusitis of odontogenic origin, Curr  Allergy Asthma Rep 9:238-243, 2009.   Narkié-Makela M, Qvarnberg Y: Endoscopic sinus surgery or  Caldwell-Luc operation in the treatment of chronic and recurrent  maxillary sinusitis, Acta Otolaryngol Suppl 529:177-180, 1997.   Ogata Y, Okinaka Y, Takahashi M: Antrolith associated with aspergil-  losis of the maxillary sinus: report of a case, J Oral Maxillofac Surg  55:1339-1341, 1997.   Puglisi S, Privitera S, Maiolino L, et al: Bacteriological findings and  antimicrobial resistance in odontogenic and non-odontogenic  chronic maxillary sinusitis, J Med Microbiol 60:1353-1359,  2011.    Infection with the yeastlike fungal organism Candida albi-  cans is termed candidiasis or, as the British prefer, candi-  dosis. An older name for this disease is moniliasis; the use  of this term should be discouraged because it is derived from  the archaic designation Monilia albicans. Other members of  the Candida genus, such as C. tropicalis, C. krusei, C. parap-  silosis, and C. guilliermondii, may also be found intraorally,  but they rarely cause disease.   Like many other pathogenic fungi, C. albicans may exist  in two forms—a trait known as dimorphism. ‘The yeast  form of the organism is believed to be relatively innocuous,  but the hyphal form is usually associated with invasion of  host tissue.   Candidiasis is by far the most common oral fungal infec-  tion in humans and has a variety of clinical manifestations,  making the diagnosis difficult at times. In fact, C. albicans  may be a component of the normal oral microflora, with as  many as 30% to 50% of people simply carrying the organ-  ism in their mouths without clinical evidence of infection.  This rate of carriage has been shown to increase with  age, and C. albicans can be recovered from the mouths of  nearly 60% of dentate patients older than 60 years who  have no sign of oral mucosal lesions. At least three general  factors may determine whether clinical evidence of infec-  tion exists:   1. The immune status of the host  2. The oral mucosal environment  3. The strain of C. albicans   In the past, candidiasis was considered to be only an  opportunistic infection, affecting individuals who were  debilitated by another disease. Certainly, such patients  make up a large percentage of those with candidal infections  today. However, now clinicians recognize that oral candidia-  sis may develop in people who are otherwise healthy. As a  result of this complex host and organism interaction, can-  didal infection may range from mild, superficial mucosal  involvement seen in most patients to fatal, disseminated  disease in severely immunocompromised patients. This  chapter focuses on those clinical presentations of candidiasis  that affect the oral mucosa.    Candidiasis of the oral mucosa may exhibit a variety  of clinical patterns, which are summarized in Table 6-1.  Many patients display a single pattern, although some  individuals exhibit more than one clinical form of oral  candidiasis.    ‘The best recognized form of candidal infection is pseudo-  membranous candidiasis. Also known as thrush, pseudo-  membranous candidiasis is characterized by the presence  of adherent white plaques that resemble cottage cheese  or curdled milk on the oral mucosa (Figs. 6-1 and 6-2).  The white plaques are composed of tangled masses of  hyphae, yeasts, desquamated epithelial cells, and debris.  Scraping them with a tongue blade or rubbing them with  a dry gauze sponge can remove these plaques. The underly-  ing mucosa may appear normal or erythematous. If bleed-  ing occurs, then the mucosa has probably also been affected  by another process, such as erosive lichen planus or cancer  chemotherapy.   Pseudomembranous candidiasis may be initiated by  exposure of the patient to broad-spectrum antibiotics (thus  eliminating competing bacteria) or by impairment of the  patient’s immune system. The immune dysfunctions seen in  leukemic patients (see page 547) or those infected with  human immunodeficiency virus (HIV) (see page 241) are  often associated with pseudomembranous candidiasis.  Infants may also be affected, ostensibly because of their  underdeveloped immune systems. Antibiotic exposure is  typically responsible for an acute (rapid) expression of the  condition; immunologic problems usually produce a  chronic (slow-onset, long-standing) form of pseudomem-  branous candidiasis.   Symptoms, if present at all, are usually relatively mild,  consisting of a burning sensation of the oral mucosa or an  unpleasant taste in the mouth, variably described as salty or  bitter. Sometimes patients complain of “blisters,” when in  fact they feel the elevated plaques rather than true vesicles.  The plaques are characteristically distributed on the buccal  mucosa, palate, and dorsal tongue.    Probably not true infection;  denture often is positive on  culture but mucosa is not    leukoplakia) removable; care must be taken not to  asymptomatic confuse this with other  keratotic lesions with  superimposed candidiasis  Mucocutaneous White plaques, some of Tongue, buccal mucosa, Rare; inherited or sporadic    e Fig. 6-1 Pseudomembranous Candidiasis. Multiple white  plaques overlying erythematous mucosal change on the soft palate.    In contrast to the pseudomembranous form, patients  with erythematous candidiasis either do not show white  flecks, or a white component is not a prominent feature.  Erythematous candidiasis is undoubtedly more common    than pseudomembranous candidiasis, although it is often  overlooked clinically. Several clinical presentations may be  seen. Acute atrophic candidiasis, or “antibiotic sore  mouth,” typically follows a course of broad-spectrum anti-  biotic therapy. Patients often complain that the mouth feels  as if a hot beverage had scalded it. This burning sensation  is usually accompanied by a diffuse loss of the filiform papil-  lae of the dorsal tongue, resulting in a reddened, “bald”  appearance of the tongue (Fig. 6-3). Burning mouth syn-  drome (see page 807) frequently manifests with a scalded  sensation of the tongue; however, the tongue appears normal  in that condition. Patients who suffer from xerostomia  for any reason (e.g., pharmacologic, postradiation therapy,  or Sjégren syndrome) have an increased prevalence of  erythematous candidiasis that is commonly symptomatic  as well.   Other forms of erythematous candidiasis are usually  asymptomatic and chronic. Included in this category is the  condition known as central papillary atrophy of the  tongue, or median rhomboid glossitis. In the past, this  was thought to be a developmental defect of the tongue,  occurring in 0.01% to 1.00% of adults. The lesion was    supposed to have resulted from a failure of the embryologic investigators have noted a consistent relationship between  tuberculum impar to be covered by the lateral processes of the lesion and C. albicans, and similar lesions have been  the tongue. Theoretically, the prevalence of central papillary induced experimentally on the dorsal tongues of rats.   atrophy in children should be identical to that seen in Clinically, central papillary atrophy appears as a well-  adults; however, in one study in which 10,000 children demarcated erythematous zone that affects the midline,  were examined, not a single lesion was detected. Other posterior dorsal tongue and often is asymptomatic (Fig    6-4). The erythema is due in part to the loss of the filiform  papillae in this area. The lesion is usually symmetrical, and  its surface may range from smooth to lobulated. Often the  mucosal alteration resolves with antifungal therapy, although  occasionally only partial resolution can be achieved.   Some patients with central papillary atrophy may also  exhibit signs of oral mucosal candidal infection at other sites.  This presentation of erythematous candidiasis has been  termed chronic multifocal candidiasis. In addition to the  dorsal tongue, the sites that show involvement include  the junction of the hard and soft palate and the angles of the  mouth. The palatal lesion appears as an erythematous area  that, when the tongue is at rest, contacts the dorsal tongue  lesion, resulting in what is called a “kissing lesion” because  of the intimate proximity of the involved areas (Fig. 6-5).    ; om er Ga Mae Ses, ee :  @ Fig. 6-4 Erythematous Candidiasis. A, Severe presentation of central papillary atrophy. In this  patient, the lesion was asymptomatic. B, Marked regeneration of the dorsal tongue papillae occurred 2  weeks after antifungal therapy with fluconazole.    @ Fig. 6-5 Candidiasis. A, Multifocal oral candidiasis characterized by central papillary atrophy of the  tongue and other areas of involvement. B, Same patient showing a “kissing” lesion of oral candidiasis on    As $ : Fe 5,  ® Fig. 6-6 Angular Cheilitis. Characteristic lesions appear as fis-  sured, erythematous alterations of the skin at the corners of the mouth.    The involvement of the angles of the mouth (angular  cheilitis, perléche) is characterized by erythema, fissuring,  and scaling (Fig. 6-6). Sometimes this condition is seen as  a component of chronic multifocal candidiasis, but it often  occurs alone, typically in an older person with reduced  vertical dimension of occlusion and accentuated folds at the  corners of the mouth. Saliva tends to pool in these areas,  keeping them moist and thus favoring a yeast infection.  Patients often indicate that the severity of the lesions waxes  and wanes. Microbiologic studies have indicated that 20%  of these cases are caused by C. albicans alone, 60% are due  to a combined infection with C. albicans and Staphylococcus  aureus, and 20% are associated with S. aureus alone. Infre-  quently, the candidal infection more extensively involves the  perioral skin, usually secondary to actions that keep the skin  moist (e.g., chronic lip licking, thumb sucking, chronic use  of petrolatum-based salves), creating a clinical pattern  known as cheilocandidiasis (Fig. 6-7). Other causes of  exfoliative cheilitis often must be considered in the differ-  ential diagnosis (see page 278).   Denture stomatitis should be mentioned because it is  often classified as a form of erythematous candidiasis, and    ® Fig. 6-7 Cheilocandidiasis. A, Candidal infection of the perioral  skin caused by use of a petrolatum-based product. The condition  started as angular cheilitis, but the patient continuously applied petro-  leur jelly to the corners of the mouth and perioral skin, sealing mois-  ture into the keratin layer of the epidermis, thereby allowing the  candidal organisms to thrive. B, Two weeks after discontinuing the  petroleum jelly and using topical iodoquinol with triamcinolone.    some authors may use the term chronic atrophic candidiasis  synonymously. This condition is characterized by varying  degrees of erythema, sometimes accompanied by petechial  hemorrhage, localized to the denture-bearing areas of a  maxillary removable dental prosthesis (Figs. 6-8 and 6-9).    ° Fig. 6-8 Denture Stomatitis. A, Maxillary denture with incomplete  palatal vault associated with midline tissue hyperplasia. B, Mucositis  corresponds to the outline of the prosthesis. C, Resolution of mucositis  after antifungal therapy and appropriate denture cleansing.    Although the clinical appearance can be striking, the process  is rarely symptomatic. Usually the patient admits to wearing  the denture continuously, removing it only periodically to  clean it. Whether this represents actual infection by C.  albicans or is simply a tissue response by the host to the  various microorganisms living beneath the denture remains  controversial. The clinician should also rule out the possibil-  ity that this reaction could be caused by improper design of  the denture (which could cause unusual pressure on the  mucosa), allergy to the denture base, or inadequate curing  of the denture acrylic.    @ Fig. 6-9 Denture Stomatitis. Denture stomatitis, not associated  with Candida albicans, confined to the denture-bearing mucosa of a  maxillary partial denture framework.    @ Fig. 6-10 Denture Stomatitis. This Sabouraud agar slant has  been streaked with swabs obtained from erythematous palatal mucosa  (left side of the slant) and the tissue-bearing surface of the denture  (right side of the slant). Extensive colonization of the denture is dem-  onstrated, whereas little evidence of yeast associated with the mucosa  is noted.    Although C. albicans is often associated with this condi-  tion, biopsy specimens of denture stomatitis seldom show  candidal hyphae actually penetrating the keratin layer of the  host epithelium. Therefore, this lesion does not meet one  of the main defining criteria for the diagnosis of infection—  host tissue invasion by the organism. Furthermore, if the  palatal mucosa and tissue-contacting surface of the denture  are swabbed and separately streaked onto a Sabouraud agar  slant, then the denture typically shows much heavier colo-  nization by yeast (Fig. 6-10).    In some patients with oral candidiasis, there may be a white  patch that cannot be removed by scraping; in this case the  term chronic hyperplastic candidiasis is appropriate. This form  of candidiasis is the least common and is also somewhat  controversial. Some investigators believe that this condition  simply represents candidiasis that is superimposed on a    preexisting leukoplakic lesion, a situation that may certainly  exist at times. In some instances, however, the candidal  organism alone may be capable of inducing a hyperkeratotic  lesion. Such lesions are usually located on the anterior buccal  mucosa and cannot clinically be distinguished from a routine  leukoplakia (Fig. 6-11). Often the leukoplakic lesion associ-  ated with candidal infection has a fine intermingling of red  and white areas, resulting in a speckled leukoplakia (see page  359). Such lesions may have an increased frequency of epi-  thelial dysplasia histopathologically.   The diagnosis is confirmed by the presence of candidal  hyphae associated with the lesion and, more importantly,  by complete resolution of the lesion after antifungal therapy  (Fig. 6-12).    Severe oral candidiasis may also be seen as a component of  a relatively rare group of immunologic disorders known as    @ Fig. 6-11 Hyperplastic Candidiasis. This lesion of the anterior  buccal mucosa clinically resembles a leukoplakia, because it is a white  plaque that cannot be removed by rubbing. With antifungal therapy,  such a lesion should resolve completely.    mucocutaneous candidiasis. Several distinct immunologic  dysfunctions have been identified, and the severity of the  candidal infection correlates with the severity of the immu-  nologic defect. Most cases are sporadic, although an auto-  somal recessive pattern of inheritance has been identified in  some families. Several recent studies have suggested that the  cytokine IL-17 is critical in mucosal immunity related to  C. albicans, and mutations of the gene responsible for pro-  ducing this cytokine result in mucocutaneous candidiasis.  The immune problem usually becomes evident during the  first few years of life, when the patient begins to have can-  didal infections of the mouth, nails, skin, and other mucosal  surfaces. The oral lesions are usually described as thick,  white plaques that typically do not rub off (essentially  chronic hyperplastic candidiasis), although the other clini-  cal forms of candidiasis may also be seen.   In some patients with mucocutaneous candidiasis, muta-  tions in the autoimmune regulator (AIRE) gene have been  documented, with the resultant formation of autoantibod-  ies directed against the person’s own tissues (Fig. 6-13). In  most instances, the immunologic attack is directed against  the endocrine glands; however, the reasons for this tissue  specificity are currently unclear. Autoimmune destruction  of the T-lymphocytes that produce interleukin-17 (IL-17)  and IL-22 appears to be responsible for the candidal infec-  tions seen in these individuals. Young patients with muco-  cutaneous candidiasis should be evaluated periodically  because any one of a variety of endocrine abnormalities  (i.e, endocrine-candidiasis syndrome, autoimmune  polyendocrinopathy-candidiasis-ectodermal dystrophy  [APECED] syndrome/autoimmune polyendocrinopathy  syndrome, type 1), as well as iron-deficiency anemia, may  develop in addition to the candidiasis. These endocrine  disturbances include hypothyroidism, hypoparathyroidism,  hypoadrenocorticism (Addison disease), and diabetes mel-  litus. Typically, the endocrine abnormality develops months  or even years after the onset of the candidal infection. One    but they actually represent an unusual presentation of hyperplastic candidiasis. B, Treatment with clotrima-  zole oral troches shows complete resolution of the white lesions within 2 weeks, essentially confirming  the diagnosis of hyperplastic candidiasis. If any white mucosal alteration had persisted, a biopsy of that    e Fig. 6-13 Autoimmune Polyendocrinopathy-Candidiasis-  Ectodermal Dystrophy (APECED) Syndrome. A, Erythematous  candidiasis diffusely involving the dorsal tongue of a 32-year-old man.  B, Same patient showing nail dystrophy. C, Corneal keratopathy is  also noted. Patient had a history of the onset of hypoparathyroidism  and hypoadrenocorticism, which were both diagnosed in the second  decade of life.    recent study has documented increased prevalence of oral  and esophageal carcinoma in this condition, with these  malignancies affecting approximately 10% of adults with  APECED syndrome. This finding represents another justi-  fication for periodic reevaluation of these individuals.  Interestingly, the candidal infection remains relatively  superficial rather than disseminating throughout the body.  Both the oral lesions and any cutaneous involvement  (usually presenting as roughened, foul-smelling cutaneous    ® Fig. 6-14 Candidiasis. This cytologic preparation demonstrates  tubular-appearing fungal hyphae and ovoid yeasts of Candida albi-  cans. (Periodic acid-Schiff [PAS] stain.)    plaques and nodules) can be usually controlled with con-  tinuous use of relatively safe systemic antifungal drugs. As  with any long-term antibiotic treatment, development of  drug-resistant organisms can occur, however.    The candidal organism can be seen microscopically in either  an exfoliative cytologic preparation or in tissue sections  obtained from a biopsy specimen. On staining with the  periodic acid-Schiff (PAS) method or the Grocott-Gomori  methenamine silver (GMS) method, the candidal hyphae  and yeasts can be readily identified (Fig. 6-14). Both tech-  niques stain carbohydrates, contained in abundance by  fungal cell walls; the organisms appear bright-magenta with  the PAS stain or black with the GMS stain. To make a  diagnosis of candidiasis, one must be able to see hyphae or  pseudohyphae (which are essentially elongated yeast cells).  These hyphae are approximately 2 [tm in diameter, vary in  their length, and may show branching. Often the hyphae  are accompanied by variable numbers of yeasts, squamous  epithelial cells, and inflammatory cells.   A 10% to 20% potassium hydroxide (KOH) preparation  may also be used to rapidly evaluate specimens for the pres-  ence of fungal organisms. With this technique, the KOH  lyses the background of epithelial cells, allowing the more  resistant yeasts and hyphae to be visualized.   ¢ Greater difficulty in identifying the fungal organisms,  compared with PAS staining   e Inability to assess the nature of the epithelial cell popula-  tion with respect to other conditions, such as epithelial  dysplasia or pemphigus vulgaris   The histopathologic pattern of oral candidiasis may vary  slightly, depending on which clinical form of the infection  has been submitted for biopsy. The features that are found  in common include an increased thickness of parakeratin    S fos Sa oS g ok A >,  e Fig. 6-15 Candidiasis. This medium-power photomicrograph  shows a characteristic pattern of parakeratosis, neutrophilic microab-  scesses, a thickened spinous layer, and chronic inflammation of the  underlying connective tissue associated with long-standing candidal  infection of the oral mucosa.    ® Fig. 6-16 Candidiasis. This high-power photomicrograph shows  the tubular hyphae of Candida albicans embedded in the parakeratin  layer. (Periodic acid-Schiff [PAS] stain.)    on the surface of the lesion in conjunction with elongation  of the epithelial rete ridges (Fig. 6-15). Typically, a chronic  inflammatory cell infiltrate can be seen in the connective  tissue immediately subjacent to the infected epithelium,  and small collections of neutrophils (microabscesses) are  often identified in the parakeratin layer and the superficial  spinous cell layer near the organisms (Fig. 6-16). The can-  didal hyphae are embedded in the parakeratin layer and  rarely penetrate into the viable cell layers of the epithelium  unless the patient is extremely immunocompromised.    The diagnosis of candidiasis is usually established by the  clinical signs in conjunction with exfoliative cytologic  examination. Although a culture can definitively identify  the organism as C. albicans, this process may not be practi-  cal in most office settings. The cytologic findings should  demonstrate the hyphal phase of the organism, and anti-  fungal therapy can then be instituted. If the lesion is    clinically suggestive of chronic hyperplastic candidiasis but  does not respond to antifungal therapy, then a biopsy should  be performed to rule out the possibility of C. albicans super-  imposed on epithelial dysplasia, squamous cell carcinoma,  or lichen planus.   ‘The definitive identification of the organism can be made  by means of culture. A specimen for culture is obtained by  rubbing a sterile cotton swab over the lesion and then  streaking the swab on the surface of a Sabouraud agar slant.  C. albicans will grow as creamy, smooth-surfaced colonies  after 2 to 3 days of incubation at room temperature.    Several antifungal medications have been developed for  managing oral candidiasis, each with its advantages and   In the 1950s, the polyene antibiotic nystatin was the first  effective treatment for oral candidiasis. Nystatin is formu-  lated for oral use as a suspension or pastille (lozenge). Many  patients report that nystatin has a very bitter taste, which  may reduce patient compliance; therefore, the taste has to be  disguised with sucrose and flavoring agents. If the candidia-  sis is due to xerostomia, the sucrose content of the nystatin  preparation may contribute to xerostomia-related caries in  these patients. The gastrointestinal tract poorly absorbs  nystatin and the other polyene antibiotic, amphotericin;  therefore, their effectiveness depends on direct contact with  the candidal organisms. This necessitates multiple daily  doses so that the yeasts are adequately exposed to the drug.  Nystatin combined with triamcinolone acetonide cream or  ointment can be applied topically and is effective for angular  cheilitis that does not have a bacterial component.   For many years in the United States, the use of amphoteri-  cin B was restricted to intravenous (IV) treatment of life-  threatening systemic fungal infections. This medication  subsequently became available as an oral suspension for the  management of oral candidiasis. Unfortunately, the interest  in this formulation of the drug was scant, and it is no longer  marketed in the United States.    The imidazole-derived antifungal agents were developed  during the 1970s and represented a major step forward  in the management of candidiasis. The two drugs of this  group that are used most frequently are clotrimazole and  ketoconazole.   Like nystatin, clotrimazole is not well absorbed and must  be administered several times each day. It is formulated as  a pleasant-tasting troche (lozenge) and produces few side    effects. The efficacy of this agent in treating oral candidiasis  can be seen in Fig. 6-12. Clotrimazole cream is also effective  treatment for angular cheilitis, because this drug has anti-  bacterial and antifungal properties.   Ketoconazole was the first antifungal drug that could be  absorbed across the gastrointestinal tract, thereby providing  systemic therapy by an oral route of administration. The  single daily dose was much easier for patients to use; however,  several disadvantages have been noted. Patients must not  take antacids or H,-blocking agents, because an acidic envi-  ronment is required for proper absorption. Ifa patient is to  take ketoconazole for more than 2 weeks, then liver function  studies are recommended because approximately 1 in 10,000  individuals experience idiosyncratic liver toxicity from the  agent. For this reason, the US Food and Drug Administra-  tion has stated that ketoconazole should not be used as  initial therapy for routine oral candidiasis. Furthermore,  ketoconazole has been implicated in drug interactions  with macrolide antibiotics (e.g., erythromycin), which may  produce potentially life-threatening cardiac arrhythmias.    ‘The triazoles are among the more recently developed anti-  fungal drugs. Both fluconazole and itraconazole have been  approved for treating candidiasis in the United States.   Fluconazole appears to be more effective than ketoconazole;  it is well absorbed systemically, and an acidic environment  is not required for absorption. A relatively long half-life  allows for once-daily dosing, and liver toxicity is rare at the  doses used to treat oral candidiasis. Some reports have sug-  gested that fluconazole may not be appropriate for long-  term preventive therapy because resistance to the drug  seems to develop in some instances. Known drug interac-  tions include a potentiation of the effects of phenytoin  (Dilantin), an antiseizure medication; warfarin compounds  (anticoagulants); and sulfonylureas (oral hypoglycemic  agents). Other drugs that may interact with fluconazole are  summarized in Table 6-2.   Itraconazole has proven efficacy against a variety of fungal  diseases, including histoplasmosis, blastomycosis, and fungal  conditions of the nails. Recently, itraconazole solution was  approved for management of oropharyngeal candidiasis, and  this appears to have an efficacy equivalent to clotrimazole  and fluconazole. As with fluconazole, significant drug inter-  actions are possible, and itraconazole is contraindicated for  patients taking erythromycin, triazolam, and midazolam.  (See Table 6-2 for other potential drug interactions.)    Posaconazole  This relatively new triazole compound has been shown  to be effective in the management of oropharyngeal    candidiasis in patients with HIV infection. Given the cost  of this drug and the proven effectiveness of other, less  expensive, oral antifungal agents, the use of this medication  for treatment of routine oral candidiasis would be difficult  to justify.   This new class of antifungal drugs acts by interfering with  candidal cell wall synthesis. The formation of B-1,3-glucan,  which is a principal component of the candidal cell wall, is  disrupted and results in permeability of the cell wall with  subsequent demise of the candidal organism. These medica-  tions are not well absorbed; consequently they must be  administered intravenously and are reserved for more life-  threatening candidal infections. Examples include caspo-  fungin, micafungin, and anidulafungin.   Although not strictly an antifungal drug, iodoquinol has  antifungal and antibacterial properties. When compounded  in a cream base with a corticosteroid, this material is very  effective as topical therapy for angular cheilitis.   In most cases, oral candidiasis is an annoying superficial  infection that is easily resolved by antifungal therapy. If  infection should recur after treatment, then a thorough  investigation of potential factors that could predispose to  candidiasis, including immunosuppression, may be neces-  sary. In only the most severely compromised patient will  candidiasis cause deeply invasive disease (Fig. 6-17).    Histoplasmosis, the most common systemic fungal infec-  tion in the United States, is caused by the organism Histo-  plasma capsulatum. Like several other pathogenic fungi, H.  capsulatum is dimorphic, growing as a yeast at body tem-  perature in the human host and as a mold in its natural    @ Fig. 6-17 Candidiasis. This necrotic lesion of the upper lip devel-  oped in a man with uncontrolled type | diabetes mellitus. Biopsy and  culture showed a rare example of invasive oral infection by Candida  albicans.    Nystatin Mycostatin Oral candidiasis One or two pastilles (200,000-400,000 units) dissolved slowly in  pastilles the mouth 4 to 5 times daily for 10 to 14 days  Mycostatin oral  suspension  Clotrimazole Mycelex oral Oral candidiasis Dissolve 1 troche (10 mg) slowly in the mouth, 5 times daily for  troches 10 to 14 days  Ketoconazole Nizoral tablets Oral candidiasis Not to be used as initial therapy for oral candidiasis  Blastomycosis One tablet (200 mg) daily for 1 to 2 weeks for candidiasis  Coccidioidomycosis Minimum treatment period for systemic mycoses is 6 months  Histoplasmosis  Paracoccidioidomycosis  Fluconazole Diflucan Oral candidiasis For oral candidiasis: two tablets (200 mg) on day 1 and then  tablets one tablet (100 mg) daily for 1 to 2 weeks  Cryptococcal meningitis  Itraconazole Sporanox Blastomycosis For blastomycosis and histoplasmosis: two capsules (200 mg)  capsules Histoplasmosis daily, increasing by 100-mg increments up to 400 mg daily in  divided doses if no clinical response is noted  Aspergillosis refractory to For aspergillosis: 200 to 400 mg daily  amphotericin B therapy  For life-threatening situations: loading dose of 200 mg t.i.d. for  first 3 days, then dose can be reduced  Treatment should continue for at least 3 months for all of the  above  Itraconazole Sporanox oral — Oral candidiasis 10 mL (100 mg) vigorously swished in the mouth and    1 mL (100 mg) rinse and hold in the mouth for as long as  possible, q.i.d., p.c., and h.s. for 2 weeks    h.s., Hora somni (at bedtime); p.c., post cibum (after meals); g.i.d., quarter in die (four times a day); t.i.d., ter in die (three times a day).    environment. Humid areas with soil enriched by bird or bat  excrement are especially suited to the growth of this organ-  ism. This habitat preference explains why histoplasmosis is  seen endemically in fertile river valleys, such as the region  drained by the Ohio and Mississippi Rivers in the United  States. Airborne spores of the organism are inhaled, pass  into the terminal passages of the lungs, and germinate.  Approximately 500,000 new cases of histoplasmosis are  thought to develop annually in the United States. Other  parts of the world, such as Central and South America,  Europe, and Asia, also report numerous cases. Epidemio-  logic studies in endemic areas of the United States suggest    that 80% to 90% of the population in these regions has  been infected.    Most cases of histoplasmosis produce either no symptoms  or such mild symptoms that the patient does not seek  medical treatment. The expression of disease depends on the  quantity of spores inhaled, the immune status of the host,  and perhaps the strain of H. capsulatum. Most individuals  who become exposed to the organism are relatively healthy  and do not inhale a large number of spores; therefore, they    Periodic assessment of liver function in patients with hepatic  impairment  Nausea, vomiting    Serious hepatotoxicity in 1: 10,000 patients  Monitoring of liver function is indicated for patients with    of hepatic failure, or patients treated for more than 28 days  Serum testosterone is lowered  Nausea, vomiting  Anaphylaxis   Metabolism of cyclosporine, tacrolimus, methylprednisolone,  midazolam, triazolam, coumarin-like drugs, phenytoin, and  rifampin may be altered    Rare cases of hepatotoxicity, ranging from mild transient  elevation of liver enzymes to hepatic failure  Headache, nausea, vomiting, abdominal pain, diarrhea    Clinically or potentially significant side effects have been  noted with the following medications: oral hypoglycemic  agents, coumarin-like drugs, phenytoin, cyclosporine,  rifampin, theophylline, rifabutin, and tacrolimus    Liver function should be monitored in patients with preexisting  hepatic problems on therapy for more than 1 month  Nausea, diarrhea, vomiting    Serious and/or life-threatening interactions with erythromycin,  pimozide, quinidine, oral triazolam, and oral midazolam    Increased plasma concentrations may be seen with warfarin,  ritonavir, indinavir, vinca alkaloid agents, diazepam,  cyclosporine, dihydropyridine medications, tacrolimus,  digoxin, and methylprednisolone    Liver function should be monitored in patients with preexisting  hepatic problems on therapy for more than 1 month  Nausea, diarrhea, vomiting    Serious and/or life-threatening interactions with erythromycin,  oral triazolam, and oral midazolam,  Lovastatin and simvastatin should be discontinued    have either no symptoms or they have a mild, flulike illness  for 1 to 2 weeks. The inhaled spores are ingested by mac-  rophages within 24 to 48 hours, and specific T-lymphocyte  immunity develops in 2 to 3 weeks. Antibodies directed  against the organism usually appear several weeks later. With  these defense mechanisms, the host is usually able to destroy  the invading organism, although sometimes the macro-  phages simply surround and confine the fungus so that  viable organisms can be recovered years later. Thus patients  who formerly lived in an endemic area may have acquired  the organism and later express the disease at some other  geographic site if they become immunocompromised.    Acute histoplasmosis is a self-limited pulmonary infec-  tion that probably develops in only about 1% of people who  are exposed to a low number of spores. With a high con-  centration of spores, as many as 50% to 100% of individu-  als may experience acute symptoms. These symptoms (e.g.,  fever, headache, myalgia, nonproductive cough, and  anorexia) result in a clinical picture similar to that of influ-  enza. Patients are usually ill for 2 weeks, although calcifica-  tion of the hilar lymph nodes may be detected as an  incidental finding on chest radiographs years later.   Chronic histoplasmosis also primarily affects the lungs,  although it is much less common than acute histoplasmosis.    The chronic form usually affects older, emphysematous,  white men or immunosuppressed patients. Clinically, it  appears similar to tuberculosis. Patients typically exhibit  cough, weight loss, fever, dyspnea, chest pain, hemoptysis,  weakness, and fatigue. Chest roentgenograms show upper-  lobe infiltrates and cavitation.   Disseminated histoplasmosis is even less common than  the acute and chronic types. It occurs in 1 of 2000 to 5000  patients who have acute symptoms. This condition is char-  acterized by the progressive spread of the infection to extra-  pulmonary sites. It usually occurs in either older, debilitated,  or immunosuppressed patients. In some areas of the United  States, 2% to 10% of patients with acquired immunode-  ficiency syndrome (AIDS) (see page 251) develop dissemi-  nated histoplasmosis. Patients who are being treated with a  tumor necrosis factor-alpha (TNF-a) inhibitor (such as,  infliximab, etanercept, or adalimumab) and who live in  endemic geographic regions also are at risk for disseminated  disease, probably due to reactivation of the organism.  Tissues that may be affected include the spleen, adrenal  glands, liver, lymph nodes, gastrointestinal tract, central  nervous system (CNS), kidneys, and oral mucosa. Adrenal  involvement may produce hypoadrenocorticism (Addison  disease) (see page 784).   Most oral lesions of histoplasmosis occur with the dis-  seminated form of the disease. The most commonly affected  sites are the tongue, palate, and buccal mucosa. The condi-  tion usually appears as a solitary, variably painful ulceration  of several weeks’ duration; however, some lesions may  appear erythematous or white with an irregular surface (Fig.  6-18). The ulcerated lesions have firm, rolled margins, and  they may be indistinguishable clinically from a malignancy    Microscopic examination of lesional tissue shows either a  diffuse infiltrate of macrophages or, more commonly, col-    ® Fig. 6-18 Histoplasmosis. This ulcerated granular lesion involves  the mandibular labial vestibule and is easily mistaken clinically for  carcinoma. Biopsy established the diagnosis. (Courtesy of Dr. John  Werther.)    lections of macrophages organized into granulomas  (Fig. 6-20). Multinucleated giant cells are usually seen in  association with the granulomatous inflammation. The  causative organism can be identified with some difficulty in  the routine hematoxylin and eosin (H8zE)-stained section;  however, special stains, such as the PAS and Grocott-  Gomori methenamine silver methods, readily demonstrate  the characteristic 1- to 3-lm yeasts of H. capsulatum  (Fig. 6-21).    The diagnosis of histoplasmosis can be made by histopatho-  logic identification of the organism in tissue sections or by  culture. Other helpful diagnostic studies include serologic  testing in which antibodies directed against H. capsulatum  are demonstrated and antigen produced by the yeast is    @ Fig. 6-19 Histoplasmosis. This chronic ulceration of the ventral  and lateral tongue represents an oral lesion of histoplasmosis that had  disseminated from the lungs. The lesion clinically resembles carci-  noma; because of this high-risk site, biopsy is mandatory.    , a = 8 Seis 3,  °® Fig. 6-20 Histoplasmosis. This medium-power photomicrograph  shows scattered epithelioid macrophages admixed with lymphocytes  and plasma cells. Some macrophages contain organisms of Histo-  plasma capsulatum (arrows).    ® Fig. 6-21 Histoplasmosis. This high-power photomicrograph of a  tissue section readily demonstrates the small yeasts of Histoplasma  capsulatum. (Grocott-Gomori methenamine silver stain.)    Acute histoplasmosis, because it is a self-limited process,  generally warrants no specific treatment other than sup-  portive care with analgesic and antipyretic agents. Often the  disease is not treated because the symptoms are so nonspe-  cific and the diagnosis is not readily evident.   Patients with chronic histoplasmosis require treatment,  despite the fact that up to half of them may recover spon-  taneously. Often the pulmonary damage is progressive if it  remains untreated, and death may result in up to 20% of  these cases. For severe cases of chronic histoplasmosis, the  treatment of choice is IV administration of one of the lipid  preparations of amphotericin B, which are significantly less  toxic than standard formulations of amphotericin B deoxy-  cholate. Itraconazole may be used in nonimmunosuppressed  patients because it is associated with even fewer side effects  and is less expensive, but this medication requires daily  dosing for at least 3 months. Although fluconazole has been  used for treatment of histoplasmosis, this agent appears to  be less effective than itraconazole and less likely to produce  a desired therapeutic response.   Disseminated histoplasmosis occurring in an immune-  suppressed individual is a very serious condition that results  in death in 80% to 90% of patients if they remain untreated.  One of the lipid preparations of amphotericin B is indicated  for such patients; once the life-threatening phase of the  disease is under control, daily itraconazole is necessary for  6 to 18 months. Despite therapy, however, a mortality rate  of 7% to 23% is observed. Itraconazole alone may be used  if the patient is nonimmunocompromised and has relatively  mild to moderate disease; however, the response rate is  slower than for patients receiving amphotericin B, and the  relapse rate may be higher.    Blastomycosis is a relatively uncommon disease caused by  the dimorphic fungus known as Blastomyces dermatitidis.    Although the organism is rarely isolated from its natural  habitat, it seems to prefer rich, moist soil, where it grows as  a mold. Much of the region in which it grows overlaps the  territory associated with H. capsulatum (affecting the eastern  half of the United States). The range of blastomycosis  extends farther north, however, including Wisconsin, Min-  nesota, and the Canadian provinces surrounding the Great  Lakes. Sporadic cases have also been reported in Africa,  India, Europe, and South America. By way of comparison,  histoplasmosis appears to be at least ten times more common  than blastomycosis. In some series of cases, a prominent  adult male predilection has been noted, often with a male-  to-female ratio as high as 9:1. Although some researchers  have attributed this to the greater degree of outdoor activity  (e.g., hunting, fishing) by men in areas where the organism  grows, others have noted that these series were typically  reported from VA hospital data, which has an inherent male  bias. The occurrence of blastomycosis in immunocompro-  mised patients is relatively rare.    Blastomycosis is almost always acquired by inhalation of  spores, particularly after a rain. The spores reach the alveoli  of the lungs, where they begin to grow as yeasts at body  temperature. In most patients, the infection is probably  halted and contained in the lungs, but it may become  hematogenously disseminated in a few instances. In order  of decreasing frequency, the sites of dissemination include  skin, bone, prostate, meninges, oropharyngeal mucosa, and  abdominal organs.   Although most cases of blastomycosis are either asymp-  tomatic or produce only very mild symptoms, patients who  do experience symptoms usually have pulmonary com-  plaints. Acute blastomycosis resembles pneumonia, char-  acterized by high fever, chest pain, malaise, night sweats,  and productive cough with mucopurulent sputum. Rarely,  the infection may precipitate life-threatening adult respira-  tory distress syndrome.   Chronic blastomycosis is more common than the acute  form, and it may mimic tuberculosis; both conditions are  often characterized by low-grade fever, night sweats, weight  loss, and productive cough. Chest radiographs may appear  normal, or they may demonstrate diffuse infiltrates or one  or more pulmonary or hilar masses. Unlike the situation  with tuberculosis and histoplasmosis, calcification is not  typically present. Cutaneous lesions usually represent the  spread of infection from the lungs, although occasionally  they are the only sign of disease. Such lesions begin as ery-  thematous nodules that enlarge, becoming verrucous or  ulcerated (Figs. 6-22 and 6-23).   Oral lesions of blastomycosis may result from either  extrapulmonary dissemination or local inoculation with the  organism. These lesions may have an irregular, erythema-  tous or white intact surface, or they may appear as ulcer-  ations with irregular rolled borders and varying degrees of  pain (Figs. 6-24 and 6-25). Clinically, because the lesions    ® Fig. 6-22 Blastomycosis. This granular erythematous plaque of  cutaneous blastomycosis has affected the facial skin. (Courtesy of Dr.  William Welton.)    ° Fig. 6-23 Blastomycosis. Severe cutaneous infection by Blasto-  myces dermatitidis. (Courtesy of Dr. Emmitt Costich.)    resemble squamous cell carcinoma, biopsy and histopatho-  logic examination are required.    Histopathologic examination of lesional tissue typically  shows a mixture of acute inflammation and granulomatous  inflammation surrounding variable numbers of yeasts.  These organisms are 8 to 20 Um in diameter. They are    ® Fig. 6-24 Blastomycosis. These irregular ulcerations of the tongue  represent blastomycosis. Direct inoculation was thought to have  occurred from the patient’s habit of chewing dried horse manure  (“Kentucky field candy”), in which the organism was probably growing.    ® Fig. 6-25 Blastomycosis. Granular exophytic and indurated mass  on the buccal mucosa.    characterized by a doubly refractile cell wall (Fig. 6-26) and  a broad attachment between the budding daughter cell and  the parent cell. Like many other fungal organisms, B. der-  matitidis can be detected more easily using special stains,  such as the Grocott-Gomori methenamine silver and PAS  methods. Identification of these organisms is especially  important, because this infection often induces a benign  reaction of the overlying epithelium in mucosal or skin  lesions called pseudoepitheliomatous (pseudocarcinoma-  tous) hyperplasia. Because this benign elongation of the  epithelial rete ridges may look like squamous cell carcinoma  at first glance under the microscope, careful inspection of  the underlying inflamed lesional tissue is mandatory.    Rapid diagnosis of blastomycosis can be performed by  microscopic examination of either histopathologic sections  or an alcohol-fixed cytologic preparation. The most rapid  means of diagnosis, however, is the KOH preparation,  which may be used for examining scrapings from a sus-  pected lesion. The most accurate method of identifying  B. dermatitidis is by obtaining a culture specimen from    e Fig. 6-26 Blastomycosis. This high-power photomicrograph  shows the large yeasts of Blastomyces dermatitidis (arrow) within a  multinucleated giant cell.    sputum or fresh biopsy material and growing the organism  on Sabouraud agar. This is a slow technique, however, some-  times taking as long as 3 to 4 weeks for the characteristic  mycelium-to-yeast conversion to take place. A specific DNA  probe has been developed, allowing immediate identifica-  tion of the mycelial phase that usually appears by 5 to 7  days in culture. Serologic studies and skin testing are usually  not helpful because of lack of reactivity and specificity.    As stated previously, most patients with blastomycosis are  asymptomatic or have only mild symptoms, so treatment  may not be given because the disease is often not suspected.  In the case of documented symptomatic acute or chronic  pulmonary blastomycosis, itraconazole should be prescribed  for mild to moderate disease, whereas systemic amphoteri-  cin B is indicated for severe cases.   Immunosuppressed patients or those with extrapulmo-  nary lesions also need treatment with amphotericin B, fol-  lowed by 6 to 12 months of itraconazole. Although  ketoconazole and fluconazole are active against B. derma-  titidis, these drugs have been shown to be less effective than  itraconazole.   Disseminated blastomycosis occurs in only a small per-  centage of infected patients and, with proper treatment, the  outlook for the patient is reasonably good. Still, mortality  rates ranging from 4% to 22% have been described over the  past 20 years, with men, blacks, and patients with HIV  infection tending to have less favorable outcomes.    Paracoccidioidomycosis is a deep fungal infection that is  caused by Paracoccidioides brasiliensis. The condition is seen    ® Fig. 6-27 Paracoccidioidomycosis. This granular, erythematous,  and ulcerated lesion of the maxillary alveolus represents infection by  Paracoccidioides brasiliensis. (Courtesy of Dr. Ricardo Santiago  Gomez.)    most frequently in patients who live in either South America  (primarily Brazil, Colombia, Venezuela, Uruguay, and  Argentina) or Central America. However, immigrants from  those regions and visitors to those areas can acquire the  infection. Within some endemic areas, the nine-banded  armadillo has been shown to harbor P brasiliensis (similar  to the situation seen with leprosy) (see page 179). Although  there is no evidence that the armadillo directly infects  humans, it may be responsible for the spread of the organ-  ism in the environment.   Paracoccidioidomycosis has a distinct predilection for  males, with a 15:1 male-to-female ratio typically reported.  This striking difference is thought to be attributable to a  protective effect of female hormones (because f-estradiol  inhibits the transformation of the hyphal form of the organ-  ism to the pathogenic yeast form). This theory is supported  by the finding of an equal number of men and women who  have antibodies directed against the yeast.    Patients with paracoccidioidomycosis are typically middle-  aged at the time of diagnosis, and most are employed  in agriculture. Most cases of paracoccidioidomycosis are  thought to appear initially as pulmonary infections after  exposure to the spores of the organism. Although infections  are generally self-limiting, P brasiliensis may spread by a  hematogenous or lymphatic route to a variety of tissues,  including lymph nodes, skin, and adrenal glands. Adrenal  involvement often results in hypoadrenocorticism (Addison  disease) (see page 784).   Oral lesions are frequently observed and appear as  mulberry-like ulcerations that most commonly affect the  alveolar mucosa, gingiva, and palate (Fig. 6-27). The lips,  tongue, oropharynx, and buccal mucosa are also involved  in a significant percentage of cases. In most patients with  oral lesions, more than one oral mucosal site is affected.    @ Fig. 6-28 Paracoccidioidomycosis. This high-power photomi-  crograph shows a large yeast of Paracoccidioides brasiliensis (arrow)  within the cytoplasm of a multinucleated giant cell. A section stained  with the Grocott-Gomori methenamine silver method (inset) illustrates  the characteristic “Mickey Mouse ears” appearance of the budding  yeasts. (Courtesy of Dr. Ricardo Santiago Gomez.)    Microscopic evaluation of tissue obtained from an oral  lesion may reveal pseudoepitheliomatous hyperplasia in  addition to ulceration of the overlying surface epithelium.  P. brasiliensis elicits a granulomatous inflammatory host  response that is characterized by collections of epithelioid  macrophages and multinucleated giant cells (Fig. 6-28).  Scattered, large (up to 30 [tm in diameter) yeasts are readily  identified after staining of the tissue sections with the  Grocott-Gomori methenamine silver or PAS method. The  organisms often show multiple daughter buds on the parent  cell, resulting in an appearance that has been described as  resembling “Mickey Mouse ears” or the spokes of a ship’s  steering wheel (“mariner’s wheel”).    Demonstration of the characteristic multiple budding yeasts  in the appropriate clinical setting is usually adequate to  establish a diagnosis of paracoccidioidomycosis. Specimens  for culture can be obtained, but P brasiliensis grows quite  slowly.    The method of management of patients with paracoc-  cidioidomycosis depends on the severity of the disease  presentation. Sulfonamide derivatives have been used  since the 1940s to treat this infection. These drugs, such as  trimethoprim/sulfamethoxazole, are still used today in  many instances to treat mild-to-moderate cases, particularly  in developing countries with limited access to the newer,  more expensive antifungal agents. For severe involvement,  IV amphotericin B is usually indicated. Non-life-threaten-  ing cases are best managed by oral itraconazole, although  therapy may be needed for several months. Ketoconazole    can also be used, although the side effects are typically  greater than those associated with itraconazole.    Recent molecular genetic studies have identified two species,  Coccidioides immitis and Coccidioides posadasii, as the fungal  organisms responsible for coccidioidomycosis. C. immitis  grows saprophytically in the alkaline, semiarid, desert soil  of the southwestern United States and Mexico, whereas C.  posadasii is generally found in similar isolated arid regions  in Central and South America, with some overlap in their  ranges. As with several other pathogenic fungi, C. immitis  and C. posadasii are dimorphic organisms, appearing as a  mold in the natural environment of the soil and as a yeast  in tissues of the infected host. Arthrospores produced by  the mold become airborne and can be inhaled into the  lungs of the human host, producing infection. Both  Coccidioides species produce clinically identical signs and  symptoms.   Coccidioidomycosis is confined to the Western hemi-  sphere and is endemic throughout the desert regions of  southwestern United States and Mexico; however, with  modern travel taking many visitors to and from the Sunbelt,  this disease can be encountered virtually anywhere in the  world. It is estimated that 100,000 people are infected  annually in the United States, although 60% of this group  are asymptomatic.    Even though most infections with C. immitis are asymp-  tomatic, approximately 40% of infected patients experience  a flulike illness and pulmonary symptoms within 1 to 3  weeks after inhaling the arthrospores. Fatigue, cough, chest  pain, myalgias, and headache are commonly reported,  lasting several weeks with spontaneous resolution in most  cases. Occasionally, the immune response may trigger a  hypersensitivity reaction that causes the development of an  erythema multiforme—like cutaneous eruption (see page  723) or erythema nodosum. Erythema nodosum is a condi-  tion that usually affects the skin of the legs and is character-  ized by the appearance of multiple painful erythematous  inflammatory nodules in the subcutaneous connective  tissue. This hypersensitivity reaction occurring in conjunc-  tion with coccidioidomycosis is termed valley fever, and  it resolves as the host cell-mediated immune response  controls the pulmonary infection.   Chronic progressive pulmonary coccidioidomycosis  is relatively rare. It mimics tuberculosis, with its clinical  presentation of persistent cough, hemoptysis, chest pain,  low-grade fever, and weight loss.   Disseminated coccidioidomycosis occurs when the  organism spreads hematogenously to extrapulmonary sites.    ® Fig. 6-29 Coccidioidomycosis. This ulcerated nodule involving  the mid-dorsal tongue represents disseminated coccidioidomycosis.  (Courtesy of Dr. Craig Fowler.)    This occurs in less than 1% of cases, but it is a more serious  problem. The most commonly involved areas include skin,  lymph nodes (including cervical lymph nodes), bone and  joints, and the meninges. Immunosuppression greatly  increases the risk of dissemination. The following groups are  particularly susceptible:   Infants and older adult patients, both of whom may have  suboptimally functioning immune systems, also may be at  increased risk for disseminated disease. Persons of color  (e.g., blacks, Filipinos, and Native Americans) also seem to  have an increased risk, but it is unclear whether their sus-  ceptibility is due to genetic causes or socioeconomic factors,  such as occupation or poor nutrition.   The cutaneous lesions may appear as papules, subcutane-  ous abscesses, verrucous plaques, and granulomatous  nodules. Of prime significance to the clinician is the predi-  lection for these lesions to develop in the area of the central  face, especially the nasolabial fold. Oral lesions are distinctly  uncommon, and these have been described as ulcerated  granulomatous nodules (Fig. 6-29).    Biopsy material shows large (20 to 60 Um), round spherules  that may contain numerous endospores. The host response  may be variable, ranging from a suppurative, neutrophilic  infiltrate to a granulomatous inflammatory response. In  some cases, the two patterns of inflammation are seen con-  currently. Special stains, such as the PAS and Grocott-  Gomori methenamine silver methods, enable the pathologist  to identify the organism more readily.    The diagnosis of coccidioidomycosis can be confirmed by  culture or identification of characteristic organisms in  biopsy material. If the organisms do not have a classic  microscopic appearance, then im situ hybridization studies  using specific complementary DNA probes for C. immitis  can be performed to definitively identify the fungus. Cyto-  logic preparations from bronchial swabbing or sputum  samples may also reveal the organisms.   Serologic studies are helpful in supporting the diagnosis,  and they may be performed at the same time as skin testing.  Skin testing by itself may be of limited value in determining  the diagnosis, because many patients in endemic areas have  already been exposed to the organism and have positive test    The decision whether or not to treat a particular patient  affected by coccidioidomycosis depends on the severity and  extent of the infection and the patient's immune status.  Relatively mild symptoms in an immunocompetent person  do not warrant treatment. Amphotericin B is administered  for the following groups:  ¢ Immunosuppressed patients  e Patients with severe pulmonary infection  e Patients who have disseminated disease  ¢ Patients who are pregnant  ¢ Patients who appear to be in a life-threatening situation  concerning the infection  For many cases of coccidioidomycosis, fluconazole or  itraconazole is the drug of choice, usually given in high  doses for an extended period of time. Although the response  of the disease to these oral azole medications may be some-  what slower than that of amphotericin B, the side effects  and complications of therapy are far fewer.    Cryptococcosis is a relatively uncommon fungal disease  caused primarily by the yeast Cryptococcus neoformans in  North America. This organism normally causes no problem  in immunocompetent people, but it can be devastating to  the immunocompromised patient. The incidence of cryp-  tococcosis increased dramatically during the 1990s, primar-  ily because of the AIDS epidemic. At that time, this was  the most common life-threatening fungal infection in these  patients. However, with the advent of combination antiret-  roviral therapy (CART) (see page 253), this complication  has become less of a problem in the United States. In coun-  tries where the population cannot afford cART, cryptococ-  cosis remains a significant cause of death for AIDS patients.  The disease has a worldwide distribution because of its  association with the pigeon (with the organism living in the  deposits of excreta left by the birds). Unlike many other  pathogenic fungi, C. neoformans grows as a yeast both in    the soil and in infected tissue. The organism usually pro-  duces a prominent mucopolysaccharide capsule that appears  to protect it from host immune defenses.   The disease is acquired by inhalation of C. neoformans  spores into the lungs, resulting in an immediate influx of  neutrophils, which destroys most of the yeasts. Macro-  phages soon follow, although resolution of infection in the  immunocompetent host ultimately depends on an intact  cell-mediated immune system.   Over the past decade, molecular genetic studies have  identified another species of Cryptococcus, designated Cryp-  tococcus gattii, which had initially been thought to be a  serotype of C. neoformans. This organism seems to be more  capable of producing infection in otherwise normal immu-  nocompetent individuals. Although C. gattii is more com-  monly found in tropical and subtropical environments,  outbreaks have been documented in the Pacific Northwest  in North America.    Primary cryptococcal infection of the lungs is often asymp-  tomatic; however, a mild flulike illness may develop. Patients  complain of productive cough, chest pain, fever, and  malaise. Most patients with a diagnosis of cryptococcosis  have a significant underlying medical problem related to  immune suppression (e.g., systemic corticosteroid therapy,  cancer chemotherapy, malignancy, and AIDS). It is esti-  mated that 5% to 10% of AIDS patients acquire this infec-  tion (see page 239).   Dissemination of the infection is common in these  immunocompromised patients, and the most frequent site  of involvement is the meninges, followed by skin, bone, and  the prostate gland.   Cryptococcal meningitis is characterized by headache,  fever, vomiting, and neck stiffness. In many instances, this  is the initial sign of the disease.   Cutaneous lesions develop in 10% to 15% of patients  with disseminated disease. These are of particular impor-  tance to the clinician, because the skin of the head and neck  is often involved. The lesions appear as erythematous  papules or pustules that may ulcerate, discharging a puslike  material rich in cryptococcal organisms (Fig. 6-30).   Although oral lesions are relatively rare, they have been  described either as craterlike, nonhealing ulcers that are  tender on palpation or as friable papillary erythematous  plaques. Dissemination to salivary gland tissue also has been  reported rarely.    Microscopic sections of a cryptococcal lesion generally show  a granulomatous inflammatory response to the organism.  The extent of the response may vary, however, depending  on the host’s immune status and the strain of the organism.  ‘The yeast appears as a round-to-ovoid structure, 4 to 6 Um  in diameter, surrounded by a clear halo that represents the    ® Fig. 6-30 Cryptococcosis. These papules of the facial skin rep-  resent disseminated cryptococcal infection in a patient infected with  human immunodeficiency virus (HIV). (Courtesy of Dr. Catherine Flaitz.)    capsule. Staining with the PAS or Grocott-Gomori methe-  namine silver method readily identifies the fungus; more-  over, a mucicarmine stain uniquely demonstrates its  mucopolysaccharide capsule.    The diagnosis of cryptococcosis can be made by several  methods, including biopsy and culture. Detection of cryp-  tococcal polysaccharide antigen in the serum or cerebrospi-  nal fluid is also useful as a diagnostic procedure.    Management of cryptococcal infections can be very difficult  because most of the affected patients have an underlying  medical problem. Before amphotericin B was developed,  cryptococcosis was almost uniformly fatal. For cryptococcal  meningitis, a combination of systemic amphotericin B and  another antifungal drug (flucytosine) is used initially for 2  weeks in most cases to treat this disease. Then, either fluco-  nazole or itraconazole is given for an additional minimal  period of 10 weeks. For relatively mild cases of pulmonary  cryptococcosis, only fluconazole or itraconazole may be  used. These drugs produce far fewer side effects than do  amphotericin B and flucytosine, and they have proven to  be important therapeutic tools for managing this type of  infection.    Mucormycosis is an opportunistic, frequently fulminant,  fungal infection that is caused by normally saprobic organ-  isms of the subphylum Mucoromycotina, including such  genera as Absidia, Mucor, Rhizomucor, and Rhizopus. The  term zygomycosis is still used extensively in the literature,  although recent molecular genetic studies have indicated    that the class Zygomycetes actually is comprised of several  unrelated fungi. Mucoromycotina organisms are found  throughout the world, growing in their natural state on a  variety of decaying organic materials. Numerous spores may  be liberated into the air and inhaled by the human host.  Mucormycosis may involve any one of several areas of  the body, but the rhinocerebral form is most relevant to the  oral health care provider. Mucormycosis is noted especially  in insulin-dependent diabetics who have uncontrolled dia-  betes and are ketoacidotic; ketoacidosis inhibits the binding  of iron to transferrin, allowing serum iron levels to rise. The  growth of these fungi is enhanced by iron, and patients who  are taking deferoxamine (an iron-chelating agent used in  the treatment of diseases, such as thalassemia) are also at  increased risk for developing mucormycosis. As with many  other fungal diseases, this infection affects immunocompro-  mised patients as well, including bone marrow transplant  recipients, patients with AIDS, and those receiving systemic  corticosteroid therapy. Only rarely has mucormycosis been  reported in apparently healthy individuals in the oral region.    The presenting symptoms of rhinocerebral mucormycosis  may be exhibited in several ways. Patients may experience  nasal obstruction, bloody nasal discharge, facial pain or  headache, facial swelling or cellulitis, and visual distur-  bances with concurrent proptosis. Symptoms related to  cranial nerve involvement (e.g., facial paralysis) are often  present. With progression of disease into the cranial vault,  blindness, lethargy, and seizures may develop, followed by  death.   If the maxillary sinus is involved, the initial presentation  may be seen as intraoral swelling of the maxillary alveolar  process, the palate, or both. If the condition remains  untreated, palatal ulceration may evolve, with the surface of  the ulcer typically appearing black and necrotic. Massive  tissue destruction may result if the condition is not treated    @ Fig. 6-31 Mucormycosis. Diffuse tissue destruction involving the  nasal and maxillary structures caused by a Mucor species. (Courtesy  of Dr. Sadru Kabari.)    Radiographically, opacification of the sinuses may be  observed in conjunction with patchy effacement of the  bony walls of the sinuses (Fig. 6-33). Such a picture may  be difficult to distinguish from that of a malignancy affect-  ing the sinus area.    Histopathologic examination of lesional tissue shows exten-  sive necrosis with numerous large (6 to 30 Lm in diameter),  branching, nonseptate hyphae at the periphery (Fig. 6-34).  The hyphae tend to branch at 90-degree angles. The exten-  sive tissue destruction and necrosis associated with this  disease are undoubtedly attributable to the preference of the  fungi for invasion of small blood vessels. This disrupts  normal blood flow to the tissue, resulting in infarction and  necrosis. A neutrophilic infiltrate usually predominates in  the viable tissue, but the host inflammatory cell response to  the infection may be minimal, particularly if the patient is  immunosuppressed.    ® Fig. 6-32 Mucormycosis. The extensive black, necrotic lesion of  the palate represents mucormycotic infection that extended from the  maxillary sinus in a patient with poorly controlled type | diabetes mel-  litus. (Courtesy of Dr. Michael Tabor.)    ° Fig. 6-33 Mucormycosis. This computed tomography (CT) scan  demonstrates the opacification of the left maxillary sinus (arrow).    e Fig. 6-34 Mucormycosis. This high-power photomicrograph  shows the large, nonseptate fungal hyphae characteristic of the  mucormycotic organisms.    Diagnosis of mucormycosis is usually based on the histo-  pathologic findings. Because of the grave nature of this  infection, appropriate therapy must be instituted in a timely  manner (often without the benefit of definitive culture  results).    Successful treatment of mucormycosis consists of rapid  accurate diagnosis of the condition, followed by radical  surgical débridement of the infected, necrotic tissue and  systemic administration of high doses of one of the lipid  formulations of amphotericin B. Magnetic resonance  imaging (MRI) of the head may be useful in determining  the extent of disease involvement so that surgical margins  can be planned. Evaluation of frozen sections of curetted  tissue, which has been stained with Calcofluor white and  examined with fluorescence microscopy, can also be used to  guide the extent of débridement. In addition, control of the  patient’s underlying disease (e.g., diabetic ketoacidosis)  must be attempted.   Despite such therapy, the prognosis is usually poor, with  approximately 40% to 50% of patients who develop rhino-  cerebral mucormycosis dying of their disease. Because their  underlying systemic disease can usually be controlled, dia-  betic patients typically have a better prognosis than those  who are immunosuppressed. If the patient survives, the  massive tissue destruction that remains presents a challenge  both functionally and aesthetically. Prosthetic obturation of  palatal defects may be necessary.    Aspergillosis is a fungal disease that is characterized by  noninvasive and invasive forms. Noninvasive aspergillosis  usually affects a normal host, appearing either as an allergic  reaction or a cluster of fungal hyphae. Localized invasive    ° Fig. 6-35 Aspergillosis. The opaque appearance of the right max-  illary sinus is due to the presence of a fungus ball (aspergilloma).  (Courtesy of Dr. Bart Farrell.)    infection of damaged tissue may be seen in a normal host,  but a more extensive invasive infection is often evident in  the immunocompromised patient. With the advent of  intensive chemotherapeutic regimens, the AIDS epidemic,  and both solid-organ and bone marrow transplantation, the  prevalence of invasive aspergillosis has increased dramati-  cally in the past 20 years. Patients with uncontrolled diabe-  tes mellitus are also susceptible to Aspergillus spp. infections.  Rarely, invasive aspergillosis has been reported to affect the  paranasal sinuses of apparently normal immunocompetent  individuals.   Normally, the various species of the Aspergillus genus  reside worldwide as saprobic organisms in soil, water, or  decaying organic debris. Resistant spores are released into  the air and inhaled by the human host, resulting in oppor-  tunistic fungal infection second in frequency only to can-  didiasis. Interestingly, most species of Aspergillus cannot  grow at 37° C; only the pathogenic species have the ability  to replicate at body temperature.   The two most commonly encountered species of Asper-  gillus in the medical setting are A. flavus and A. fumigatus,  with A. fumigatus being responsible for most cases of asper-  gillosis. The patient may acquire such infections in the  hospital (“nosocomial” infection), especially if remodeling  or building construction is being performed in the immedi-  ate area. Such activity often stirs up the spores, which are  then inhaled by the patient.    The clinical manifestations of aspergillosis vary, depending  on the host immune status and the presence or absence of  tissue damage. In the normal host, the disease may appear  as an allergy affecting either the sinuses (allergic fungal  sinusitis) or the bronchopulmonary tract. An asthma attack  may be triggered by inhalation of spores by a susceptible  person. Sometimes a low-grade infection becomes estab-  lished in the maxillary sinus, resulting in a mass of fungal  hyphae called a fungus ball, although aspergilloma and  mycetoma are terms that are also sometimes used (Fig.  6-35). Occasionally, the mass will undergo dystrophic cal-  cification, producing a radiopaque body called an antrolith  within the sinus.    ® Fig. 6-36 Aspergillosis. This young woman developed a painful  purplish swelling of her hard palate after induction chemotherapy for  leukemia.    Another presentation that may be encountered by the  oral health care provider is aspergillosis after tooth extraction  or endodontic treatment, especially in the maxillary poste-  rior segments. Presumably, tissue damage predisposes the  sinus to infection, resulting in symptoms of localized pain  and tenderness accompanied by nasal discharge. Immuno-  compromised patients are particularly susceptible to oral  aspergillosis, and some investigators have suggested that the  portal of entry may be the marginal gingiva and gingival  sulcus. Painful gingival ulcerations are initially noted, and  peripherally the mucosa and soft tissue develops diffuse  swelling with a gray or violaceous hue (Fig. 6-36). If the  disease is not treated, extensive necrosis, which is seen clini-  cally as a yellow or black ulcer, and facial swelling evolve.   Disseminated aspergillosis occurs principally in immu-  nocompromised patients, particularly in those who have  leukemia or who are taking high daily doses of corticoste-  roids. Such patients usually exhibit symptoms related to the  primary site of inoculation: the lungs. The patient typically  has chest pain, cough, and fever, but such symptoms are  vague. Therefore, obtaining an early, accurate diagnosis  may be difficult. Once the fungal organism obtains access  to the bloodstream, infection can spread to such sites as the  CNS, eye, skin, liver, gastrointestinal tract, bone, and  thyroid gland.    Tissue sections of invasive Aspergillus spp. lesions show  varying numbers of branching, septate hyphae, 3 to 4 Um  in diameter (Figs. 6-37 and 6-38). These hyphae show a  tendency to branch at an acute angle and to invade adjacent  small blood vessels. Occlusion of the vessels often results in  the characteristic pattern of necrosis associated with this  disease. In the immunocompetent host, a granulomatous  inflammatory response—in addition to necrosis—can be  expected. In the immunocompromised patient, however,  the inflammatory response is often weak or absent, leading  to extensive tissue destruction.    ® Fig. 6-37 Aspergillosis. This photomicrograph reveals fungal  hyphae and a fruiting body of an Aspergillus species.    ® Fig. 6-38 Aspergillosis. This high-power photomicrograph shows  the characteristic septate hyphae of Aspergillus species. (Grocott-  Gomori methenamine silver stain.)    Noninvasive forms of aspergillosis have histopathologic  features that differ from invasive aspergillosis, however. The  fungus ball, for example, is characterized by a tangled mass  of hyphae with no evidence of tissue invasion. Because  the fungus ball develops in a paranasal sinus (where it is  exposed to air), spore-bearing structures called fruiting  bodies are formed (see Fig. 6-37). Allergic fungal sinusitis,  on the other hand, histopathologically exhibits large  pools of eosinophilic inspissated mucin with interspersed  sheetlike collections of lymphocytes and eosinophils. Rela-  tively few fungal hyphae are identified, and then only with  careful examination after Grocott-Gomori methenamine  silver staining.    Although the diagnosis of fungal infection can be estab-  lished by identification of hyphae within tissue sections, this  finding is only suggestive of aspergillosis because other  fungal organisms may appear similar microscopically.  Ideally, the diagnosis should be supported by culture of the  organism from the lesion; however, from a_ practical    standpoint, treatment may need to be initiated immediately  to prevent the patient’s demise. Culture specimens of  sputum and blood are of limited value, because they are  often negative despite disseminated disease.    Treatment depends on the clinical presentation of aspergil-  losis. For immunocompetent patients with a noninvasive  aspergilloma, surgical débridement may be all that is neces-  sary. Patients who have allergic fungal sinusitis are treated  with débridement and corticosteroid drugs. For localized  invasive aspergillosis in the immunocompetent host,  débridement followed by antifungal medication is indi-  cated. Although systemic amphotericin B deoxycholate  therapy was considered appropriate in the past, studies have  shown that voriconazole, a triazole antifungal agent, is more  effective for treating these patients. In one large series of  patients with invasive aspergillosis, 71% of those treated  with voriconazole were alive after 12 weeks of therapy,  compared with 58% survival in the group who received  standard amphotericin B treatment. For patients who  cannot tolerate voriconazole, alternative drugs include lipo-  somal amphotericin B or caspofungin. Immunocompro-  mised patients who have invasive aspergillosis should be  treated by aggressive débridement of necrotic tissue, com-  bined with systemic antifungal therapy as described  previously.   The prognosis for immunocompromised patients is  much worse compared with immunocompetent individu-  als, particularly if the infection is disseminated. Even with  appropriate therapy, only about one third of these patients  survive. Because aspergillosis in the immunocompromised  patient usually develops while the individual is hospitalized,  particular attention should be given to the ventilation  system in the hospital to prevent patient exposure to the  airborne spores of Aspergillus spp.    Toxoplasmosis is a relatively common disease caused by the  obligate intracellular protozoal organism Toxoplasma gondii.  For normal, healthy adults, the organism poses no prob-  lems, and an estimated 16% to 23% of adults in the United  States may have had asymptomatic infection, based on an  epidemiologic study that examined serologic samples from  more than 4000 randomized individuals. However, the  prevalence of infection has considerable geographic varia-  tion around the world. Unfortunately, the disease can be  devastating for the developing fetus or the immunocompro-  mised patient. Other mammals, particularly members of  the cat family, are vulnerable to infection, and cats are con-  sidered to be the definitive host. 7’ gondii multiplies in the  intestinal tract of the cat by means of a sexual life cycle,  discharging numerous oocysts in the cat feces. Another  animal or human can ingest these oocysts, resulting in the  production of disease.    In the normal, immunocompetent individual, infection  with 7) gondii is often asymptomatic. If symptoms develop,  they are usually mild and resemble infectious mononucleo-  sis; patients may have a low-grade fever, cervical lymphade-  nopathy, fatigue, and muscle or joint pain. These symptoms  may last from a few weeks to a few months, although the  host typically recovers without therapy. Sometimes the  lymphadenopathy involves one or more of the lymph nodes  in the paraoral region, such as the buccal or submental  lymph node. In such instances, the oral health care provider  may discover the disease.   In immunosuppressed patients, toxoplasmosis may rep-  resent a new, primary infection or, more frequently, reacti-  vation of previously encysted organisms. The principal  groups at risk include the following:   Manifestations of infection can include necrotizing  encephalitis, pneumonia, and myositis or myocarditis. In  the United States, it is estimated that from 3% to 10% of  AIDS patients who are not being treated with combination  antiretroviral therapy (cART) (see page 239) will experience  CNS involvement. CNS infection is very serious. Clinically,  the patient may complain of headache, lethargy, disorienta-  tion, and hemiparesis.   Congenital toxoplasmosis occurs when a non-immune  mother contracts the disease during her pregnancy and  the organism crosses the placental barrier, infecting the  developing fetus. The potential effects of blindness, intel-  lectual impairment, and delayed psychomotor development  are most severe if the infection occurs during the first tri-  mester of pregnancy.    Histopathologic examination of a lymph node obtained  from a patient with active toxoplasmosis shows characteris-  tic reactive germinal centers exhibiting an accumulation of  eosinophilic macrophages. The macrophages encroach on  the germinal centers and accumulate within the subcapsular  and sinusoidal regions of the node (Fig. 6-39).    The diagnosis of toxoplasmosis is usually established by  identification of rising serum antibody titers to T’ gondii  within 10 to 14 days after infection. Immunocompromised  patients, however, may not be able to generate an antibody  response; therefore, the diagnosis may rest on the clinical  findings and the response of the patient to therapy.   Biopsy of an involved lymph node may suggest the  diagnosis, and the causative organisms can sometimes  be detected immunohistochemically using antibodies  directed against 7’ gondii—specific antigens (Fig. 6-40). The    shows an accumulation of eosinophilic macrophages within a lymph  node. (Courtesy of Dr. John Kalmar.)    ate oe aaa — > aoe ES  ® Fig. 6-40 Toxoplasmosis. In this high-power photomicrograph, an  encysted organism of toxoplasmosis is highlighted by an immunchis-  tochemical study. (Courtesy of Dr. John Kalmar.)    Most healthy adults with toxoplasmosis require no specific  treatment because of the mild symptoms and self-limiting  course. Perhaps more importantly, pregnant women should  avoid situations that place them at risk for the disease.  Handling or eating raw meat, eating raw, unpeeled fruits or  vegetables, or cleaning a cat litter box should be avoided  until after delivery. If exposure during pregnancy is sus-  pected, treatment with a combination of sulfadiazine and  pyrimethamine often prevents transmission of 7’ gondii to  the fetus, although pyrimethamine is contraindicated in the  first trimester due to its potential teratogenicity. Because  these drugs act by inhibiting folate metabolism of the pro-  tozoan, folinic acid is given concurrently to help prevent  hematologic complications in the patient. A similar drug  regimen is used to treat immunosuppressed individuals with  toxoplasmosis, although clindamycin may be substituted    for sulfadiazine in managing patients who are allergic to  sulfa drugs. Because most cases of toxoplasmosis in AIDS  patients represent reactivation of encysted organisms, pro-  phylactic administration of trimethoprim and sulfamethox-  azole is generally recommended, particularly if the patient’s  CD4+ T-lymphocyte count is less than 100 cells/WL.    Leishmaniasis is a protozoal infection that is transmitted to  humans by the bite of certain species of sandfly. Both Old  World and New World forms of the disease are recognized,  and they are caused by different species of sandfly as well as  different species of Leishmania. Although the disease has  been reported on every continent except Australia and Ant-  arctica, most of the cases are found in relatively few coun-  tries, particularly India (Bihar State), Afghanistan, Saudi  Arabia, Syria, Algeria, Peru, and Brazil. Of course, because  of international travel to these areas, leishmaniasis can be  seen in virtually every corner of the earth.   Dogs and other mammals are the primary reservoir for  leishmaniasis, and in the mammalian host, the organism is  an obligate intracellular parasite. When an infected animal  is bitten by the female sandfly, macrophages containing the  amastigote (lacking flagella) phase of the organism are  ingested by the fly as it drinks the animal’s blood. In the  gut of the sandfly, the amastigote organisms develop into  free-living promastigotes (having flagella). When the fly  later bites a human (or another mammal), the promastigote  organisms are injected into the subcutaneous tissues, where  they are phagocytosed by macrophages, neutrophils, or den-  dritic cells. Once ingested, the promastigote transforms into  an amastigote, which multiplies within the host cells, com-  pleting the parasitic cycle. Sometimes the replication is so  pronounced that the phagocytic host cells ruptures, releas-  ing amastigotes into the bloodstream, and causing infection  of more host cells.   ¢ Cutaneous—either Old World or New World; New  World cases caused by Leishmania mexicana complex   ¢ Visceral (“kala-azar”)—either Old World or New World;  caused primarily by Leishmania donovani in the Old  World; Leishmania braziliensis in the New World  Cutaneous leishmaniasis is by far the most common   form of the disease. Individual lesions develop 3 to 6 weeks    @ Fig. 6-41 Leishmaniasis. Ulceration and granulomatous enlarge-  ment of the palatal mucosa in a patient with mucocutaneous leish-  maniasis. (Courtesy of Dr. Ricardo Santiago Gomez.)    Mucocutaneous leishmaniasis is not as common as cuta-  neous leishmaniasis, but it is much more destructive. Most  of the Leishmania species responsible for this form of the  disease are found in South America. The skin of affected  patients shows more diffuse involvement, characterized by  scaly and ulcerative plaques and nodules. From several  months to as long as 5 years later, mucosal involvement  develops. Typically this begins with the nasal mucosa, but  oral, pharyngeal, tracheal, and laryngeal mucosa often are  involved eventually (Fig. 6-41). Perforation of the nasal  septum or the hard and soft palate, as well as destruction of  the alveolar bone, may be present. The extent of the damage  may be so severe that it can be a life-threatening process.   Visceral leishmaniasis (also known as kala-azar, which is  Hindi for “black fever”) is characterized by grayish discol-  oration of the skin in some patients, hepatosplenomegaly,  fever (usually related to pancytopenia), and weight loss. The  severity of disease expression is undoubtedly related to the  health of the patient prior to infection.    The amastigote Leishmania organisms can be detected  within the cytoplasm of histiocytes in touch preparations of  infected tissue or in histopathologic sections. The protozo-  ans may be seen in routine H&E-stained sections, but other  stains such as Giemsa, Brown-Hopps (a tissue Gram stain),  or Leishman methods may aid identification. In older,  chronic lesions, the organisms may be sparse, making the  diagnosis more challenging.    Although the diagnosis of leishmaniasis often can be made  on the cytologic or histopathologic findings, it is sometimes  necessary to obtain tissue for culture or polymerase chain    reaction (PCR) studies. These latter techniques are usually  available only at specialized laboratories. Serologic studies  can be difficult to interpret at times because many individu-  als in endemic areas have had exposure to the organism,  although they may not have active disease.    Since the 1920s, antimony compounds have been used to  treat leishmaniasis, but these drugs often have significant  side effects because they are heavy metals. Liposomal  amphotericin B is ideally the drug of choice, but this less  toxic compound is often too expensive for widespread use  in developing countries. Most leishmaniasis patients receive  treatment with pentavalent antimonial compounds, with  the antiprotozoal drug pentamidine used for patients who  cannot tolerate antimonial compounds. Attempts to develop  a vaccine have not met with success.   The prognosis of leishmaniasis can be affected by both  host factors (e.g., malnutrition and immune suppression)  and organism factors, which are related to the Leishmania  species responsible for infection. Without treatment, vis-  ceral leishmaniasis has an ominous prognosis and often  results in death, whereas cutaneous leishmaniasis is typically  a chronic, bothersome superficial infection. Mucocutaneous  leishmaniasis has an intermediate course, although signifi-  cant morbidity results from tissue destruction by the infec-  tion. All forms of leishmaniasis generally require weeks to  months of therapy, and relapses are relatively common.   Allen CM: Diagnosing and managing oral candidiasis, / Am Dent  Assoc 123:77—-82, 1992.   Arendoff TM, Walker DM: The prevalence and intra-oral distribution  of Candida albicans in man, Arch Oral Biol 25:1-10, 1980.   Barbeau J, Séguin J, Goulet JP, et al: Reassessing the presence of  Candida albicans in denture-related stomatitis, Oral Surg Oral Med  Oral Pathol Oral Radiol Endod 95:51-59, 2003.   Baughman RA: Median rhomboid glossitis: a developmental anomaly?  Oral Surg Oral Med Oral Pathol 31:56-65, 1971.   Bergendal T, Isacsson G: A combined clinical, mycological and his-  tological study of denture stomatitis, Acta Odontol Scand 41:33-  44, 1983.   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The best-known member of this family is herpes simplex  virus (HSV), which includes HSV type 1 (HSV-1 or  HHV-1) and HSV type 2 (HSV-2 or HHV-2). Other  members of the HHV family include varicella-zoster virus  (VZV or HHV-3), Epstein-Barr virus (EBV or HHV-4),  cytomegalovirus (CMV or HHV-5), and more recently  discovered members, HHV-6, HHV-7, and HHV-8.  Humans are the only natural reservoir for these viruses,  which are endemic worldwide.   The term herpes derives from the ancient Greek word  meaning to creep or crawl, which apparently alludes to a  tendency for spreading, latent, or recurrent infection. All  eight types cause a primary infection and remain latent  within specific cell types for the life of the individual. On  reactivation, these viruses cause recurrent infections that  may be symptomatic or asymptomatic. ‘The viruses are shed  in saliva or genital secretions, providing an avenue for infec-  tion of new hosts. Each type is known to transform cells in  tissue culture, with several strongly associated with specific  malignancies. The following sections concentrate on HSV,  VZV, CMV and EBV. Much less is known about herpesvirus  types 6, 7, and 8.   Human herpesvirus 6 (HHV-6) and 7 (HHV-7) are  closely related, usually transmitted by saliva or respiratory  droplets, and exhibit infection rates close to 90% by age 5  in the United States. Primary infection usually is asymp-  tomatic but may cause an acute febrile illness followed by  an erythematous maculopapular eruption. This pattern of  symptomatic primary infection—termed roseola (exan-  thema subitum, sixth disease)—most often is caused by  HHV-6 but also may be caused by HHV-7. Both viruses  may replicate in salivary glands and establish latency in  CD4+ T lymphocytes or other cell types. Reactivation  occurs most frequently in immunocompromised patients  and can result in widespread multiorgan infection, includ-  ing encephalitis, pneumonitis, bone-marrow suppression,  and hepatitis.   Human herpesvirus 8 (HHV-8) is involved in the  pathogenesis of Kaposi sarcoma (KS) (see page 520) and    has been termed Kaposi sarcoma—associated herpesvirus  (KSHV). In immunocompetent persons, primary infection  usually is asymptomatic, with male-to-male sexual contact  being the most common mode of transmission in Western  countries. The virus is found without difficulty in saliva,  suggesting another possible pattern of transmission. Associ-  ated symptoms, such as transient fever, lymphadenopathy,  and arthralgias, are rarely reported. Circulating B lympho-  cytes appear to be the major cell of latency. In addition to  Kaposi sarcoma, HHV-8 is associated with certain types of  lymphoma and a benign lymphoid proliferation known as  Castleman disease.   Interestingly, several studies have demonstrated genetic  material from herpesviruses (including EBV, CMV, HHV-6,  and HHV-7) in periapical inflammatory lesions and peri-  odontitis. The significance of these findings is uncertain,  although some investigators speculate that interactions  between herpesviruses, bacteria, and the host immune  response might play a role in the pathogenesis of such  lesions.    The two herpes simplex viruses are similar in structure and  disease mechanisms but differ in antigenicity, anatomic site  predilection, and epidemiology. Differences in envelope gly-  coproteins account for their distinct antigenicity. Neverthe-  less, there is potential for antibody cross-reactivity, and  antibodies directed against one type may decrease the likeli-  hood or severity of infection with the other type.   HSV-1 is spread predominantly through infected saliva  or active perioral lesions and adapted best to the oral, facial,  and ocular areas. The pharynx, intraoral mucosa, lips, eyes,  and skin above the waist are involved most frequently.  Genital HSV-1 infection is uncommon, although recent  studies have shown an increase in the proportion of genital  herpes caused by HSV-1 in developed nations. This trend  has been attributed to an increase in oral-genital sexual  behavior and lower rates of nonsexual HSV-1 acquisition in  childhood.   HSV-2 is adapted best to the genital zones, is transmitted  predominantly through sexual contact, and typically  involves the genitalia and skin below the waist. Oral and   The natural history of HSV infection includes primary  infection, latency, and recurrent infection. Primary infec-  tion refers to initial exposure of an individual without anti-  bodies to the virus. Primary infection with HSV-1 typically  occurs at a young age, often is asymptomatic, and usually  does not cause significant morbidity. For symptomatic  cases, the usual incubation period is 3 to 9 days. After  primary infection is established, the virus is taken up by  sensory nerves and transported to the associated sensory or,  less frequently, autonomic ganglia where the virus remains  in a latent state. The most common site of latency for  HSV-1 is the trigeminal ganglion, but other possible sites  include the nodose ganglion of the vagus nerve, dorsal root  ganglia, and brain. The virus uses the axons of the sensory  neurons to travel back and forth to the skin or mucosa.   Recurrent (secondary or recrudescent) infection  occurs with reactivation of the virus. Old age, ultraviolet  light, physical or emotional stress, fatigue, heat, cold,  pregnancy, allergy, trauma, dental treatment, respiratory  illnesses, fever, menstruation, systemic diseases, and malig-  nancy have been associated with reactivation. Symptomatic  recurrences are fairly common and affect the epithelium  supplied by the sensory ganglion; however, reactivation with  asymptomatic viral shedding greatly exceeds clinically  evident recurrences. Spread to an uninfected host can occur  from symptomatic, active lesions or asymptomatic viral  shedding. In addition, the virus may spread to other sites  in the same host to establish residency at the sensory gan-  glion of the new location. Based upon cultures of samples  from otherwise healthy individuals, investigators have esti-  mated that asymptomatic, oral HSV-1 shedding occurs in  approximately 6% of the population on any given day.  However, sensitive polymerase chain reaction (PCR) assays  performed on oral samples obtained over several weeks  suggest that at least 70% of the population sheds HSV-1  asymptomatically at least once a month.   Crowding and poor hygiene promote exposure to HSV-1.  Furthermore, lower socioeconomic status correlates with  earlier exposure. In developing countries, more than 50%  of the population is exposed by 5 years of age, 95% by 15  years of age, and nearly 100% by 30 years of age. In con-  trast, upper socioeconomic groups in developed nations  exhibit less than 20% exposure at 5 years of age and only  50% to 60% in adulthood. The low childhood exposure  rate in privileged groups is followed by a second peak during  the college years. The age of initial infection also affects the  clinical presentation of symptomatic primary HSV-1 infec-  tion, with individuals infected at an early age tending to  exhibit gingivostomatitis and those exposed later in life  often demonstrating pharyngotonsillitis.   HSV-2 infection represents one of the most common  sexually transmitted infections worldwide. In the United  States, HSV-2 seroprevalence among individuals between  14 and 49 years of age is approximately 16% and has  remained relatively stable in recent years. Exposure of those    younger than age 14 is close to zero, and most initial infec-  tions occur between the ages of 15 and 35. Because many  infected with HSV-2 refrain from sexual activity when  active lesions are present, investigators believe that at least  70% of primary infections are contracted from individuals  during asymptomatic viral shedding. Importantly, HSV-2  infection is associated with at least a twofold increase in risk  for human immunodeficiency virus (HIV) infection (see  page 239). Apparently, HSV-2 infection triggers a persistent  microenvironment rich in immune cells that are susceptible  to HIV infection.   In addition to clinically evident infections, HSV has  been implicated in several noninfectious processes. More  than 15% of cases of erythema multiforme are preceded  by a symptomatic recurrence of HSV 3 to 10 days earlier  (see page 723), and some investigators believe that up to  60% of mucosal erythema multiforme may be triggered by  HSV. In some individuals, erythema multiforme outbreaks  are frequent enough to warrant antiviral prophylaxis. An  association with cluster headaches and several cranial neu-  ropathies (e.g., Bell palsy [see page 801] and trigeminal  sensory neuropathy) also has been proposed, but definitive  proof is lacking.   In a small subset of patients, asymptomatic release of  HSV coincides with attacks of aphthous ulcerations (see  page 303). In these cases, the ulcerations are not infected  with the virus. Instead the virus may be responsible for the  initiation of immune dysregulation, or the immune dys-  regulation that produces aphthae may allow the release of  virions. Nevertheless, the association between HSV and  aphthae is weak, and prophylactic antiviral therapy generally  does not decrease the recurrence of aphthous stomatitis.   HSV also has been associated with oral carcinomas, but  much of the evidence is circumstantial. HSV DNA has been  extracted from some tumors but not others. HSV may aid  carcinogenesis through the promotion of mutations, but its  oncogenic role, if any, is uncertain.    Acute herpetic gingivostomatitis (primary herpes) is the  most common pattern of symptomatic primary HSV infec-  tion, and more than 90% of cases are caused by HSV-1.  Most affected individuals are between the ages of 6 months  and 5 years, with the peak prevalence occurring between 2  and 3 years of age. However, occasional cases have been  reported in patients over 60 years of age. Development  before 6 months of age is rare because of protection by  maternal anti-HSV antibodies. The onset is abrupt and  often accompanied by anterior cervical lymphadenopathy,  chills, fever (103° F to 105° F), nausea, anorexia, irritability,  and sore mouth lesions. The manifestations vary from mild  to severely debilitating.   Initially the affected mucosa develops numerous pinhead  vesicles, which rapidly collapse to form numerous small, red  lesions. These lesions enlarge slightly and develop central  ulceration covered by yellow fibrin (Fig. 7-1). Adjacent    ® Fig. 7-1 Acute Herpetic Gingivostomatitis. Widespread yellow-  ish mucosal ulcerations. (Courtesy of Dr. David Johnsen.)    aad : PS OT ny ent ar wi id gine  ® Fig. 7-2 Acute Herpetic Gingivostomatitis. Numerous coalesc-  ing, irregular, and yellowish ulcerations of the dorsal surface of the  tongue.    ulcerations may coalesce to form larger, shallow, irregular  ulcerations (Fig. 7-2). Both the movable and attached oral  mucosa can be affected, and the number of lesions is highly  variable. In all cases, the gingiva is enlarged, painful, and  extremely erythematous (Fig. 7-3). In addition, the affected  gingiva often exhibits distinctive punched-out erosions  along the midfacial free gingival margins (Fig. 7-4). It is not  unusual for involvement of the labial mucosa to extend past  the wet line to include the adjacent vermilion border. Satel-  lite vesicles of the perioral skin are fairly common. Self-  inoculation of the fingers, eyes, and genital areas can occur.  Mild cases usually resolve within 5 to 7 days; severe cases  may last 2 weeks. Rare complications include kerato-  conjunctivitis, esophagitis, pneumonitis, meningitis, and  encephalitis.   As mentioned previously, primary infection in adults  may cause pharyngotonsillitis. Sore throat, fever, malaise,  and headache are the initial symptoms. Numerous small  vesicles develop on the tonsils and posterior pharynx. The  vesicles rapidly rupture to form shallow ulcers, which often  coalesce and develop an overlying diffuse, gray-yellow  exudate. Involvement of the oral mucosa anterior to  Waldeyer ring occurs in less than 10% of cases. HSV appears    ® Fig. 7-3 Acute Herpetic Gingivostomatitis. Painful, enlarged,  and erythematous palatal gingiva.    © Fig. 7-4 Acute Herpetic Gingivostomatitis. Painful, enlarged,  and erythematous facial gingiva. Note erosions of the free gingival  margin. (Courtesy of Dr. Gina Liford.)    to be a significant cause of pharyngotonsillitis in young  adults who are from higher socioeconomic groups with  previously negative test findings for HSV antibodies. Most  cases are caused by HSV-1, but the proportion caused by  HSV-2 is increasing. The clinical presentation closely resem-  bles pharyngitis secondary to streptococci or infectious  mononucleosis, making the true frequency difficult to  determine.   Recurrent herpes simplex infections (secondary  herpes, recrudescent herpes) may occur either at the site  of primary inoculation or in adjacent areas of surface epi-  thelium supplied by the involved ganglion. The most  common site of recurrence for HSV-1 is the vermilion  border and adjacent skin of the lips. This is known as herpes  labialis (“cold sore” or “fever blister”). Prevalence studies  suggest that 15% to 45% of the United States population  has a history of herpes labialis. In some patients, ultraviolet  light or trauma can trigger recurrences. Prodromal signs and  symptoms (e.g., pain, burning, itching, tingling, localized  warmth, and erythema of the involved epithelium) arise 6  to 24 hours before the lesions develop. Multiple small,  erythematous papules develop and form clusters of    @ Fig. 7-5 Herpes Labialis. Multiple fluid-filled vesicles on the lip  vermilion.    ® Fig. 7-6 Herpes Labialis. Multiple sites of recurrent herpetic infec-  tion secondary to spread of viral fluid over cracked lips.    fluid-filled vesicles (Fig. 7-5). The vesicles rupture and crust  within 2 days. Healing usually occurs within 7 to 10 days.  Symptoms are most severe in the first 8 hours, and most  active viral replication is complete within 48 hours. Rupture  of vesicles and the release of the virus-filled fluid may result  in spreading of the lesions on lips previously cracked from  sun exposure (Fig. 7-6). Recurrences are observed less com-  monly on the skin of the nose, chin, or cheek. The majority  of those affected experience approximately two recurrences  annually, but a small percentage may experience outbreaks  that occur monthly or even more frequently.   On occasion, some lesions arise almost immediately after  a known trigger and appear without any preceding prodro-  mal symptoms. These rapidly developing recurrences tend  to respond less favorably to treatment.   Recurrences also can affect the intraoral mucosa. In the  immunocompetent patient, involvement is limited almost  always to keratinized mucosa bound to bone (attached  gingiva and hard palate). These sites often exhibit subtle  changes, and the symptoms are less intense. The lesions  begin as 1- to 3-mm vesicles that rapidly collapse to form  a cluster of erythematous macules that may coalesce or    @ Fig. 7-7 Intraoral Recurrent Herpetic Infection. Early lesions  exhibiting as multiple erythematous macules on the hard palate.  Lesions appeared a few days after extraction of a tooth.    e Fig. 7-8 Intraoral Recurrent Herpetic Infection. Multiple  coalescing ulcerations on the hard palate.    @ Fig. 7-9 Herpetic Whitlow. Recurrent herpetic infection of the  finger.    epithelium is lost, and a central yellowish ulceration devel-  ops. Healing occurs within 7 to 10 days.   Several less common presentations also exist. Primary or  recurrent HSV infection of the fingers is known as herpetic  whitlow (herpetic paronychia) (Fig. 7-9). This condition    may result from self-inoculation in children with orofacial  HSV-1 infection or adults with genital HSV-2 infection.  Before the uniform use of gloves, medical and dental per-  sonnel could infect their digits from contact with infected  patients and represented the most commonly affected  group. Recurrent digital infection may result in paresthesia  and permanent scarring.   Cutaneous herpetic infections also can arise in areas of  previous epithelial damage. Parents kissing skin injuries in  children represent one vector. Wrestlers and rugby players  also may contaminate areas of abrasion and develop lesions  known as herpes gladiatorum or scrumpox. On occasion,  herpes simplex has been spread over the bearded region of  the face into minor injuries created by daily shaving, leading  to a condition known as herpes barbae. Ocular involve-  ment may occur by self-inoculation in children and, with  multiple recurrences, may result in blindness. Patients with  diffuse, chronic skin diseases, such as eczema, pemphigus,  and Darier disease, may develop diffuse life-threatening  HSV infection, known as eczema herpeticum (Kaposi  varicelliform eruption). Newborns may become infected  after delivery through a birth canal contaminated with  HSV, usually HSV-2. Without treatment, there is a greater  than 50% mortality rate.   HSV recurrence in immunocompromised hosts can be  significant. Without proper immune function, recurrent  herpes can persist, spread, and potentially be fatal. Skin  lesions may continue to enlarge with formation of broad  zones of superficial erosion. Likewise, herpes labialis may be  severe, with extensive areas of involvement. Intraoral lesions  usually begin on bound mucosa but often spread to unbound  mucosa as well. The lesions may appear as brownish, necrotic  epithelium raised above the surface of the adjacent intact  epithelium. Typically, these areas are much larger than the  usual pinhead lesions in immunocompetent patients. With  continued enlargement, a zone of superficial necrosis or  erosion with a distinctive circinate, raised, yellow border  develops (Figs. 7-10 and 7-11). HSV infection in a chronic    @ Fig. 7-10 Chronic Herpetic Infection. Numerous mucosal ero-  sions, each of which is surrounded by a slightly raised, yellow-white  border, in a patient receiving systemic corticosteroid therapy for sys-  temic sclerosis and rheumatoid arthritis.    ulcer on the movable oral mucosa is ominous and should  prompt thorough evaluation for possible immune  dysfunction.   In addition, in patients with acquired immunodefi-  ciency syndrome (AIDS), several authors have reported  persistent oral ulcers that lack the distinctive curvilinear  border, are nonspecific clinically, and may mimic aphthous  ulcerations, necrotizing stomatitis, or ulcerative periodontal  disease. Biopsy of persistent ulcers in patients with AIDS is  mandatory and may reveal any of a number of infectious  or neoplastic processes. Such ulcers may exhibit HSV  infection, often combined with CMV (HHV-5) infection  (see page 231).    HSV-infected epithelial cells exhibit acantholysis, nuclear  clearing, and nuclear enlargement (termed ballooning  degeneration) (Fig. 7-12). The acantholytic epithelial cells  may be referred to as Tzanck cells. (Ihis term refers to  free-floating epithelial cells in any intraepithelial vesicle and  is not specific for herpes.) Nucleolar fragmentation occurs  with a condensation of chromatin around the periphery of  the nucleus. Multinucleated epithelial cells are formed by  fusion between adjacent cells (see Fig. 7-12). Intercellular  edema develops and leads to the formation of an intraepi-  thelial vesicle (Fig. 7-13). Mucosal vesicles rupture rapidly;  those on the skin often persist and become infiltrated by  inflammatory cells. Once they have ruptured, the mucosal  lesions demonstrate a surface fibrinopurulent membrane.  Often at the edge of the ulceration or mixed within the  fibrinous exudate are the scattered Tzanck or multinucle-  ated epithelial cells.    The clinician often can make a strong presumptive clinical  diagnosis of HSV infection. However, on occasion, HSV    @ Fig. 7-11 Chronic Herpetic Infection. Numerous shallow her-  petic erosions with raised, yellow and circinate borders on the maxillary  alveolar ridge in an immunocompromised patient.    ® Fig. 7-12 Herpes Simplex. Altered epithelial cells exhibiting bal-  looning degeneration, margination of chromatin, and multinucleation.    infection can be confused with other diseases, and labora-  tory confirmation is desirable.   The traditional method for diagnosis is viral isolation  from tissue culture inoculated with the fluid of intact vesi-  cles. However, intact vesicles are rare in the oral cavity, and  culture of ruptured oral lesions is unreliable because of the  potential for contamination with saliva that may contain  coincidentally released HSV from asymptomatic viral shed-  ding. Another problem with viral culture is that up to 2  weeks may be required for a definitive result.   The most commonly used sampling methods for diag-  nosis are the cytologic smear and tissue biopsy, with the  former being the least invasive and most cost-effective.  Microscopic examination shows characteristic changes in  infected epithelial cells. Only VZV produces similar changes,  but these two infections usually can be differentiated on a  clinical basis. If necessary, direct immunofluorescence,  immunohistochemistry, in situ hybridization, or PCR may  be performed for more definitive HSV detection and typing.   If diagnostic features of HSV are discovered in a biopsy  of a persistent ulceration in an immunocompromised  patient, additional studies for CMV should be performed  to rule out coinfection. The histopathologic features of  CMV can be missed easily, resulting in patients not receiv-  ing the most appropriate therapy.   Serologic testing is useful in documenting recent or past  exposure to HSV and is used primarily in epidemiologic  studies. HSV antibodies typically begin to appear 4 to 8  days after initial exposure. Confirmation of primary infec-  tion by serology requires a negative sample obtained within  3 days of initial presentation and a positive sample obtained  approximately 4 weeks later.    In the past, primary herpetic gingivostomatitis was treated  only symptomatically; however, if administered early, anti-  viral medications can be beneficial. When acyclovir suspen-  sion is initiated during the first 3 symptomatic days and    e Fig. 7-13 Herpes Simplex. Intraepithelial vesicle demonstrating  acantholytic and virally altered epithelial cells.    administered by a rinse-and-swallow technique 5 times  daily for 5 days (children: 15 mg/kg up to the adult dose  of 200 mg), significant acceleration of clinical resolution is  seen. Once therapy is initiated, development of new lesions  ceases. In addition, associated eating and drinking difficul-  ties, pain, healing time, duration of fever, and viral shedding  are shortened dramatically. In conjunction with acyclovir,  additional medications—such as dyclonine hydrochloride  spray, tetracaine hydrochloride lollipops (prepared by a  compounding pharmacist), or nonsteroidal antiinflamma-  tory drugs (NSAIDs)—may be used for more immediate  pain relief. Viscous lidocaine and topical benzocaine should  be avoided in pediatric patients because of reports of  lidocaine-induced seizures in children and an association  between topical benzocaine and methemoglobinemia.  Patients also should be instructed to restrict contact with  active lesions to prevent autoinoculation or spread to others.  Recurrent herpes labialis has been treated with every-  thing from ether to voodoo; nothing has solved the problem  for all patients. Acyclovir ointment in polyethylene glycol  was the first topical antiviral formulation available. Acyclo-  vir ointment has been of limited benefit for herpes labialis  in immunocompetent patients, because its base is thought  to prevent significant absorption. Subsequently, penciclovir  cream became available in a base that allows increased  absorption through the vermilion border. This formulation  has produced reduction in healing time and pain by approx-  imately 1 day. Although the best results are obtained if  penciclovir cream is initiated during the prodrome, late  application also has produced a measurable clinical benefit.  Additional choices are acyclovir cream and over-the-counter  10% docosanol cream. All three of these creams are associ-  ated with statistically significant, albeit clinically minimal,  reduction in healing time and pain, with penciclovir exhib-  iting the greatest efficacy and docosanol the least efficacy.  Systemic acyclovir and two newer medications, valacy-  clovir and famciclovir, demonstrate similar effectiveness  against HSV. However, valacyclovir and famciclovir exhibit  improved bioavailability and more convenient oral dosing    schedules. In particular, a valacyclovir regimen—consisting  of 2 g during the prodrome followed by another 2 g 12  hours later—has been most successful in minimizing recur-  rences. The effects of this treatment are reduced significantly  if it is not initiated during the prodrome. Although much  less convenient, 400 mg of acyclovir taken five times daily  for 5 days appears to produce similar results. For patients  whose recurrences appear to be associated with dental pro-  cedures, a regimen of 2 g of valacyclovir taken twice on the  day of the procedure and 1 g taken twice the next day may  suppress or minimize an attack. In individuals with a known  trigger that extends over a period of time (e.g., skiing or  beach vacation), prophylactic short-term use of an antiviral  (acyclovir, 400 mg twice daily; valacyclovir, 1 g daily; or  famciclovir, 250 mg twice daily) has been shown to reduce  the prevalence and severity of recurrences.   Long-term suppressive therapy with an antiviral medica-  tion typically is reserved for patients with more than six  recurrences per year, HSV-triggered erythema multiforme,  or an immunocompromised status. Over the past several  decades, acyclovir-resistant strains of HSV have emerged,  mainly among immunocompromised patients receiving  long-term treatment or prophylaxis. In immunocompro-  mised patients, the viral load tends to be high and replica-  tion is not suppressed completely by antiviral therapy,  creating a favorable environment for generating drug-  resistant mutants. Although resistance is seen primarily in  immunocompromised patients, cavalier use of antiviral  medications for mild cases of recurrent herpes infection  probably is inappropriate.   The pain associated with intraoral secondary herpes  usually is not intense, and many patients do not require  treatment. Some studies have shown chlorhexidine to exert  antiviral effects. In addition, acyclovir appears to function  synergistically with chlorhexidine. Extensive clinical trials  have not been performed, but chlorhexidine alone or in  combination with acyclovir suspension may be beneficial  for patients who desire or require therapy of intraoral  lesions.   Immunocompromised hosts with HSV infection often  require intravenous (IV) antiviral medications. Further-  more, severely immunosuppressed individuals, such as bone  marrow transplant patients and those with AIDS, often  need prophylactic oral acyclovir, valacyclovir, or famciclovir.  Herpes lesions that do not respond to appropriate therapy  within 5 to 10 days most likely are the result of resistant  strains. At this point, the initial antiviral therapy should be  repeated at an elevated dose. If this intervention fails, addi-  tional alternatives include IV trisodium phosphonoformate  hexahydrate (foscarnet), IV cidofovir, and adenine arabino-  side (vidarabine). Ulcerations that reveal coinfection with  HSV and CMV respond well to ganciclovir, with foscarnet  used in refractory cases. Although an effective vaccine for  the closely related varicella virus initially was developed over  35 years ago, similar approaches against HSV have pro-  duced less satisfactory results. Research for a potential  vaccine is ongoing.    Varicella (chickenpox) represents primary infection with  the varicella-zoster virus (VZV or HHV-3). Subsequently,  latency ensues, and recurrence is possible as herpes zoster  (see page 227), often after many decades. The virus may be  spread through air droplets or direct contact with active  lesions. In contrast to primary HSV infection, most cases  of primary VZV infection are symptomatic. The incubation  period is 10 to 21 days, with an average of 15 days.   In the pre-vaccine era, the annual incidence of chicken-  pox in the United States was approximately 4 million, with  most cases arising in children younger than 10 years of age.  However, since the introduction of universal varicella  immunization in the United States in 1995, the incidence  has declined across all age groups, and the age range of peak  incidence has shifted to between 10 and 14 years. In surveil-  lance areas with high vaccine coverage, the incidence of  varicella decreased from 1995 to 2005 by approximately  90%; even further declines have occurred since 2006, when  a two-dose vaccine regimen became routine. It is estimated  that each year varicella vaccination prevents more than 3.5  million cases of chickenpox, 9,000 hospitalizations, and  100 deaths in the United States.    Because of increasing varicella vaccination rates, the major-  ity of new varicella cases now represent breakthrough  infection (i.e., infection with wild-type virus in a previously  immunized patient). A maculopapular, cutaneous rash with  only a small number of lesions, few or no vesicles, low or  no fever, and a shortened disease course of approximately 4  to 6 days are characteristic findings. The atypical presenta-  tion of breakthrough disease may be difficult to recognize.  Patients are contagious until no new lesions appear within  a 24-hour period, although transmission is less frequent  with mild breakthrough infection compared with symp-  tomatic infection in unimmunized individuals.   Among unimmunized individuals, the symptomatic  phase of primary VZV infection usually begins with malaise,  pharyngitis, and rhinitis. In older children and adults, addi-  tional symptoms (e.g., headache, myalgia, nausea, anorexia,  and vomiting) occasionally are seen. This is followed by a  characteristic, intensely pruritic exanthem. The rash begins  on the face and trunk and spreads to the extremities. Each  lesion rapidly progresses through stages of erythema, vesicle,  pustule, and hardened crust (Figs. 7-14 and 7-15). The  vesicular stage is the classic presentation. Each vesicle is  surrounded by a zone of erythema and has been described  as “a dewdrop on a rose petal.” In contrast to herpes simplex,  the lesions typically continue to erupt for 4 or more days.  Old crusted lesions intermixed with newly formed, intact  vesicles are commonplace. Affected individuals are conta-  gious from 2 days before the exanthem until all the lesions  crust. Fever usually is present during the active phase of the  exanthem.    @ Fig. 7-14 Varicella. Infant with diffuse erythematous and vesicular  rash. (Courtesy of Dr. Sherry Parlanti.)    @ Fig. 7-15 Varicella. Numerous vesicles with surrounding erythema  and early crusting.    Perioral and oral manifestations are fairly common and  may precede the skin lesions. The vermilion border and  palate are involved most often, followed by the buccal  mucosa. Occasionally, gingival lesions resemble those noted  in primary HSV infection, but distinguishing between the  two is not difficult because the lesions of varicella tend to  be relatively painless. The lesions begin as 3- to 4-mm,  white, opaque vesicles that rupture to form 1- to 3-mm  ulcerations (Fig. 7-16). The prevalence and number of oral  lesions correlate with the severity of extraoral infection. In  mild cases, oral lesions are present in about one-third of  affected individuals; often there are only one or two oral    @ Fig. 7-16 Varicella. White opaque vesicles on the hard palate.  (Courtesy of Tristan Neville.)    ulcers that heal within 1 to 3 days. On the other hand,  patients with severe infections almost always have oral ulcer-  ations, often numbering up to 30 and persisting for 5 to  10 days.   Infants, adults, and immunocompromised individuals  are at increased risk for severe disease and complications. In  addition, household members who become secondarily  infected often suffer more severe disease than those initially  infected.   In childhood, the most frequent complications of vari-  cella are secondary skin infections, followed by encephalitis  and pneumonia. In particular, secondary skin infection with  group A, B-hemolytic streptococci may progress to necrotiz-  ing fasciitis, septicemia, toxic shock syndrome, or other  life-threatening conditions. With enhanced public educa-  tion and decreased use of aspirin in children, Reye syn-  drome (a potentially fatal condition characterized by acute  encephalopathy, liver failure, and other major organ damage)  is now rare.   The prevalence of complications in adults exceeds that  in children. The most common and serious complication is  pneumonitis, characterized by dry cough, tachypnea,  dyspnea, hemoptysis, chest pain, and cyanosis. Other  potential complications include pneumonia, encephalitis,  gastrointestinal disturbance, and hematologic events (i.e.,  thrombocytopenia, pancytopenia, hemolytic anemia, sickle  cell crisis). Central nervous system (CNS) involvement  typically produces ataxia but also may result in headaches,  drowsiness, convulsions, or coma. The risk of death is  reported to be 15 times greater in adults compared with  children, mostly because of an increased prevalence of  encephalitis.   Infection during pregnancy can produce congenital or  neonatal chickenpox. Involvement early in pregnancy can  result in spontaneous abortion or congenital defects. When  infection occurs before 20 weeks of gestation, the prevalence  of congenital varicella syndrome is approximately 1% to  2%. In addition, infection of the mother close to delivery  can result in severe neonatal infection caused by a lack of  maternal antibodies.    Infection in immunocompromised patients also can be  severe. Cutaneous involvement typically is extensive and  may be associated with secondary bacterial infection, high  fever, hepatitis, pneumonitis, pancreatitis, gastrointestinal  obstruction, and encephalitis. Before effective antiviral  therapy, the mortality rate in immunocompromised indi-  viduals was approximately 7%.    The cytologic alterations are virtually identical to those  described for HSV. The virus causes acantholysis, with for-  mation of numerous free-floating Tzanck cells, which  exhibit nuclear margination of chromatin and occasional  multinucleation.    Since the institution of universal vaccination in the United  States, the annual incidence of typical varicella disease has  decreased, whereas the incidence of atypical breakthrough  disease has increased; consequently, the need for laboratory  confirmation has grown. Confirmation can be obtained  through demonstration of viral cytopathologic effects  present within epithelial cells harvested from vesicular fluid.  These cytologic changes are identical to those found in HSV  infection, although correlation with the clinical findings  may aid in distinguishing between HSV and VZV infec-  tion. The most definitive method for diagnosis is PCR  performed on vesicular fluid, cells from the base of a lesion,  or ascab from a resolving skin lesion. PCR is preferred over  viral isolation in cell culture and direct fluorescent antibody  assay, because it is more sensitive and allows for distinction  between wild-type and vaccine strains of VZV. In addition,  a diagnosis can be made retrospectively in immunocompe-  tent hosts by demonstrating a fourfold or greater increase  in VZV antibody titers between acute and convalescent  serum samples; however, in vaccinated persons an increase  of this magnitude may not be evident.    Before antiviral medications became available, the treat-  ment of varicella primarily was symptomatic. Warm baths  with soap, baking soda, or colloidal oatmeal; application of  calamine lotion; and systemic diphenhydramine still are  used to relieve pruritus. Diphenhydramine lotions are not  recommended because of reports of toxicity secondary to  percutaneous absorption. Acetaminophen is the preferred  antipyretic for childhood cases. In this age group, aspirin  should be avoided because of the risk of Reye syndrome,  and NSAIDs are discouraged because they have been associ-  ated with an increased risk for severe skin and soft tissue  complications.   Peroral antiviral medications (such as, acyclovir, valacy-  clovir, and famciclovir) have been shown to reduce the  duration and severity of infection if administered within 24    hours of the rash. Routine use of antiviral medications is  not recommended in immunocompetent children with  uncomplicated chickenpox. Instead, such therapy is reserved  for those at risk for more severe disease, such as unvacci-  nated individuals over 12 years of age, patients with chronic  cutaneous or pulmonary disease, patients receiving long-  term salicylate therapy, and those receiving short, intermit-  tent, or aerosolized courses of corticosteroids. In addition,  some experts recommend antiviral therapy for individuals  who contract the disease from a household member, because  secondary household cases often are more severe than cor-  responding index cases. IV formulations are used in immu-  nosuppressed patients or those exhibiting progressive, severe  infection.   In patients who lack evidence of immunity and become  exposed to VZV, postexposure immunization or purified  varicella-zoster immune globulin administration may be  considered. Postexposure vaccination is appropriate for non-  immune individuals 12 months or older. Ideally it should  be administered within 3 days, although it may be given up  to 5 days after exposure in order to prevent or modify  disease. A second dose of vaccine should be administered at  the age-appropriate interval following the first dose. Alter-  natively, for nonimmune individuals at high risk for severe  disease or complications, purified varicella-zoster immune  globulin (VariZIG) can be given postexposure. Individuals  at elevated risk include immunocompromised patients,  pregnant women, premature infants, and neonates whose  mothers do not have evidence of immunity. VariZIG ideally  should be administered as soon as possible, with the FDA  approving administration up to 10 days postexposure.   In the United States, the FDA has approved a monova-  lent varicella virus vaccine (Varivax) as well as a quadrivalent  measles, mumps, rubella, and varicella virus (MMRV)  vaccine (ProQuad). Both vaccines are licensed for use in  healthy children 12 months through 12 years of age, with  the first dose of varicella-containing vaccine recommended  at 12 through 15 months and a second dose at 4 through  6 years. Either MMRV vaccine or separate injections of  measles, mumps, and rubella (MMR) vaccine and monova-  lent varicella vaccine may be administered to toddlers  receiving their first dose; the latter method minimizes the  generally small risk of vaccine-related febrile seizures in this  age group. For the second dose, MMRY is preferred over  separate injections of MMR and varicella virus vaccines. In  addition, the monovalent varicella vaccine is licensed for  routine use in individuals 13 years or older without evi-  dence of immunity; in this age group, two doses separated  by at least 28 days are recommended. Children, adolescents,  and adults who have received only one dose of varicella virus  vaccine as per past recommendations should receive a  second. “catch-up” dose.   The varicella virus vaccine is a live, attenuated virus that  can be spread to individuals in close contact. Therefore,  vaccine recipients who develop a rash should avoid contact  with those at risk, such as immunocompromised or preg-  nant individuals.    After primary infection with VZV (chickenpox), the virus  is transported up the sensory nerves and establishes latency  in the dorsal root ganglia. Clinically evident herpes zoster  develops after reactivation of the virus, with involvement of  the distribution of the affected sensory nerve. Unlike HSV,  single rather than multiple recurrences are the rule. Herpes  zoster occurs during the lifetime of approximately one in  three individuals, and it is estimated that 1 million new  episodes of herpes zoster occur annually in the United  States. The prevalence of attacks increases with age, appar-  ently due to age-related decline in cell-mediated immunity.  The incidence is low among young people but increases  dramatically after 50 years of age, with studies suggesting  that as many as 50% of individuals who live to 85 years of  age will be affected at some time. Immunosuppression, HIV  infection, treatment with cytotoxic or immunosuppressive  drugs, radiation, malignancy, old age, alcohol abuse, stress  (emotional or physical), and dental manipulation are addi-  tional predisposing factors for reactivation.   The long-term impact of varicella virus vaccination on  herpes zoster prevalence is controversial and presently under  evaluation. Interestingly, it is possible to develop herpes  zoster by reactivation of either the wild-type or vaccine-  strain virus, although the risk for vaccine-strain zoster seems  to be much lower than that for wild-type zoster.    The clinical features of herpes zoster can be grouped into  three phases: prodrome, acute, and chronic. During initial  viral replication, ganglionitis develops with resultant neuro-  nal necrosis and severe neuralgia. This inflammatory reac-  tion is responsible for the prodromal pain present in more  than 90% of cases. As the virus travels down the nerve, the  pain intensifies and has been described as burning, tingling,  itching, boring, prickly, or knifelike. The pain develops in  the area of epithelium innervated by the affected sensory  nerve (dermatome) and may be accompanied by fever,  malaise, and headache. Typically, one dermatome is affected,  but involvement of two or more can occur. The thoracic  dermatomes are affected in about two-thirds of cases. This  prodromal pain normally precedes the acute phase rash by  1 to 4 days and, depending on which dermatome is affected,  may masquerade as sensitive teeth, otitis media, migraine  headache, myocardial infarction, or appendicitis.   The acute phase begins as the involved skin develops  clusters of vesicles set on an erythematous base (Fig. 7-17).  The lesions tend to follow the path of the affected nerve and  terminate at the midline (Fig. 7-18). Within 3 to 4 days,  the vesicles become pustular and ulcerate, with crusts devel-  oping after 7 to 10 days. The lesions are contagious until  they crust, although the rate of VZV transmission from  herpes zoster lesions is lower than that from varicella lesions.  The exanthem typically resolves within 2 to 3 weeks in  otherwise healthy individuals. On healing, scarring with    ° Fig. 7-18 Herpes Zoster. Numerous crusting facial vesicles that  extend to the midline.    hypopigmentation or hyperpigmentation is not unusual.  Infrequently, there is dermatomal pain without develop-  ment of a rash; this pattern is called zoster sine herpete  (zoster without rash).   Oral lesions occur with trigeminal nerve involvement  and may be present on the movable or bound mucosa. The  lesions often extend to the midline and frequently are  accompanied by involvement of the skin overlying the  affected quadrant. Like varicella, the individual lesions  manifest as 1- to 4-mm vesicles or pustules that rupture to  form shallow ulcerations (Fig. 7-19). The teeth in affected  areas may develop pulpitis, pulpal necrosis, pulpal calcifica-  tion, or root resorption. In addition, several reports have    ° Fig. 7-19 Herpes Zoster. Numerous white opaque vesicles on the  right buccal mucosa of the same patient depicted in Fig. 7-18.    documented significant bone necrosis with tooth loss. It is  postulated that gnathic osteonecrosis may be secondary to  extension of inflammation from affected nerves to adjacent  blood vessels, leading to ischemic necrosis. The osteonecro-  sis may develop either during or following the exanthem,  with reported lag periods as long as 150 days.   Ocular involvement is present in approximately 10% to  25% of cases and can cause significant morbidity, including  permanent blindness. The ocular manifestations are highly  variable and may arise from direct viral-mediated epithelial  damage, neuropathy, immune-mediated damage, or sec-  ondary vasculopathy. Lesions on the tip of the nose  (Hutchinson sign) indicate involvement of the nasociliary  branch of the trigeminal nerve and an increased risk for  severe ocular infection. In these cases, referral to an oph-  thalmologist is mandatory.   Reactivation of VZV in the geniculate ganglion may  cause Ramsay Hunt syndrome, which is characterized by  cutaneous lesions of the external auditory canal and involve-  ment of the ipsilateral facial and auditory nerves. Affected  individuals may exhibit facial paralysis as well as hearing  deficits, vertigo, and other auditory and vestibular symp-  toms. In addition, some patients may develop loss of taste  in the anterior two-thirds of the tongue. By using PCR or  serology, investigators have detected active VZV infection  in approximately 30% of patients thought to have Bell palsy  (see page 801). Similar associations also have been demon-  strated with HSV and EBV. These findings suggest an  underlying viral cause for many cases of “idiopathic” facial  paralysis.   Approximately 15% of patients progress to the chronic  phase of herpes zoster (termed postherpetic neuralgia),  which is characterized by persistent pain after resolution of  the rash. In defining postherpetic neuralgia, there is a lack  of consensus regarding the duration of pain persistence fol-  lowing the rash, although many investigators consider a  minimum period of 1 to 3 months. Risk factors include  female gender, older age, history of prodromal pain, moder-  ate to severe rash and/or pain during the acute phase, and  ophthalmic involvement. The pain is described as burning,    throbbing, aching, itching, or stabbing, often with flares  caused by light stroking or contact with clothing. Most of  these neuralgias resolve within 1 year, with half of patients  experiencing resolution after 2 months. Rare cases may last  up to 20 years, and patients have been known to commit  suicide because of the extreme pain. Although the cause is  unknown, some investigators believe chronic VZV gangli-  onitis is responsible.   In rare cases, a potentially fatal ischemic stroke syn-  drome, termed granulomatous angiitis, may develop  weeks to months after resolution of a zoster rash involving  the trigeminal nerve distribution. This condition appears to  result from direct extension of VZV and associated inflam-  mation from the trigeminal ganglion to the internal carotid  artery.   In immunocompromised individuals, herpes zoster is  often severe, with an overall increased risk for complica-  tions. The cutaneous rash may become disseminated as a  result of VZV viremia; in some cases, viremia may occur  even without skin involvement. Potentially life-threatening  complications include pneumonia, hepatitis, disseminated  intravascular coagulopathy, and encephalitis. However,  immunocompromised status does not appear to increase the  risk for developing postherpetic neuralgia significantly.    The active vesicles of herpes zoster are microscopically iden-  tical to those seen in the primary infection, varicella. For  more information, see the previous sections regarding the  histopathologic features of varicella and herpes simplex.    Herpes zoster often is diagnosed from the clinical presenta-  tion, but laboratory testing may be necessary for atypical  cases or exclusion of zosteriform recurrent HSV infection.  Viral culture can provide confirmation. However, the results  take at least 24 hours, and false negatives often occur  because it is difficult to recover viable virus from cutaneous  lesions. Cytologic smears demonstrate viral cytopathologic  effects, as seen in varicella and HSV infection. A rapid  diagnosis can be obtained by direct staining of cytologic  smears with fluorescent monoclonal VZV _ antibodies.  Molecular techniques, such as dot-blot hybridization and  PCR, also can be used to detect VZV.    Supportive therapy for herpes zoster may include antiprurit-  ics, such as diphenhydramine, and non-aspirin antipyretics.  Skin lesions should be kept dry, clean, and, if possible,  covered to prevent secondary infection; antibiotics may be  administered to treat such secondary infections.   Prompt therapy with antiviral medications, such as acy-  clovir, valacyclovir, and famciclovir, has been found to accel-  erate healing of mucocutaneous lesions and reduce pain    during the acute phase. These medications are most effective  if initiated within 72 hours after development of the first  vesicle. Supplementation of antiviral agents with analgesics  (such as, acetaminophen, NSAIDs, tramadol, and opioids),  tricyclic antidepressants, antiepileptics (including gabapen-  tin and pregabalin), or systemic corticosteroids may provide  additional pain control.   Investigations regarding whether antiviral treatment  administered alone or in combination with gabapentin  during the acute phase may prevent or lessen the severity of  postherpetic neuralgia have yielded variable results. Simi-  larly, combination therapy with antivirals and corticoste-  roids may be helpful in the treatment of acute herpes zoster  but does not appear to prevent postherpetic neuralgia.   In postherpetic neuralgia, tricyclic antidepressants, anti-  convulsants (including gabapentin and pregabalin), and  opioids may reduce pain. In addition, the FDA has approved  the lidocaine patch, capsaicin patch, and capsaicin cream  for the treatment of postherpetic neuralgia. However, the  evidence in support of these topical therapies is of limited  quality. Also, capsaicin—which is derived from peppers—  may cause significant burning or stinging of the skin as a  side effect. Nonpharmacologic treatments include nerve  blocks and percutaneous electrical nerve stimulation, but  there are few well-controlled studies to support these alter-  natives. Because postherpetic neuralgia often is difficult  to treat, emphasis should be placed on herpes zoster  prevention.   A herpes zoster vaccine (Zostavax) has been approved by  the FDA for use in adults 50 years and older. However,  because of concerns regarding adequate vaccine supply, the  Centers for Disease Control and Prevention (CDC) have  maintained their recommendation for routine herpes zoster  vaccination in adults 60 years and older. Zostavax contains  the same live, attenuated strain of VZV used in the varicella  vaccines; however, it is 14 times more potent than Varivax,  the monovalent varicella vaccine. Large-scale studies of Zos-  tavax vaccination in older adults have shown an approxi-  mately 50% to 70% decrease in herpes zoster incidence and  67% decrease in postherpetic neuralgia incidence, with sig-  nificantly reduced morbidity among those who do develop  the disease. Because the zoster vaccine contains live, attenu-  ated virus, it generally should not be administered to  immunocompromised persons. However, vaccination of  immunocompetent patients in anticipation of immunosup-  pressive therapy or disease states is appropriate.    Infectious mononucleosis is a symptomatic disease result-  ing from exposure to Epstein-Barr virus (EBV or HHV-4).  The infection usually occurs by intimate contact. Intrafa-  milial spread is common, and once a person is exposed, EBV  remains in the host for life. Children usually become infected    through contaminated saliva on fingers, toys, or other  objects. Adults usually contract the virus through direct  salivary transfer, such as shared straws or kissing, hence, the  nickname “kissing disease.” In developing nations, exposure  usually occurs by age 3 and is universal by adolescence. In  the United States, introduction to the virus often is delayed,  with approximately 50% of college students lacking previ-  ous exposure. These unexposed adults become infected at  a rate of 10% to 15% per year while in college. Infected  children are typically asymptomatic, whereas young adults  are at greatest risk for symptomatic disease. Similar  mononucleosis syndromes may be produced by other patho-  gens, including cytomegalovirus (see page 231), HIV-1 (see  page 239), and Toxoplasma gondii (see page 212).   Besides infectious mononucleosis, EBV is associated  with oral hairy leukoplakia (OHL) (see page 242), various  lymphoproliferative disorders and lymphomas (most  notably Burkitt lymphoma [see page 560]), nasopharyngeal  carcinoma (see page 395), salivary lymphoepithelial carci-  noma, some gastric carcinomas, possibly breast and  hepatocellular carcinomas, and occasional smooth muscle  tumors.    The clinical presentation varies by age. Most EBV infections  in children are asymptomatic. In symptomatic children  younger than 4 years, typical findings include fever, lymph-  adenopathy, pharyngitis, hepatosplenomegaly, and rhinitis  or cough. Children 4 years and older are affected similarly  but exhibit a much lower prevalence of hepatosplenomeg-  aly, rhinitis, and cough. Most young adults experience fever,  lymphadenopathy, pharyngitis, and tonsillitis. In adults  older than 40 years, fever and pharyngitis are the predomi-  nant findings.   Complications are uncommon at any age but most fre-  quently arise in children. Possible significant complications  include splenic rupture, thrombocytopenia, autoimmune  hemolytic anemia, aplastic anemia, neurologic problems,  myocarditis, and hemophagocytic lymphohistiocytosis. The  latter appears to be caused by massive activation of T lym-  phocytes and histiocytes and is often fatal without prompt  treatment.   In classic infectious mononucleosis in a young adult,  prodromal fatigue, malaise, and anorexia occur up to 2  weeks before the development of pyrexia. Fever may reach  104° F and last from 2 to 14 days. Prominent lymphade-  nopathy is noted in more than 90% of cases and typically  appears as symmetrically enlarged and tender nodes, with  frequent involvement of the posterior and anterior cervical  chains. Enlargement of parotid lymphoid tissue rarely has  been reported and can be associated with facial nerve palsy.  More than 80% of affected young adults have oropharyn-  geal tonsillar enlargement, sometimes with diffuse surface  exudates and secondary abscesses (Fig. 7-20). The lingual  tonsils, which are located on the base of the tongue and  extend from the circumvallate papillae to the epiglottis, can    ® Fig. 7-20 Infectious Mononucleosis. Hyperplastic pharyngeal  tonsils with yellowish crypt exudates. (Courtesy of Dr. George Blozis.)    ® Fig. 7-21 Infectious Mononucleosis. Numerous petechiae of the  soft palate. (Courtesy of Dr. George Blozis.)    become hyperplastic and compromise the airway. Rare  fatalities have been reported from respiratory difficulties  secondary to tonsillar hyperplasia, arytenoid hypertrophy,  pharyngeal edema, and epiglottal swelling.   Oral lesions other than lymphoid enlargement also may  be seen. Petechiae on the hard or soft palate are present in  about 25% of patients (Fig. 7-21). The petechiae usually  disappear within 24 to 48 hours. Necrotizing ulcerative  gingivitis (NUG) (see page 143) also is fairly common.  NUG-like pericoronitis (see page 156) and necrotizing ulcer-  ative mucositis (see page 144) occur less frequently. Cases of  NUG that are refractory to conventional therapy should be  evaluated to rule out the possibility of EBV infection.   In less than 10% of classic infectious mononucleosis  cases, patients experience fatigue persisting for several weeks  to months. However, active EBV infection beyond 4 months  is rare. Several investigators have attempted to associate  EBV with a controversial symptom complex called chronic  fatigue syndrome, characterized by profound fatigue  lasting more than 6 months, pharyngitis, myalgias, arthral-  gias, headaches, lymphadenopathy, post-exertional malaise,  unrestful sleep, and cognitive impairment. Nevertheless,  current evidence does not support EBV as a specific cause    of this condition, which likely may be triggered by a variety  of illnesses or conditions.   Furthermore, some studies suggest that infectious mono-  nucleosis increases the risk for developing multiple sclerosis  later in life. However, whether EBV is a cause of multiple  sclerosis or merely an innocent bystander remains highly  controversial.    The diagnosis of infectious mononucleosis commonly is  based upon the clinical presentation combined with the  presence of greater than 10% atypical lymphocytes on a  peripheral blood smear and a positive heterophile antibody  test. Heterophile antibodies are IgM antibodies that are  directed against viral antigens and cross-react with sheep  and horse erythrocytes. The Paul-Bunnell test and rapid  slide agglutination (Monospot) assay are frequently used  methods for detection of heterophile antibodies. More than  90% of infected young adults test positive for heterophile  antibodies, but infected children younger than 4 years fre-  quently test negative.   In suspected cases of EBV infection for which hetero-  phile antibody testing is negative, EBV-specific antibody  testing may be required. Indirect immunofluorescent assays  can be performed during various stages of infection and  resolution in order to quantify antibodies directed against  viral capsid antigens (VCA) and EBV nuclear antigens  (EBNA). Also, for immunocompromised patients or those  with inconclusive serologic test results, real-time PCR may    In most cases, infectious mononucleosis resolves within 4  to 6 weeks. NSAIDs can be used to minimize the most  common symptoms. Adequate fluid intake and nutrition  also are important. Patients with significant enlargement of  the spleen should avoid contact sports to prevent the rare  possibility of splenic rupture.   Tonsillar involvement may resemble streptococcal phar-  yngitis or tonsillitis (see page 166). However, ampicillin,  amoxicillin, or other penicillins should be avoided because  these antibiotics commonly cause nonallergic morbilliform  skin rashes in patients with infectious mononucleosis.   Some clinicians advocate short-term corticosteroid  administration in order to minimize acute symptoms.  However, there is insufficient evidence from clinical studies  to support the routine use of corticosteroid treatment for  infectious mononucleosis. In addition, there is concern  regarding an increased risk for complications, including  encephalitis and myocarditis. In practice, most clinicians  reserve corticosteroid treatment for management of severe  complications, such as impending airway obstruction,  hemolytic anemia, thrombocytopenia, or hemophagocytic  lymphohistiocytosis. The latter also typically requires treat-  ment with cyclosporine or etoposide.    Although antiviral medications, such as acyclovir, vala-  cyclovir, and famciclovir, have been used successfully for  temporary resolution of oral hairy leukoplakia (OHL),  these medications do not demonstrate clinically obvious  benefit for patients with infectious mononucleosis. These  agents likely have an effect on viral replication; however, the  main clinical manifestations of infectious mononucleosis  appear to be secondary to the immune response to EBV-  infected B lymphocytes and are not altered by this  intervention.    Similar to other human herpesviruses, cytomegalovirus  (CMV or HHV-5) may establish latency after initial infec-  tion and reactivate under certain conditions. CMV can  reside latently in salivary gland cells, endothelium, macro-  phages, and lymphocytes. The virus can be found in most  bodily fluids, including saliva, blood, urine, tears, respira-  tory secretions, genital secretions, and breast milk. Most  clinically evident disease is found in neonates or immuno-  suppressed adults. In infants, the virus is contracted through  the placenta, during delivery, or during breast-feeding. The  next peak of transmission occurs during adolescence, pre-  dominantly from sexual contact. Transmission also has been  documented through blood transfusion and organ trans-  plantation. In the United States, seroprevalence is approxi-  mately 50% for individuals 6 to 49 years of age and greater  than 90% for those older than 80 years. In addition to  increasing age, other risk factors for CMV seropositivity  include female gender, low socioeconomic status, household  crowding, and foreign birthplace.    At any age, almost 90% of CMV infections are asymptom-  atic. In clinically evident congenital and neonatal infection,  typical features include jaundice, hepatosplenomegaly, cuta-  neous erythropoiesis, and thrombocytopenia (often with  associated petechiae and purpura). CNS involvement may  cause microcephaly, seizures, and mental and motor impair-  ment. In addition, CMV infection represents the most  common cause of nonhereditary sensorineural hearing loss,  with infected infants often developing hearing loss at birth  or later in childhood.   Among immunocompetent individuals, symptomatic  acute CMV infection is rare and exhibits nonspecific fea-  tures, ranging from an infectious mononucleosis-like  presentation to lethal multiorgan involvement. CMV  mononucleosis typically is characterized by fever, chills, sore  throat, headache, and fatigue. Compared with classic EBV  mononucleosis, this condition is much less commonly asso-  ciated with exudative pharyngitis, lymphadenopathy, and  hepatosplenomegaly. Other possible findings in symptom-  atic CMV infection include joint and muscle pain, abdomi-  nal pain, nonproductive cough, maculopapular rash, and  diarrhea. Persistent fever of unknown origin may be the    primary finding in some cases. Rarely, immunocompetent  patients may develop acute sialadenitis diffusely involving  the major and minor salivary glands. In such cases, xerosto-  mia often is noted, and the affected glands are painful and  enlarged. Unusual complications include myocarditis, peri-  carditis, pneumonitis, anterior uveitis, and meningitis.   Clinically evident CMV involvement frequently arises in  immunocompromised transplant patients. In some cases a  temporary, mild fever is the only finding; in others, the  infection becomes aggressive and is characterized by hepa-  titis, leukopenia, pneumonitis, gastroenteritis, and, more  rarely, a progressive wasting syndrome.   Patients with AIDS (see page 239) also are at increased  risk for symptomatic CMV disease, although a decrease in  prevalence has been reported with the introduction of com-  bination antiretroviral therapy (cART). The two most  common manifestations of CMV infection in patients with  AIDS are chorioretinitis and gastrointestinal involvement.  The former may result in blindness, and the latter may cause  bloody diarrhea or odynophagia.   Chronic oral ulcerations caused by CMV infection have  been documented in association with HIV infection as  well as other immunosuppressive conditions. Occasionally,  chronic oral ulcerations in immunocompromised patients  will demonstrate coinfection by CMV and HSV. In addi-  tion, neonatal CMV infection can produce developmental  tooth defects. In a study of 118 people with a history of  neonatal CMV infection, examination revealed tooth  defects in 40% of those with symptomatic infections  and slightly more than 5% of those with asymptomatic  infections. The teeth exhibited diffuse enamel hypoplasia,  significant attrition, enamel hypomaturation, and yellow  coloration from the underlying dentin.    Biopsy specimens of intraoral CMV lesions may demon-  strate changes within vascular endothelial cells or salivary  duct epithelial cells (Fig. 7-22). Scattered infected cells are  extremely swollen, showing both intracytoplasmic and    intranuclear inclusions and prominent nucleoli. These  enlarged cells have been called “owl eye” cells. Grocott-  Gomori methenamine silver and periodic acid-Schiff (PAS)  stains demonstrate the cytoplasmic inclusions but not the  intranuclear changes.    The diagnosis of CMV infection is based upon the clinical  features combined with laboratory findings. Tissue biopsy  may demonstrate cells with viral inclusions suggestive of  CMV infection; however, these inclusions may be scant and  difficult to demonstrate on routine light microscopy. More  sensitive and specific methods for confirmation of CMV  infection in biopsy specimens include immunohistochem-  istry and in situ hybridization. Because specific treatments  exist for CMV infection in immunocompromised patients,  biopsy is recommended for chronic ulcerations refractory  to conservative therapy. In addition, in such cases HSV  coinfection should be excluded.   Additional CMV detection methods include serology,  viral culture, and PCR. Serologic testing by enzyme-linked  immunosorbent assay (ELISA) is commonly available and  relatively inexpensive. A diagnosis of active CMV infection  is supported by acute and convalescent serum samples  showing a fourfold rise in IgG antibodies to CMV com-  bined with the presence of either IgM antibodies to CMV  or a positive CMV culture. In transplant patients and other  immunocompromised individuals, plasma viral load—  determined by real-time quantitative PCR—may be moni-  tored in order to assess the need for CMV treatment or  response to CMV therapy.   In CMV mononucleosis, peripheral blood typically  shows a 50% or greater relative lymphocytosis, with at least  10% atypical lymphocytes. Unlike EBV mononucleosis,  this condition usually is heterophile antibody-negative.    Although most CMV infections resolve spontaneously,  therapy often is required in the immunosuppressed patient.  Ganciclovir has resolved clinical symptoms in more than  75% of treated immunocompromised patients. However,  the medication must be continued to prevent a relapse if  the immune dysfunction persists. In patients with oral  ulcerations coinfected with CMV and HSV, IV ganciclovir  will produce resolution in most instances. However, resis-  tance to ganciclovir has been reported; other effective medi-  cations include foscarnet, cidofovir, and valganciclovir. In  transplant patients, prophylactic antiviral therapy for CMV  may be considered. Nevertheless, the best preventive and  interventional therapy in immunocompromised patients  remains improvement of immune status, such as that  achieved with combination antiretroviral therapy (cART)  for HIV infection (see page 253).   Immunocompetent patients with clinically evident  CMV infection usually are treated symptomatically with    NSAIDs. Corticosteroids or IV gamma globulins have been  used in patients with hemolytic anemia or severe thrombo-  cytopenia. Use of antiviral agents in immunocompetent  patients typically is reserved for severe disease because of the  risk of drug-related toxicity.   No licensed vaccine is currently available for prevention  of CMV infection; however, several vaccines are under  investigation and may be used in the future to protect  women of reproductive age and children.    Human enteroviruses (family Picornaviridae, genus Entero-  virus) traditionally have been classified into echoviruses,  coxsackieviruses A and B, and polioviruses, with numerical  designations for individual serotypes (e.g., Coxsackie virus  Al). Beginning in the 1960s, newly discovered enterovirus  serotypes have been designated numerically without being  placed into one of the traditional groups (e.g., enterovirus  71). Current classification, based upon molecular and bio-  logic features, divides the human enteroviruses into four  species (A through D) but maintains the traditional names  for individual serotypes. More than 100 serotypes have been  identified. Recently, a few enteroviruses (echoviruses 22 and  23) have been reclassified into the distinct Parechovirus  genus. Polioviruses largely have been eradicated in devel-  oped countries by vaccination. However, the non-polio  enteroviruses continue to cause disease worldwide.   Most enterovirus infections are asymptomatic or sub-  clinical. Among symptomatic cases, the clinical presenta-  tion is variable and may range from a minor febrile illness  to a severe and potentially fatal infection. More than 30  subtypes are associated with skin rashes. In addition, some  of these viruses have been associated with an increased  prevalence of type 1 diabetes mellitus and dilated  cardiomyopathy.   The estimated annual incidence of symptomatic entero-  virus infections in the United States is 10 to 15 million,  with most cases affecting infants and young children. In  many countries, epidemics occur every 2 to 3 years and  primarily affect children 1 to 4 years old. The timing of the  epidemics appears to correlate with the accumulation of a  new population of susceptible young children. A male pre-  dominance has been observed among patients younger than  20 years; in contrast, a female predominance has been noted  among those 20 years and older, most likely because of  exposure as primary caregivers to infected children.   The present discussion focuses upon the following  clinical patterns of enteroviral infection: herpangina,  hand-foot-and-mouth disease, and acute lymphonodu-  lar pharyngitis. These conditions are closely related and  should not be considered entirely separate. In epidemics  involving the same viral strain, the clinical presentations  often vary and may include both herpangina and hand-foot-  and-mouth disease. Also, many authorities regard acute  lymphonodular pharyngitis as a variant of herpangina rather  than a distinct entity.    Herpangina usually is produced by coxsackievirus Al to  AG, A8, A10, or A22. However, it also may represent infec-  tion by coxsackievirus A7, A9, or Al6; coxsackievirus B2  to B6; echovirus 9, 16, or 17; or enterovirus 71. Hand-foot-  and-mouth disease usually is caused by coxsackievirus A16,  but also may arise from coxsackievirus A5, A9, or A10;  echovirus 11; or enterovirus 71. In particular, in the  Asia-Pacific region over the past few decades, enterovirus  71 has caused several large outbreaks of hand-foot-and-  mouth disease, often associated with major neurologic  complications. Acute lymphonodular pharyngitis is less rec-  ognized, and coxsackievirus A10 has been found in the few  reported cases.   In nontropical areas, most cases arise in the summer or  early fall, with crowding and poor hygiene aiding their  spread. The fecal-oral route is the major mode of transmis-  sion, and frequent hand washing is important to diminish  spread during epidemics. The incubation period is 4 to 7  days. During the acute phase, the virus also can be transmit-  ted through saliva or respiratory droplets. Infection confers  immunity against reinfection by a particular strain. Over  time an individual may develop immunity against numer-  ous enterovirus types but still remain susceptible to addi-  tional strains.    In all three clinical patterns, the severity varies by strain.  Most strains produce a self-limiting disease that requires no  therapy, but some strains can produce epidemics with sig-  nificant complications and occasional fatalities. Potential  complications include pneumonia, pulmonary edema and  hemorrhage, acute flaccid paralysis, encephalitis, meningi-  tis, and carditis. Infection with coxsackievirus B during  pregnancy has been associated with fetal and neonatal  death, whereas cardiac anomalies have been noted in infants  who survive the initial infection.   Herpangina begins with an acute onset of sore throat,  dysphagia, and fever, occasionally accompanied by cough,  rhinorrhea, anorexia, vomiting, diarrhea, myalgia, and  headache. Most cases, however, are mild or subclinical.  Typically a small number of lesions (usually two to six)  develop on the soft palate or tonsillar pillars (Fig. 7-23).  The lesions begin as red macules, which form fragile vesicles  that rapidly ulcerate. The ulcerations average 2 to 4 mm in  diameter. The systemic symptoms resolve within a few days;  the ulcerations usually take 7 to 10 days to heal.    Hand-foot-and-mouth disease is the best-known presenta-  tion of enterovirus infection. Like herpangina, the skin rash  and oral lesions typically are associated with flulike symp-  toms (e.g., sore throat, dysphagia, and fever), occasionally  accompanied by cough, rhinorrhea, anorexia, vomiting,  diarrhea, myalgia, and headache.    ® Fig. 7-23 Herpangina. Numerous aphthous-like ulcerations of the  soft palate.    © Fig. 7-24 Hand-foot-and-mouth Disease. Multiple vesicles of  the skin of the toe. (Courtesy of Dr. Samuel J. Jasper.)    The name fairly well describes the location of the lesions.  Oral and hand lesions almost always are present. The oral  lesions arise without prodromal symptoms and precede the  development of the cutaneous lesions. Sore throat and mild  fever usually are present also. The cutaneous lesions range  from a few to dozens and primarily affect the borders of the  palms and soles and the ventral surfaces and sides of the  fingers and toes (Fig. 7-24). Rarely other sites, especially  the buttocks, external genitals, and legs, may be involved.  The cutaneous lesions begin as erythematous macules that  develop central vesicles and heal without crusting (Fig.  7-25). In some cases, nail loss or ridges (Beau lines) may  ensue after several weeks.   The oral lesions resemble those of herpangina but may  be more numerous and more frequently involve anterior  regions of the mouth. The number of lesions ranges from  1 to 30. The buccal mucosa, labial mucosa, and tongue are  the most common sites, but any area of the oral mucosa  may be involved (Fig. 7-26). The individual lesions typically  measure 2 to 7 mm in diameter but may be larger than  1 cm. The lesions rapidly ulcerate and then typically heal  within 1 week.    @ Fig. 7-25 Hand-foot-and-mouth Disease. Numerous cutaneous  vesicles on the sides of the fingers.    ® Fig. 7-26 Hand-foot-and-mouth Disease. Multiple aphthous-like  ulcerations of the mucobuccal fold.    ® Fig. 7-27 Acute Lymphonodular Pharyngitis. Numerous dark-  pink and yellow lymphoid aggregates. (Courtesy of Dr. George Blozis.)    Acute lymphonodular pharyngitis is characterized by sore  throat, fever, and mild headache, which may last from 4 to  14 days. Low numbers (one to five) of yellow to dark-pink  nodules develop on the soft palate or tonsillar pillars  (Fig. 7-27). The nodules represent hyperplastic lymphoid    In patients with herpangina and hand-foot-and-mouth  disease, the affected epithelium exhibits intracellular and  intercellular edema, which lead to the formation of an  intraepithelial vesicle. The vesicle enlarges and ruptures  through the epithelial basal cell layer, with formation of a  subepithelial vesicle. Epithelial necrosis and ulceration soon  follow. Inclusion bodies and multinucleated epithelial cells  are absent.    Herpangina, hand-foot-and-mouth disease, and acute lym-  phonodular pharyngitis usually are diagnosed based upon  the clinical manifestations. In patients with atypical presen-  tations, laboratory confirmation appears prudent. Viral iso-  lation from culture can be performed. Throat cultures tend  to be positive predominantly during the early acute stage.  Cultures from stool specimens are best for patients with  mucosal lesions only, whereas cultures from cutaneous  lesions are best for the diagnosis of hand-foot-and-mouth  disease. Serologic demonstration of rising enteroviral anti-  body titers between the acute and convalescent stages can  be used to confirm the diagnosis in questionable cases. PCR  assay is increasingly available and replacing viral culture in  many diagnostic laboratories.    In most instances, enterovirus infections are self-limiting  and without significant complications. Therapy is directed  toward symptomatic relief; nonaspirin antipyretics and  topical anesthetics, such as dyclonine hydrochloride, often  are beneficial.   Occasionally, certain strains produce infections with a  more aggressive clinical course. Body temperature above  102° E fever for longer than 3 days, severe vomiting,  and lethargy have been associated with increased risk for  serious disease complications and warrant close patient  monitoring.    Measles (rubeola) is a highly contagious infection pro-  duced by a virus in the family Paramyxoviridae and genus  Morbillivirus. Prior to the development of an effective  measles vaccine, the disease caused millions of deaths annu-  ally worldwide. In the pre-vaccine era in the United States,  greater than 90% of individuals were infected by 15 years  of age, with over 500,000 measles cases and about 500  measles-related deaths reported annually.   Eradication through widespread immunization is achiev-  able yet remains a challenge. In the United States, following    the introduction of universal measles vaccination in 1963,  the annual incidence of measles decreased by more than  99%. A major resurgence occurred from 1989 to 1999,  mainly among unvaccinated preschool-aged children. This  resurgence led to the recommendation for a second vaccine  dose and intensive, widespread immunization efforts. In  2000, the CDC declared that measles had been eliminated  in the United States. Nevertheless, outbreaks of measles—  often linked to unvaccinated individuals and importation  of the virus from abroad—continue to occur, with approxi-  mately 40 to 220 cases reported per year since 2001. Like-  wise, international efforts toward measles elimination by the  World Health Organization, United Nations Children’s  Fund, and other organizations have made progress but are  ongoing. Political, financial, and logistical barriers as well  as public complacency and concerns regarding vaccine  safety have made measles control difficult.    Most cases of measles arise in late winter or spring and are  spread through respiratory droplets. The average incubation  period is 14 days, and affected individuals are infectious  from 4 days before until 4 days after appearance of the  associated rash. The virus is associated with significant lym-  phoid hyperplasia that often involves the lymph nodes,  tonsils, adenoids, and Peyer patches.   There are three stages of infection, with each stage lasting  3 days—hence the designation 9-day measles. The first 3  days are dominated by the three Cs: coryza (runny nose),  cough (typically brassy and uncomfortable), and conjunc-  tivitis (red, watery, and photophobic eyes). Fever typically  accompanies these symptoms. During this initial stage, the  most distinctive oral manifestation, Koplik spots, is seen.  These lesions represent foci of epithelial necrosis and appear  as numerous small, blue-white macules (or “grains of salt”)  surrounded by erythema (Fig. 7-28). Typical sites of involve-  ment include the buccal and labial mucosa, and less often  the soft palate.   As the second stage begins, the fever continues, the  Koplik spots fade, and a maculopapular and erythematous  (morbilliform) rash begins. The face is involved first, with  eventual downward spread to the trunk and extremities.  Ultimately, a diffuse erythematous eruption is formed,  which tends to blanch on pressure (Fig. 7-29). Abdominal  pain secondary to lymphatic involvement is not rare.   In the third stage, the fever ends. The rash begins to fade,  with downward progression and replacement by brown pig-  mentation. Ultimately, desquamation of the skin is noted  in areas previously affected by the rash.   Complications may affect up to 40% of patients,  especially those who are younger than 5 years, older  than 20 years, malnourished, or immunocompromised.  Common complications in young children are otitis media,  pneumonia, laryngotracheobronchitis (croup), and diar-  rhea. Another fairly common sequela is keratoconjunctivi-  tis, which tends to affect children with vitamin A deficiency    @ Fig. 7-28 Rubeola. Numerous blue-white Koplik spots of buccal  mucosa. (Courtesy of Dr. Robert J. Achterberg.)    ® Fig. 7-29 Rubeola. Erythematous maculopapular rash of the face.  (Courtesy of Dr. Robert J. Achterberg.)    and may cause blindness. Acute appendicitis occasionally is  seen secondary to vascular obstruction created by the swell-  ing of Peyer patches. Encephalitis develops in approximately  1 in 1000 cases, often resulting in death or permanent brain  damage and intellectual disability. In about 1 in 100,000  cases, a delayed complication termed subacute sclerosing  panencephalitis (SSPE) arises as late as 11 years after the  initial infection. This degenerative CNS disorder leads to  personality changes, seizures, coma, and death. Widespread  vaccine use virtually has eliminated SSPE in developed  nations.   Measles in immunocompromised patients can be serious,  with a high risk for complications and death. Most of these  patients exhibit either an atypical rash or no exanthem.  Pneumonitis is the primary complication.   Koplik spots are not the only oral manifestation that may  be associated with measles. Candidiasis, necrotizing ulcer-  ative gingivitis (NUG), and necrotizing stomatitis may  occur if significant malnutrition also is present. Severe  measles in early childhood can cause pitted enamel hypo-  plasia of the developing permanent teeth. Enlargement of  accessory lymphoid tissues, such as the lingual and pharyn-  geal tonsils, also may be noted.    Because of the reduced prevalence of measles and the tran-  sient nature of Koplik spots, few oral and maxillofacial  pathologists have had the opportunity to view these lesions  microscopically. Initially, Koplik spots represent areas of  hyperparakeratotic epithelium with spongiosis, dyskerato-  sis, and epithelial syncytial giant cells. The number of nuclei  within these giant cells ranges from 3 to more than 25.  Close examination of the epithelial cells often reveals pink-  staining inclusions in the nuclei or, less commonly, cyto-  plasm. Electron microscopy has shown that the inclusions  represent microtubular aggregates characteristic of para-  myxovirus infection. As the spot ages, the epithelium  exhibits heavy neutrophilic exocytosis leading to micro-  abscess formation, epithelial necrosis, and, ultimately,  ulceration. Frequently, examination of the epithelium  adjacent to the ulceration reveals the suggestive syncytial  giant cells.   Examination of hyperplastic lymphoid tissue during the  prodromal stage of measles often reveals a similar alteration.  In 1931, Warthin and Finkeldey, in two separate publica-  tions, reported an unusual finding in patients who had their  tonsils removed within 1 to 5 days of the clinical appearance  of measles. Within the hyperplastic lymphoid tissue, there  were numerous multinucleated giant lymphocytes (Fig.  7-30). These multinucleated cells subsequently have been  termed Warthin-Finkeldey giant cells and once were  thought to be specific for measles. However, similar cells  have been noted in a variety of conditions, such as lym-  phoma, Kimura disease, AIDS-related lymphoproliferative  disease, and lupus erythematosus.    The diagnosis of measles in an epidemic setting usually is  based on the clinical features and history. Laboratory con-  firmation can be of value in isolated or atypical cases. The    ® Fig. 7-30 Rubeola. Histopathologic section of pharyngeal tonsil  demonstrating lymphoid hyperplasia with scattered multinucleated  giant cells. Inset reveals high-power magnification of Warthin-Finkeldey  giant cells.    most commonly used method is IgM antibody assay per-  formed on a single serum sample. The antibodies usually  appear within 1 to 3 days after the beginning of the exan-  them and persist for 1 to 2 months. Confirmation by rising  IgG titers, viral culture, and reverse transcription PCR also  are possible.    Primary prevention is essential for reducing measles-  associated morbidity and mortality. The measles vaccine is  a live, attenuated virus, which is included in the widely used  MMR (measles, mumps, and rubella) and MMRV (measles,  mumps, rubella, and varicella) vaccines. Routine childhood  measles vaccination is recommended, with the first dose  administered between the ages of 12 and 15 months and a  second dose between the ages of 4 and 6 years. The vaccine  is highly effective, with over 99% of individuals developing  long-term immunity after receiving two doses. In a given  population, measles eradication typically is attained with  95% vaccine coverage. Despite controversy regarding  vaccine safety, adverse reactions from measles vaccination  are rare and typically mild or transient. Extensive research  shows no increased risk of permanent neurologic sequelae,  and no scientific evidence supports an increased risk for  autism or inflammatory bowel disease.   In otherwise healthy patients with measles, fluids and  nonaspirin antipyretics are recommended for symptomatic  relief. Children with measles also should receive vitamin A  supplementation. For immunocompromised patients, riba-  virin and interferon have shown promise, but controlled  trials assessing their efficacy are lacking. In addition,  immune globulin may be administered to prevent or modify  disease in exposed immunocompromised patients.   In the United States, less than 1% of measles cases result  in death, whereas in developing countries with low vaccine  coverage, the case-fatality rate can be as high as 25%. The  most common causes of death are pneumonia and acute  encephalitis. The prognosis is especially poor for immuno-  compromised patients, with greater than 50% mortality for  infected patients with underlying malignancy and more  than 30% mortality for AIDS-associated measles.    Rubella is a mild illness caused by a virus in the family  Togavirus and genus Rubivirus. The greatest importance of  this infection lies not in its effects on those who contract  the acute illness but in its capacity to induce birth defects  in the developing fetus. The infection occurs primarily in  late winter and early spring. It is contracted through respira-  tory droplets, with nearly 100% transmission among indi-  viduals in close living conditions. The incubation time is  from 12 to 23 days, and infected patients are contagious  from 1 week before to 1 week after onset of the exanthem.  Infants with a congenital infection may release the virus for  up to | year.    In the past, this infection occurred in cycles, with local-  ized epidemics every 6 to 9 years and pandemics every 10  to 30 years. The last pandemic occurred from 1962 to 1964.  In 1964 and 1965, the United States alone had more than  12.5 million cases, which resulted in more than 11,000  spontaneous or therapeutic abortions, 2,100 neonatal  deaths, and 20,000 infants born with congenital rubella  syndrome (CRS).   An effective vaccine, first released in 1969, has dramati-  cally affected the epidemiology of the infection and broken  the cycle of occurrences. In the United States, during the  two decades immediately following introduction of the  vaccine, the number of rubella and CRS cases reported  annually decreased 99% and 97%, respectively. Like rubeola,  rubella exhibited a slight resurgence from 1989 to 1990,  primarily due to a lack of vaccination diligence; this resur-  gence prompted intensification of vaccination efforts and a  new two-dose schedule. These measures resulted in an  overall decline in rubella cases but a shift in epidemiology.  During the early 1990s, children younger than 15 years  mainly were affected; however, since the mid-1990s, most  reported rubella cases have occurred in patients 15 years and  older, especially among Hispanic and foreign-born indi-  viduals. Notwithstanding, since 2001, the overall annual  incidence has remained low (less than 1 per 10,000,000  population). In 2004, a panel of experts declared that  rubella elimination (i.e., absence of endemic transmission)  had been achieved in the United States. From 2005 through  2011, only 62 cases of rubella and 4 cases of CRS were  reported in the United States. However, rubella remains  endemic in several parts of the world, with more than  120,000 cases reported annually worldwide.    A large percentage of infections are asymptomatic; the fre-  quency of symptoms is greater in adolescents and adults.  Prodromal symptoms may be seen 1 to 5 days before the  exanthem and include fever, headache, malaise, anorexia,  myalgia, mild conjunctivitis, coryza, pharyngitis, cough,  and lymphadenopathy. The lymphadenopathy may persist  for weeks and is noted primarily in the suboccipital, post-  auricular, and cervical chains. The most common complica-  tion is arthritis, which increases in frequency with age and  usually arises subsequent to the rash. Rare complications  include encephalitis and thrombocytopenia.   The rash is often the first sign of the infection and begins  on the face and neck, with spread to the entire body within  1 to 3 days. The exanthem forms discrete pink macules,  then papules, and finally fades with flaky desquamation.  Facial involvement often clears before the rash completes its  spread into the lower body areas. Generally, the rash com-  pletely resolves by day 3—hence the designation 3-day  measles.   Oral lesions, known as Forchheimer sign, have been  reported in about 20% of cases. These lesions consist of  small, discrete, dark-red papules that develop on the soft    palate and may extend onto the hard palate. This enanthem  arises simultaneously with the rash, becoming evident  in about 6 hours after the first symptoms and not  lasting longer than 12 to 14 hours. Palatal petechiae also  may occur.   The risk of CRS correlates with the time of infection.  The frequency of transmission from an infected mother is  greater than 80% during the first 12 weeks of pregnancy,  with the risk of fetal damage decreasing dramatically at 8  weeks and becoming rare after 20 weeks of gestation. The  classic triad of CRS consists of deafness, heart disease, and  cataracts. Deafness is the most common manifestation,  affecting more than 80% of patients. This hearing loss may  not become evident until 2 years of age and usually is bilat-  eral. Less common, late-emerging complications include  encephalopathy, intellectual impairment, diabetes mellitus,  and thyroid disorders.    The diagnosis of rubella is contingent on laboratory tests  because the clinical presentation of the acquired infection  is typically subclinical, mild, or nonspecific. Serologic anal-  ysis is the mainstay of diagnosis, although viral culture and  PCR also are possible.    Rubella is mild, and therapy usually is not required. Non-  aspirin antipyretics and antipruritics may be useful in  patients with significant fever or symptomatic cutaneous  involvement. Passive immunity may be provided by the  administration of rubella immunoglobulin. If immuno-  globulin is given within a few days of exposure, it decreases  the severity of the infection. This therapy typically is reserved  for pregnant patients who decline abortion.   High vaccination coverage—particularly among chil-  dren, women of childbearing age, and foreign-born  individuals—is essential for prevention of rubella. In the  United States, both the MMR (measles, mumps, and  rubella) and MMRV (measles, mumps, rubella, and vari-  cella) vaccines are licensed for rubella prevention. Routine  childhood administration of either MMR or MMRV is  recommended, with the first dose at 12 to 15 months of  age and the second dose at 4 to 6 years of age. In addition,  in the absence of evidence of rubella immunity, the follow-  ing groups should receive at least one dose of MMR: adults  born during or after 1957, nonpregnant women of child-  bearing age, and health care personnel. Evidence of immu-  nity may include serologic testing or documentation of at  least one dose of rubella-containing vaccine at 12 months  of age or older; immunity also generally can be presumed  in those born before 1957, as long as the individual is  neither a woman who might become pregnant nor a health  care worker. Contraindications for the MMR and MMRV  vaccines include pregnancy, immunodeficiency, allergy to  any of the vaccine components, and acute febrile illness.    Mumps is an infection caused by a virus in the family  Paramyxoviridae and genus Rubulavirus. This infection  causes diffuse swelling of the exocrine glands; although the  salivary glands are the best known sites of involvement, the  pancreas, choroid plexus, and mature ovaries and testes also  are affected frequently. The virus can be transmitted through  respiratory droplets, saliva, and urine. The incubation  period usually is 16 to 18 days, with a range of about 2 to  4 weeks. Patients are contagious from 1 day before the clini-  cal appearance of infection to 14 days after its clinical reso-  lution. In temperate climates, mumps most commonly  occurs in winter and spring.   As with measles and rubella, the epidemiology has been  affected dramatically by vaccination. Before the advent of  widespread vaccination, mumps epidemics developed every  2 to 5 years; nearly everyone was exposed with 90% of  infections occurring before age 15. In the United States, the  mumps vaccine was licensed in 1967, although the Advisory  Committee on Immunization Practices (ACIP) did not rec-  ommend universal childhood mumps vaccination until  1977. At that time, MMR (measles, mumps, and rubella)  vaccine administration became the norm for children 12 to  15 months of age. Subsequently, the annual incidence of  mumps decreased by 98% and reached an all-time low in  1985. In 1989, the ACIP issued a two-dose recommenda-  tion for MMR vaccination, primarily in response to a resur-  gence of measles. Compared with the pre-vaccine era, the  two-dose vaccination schedule has reduced the prevalence  of mumps by more than 99%.   Nevertheless, several mumps resurgences have occurred  over the past three decades. These resurgences often have  developed among adolescents and young adults, particularly  in the college setting. This shift in peak age from childhood  to adolescence and young adulthood is clinically significant,  because certain disease complications, such as epididymo-  orchitis and oophoritis, primarily affect postpubertal  patients. Although outbreaks in the mid-1980s to early  1990s were attributed to single-dose vaccine failure or a lack  of vaccination, several outbreaks in the 2000s have occurred  despite high levels of two-dose vaccine coverage. The effi-  cacy of the mumps component of the MMR vaccine is  approximately 88% after two doses and is lower than that  of the measles and rubella components. During outbreaks  from 2009 to 2010, individuals in affected populations were  administered a third dose of MMR vaccine under experi-  mental protocols. Some experts believe a routine third dose  of MMR vaccine may be recommended in the future.    Approximately 30% of mumps infections are subclinical. In  symptomatic cases, prodromal symptoms of low-grade    @ Fig. 7-31 Mumps. Bilateral parotid enlargement. (From Neville BW,  Damm DD, White DK: Color atlas of clinical oral pathology, ed 2,  Hamilton, 1999, BC Decker.)    fever, headache, malaise, anorexia, and myalgia develop  first. These nonspecific findings typically are followed within  1 day by significant salivary gland changes. The parotid  glands are involved most often, but the sublingual and  submandibular glands also can be affected. Discomfort and  swelling develop in the tissues surrounding the lower half  of the external ear and extending down along the posterior  inferior border of the adjacent mandible (Fig. 7-31). The  enlargement and pain typically peak within 2 to 3 days.  Chewing movements of the jaw or eating saliva-stimulating  foods tends to increase the pain. Enlargement of the glands  usually begins on one side, followed by contralateral involve-  ment within a few days. Unilateral involvement is seen in  about 25% of patients.   The second most common finding is epididymo-orchitis,  which occurs in about 25% of postpubertal males. The tes-  ticle exhibits rapid swelling, with significant pain and ten-  derness. The enlargement can range from a minimal swelling  to a fourfold increase in size. Unilateral involvement is most  common. Upon resolution of the swelling, testicular atrophy  may occur; permanent sterility is rare, but subfertility devel-  ops in approximately 13% of patients with epididymyo-  orchitis. Less commonly, oophoritis and mastitis can be seen  in postpubertal females. In addition, spontaneous abortion  occurs in approximately 25% of women who contract  mumps during the first trimester of pregnancy.   Less commonly, meningoencephalitis, cerebellar ataxia,  hearing loss, pancreatitis, arthritis, carditis, and decreased    renal function may occur. The most common symptom  associated with CNS involvement is headache, whereas  involvement of the pancreas can lead to nausea and vomit-  ing. Isolated changes, such as orchitis or meningitis, may  occur in the absence of salivary gland involvement, thereby  making diagnosis difficult in nonepidemic settings.   The most frequently reported oral manifestation is  redness and enlargement of Wharton and Stensen salivary  gland duct openings. In addition, involvement of the sub-  lingual glands may produce bilateral enlargement of the  floor of the mouth.    The diagnosis of mumps in an epidemic setting usually can  be made easily from the clinical presentation; however, iso-  lated cases often require laboratory confirmation. The most  frequently used diagnostic procedure is demonstration of  either mumps-specific IgM or a fourfold rise of mumps-  specific IgG titers between the acute and convalescent  phases. In addition, a swab of secretions obtained from  parotid or other affected salivary gland ducts can be used for  viral culture or real-time reverse transcription PCR testing.    The treatment of mumps is palliative in nature. Frequently,  nonaspirin analgesics and antipyretics are administered. In  an attempt to minimize orchitis, bed rest is recommended  for males until the fever breaks. Avoidance of sour foods  and drinks helps to decrease the salivary gland discomfort.  Mumps-related mortality is exceedingly rare and primarily  associated with encephalitis.   As with measles and rubella, vaccination is important for  controlling disease. The mumps vaccine is a live, attenuated  virus, which is incorporated into the MMR and MMRV  (measles, mumps, rubella, and varicella) vaccines. Monova-  lent mumps vaccine is no longer available in the United  States. The current recommendation is for routine child-  hood administration of two doses of mumps-containing  vaccine, with the first dose administered between the ages  of 12 and 15 months and the second dose between the ages  of 4 and 6 years. In addition, two doses of MMR vaccine  should be administered to adults who lack immunity and  fall into any of the following categories: health care workers  born in or after 1957, college students, and international  travelers. One dose of MMR vaccine is recommended for  all other adults who lack evidence of immunity and were  born in or after 1957.    More articles have been written on human immunodefi-  ciency virus (HIV) and its related disease states than any    other infectious process. A complete bibliography easily  would be longer than this chapter. Entire texts dedicated to  HIV infection and acquired immunodeficiency syndrome  (AIDS) are available for more detailed information.   HIV is a single-stranded RNA virus belonging to the  family Retroviridae. There are two species: HIV-1 and  HIV-2. The former exhibits a worldwide distribution and  is responsible for the majority of cases, whereas the latter  predominates in western Africa and is associated with a  somewhat lower risk of transmission and slower disease  progression.   In 1981, the CDC published the first scientific report of  AIDS. This report detailed Pneumocystis carinii (since  renamed Pneumocystis jiroveci) pneumonia in five previously  healthy men from Los Angeles, California. A few years later,  HIV was isolated and identified as the cause of AIDS. Since  this initial description, more than 30 years have passed.  During this time, more than 65 million individuals world-  wide have become infected with HIV, and more than 30  million individuals have died of AIDS. Worldwide in 2011  alone, 2.5 million new infections occurred, 34 million  people were living with HIV, and an estimated 1.7 million  individuals died of AIDS. According to the most recent  report by the Joint United Nations Programme on HIV/  AIDS, HIV infection is most prevalent in sub-Saharan  Africa—which accounts for nearly 70% of people living  with HIV worldwide and more than half of global AIDS  deaths—followed by the Caribbean, Eastern Europe, and  Central Asia. The toll has been devastating, although  through global public health efforts and treatment advances,  there has been a slow decline in the number of newly  infected individuals worldwide over the past decade.   In the United States, more than 619,000 people with  AIDS have died since the epidemic began, and approxi-  mately 1.1 million individuals currently are living with HIV  infection. The annual number of AIDS diagnoses in the  United States expanded rapidly during the 1980s, peaked  at around 78,000 in 1992, and subsequently sharply  declined to about 40,000 in 1998. Presently, the number  of AIDS cases diagnosed annually in the United States has  stabilized at around 33,000. In the early years of the HIV/  AIDS epidemic, the disease was nearly 100% fatal; however,  since the introduction of combination antiretroviral therapy  (cART) (see the Treatment and Prognosis section) in 1996,  there has been significant improvement in patient survival  and, thus, an increased percentage of the population living  with the virus. The percentage of individuals surviving 2  years after AIDS diagnosis has increased from 44% in 1981  to 1992, to 64% in 1993 to 1995, and to 85% in 1996  to 2006.   In infected individuals, the virus can be found in most  bodily fluids, including serum, blood, saliva, semen, tears,  urine, breast milk, ear secretions, and vaginal secretions. In  the United States, the most frequent mode of transmission  is male-to-male sexual contact (accounting for nearly two-  thirds of HIV infections diagnosed annually), followed by  heterosexual contact and injection drug use. Perinatal    exposure and blood transfusion currently account for a  small proportion of cases. Infection by artificial insemina-  tion, breast-feeding from infected mothers, and organ trans-  plantation also has been documented rarely.   Transmission by oral fluids is somewhat controversial  and has been reported only anecdotally. In rare cases, HIV  transmission has occurred during breast-feeding from the  oral fluids of postpartum infected infants to their previously  noninfected mothers. In addition, possible transmission  from oral cunnilingus or repeated passionate kissing very  rarely has been described. Saliva contains a number of HIV  inhibitory factors, which appear to reduce the ability of the  virus to infect its target cells. However, the presence of ero-  sions, ulcerations, and hemorrhagic inflammatory pathoses  (e.g., gingivitis, periodontitis) may predispose an individual  to oral transmission. In summary, the best precaution is  avoidance of all body fluids of infected patients.   Initially in the United States, AIDS primarily affected  whites and male homosexuals. Today, male-to-male sexual  contact remains the largest single risk factor; however, the  epidemiology of the HIV/AIDS epidemic has shifted over  time, with a greater proportion of cases arising in blacks,  Hispanics, females, and heterosexuals and a smaller propor-  tion of cases attributed to blood transfusion, infected blood  products, or perinatal transmission.   Since the initial years of the epidemic, blood-screening  methods have improved dramatically and reduced the risk  for HIV infection to as low as 1 in 2 million blood dona-  tions. Furthermore, because of improved viral inactivation  methods and increasing use of recombinant clotting factors,  HIV transmission from factor VII and IX preparations has  not occurred in the United States since 1986. Consequently,  the proportion of hemophiliacs with HIV has declined from  more than 50% during the early years of the epidemic to  approximately 10% at present. In addition, the risk of trans-  mission from infected mothers to newborns has decreased  from approximately 25% to less than 2% because of wide-  spread prenatal HIV testing, prophylactic use of antivirals,  elective cesarean section performed before onset of labor,  and avoidance of breast-feeding.   In the early years of the HIV/AIDS epidemic in the  United States, non-Hispanic whites predominantly were  affected, whereas currently blacks and Hispanics are the  most commonly affected ethnic groups. According to the  CDC, in 2010 the estimated rates of HIV infection per  100,000 population among blacks, Hispanics, and whites  were 69, 28, and 9, respectively. Although blacks repre-  sented only about 14% of the United States population,  they accounted for 44% of new HIV infections. Similarly,  Hispanics were disproportionately affected, with this group  accounting for about 16% of the population but 21% of  new HIV infections. Factors contributing to these dispari-  ties may include poverty; limited access to health care and  HIV education; cultural and language barriers; lack of  awareness of HIV status; high rates of other sexually trans-  mitted infections (such as, HSV-2 infection) that increase  the risk of contracting HIV; and avoidance of testing and    treatment for fear of discrimination. In recent years, the  overall annual incidence of HIV among blacks and Hispan-  ics has not changed significantly, although preliminary data  suggests HIV incidence among black women may be  declining.   Furthermore, compared to the beginning of the epi-  demic, a greater proportion of new HIV infections are  occurring in females and heterosexuals. In 2010, approxi-  mately 25% of new HIV infections in the United States  occurred in heterosexuals, and approximately two-thirds of  those infected through heterosexual contact were female.   The primary target cell of HIV is the CD4+ helper T  lymphocyte, although other CD4+ cells (such as, macro-  phages and dendritic cells) may be infected as well. The  virus binds to CD4 and additional cell surface molecules in  order to gain entry, upon which the viral RNA genome is  reverse transcribed into complementary DNA. This com-  plementary DNA may become incorporated into the host  cell DNA. In people with HIV infection, antibodies against  the virus are developed but are not protective. The virus  may remain silent, cause cell death, or produce syncytial  fusion of cells, which disrupts their normal function. A  subsequent decrease in T-helper cell numbers occurs, with  a resultant loss of immune function. The normal response  to viruses, fungi, and encapsulated bacteria is diminished.  In addition, infection of macrophages and microglia in the  CNS may lead to neurologic disease manifestations,  although the exact mechanisms of HIV-induced CNS  damage are not completely understood.    The clinical stages of HIV infection include an acute phase,  a chronic phase (or latency period), and AIDS. During the  acute phase, the patient may be asymptomatic or exhibit a  self-limited acute retroviral syndrome. This syndrome  typically develops within 1 to 6 weeks after exposure in 50%  to 70% of infected patients. The symptoms resemble those  of infectious mononucleosis (e.g., generalized lymphade-  nopathy, sore throat, fever, maculopapular rash, headache,  myalgia, arthralgia, diarrhea, photophobia, and peripheral  neuropathies). Oral changes may include mucosal erythema  and focal ulcerations. During this initial phase, HIV infec-  tion often is not considered or investigated, and HIV anti-  bodies are not yet detectable. Nevertheless, during this  period, patients exhibit high levels of viremia and are  extremely infectious.   After infection is established, an immune response is  developed, viremia declines, and the patient enters a clinical  latency period. Latency may last anywhere from several  months to more than 15 years. Without treatment, the  median duration is approximately 10 years, with much  shorter periods typically seen in infants, children, or those  infected via blood transfusion. Patient age, host immune  responsiveness, type of exposure, viral strain, and cART may  impact the duration of latency. Most patients are asymp-  tomatic, but some patients have persistent generalized    lymphadenopathy (PGL). In some cases, before develop-  ment of overt AIDS, there is a period of chronic fever,  weight loss, diarrhea, oral candidiasis, herpes zoster, and/or  oral hairy leukoplakia (OHL). This presentation has been  termed AIDS-related complex (ARC).   Over time, the immune system fails to control the virus.  There is a dramatic increase in viremia, and the CD4+ cell  count declines, resulting in the development of AIDS. The  presentation of this symptomatic phase is highly variable  and often affected by a person's prior exposure to a number  of chronic infections. The signs and symptoms described  under ARC are often present, along with an increasing  number of opportunistic infections or neoplastic processes.  In many cases, pneumonia caused by the fungus Pueumo-  cystis jiroveci is the presenting feature leading to AIDS diag-  nosis. Other infections of diagnostic significance include  disseminated cytomegalovirus infection, severe herpes  simplex virus infection, atypical mycobacterial infection,  cryptococcal meningitis, and CNS toxoplasmosis. Persistent  diarrhea is commonplace and may be bacterial or protozoal  in origin. Clinically significant neurologic dysfunction is  present in 30% to 50% of patients and most commonly  manifests as progressive encephalopathy known as AIDS-  dementia complex.   The most widely accepted classification of the oral  manifestations of HIV disease was compiled by the  EC-Clearinghouse on Problems Related to HIV Infection  and the WHO Collaborating Centre on Oral Manifesta-  tions of the Immunodeficiency Virus. This classification  divides the manifestations into three groups: 1) strongly  associated, 2) less commonly associated, and 3) seen in HIV  infection (Box 7-1).   The prevalence and types of oral manifestations of HIV  disease have been altered dramatically by the introduction  of cART. Numerous investigations of patients receiving  cART have correlated an increase in CD4+ cell count and  a reduction in viral load with a reduced prevalence of many  oral manifestations. In particular, there have been signifi-  cant reductions in the frequency of oral candidiasis, OHL,  HIV-associated periodontal disease, and Kaposi sarcoma.  Although the prevalence of certain lymphomas has decreased  because of cART, the frequency of all HIV-related lympho-  mas has not demonstrated significant change. In contrast,  many researchers have reported an increased prevalence of  benign human papillomavirus (HPV)-induced pathoses. A  similar increased frequency of HIV-associated salivary gland  disease has been noted by some but disputed by others.   Importantly, the detection of oral manifestations may  suggest possible HIV infection in an undiagnosed individ-  ual. In addition, the discovery of oral manifestations in a  patient with known HIV infection may signal HIV disease  progression and the need for initiation or adjustment of  antiretroviral therapy.   The following discussion of oral manifestations concen-  trates primarily on the clinical presentations and special  treatment considerations for HIV-infected patients. (For  more detailed information regarding these conditions in the   e Salivary gland disease: Dry mouth and unilateral or bilateral  swelling of major salivary glands   e Viral infections: Herpes simplex virus (HSV), human  papillomavirus (HPV), and varicella-zoster virus (VZV)   e Fungal infections other than candidiasis: Cryptococcus  neoformans, Geotrichum candidum, Histoplasma  capsulatum, Mucoraceae (mucormycosis/zygomycosis), and  Aspergillus flavus    general patient population, see the discussion of each disease  elsewhere in this text.) The most common oral manifesta-  tions are presented first, followed by a selection of less fre-  quently encountered conditions.    Candidiasis is the most common intraoral manifestation of  HIV infection and often is the presenting sign that leads to  the initial diagnosis (Fig. 7-32). Although a number of  Candida species have been encountered intraorally, the most  common organism identified in oral candidiasis is Candida  albicans. The presence of oral candidiasis in a patient  infected with HIV is not diagnostic of AIDS but appears  to be predictive for the subsequent development    of full-blown AIDS in untreated patients within 2 years.  Prevalence studies vary widely, but approximately one-third  of HIV-infected individuals and more than 90% of patients  with AIDS develop oral candidiasis at some time during  their disease course. The following four clinical patterns are  seen (see page 191):   ‘The first two variants constitute most cases. Although  infrequently seen in immunocompetent patients, chronic  multifocal oral involvement is common in HIV-infected  patients. Erythematous candidiasis typically appears when  the CD4+ lymphocyte count drops below 400 cells per  mm’, whereas the pseudomembranous pattern usually  develops when the count drops below 200 cells per mm’.  Among patients with various types of immunocompro-  mised status, those with HIV infection have a greater preva-  lence of oral candidiasis, suggesting that HIV may play a  role in initiation of candidal infection. Some studies have  shown that development of candidiasis correlates more  closely with viral load than CD4+ cell count. Oral candi-  diasis can be painful and associated with a reduction in taste  and smell, which may lead to decreased food intake and  further wasting.   The diagnosis of candidiasis often is obvious from the  clinical presentation but can be confirmed by cytologic  smear or biopsy. Biopsy specimens of involved mucosa dem-  onstrate the candidal organisms embedded in the superficial  keratin, but the typical inflammatory reaction may be defi-  cient (Fig. 7-33).   Treatment is often difficult in patients with AIDS.  Among topical agents, nystatin typically is ineffective.  Gentian violet is more effective than nystatin but is not used  much because its application is messy; in areas with inad-  equate funding or limited access to newer medications, this  agent may be a low-cost alternative. Clotrimazole is the  treatment of choice for patients who are receiving effective  antiretroviral therapy, have a CD4+ cell count exceeding 50    ° Fig. 7-33 HIV-associated Candidiasis. Periodic acid-Schiff (PAS)  stain of histopathologic section exhibiting numerous fungal organisms  embedded in superficial keratin.    cells/mm’, and have no signs of esophageal involvement.  However, recurrence is more common following topical  than systemic therapy.   Systemic antifungal therapy is recommended for patients  not receiving effective antiretroviral therapy or those with  either esophageal involvement, a CD4+ cell count below 50  cells/mm’, or a high viral load. Fluconazole is considered  by many to be the drug of choice; nevertheless, non-albicans  species (such as, C. glabrata, C. dubliniensis, and C. krusei)  have been isolated in HIV-infected patients, and these  organisms may exhibit limited susceptibility or frank resis-  tance to fluconazole. Itraconazole oral solution, voricon-  azole, and posaconazole are also effective but considered  second-line agents. Clinicians should be aware that poten-  tial drug interactions exist between the antifungal azoles and  antiretrovirals. For refractory cases, amphotericin B oral  solution, [V amphotericin B, or IV echinocandins may be  considered. Because of the potential for developing resis-  tance, prophylactic antifungal therapy typically is reserved  for patients with especially frequent and severe recurrences.  Preventive regimens usually consist of either continuous or  intermittent administration of fluconazole.   Interestingly, HIV protease inhibitors used in cART have  been associated with a decrease in frequency and recurrence  of oral candidiasis. These findings may be related to the  ability of these agents to inhibit a candidal virulence factor,  known as secreted aspartic proteinase, and exert a synergis-  tic effect with antifungals against fungal resistance. Further-  more, in one large-scale retrospective study, investigators  noted a significantly lower risk of oral candidiasis among  patients receiving cART with a non-nucleoside reverse tran-  scriptase inhibitor compared to those receiving cART  without this medication type.    Although EBV is associated with several forms of lym-  phoma in HIV-infected patients, the most common EBV-  related lesion in patients with AIDS is oral hairy  leukoplakia (OHL). The presence of OHL in HIV-infected    °@ Fig. 7-34 HIV-associated Oral Hairy Leukoplakia (OHL). Verti-  cal streaks of keratin along the lateral border of the tongue.    ® Fig. 7-35 HIV-associated Oral Hairy Leukoplakia (OHL). Oral  mucosa exhibiting hyperparakeratosis with surface corrugations.    patients is a sign of severe immunosuppression and advanced  disease. OHL also has been reported in transplant recipi-  ents, but its presence in the absence of a known cause of  immunosuppression strongly suggests HIV infection. The  lesion only very rarely has been described in immunocom-  petent individuals, and discovery of OHL in “normal”  patients mandates a thorough physical evaluation to rule  out immunocompromise.   OHL clinically presents as a white mucosal plaque that  does not rub off. Most cases occur on the lateral border of  the tongue and range in appearance from faint, white verti-  cal streaks to thickened, furrowed areas of leukoplakia with  a shaggy surface (Fig. 7-34). The lesions infrequently may  extend to cover the entire dorsal and lateral surfaces of the  tongue. Rarely, the buccal mucosa, soft palate, pharynx, or  esophagus may be involved.   Histopathologically, OHL exhibits thickened parakera-  tin with surface corrugations or thin projections (Fig. 7-35).  The epithelium is acanthotic and exhibits a bandlike zone  of lightly stained cells with abundant cytoplasm (“balloon  cells”) in the upper spinous layer (Fig. 7-36). Close exami-  nation of the superficial epithelial cells reveals nuclear clear-  ing and a characteristic pattern of peripheral margination    ® Fig. 7-36 HIV-associated Oral Hairy Leukoplakia (OHL). Oral  epithelium exhibiting hyperparakeratosis and layer of “balloon cells” in  the upper spinous layer. Inset reveals high-power magnification of  epithelial cells that demonstrate nuclear beading.    ® Fig. 7-37 HIV-associated Oral Hairy Leukoplakia (OHL). Immu-  noperoxidase evaluation for Epstein-Barr virus (EBV) revealing positive  reaction within numerous epithelial cells.    of chromatin termed nuclear beading (see Fig. 7-36, inset),  caused by extensive EBV replication that displaces the chro-  matin to the nuclear margin. Dysplasia is not noted. Heavy  candidal infestation of the parakeratin layer may be seen,  although the normal inflammatory reaction to the fungus  usually is absent.   In a patient with known HIV infection, the clinical  features of OHL typically are sufficient for a presumptive  diagnosis. When definitive diagnosis is necessary, demon-  stration of EBV can be achieved by in situ hybridization,  PCR, immunohistochemistry (Fig. 7-37), Southern blot-  ting, or electron microscopy.   Treatment of OHL usually is not needed, although slight  discomfort or aesthetic concerns may necessitate therapy.  Systemic anti-herpesviral drugs produce rapid resolution,  but recurrence is expected with discontinuation of therapy.  Topical treatment with retinoids or podophyllum resin has  resulted in temporary remissions. A few small-scale studies  have demonstrated prolonged resolution after combined  treatment with acyclovir cream and podophyllum resin.  Surgical excision or cryotherapy also has been used by some.    A significantly reduced prevalence of OHL has been noted  in patients well-controlled with cART; in resource-poor  settings, the presence or absence of OHL and oral candidia-  sis can be used as a clinical guide to assist in judging the  effectiveness of antiretroviral therapy.    Kaposi sarcoma (KS) is a vascular endothelial neoplasm  caused by human herpesvirus 8 (HHV-8, Kaposi sarcoma—  associated herpesvirus [KSHV]). Since the beginning of the  AIDS epidemic, most cases in the United States have arisen  in association with HIV infection. At the height of the  epidemic in the early 1990s, the annual incidence of KS in  the United States peaked at 4.7 cases per 100,000 popula-  tion. However, since the introduction of cART in 1996, the  annual incidence has declined substantially and currently is  estimated at less than 0.7 cases per 100,000 population. The  incidence of KS among HIV-infected individuals receiving  antiretroviral therapy is approximately 20% to 40% lower  than that among those not receiving therapy. KS currently  represents the second most common malignancy among  people with AIDS in the United States.   In Western countries, KS has been reported primarily in  HIV-infected, adult, male homosexuals and is thought to  be related to sexual transmission of HHV-8. However, in  Africa both AIDS-related and endemic types of KS fre-  quently are seen, with no gender predilection and a signifi-  cant number of children affected. Infection before sexual  activity suggests alternate transmission pathways. Relatively  high titers of HHV-8 have been found in saliva, and HHV-8  exhibits tropism for oral and oropharyngeal epithelial cells;  these observations suggest that the oral cavity may represent  an important reservoir of infectious virus and saliva may be  a major transmission route.   KS mainly manifests as multiple lesions on the skin or  oral mucosa, although visceral and lymph node involve-  ment also may occur. Occasionally a solitary lesion is identi-  fied first. Among AIDS-related cases, the skin lesions exhibit  a predilection for the face (Fig. 7-38) and lower extremities.  The oral cavity is the initial site of involvement in 22% of    ° Fig. 7-38 HIV-associated Kaposi Sarcoma (KS). Multiple purple  macules on the right side of the face.    patients with KS, and oral lesions are found more often in  AIDS-related KS than other types of KS. Approximately  70% of individuals with AIDS-related KS demonstrate oral  lesions at some point. The hard palate, gingiva, and tongue  are the most frequently affected oral sites (Figs. 7-39 and  7-40). When present on the palate or gingiva, the neoplasm  can invade bone and cause tooth mobility. The lesions  usually begin as erythematous blue or brown macules that  do not blanch with pressure. Nonpigmented lesions have  been reported very rarely. With time, the macules typically  develop into plaques or nodules (Fig. 7-41), which may  coalesce into a diffuse, exophytic mass (Fig. 7-42). Pain,  bleeding, and necrosis may necessitate therapy. Uncom-  monly, advanced oral lesions may cause secondary lymph-  edema of the face and neck.   A biopsy is required for definitive diagnosis, although a  presumptive clinical diagnosis sometimes is made. Other  lesions can have a similar clinical appearance in HIV-  infected patients, including bacillary angiomatosis (a mul-  tifocal vascular proliferation associated with the cat-scratch  bacillus [see page 185]) and lymphoma.   Initiation of CART may induce regression of KS lesions,  and patients who develop KS despite already receiving    ° Fig. 7-39 HIV-associated Kaposi Sarcoma (KS). Large zones of  KS appearing as flat, brownish, and M-shaped discoloration of the  hard palate.    @ Fig. 7-40 HIV-associated Kaposi Sarcoma (KS). Raised, dark-  red enlargement of the left mandibular anterior facial gingiva.    @ Fig. 7-41 HIV-associated Kaposi Sarcoma (KS). Diffuse, red-  blue nodular enlargement of the left hard palate.    @ Fig. 7-42 HIV-associated Kaposi Sarcoma (KS). Diffuse, red-  blue gingival enlargement with widespread necrosis.    cART tend to have relatively mild disease without visceral  involvement. Because KS typically regresses upon return of  immunocompetence, many researchers question whether  KS is a true sarcoma. Locoregional therapy may be used for  limited, asymptomatic mucocutaneous lesions nonrespon-  sive to cART or for palliation of advanced mucocutaneous  lesions. Treatment options include topical therapy (e.g.,  alitretinoin gel or imiquimod cream for skin lesions), intra-  lesional injection of chemotherapeutic or immunomodula-  tory agents (e.g., vinblastine, vincristine, bleomycin, and  interferon-alpha), radiation, surgical excision, cryotherapy  (for skin lesions), sclerotherapy, and laser therapy. Radiation  therapy generally is not advised for oral lesions because of  the potential for severe mucositis. For advanced AIDS-  related KS, systemic chemotherapy or immunomodulatory  therapy in conjunction with cART is indicated. In addition,  some authorities have suggested systemic therapy for oral  lesions of AIDS-related KS even at the early macular stage,  because progression to the exophytic stage in the oral cavity  is associated with a poor prognosis.   Negative prognostic indicators for AIDS-related KS  include tumor-associated edema; ulceration; extensive oral  disease; visceral involvement; and a history of opportunistic    @ Fig. 7-43 HIV-associated Lymphadenopathy. Enlarged cervical  lymph nodes in a patient with persistent generalized lymphadenopathy  (PGL).    infections, B symptoms (i.e., unexplained fever, night  sweats, greater than 10% involuntary weight loss, diarrhea  for more than 2 weeks), or other HIV-related illnesses.  Interestingly, KS arising in lymph nodes does not necessar-  ily represent metastasis or a poor prognosis. In the United  States, the 5-year survival rate for individuals diagnosed  with KS in recent years is approximately 70%. However,  survival rates are much lower in regions where treatment is  not widely available.    After seroconversion, HIV disease often remains silent  except for persistent generalized lymphadenopathy  (PGL). The prevalence of this early clinical sign varies;  however, in several studies it approaches 70%. PGL consists  of lymphadenopathy that has been present for longer than  3 months and involves two or more extrainguinal sites. The  most frequently involved sites are the posterior and anterior  cervical, submandibular, occipital, and axillary nodes.  Nodal enlargement fluctuates, usually is larger than 1 cm,  and varies from 0.5 to 5.0 cm (Fig. 7-43).   Because lymphoma is known to occur in this population,  a lymph node biopsy may be indicated for localized or bulky  adenopathy, when cytopenia or an elevated erythrocyte  sedimentation rate is present, or when requested for patient  reassurance. Histopathologic examination reveals florid fol-  licular hyperplasia. Although not as predictive as oral can-  didiasis or OHL, PGL does warn of progression to AIDS;  almost one-third of affected and untreated patients will have  diagnostic features of AIDS within 5 years.   Non-Hodgkin lymphoma (NHL) currently represents the  most common malignancy among the AIDS population in  the United States. Similar to KS, NHL has become signifi-  cantly less common among HIV-infected individuals  since the introduction of cART. Nevertheless, the risk of  NHL for people with AIDS in the United States remains  high, with a relative risk of 23% compared to the general   1. Lymphomas also occurring in immunocompetent  patients (most commonly Burkitt lymphoma and diffuse  large B-cell lymphoma; rarely, extranodal marginal zone  lymphoma of mucosa-associated lymphoid tissue [MALT  lymphoma], peripheral T-cell, and natural killer cell  lymphoma)   2. Lymphomas more specifically occurring in HIV-positive  patients (e.g., primary effusion lymphoma and plasma-  blastic lymphoma)   3. Lymphoma also occurring in other immunodeficiency  states (e.g., cases resembling post-transplant associated  lymphoproliferative disease [PTLD]).   Although many of these neoplasms demonstrate a rela-  tionship with EBV, studies have suggested that plasmablas-  tic lymphoma and primary effusion lymphoma may be  associated with both EBV and HHV-8.   Lymphoma in patients with AIDS usually occurs in  extranodal locations. Oral lesions are seen in approximately  4% of patients with AIDS-related NHL and most fre-  quently involve the gingiva, palate, and tongue (Fig. 7-44).  Intraosseous involvement also has been documented and  may resemble diffuse progressive periodontitis with loss of  periodontal attachment and loosening of teeth. In these  cases, widening of the periodontal ligament and loss of  lamina dura may represent radiographic clues to the  diagnosis.   Treatment for HIV-associated NHL usually consists of  combination chemotherapy in conjunction with cART.  Early in the AIDS epidemic, people with AIDS typically  suffered from severe opportunistic infections at the time of  lymphoma diagnosis and, thus, could not tolerate intensive  chemotherapy. However, with the introduction of cART,  there has been a significant reduction in comorbidity,  thereby allowing for intensive lymphoma treatment. For  AIDS-related lymphoma patients, an improvement in  median survival from 6 months in the pre-cART era to 21    @ Fig. 7-44 HIV-associated Lymphoma. Erythematous and ulcer-  ated soft tissue enlargement of the posterior mandibular gingiva and  mucobuccal fold on the right side.    months in the cART era has been reported. Prognosis varies  by specific lymphoma type. However, with the inclusion of  cART, lymphoma survival for the HIV-infected population  often approaches that for the general population.    Three atypical patterns of periodontal disease are associated  strongly with HIV infection:   Linear gingival erythema initially was termed HIV-  related gingivitis, but ultimately was noted in association  with other disease processes. This unusual pattern of gingi-  vitis appears with a distinctive linear band of erythema that  involves the free gingival margin and extends 2 to 3 mm  apically (Fig. 7-45). In addition, the alveolar mucosa and  gingiva may demonstrate punctate or diffuse erythema in a  significant percentage of cases. This diagnosis should be  reserved for gingivitis that does not respond to improved  plaque control and exhibits a greater degree of erythema  than would be expected for the amount of plaque present.  The literature related to linear gingival erythema is difficult  to evaluate, because well-defined diagnostic criteria are  lacking and the condition often is confused with conven-  tional marginal gingivitis. Although some investigators  believe linear gingival erythema results from an abnormal  host immune response to subgingival bacteria, data suggest  that this condition may represent an unusual pattern of  candidiasis. Treatment may include débridement, povidone-  iodine irrigation, chlorhexidine mouth rinse, and/or anti-  fungal medication.   Necrotizing ulcerative gingivitis (NUG) (see page 143)  refers to ulceration and necrosis of one or more interdental  papillae with no periodontal attachment loss. Patients with  NUG have interproximal gingival necrosis, bleeding, pain,  and halitosis (Fig. 7-46).   Necrotizing ulcerative periodontitis (NUP) previously  was termed HIV-associated periodontitis; however, it is not  specific for HIV infection. NUP is characterized by gingival    ° Fig. 7-45 HIV-associated Gingivitis. Band of erythema involving  the free gingival margin.    =  e Fig. 7-46 HIV-associated Necrotizing Ulcerative Gingivitis  (NUG). Multiple punched-out interdental papillae of the mandibular  gingiva. Note diffuse pseudomembranous candidiasis of the surround-  ing mucosa.    @ Fig. 7-47 HIV-associated Periodontitis. Extensive loss of peri-  odontal support without deep pocketing.    ulceration and necrosis associated with rapidly progressing  loss of periodontal attachment. Although severe cases can  affect all teeth, multiple isolated defects often are seen and  contrast with the diffuse pattern associated with typical  chronic periodontitis. Edema, severe pain, and spontaneous  hemorrhage are common. Deep pocketing usually is not  seen because extensive gingival necrosis typically coincides  with loss of the adjacent alveolar bone (Fig. 7-47). Attach-  ment loss of more than 6 mm within a 6-month period is  not unusual   The treatment of NUG and NUP revolves around  débridement, antimicrobial therapy, pain management,  immediate follow-up care, and long-term maintenance. The  initial removal of necrotic tissue typically is combined with  povidone-iodine irrigation. The use of systemic antibiotics  usually is not necessary, but metronidazole (narrow spec-  trum to suppress periodontal pathogens without strongly  promoting candidal overgrowth) has been administered to  patients with extensive involvement and severe acute pain.  All patients should use chlorhexidine mouth rinses initially  and for long-term maintenance. After initial débridement,  removal of additional diseased tissue should be performed    e Fig. 7-49 HIV-associated Necrotizing Stomatitis. Massive  necrosis of soft tissue and bone of the anterior maxilla.    within 24 hours and again every 7 to 10 days for two to  three appointments, depending on the patient’s response.  At this point, monthly recalls are necessary until the process  stabilizes; evaluations then are performed every 3 months.   In patients with gingival necrosis, the process occasion-  ally extends away from the alveolar ridges and creates  massive areas of tissue destruction termed necrotizing sto-  matitis (Fig. 7-48). This process clinically resembles noma  (see page 181) and may involve predominantly soft tissue  or extend into the underlying bone, resulting in extensive  sequestration (Fig. 7-49). Although this process initially was  thought to be an extension of NUP, necrotizing stomatitis  may begin in areas of the oral mucosa other than the gingiva.   In the absence of gingival involvement, the clinical fea-  tures of necrotizing stomatitis are nonspecific and mandate  biopsy. In many instances, the areas of ulceration and necro-  sis demonstrate infection with one or more pathogens, such  as HSV, CMV, and EBV.   In addition to these three forms of HIV-related peri-  odontal disease, patients may demonstrate conventional  gingivitis, chronic periodontitis, and progressive nonnecro-  tizing periodontitis. Studies have shown that periodontal  attachment loss can be combated successfully with regular    professional scaling and root planing, plus optimization of  oral hygiene. Because smoking has been associated strongly  with all forms of periodontal disease, patients should be  encouraged to discontinue their tobacco habit.    Less Common Oral and Maxillofacial  Manifestations of HIV Infection  Mycobacterial Infection    The best known mycobacterial infection is tuberculosis  (TB), which is caused mainly by Mycobacterium tuberculosis  (see page 176). Less common TB-causing mycobacteria  include M. bovis, M. africanum, M. canetti, and M. microti.  In addition, atypical mycobacterial infection with M. avium  and M. intracellulare (M. avium-intracellulare complex) can  cause clinically evident disease, particularly in advanced  stages of AIDS.   Approximately one-third of the world’s population is  infected with TB. In 2011 there were 8.7 million new cases  of TB worldwide, of which 1.1 million (13%) arose in HIV-  positive individuals. Coinfection with HIV is associated  with an increased risk for TB activation and death. Among  1.4 million TB deaths reported annually, approximately  430,000 occur in association with HIV.   There is an unusual predilection for extrapulmonary  involvement among HIV-infected individuals with TB.  Nevertheless, oral lesions are uncommon and occur in less  than 5% of all individuals with active TB. The tongue is  the most frequently involved oral site, but lesions also can  develop on the buccal mucosa, gingiva, floor of mouth, lips,  and palate. The affected areas present as chronic ulcerations,  granular leukoplakias, or exophytic proliferative masses. Jaw  involvement also has been reported.   Confirming TB often is difficult in AIDS patients,  because tuberculin skin tests, microscopic examination of  sputum smears for acid-fast bacilli, and chest radiographs  lack sensitivity in this patient population. Liquid culture or  PCR may facilitate diagnosis. In resource-limited settings,  screening for a history of cough, fever, and/or night sweats  is useful for identification of HIV-infected patients requir-  ing diagnostic testing for TB.   In conjunction with cART, standard TB therapy with  rifampin, isoniazid, pyrazinamide, and ethambutol typically  is effective for HIV-related TB. In addition, TB prevention  by early antiretroviral therapy and prophylactic isoniazid is  important for HIV-infected individuals; according to one  meta-analysis, antiretroviral therapy reduces the risk of TB  illness among HIV-infected individuals by 65%.    Hyperpigmentation of the skin, nails, and mucosa has  been reported in HIV-infected patients. The changes are  similar microscopically to focal melanosis, with increased  melanin pigmentation observed in the basal cell layer of the  affected epithelium. Several medications taken by AIDS  patients (e.g., ketoconazole, clofazimine, pyrimethamine,  zidovudine, and emtricitabine) may cause increased melanin    pigmentation. Adrenocortical destruction from several  AIDS-associated opportunistic infections has been reported,  resulting in an Addisonian pattern of pigmentation. Finally,  pigmentation with no apparent cause has arisen in HIV-  infected patients, and some investigators have theorized that  this may be a direct result of HIV infection.    HIV-associated salivary gland disease can arise anytime  during HIV infection. Clinically obvious salivary gland  disease is evident in approximately 5% to 10% of HIV-  infected patients, with a greater prevalence among children.  The etiopathogenesis is unknown, although some investiga-  tors hypothesize that autoimmune dysregulation and under-  lying viral opportunistic infection (e.g., with EBV or BK  virus) may play a role. The main clinical sign is salivary gland  enlargement, particularly affecting the parotid. Bilateral  involvement is seen in about 60% of cases and often is associ-  ated with cervical lymphadenopathy. Xerostomia is a variable  finding. Microscopic changes within the affected glands may  include lymphocytic infiltration, hyperplasia of intraparotid  lymph nodes, and, in long-standing cases, lymphoepithelial  cyst formation. Interestingly, a few authors have reported an  increased frequency of ranulas (see page 424) in HIV-infected  patients; the significance of this finding is uncertain, although  some hypothesize that ranulas may result from long-standing  HIV-associated salivary gland disease.   HIV-associated salivary gland disease is considered a  localized manifestation of diffuse infiltrative lymphocyto-  sis syndrome (DILS). DILS is characterized by CD8+  lymphocytosis with diffuse lymphocytic infiltration of  various sites, such as the major or minor salivary glands,  lacrimal glands, lungs, kidneys, muscle, nerve, and liver. In  addition to salivary gland enlargement and lymphadenopa-  thy, many patients develop interstitial pneumonia. There is  an association between DILS and certain human leukocyte  antigen (HLA) types.   The most widely accepted treatments for DILS are oral  prednisone and antiretroviral therapy, although some  patients have been treated with parotidectomy or radiation  therapy. Some investigators have noted regression after ini-  tiation of cART, whereas others have reported an increased  prevalence with cART, possibly due to immune reconstitu-  tion syndrome (see the Treatment and Prognosis section).  In patients with large lymphoepithelial cysts, aspiration or  sclerotherapy with tetracycline or doxycycline may produce  temporary improvement. Associated xerostomia is treated  in a conventional manner (i.e., maintenance of good oral  health and use of sialogogues and saliva substitutes). DILS  is associated with a relatively favorable HIV disease prog-  nosis but also an increased risk for lymphoma; therefore,  some authors recommend periodic monitoring for lym-  phoma development by fine-needle aspiration.    Thrombocytopenia (see page 545) has been reported in up  to 40% of patients with HIV infection. It is frequently the    first clinical manifestation of HIV infection but may occur  at any time during the course of HIV disease. The underly-  ing mechanisms may include direct infection of platelet  progenitor cells, platelet destruction by anti-HIV antibodies  that cross-react with platelet glycoproteins, platelet destruc-  tion by nonspecific binding of immune complexes, and  defective modulation of hematopoiesis by HIV-infected T  lymphocytes. In addition, thrombocytopenia may develop  secondary to medications, concurrent infections, or malig-  nancy. Cutaneous lesions are present in most cases, but oral  lesions also may occur; typical findings include petechiae,  ecchymosis, and spontaneous gingival hemorrhage.  Platelets have been shown to engulf HIV and play an  important role in the immune response to the virus. HIV-  infected patients with extended thrombocytopenia have  decreased survival. cART is considered first-line treatment.  For severe or refractory cases, additional treatment options  may include interferon-alpha, intravenous immunoglobulin  (IVIG), IV anti-Rho immunoglobulin (anti-D), platelet  transfusion, corticosteroids, danazol, and splenectomy.    The prevalence of oral recurrent HSV infection among  HIV-infected individuals increases significantly once the  CD4+ cell count drops below 50 per mm*. Within the  setting of HIV infection, recurrent herpetic lesions may be  widespread, occur in an atypical pattern, and persist for  months (Fig. 7-50). Herpes labialis may extend to the facial  skin and exhibit extensive lateral spread. Persistence of  active HSV infection for more than 1 month in a patient  infected with HIV is one accepted definition of AIDS. The  clinical presentation and management of recurrent HSV  infection in immunocompromised patients have been dis-  cussed previously in the section on HSV (see page 222).   Evaluation for HSV should be performed on all persis-  tent oral ulcerations in HIV-infected individuals. Investiga-  tors have discovered HSV in 10% to 19% of such cases  (with an additional 10% to 28% exhibiting coinfection by  HSV and CMY).    e Fig. 7-50 HIV-associated Recurrent Herpetic Infection.  Mucosal erosion of the anterior dorsal surface of the tongue on the  left side. Note the yellowish circinate border.    During the cART era, the prevalence of recurrent varicella-  zoster virus (VZV) infection (herpes zoster) in HIV-  infected patients has decreased significantly but still remains  greater than that in the general population. Some patients  paradoxically develop herpes zoster shortly after initiating  cART, as a result of immune reconstitution syndrome (see  the Treatment and Prognosis section). Among patients with  HIV infection, herpes zoster is often severe, with increased  morbidity and mortality rates. Many of these patients are  younger than 40 years, in contrast to immunocompetent  patients who typically develop herpes zoster later in life. In  patients with well-controlled HIV disease, herpes zoster  usually is confined to a single dermatome but persists longer  than usual. In full-blown AIDS, dissemination to multiple  dermatomes is not unusual. Severe intraoral involvement  may lead to bone sequestration and loss of teeth; these  sequelae may be delayed a month or more after the initial  onset of herpes zoster. Associated pain typically is intense.   Although peroral antiviral medications are beneficial in  immunocompetent patients, IV acyclovir is recommended  for severe herpes zoster in immunocompromised individu-  als. Routine zoster vaccination for HIV-infected patients is  not recommended currently; however, according to some  experts, zoster vaccination may be considered for those with  well-controlled HIV disease and CD4+ cell counts greater  than 200 per mm’.    Among HIV-infected individuals, most human papilloma-  virus (HPV) lesions arise in the anogenital region, although  oral involvement also is possible. Benign oral lesions caused  by HPV (commonly referred to as “oral warts”) include oral  squamous papilloma (see page 332), verruca vulgaris (see  page 334), condyloma acuminatum (see page 335), and  multifocal epithelial hyperplasia (see page 336). The  prevalence of these oral HPV lesions in HIV-infected  patients is approximately 1% to 4% and greater than that  observed among immunocompetent individuals. Unusual  HPV types (such as, HPV-7 [associated with butcher’s  warts], HPV-13, and HPV-32 [associated with multifocal  epithelial hyperplasia]) frequently are identified in oral  HPV lesions arising in HIV-infected patients.   In contrast to most other HIV-associated lesions, HPV  lesions have increased in frequency since the introduction  of cART. In particular, many studies have noted that the  appearance of oral HPV lesions increases with the effective-  ness of antiretroviral therapy. The reason for this increase is  unclear. Some authors have hypothesized that immune  reconstitution by cART may lead to an inflammatory  response that stimulates HPV activation (i.e., immune  reconstitution syndrome [see the Treatment and Prognosis  section]); however, markers of local immunity, including  T-cell infiltrates and cytokine expression, are notably absent  in these lesions. Among HIV-infected patients, some inves-  tigators have reported a positive correlation between oral    @ Fig. 7-51 HIV-associated Human Papillomavirus (HPV) Infec-  tion. Multiple exophytic and somewhat papillary nodules of the lip,  buccal mucosa, and gingiva.    HPV lesions, age, and duration of cART. Thus, some  researchers have proposed that cART may extend patient  survival without full restoration of HPV-specific immunity  or that extended survival may allow increased cumulative  risk for HPV infection acquisition over time despite restora-  tion of immune function.   The oral lesions usually are multiple and may be located  on any mucosal surface, with the labial mucosa, tongue,  buccal mucosa, and gingiva most frequently involved. The  lesions may exhibit a cluster of white, spikelike projections,  pink cauliflower-like growths, or slightly elevated sessile  papules (Fig. 7-51).   Histopathologically, the lesions may be sessile or papil-  lary and covered by acanthotic or hyperplastic stratified  squamous epithelium (Fig. 7-52). The affected epithelium  often demonstrates vacuolization of numerous epithelial  cells (ie., koilocytosis) and occasionally may exhibit mild  variation in nuclear size (Fig. 7-53). Immunohistochemistry  or DNA in situ hybridization may be used to confirm the  presence and type of HPV within histopathologic speci-  mens (Fig. 7-54).   Dysplasia has been noted within HPV-related lesions in  patients with AIDS and mandates close observation for  development of squamous cell carcinoma. Surgical excision  is the most commonly used treatment for oral HPV lesions;    e Fig. 7-52 HIV-associated Human Papillomavirus (HPV)  Infection. Oral mucosa exhibiting acanthosis and mild nuclear  pleomorphism.    @ Fig. 7-53 HIV-associated Human Papillomavirus (HPV) Infec-  tion. Oral mucosa exhibiting extensive koilocytosis in the superficial  spinous cell layer.    ® Fig. 7-54 HIV-associated Human Papillomavirus (HPV) Infec-  tion. DNA in situ hybridization of oral mucosal biopsy that reveals  diffuse cellular positivity for HPV.    @ Fig. 7-55 HIV-associated Histoplasmosis. Indurated ulceration  with a rolled border on the dorsal surface of the tongue on the right  side.    additional surgical options include cryosurgery, electrocau-  tery, and laser ablation. However, all of these surgical  methods are associated with frequent recurrence, and the  latter two methods may expose the surgical team and patient  to a plume containing infectious HPV. Alternative treat-  ments with anecdotal evidence of efficacy include topical  cidofovir, intralesional or systemic interferon-alpha, oral  cimetidine, and topical podophyllin.    Histoplasmosis, the most common endemic respiratory  fungal infection in the United States, is produced by Histo-  plasma capsulatum (see page 199). In healthy patients the  infection typically is subclinical and self-limiting, but clini-  cally evident infections often occur in immunocompro-  mised individuals. Although a number of deep fungal  infections are possible in patients with AIDS, histoplasmo-  sis is the most common, with disseminated disease noted in  approximately 5% of AIDS patients residing in areas where  the fungus is endemic. Histoplasmosis also has been docu-  mented in nonendemic areas, possibly from reactivation of  a previous subclinical infection.   The signs and symptoms associated with dissemination  are nonspecific and include fever, weight loss, splenomegaly,  and pulmonary infiltrates. Oral lesions are not uncommon  and usually are caused by bloodborne organisms or spread  from pulmonary involvement. On occasion, the initial diag-  nosis is made from the oral changes, with some patients  demonstrating involvement isolated to the oral cavity.  Although intrabony infection of the jaws has been reported,  the most common oral presentation is a chronic, indurated  mucosal ulceration with a raised border (Fig. 7-55). The oral  lesions may be single or multiple and may involve any area  of the mucosa.   First-line agents for progressive disseminated histoplas-  mosis in HIV-infected patients include IV liposomal    ® Fig. 7-56 HIV-associated Aphthous Ulceration. Large superfi-  cial ulceration of the posterior soft palate.    amphotericin B and oral itraconazole. Fluconazole is less  effective but may be used as a second-line agent. Lifelong  suppressive therapy with itraconazole may be required for  patients who relapse or develop irreversible immunosup-  pression. Primary prophylaxis with itraconazole should be  considered for HIV-infected patients who have CD4+ cell  counts less than 150 per mm’ and live in endemic areas  with an especially high incidence of histoplasmosis.    Lesions that are clinically similar to aphthous ulcerations  (see page 303) occur with increased frequency in patients  infected with HIV. All three forms (minor, major, and her-  petiform) are seen; surprisingly, however, almost two-thirds  of affected patients have the usually uncommon herpeti-  form and major variants (Fig. 7-56). As immunosuppres-  sion becomes more profound, major aphthous ulcerations  demonstrate an increased prevalence.   Initiation of cART is important for inducing remission  and limiting recurrences of aphthae. In addition, treatment  with potent topical or intralesional corticosteroids has been  successful in many patients. However, not all lesions  respond, and recurrences are common. Systemic corticoste-  roid drugs also may prove beneficial but typically are avoided  in order to prevent further immunosuppression. Secondary  candidiasis may be a complication of topical or systemic  corticosteroid therapy. For lesions nonresponsive to topical  corticosteroids, thalidomide may be effective. However, tha-  lidomide must be used cautiously because of its association  with increased viral load and potentially serious adverse  effects, including peripheral neuropathy, neutropenia, and  thrombosis. In addition, there are anecdotal reports of  resolution with systemic granulocyte colony—stimulating  factor (G-CSF) and topical granulocyte-macrophage  colony-stimulating factor (GM-CSF).   Biopsy of any chronic mucosal ulceration clinically diag-  nosed as an aphthous ulceration should be considered if the  lesion is atypical clinically or does not respond to therapy  (Fig. 7-57). In such cases, biopsy often reveals another    @ Fig. 7-57 HIV-associated Ulceration. Atypical mucosal ulceration  that mandates biopsy and may be attributable to a variety of causes.    Molluscum contagiosum (see page 340) is an infection  caused by the molluscum contagiosum virus (MCV), which  is a member of the poxvirus family. The lesions classically  appear on the skin and genitals as small, waxy, dome-shaped  papules with central umbilication. In immunocompetent  individuals, the lesions are usually localized and self-limiting.  However, in patients with AIDS, the lesions may be wide-  spread, persistent, more numerous, and larger in size.  Approximately 5% to 10% of HIV-infected patients are  affected, and the facial skin commonly is involved (Fig.  7-58). Rare intraoral cases have been described as erythema-  tous, white, or pink papules on either keratinized or non-  keratinized mucosa.   The most effective treatment for molluscum contagio-  sum in HIV-infected patients is CART. Paradoxical worsen-  ing of lesions shortly after initiation of CART due to immune  reconstitution syndrome (see the Treatment and Prognosis  section) is possible but typically is transient. For lesions that  persist despite cART, there is limited evidence for treatment  with topical imiquimod, topical or IV _ cidofovir, or    @ Fig. 7-59 HIV-associated Squamous Cell Carcinoma. Ulcer-  ation with raised, indurated borders on the lateral tongue.    intralesional interferon-alpha. Because MCV may be present  in perilesional skin of HIV-infected patients, conventional  local therapy (e.g., curettage, cryosurgery, cautery, or topical  podophyllotoxin) often is associated with recurrence.    Relative to the general population, HIV-infected individu-  als have an estimated twofold increased risk of developing  oral cavity and pharyngeal cancer. Studies of various HIV/  AIDS cohorts have demonstrated a high prevalence of  known risk factors for oral and pharyngeal cancers (e.g.,  tobacco use and HPV infection). Furthermore, the preva-  lence of these cancers has been shown to increase with the  degree of immunosuppression, and oral squamous cell car-  cinoma tends to occur at a younger age among HIV-infected  individuals than non-HIV-infected individuals. These find-  ings suggest that in addition to conventional risk factors,  HIV-related immunosuppression contributes to elevated  cancer risk and accelerated cancer development.   With respect to oral squamous cell carcinoma, the clini-  cal appearance and anatomic distribution are similar among  HIV-infected persons and the general population (Fig.  7-59). Treatment also is not significantly different for HIV-  infected patients and consists of surgical resection, radiation  therapy, and/or chemotherapy. Clinical staging can be prob-  lematic because of HIV-related cervical lymphadenopathy.  In these cases, cross-sectional computed tomography (CT)  or magnetic resonance imaging (MRI) may be performed  in an attempt to distinguish lymph nodes enlarged by lym-  phoproliferative disease from those containing metastatic  carcinoma. The majority of HIV-infected patients with a  diagnosis of oral squamous cell carcinoma have advanced  disease and an unfavorable prognosis.    Confirmation of HIV infection most commonly is obtained  by antibody testing. The standard screening tool is the  enzyme immunoassay (EIA); rapid HIV antibody tests also  are available. Both tests may be performed on blood, oral    fluid, or urine. False-positive results are possible, and a posi-  tive or indeterminate result should be confirmed by the  more specific Western blot assay. Seroconversion generally  takes 3 to 12 weeks following infection; thus, repeat testing  may be considered after a negative result, if there is a strong  reason to suspect recent HIV infection. HIV home testing  kits also are available. These kits allow the user to send a  sample into a laboratory for antibody testing, although  positive results still need to be confirmed by standard EIA  and Western blot assay.   Less commonly used methods include HIV antigen tests  (such as the p24 antigen capture assay), which are designed  to detect viral antigens in blood before the development of  antibodies.   In addition, reverse transcriptase polymerase chain reac-  tion (RT-PCR) and branched-chain DNA assay can be used  to detect HIV RNA in the blood of recently infected indi-  viduals. These tests also may be useful for infants born to  HIV-infected mothers, because infants carry maternal anti-  bodies for several months after birth. More commonly, such  assays are used to monitor viral load for patients already  diagnosed. In most developed countries, RI-PCR is used  for blood supply screening as well.   AIDS is diagnosed when a patient has laboratory evi-  dence of HIV infection combined with any of the  following:   1. CD4+ T-lymphocyte count less than 200 per  microliter  2. CD4+ T-lymphocyte percentage of total lymphocytes    As mentioned previously, the introduction of cART has  resulted in dramatically reduced morbidity and mortality.  A wide variety of antiretroviral agents is available and con-  tinues to expand (Box 7-3). These agents are administered  in combination in order to reduce the emergence of viral  resistance. Although numerous combinations are possible,  cART often consists of two nucleoside reverse transcriptase  inhibitors combined with a non-nucleoside reverse tran-  scriptase inhibitor, boosted protease inhibitor, or integrase  inhibitor (2 NRTI + NNRTI/PI/ID. With such treatment,  viremia typically declines to undetectable levels, and  there is clinically significant immune reconstitution. Early  initiation of cART reduces the risk for AIDS, death, and  disease transmission. Although cART works well for most  patients, downsides of such therapy include cost, toxicity,  adverse reactions, and difficulty with compliance. Some  patients who receive antiretroviral therapy during advanced  stages of disease develop a paradoxical worsening of their  condition—termed immune reconstitution syndrome—  despite decreasing viral load and increasing CD4+ cell  counts. The underlying mechanism may be related to a  hyper-inflammatory response to pathogens and pathogenic   8. CMV disease (other than liver, spleen, or nodes), onset at   11. Herpes simplex: Chronic ulcer or ulcers (more than 1 month  duration) or bronchitis, pneumonitis, or esophagitis   disseminated, or extrapulmonary  21. Mycobacterium, other species or unidentified species,  disseminated or extrapulmonary   26. Toxoplasmosis of brain, onset at age of more than 1 month    Adapted from Centers for Disease Control and Prevention: Appendix A,  AIDS-Defining Conditions, MMWR Recomm Rep 57(RR-10):9, 2008.  AIDS, acquired immune deficiency syndrome; CMV, cytomegalovirus;  HIV, human immunodeficiency virus.    antigens present at the time of rapid immune reconstitu-  tion. Long-term cART recipients are at increased risk for  premature cardiovascular disease, liver disease, kidney  disease, and both HIV-related and non-HIV-related cancers.  cART alone is unable to cure HIV infection, apparently  because of persistence of viral reservoirs in the peripheral  blood and lymphoid tissues.   Significant gains also have been achieved through public  health interventions. In the United States, the CDC has  recommended routine HIV screening of adults, adolescents,  and pregnant women in health care settings. Routine testing  is critical for life-saving early diagnosis and therapy as well  as prevention of HIV transmission to others. Work is pro-  ceeding toward the development of a safe and effective  vaccine, but complex issues have slowed progress.   Some health professionals have been concerned about the  risk of occupational transmission of HIV. The estimated  average risk for seroconversion is 0.3% following percutane-  ous exposure and 0.09% following mucous membrane    1. Nucleoside reverse transcriptase inhibitors  e Abacavir (Ziagen), didanosine (Videx), emtricitabine   e Abacavir + lamivudine (Epzicom), elvitegravir + cobicistat +  emtricitabine + tenofovir (Stribild), emtricitabine + tenofovir  + rilpivirine (Complera), lopinavir + ritonavir (Kaletra),  emtricitabine + tenofovir (Truvada), emtricitabine +  tenofovir + efavirenz (Atripla), zidovudine + abacavir +  lamivudine (Trizivir), and zidovudine + lamivudine  (Combivir)    exposure to HIV-infected blood. The risk of transmission by  exposure to infected fluids or tissues other than blood has  not been quantified but likely is considerably lower. In the  occupational setting, postexposure prophylaxis with antiret-  roviral medications has been found to reduce the risk for  infection by greater than 80% if initiated within hours of the  event. Four weeks of therapy is recommended. 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Volberding P, Greene W, Lange JMA, et al, editors: Sandes HIV/AIDS  medicine: medical management of AIDS 2013, ed 2, Philadelphia,  2012, Elsevier/Saunders.   Webster-Cyriaque J, Duus K, Cooper C, et al: Oral EBV and KSHV  infection in HIV, Adv Dent Res 19:91—-95, 2006.   Wheat LJ, Freifeld AG, Kleiman MB: Clinical practice guidelines for  the management of patients with histoplasmosis: 2007 update by  the Infectious Diseases Society of America, Clin Infect Dis 45:807—  825, 2007.   Younai FS: Oral HIV transmission, J Can Dent Assoc 29:142-148,  2001.    Linea alba (“white line”) is a common alteration of the  buccal mucosa that most likely is associated with pressure,  frictional irritation, or sucking trauma from the facial sur-  faces of the teeth. No other associated problem, such as  insufficient horizontal overlap or rough restorations of the  teeth, is necessary for the development of linea alba.    As the name implies, the alteration consists of a white line  that usually is bilateral. It may be scalloped and is located  on the buccal mucosa at the level of the occlusal plane of  the adjacent teeth (Fig. 8-1). The line varies in prominence  and usually is restricted to dentulous areas. It often is more  pronounced adjacent to the posterior teeth. In clinical  surveys of oral alterations, linea alba appears to be one of  the more common oral pathoses. Several studies have  reported a female predominance.    Biopsy is rarely indicated. If a biopsy is performed, hyper-  orthokeratosis is seen overlying otherwise normal oral  mucosa. On occasion, intracellular edema of the epithelium  and mild chronic inflammation of the underlying connec-  tive tissue may be noted.    No treatment is required for patients with linea alba, and  no difficulties are documented as a result of its develop-  ment. Spontaneous regression may occur.    Morsicatio mucosae oris is a classic example of medical  terminology gone astray; it is the scientific term for chronic  chewing of the oral mucosa. Morsicatio comes from the  Latin word morsus, or bite. Chronic nibbling produces  lesions that are located most frequently on the buccal    mucosa (morsicatio buccarum); however, the labial mucosa  (morsicatio labiorum) and the lateral border of the tongue  (morsicatio linguarum) also may be involved. Similar  changes have been seen as a result of suction and in glass-  blowers whose technique produces chronic irritation of the  buccal mucosa.   A higher prevalence of classic morsicatio mucosae oris  has been found in people who are under stress or who  exhibit psychologic conditions. Most patients are aware of  their habit, although many deny the self-inflicted injury or  perform the act subconsciously. An increased prevalence has  been noted in women and in patients older than 35 years.    Most frequently, the lesions in patients with morsicatio are  found bilaterally on the anterior buccal mucosa. They also  may be unilateral, combined with lesions of the lips or the  tongue, or isolated to the lips or tongue. Thickened, shred-  ded, white areas may be combined with intervening zones  of erythema, erosion, or focal traumatic ulceration (Figs.  8-2 and 8-3). The areas of white mucosa demonstrate an  irregular ragged surface, and the patient may describe being  able to remove shreds of white material from the involved  area. Although dysplastic leukoplakias tend to have more  sharply demarcated borders, the periphery of morsicatio-  related lesions gradually blends with the adjacent mucosa.   The altered mucosa typically is located in the midportion  of the anterior buccal mucosa along the occlusal plane.  Large lesions may extend some distance above or below the  occlusal plane in patients whose habit involves pushing the  cheek between the teeth with a finger.    Biopsy reveals extensive hyperparakeratosis that often results  in an extremely ragged surface with numerous projections of  keratin. Surface bacterial colonization is typical (Fig. 8-4).  On occasion, clusters of vacuolated cells are present in the  superficial portion of the prickle cell layer. This histopatho-  logic pattern is not pathognomonic of morsicatio and may  bear a striking resemblance to oral hairy leukoplakia  (OHL), a lesion that most often occurs in people who are  infected with the human immunodeficiency virus (HIV)    @ Fig. 8-1 Linea Alba. White line of hyperkeratosis on the right  buccal mucosa at the level of the occlusal plane.    @ Fig. 8-2 Morsicatio Buccarum. Thickened, shredded areas of  white hyperkeratosis of the left buccal mucosa.    @ Fig. 8-3 Morsicatio Linguarum. Thickened, rough areas of white  hyperkeratosis of the lateral border of the tongue on the left side.    (see page 242), or to uremic stomatitis (see page 793). In  contrast to OHL, the superficial epithelial cells will not  demonstrate the characteristic nuclear beading associated  with infection with Epstein-Barr virus. Lesions in patients  who chronically chew betel quid (betel chewer’s mucosa;  see page 368) may resemble morsicatio microscopically.  Similarities with linea alba and leukoedema also may be seen.    In most cases, the clinical presentation of morsicatio is suf-  ficient for a strong presumptive diagnosis, and clinicians  familiar with these alterations rarely perform biopsy. Some  cases of morsicatio may not be diagnostic from the clinical  presentation, and biopsy may be necessary.    No treatment of the oral lesions is required, and no long-  term difficulties arise from the presence of the mucosal  changes. For patients desiring either confirmation of the  cause or preventive therapy, construction and use of acrylic  shields to separate the teeth from the adjacent mucosa can  provide quick resolution of the lesions.    Acute and chronic injuries of the oral mucosa are common  and may be associated with surface ulcerations. The ulcer-  ations may remain for extended periods of time but most  usually heal within days. A histopathologically unique type  of chronic traumatic ulceration of the oral mucosa is the  eosinophilic ulceration (traumatic granuloma; trau-  matic ulcerative granuloma with stromal eosinophilia  [TUGSE]; eosinophilic granuloma of the tongue), which  exhibits a deep pseudoinvasive inflammatory reaction and  is typically slow to resolve. Interestingly, many of these  traumatic granulomas undergo resolution after incisional  biopsy. Lesions microscopically similar to eosinophilic  ulceration have been reproduced in rat tongues after  repeated crushing trauma and in traumatic lesions noted in  patients with familial dysautonomia, a disorder character-  ized by indifference to pain. In addition, similar sublingual  ulcerations may occur in infants as a result of chronic  mucosal trauma from adjacent anterior primary teeth, often    associated with nursing. These distinctive ulcerations of  infancy have been termed Riga-Fede disease and should  be considered a variation of the traumatic eosinophilic  ulceration.   In rare subsets of TUGSE, the lesion does not appear to  be associated with trauma, and sheets of large, atypical cells  are seen histopathologically. In these atypical eosinophilic  ulcerations, the nature of these atypical cells remains in  dispute, although it has been suggested that they may rep-  resent reactive myofibroblasts, histiocytes, or T lympho-  cytes. Whether these atypical eosinophilic ulcerations  represent a single pathosis or a variety of disorders that share  stromal eosinophilia is an area for future research. Of these  theories, several current investigations have shown the atyp-  ical cells to be T lymphocytes with strong immunoperoxi-  dase reactivity for CD30. In these cases, it is thought that  this subset of TUGSE may represent the oral counterpart  of the primary cutaneous CD30+ lymphoproliferative  disorder, which also exhibits sequential ulceration, necrosis,  and self-regression.   In most cases of traumatic ulceration, there is an adjacent  source of irritation, although this is not present invariably.  ‘The clinical presentation often suggests the cause, but many  cases resemble early ulcerative squamous cell carcinoma;  biopsy is performed to rule out that possibility.    As would be expected, simple chronic traumatic ulcerations  occur most often on the tongue, lips, and buccal mucosa—  sites that may be injured by the dentition (Fig. 8-5). Lesions  of the gingiva, palate, and mucobuccal fold may occur from  other sources of irritation. The individual lesions appear as  areas of erythema surrounding a central removable, yellow  fibrinopurulent membrane. In many instances, the lesion  develops a rolled white border of hyperkeratosis immedi-  ately adjacent to the area of ulceration (Fig. 8-6).  Eosinophilic ulcerations are not uncommon but fre-  quently are not reported. The lesions occur in people of all  ages, with a significant male predominance. Most have been    . . 4s i  @ Fig. 8-5 Traumatic Ulceration. Well-circumscribed ulceration of  the posterior buccal mucosa on the left side.    reported on the tongue, although cases have been seen on  the gingiva, buccal mucosa, floor of mouth, palate, and lip.  The lesion may last from 1 week to 8 months. The ulcer-  ations appear very similar to the simple traumatic ulcer-  ations; however, on occasion, underlying proliferative  granulation tissue can result in a raised lesion similar to a  pyogenic granuloma (see page 483) (Fig. 8-7).   Riga-Fede disease typically appears between 1 week and  1 year of age. The condition often develops in association  with natal teeth (see page 74). The anterior ventral surface  of the tongue is the most common site of involvement,  although the dorsal surface also may be affected (Fig. 8-8).  Ventral lesions contact the adjacent mandibular anterior  incisors; lesions on the dorsal surface are associated with the  maxillary incisors. A presentation similar to Riga-Fede  disease can be the initial finding in a variety of neurologic  conditions related to self-mutilation, such as familial dys-  autonomia (Riley-Day syndrome), congenital indifference  to pain, Lesch-Nyhan syndrome, Gaucher disease, cerebral  palsy, or Tourette syndrome.   The atypical eosinophilic ulceration occurs in older  adults, with most cases developing in patients older than  age 40. Surface ulceration is present, and an underlying    © Fig. 8-6 Traumatic Ulceration. Mucosal ulceration with a hyper-  keratotic collar located on the ventral surface of the tongue.    2 .  ° Fig. 8-7 Traumatic Granuloma. Exophytic ulcerated mass on the  ventrolateral tongue associated with multiple jagged teeth.    @ Fig. 8-8 Riga-Fede Disease. Newborn with traumatic ulceration  of anterior ventral surface of the tongue. Mucosal damage occurred  from contact of tongue with adjacent tooth during breastfeeding.    @ Fig. 8-9 Atypical Eosinophilic Ulceration. Large ulceration of the  anterior dorsal surface of the tongue.    tumefaction also is seen. The tongue is the most common  site, although the gingiva, alveolar mucosa, mucobuccal  fold, buccal mucosa, and lip may be affected (Fig. 8-9).    Simple traumatic ulcerations are covered by a fibrinopuru-  lent membrane that consists of fibrin intermixed with neu-  trophils. The membrane is of variable thickness, and the  adjacent surface epithelium may be normal or may demon-  strate slight hyperplasia with or without hyperkeratosis. The  ulcer bed consists of granulation tissue that supports a  mixed inflammatory infiltrate of lymphocytes, histiocytes,  neutrophils, and, occasionally, plasma cells. In patients with  eosinophilic ulcerations, the pattern is very similar; however,  the inflammatory infiltrate extends into the deeper tissues  and exhibits sheets of lymphocytes and histiocytes inter-  mixed with eosinophils. In addition, the vascular connective  tissue deep to the ulceration may become hyperplastic and  cause surface elevation.   Atypical eosinophilic ulcerations exhibit numerous fea-  tures of the traumatic eosinophilic ulceration, but the  deeper tissues are replaced by a highly cellular proliferation    of large lymphoreticular cells. The infiltrate is pleomorphic,  and mitotic features are somewhat common. Intermixed  with the large atypical cells are mature lymphocytes and  numerous eosinophils. Although an associated immunohis-  tochemical profile rarely has been reported, several investi-  gators have shown the large cells to be T lymphocytes, the  majority of which react with CD30 (Ki-1). In many  instances, molecular studies for T-cell clonality by poly-  merase chain reaction (PCR) have been performed on the  CD30+ cells and demonstrated monoclonal rearrangement.  Whether this monoclonal infiltrate represents a true low-  grade lymphoma or an unusual reactive lymphoproliferative  process has not been determined.    For traumatic ulcerations that have an obvious source of  injury, the irritating cause should be removed. A topical  anesthetic or protective film can be applied for temporary  pain relief. If the cause is not obvious, or if a patient does  not respond to therapy, then biopsy is indicated. Rapid  healing after a biopsy is typical even with large eosinophilic  ulcerations (Fig. 8-10). Recurrence is not expected.   The use of corticosteroids in the management of trau-  matic ulcerations is controversial. Some clinicians have sug-  gested that use of such medications may delay healing. In  spite of this, other investigators have reported success using  corticosteroids to treat chronic traumatic ulcerations.   Although extraction of the anterior primary teeth is not  recommended, this procedure has resolved the ulcerations  in Riga-Fede disease. The teeth should be retained if they  are stable. Grinding the incisal mamelons, coverage of the  teeth with a light-cured composite or cellulose film, con-  struction of a protective shield, or discontinuation of  nursing have been tried with variable success.   In patients demonstrating histopathologic similarities to  the cutaneous CD30+ lymphoproliferative disorder, a thor-  ough evaluation for systemic lymphoma is mandatory,  along with lifelong follow-up. Although recurrence fre-  quently is seen, the ulcerations typically heal spontaneously,  and the vast majority of patients do not demonstrate dis-  semination of the process. Further documentation is critical  to define more fully this poorly understood process.    Electrical burns to the oral cavity are fairly common, con-  stituting approximately 5% of all burn admissions to hos-  pitals. Two types of electrical burns can be seen: 1) contact  and 2) are.   Contact burns require a good ground and involve electri-  cal current passing through the body from the point of  contact to the ground site. The electric current can cause  cardiopulmonary arrest and may be fatal. Most electrical  burns affecting the oral cavity are the arc type, in which the  saliva acts as a conducting medium and an electrical arc  flows between the electrical source and the mouth. Extreme    ulceration of the dorsal surface of the tongue. B, Significant resolution  noted 2 weeks after incisional biopsy. C, Subsequent healing noted 4  weeks after biopsy.    heat, up to 3000° C, is possible with resultant significant  tissue destruction. Most cases result from chewing on the  female end of an extension cord or from biting through a  live wire.   Most thermal burns of the oral cavity arise from inges-  tion of hot foods or beverages. Microwave ovens have been  associated with an increased frequency of thermal burns  because of their ability to cook food that is cool on the  exterior but extremely hot in the interior.    The hands are the most common site of electrical burns in  adults. In contrast, the oral cavity is the most commonly  affected location in children, with 90% of these accidents  occurring before age 4. The lips are affected most frequently,  and the commissure commonly is involved. Initially, the  burn appears as a painless, charred, yellow area that exhibits  little to no bleeding (Fig. 8-11). Significant edema often    ¢ Fig. 8-11 Electrical Burn. Yellow charred area of necrosis along  the left oral commissure. (Courtesy of Dr. Patricia Hagen.)    @ Fig. 8-12 Thermal Food Burn. Area of yellow-white epithelial  necrosis of the left posterior hard palate. Damage was the result of  attempted ingestion of a hot pizza roll.    develops within a few hours and may persist up to 12 days.  Beginning on the fourth day, the affected area becomes  necrotic and begins to slough. Bleeding may develop during  this period from exposure of the underlying vital vascula-  ture, and the presence of this complication should be moni-  tored closely. The adjacent mucobuccal fold, the tongue, or  both also may be involved. On occasion, adjacent teeth may  become nonvital, with or without necrosis of the surround-  ing alveolar bone. Malformation of developing teeth also  has been documented. In patients receiving high-voltage  electrical injury, resultant facial nerve paralysis is reported  infrequently and typically resolves over several weeks to  months. Focal enamel cavitation, which was thought to  represent a high voltage exit point, also has been reported  in association with an electrocution injury.   The injuries related to thermal food burns usually appear  on the palate or posterior buccal mucosa (Fig. 8-12). The  lesions appear as zones of erythema and ulceration that  often exhibit remnants of necrotic epithelium at the periph-  ery. If hot beverages are swallowed, swelling of the upper  airway can occur and lead to dyspnea, which may develop  several hours after the injury.    For patients with electrical burns of the oral cavity, tetanus  immunization, if not current, is required. Most clinicians  prescribe a prophylactic antibiotic, usually penicillin, to  prevent secondary infection in severe cases. The primary  problem with oral burns is contracture of the mouth  opening during healing. Without intervention, significant  microstomia can develop and may produce such restricted  access to the mouth that hygiene and eating become impos-  sible in severe cases. Extensive scarring and disfigurement  are typical in untreated patients.   To prevent the disfigurement, a variety of microstomia  prevention appliances can be used to eliminate or reduce  the need for subsequent surgical reconstruction. Compli-  ance is the most important consideration when choosing  the most appropriate device. Tissue-supported appliances  appear most effective for infants and young children; older,  more cooperative patients usually benefit from tooth-  supported devices. In most cases, splinting is maintained for  6 to 8 months to ensure proper scar maturation. Evaluation  for possible surgical reconstruction is usually performed  after a 1-year follow-up.   Most thermal burns are of little clinical consequence and  resolve without treatment. When the upper airway is  involved and associated with breathing difficulties, antibiot-  ics and corticosteroids often are administered. In rare cases,  swelling of the airway mandates intubation or tracheotomy  to resolve the associated dyspnea. In these severe cases, oral  intake of food often is discontinued temporarily with nutri-  tion provided by a nasogastric tube.    A large number of chemicals and drugs come into contact  with the oral tissues. A percentage of these agents are caustic  and can cause clinically significant damage.   Patients often can be their own worst enemies. The  array of chemicals that have been placed within the mouth  in an attempt to resolve oral problems is amazing. Aspirin,  sodium perborate, hydrogen peroxide, gasoline, turpen-  tine, rubbing alcohol, and battery acid are just a few of the  more interesting examples. In addition, mucosal damage  has been documented from many of the topical medica-  ments sold as treatments for toothache or mouth sores.  Over-the-counter products containing isopropyl alcohol,  phenol, hydrogen peroxide, or eugenol have produced  adverse reactions in patients. Tooth-whitening products  also contain hydrogen peroxide or one of its precursors,  carbamide peroxidase, which has been shown to create  mucosal necrosis (Fig. 8-13). A surprising number of  medications also are potentially caustic when held in the  mouth long enough. Aspirin, bisphosphonates, and two  psychoactive drugs, chlorpromazine and promazine, are  well-documented examples.    @ Fig. 8-13 Mucosal Burn from Tooth-whitening Strips. Sharply  demarcated zone of epithelial necrosis on the maxillary facial gingiva,  which developed from the use of tooth-whitening strips. Less severe  involvement also is present on the mandibular gingiva.    ° Fig. 8-14 Aspirin Burn. Extensive area of white epithelial necrosis  of the left buccal mucosa caused by aspirin placement in an attempt  to alleviate dental pain.    Health care practitioners also are responsible for the use  of many caustic materials. Silver nitrate, formocresol, sodium  hypochlorite, paraformaldehyde, chromic acid, trichloro-  acetic acid, dental cavity varnishes, and acid-etch materials  all can cause patient injury. Education and use of the rubber  dam have reduced the frequency of such injuries.   The improper use of aspirin, hydrogen peroxide, silver  nitrate, phenol, and certain endodontic materials deserves  further discussion because of their frequency of misuse, the  severity of related damage, and the lack of adequate docu-  mentation of these materials as harmful agents.    Mucosal necrosis from aspirin being held in the mouth is  not rare (Fig. 8-14). Aspirin is available not only in the  well-known tablets but also as powder.    Hydrogen peroxide became a popular intraoral medication  for prevention of periodontitis in the late 1970s. Since that    @ Fig. 8-15 Hydrogen Peroxide Burn. Extensive epithelial necrosis  of the anterior maxillary gingiva secondary to interproximal placement  of hydrogen peroxide with cotton swabs.    time, mucosal damage has been seen more frequently as a  result of this application. Concentrations at 3% or greater  are associated most often with adverse reactions. Epithelial  necrosis has been noted with dilutions as low as 1%, and  many over-the-counter oral medications exceed this con-  centration (Fig. 8-15).    Silver nitrate remains a popular treatment for aphthous  ulcerations, because the chemical cautery brings about rapid  pain relief by destroying nerve endings. In spite of this, its  use should be strongly discouraged. In all cases, the extent  of mucosal damage is increased by its use. In some patients,  an abnormal reaction is seen, with resultant significant  damage and enhanced pain. In addition, rare reports have  documented irreversible systemic argyria secondary to  habitual intraoral use of topical silver nitrate after recom-  mendation by a dentist (see page 288).    Occasionally, phenol has been used in dentistry as a cavity-  sterilizing agent and cauterizing material. It is extremely  caustic, and judicious use is required. Over-the-counter  agents advertised as “canker sore” treatments may contain  low concentrations of phenol, often combined with high  levels of alcohol. Extensive mucosal necrosis and rarely  underlying bone loss have been seen in patients who placed  this material (phenol concentration 0.5%) in attempts to  resolve minor mucosal sore spots (Fig. 8-16).   A prescription therapy containing 50% sulfuric acid, 4%  sulfonated phenol, and 24% sulfonated phenolic agents  is being marketed heavily to dentists for treatment of  aphthous ulcerations. Because extensive necrosis has been  seen from use of medicaments containing 0.5% phenol,  this product must be closely monitored and used with  great care.    @ Fig. 8-16 Phenol Burn. Extensive epithelial necrosis of the man-  dibular alveolar mucosa on the left side. Damage resulted from place-  ment of an over-the-counter, phenol-containing, antiseptic and  anesthetic gel under a denture. (Courtesy of Dr. Dean K. White.)    e Fig. 8-17 Formocresol Burn. Tissue necrosis secondary to  leakage of endodontic material between a rubber dam clamp and the  tooth.    Because of the past difficulty of obtaining profound anes-  thesia in some patients undergoing root canal therapy, some  clinicians have used arsenical paste or paraformaldehyde  formulations to devitalize the inflamed pulp. Gingival and  bone necrosis have been documented as a consequence of  leakage of this material from the pulp chamber into the  surrounding tissues. Endodontic irrigants, such as formo-  cresol (Fig. 8-17) or sodium hypochlorite, produce similar  necrosis if the material leaks into the surrounding support-  ing tissues or is injected past the apex, leading some to  suggest chlorhexidine as a safer irrigant. Because chlorhexi-  dine lacks the tissue-dissolving properties of sodium  hypochlorite, some clinicians have suggested alternating  between chlorhexidine and sodium hypochlorite. Others  have warned that contact of these two compounds results  in formation of a precipitate, para-chloroaniline, which is  thought to be potentially toxic and carcinogenic.    The following can reduce the chances of tissue damage  during irrigation with sodium hypochlorite:  e Using a rubber dam  e Avoiding excessive pressure during application  ¢ Keeping the syringe needle away from the apex   In some countries, clinicians have used recycled anes-  thetic cartridges to keep solutions of sodium hypochlorite  for endodontic irrigation. A number of reports have docu-  mented massive necrosis from inadvertent injection of  sodium hypochlorite into soft tissue when these cartridges  were mistaken for a local anesthetic.    The previously discussed caustic agents produce similar  damage. With short exposure, the affected mucosa exhibits  a superficial white, wrinkled appearance. As the duration of  exposure increases, the necrosis proceeds, and the affected  epithelium becomes separated from the underlying tissue  and can be desquamated easily. Removal of the necrotic  epithelium reveals red, bleeding connective tissue that sub-  sequently will be covered by a yellowish, fibrinopurulent  membrane. Mucosa bound to bone is keratinized and more  resistant to damage, whereas the nonkeratinized movable  mucosa is destroyed more quickly. In addition to mucosal  necrosis, significant tooth erosion has been seen in patients  who chronically chew aspirin or hold the medication in  their teeth as it dissolves.   The use of the rubber dam can dramatically reduce iat-  rogenic mucosal burns. When cotton rolls are used for  moisture control during dental procedures, two problems  may occur. On occasion, caustic materials can leak into the  cotton roll and be held in place against the mucosa for an  extended period, with mucosal injury resulting from the  chemical absorbed by the cotton. In addition, oral mucosa  can adhere to dry cotton rolls, and rapid removal of the  rolls from the mouth often can cause stripping of the epi-  thelium in the area. The latter pattern of mucosal injury  has been termed cotton roll burn (cotton roll stomatitis)  (Fig. 8-18).    @ Fig. 8-18 Cotton Roll Burn. Zone of white epithelial necrosis and  erythema of the maxillary alveolar mucosa.    Caustic materials injected into bone during endodontic  procedures can result in significant bone necrosis, pain, and  perforation into soft tissue. Necrotic surface ulceration and  edema with underlying areas of soft tissue necrosis may  occur adjacent to the site of perforation.    Microscopic examination of the white slough removed from  areas of mucosal chemical burns reveals coagulative necrosis  of the epithelium, with only the outline of the individual  epithelial cells and nuclei remaining. The necrosis begins  on the surface and moves basally. The amount of epithelium  affected depends on the duration of contact and the  concentration of the offending agent. The underlying  connective tissue contains a mixture of acute and chronic  inflammatory cells.    The best treatment of chemical injuries is prevention of  exposure of the oral mucosa to caustic materials. When  prescribing potentially caustic drugs, the clinician must  instruct the patient to swallow the medication and not allow  it to remain in the oral cavity for any significant length of  time. Children should not use chewable aspirin immedi-  ately before bedtime, and they should rinse after use.  Superficial areas of necrosis typically resolve completely  without scarring within 10 to 14 days after discontinuation  of the offending agent. For temporary protection, some  clinicians have recommended coverage with a protective  emollient paste or a hydroxypropyl cellulose film. Topical  anesthetics also may be used to provide temporary pain  relief. When large areas of necrosis are present, surgical  débridement and antibiotic coverage often are required to  promote healing and prevent spread of the necrosis.    No systemic anticancer therapy currently available is able to  destroy tumor cells without causing the death of at least  some normal cells, and tissues with rapid turnover (e.g., oral  epithelium) are especially susceptible. The mouth is a  common site (and one of the most visible areas) for com-  plications related to cancer therapy. Both radiation therapy  and systemic chemotherapy may cause significant oral  problems—the more potent the treatment, the greater the  risk of complications.    A variety of noninfectious oral complications are seen  regularly as a result of both radiation and chemotherapy.  Two acute changes, mucositis and hemorrhage, are    the predominant problems associated with chemotherapy,  especially in cancers, such as leukemia, that involve high  treatment doses.   Painful acute mucositis and dermatitis are the most fre-  quently encountered side effects of radiation, but several  chronic alterations continue to plague patients long after  their courses of therapy are completed. Depending on the  fields of radiation, the radiation dose, and the age of the  patient, the following outcomes are possible:  ¢ Xerostomia  ¢ Loss of taste (hypogeusia)  ¢ Osteoradionecrosis  ¢ Trismus  ¢ Chronic dermatitis  ¢ Developmental abnormalities    Intraoral hemorrhage is typically secondary to thrombocy-  topenia, which develops from bone marrow suppression.  Intestinal or hepatic damage, however, may cause lower  vitamin K-—dependent clotting factors, with resultant  increased coagulation times. Conversely, tissue damage  related to therapy may cause release of tissue thromboplas-  tin at levels capable of producing potentially devastating  disseminated intravascular coagulation (DIC). Oral pete-  chiae and ecchymosis secondary to minor trauma are the  most common presentations. Any mucosal site may be  affected, but the labial mucosa, tongue, and gingiva are  involved most frequently.    Oral mucositis has been shown to be the single most debili-  tating complication of high-dose chemotherapy and radia-  tion therapy to the head and neck. In addition to significant  local discomfort, the mucositis may be associated with an  increased need for total parenteral nutrition, prolonged hos-  pital stays, and most importantly, systemic bacteremia and  sepsis.   Approximately 80% of patients treated with head and  neck radiation develop oral mucositis, and this prevalence  approaches 100% for those being treated for mouth and  oropharyngeal cancers. The prevalence associated with che-  motherapy is variable, depending on the regimen being used.  Agents strongly associated with oral mucositis include meth-  otrexate, 5-fluorouracil, etoposide, irinotecan, cytarabine,  6-mercaptopurine, 6-thioguanine, busulfan, melphalan,  cyclophosphamide, idarubicin, doxorubicin (Adriamycin),  daunorubicin, dactinomycin, bleomycin, and vinblastine.  Beyond the direct effects of the antineoplastic agent, addi-  tional risk factors include young age, female sex, poor oral  hygiene, oral foci of infection, poor nutrition, impaired sali-  vary function, tobacco use, and alcohol consumption.   Cases of oral mucositis related to radiation or chemo-  therapy are similar in their clinical presentations. The mani-  festations of chemotherapy develop after a few days of  treatment; radiation mucositis may begin to appear during  the second week of therapy. Both chemotherapy and    radiation-induced mucositis resolve slowly 2 to 3 weeks  after cessation of treatment. Oral mucositis associated with  chemotherapy typically involves the nonkeratinized surfaces  (ie., buccal mucosa, ventrolateral tongue, soft palate, and  floor of the mouth), whereas radiation therapy primarily  affects the mucosal surfaces within the direct portals of  radiation.   The earliest manifestation is development of a whitish  discoloration from a lack of sufficient desquamation of  keratin. This is soon followed by loss of this layer with  replacement by atrophic mucosa, which is edematous, ery-  thematous, and friable. Subsequently, areas of ulceration  develop with formation of a removable yellowish, fibrino-  purulent surface membrane (Figs. 8-19 to 8-21). Pain,  burning, and discomfort are significant and can be wors-  ened by eating and oral hygiene procedures.    Acute dermatitis of the skin in the fields of radiation is  common and varies according to the intensity of the therapy.  Patients with mild radiation dermatitis experience    ns Care ran Re Meer.  ® Fig. 8-19 Chemotherapy-related Epithelial Necrosis. Vermilion  border of the lower lip exhibiting epithelial necrosis and ulceration in a  patient receiving systemic chemotherapy.    © Fig. 8-20 Chemotherapy-related Ulceration. Ulceration of the  right lateral border of the tongue in a patient receiving systemic  chemotherapy.    © Fig. 8-21 Radiation Mucositis. A, Squamous cell carcinoma  before radiation therapy. Granular erythroplakia of the floor of the  mouth on the patient’s right side. B, Same lesion after initiation of  radiation therapy. Note the large, irregular area of epithelial necrosis  and ulceration of the anterior floor of the mouth on the patient’s right  side. C, Normal oral mucosa after radiation therapy. Note resolution of  the tumor and the radiation mucositis.    erythema, edema, burning, and pruritus. This condition  resolves in 2 to 3 weeks after therapy and is replaced by  hyperpigmentation and variable hair loss. Moderate radia-  tion causes erythema and edema in combination with ero-  sions and ulcerations. Within 3 months these alterations  resolve, and permanent hair loss, hyperpigmentation, and  scarring may ensue. Necrosis and deep ulcerations can occur  in severe acute reactions. Radiation dermatitis also may  become chronic and be characterized by dry, smooth, shiny,    @ Fig. 8-22 Radiation Dermatitis. Cutaneous atrophy and telangi-  ectasia secondary to radiation therapy. (Courtesy of Dr. Terry Day.)    Salivary glands are very sensitive to radiation, and xerosto-  mia is a common complication. When a portion of the  salivary glands is included in the fields of radiation, the  remaining glands undergo compensatory hyperplasia in an  attempt to maintain function. The changes begin within 1  week of initiation of radiation therapy, with a dramatic  decrease in salivary flow noted during the first 6 weeks of  treatment. Even further decreases may be noted for up to 3  years.   Serous glands exhibit an increased radiosensitivity when  compared with the mucous glands. On significant exposure,  the parotid glands are affected dramatically and irreversibly.  In contrast, the mucous glands partially recover and, over  several months, may achieve flow that approaches 50% of  preradiation levels. In addition to the discomfort of a mouth  that lacks proper lubrication, diminished flow of saliva leads  to a significant decrease of the bactericidal action and self-  cleansing properties of saliva.   Without intervention, patients often develop symptom-  atic dry mouth that affects their ability to eat comfortably,  wear dentures, speak, and sleep. In addition, there often is  an increase in the caries index (xerostomia-related caries),  regardless of the patient’s past caries history (Fig. 8-23). The  decay is predominantly cervical in location and secondary  to xerostomia (not a direct effect of the radiation).   Several interventions to reduce radiation-related xerosto-  mia have demonstrated promise. Intensity-modulated radia-  tion therapy (IMRT) appears to be more gland-sparing than  conventional radiation therapy and is emerging as the stan-  dard of care for head and neck cancer. Amifostine is a cyto-  protective agent that has been shown to reduce the severity  and duration of xerostomia in patients receiving radiother-  apy (but not chemoradiotherapy) for head and neck cancer.  On the downside, this medication has significant side effects,  and there are lingering concerns related to possible tumor  protective effects. Surgical transfer of a single submandibular    — a .  @ Fig. 8-23 Xerostomia-related Caries. Extensive cervical caries of  mandibular dentition secondary to radiation-related xerostomia.    © Fig. 8-24 Osteoradionecrosis (ORN). Ulceration overlying left  body of the mandible with exposure and sequestration of superficial  alveolar bone.    salivary gland outside of the radiation field to the submental  space has proven successful in selected patients.    In patients who receive significant radiation to the oral  cavity, a substantial loss of all four tastes (hypogeusia) often  develops within several weeks. Although these tastes return  within 4 months for most patients, some patients are left  with permanent hypogeusia; others may have persistent  dysgeusia (altered sense of taste) (see page 809).    Osteoradionecrosis (ORN) is defined as exposed nonvital  irradiated bone that persists longer than 3 months in the  absence of local neoplastic disease. It represents one of the  most serious complications of radiation to the head and  neck. In earlier studies, the prevalence approached 15%, but  the risk has been reduced to less than 5% secondary to  modern therapeutic advances such as IMRT and three-  dimensional conformal radiation therapy (3DCRT). These  newer techniques have the ability to maintain therapeutic  effectiveness but decrease the total maximum radiation to  the jaw bones. Most cases of ORN occur in patients who    @ Fig. 8-25 Osteoradionecrosis (ORN). Multiple ill-defined areas of  radiolucency and radiopacity of the mandibular body.    °® Fig. 8-26 Osteoradionecrosis (ORN). Same patient as depicted  in Fig. 8-25. Note fistula formation of the left submandibular area  resulting from ORN of the mandibular body.    have received greater than 60 Gy, with the majority of cases  occurring between 4 months and 3 years after completion  of radiation therapy.   Although most instances of ORN arise secondary to  local trauma (such as, tooth extraction), a minority appear  spontaneous. Most spontaneous cases arise within the first  few years, but patients remain at risk for trauma-induced  ORN for the remainder of their lives. The mandible is  involved 24 times more frequently than the maxilla (Fig.  8-24), and the process is three times more common in  dentate patients. Affected areas of bone reveal ill-defined  areas of radiolucency that may develop zones of relative  radiopacity as the dead bone separates from the residual  vital areas (Fig. 8-25). Intractable pain, cortical perforation,  fistula formation, surface ulceration, and pathologic frac-  ture may be present (Fig. 8-26).   The radiation dose is the main factor associated with  bone necrosis, although the proximity of the tumor to bone,  the presence of remaining dentition, and the type of treat-  ment also exert an effect. Additional factors associated with  an increased prevalence include older age, male sex, poor  health or nutritional status, and continued use of tobacco  or alcohol.    Prevention of bone necrosis is the best course of action.  Before therapy, all unrestorable teeth and those with  advanced periodontal disease should be extracted, all oral  foci of infection should be eliminated, and excellent oral  hygiene should be initiated and maintained. A healing time  of at least 3 weeks between extensive dental procedures and  the initiation of radiotherapy significantly decreases the  chance of bone necrosis. Extraction of teeth or any bone  trauma is strongly contraindicated during radiation therapy.  Following radiation, there is a 4-month window of time  during which dental extractions can be performed with a  reduced prevalence of ORN. During this time, tissue repair  and healing are relatively normal, but eventually progressive  fibrosis and hypovascularity develop and predispose the  patient to ORN.   If extractions are mandatory, several investigators believe  pentoxifylline and tocopherol initiated prior to the proce-  dure may reduce the prevalence of ORN. If necrosis devel-  ops, continuation of these medications is recommended  with the addition of clodronate, a first-generation bisphos-  phonate thought to stimulate osteoblasts and new bone  formation.    Trismus may develop and can produce extensive difficulties  concerning access for hygiene and dental treatment. Tonic  muscle spasms with or without fibrosis of the muscles of  mastication and the temporomandibular joint (TMJ)  capsule can cause difficulties in jaw opening. When these  structures are radiated heavily, jaw-opening exercises may  help to decrease or prevent problems.    Antineoplastic therapy during childhood can affect growth  and development. The changes vary according to the age at  treatment and the type and severity of therapy. Radiation  can alter the facial bones and result in micrognathia, retrog-  nathia, or malocclusion. Developing teeth are very sensitive  and can exhibit a number of changes, such as root dwarfism,  blunting of roots, dilaceration of roots, incomplete calcifica-  tion, premature closure of pulp canals in deciduous teeth,  enlarged canals in permanent teeth, microdontia, and  hypodontia (see page 52).    Optimal treatment planning involves the oral health  practitioner before initiation of antineoplastic therapy.  Elimination of all current or potential oral foci of infection  is paramount, along with patient education about main-  taining ultimate oral hygiene. Proper nutrition, cessation  of tobacco use, and alcohol abstinence minimize oral  complications. Once cancer therapy is initiated, efforts  must be directed toward relieving pain, preventing dehy-  dration, maintaining adequate nutrition, eliminating foci  of infection, and ensuring continued appropriate oral  hygiene.    Interventions can attempt to prevent mucositis or treat the  damage once it occurs. Cryotherapy (placement of ice chips  in the mouth 5 minutes before chemotherapy and continued  for 30 minutes) has been shown to reduce significantly the  prevalence and severity of oral mucositis secondary to bolus  injection of chemotherapeutic drugs with a short half-life. It  has been suggested that the cold may produce local vasocon-  striction leading to reduced exposure of the oral mucosa to  the chemotherapeutic medications. Cryotherapy has no  effect on the prevalence or severity of radiation mucositis.   Intravenous recombinant human keratinocyte growth  factor (palifermin) given 3 days prior to the initiation of  chemotherapy has been shown in clinical studies to dem-  onstrate a statistically significant reduction in the severity  of oral mucositis. Concern remains that this epithelial  growth factor may promote growth of tumor cells in patients  with carcinoma, and most clinicians are limiting its use to  sarcomas and hematologic malignancies.   One of the more effective mechanisms to reduce  radiation-associated mucositis has been placement of  midline radiation blocks or use of three-dimensional radia-  tion treatment to limit the volume of irradiated mucosa. In  addition, cotton rolls or custom splints have been used to  cover metallic dental restorations to prevent localized  enhanced scatter effect of the radiation. Other interventions  to reduce the severity of mucositis with lesser evidence of  benefit include aloe vera, allopurinol, amifostine, benzyda-  mine, honey, intravenous glutamine, and antibiotic loz-  enges containing polymyxin/tobramycin/amphotericin.   Once present, the lesions are difficult to manage, and a  large number of treatments (such as, anesthetic, analgesic,  antimicrobial, and coating agents) have been tried with  mixed reviews. Low-level laser irradiation, light-emitting  diode (LED) phototherapy, and coating with sucralfate  represent current interventions to reduce the severity of  active mucositis. Palliative therapies include salt and  soda rinse, viscous lidocaine, and “magic mouthwash” (lido-  caine, diphenhydramine, and kaolin or milk of magnesia).  When all treatments fail, the standard of care for the severe  pain associated with oral mucositis remains intravenous  morphine.    Xerostomic patients should be counseled to avoid all agents  that may decrease salivation, especially the use of tobacco  products and alcohol. To combat xerostomia-related caries,  a regimen of daily topical fluoride (1.1% neutral sodium  fluoride) application should be instituted.   The problem of chronic xerostomia has been approached  through the use of salivary substitutes and sialagogues.  Use of liquids with a low pH or significant sugar content  should be avoided as a mouth moistener. Because the  mucous glands often demonstrate significant recovery after  radiation, the sialagogues show promise because they stimu-  late the residual functional glands. Moisturizing gels and    sprays, sugar-free candies, chewing gum, and various artifi-  cial salivary substitutes are available. Gums and mints con-  taining xylitol have an added benefit of inhibition of  cariogenic bacteria. Many salivary substitutes are expensive  and of short duration, with patients often alternatively  choosing frequent use of water. In these cases, use of unfil-  tered fluoridated tap water is recommended over bottled  water that may not contain sufficient fluoride. In controlled  clinical studies, some of the most effective and longer-  lasting products are one of the systemic sialogogues, such  as pilocarpine, cevimeline, bethanechol, carbocholine, or  anetholtrithione. Of these, the most widely used are pilo-  carpine and cevimeline. Although these drugs may be ben-  eficial for many patients, they are contraindicated in patients  with asthma, gastrointestinal ulcerations, labile hyperten-  sion, glaucoma, chronic obstructive pulmonary disease, and  significant cardiovascular disease. Adverse reactions are  uncommon but include excess sweating, rhinitis, headache,  nausea, uropoiesis, flatulence, and circulatory disorders.  Bethanechol also appears effective, is not contraindicated in  patients with asthma and narrow angle glaucoma, and has  been associated with fewer side effects than pilocarpine.    Although the taste buds often regenerate within 4 months  after radiation therapy, the degree of long-term impairment  is highly variable. In those with continuing symptoms, zinc  sulfate supplements greater than the usual recommended  daily doses may be beneficial.    Although prevention must be stressed, cases of ORN do  occur. Use of hyperbaric oxygen has numerous contraindi-  cations and possible adverse reactions. Because of the newer  theories of pathogenesis for ORN, most clinicians are less  inclined to use hyperbaric oxygen in extensive cases that  involve large segments of the jawbone. Some clinicians have  begun use of ultrasound in place of hyperbaric oxygen due  to its low adverse reaction profile and its ability to stimulate  tissue regeneration and angiogenesis. Therapy consists of  antibiotics, débridement, irrigation, and removal of dis-  eased bone. In extensive cases, this often involves extensive  resection and immediate reconstruction. The amount of  bone removed is determined by clinical judgment, with the  surgery extended until brightly bleeding edges are seen.    ¢ MEDICATION-RELATED  OSTEONECROSIS OF THE JAW  (BISPHOSPHONATE-RELATED  OSTEONECROSIS; ANTIRESORPTIVE-  RELATED OSTEONECROSIS)    In 2003, a pattern of gnathic osteonecrosis began to be  recognized, which was difficult to treat and appeared to be  associated with certain medications. This process was   e Exposed bone in maxillofacial region for longer than 8 weeks   e No history of radiation therapy or obvious metastatic disease  to the jaws    correlated initially to bisphosphonates, leading to the name  bisphosphonate-related osteonecrosis of the jaw  (BRONJ). In the 2011 position paper of the American  Dental Association (ADA), the name was modified to  antiresorptive-related osteonecrosis of the jaw (ARONJ)  due to the discovery of an association with a monoclonal  antibody designed to prevent osteoclastic maturation (deno-  sumab). Subsequently, the 2014 position paper of the  American Association of Oral and Maxillofacial Surgeons  (AAOMS) changed the name again to medication-related  osteonecrosis of the jaw (MRONJ) due to the discovery  that antiangiogenic therapies also may be implicated (Box  8-1). This last term is sufficiently generic and hopefully will  stand the test of time.   The antiangiogenic agents are prescribed for a variety of  cancers and include tyrosine kinase inhibitors and mono-  clonal antibodies directed against vascular endothelial  growth factor (Box 8-2). The evidence supporting an asso-  ciation with osteonecrosis is based primarily on case reports,  but a low risk does appear to exist. This risk is increased if  these agents are combined with bisphosphonates. Currently,  little research exists on the association between these agents  and gnathic osteonecrosis.   Currently, the medications most strongly associated with  gnathic osteonecrosis include the aminobisphosphonates  (nitrogen-containing bisphosphonates) and denosumab  (Box 8-3). These antiresorptive medications are used pri-  marily to treat patients with osteoporosis or various cancers  that involve bone (predominantly multiple myeloma, breast  carcinoma, and prostate carcinoma). Less frequent uses  include treatment for Paget disease, osteogenesis imperfecta,  rheumatoid arthritis, and giant cell tumors of bone. The  vast majority of osteonecrosis cases occur in patients receiv-  ing the medication as part of their therapy for cancer.   Once in the serum, 50% of bisphosphonates is cleared  rapidly by the kidneys with the remainder going to bone.    Aminobisphosphonate antineoplastics:  e Pamidronate disodium (Aredia)  e Relative potency of 100  e |V infusion every 4 weeks  e lbandronate sodium (Boniva)  e Relative potency of 10,000  e lV infusion every 4 weeks  e Zoledronic acid (Zometa)  e Relative potency of 100,000  e |V infusion every 4 weeks    Aminobisphosphonates for osteoporosis:  e Risedronate sodium (Actonel)  e Relative potency of 5,000  e PO weekly  Delayed release risedronate sodium (Atelvia)  e Relative potency of 5,000  e PO weekly  e lbandronate sodium (Boniva)  e Relative potency of 10,000  e PO monthly  e |V infusion every 3 months  e Alendronate sodium (Fosamax)  e Relative potency of 1,000  e PO weekly  e Zoledronic acid (Reclast)  e Relative potency of 100,000  e IV annually    Denosumab for osteoporosis:  e Denosumab (Prolia)  e Injection every 6 months    The medications are not distributed evenly throughout the  skeleton. Osteocytes represent 85% of the cells associated  with bone and do not retain the medication. In contrast,  osteoclasts demonstrate an affinity eight times greater than  osteocytes, but they release the drug for recycling at the end  of their short 2-week life span. Osteoblasts exhibit four  times the affinity of osteocytes and incorporate the medica-  tion into the bone matrix. Due to a half-life longer than 10  years, deposits of bisphosphonates have the ability to remain  in place for over four decades. The effect of the medication  on the bone varies with concentration. At low concentra-  tions, the medication diminishes the ability of osteoclasts  to resorb and degrade bone matrix, whereas high local con-  centration induces osteoclastic apoptosis. ‘Therefore,  bisphosphonates are selectively concentrated into areas of  bone repair and remodeling, with potential effects over the  patient’s lifetime. In addition, the impact on the bone  worsens as the local concentration is increased.  Denosumab is a monoclonal antibody that also reduces  osteoclastic function, but it does this by inhibiting osteo-  clastic differentiation. Due to the short life span of    @ Fig. 8-27 Basic Multicellular Unit (BMU). Organized synergy of  osteoclasts, osteoblasts, and vasculature working together to trans-  form immature woven bone into structural sound lamellar bone.    osteoclasts, this medication quickly reduces osteoclastic  activity by 85% with maximal reduction occurring within  1 month of an injection. The medication is not deposited  in bone and has a half-life of 24.5 days, with complete  clearance in 4 to 5 months.   Any discussion of antiresorptive agents also must include  information on bone healing. When a traumatic event such  as an extraction occurs, the initial clot is replaced with  granulation tissue and eventually woven bone. The remodel-  ing period of this immature bone into structurally sound  lamellar bone typically is 4 months but can range from 2  to 8 months. The final remodeling is performed by an  organized synergism of osteoclasts, osteoblasts, and the local  vascular supply, which work together in a cell packet known  as the basic multicellular unit (BMU). This is a moving  structure that requires continual replacement of participat-  ing cells at exactly the correct time and place in an ever-  changing position. The osteoclasts are critical cells of the  BMU and are largely responsible for the signaling necessary  for the participation of the other cellular components (Fig.  8-27). Functional impairment or loss of the osteoclasts by  antiresorptive drugs disrupts not only resorption but also  new lamellar bone deposition and angiogenesis.   Although the vast majority of osteonecrosis cases have  occurred in the jaws, problems are beginning to surface  elsewhere in the skeleton. Osteonecrosis of the ear has been  documented following removal of an exostosis. More sig-  nificantly, numerous orthopedic surgeons have reported an  increased prevalence of subtrochanteric or femoral shaft  fractures associated with aminobisphosphonates, leading  the US Food and Drug Administration (FDA) to add this  complication to the drug information.    In an excellent comprehensive review of 2,408 reported cases  of BRONJ, 89% were discovered in patients who were  treated with the IV formulations (primarily pamidronate and    ® Fig. 8-28 Medication-related Osteonecrosis. Bilateral necrotic  exposed bone of the mandible in a patient receiving zoledronic acid  for metastatic breast cancer. (Courtesy of Dr. Brent Mortenson.)    zoledronic acid) for cancer, with 43% being reported in  patients with multiple myeloma. In another summary review,  the prevalence of osteonecrosis associated with the IV formu-  lations in cancer patients has been estimated to be 100 cases  per 10,000 patients. Unfortunately all of the information  now available is based on reported cases, and such reports  frequently have inherent biases. Randomized prospective  trials with appropriate controls will be necessary to obtain  reliable data with respect to prevalence and management.   Osteonecrosis related to use of aminobisphosphonates  for osteoporosis is most uncommon. A conservative esti-  mate by the drug industry suggested an annual incidence  of 0.7 per 100,000, but a more recent review suggested a  single case occurs per 10,000 patients (100 times less fre-  quent than that seen in cancer patients treated with antire-  sorptive medications). However, appropriate prospective  trials for the true frequency of this complication have yet  to be performed. Additional risk factors for MRONJ include  advanced patient age (older than 65 years), corticosteroid  use, use of chemotherapy drugs, diabetes, smoking or  alcohol use, poor oral hygiene, and duration of drug use  exceeding 3 years. A predictive test for those at risk for  bisphosphonate osteonecrosis has not been confirmed.  Some investigators have suggested use of a serum marker  for bone turnover, serum C-telopeptide (CTX), but the test  has demonstrated insufficient reliability and accuracy in  predicting the risk of developing of MRONJ.   In the previously mentioned comprehensive review, the  mandible was involved in 65%, the maxilla in 27%, and  both jaws in 8% (Fig. 8-28). In 67% of these patients, the  necrosis followed a dental extraction, with another 26%  arising spontaneously, and 7% associated with a variety of  triggers such as denture pressure or minor trauma of a torus  (Figs. 8-29 and 8-30). In patients with exposed bone, 16%  were asymptomatic, 66% were painful, and another 18%  demonstrated extensive involvement in which the associ-  ated pain was not responsive to antibiotics.   Research related to denosumab-associated osteonecrosis  is in its infancy when compared to BRONJ, but reviews of    @ Fig. 8-29 Medication-related Osteonecrosis. Multifocal areas of  exposed necrotic bone of the mandible in a patient receiving zoledronic  acid for cancer.    ® Fig. 8-30 Medication-related Osteonecrosis. Lobulated palatal  torus with an area of exposed necrotic bone in a patient taking alen-  dronate for osteoporosis.    cancer patients randomized to zoledronic acid or deno-  sumab have demonstrated a similar frequency of osteone-  crosis with these two medications. The frequency of MRONJ  appears to range from 70 to 90 cases per 10,000 cancer  patients receiving denosumab.   Investigators have suggested that bone at imminent risk  for osteonecrosis often will demonstrate increased radiopac-  ity before clinical evidence of frank necrosis. These changes  typically occur predominantly in areas of increased bone  remodeling, such as the alveolar ridges. Panoramic radio-  graphs often will reveal a marked radiodensity of the crestal  portions of each jaw, with a more normal appearance of the  bone away from tooth-bearing portions. Periosteal hyper-  plasia also is not rare. In more severe cases, the osteonecrosis  creates a moth-eaten and ill-defined radiolucency with or  without central radiopaque sequestra (Fig. 8-31). In some  cases the necrosis can lead to development of a cutaneous  sinus or pathologic fracture (Fig. 8-32).    Biopsy of vital bone altered by aminobisphosphonates is not  common. In such cases, the specimen often reveals irregular    @ Fig. 8-31 Medication-related Osteonecrosis. Panoramic radio-  graph of patient depicted in Fig. 8-28. Note sclerosis of tooth-bearing  areas along with multiple radiolucencies and periosteal hyperplasia of  the lower border of the mandible. (Courtesy of Dr. Brent Mortenson.)    @ Fig. 8-32 Medication-related Osteonecrosis. Patient with mul-  tiple cutaneous sinuses associated with extensive necrosis of the left  side of the mandible. The patient was taking zoledronic acid for mul-  tiple myeloma. (Courtesy of Dr. Molly Rosebush.)    trabeculae of pagetoid bone, with adjacent enlarged and  irregular osteoclasts that often demonstrate numerous  intracytoplasmic vacuoles (Fig. 8-33). Specimens of active  areas of MRONJ reveal trabeculae of sclerotic lamellar  bone, which demonstrate loss of the osteocytes from  their lacunae and frequent peripheral resorption with bacte-  rial colonization (Fig. 8-34). Although the peripheral bacte-  rial colonies often resemble actinomycetes, the infestation  is not supportive of a diagnosis of invasive cervicofacial  actinomycosis.    Virtually all recommendations regarding management of  patients who are taking or have been exposed to anti-  resorptive agents are empirical. No large, randomized, con-  trolled studies have been done with respect to prevention  or treatment of the complications of this therapy. The  best therapeutic approach to MRONJ is prevention. In  cancer patients evaluated before initiation of bisphospho-  nate therapy, the goal is to improve dental health to pre-  vent future procedures that disrupt bone; this includes    e Fig. 8-33 Medication-related Osseous Changes. Pagetoid  bone exhibiting enlarged, irregular osteoclasts that contain numerous  intracytoplasmic vacuoles. (Courtesy of Dr. Don Cohen.)    @ Fig. 8-34 Medication-related Osteonecrosis. Sclerotic lamellar  bone exhibiting loss of the osteocytes from their lacunae and periph-  eral resorption with bacterial colonization.    elimination of oral foci of infection and removal of large  tori or partially impacted teeth. If only noninvasive oral care  is indicated, then the initiation of the medication need not  be delayed. If surgical procedures need to be performed,  then a month-long delay in initiation of the medication is  recommended, along with prophylactic antibiotic therapy.   For cancer patients actively being treated with antire-  sorptive therapy, manipulation of bone should be avoided  if possible. Conventional endodontics is a better option  than extraction. If a nonvital tooth is not restorable, then  endodontics should be performed and followed by crown  amputation. Teeth with 1+ or 2+ mobility should be  splinted; those with 3+ mobility can be extracted.   Despite the desire to avoid jaw surgery during IV therapy,  occasional clinical situations may make surgical interven-  tion unavoidable. Several investigators have suggested that  the likelihood of osteonecrosis can be minimized by antibi-  otic prophylaxis starting 1 day prior and extending 3 days  after any invasive dental procedure.    For patients with MRONJ, the primary goal of therapy  is to minimize pain. Aggressive removal of dead bone typi-  cally results in further bone necrosis, and hyperbaric oxygen  has not been significantly beneficial. Asymptomatic patients  should rinse daily with chlorhexidine and be monitored  closely. Any rough edges of exposed bone should be smoothed  and loose sequestra can be removed carefully. If the exposed  bone irritates adjacent tissues, then coverage with a soft  splint may provide some relief. In symptomatic patients,  systemic antibiotic therapy and chlorhexidine usually reduce  discomfort. If the antibiotics fail to stop the pain, then hos-  pitalization with IV antibiotic therapy can be considered. In  recalcitrant cases, the bulk of the dead bone is reduced surgi-  cally, followed by administration of systemic antibiotics.  Because of the long half-life of bisphosphonates, discontinu-  ation of the drug offers no short-term benefit. In isolated  anecdotal reports of recalcitrant cases, discontinuation of the  medication for 6 to 12 months occasionally has been associ-  ated with spontaneous sequestration and resolution.   Prevention also represents the best approach for patients  taking antiresorptive medications for osteoporosis. In the  original ADA position paper, a 3-month drug holiday  before and after osseous surgery was suggested for any  patient using bisphosphonates longer than 3 years. In the  2011 update, the ADA removed this suggestion due to the  fear of increasing the skeletally related risks of low bone  mass during the drug-free period. In spite of this, the 2014  AAOMS update recommended use of a drug holiday for  patients using bisphosphonates longer than 4 years or  patients who also are utilizing systemic corticosteroids or  antiangiogenic agents.   A possible alternative to minimize the risk of osteone-  crosis without a drug holiday has been proposed. As previ-  ously mentioned, bisphosphonates concentrate in healing  or remodeling bone. Once deposited, the medications  remain for decades. As the concentration increases, the  impact on the bone worsens. The best method to avoid  osteonecrosis is to minimize the osseous deposition of  bisphosphonates by ensuring the serum is free of the medi-  cation at the time of a surgical procedure and for the sub-  sequent healing period. This can be accomplished by  suggesting use of annual IV administration of zoledronic  acid and timing all surgical procedures to occur 2 months  after the annual infusion. At this time, the serum will be  essentially free of bisphosphonate with an additional 10  months of healing time prior to the next infusion. Alterna-  tively, biannual injections with denosumab could be substi-  tuted for bisphosphonate therapy with any surgical  procedure planned to occur 2 months after an injection (at  which time 79.9% of the medication would be degraded)  with 4 months of healing time prior to the next injection.  The worst approach would be to ignore totally the dates of  drug administration. Surgery occurring close to the time of  bisphosphonate infusion or denosumab injection would  maximize the adverse effects on healing and future bone  health. Due to the frequent administration pattern of the  oral bisphosphonates, none of these medications can be    utilized in a manner that would prevent concentration of  the drug into surgical sites.   For patients with osteoporosis, all restorative, prosth-  odontic, conventional endodontic, and routine periodontic  procedures can be implemented as needed. Although orth-  odontic treatment is not contraindicated, progress should  be evaluated after 2 to 3 months of active therapy. At that  point, therapy can proceed if the tooth movement is occur-  ring predictably with normal forces. Invasive orthodontic  techniques such as orthognathic surgery, four-tooth extrac-  tion cases, and miniscrew anchorage should be avoided, if  possible.   When an osseous procedure is considered, the patient  should be advised of the potential complications of antire-  sorptive use and the risk of MRONJ. Written informed  consent and documentation of a discussion of the benefits,  risks, and alternative therapies are highly advised.   Osteonecrosis associated with antiresorptive therapy for  osteoporosis tends to be less extensive and more responsive  to conservative therapy when compared to MRONJ in  cancer patients. When the antiresorptive therapy can be  discontinued, many cases of MRONJ resolve without surgi-  cal intervention. This spontaneous resolution occurs slowly  over many months, but reports have documented greatly  reduced healing times secondary to administration of terip-  aratide (recombinant human parathyroid hormone).   The clinical approach to patients treated with antiresorp-  tive medications varies according to the formulation of the  drug, the disease being treated, and the duration of drug  use. All patients who take these medications should be  warned of the risks and instructed to obtain and maintain  ultimate oral hygiene. The oral bisphosphonates are  extremely caustic; patients should be warned to minimize  oral mucosal contact and ensure the medication is swal-  lowed completely.   Overall, the benefits of antiresorptive therapy for osteo-  porosis and metastatic cancer appear to greatly outweigh the  risk of developing MRONJ. No patient should discontinue  his or her medication against medical advice. An osteopo-  rotic hip fracture is a life-altering event, with 75% of  patients never fully recovering and a mortality rate of 20%  in women and 30% in men. The antiresorptive medications  reduce hip fractures by approximately 50%. A similar  success has been seen in cancer patients where antiresorptive  medications are associated with a significant reduction in  skeletal-related adverse events.   In spite of the obvious benefits of antiresorptive drugs,  increased bone density does not correlate necessarily to  good bone quality. The negative effects of oversuppression  of bone metabolism must be considered. Reports are con-  tinuing to document spontaneous nontraumatic stress frac-  tures with associated delayed healing in patients on  long-term antiresorptive therapy for osteoporosis. Many  physicians now believe that such therapy should be stopped  after 5 years. Patients no longer osteoporotic could be  removed from active therapy until bone density studies  confirm redevelopment of significant osteoporosis. For    those with continuing osteoporosis, alternatives such as  teriparatide or raloxifene could be considered.    Over the last decade, numerous reports have described sig-  nificant oral manifestations of drug abuse, most commonly  the illegal stimulants cocaine and methamphetamine.   After marijuana, cocaine represents one of the more  commonly utilized illicit drugs with 1.4 million active (past  month) users in the United States during 2011. Cocaine  can be ingested by snorting, injecting, or smoking as free  base or crack cocaine. The drug is known by nicknames that  include blow, bump, C, candy, Charlie, coke, crack, flake,  rock, snow, and toot. Snorting is the main method of admin-  istration due to the associated euphoric high that lasts from  20 to 90 minutes. When snorted, cocaine is associated with  a sympathetic-mediated vasoconstriction that can be associ-  ated with significant local ischemia combined with inflam-  mation and ulceration secondary to the adulterants utilized  to “cut” the cocaine.   Methamphetamine is a drug with stimulant effects on  the central nervous system (CNS). In 1937, the drug was  approved in the United States for the treatment of narco-  lepsy and attention deficit hyperactivity disorder. Within a  few years, many began to use the drug to increase alertness,  control weight, and combat depression. Because metham-  phetamine users perceive increased physical ability, greater  energy, and euphoria, illegal use and manufacture of the  drug began to develop. Because of greater control over the  main ingredient, pseudoephedrine, production of home-  made methamphetamine is decreasing but often being  replaced by illegal importation of the finished product.  Although illicit use of methamphetamine dropped in 2011  to 439,000 active users, the drug remains a serious problem  in many areas of the nation. The drug is a powdered crystal  that dissolves easily in liquid and can be smoked, snorted,  injected, or taken orally. The drug is known by nicknames  that include chalk, crank, crystal, fire, glass, go fast, ice, meth,  and. speed.    As mentioned, cocaine creates a feeling of euphoria and  arousal. Other less desirable symptoms include aggressive  behavior, blurred vision, dilated pupils, delirium, dizziness,  light-headedness, restlessness, tinnitus, tremors, shivering,  insomnia, and vomiting. Physical signs include tachycardia,  tachypnea, hypertension, and hyperthermia. The sympatho-  mimetic effects increase the oxygen demands of the myocar-  dium, and the vasoconstrictive effects reduce oxygen delivery  by the coronary arteries. This combination may trigger  angina, myocardial infarction, or heart dysrhythmias.   One of the more common local complications to cocaine  snorting is perforation of the nasal septum, a finding noted    in approximately 5% of abusers. Loss of the nasal septum  can lead to complete nasal collapse resulting in a saddle nose  deformity. Less frequently, the necrosis can spread to the  orbital wall, lateral nasal wall, or the hard palate and may  cause palatal perforation that has been termed cocaine-  induced midline destructive lesion (CIMDL). Associated  findings include recurrent epistaxis, a nasal tone of voice  (rhinolalia), regurgitation of food/drink, intranasal crust-  ing, rhinitis, and sinusitis. The majority of the reported  palatal perforations are limited to the hard palate, followed  by involvement of both the hard and soft palates. Perfora-  tion isolated to the soft palate is most uncommon. Although  very rare, similar nasal collapse and palatal perforations have  been reported from intranasal abuse of narcotics, such as  hydrocodone/acetaminophen or oxycodone/acetaminophen  (Figs. 8-35 and 8-36). On occasion, mucosal burns of the  lips may be seen in users of crack pipes (Fig. 8-37).  Although methamphetamine abuse may occur through-  out society, most users are men between the ages of 19 and  40 years. The effects of the medication last up to 12 hours,  and the typical abuser reports use that exceeds 20 days  per month, creating an almost continuous effect of the  drug. The short-term effects of methamphetamine include    @ Fig. 8-35 Oxycodone-related Saddle Nose Deformity. Loss of  nasal septum leading to nasal collapse in abuser of oxycodone.    @ Fig. 8-36 Oxycodone-related Palatal Perforation. Midline per-  foration of the palate in abuser of oxycodone.    @ Fig. 8-37 Crack Pipe Burn. Multiple erosions of the upper and  lower vermilion borders secondary to burns inflicted by use of a crack  pipe.    insomnia, aggressiveness, agitation, hyperactivity, decreased  appetite, tachycardia, tachypnea, hypertension, hyperther-  mia, vomiting, tremors, and xerostomia. Long-term effects  additionally include strong psychologic addiction, violent  behavior, anxiety, confusion, depression, paranoia, auditory  hallucinations, delusions, mood changes, skin lesions, and  a number of cardiovascular, CNS, hepatic, gastrointestinal,  renal, and pulmonary disorders.   Many addicts develop delusions of parasitosis (formica-  tion, from the Latin word formica, which translates to ant),  a neurosis that produces the sensation of snakes or insects  crawling on or under the skin. This sensation causes the  patient to attempt to remove the perceived parasites, usually  by picking at the skin with fingernails, resulting in wide-  spread traumatic injury. The factitial damage can alter dra-  matically the facial appearance in a short period of time,  and these lesions have been nicknamed speed bumps, meth  sores, or crank bugs.   Rampant dental caries is another common manifestation  and exhibits numerous similarities with milk-bottle caries.  The carious destruction initially affects the facial smooth  and interproximal surfaces, but without intervention, the  coronal structure of the entire dentition can be destroyed  (Fig. 8-38). The carious destruction appears to be caused by  poor oral hygiene combined with extreme drug-related  xerostomia, which leads to heavy consumption of acidic and  sugar-filled soft drinks or other refined carbohydrates.    Cessation of illicit drug use is paramount in both cocaine  and methamphetamine abuse. In patients with palatal per-  foration, complete cessation of cocaine use must be stopped  6 months prior to surgical reconstruction. If surgical recon-  struction fails, a removable maxillary obturator can be con-  structed. Although cessation of the illicit drug use is critical,  methamphetamine addicts should be encouraged during  periods of xerostomia to discontinue use of highly acidic  and sugar-filled soft drinks and to avoid diuretics, such as    @ Fig. 8-38 Methamphetamine-related Dental Caries. Extensive  smooth-surface decay of the anterior dentition.    caffeine, tobacco, and alcohol. In addition, the importance  of personal and oral hygiene should be stressed. Preventive  measures such as topical fluorides may assist in protecting  the remaining dentition.   The oral health practitioner should be alerted when an  agitated, nervous adult presents with tachycardia, tachy-  pnea, hypertension, and hyperthermia. Failure to recognize  these signs can be serious. For up to 24 hours after inges-  tion, both cocaine and methamphetamine potentiate the  effects of sympathomimetic amines. Use of local anesthetics  with epinephrine or levonordefrin can lead to a hyperten-  sive crisis, cerebrovascular accident, or myocardial infarc-  tion. Caution also should be exercised when administering  sedatives, general anesthesia, nitrous oxide, or prescriptions  for narcotics. A medical consultation with referral to a sub-  stance abuse center should be encouraged.    Administration of a local anesthetic agent can, on rare occa-  sions, be followed by ulceration and necrosis at the site of  injection. Researchers believe that this necrosis results from  localized ischemia, although the exact cause is unknown and  may vary from case to case. Faulty technique, such as subperi-  osteal injection or administration of excess solution in tissue  firmly bound to bone, has been blamed. The epinephrine  contained in many local anesthetics also has received atten-  tion as a possible cause of ischemia and secondary necrosis.    Anesthetic necrosis usually develops several days after the  procedure and most commonly appears on the hard palate  (Fig. 8-39). A well-circumscribed area of ulceration devel-  ops at the site of injection.    Treatment of anesthetic necrosis usually is not required  unless the ulceration fails to heal. Minor trauma, such as    e Fig. 8-39 Anesthetic Necrosis. Mucosal necrosis of the hard  palate secondary to palatal injection with a local anesthetic agent  containing epinephrine.    that caused by performing a cytologic smear, has been  reported to induce resolution in these chronic cases. Recur-  rence is unusual but has been reported in some patients in  association with use of epinephrine-containing anesthetics.  In these cases the use of a local anesthetic without epineph-  rine is recommended.    Exfoliative cheilitis is a persistent scaling and flaking of the  vermilion border, usually involving both lips. The process  arises from excessive production and subsequent desquama-  tion of superficial keratin. A significant percentage of  cases appear related to chronic injury secondary to habits,  such as lip licking, biting, picking, or sucking. Those cases  proven to arise from chronic injury are termed factitious  cheilitis.   Many patients deny chronic self-irritation of the area.  ‘The patient may be experiencing associated personality dis-  turbances, psychologic difficulties, or stress. In a review of  48 patients with exfoliative cheilitis, 87% exhibited psychi-  atric conditions and 47% also demonstrated abnormal  thyroid function. Evidence suggests that there may be a  link between thyroid dysfunction and some psychiatric  disturbances.   In other cases, no evidence of chronic injury is evident.  In these patients other causes should be ruled out (e.g.,  atopy; chronic candidal infection, actinic cheilitis, cheilitis  glandularis, hypervitaminosis A, and photosensitivity). In a  review of 165 patients with acquired immunodeficiency  syndrome (AIDS), more than one-quarter had alterations  that resembled exfoliative cheilitis. In this group the lip  alterations appeared secondary to chronic candidal infesta-  tion. The most common presentation of bacterial or fungal  infections of the lips is angular cheilitis (see page 194).  Diffuse primary infection of the entire lip is very unusual;  most diffuse cases represent a secondary candidal infection  in areas of low-grade trauma of the vermilion border of the  lip (cheilocandidiasis).    @ Fig. 8-40 Exfoliative Cheilitis. Scaling and erythema of the ver-  milion border of the lower lip.    In one review of 75 patients with chronic cheilitis, a  thorough evaluation revealed that more than one-third rep-  resented irritant contact dermatitis (often secondary to  chronic lip licking). In 25% of the patients, the cheilitis was  discovered to be an allergic contact mucositis (see page  320). Atopic eczema was thought to be the cause in 19%  of cases; the remaining portion was related to a wide variety  of pathoses.   In spite of a thorough investigation, there often remain  a number of patients with classic exfoliative cheilitis for  which no underlying cause can be found. These idiopathic  cases are most troublesome and often resistant to a wide  variety of interventions.    A marked female predominance is seen in cases of factitious  origin, with most cases affecting those younger than 30  years of age. Mild cases feature chronic dryness, scaling, or  cracking of the vermilion border of the lip (Fig. 8-40). With  progression, the vermilion can become covered with a thick-  ened, yellowish hyperkeratotic crust that can be hemor-  rhagic or that may exhibit extensive fissuring. The perioral  skin may become involved and exhibit areas of crusted  erythema (Fig. 8-41). Although this pattern may be con-  fused with perioral dermatitis (see page 322), the most  appropriate name for this process is circumoral dermatitis.  Both lips, or just the lower lip, may be involved. On occa-  sion, the alterations can present in a cyclical pattern in  which the changes resolve but subsequently redevelop over  a relatively consistent period of time.   In patients with chronic cheilitis, development of fissures  on the vermilion border is not rare. In a prevalence study  of more than 20,000 patients, these fissures involved either  lip and were slightly more common in the upper lip. In  contrast to typical exfoliative cheilitis, these fissures demon-  strate a significant male predilection and a prevalence rate  of approximately 0.6%. The majority arise in young adults,  with rare occurrence noted in children and older adults.    Although the cause is unknown, proposed contributing  factors include overexposure to sun, wind, and cold weather;  mouth breathing; bacterial or fungal infections; and  smoking. An increased prevalence of lip fissures has been  noted in patients with Down syndrome and may be the  result of the high frequency of mouth breathing or the  tendency to develop orofacial candidiasis. Application of  lipstick or lip balm appears to be protective. Fissure occur-  rence also may be related to a physiologic weakness of the  tissues. Those affecting the lower lip typically occur in the  midline, whereas fissures on the upper vermilion most  frequently involve a lateral position. These are the sites  of prenatal merging of the mandibular and maxillary  processes.    In those cases associated with an obvious cause, elimination  of the trigger typically results in resolution of the changes.  In those cases with no underlying physical, infectious, or  allergic cause, psychotherapy (often combined with mild  tranquilization or stress reduction) may achieve resolution.    @ Fig. 8-41 Circumoral Dermatitis. Crusting and erythema of the  skin surface adjacent to the vermilion border in a child who chronically  sucked on both lips.    In cases for which no cause can be found, therapeutic inter-  ventions often are not successful.   Cases that result from candidal infections often do not  resolve until the chronic trauma also is eliminated. Initial  topical antifungal agents, antibiotics, or both can be admin-  istered to patients in whom chronic trauma is not obvious  or is denied. If the condition does not resolve, then further  investigation is warranted in an attempt to discover the true  source of the lip alterations.   Hydrocortisone and iodoquinol (antibacterial and anti-  mycotic) cream has been used to resolve chronic lip fissures  in some patients (Fig. 8-42). Other reported therapies  include various corticosteroid preparations, topical tacroli-  mus, sunscreens, and moisturizing preparations. In many  cases, resistance to topical therapy or frequent recurrence is  noted. In these cases, cryotherapy or excision with or  without Z-plasty has been used successfully.   e Minute hemorrhages into skin, mucosa, or serosa are  termed petechiae.   e Any accumulation greater than 2 cm is termed an  ecchymosis.   e If the accumulation of blood within tissue produces a  mass, this is termed a hematoma.   Blunt trauma to the oral mucosa often results in hema-  toma formation. Less well known are petechiae and purpura,  which can arise from repeated or prolonged increased intra-  thoracic pressure (Valsalva maneuver) associated with such  activities as repeated coughing, vomiting, convulsions, or  giving birth (Fig. 8-43). When considering a diagnosis of  traumatic hemorrhage, the clinician should keep in mind  that hemorrhages can result from nontraumatic causes, such    ® Fig. 8-42 Lip Fissure. A, Chronic fissure of the vermilion border of the upper lip. B, Same site 2  weeks later, after use of hydrocortisone and iodoquinol cream.    as anticoagulant therapy, thrombocytopenia, disseminated  intravascular coagulation (DIC), and a number of viral  infections, especially infectious mononucleosis and measles.    Submucosal hemorrhage appears as a nonblanching flat or  elevated zone with a color that varies from red or purple to  blue or blue-black (Fig. 8-44). As would be expected, trau-  matic lesions are located most frequently on the labial or  buccal mucosa. Blunt facial trauma often is responsible, but  injuries as minor as cheek biting may produce a hematoma  or areas of purpura (Fig. 8-45). Mild pain may be present.   The hemorrhage associated with increased intrathoracic  pressure usually is located on the skin of the face and neck  and appears as widespread petechiae that clear within 24 to  72 hours. Although it has not been as well documented as  the cutaneous lesions, mucosal hemorrhage can be seen in  the same setting and most often appears as soft palatal  petechiae or purpura.    Often, no treatment is required if the hemorrhage is not  associated with significant morbidity or related to systemic  disease. The areas should resolve spontaneously. Large hema-  tomas may require several weeks to resolve. If the hemor-  rhage occurs secondary to an underlying disorder, then  treatment is directed toward control of the associated disease.    Although orogenital sexual practices are illegal in many  jurisdictions, they are extremely common. Among homo-  sexual men and women, orogenital sexual activity almost is  universal. For married heterosexual couples younger than age  25, the frequency has been reported to be as high as 90%.  Considering the prevalence of these practices, the frequency  of associated traumatic oral lesions is surprisingly low.    @ Fig. 8-43 Petechiae. Submucosal hemorrhage of the soft palate  caused by violent coughing.    @ Fig. 8-44 Purpura. Submucosal hemorrhage of the lower labial  mucosa on the left side secondary to blunt trauma.    @ Fig. 8-45 Hematoma. A, Dark-purple nodular mass of the buccal mucosa in a patient on Coumadin  therapy. B, Near resolution of the lesion 8 days later after discontinuation of the medication. (Courtesy of    ° Fig. 8-46 Palatal Petechiae from Fellatio. Submucosal hemor-  rhage of the soft palate resulting from the effects of negative  pressure.    The most commonly reported lesion related to orogenital  sex is submucosal palatal hemorrhage secondary to fellatio.  The lesions appear as erythema, petechiae, purpura, or  ecchymosis of the soft palate. The areas often are asymp-  tomatic and resolve without treatment in 7 to 10 days (Fig.  8-46). Recurrences are possible with repetition of the incit-  ing (exciting?) event. The erythrocytic extravasation is  thought to result from the musculature of the soft palate  elevating and tensing against an environment of negative  pressure. Similar lesions have been induced from coughing,  vomiting, or forceful sucking on drinking straws and glasses.  Forceful thrusting against the vascular soft palate has been  suggested as another possible cause.   Oral lesions also can occur from performing cunnilingus,  resulting in horizontal ulcerations of the lingual frenum. As  the tongue is thrust forward, the taut frenum rubs or rakes  across the incisal edges of the mandibular central incisors.  The ulceration created coincides with sharp tooth edges  when the tongue is in its most forward position. The lesions  resolve in 7 to 10 days but may recur with repeated perfor-  mances. Linear fibrous hyperplasia has been discovered in  the same pattern in individuals who chronically perform the  act (Fig. 8-47).    With an appropriate index of suspicion, biopsy usually is  not required; however, a biopsy has been performed in some  cases of palatal lesions secondary to fellatio. These suction-  related lesions reveal subepithelial accumulations of red  blood cells that may be extensive enough to separate the  surface epithelium from underlying connective tissue.  Patchy degeneration of the epithelial basal cell layer can  occur. The epithelium classically demonstrates migration of  erythrocytes and leukocytes from the underlying lamina  propria.    ° Fig. 8-47 Fibrous Hyperplasia from Repeated Cunnilingus.  Linear fibrous hyperplasia of the lingual frenum caused by repeated  irritation from lower incisors.    No treatment is required, and the prognosis is good. In  patients who request assistance, palatal petechiae can be  prevented through the use of less negative pressure and  avoidance of forceful thrusting. Smoothing and polishing  the rough incisal edges of the adjacent mandibular teeth can  minimize the chance of lingual frenum ulceration.    A number of pigmented materials can be implanted within  the oral mucosa, resulting in clinically evident pigmenta-  tions. Implantation of dental amalgam (amalgam tattoo)  occurs most often, with a frequency that far outdistances  that for all other materials. Localized argyrosis has been used  as another name for amalgam tattoo, but this nomenclature  is inappropriate because amalgam contains not only silver  but also mercury, tin, copper, zinc, and other metals.   Amalgam can be incorporated into the oral mucosa in  several ways. Previous areas of mucosal abrasion can be con-  taminated by amalgam dust within the oral fluids. Broken  amalgam pieces can fall into extraction sites. If dental floss  becomes contaminated with amalgam particles of a recently  placed restoration, then linear areas of pigmentation can be  created in the gingival tissues as a result of hygiene proce-  dures (Fig. 8-48). Amalgam from endodontic retrofill proce-  dures can be left within the soft tissue at the surgical site (Fig.  8-49). Finally, fine metallic particles can be driven through  the oral mucosa from the pressure of high-speed air turbines.  Theoretically, the use of the rubber dam should decrease the  risk; however, immediately after removal of the dam, the  occlusion often is adjusted with the potential for amalgam  contamination of any areas of mucosal damage.   In one interesting report, metal from silver solder on  orthodontic brackets leached into adjacent gingival crevices    @ Fig. 8-48 Floss-related Amalgam Implantation. Linear strips of  mucosal pigmentation that align with the interdental papillae. The  patient used dental floss on the mandibular first molar immediately  after the placement of the amalgam restoration. Because the area was  still anesthetized, the patient impaled the floss on the gingiva and then  continued forward using the amalgam-impregnated floss in the bicus-  pid area to create additional amalgam tattoos.    ® Fig. 8-49 Endodontic-related Amalgam Implantation. Multifo-  cal areas of mucosal discoloration overlying the maxillary anterior inci-  sors, which have been treated with apical retrofill procedures.    and created discolorations that were thought to be second-  ary to formation of insoluble precipitates from metabolic  bacterial byproducts. Submucosal implantation of pencil  graphite, coal and metal dust, fragments of broken carbo-  rundum disks, dental burs, and, in the past, charcoal  dentifrices, have resulted in similar-appearing areas of  discoloration.   Intentional tattooing, which can be found in approxi-  mately 25% of the world’s population, also may be per-  formed in the oral cavity. Although some cases are culturally  related, health professionals also are responsible for a  number of intentional oral and facial tattoos for the purpose  of demonstrating landmarks, establishing progress of orth-  odontic treatment, marking sites of uncovered dental  implants, judging tumor response to antineoplastic thera-  pies, repigmenting areas of vitiligo, cosmetically disguising  disfigured areas, and applying permanent cosmetic makeup.  Injudicious intraoral use of these marking agents can cause    @ Fig. 8-50 Amalgam Tattoo. Area of mucosal discoloration of the  floor of the mouth on the patient’s left side.    diffusion of the pigment with discoloration of the adjacent  skin surface.    Amalgam tattoos appear as macules or, rarely, as slightly  raised lesions. They may be black, blue, or gray. The borders  can be well defined, irregular, or diffuse (Fig. 8-50). Lateral  spread may occur for several months after the implantation.  Any mucosal surface can be involved, but the most common  sites are the gingiva, alveolar mucosa, and buccal mucosa  (Fig. 8-51).   Periapical radiographs, when taken, are negative in many  cases. When metallic fragments are visible radiographically,  the clinical area of discoloration typically extends beyond  the size of the fragment. The fragments are densely radi-  opaque, varying from several millimeters to pinpoint in size  (see Fig. 8-51). On occasion, the pattern of the amalgam  dispersal has been sufficiently unique to be used as a distinc-  tive characteristic in the identification of unknown deceased  individuals.   Cosmetic tattooing is gaining in popularity and may  include injection of permanent cosmetic inks into the  eyelids and vermilion border of the upper and lower lips.  On occasion, patients may react to the material and experi-  ence swelling, burning, and itching at the site, followed by  enlargement and induration. In such cases, biopsy often  reveals a granulomatous reaction to the foreign material.  One report documented rapid development of squamous  cell carcinoma of the upper vermilion border arising in a  patient with minimal sun exposure and recent placement of  permanent red makeup tattoo.   Intentional intraoral tattoos occur most frequently on  the anterior maxillary facial gingiva of individuals from a  number of African countries and have been documented at  institutions in the United States (Fig. 8-52). In these cases,  the anterior maxillary facial gingiva is given a blue-black  discoloration that tends to fade to mostly gray over time.  Occasionally, tattoos are placed on the labial mucosa of    @ Fig. 8-51 Amalgam Tattoo. A, Area of mucosal discoloration of  the mandibular alveolar ridge immediately below the bridge pontic.  B, Radiograph of the same patient showing radiopaque metallic frag-  ment present at the site of mucosal discoloration.    @ Fig. 8-52 Intentional Intraoral Tattoo. Cultural tattoo of the maxil-  lary facial gingiva in a patient from Senegal. (Courtesy of Dr. Kristin  McNamara.)    adults in the United States to convey a personal, often  vulgar, message (Fig. 8-53).    Microscopic examination of amalgam tattoos reveals pig-  mented fragments of the metal within the connective tissue.  Scattered, large, dark, solid fragments or numerous fine,    @ Fig. 8-53 Intentional Intraoral Tattoo. Amateur tattoo of the  lower labial mucosa. (Courtesy of Dr. Edward Herschaft.)    ° Fig. 8-55 Amalgam Tattoo. Dark amalgam stain encircling numer-  ous vascular channels.    black, or dark-brown granules may be seen (Fig. 8-54). The  silver salts of the dental amalgam preferentially stain the  reticulin fibers, especially those encircling nerves and vascu-  lar channels (Fig. 8-55).   The biologic response to amalgam appears related to  particle size and the elemental composition of the amalgam.    Large fragments often become surrounded by dense fibrous  connective tissue with mild inflammation. Smaller particles  typically are associated with a more significant inflamma-  tory response that may be granulomatous or a mixture of  lymphocytes and plasma cells. Graphite implantation  appears similar microscopically to amalgam but can be dif-  ferentiated by its pattern of birefringence after treatment  with ammonium sulfide and by the lack of staining of the  reticulin fibers. In addition, energy dispersive x-ray micro-  analysis can be used to identify the type of material present  within areas of foreign body tattoos.    To confirm the diagnosis of amalgam tattoo, the clinician  can obtain radiographs of the areas of mucosal discoloration  in an attempt to demonstrate the metallic fragments. The  films should be capable of high detail, because many of the  fragments are no larger than the point of a pin.   No treatment is required if the fragments can be detected  radiographically. If no metallic fragments are found and the  lesion cannot be diagnosed clinically, then biopsy may be  needed to rule out the possibility of melanocytic neoplasia.  On occasion, the amalgam implantation may create pig-  mentation in a cosmetically objectionable location such as  the anterior maxillary facial gingiva. In such cases, conserva-  tive surgical excision can be performed; alternatively  amalgam tattoos have been removed successfully with  Q-switched ruby or alexandrite lasers. With respect to cos-  metic tattoos, a variety of treatments such as corticosteroids  and lasers have been used with variable results.    Historical evidence from almost every continent shows that  body piercing is an ancient practice with a strong associa-  tion with religious, cultural, or superstitious beliefs. In the  Western world, body piercing beyond the earlobes has  become increasingly popular as a method of self-expression  in recent years. In a survey of 481 college students in the  United States, 51% admitted body piercing, and the preva-  lence still appears to be rising. Usually, the piercing is per-  formed to place jewelry in sites such as the eyebrows, helix  of the ears, nose, navel, nipples, genitals, and a number of  intraoral sites.   Forked tongue (split tongue, bifid tongue) is a rather  recent addition to the art of body modification, with few  associated publications. In this practice the anterior one-  third of the tongue is split down the middle. This has been  performed slowly by pulling fishing line through a pierced  hole and tightening the loop over a period of 3 weeks or  using a surgical instrument or laser to quickly separate the  two halves. Some form of cautery is necessary to prevent  the halves from reuniting. Forked tongue also has been  reported as a complication of tongue piercing.    Another practice with unique orofacial manifestations is  implantation of a form of talisman (magical charm) called  susuk (charm needles, charm pins). This practice is  common in Southeast Asia, especially Malaysia, Thailand,  Singapore, Indonesia, and Brunei. The susuk is placed by a  native magician or medicine man termed bomoh and is  thought to enhance or preserve beauty, relieve pain, bring  success in business, or provide protection against harm. The  majority of the individuals with susuk are Muslims, although  Islam strictly prohibits black magic. Therefore, many  affected individuals will deny placement of susuk, even  when confronted directly with hard evidence.    Intraoral piercings are noted most frequently in adolescents  and young adults, with a female predominance. The most  commonly affected sites are the tongue, lips, buccal mucosa,  and, rarely, the uvula. If no complications occur, healing of  the piercing site takes place within 4 to 6 weeks. Currently,  the jewelry most often is niobium, surgical steel, or tita-  nium; however, a wide variety of materials such as horn,  ivory, plastic, stone, wood, aluminum, brass, copper wire,  platinum, silver, and gold are used. In the tongue, the most  frequent adornment is a barbell (Dumbbell might be a  better name!) consisting of a metal rod with a ball that  screws onto each end (Fig. 8-56). The lip jewelry is termed  a labret and most often consists of a ring or a rod with a  flat end attached to the mucosal side and a round ball for  the cutaneous surface (Fig. 8-57).   In a review of US hospital emergency departments from  2002 to 2008, an estimated 24,459 patients presented with  oral piercing-related injuries. Complications during the pro-  cedure include bleeding, nerve damage, localized infection,  and the risk of transmission of infectious diseases, such as  hepatitis or HIV. Immediate postoperative complications  include pain, swelling, hematoma formation, increased  salivary flow, speech impediment, and a local allergic  reaction. Serious complications such as Ludwig angina,  infective endocarditis, and fatal brain abscesses have been    @ Fig. 8-56 Lingual Piercing. Tongue pierced with a jewelry item  known as a barbell.    documented. Chronic complications include mucosal or  gingival trauma, chipped or fractured teeth, hypersalivation,  aspiration or swallowing of jewelry, tissue hyperplasia around  the posts, and embedded jewelry. Gingival recession (labrets,  barbells) and tooth fracture (barbells) are extremely common,  with the prevalence closely related to the duration of use.  Habitual biting or chewing the jewelry often is associated  with severe dental abrasion or movement of teeth. A fatal  squamous cell carcinoma of the tongue arising at the site of  a metal piercing has been reported in a 26-year-old patient.   In individuals with forked tongues, the anterior half of  the tongue is split down the middle (Fig. 8-58). Risks of  the procedure include inflammation, infection, profuse or  prolonged hemorrhage, and permanent neurovascular  damage. After healing, some individuals have developed the  ability to control each half independently.   Susuk usually is shaped like a needle that is pointed on  one end and blunt on the other. Most are made from silver  or gold, measure 0.5 mm in diameter, and vary from 0.5 to  1.0 cm in length. Rarely, they are made from diamonds.  ‘The pins vary in number from one to many and are inserted  subcutaneously, often in a symmetrical fashion. The    ° Fig. 8-57 Labial Piercing. Lower lip pierced bilaterally with labrets  consisting of a circular rod with terminating balls. The patient also has  a lingual barbell.    orofacial region is the most common location (forehead,  cheeks, and lips), but some choose the chest, arms, breasts,  pubic region, and spinal area. In most instances, the indi-  viduals are middle-aged adults. Normally, no clinical evi-  dence exists, either visually or by palpation, and the pins  are discovered during routine radiography for unrelated  medical or dental problems (Fig. 8-59).    As mentioned, intraoral barbells and labrets are associated  with an increasing prevalence of oral complications that  relate closely with duration of use. The patient should be  strongly encouraged to remove the jewelry. On removal, if  the site demonstrates significant inflammation, local  débridement, antibiotic therapy, and chlorhexidine mouth-  wash may be appropriate.   Except for slight sibilant distortions and shortening of  the protrusive length of the tongue, few long-term adverse  events have been noted in patients with forked tongues.   Susuk have not been associated with harmful effects, and  no treatment is required. If the needles have a ferrous    @ Fig. 8-58 Forked Tongue. Anterior portion of the tongue divided  into two separate lobes, each of which can be controlled indepen-  dently. (Courtesy of Dr. Fleming Chisholm.)    @ Fig. 8-59 Susuk (Charm Needles). Panoramic radiograph showing multiple radiopaque needles  superimposed on the jaws. (Courtesy of Dr. Jeff Bayme.)    content, then magnetic resonance imaging (MRI) would be  contraindicated. On occasion, affected individuals request  removal of the susuk before they die because they believe  their death will be excruciatingly painful. In spite of this,  the needles should not be removed without consent.    In recent years, oral health care providers have encountered  a variety of oral lesions secondary to injection of cosmetic  fillers. These substances are used to augment the lips, cheeks,  and chin or utilized to minimize skin folds in the forehead,  around the nose, and perioral surfaces. Nonpermanent  fillers such as collagen, fat transfer, dextran, hyaluronic acid  (Restylane, Juvederm), and poly-L-lactic acid (Sculptra)  usually are biodegraded over several months to years. Per-  manent fillers such as liquid silicone, polyacrylamide  (Aquamid), polytetrafluoroethylene (GORE-TEX, Soft-  Form), polymethylmethacrylate (Artecoll, ArteFill), and  hydroxyapatite (Radiesse) cannot be metabolized and typi-  cally are encased by fibrous tissue, often intermixed with  granulomatous inflammation. Although liquid silicone is  no longer approved by the FDA due to major safety con-  cerns, this material continues to be discovered in patients  who received the filler prior to the current ban. Problems  have occurred when these materials present as tumor-like  masses in patients who do not make the connection to their  previous cosmetic procedure or are reluctant to mention  prior use of dermal filler. In order to help pathologists  identify these various compounds, an online atlas of foreign  materials has been established by the American Academy of  Oral & Maxillofacial Pathology (AAOMP).    Acute adverse reactions are the most common and include  bruising, erythema, itching, pain, and localized infection.  Severe adverse reactions occur with some materials but  are rare. These reactions include local allergic response,  anaphylaxis, arthralgia, myalgia, retinal artery thrombosis,  facial paralysis, and renal failure. The most common  presentations in the dental office are latent tumor-like  nodules usually presenting in the lips, anterior buccal  mucosa, and mandibular vestibule (Fig. 8-60). In patients  with hydroxyapatite filler, clusters of radiopaque material  have been discovered on panoramic and cone beam  radiographs.    The histopathologic features are variable but often distinc-  tive. In many cases, the identification of the specific material  by the pathologist allows the clinician to present the patient  with a brand name that often convinces the reluctant indi-  vidual to admit a previous cosmetic procedure.    ® Fig. 8-60 Cosmetic Filler Material. Yellow submucosal mass of  the mandibular labial vestibule. Biopsy revealed hydroxyapatite  (Radiesse) with fibrosis and granulomatous inflammation. (From Daley  T, Damm DD, Haden JA, et al: Oral lesions associated with injected  hydroxyapatite cosmetic filler, Oral Surg Oral Med Oral Pathol Oral  Radiol 114:107-111, 2012.)    The nonpermanent filler, hyaluronic acid, is non-  immunogenic and presents as pools of amorphous and  lightly basophilic material surrounded by dense bands of  collagen without a foreign body reaction. Poly-L-lactic acid  and most of the permanent materials are surrounded  by dense collagen and granulomatous inflammation  (Fig. 8-61). In many instances, the microscopic appearance  of the material is sufficient for identification.    In many instances, the diagnostic biopsy is excisional and  completely eradicates the problematic mass. In patients  with larger lesions, surgical excision can be problematic due  to numerous finger-like extensions of the material into the  surrounding tissues. Intralesional or systematic corticoste-  roids have resulted in a satisfactory reduction in lesional size  in many patients. Other therapeutic approaches include  locally injected 5-fluorouracil and antibiotics, such as  clindamycin or minocycline.    Ingestion or exposure to any one of several heavy metals can  cause significant systemic and oral abnormalities. Exposure  to heavy metals may be massive, resulting in acute reactions,  or it may be minimal over a longer period, producing  chronic changes. Oral alterations from ingestion of lead,  mercury, silver, bismuth, arsenic, and gold are rare but may  occur and warrant discussion. Oral complications from  excessive zinc, iron, tin, and manganese are extremely rare.    Little is known about the prevalence of lead poisoning  (plumbism), but lead is one of the most widespread envi-  ronmental toxins affecting children in the United States.    e Fig. 8-61 Cosmetic Filler Material. Cosmetic filler materials  embedded in dense fibrous connective tissue with associated granu-  lomatous inflammation. A, Hydroxyapatite (Radiesse) as seen in the  biopsy of lesion depicted in Fig. 8-60. B, Different patient exhibiting  polymethylmethacrylate (ArteFill). C, Different patient exhibiting poly-L-  lactic acid (Sculptra).    Lead solder for plumbing was not banned until 1986.  Homes built before then have the potential for significant  water contamination, and one of the primary causes of lead  intoxication in infants is formula preparation using tap  water tainted by the metal.   Another significant source of lead poisoning in children  is lead-based paint; children may ingest chips of the paint  in older homes or be exposed to the fumes or dust during  sanding and renovation. Paint with a high lead content was  not restricted until 1977 and still remains in many homes.  Removal of lead from gasoline began in 1972 but was not  completed in the United States until 1995.   Adult exposure also occurs and often is related to indus-  try. The potential for exposure exists during handling of lead  oxide batteries, in lead-processing industries, and from the  welding of lead-covered surfaces. Some food and drink con-  tainers or vegetables grown in lead-contaminated soil also  may contain inappropriate levels of the metal. Lead con-  tamination in illicit alcohol has made the distinction  between symptoms of lead intoxication and chronic alcohol  abuse very difficult in certain sections of the American Deep  South. Lead also can be found in brass fixtures, ceramics,  crystal, electrical cable, radiation shielding, folk remedies,  and cosmetics. Rarely, plumbism arises from retained lead  bullet fragments in gunshot victims.    The danger of mercury exposure is well known. Elemental  mercury is poorly absorbed, and its ingestion is relatively  harmless. In contrast, inhalation of mercury vapor is very  hazardous, with a high rate of absorption and systemic  retention. Ingestion of mercury salts (e.g., mercurous chlo-  tide) also is associated with significant adverse reactions.  Exposure has occurred in association with the use of mercury  in teething powders, baby powders, diapers, cathartic  agents, and anthelmintic preparations. Investigators also  have implicated thimerosal, an ethyl mercury antiseptic uti-  lized in some vaccinations.   A great deal of attention has been directed toward the  mercury released from dental amalgams, but no well-  documented adverse health effects have been identified  (except for relatively rare contact hypersensitivity to mercury,  see page 324). The level of mercury that is released from  amalgams has been shown not to exceed the range expected  from background exposure to environmental mercury. In  2009, the FDA issued a final regulation on dental amalgam,  which stated the levels of mercury released by dental  amalgam fillings are not high enough to cause harm in  patients. In an attempt to shed light on this controversy, the  National Institutes of Health (NIH) funded two large ran-  domized clinical trials that compared the neurologic and  renal effects of dental amalgam in a 7-year study of a large  cohort of children. In these pivotal investigations, no  adverse effects from dental amalgam were seen. Interest-  ingly, the control group that received only composite resto-  rations demonstrated a 50% higher need for additional  restorative treatment because of the failure of their restora-  tions during the long-term study.    Silver has known antibacterial properties and has been asso-  ciated with a number of additional health benefits. In the  past, silver compounds were used topically in nose drops  and systemically for a variety of disorders including mental  illness, epilepsy, nicotine addition, common colds, sinusitis,  gastrointestinal ulcerations, syphilis, and gonorrhea. Because  of the numerous complications, including silver intoxica-  tion, in 1999 the FDA concluded that colloidal silver or  silver salts generally are not recognized as safe and effective  and are misbranded. Several silver nitrate and silver sulfa-  diazine formulations remain available by prescription. These  products should be used only under strict supervision. Well-  documented examples of generalized argyria have been seen  secondary to long-term treatment of aphthous ulcerations,  denture sores, and minor gingival hemorrhage with topical  silver nitrate.   Despite the efforts of the FDA, devices for production  of homemade colloidal silver suspension and a number of  colloidal silver formulations continue to be marketed over  the Internet and in health food stores as essential mineral  supplements for diseases such as arthritis, cancer, diabetes,    AIDS, and herpes. These unregulated silver products have  no known physiologic function, and their continued use  cannot be supported.    In the United States, excess exposure to bismuth and arsenic  currently is rare. The medical use of these metals has dimin-  ished dramatically. Most current cases arise from occupa-  tional exposure except for excessive arsenic in drinking  water seen predominantly in isolated areas of India and  Southeast Asia. Bismuth was used in the past for treatment  of venereal diseases and various dermatoses, whereas arsenic  compounds were prescribed for asthma and skin disorders,  such as psoriasis. Bismuth iodoform paraffin paste contin-  ues to be used by otolaryngologists and oral surgeons as a  surgical pack, with rare reports of associated toxicity. In  addition, bismuth subsalicylate tablets (Pepto-Bismol) have  been reported to produce localized mucosal discoloration.  Chronic exposure to arsenic continues in some lesser devel-  oped areas of the world from drinking contaminated water.    Gold has been used in medical treatment in the past and  continues to be used today in selected cases of active rheu-  matoid arthritis and other immunologically mediated dis-  eases. In these cases the side effects are well known, and  physicians observe the patients closely. In reviews of large-  scale skin testing, gold has been found to be among the top  ten most frequent allergens, with positive reactions seen in  about 10% of the population, including increased preva-  lence in patients who have gold dental restorations.    Lead poisoning results in nonspecific systemic signs and  symptoms, thereby making the ultimate diagnosis very dif-  ficult. The presentation is extremely variable and deter-  mined by the type of lead and the age of the patient.  Patients with acute cases most often have abdominal colic,  which may occur along with anemia, fatigue, irritability,  and weakness. Encephalopathy and renal dysfunction also  may occur. Chronic exposure causes dysfunction of the  nervous system, kidneys, marrow, bone, and joints. Symp-  toms generally include fatigue, musculoskeletal pain, and  headache. Bones and teeth represent a major reservoir in  patients with chronic plumbism, with 90% of the body’s  deposition being within bone. In radiographs of the long  bones in infants, a radiopaque lead line often is noted along  the epiphyseal plates.   Oral manifestations include ulcerative stomatitis and a  gingival lead line (Burton line). The lead line appears as a  bluish line along the marginal gingiva resulting from the  action of bacterial hydrogen sulfide on lead in the gingival  sulcus to produce a precipitate of lead sulfide. Gray areas  also may be noted on the buccal mucosa and tongue.    Mercury poisoning also may be acute or chronic. With  acute cases, abdominal pain, vomiting, diarrhea, thirst,  pharyngitis, and gingivitis typically are present. With  chronic cases, gastrointestinal upset and numerous neuro-  logic symptoms occur. The neurologic symptoms are termed  erethism and include excitability, tremors, memory loss,  insomnia, shyness, weakness, and delirium. Because mercury  salts formerly were used in the processing of felt, hat makers  in past centuries were exposed to the metal and experienced  similar symptoms, giving rise to the phrase “mad as a hatter.”  Oral changes include a metallic taste and ulcerative stoma-  titis combined with inflammation and enlargement of the  salivary glands, gingiva, and tongue. The gingiva may  become blue-gray to black. Mercuric sulfide can be gener-  ated by the bacterial action on the metal and can cause  significant destruction of the alveolar bone with resultant  exfoliation of teeth.   Chronic mercury exposure in infants and children is  termed acrodynia (pink disease or Swift-Feer disease). An  erythematous and pruritic rash is present, often with des-  quamation of the palms and soles. Severe sweating, increased  lacrimation, photophobia, neurologic symptoms, hyperten-  sion, tachycardia, and gastrointestinal upset also may be  present. On occasion, these highly irritable children have  torn out patches of their hair. Oral signs include excessive  salivation, ulcerative gingivitis, bruxism, and premature loss  of teeth. The triad of red, painful desquamating fingers and  toes, neurologic symptoms, and hypertension should warn  of the possibility of mercury intoxication. Overlap with  Kawasaki disease has been noted, suggesting evaluation  of 24-hour urine mercury levels when considering that  diagnosis.    Acute silver intoxication can produce coma, pleural edema,  hemolysis, and bone marrow failure. Chronic systemic silver  intoxication is known as argyria and may have toxic effects  on the liver, spleen, kidney, intestinal tract, and respiratory  system. Silver is disseminated throughout the body with  substantial amounts accumulating as subepithelial deposits  in the skin. These deposits result in a diffuse grayish discol-  oration that develops primarily in the sun-exposed areas  (Fig. 8-62). The conjunctivae, sclerae, and nails also may be  pigmented. One of the first signs of argyria occurs in the  oral cavity and appears as a slate-blue silver line along the  gingival margins. This discoloration is secondary to deposi-  tion of metallic silver and silver sulfide pigments. In addi-  tion, the oral mucosa often exhibits a diffuse blue-black  discoloration.    Systemic bismuth toxicity presents with confusion, enceph-  alopathy, hepatorenal impairment, and methemoglobin-  emia. Chronic bismuth exposure also can result in a diffuse  blue-gray discoloration of the skin, conjunctivae, or oral    ® Fig. 8-62 Argyria. Grayish discoloration of the face compared with  a more normal facial complexion in an individual who used a silver-  containing nutritional supplement. Before development of silver intoxi-  cation, this blue-eyed, red-haired individual had a very light complexion.  (Courtesy of Bradford R. Williams.)    cavity. A blue-gray line along the gingival margin similar to  that seen from lead intoxication is the most common intra-  oral presentation. Associated ptyalism, burning, stomatitis,  and ulceration may be seen. Intoxication from bismuth-  containing surgical packs has been associated with CNS  symptoms, such as delirium. Chronic use of bismuth sub-  salicylate tablets can create a removable black discoloration  of the otherwise normal filiform papillae (see Fig. 1-26,  page 13).    Arsenic is a potent human carcinogen associated with  cancers of the skin, lungs, kidney, urinary bladder, and pos-  sibly liver. Additional health effects from chronic excess  arsenic include hypertension, diabetes mellitus, neurologic  abnormalities, and disorders of the cardiovascular, pulmo-  nary, hepatic, and renal systems. Progressive arterial occlu-  sion can result in dry gangrene and spontaneous amputation  of extremities, which has been termed “blackfoot disease.”  Significant cutaneous hyperkeratosis and a diffuse macular  hyperpigmentation are seen frequently. The discoloration  rarely may involve the oral mucosa and is due to both the  presence of the metal and an increased melanin production.  Additional oral manifestations are very uncommon and  typically appear as excessive salivation and painful areas of  necrotizing ulcerative stomatitis. In the past, extensive  dorsal hyperkeratosis of the tongue was seen in patients with  syphilis and may be related to arsenic therapy used before  the advent of antibiotic therapy.    The most common complication of gold therapy is derma-  titis, which often is preceded by a warning signal: pruritus.  Although a generalized exfoliative dermatitis with resultant  alopecia and loss of nails can be seen, dermatitis about the  face, eyelids, and at direct sites of skin contact is the most  common presentation. Because of the high frequency of    allergy to gold, skin testing often is performed before  administration of gold drug therapy.   The second most common adverse reaction to gold is  severe oral mucositis, which most frequently involves the  buccal mucosa, lateral border of the tongue, palate, and  pharynx. These mucosal changes represent a systemic aller-  gic reaction and are different from intraoral contact gold  hypersensitivity (see page 317). A metallic taste often pre-  cedes development of the oral lesions and should be con-  sidered another warning signal. Therapy with gold rarely  can bring about a slate-blue discoloration of sun-exposed  skin (chrysiasis).    The management of heavy metal intoxication involves  removal from further exposure to the agent, supportive care,  decontamination, and use of chelating agents. In some cases  a medication may be responsible and can be discontinued;  however, sometimes the source of the metal may be difficult  to determine. In infants with radiographic evidence of gas-  trointestinal lead-containing paint chips, bowel irrigation  with a polyethylene glycol electrolyte lavage solution may  be warranted. In the past, two chelators, ethylenediamine-  tetraacetic acid (EDTA) (calcium disodium ethylenediami-  netetraacetate) and BAL (2,3-dimercaptopropanol), were  first-line therapy in the treatment of lead poisoning, whereas  arsenic and mercury intoxication were treated with BAL.  These medications may have significant side effects, and less  toxic alternatives such as DMSA (2,3-dimercaptosuccinic  acid) and DMPS (2,3-dimercaptopropane-1-sulfonate)  now are available. No antidote exists for silver intoxication.  Attempts to remove the bluish discoloration of facial argyria  with dermabrasion have been unsuccessful. Sunscreen,  avoiding sunlight, and cosmetics may be somewhat benefi-  cial in minimizing the skin discoloration. Several publica-  tions have documented successful treatment of facial argyria  with a low-fluence Q-switched 1064-nm Nd:YAG laser.  Encephalopathy associated with use of bismuth-containing  surgical packs clears on removal of the material, often com-  bined with use of DMPS.    Oral pigmentations are increased significantly in heavy  smokers. In one investigation of more than 31,000 whites,  21.5% of tobacco smokers exhibited areas of melanin pig-  mentation compared with 3% among those not using  tobacco. In another study of an ethnically pigmented popu-  lation, smokers had more oral surfaces exhibiting melanin  pigmentation.   Melanin pigmentation in the skin exerts a well-known  protective effect against ultraviolet (UV) damage. Investiga-  tions of melanocytes located away from sun-exposed areas  have shown the ability of melanin to bind to noxious  substances. Exposure to polycyclic amines (e.g., nicotine  and benzpyrene) has been shown to stimulate melanin    ® Fig. 8-63 Smoker’s Melanosis. Light, diffuse melanin pigmenta-  tion in a white female who is a heavy smoker. Pigmentary changes are  limited to the anterior facial gingiva.    production by melanocytes that also are known to bind  strongly to nicotine. Research has suggested that melanin  production in the oral mucosa of smokers serves as a protec-  tive response against some of the harmful substances  in tobacco smoke. This concept is supported by the findings  in “reverse” smokers, who smoke with the lit end of  the cigarette inside the mouth and demonstrate heavy  melanin pigmentation of the palate. In some reverse  smokers, areas of melanocytes are lost and zones of depig-  mented red mucosa can develop. Cancer is found in 12%  of patients with these red zones, further delineating the  probable protective effects of melanocytes against toxic  substances.    Although any mucosal surface may be affected, smoker's  melanosis most commonly affects the anterior facial gingiva  (Fig. 8-63). Most people affected by this condition are ciga-  rette users. In contrast, pipe smokers frequently exhibit  pigmentations located on the commissural and_ buccal  mucosae. Reverse smokers show alterations of the hard  palate.   The areas of pigmentation significantly increase during  the first year of smoking and appear correlated to the  number of cigarettes smoked each day. A higher frequency  is seen in females, and researchers have suggested that  female sex hormones exert a synergistic effect when com-  bined with smoking. Reports from Sweden, Germany, and  Japan have shown tobacco smoking to be the most common  cause for mucosal pigmentation in light-skinned adult  populations.    Biopsy specimens of affected areas in people with smoker's  melanosis reveal increased melanin pigmentation of the basal  cell layer of the surface epithelium, similar to a melanotic  macule (see page 348). In addition, collections of inconti-    nent melanin pigmentation are seen free within the superfi-  cial connective tissue and in scattered melanophages.    The clinician can make the diagnosis by correlating the  smoking history with the clinical presentation and medical  history. Other causes of melanin pigmentation, such as  trauma, neurofibromatosis, Peutz-Jeghers syndrome, drug-  related pigmentation, endocrine disturbances, hemochro-  matosis, chronic pulmonary disease, and racial pigmentation    Cessation of smoking results in gradual disappearance of  the areas of related pigmentation over a 3-year period.  Biopsy should be considered when the pigmentation is in  unexpected locations, such as the hard palate, or when there  are unusual clinical changes, such as increased melanin  density or surface elevation.    An expanding number of medications have been implicated  as a cause of oral mucosal discolorations. Although many  medications stimulate melanin production by melanocytes,  deposition of drug metabolites is responsible for the color  change in others. These pigmentary alterations have been  associated with use of phenolphthalein, minocycline, tran-  quilizers, antimalarial medications, estrogen, chemothera-  peutic agents, and some medications used in the treatment  of patients with AIDS.   The antimalarial agents that are most frequently impli-  cated are chloroquine, hydrochloroquine, quinidine, and  quinacrine; chlorpromazine represents the most frequently  implicated tranquilizer. Besides treating malaria, antima-  larial agents are used for many other disorders, including  lupus erythematosus and rheumatoid arthritis.   Oral mucosal pigmentation also has been associated with  the use of chemotherapeutic medications, such as doxoru-  bicin, busulfan, cyclophosphamide, 5-fluorouracil, or ima-  tinib. Although idiopathic hyperpigmentation also may  occur, AIDS patients receiving zidovudine (AZT), clofazi-  mine, or ketoconazole have demonstrated increased melanin  pigmentation.    The clinical presentations of pigmentations related to drug  use vary. Most agents produce a diffuse melanosis of the  skin and mucosal surfaces, but others may cause a unique  pattern. As in many cases of increased melanin pigmenta-  tion, females are more sensitive, most likely as a result of an  interaction with sex hormones.    ® Fig. 8-64 Minocycline-related Discoloration. Blue-gray discol-  oration of the facial surface of the anterior mandibular alveolus because  stained alveolar bone is visible through the thin mucosa.    Use of phenolphthalein as a laxative has been associated  with numerous small, well-circumscribed areas of hyperpig-  mentation on the skin. Similar areas of oral mucosal mela-  nosis also can occur. Administration of peginterferon alfa  in ethnically pigmented patients with hepatitis C has been  associated with hyperpigmentation of the scattered filiform  papillae on dorsal surface of the tongue.   Long-term use of minocycline, a semisynthetic derivative  of tetracycline, results in discoloration of the bone and  developing teeth. The affected bone is dark green but creates  a blue-gray discoloration as seen through the translucent  oral mucosa. The most common presentations include a  linear band above the facial attached gingiva near the muco-  gingival junction and a broad zone of discoloration on the  hard palate (Fig. 8-64). In addition, the dental pulp can  become darkly stained, leading to clinically obvious dark-  ened teeth (see page 65).   Minocycline-related pigmentation of the skin and oral  mucosa unrelated to discoloration of the underlying bone  also has been reported, with patients exhibiting either wide-  spread increased melanosis or focal accumulations of iron-  containing particles (Figs. 8-65 and 8-66). The cutaneous  pigmentation appears to be dose-dependent and is seen in  up to 15% of patients being treated for acne and as many  as 70% of those treated for rheumatoid arthritis. Although  the cutaneous and oral mucosal staining fades after discon-  tinuation of the medication, the dental discoloration  remains.   The classic presentation of intraoral pigmentation from  use of antimalarial medications or tranquilizers is a blue-  black discoloration limited to the hard palate (Fig. 8-67).  In addition, the intake of antimalarial medications may  occasionally lead to a more diffuse brown melanosis of the  oral mucosa and skin.   Estrogen, chemotherapeutic agents, and medications  used in the treatment of AIDS patients may result in a  diffuse brown melanosis of the skin and mucosal surfaces.  Any mucosal surface may be involved, but the attached    e Fig. 8-65 Minocycline-associated Pigmentation. Sharply  demarcated brown pigmentation on the vermilion border of the lips,  which arose in association with long-term minocycline use and is the  result of increased melanin deposition.    e Fig. 8-66 Minocycline-associated Pigmentation. Multifocal  areas of palatal pigmentation secondary to deposition of drug metabo-  lites chelated to iron in association with long-term minocycline use.  (From Treister NS, Magalnick D, Woo S-B: Oral mucosal pigmentation  secondary to minocycline therapy: report of two cases and a review  of the literature, Oral Surg Oral Med Oral Pathol Oral Radiol Endod  97:718-725, 2004.)    gingiva and buccal mucosa are most frequently affected. The  pattern and appearance of the oral mucosal involvement are  similar to those seen in racial pigmentation.    Although the discolorations of the oral mucosa may be  aesthetically displeasing, they cause no long-term problems.  In most instances, discontinuing the medication results in  gradual fading of the areas of hyperpigmentation.    @ Fig. 8-67 Hydroxychloroquine Pigmentation. Diffuse grayish  pigmentation of the hard palate. (Courtesy of Dr. John Wright.)    On occasion, cartilage or bone may be discovered within  soft tissue specimens removed from the oral cavity. Carti-  laginous rests are known to exist in the area of the nasopala-  tine duct. In the past, several investigators have reported the  presence of cartilage within flabby soft tissue removed from  maxillary edentulous alveolar ridges of long-term denture  wearers. This finding was thought to represent cartilaginous  metaplasia secondary to chronic denture trauma. In retro-  spect, the islands of cartilage within these cases most likely  represent embryologic remnants, not traumatic metaplasia.  These rests also are occasionally discovered during histo-  pathologic examination of nasopalatine duct cysts and max-  illary gingivectomy specimens.   Despite the suggestion that the anterior maxillary lesions  are embryologic and not traumatic, development of osseous  and chondromatous metaplasia from mechanical denture  irritation does occur. Although such metaplasia is probably  uncommon in the anterior maxilla, its development is not  rare along the crest of the posterior mandibular alveolar  ridge in long-term denture wearers with atrophic ridges.    In patients with reactive osseous and chondromatous meta-  plasia, an extremely tender and localized area of the alveolar  ridge typically is noted that may be associated with local  enlargement (Fig. 8-68). These changes almost always arise  in patients with extensive atrophy of the mandibular alveo-  lar ridge leading to a knife edge—like crest. Although most  examples involve the posterior mandible, similar areas rarely  may be seen overlying the maxillary alveolar ridge or associ-  ated with anterior portions of the mandible. Because of  significant associated symptoms and occasional enlarge-  ment, biopsy frequently is performed.    ° Fig. 8-68 Periosteal Hyperplasia with Osseous And Chon-  dromatous Metaplasia. Tender, elevated nodule along the thin crest  of the mandibular alveolar ridge. (Courtesy of Dr. Steven Tucker.)    Histopathologic examination of reactive osseous and chon-  dromatous metaplasia typically demonstrates a mass of  hypercellular periosteum that blends into areas of osseous  and chondromatous tissue. The bone and cartilage fre-  quently exhibit atypical features, such as hypercellularity,  pleomorphism, nuclear hyperchromatism, and occasional  binucleated or multinucleated cells (Fig. 8-69). These altera-  tions are worrisome for sarcoma, but the appropriate diag-  nosis can be made when an appropriate clinicopathologic  correlation is made. In contrast, the cartilaginous rest dis-  covered incidentally in maxillary specimens is usually very  bland without any atypical features that would suggest  malignancy.    The thin mandibular ridges may be recontoured or supple-  mented with graft material to improve shape and to alleviate  the symptoms associated with the localized periosteal hyper-  plasia. Implants also may reduce the traumatic injury to the  ridge and lessen the chance of recurrence. If the ridge    modification is not made, then the continued injury to the  site occasionally results in recurrence of the lesion.    Focal superficial sequestration of a fragment of cortical bone  not related to systemic disease, infection, or a major trau-  matic event is uncommon. In such instances, the cause of  the focal osteonecrosis is not known, although many believe  the primary event is a traumatic or aphthous ulceration that  leads to osteitis and necrosis of a small focus of adjacent  cortical bone. Others have suggested the blood supply of  the peripheral cortical plate may be delivered by the peri-  osteal microvasculature, and loss of this supply leads to focal  bone necrosis and sequestration. Such lesions tend to occur  in anatomically unique sites in which a bony prominence  is covered by a thin mucosal surface.    In most instances, the sequestration arises without the  patient’s awareness of any preceding trauma. The most fre-  quent site of sequestrum development is the lingual surface  of the posterior mandible along the mylohyoid ridge (Fig.  8-70). Focal involvement of exostoses also may occur.  Although any exostosis may be involved, mandibular tori  are affected most frequently.   The overlying mucosa typically demonstrates a focal area  of ulceration that has been present for a period of time that  varies from a few days to several months. The presence and  intensity of associated pain are variable. Although most  cases are unilateral, bilateral involvement may occur. On  occasion, an occlusal radiograph will reveal a faint radi-  opaque mass superimposed and partially lingual to the  intact cortical plate.    ® Fig. 8-70 Spontaneous Sequestration. Mucosal ulceration with  exposed bone of the posterior lingual surface of the mandible.    The mylohyoid ridge often is prominent but typically  protected from trauma by the lingual inclination of the  adjacent molars. Absence of the adjacent molars or restora-  tions that do not replace the normal inclination could pre-  dispose the area to repeated trauma; such alterations have  been noted in the majority of affected patients.    The sequestra consist of well-organized lamellar bone that  exhibits loss of the osteocytes from their lacunae, along with  peripheral resorption and bacterial colonization.    Spontaneous loss of the dead bone or surgical removal of  the sequestrum results in rapid healing. Recurrence is  uncommon. In some instances, the dead bone is freely  movable and easily removed. In other cases, the fragment is  adherent to the underlying vital bone and must be surgically  excised. In an attempt to avoid surgery, some clinicians use  a tetracycline rinse in addition to topical corticosteroids.  Alternatively, these patients can be recalled weekly for 2 to  4 weeks, during which time the dead bone may exfoliate  spontaneously without the need for invasive therapy.    Antral pseudocysts are common findings on panoramic  radiographs. The lesion appears as a dome-shaped, faintly  radiopaque lesion often arising from the floor of the maxil-  lary sinus. This condition continues to be misunderstood  and is inappropriately termed sinus mucocele or sinus  retention cyst by many clinicians (see next section). The  antral pseudocyst develops due to an accumulation of an  inflammatory exudate (serum, not mucus) beneath the  maxillary sinus mucosa, causing a sessile elevation (Fig.  8-71). It must be stressed that the edematous fluid is in the  stroma underneath the epithelium, not surrounded by it.   Reviews of large numbers of radiographs have reported  a prevalence that ranges from 1.5% to 14% of the popula-  tion. The cause of the inflammatory infiltrate has not been  determined definitively, but in a radiographic review, many  cases showed a possible source from an adjacent odonto-  genic infection. Primary irritation of the sinus lining, such  as that seen from a sinus infection or allergies, also can  theoretically result in the inflammatory infiltrate.   An increased prevalence of pseudocysts has been noted  during the cold winter months, leading some investigators  to associate these lesions with an increased frequency of  upper respiratory tract infections or irritation from dry,  forced-air heating. This association is difficult to confirm  because these lesions often are asymptomatic, making the  timing of their development difficult to pinpoint. Although  allergies have been proposed as a cause, no increased preva-  lence has been noted during the time of peak pollen  exposure.    cyst  @ Fig. 8-71 Antral Pseudocyst and Surgical Ciliated Cyst. An  antral pseudocyst is an accumulation of serum beneath the sinus  lining. A surgical ciliated cyst is an epithelium-lined cystic structure  separate from the sinus.    e Fig. 8-72 Antral Pseudocyst. Three-dimensional cone-beam  radiograph showing dome-shaped radiopacity within the maxillary  sinus. (Courtesy of Dr. Scott Jenkins and Dr. Nick Morrow.)    Most pseudocysts are asymptomatic. On occasion, affected  patients report symptoms, such as headache, facial sinus  pain, nasal obstruction, postnasal drip, and nasal discharge.  Some studies have suggested these symptoms are secondary  to other sinus disease and are not relieved by removal of the  pseudocyst. Radiographically, an antral pseudocyst typically  presents as a uniform and spherical or dome-shaped  radiodensity arising from the floor of the maxillary sinus  (Figs. 8-72 and 8-73). Maxillary cysts and neoplasms can    ° Fig. 8-73 Antral Pseudocyst. Three-dimensional cone-beam sag-  ittal section of same patient depicted in Fig. 8-72. Note that the floor  of the sinus remains intact below the lesion. (Courtesy of Dr. Scott  Jenkins and Dr. Nick Morrow.)    simulate the dome-shaped pattern of an antral pseudocyst,  but close examination of a pseudocyst typically reveals the  radiopaque floor of the sinus extending over the superior  aspect of the lesion. Less frequently, pseudocysts also may  be arise from the lateral wall, medial wall, or roof of the  antrum.    Antral pseudocysts are covered by sinus epithelium and  demonstrate a subepithelial inflammatory exudate that con-  sists of serum, occasionally intermixed with inflammatory  cells (Fig. 8-74). Collections of cholesterol clefts and scat-  tered small dystrophic calcifications may be seen.    Typically, pseudocysts of the maxillary sinus are harmless,  and no treatment is necessary. The adjacent teeth should be  evaluated thoroughly, and any foci of infection should be  eliminated. A few clinicians prefer to confirm their radio-  graphic impression and rule out a tumor through drainage of  the inflammatory exudate. Removal by means of a Caldwell-  Luc operation endoscopic surgery should be performed on  any radiographically diagnosed lesion that produces signifi-  cant expansion or is associated definitively with symptoms.    ¢ TRUE CYSTS OF THE SINUSES (SINUS  MUCOCELE; SURGICAL CILIATED CYST;  TRAUMATIC CILIATED CYST;  POSTOPERATIVE MAXILLARY CYST;  RETENTION CYST)    In contrast to the antral pseudocyst, which arises from  subepithelial accumulation of edema fluid, true epithelium-  lined cysts also may arise from the sinonasal mucosa and  glands. They occur in three situations.   One type of cyst occurs after trauma or surgery to the  sinus; this type is best known as a surgical ciliated cyst,  traumatic ciliated cyst, or postoperative maxillary cyst.  A portion of the sinus lining becomes separated from the    main body of the sinus and forms an epithelium-lined  cavity into which mucus is secreted. The cyst most fre-  quently originates after a Caldwell-Luc operation but may  arise from difficult extraction of a maxillary tooth in which  the floor of the maxillary sinus is damaged. In addition,  sinus or nasal epithelium rarely can be transplanted acci-  dentally to the mandible during genioplasty or chin aug-  mentation procedures and lead to formation of ciliated cysts  in ectopic locations (Fig. 8-75).   The second type of cyst, known as a sinus mucocele,  arises from an obstruction of the sinus ostium, thereby  blocking normal drainage. This blocked sinus then acts like  a separate cyst-like structure lined by epithelium and filled  with mucus. Sinus mucoceles enlarge in size as the intralu-  minal pressure increases and can distend the walls of the  sinus and erode through bone; they often clinically mimic  malignancy of sinus origin. (It should be emphasized that  asinus mucocele is a distinct, separate pathologic entity that  is unrelated to the common mucocele of minor salivary  gland origin [see page 422]).   Retention cysts of the maxillary sinus are the third type  of true cyst. These lesions arise from the partial blockage of  a seromucous gland duct within the sinus wall, or from an  invagination of the respiratory epithelium. Most retention  cysts are located around the ostium or within antral polyps.  The majority of retention cysts are small, not evident clini-  cally, and discovered during histopathologic examination of  antral polyps.    tory epithelium was carried from LeFort 1 osteotomy site to mandible during genioplasty procedure.    e Fig. 8-76 Surgical Ciliated Cyst. Well-defined radiolucency  between vital maxillary bicuspids. (Courtesy of Dr. Patrick Coleman.)    Postoperative surgical ciliated cysts appear to be uncom-  mon in the United States and Europe but are reported more  frequently in Japan due to the high prevalence of surgical  therapy rather than antibiotic treatment for sinusitis prior  to the 1970s. Sinus mucoceles arising from ostial obstruc-  tion are much more numerous and most frequently involve  the frontal sinus, with the ethmoid and sphenoid sinuses  being affected less often. Maxillary sinus mucoceles arising  from blockage of the ostium are relatively rare and account  for less than 10% of paranasal sinus mucoceles.    Surgical ciliated cysts are spherical lesions that are separate  from the sinus and lack the dome-shaped appearance of  pseudocysts (Fig. 8-76). As these postoperative cysts enlarge,  they can lead to perforation of the sinus walls. When the  maxillary sinus is involved by a true sinus mucocele,  the entire sinus will appear cloudy. As the lesion enlarges,  the walls of the sinus may become thinned and eventually  eroded. Retention cysts rarely reach a size that would  produce detectable radiographic changes.    Surgical ciliated cysts and sinus mucoceles are true cystic  structures lined by ciliated pseudostratified columnar epi-  thelium, squamous epithelium with mucous cells, or meta-  plastic squamous epithelium (Fig. 8-77). A sinus retention  cyst shows focal dilation of a duct associated with the sero-  mucous glands of the sinus lining. The lumen of the dilated  duct is filled with thick mucus, often intermixed with  chronic inflammatory cells.    Because surgical ciliated cysts and sinus mucoceles are  expansile and destructive lesions, the traditional therapy for  these pathoses is assured surgical removal. Numerous inves-  tigators also have shown that sinus mucoceles arising from   ® Fig. 8-77 Surgical Ciliated Cyst. True cyst lined by respiratory  epithelium. Inset provides high-power view of the ciliated pseudostrati-  fied columnar epithelium that lines the cyst.    ostial obstruction often do not require surgical excision, but  they respond well to endoscopic middle meatal antrostomy  and marsupialization of the mucocele.    Cervicofacial emphysema arises from the introduction of  air into subcutaneous or fascial spaces of the face and neck.  The forced air may spread through the spaces to the retro-  pharyngeal and mediastinal areas. The first case was reported  almost 100 years ago and occurred as a result of blowing  into a bugle a short time after tooth extraction.   Cervicofacial emphysema of dental origin may arise in  several ways:  e After the use of compressed air by the clinician  e After difficult or prolonged extractions  e Asa result of increased intraoral pressure (e.g., sneezing,   Introduction of air within tissue has been seen after a  large number of dental procedures, but most instances  involve either surgical extraction of teeth, endodontic pro-  cedures, osteotomies, significant trauma, or the use of air  or water syringes. In addition, the prevalence has increased  as a result of the use of air-driven handpieces during oral  surgery or use of lasers with compressed air systems designed  to remove tissue debris from the operative field. On occa-  sion, cervicofacial emphysema has resulted from compressed  air being accidentally forced into small intraoral lacerations  located away from the field of operation. An analogous  problem termed pneumoparotid can arise when air enters  the parotid duct, leading to enlargement of the parotid  gland caused by air insufflation. This can be accidental,  self-induced, or occupational (e.g., glassblowers and wind  instrument players). Stensen duct has numerous redundant  mucosal folds that seal as intraoral pressure is increased; in  addition, contraction of the buccinator muscle further pre-  vents entrance of air by compressing the duct. In spite of  this protection, dramatic increases in intraoral pressures can  result in air filling the parotid ductal system.    More than 90% of cases of cervicofacial emphysema develop  during surgery or within the first postoperative hour. Cases  with delayed onset are associated with increased postopera-  tive pressure created by the patient. The initial change is one  of soft tissue enlargement from the presence of the air in  deeper tissues (Fig. 8-78). Pain usually is minimal, and crepi-  tus is detected easily with gentle palpation. Subsequently,  the enlargement increases and spreads because of secondary  inflammation and edema. Variable pain, facial erythema,  dysphagia, dysphonia, vision difficulties, and mild fever may  occur. The facial enlargement often is confused with an  angioedema, but the diagnosis can be made by identifying  crepitus within the swelling. In addition, computed tomog-  raphy (CT) using the Hounsfield density measuring scale  can confirm the presence of soft tissue air pockets.   Significant spread into the mediastinum can result in  dysphonia, dysphagia, or dyspnea. Cardiac auscultation  often reveals crepitus synchronous with the heartbeat  (Hamman’s crunch) in cases with mediastinal involvement.  Pneumomediastinum can be confirmed on chest radio-  graphs by observing displacement of the mediastinal  pleura.   Pneumoparotid typically appears as a unilateral enlarge-  ment of the parotid that demonstrates crepitus on  gentle palpation. Milking the parotid duct produces frothy,  air-filled saliva, rather than the typical clear, water-like  secretion.    e Fig. 8-78 Cervicofacial Emphysema. Periorbital and_ facial  enlargement caused by use of an air-driven handpiece during third  molar removal.    Broad-spectrum antibiotic coverage is recommended in all  dental-related cases of cervicofacial emphysema. The body  gradually removes the entrapped air during a 2- to 5-day  period. Most cases spontaneously resolve without signifi-  cant difficulty. Administration of 100% oxygen with a non-  rebreather mask can shorten recovery, because the oxygen  will replace the air (78% nitrogen, 21% oxygen) and is  absorbed more readily. Rare cases of respiratory distress have  been noted, and assisted ventilation was required.   The first goal of therapy for pneumoparotid is discovery  of the inciting event. In occupation-related cases, such as  those seen in trumpet players, the individual should be  coached to compress the cheeks during playing. This pro-  cedure contracts the buccinator muscle and compresses the  parotid duct. Acute symptoms are treated with antibiotics,  massage, hydration, sialogogues, and warm compresses.    Placement of topical antibiotic in a petrolatum base into a  surgical site occasionally may result in a unique foreign  body reaction, known as myospherulosis. The resultant  histopathologic pattern is most unusual and was thought  initially to represent a previously undescribed endosporulat-  ing fungus.    Myospherulosis may occur at any site within soft tissue or  bone where the antibiotic has been placed. Most cases in  the dental literature have occurred within bone at previous  extraction sites where an antibiotic had been placed in an  attempt to prevent alveolar osteitis. Although maxillary and  oral soft tissue examples have been documented, most cases  have occurred within mandibular surgical sites. In addition,  myospherulosis is reported occasionally in a paranasal sinus  after a surgical procedure in which a gauze packing coated  with an antibiotic ointment was used.   The involved area may exhibit swelling or be discovered  as an asymptomatic and circumscribed radiolucency in a  previous extraction site (Fig. 8-79). In some cases, pain and  purulent drainage have resulted. On exploration of the  lesion, a black, greasy, tarlike material is found.    The histopathologic pattern is unique; it is the result of a  tissue interaction with both the petroleum base and the  antibiotic. Dense collagenous tissue is intermixed with a  granulomatous inflammatory response showing macro-  phages and multinucleated giant cells. Within the connective  tissue are multiple cystlike spaces that contain numerous  brown- to black-staining spherules (Fig. 8-80). The collec-  tions of spherules sometimes are surrounded by an outer  membrane known as a parent body, forming structures that  resemble a “bag of marbles.” The spherules represent red    e Fig. 8-79 Myospherulosis. Radiolucency has persisted after  extraction of the mandibular third molar. An antibiotic ointment was  placed at the time of initial surgery.    blood cells that have been altered by the medication. The  unusual dark coloration is due to the degradation of hemo-  globin. To complicate matters, myospherulosis arising in a  paranasal sinus occasionally is contaminated with respiratory  fungal organisms, such as the Zygomycetes or Aspergillus.    Myospherulosis is treated by surgical removal of the foreign  material and associated tissue. Histopathologic examination  of the altered tissue provides the definitive diagnosis. Recur-  rence is not expected. 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Lello GE, Makek M: Submucosal nodular chondrometaplasia in  denture wearers, / Prosthet Dent 54:237—240, 1985.   Magnusson BC, Engstrém H, Kahnberg K-E: Metaplastic formation  of bone and chondroid in flabby ridges, Br J Oral Maxillofac Surg  24:300-305, 1986.   Kessler HP: Lingual mandibular sequestration with ulceration, Tex  Dent J 122:198-199, 206-207, 2005.   Peters E, Lovas GL, Wysocki GP: Lingual mandibular sequestration  and ulceration, Oral Surg Oral Med Oral Pathol Oral Radiol Endod  75:739-743, 1993.   Scully C: Oral ulceration: a new and unusual complication, Br Dent  J 192:139-140, 2002.   Sonnier KE, Horning GM: Spontaneous bony exposure: a report of  4 cases of idiopathic exposure and sequestration of alveolar bone,   Albu S: Symptomatic maxillary sinus retention cysts: should they be  removed, Laryngoscope 120:1904—1909, 2010.   Allard RHB, van der Kwast WAM, van der Waal I: Mucosal antral  cysts: review of the literature and report of a radiographic survey,    Bourgeois SL, Nelson BL: Surgical ciliated cyst of the mandible sec-  ondary to simultaneous LeFort I osteotomy and genioplasty:  report of case and review of the literature, Oral Surg Oral Med  Oral Pathol Oral Radiol Endod 100:36-39, 2005.   Gardner DG: Pseudocysts and retention cysts of the maxillary sinus,  Oral Surg Oral Med Oral Pathol 58:561-567, 1984.   Gardner DG, Gullane PJ: Mucoceles of the maxillary sinus, Oral Surg  Oral Med Oral Pathol 62:538-543, 1986.   Kaneshiro S, Nakajima T, Yoshikawa Y, et al: The postoperative maxil-  lary cyst: report of 71 cases, J Oral Surg 39:191-198, 1981.   Wang JH, Jang YJ, Lee B-J: Natural course of retention cysts of the  maxillary sinus: long-term follow-up results, Laryngoscope 117:   Horowitz I, Hirshberg A, Freedman A: Pneumomediastinum and  subcutaneous emphysema following surgical extraction of man-  dibular third molars: three case reports, Oral Surg Oral Med Oral  Pathol 63:25-28, 1987.   Kim Y, Kim M-R, Kim S-J: Iatrogenic pneumomediastinum with  extensive subcutaneous emphysema after endodontic treatment:  report of 2 cases, Oral Surg Oral Med Oral Pathol Oral Radiol  Endod 109:e114-e119, 2010.   Lépez-Peléez ME, Roldan J, Mateo S: Cervical emphysema, pneumo-  mediastinum, and pneumothorax following self-induced oral    injury: report of four cases and review of the literature, Chest  120:306-309, 2001.   Martin-Granizo R, Herrera M, Garcia-Gonzalez D, et al: Pneumop-  arotid in childhood: report of two cases, J Oral Maxillofac Surg  57:1468-1471, 1999.   Patel N, Lazow SK, Berger J: Cervicofacial subcutaneous emphysema:  case report and review of the literature, J Oral Maxillofac Surg  68:1976-1982, 2010.   Dunlap CL, Barker BF: Myospherulosis of the jaws, Oral Surg Oral  Med Oral Pathol 50:238-243, 1980.   Lynch DP, Newland JR, McClendon JL: Myospherulosis of the  oral hard and soft tissues, J Oral Maxillofac Surg 42:349-355,  1984.   Sarkar S, Gangane N, Sharma S: Myospherulosis of maxillary sinus—a  case report with review of literature, Indian J Pathol Microbiol  41:491-493, 1998.   Sindwani R, Cohen JT, Pilch BZ, et al: Myospherulosis following  sinus surgery: pathological curiosity or important clinical entity,  Laryngoscope 113:1123-1127, 2003.   Wallace ML, Neville BW: Myospherulosis: report of a case, J Peri-  odontol 61:55-57, 1990.    Transient lingual papillitis (lie bumps, tongue torches)  represents a common oral pathosis that rarely has been  documented. Affected patients experience clinical altera-  tions that involve a variable number of fungiform papillae  of the tongue. The pathogenesis currently is unknown, but  the lesions most likely arise from a variety of influences.  Suggested. causes include local irritation, stress, gastrointes-  tinal disease, hormonal fluctuation, upper respiratory tract  infection, viral infection, and topical hypersensitivity to  foods, drinks, or oral hygiene products.    Three patterns of transient lingual papillitis have been docu-  mented. The first pattern is localized and involves one to  several fungiform papillae that become enlarged and present  as elevated papules that are red but may demonstrate a  yellow, ulcerated cap (Fig. 9-1). The lesions appear most  frequently on the anterior portion of the dorsal surface, are  associated with mild to moderate pain, and resolve sponta-  neously within hours to several days. In a survey of 163  dental school staff members, 56% reported previous epi-  sodes of transient lingual papillitis. There was a female  predominance, and the vast majority reported a single  affected papilla. In one report, the occurrence of the lesions  appeared to be associated with a food allergy.   In the second pattern, the involvement is more general-  ized and affects a large percentage of the fungiform papillae  on the tip and lateral portions of the dorsal surface (Fig.  9-2). Individual papillae are very sensitive, enlarged, ery-  thematous, and occasionally display focal surface erosion.  Fever and cervical lymphadenopathy are not rare. In these  cases, spread of the process among family members has been  reported, suggesting a possible correlation to an unknown  virus. Spontaneous resolution occurs in about 7 days with  occasional recurrences reported.   The third pattern of transient lingual papillitis also dem-  onstrates more diffuse involvement. The altered papillae are  asymptomatic, appear as elevated white to yellow papules,  and have been termed the papulokeratotic variant because of  a thickened parakeratotic cap (Fig. 9-3). Although these  lesions could be the result of a topical allergy, the    histopathology demonstrates features similar to chronic  nibbling and suggests the possibility of an unusual pattern  of frictional hyperkeratosis.    On histopathologic examination of the first two variants,  affected papillae demonstrate normal surface epithelium  that may reveal focal areas of exocytosis or ulceration. The  underlying lamina propria exhibits a proliferation of numer-  ous small vascular channels and a mixed inflammatory cel-  lular infiltrate. Investigation for evidence of human  papillomavirus (HPV), herpes simplex, and fungal infesta-  tion has been negative. The papulokeratotic variant demon-  strates marked hyperparakeratosis in which the surface is  ragged and reveals bacterial colonization. A chronic lym-  phocytic infiltrate is noted in the superficial lamina propria  with extension into the basilar portion of the adjacent  epithelium.    Although transient lingual papillitis resolves without  therapy, topical corticosteroids, anesthetics, and coating  agents have been used to reduce the pain or duration. In an  attempt to eliminate the pain, occasional patients have  reported removing the affected papillae with devices such  as fingernail clippers. The papulokeratotic variant is asymp-  tomatic and requires no therapy. Although frequently  unsuccessful, search for a local or systemic triggering event  seems prudent.    Recurrent aphthous stomatitis is one of the most common  oral mucosal pathoses. The reported prevalence in the  general population varies from 5% to 66%, with a mean of  20%. Different subgroups of patients appear to have differ-  ent causes for the occurrence of aphthae. These factors  suggest a common disease process that may be initiated by  a variety of causative agents, each of which is capable of    @ Fig. 9-1 Transient Lingual Papillitis. Tender, yellow-pink papule  on the dorsum of the tongue.    e Fig. 9-2 Transient Lingual Papillitis. Multiple painf  papules on the lateral dorsum and tip of tongue.    ® Fig. 9-3 Transient Lingual Papillitis. Clusters of asymptomatic,  elevated, yellow papules on the dorsolateral surface of the tongue.  (Courtesy of Dr. Craig Fowler.)   Although no single triggering agent is responsible, the  mucosal destruction appears to represent a T cell-mediated  immunologic reaction with production of tumor necrosis  factor-alpha (TNF-a). This factor is a major inflammatory  cytokine and assists in the ultimate targeting of the surface  epithelium for destruction by cytotoxic T cells (CD8+).  Evidence of the destruction of the oral mucosa mediated by  these lymphocytes is strong, but the initiating causes are  elusive and most likely highly variable.   The following all have been reported to be responsible  in certain subgroups of patients (and each discounted in  other subgroups!):  ¢ Allergies  ¢ Genetic predisposition  ¢ Hematologic abnormalities  ¢ Hormonal influences  ¢ Immunologic factors  ¢ Infectious agents  e Nutritional deficiencies  ¢ Smoking cessation  e Stress (mental and physical)   Investigators have theorized that aphthous ulcerations  develop from an immunologic reaction to an oral antigen.  This reaction may arise due the presence of a highly anti-  genic reagent, a decrease in the mucosal barrier that previ-  ously masked the antigen, or immunodysregulation resulting  in an abnormal response to a normally present antigen. All  previously described triggers can be grouped into one of  these three categories. One or more of these three factors  may be involved in subgroups of patients.   An antigenic stimulus appears to be the primary initiat-  ing factor in the immune-mediated cytotoxic destruction of  the mucosa in many patients. The list seems endless, and  every item on the list may be important in small subsets of  patients. Commonly mentioned potential antigens include  sodium lauryl sulfate in toothpaste, many systemic medica-  tions (e.g., nonsteroidal antiinflammatory drugs [NSAIDs],  various beta blockers, and nicorandil), microbiologic agents  (e.g., L forms of streptococci, Helicobacter pylori, herpes  simplex virus [HSV], varicella-zoster virus [VZV], adeno-  virus, and cytomegalovirus [CMV]), and many foods (e.g.,  cheese, chocolate, coffee, cow’s milk, gluten, nuts, strawber-  ries, tomatoes, dyes, flavoring agents, and preservatives).   The mucosal barrier appears to be important in the pre-  vention of aphthous stomatitis and might explain the almost  exclusive presence of aphthous stomatitis on nonkeratinized  mucosa. Numerous factors that decrease the mucosal barrier  increase the frequency of occurrence (e.g., trauma, nutri-  tional deficiencies, and smoking cessation); conversely,  those associated with an increased mucosal barrier have  been correlated with decreased ulcerations (e.g., smoking,  hormonal changes, and marked absence of aphthae on  mucosa bound to bone).   Nutritional deficiencies (iron, folate, zinc, B,, Bs, Bg, and B,»)  Immunoglobulin A (IgA) deficiency    An increased prevalence of aphthous-like ulcerations has  been noted in a variety of systemic disorders (Box 9-1).  These ulcerations typically are identical clinically and histo-  pathologically to those noted in otherwise healthy individu-  als. In many cases, resolution of the systemic disorder  produces a decreased frequency and severity of the mucosal  ulcerations.   Minor aphthous ulcerations (Mikulicz aphthae) are  the most common and represent the pattern present in  more than 80% of those affected. Major aphthous ulcer-  ations (Sutton disease or periadenitis mucosa necrotica  recurrens [PMNR]) occur in approximately 10% of the  patients referred for treatment. The remaining patients have  herpetiform aphthous ulcerations. The minor and major  forms most likely represent variations of the same process,  although herpetiform aphthae demonstrate a unique  pattern. Some investigators differentiate the herpetiform  variant because of supposed evidence of a viral cause, but  the proof is weak and does not justify its distinction from  the other aphthous ulcerations. Some authors include  Behcet syndrome as an additional variation of aphthous  stomatitis, but this multisystem disorder is more complex  and is considered later in this chapter.    Aphthous ulcerations are noted more frequently in children  and young adults, with approximately 80% of affected indi-  viduals reporting their first ulceration before the age of 30.    Patients with minor aphthous ulcerations experience the  fewest recurrences, and the individual lesions exhibit the    © Fig. 9-4 Minor Aphthous Ulceration. Erythematous halo encircl-  ing a yellowish ulceration of the soft palate on the left side.    @ Fig. 9-5 Minor Aphthous Ulcerations. Two ulcerations of different  sizes located on the maxillary labial mucosa.    shortest duration of the three variants. The ulcers arise  almost exclusively on nonkeratinized mucosa and may be  preceded by an erythematous macule in association with  prodromal symptoms of burning, itching, or stinging. The  ulceration demonstrates a yellow-white, removable fibrino-  purulent membrane that is encircled by an erythematous  halo (Fig. 9-4). Classically, the ulcerations measure between  3 and 10 mm in diameter, demonstrate a variable recur-  rence rate, and heal without scarring in 7 to 14 days (Fig.  9-5). Although scores of ulcerations may be present at once,  from one to five lesions typically are present during a single  episode, and the pain often is out of proportion for the size  of the ulceration. The buccal and labial mucosae are affected  most frequently, followed by the ventral surface of the  tongue, mucobuccal fold, floor of the mouth, and soft  palate (Fig. 9-6). Involvement of keratinized mucosa (e.g.,  hard palate, gingiva, dorsal surface of the tongue, and ver-  milion border) is rare and usually represents extension from  adjacent nonkeratinized epithelium.    Major aphthous ulcerations are larger than minor aphthae  and demonstrate the longest duration per episode. The    @ Fig. 9-6 Minor Aphthous Ulceration. Single ulceration of the  anterior buccal mucosa.    @ Fig. 9-7 Major Aphthous Ulceration. Large, deep, and irregular  ulceration of the posterior buccal mucosa. Note extensive scarring of  the anterior buccal mucosa from previous ulcerations.    ® Fig. 9-8 Major Aphthous Ulceration. Large, irregular ulceration  of the soft palate.    ulcerations are deeper than the minor variant, measure from  1 to 3 cm in diameter, take from 2 to 6 weeks to heal, and  may cause scarring (Fig. 9-7). The number of lesions varies  from 1 to 10. Any oral surface area may be affected, but the  labial mucosa, soft palate, and tonsillar fauces are involved  most commonly (Fig. 9-8). The onset of major aphthae is    @ Fig. 9-9 Herpetiform Aphthous Ulcerations. Numerous pinhead  ulcerations of the ventral surface of the tongue, several of which have  coalesced into larger, more irregular areas of ulceration.    after puberty, and recurrent episodes may continue to  develop for up to 20 years or more. With time, the associ-  ated scarring can become significant, and in rare instances  may lead to a restricted mouth opening.    Herpetiform aphthous ulcerations demonstrate the greatest  number of lesions and the most frequent recurrences. The  individual lesions are small, averaging 1 to 3 mm in diam-  eter, with as many as 100 ulcers present in a single recur-  rence. Because of their small size and large number, the  lesions bear a superficial resemblance to a primary HSV  infection, leading to the confusing designation, herpeti-  form. It is common for individual lesions to coalesce into  larger irregular ulcerations (Fig. 9-9). The ulcerations heal  within 7 to 10 days, but the recurrences tend to be closely  spaced. Although the nonkeratinized, movable mucosa is  affected most frequently, any oral mucosal surface may be  involved. There is a female predominance, and typically the  onset is in adulthood.   Further classification of all three types is valuable when  planning the most appropriate diagnostic evaluation and  therapy. The lesions are diagnosed as simple aphthosis  when they appear in patients with few lesions that heal  within 1 to 2 weeks and recur infrequently. In contrast,  patients with complex aphthosis have multiple (three or  more) and almost constant oral ulcerations that often  develop as older lesions resolve. Severe pain and large size  are common. Although associated genital or perianal lesions  also may be present, there is no other evidence of an associ-  ated systemic disease.    The histopathologic picture of aphthous stomatitis is char-  acteristic but not pathognomonic. The early ulcerative  lesions demonstrate a central zone of ulceration, which is  covered by a fibrinopurulent membrane. Deep to the area  of ulceration, the connective tissue exhibits an increased    @ Fig. 9-10 Major Aphthous Ulceration. A, Large ulceration of the left anterior buccal mucosa.  B, Same lesion after 5 days of therapy with betamethasone syrup used in a swish-and-swallow method.  The patient was free of pain by the second day of therapy. The ulceration healed completely during the    vascularity and a mixed inflammatory cellular infiltrate that  consists of lymphocytes, histiocytes, and polymorphonu-  clear leukocytes. The epithelium at the margin of the lesion  demonstrates spongiosis and numerous mononuclear cells  in the basilar one-third. A band of lymphocytes intermixed  with histiocytes is present in the superficial connective tissue  and surrounding deeper blood vessels.    No laboratory procedure provides definitive diagnosis. The  diagnosis is made from the clinical presentation and from  exclusion of other diseases that produce ulcerations that  closely resemble aphthae (see Box 9-1). In patients with  complex aphthous ulcerations, a systematic evaluation for  an underlying trigger or associated systemic condition is  prudent. In a review of 244 patients with complex aph-  thous ulcerations, an associated triggering condition (e.g.,  hematologic deficiency, gastrointestinal disease, immuno-  deficiency, and drug reaction) was discovered in almost  60%. Because the histopathologic features are nonspecific,  a biopsy is useful only in eliminating differential possibili-  ties and is not beneficial in arriving at the definitive  diagnosis.    ‘The patient’s medical history should be reviewed for signs  and symptoms of any systemic disorder that may be associ-  ated with aphthous-like ulcerations. Most patients with  mild aphthosis receive either no treatment, therapy with a  number of over-the-counter anesthetics or protective bio-  adhesive products, or periodic topical medicaments that  minimize the frequency and severity of the attacks.   In patients with mild disease, the mainstay of therapy is  the use of topical corticosteroids, and the list of possible  choices is long. Most patients with diffuse minor or her-  petiform aphthae respond well to dexamethasone solution    (0.5 mg/5 mL) used in a rinse-and-expectorate method.  Patients with localized ulcerations can be treated success-  fully with 0.05% augmented betamethasone dipropionate  gel or 0.05% fluocinonide gel. Adrenal suppression does  not occur with appropriate use of these medications. Major  aphthous ulcerations are more resistant to therapy and  often warrant more potent corticosteroids (Fig. 9-10). The  individual lesions may be injected with triamcinolone ace-  tonide or covered with 0.05% clobetasol propionate gel or  0.05% halobetasol propionate ointment. Triamcinolone  tablets also can be dissolved directly over the lesions. In  hard-to-reach areas, such as the tonsillar pillars, beclometh-  asone dipropionate aerosol spray can be used. In resistant  cases, systemic corticosteroids may be required to supple-  ment the topical medications and gain control. In such  instances, prednisolone oral suspension in a swish-and-  swallow method is preferable to prednisone tablets. In this  way, the ulcerations receive both topical and systemic  therapy.   An almost endless list of alternatives to corticosteroid  agents has been used to treat patients suffering from aph-  thous ulcerations. Caution should be exercised, however,  because many of these agents have not been examined in a  double-blind, placebo-controlled fashion to assess the degree  of effectiveness compared with placebo. Furthermore, some  of these treatments may have significant side effects or may  be quite expensive. Widely accepted topical alternatives  include amlexanox paste, chlorhexidine, tetracycline oral  suspension, and triclosan mouthrinse. In a recent Cochran  meta-analysis, no single systemic therapy was found to be  effective in a wide variety of patients. Frequently mentioned  systemic therapies include a number of immunomodulatory  agents, such as adalimumab, colchicine, dapsone, levami-  sole, pentoxifylline, and thalidomide.   Although laser ablation shortens the duration and  decreases associated symptoms, its use is of very limited  practical benefit because patients cannot return on each  recurrence. Chemical cautery with silver nitrate continues    to be suggested as an effective therapy, but it can no longer  be recommended because of the numerous safer alternatives  and its rare association with massive necrosis (see page 265)  and systemic argyria (see page 288). A cautery that uses  sulfuric acid and phenolic agents is indicated in certain situ-  ations, but must be used with caution due to the potential  for significant local tissue necrosis related to its misuse.   The success of these different therapeutic approaches is  variable from patient to patient. In addition, these interven-  tions do not resolve the underlying problem and are merely  an attempt to “beat back brush fires.” Recurrences often  continue, although breaking up the cycle may induce longer  disease-free intervals between attacks. Surgical removal of  aphthous ulcerations has been used but is an inappropriate  therapy.   Patients with complex aphthosis require a more extensive  evaluation for occult systemic disease and a search for pos-  sible triggers of the immune-mediated mucosal destruction.  To go beyond the management of individual recurrences is  difficult, expensive, and often frustrating. In spite of this,  patients with severe disease should be offered the opportu-  nity to investigate the underlying causes.    The combination of chronic ocular inflammation and oro-  genital ulcerations was reported as early as the era of the  ancient Greeks and later described in 1931 by a Greek  ophthalmologist, Benedict Adamantiades. The classic triad  was not delineated until 1937, when a Turkish dermatolo-  gist, Hulusi Behcet, defined the disease that bears his name.  Although the disease traditionally has been thought primar-  ily to affect the oral, genital, and ocular regions, it now is  recognized to be a systemic vasculitis.   Although no clear causation has been established, Behget  syndrome appears to represent an abnormal immune  process triggered by an infectious or environmental antigen  in a genetically predisposed individual. Investigators have  correlated attacks to a number of environmental agents,  including bacteria (especially streptococci), viruses, pesti-  cides, and heavy metals. Interestingly, reduction of oral  bacterial load via periodontal therapy has been shown to  reduce the prevalence of associated oral ulcerations in  patients with Behcet syndrome.   Histocompatibility antigen B-51 (HLA-B51) has been  linked closely to Behcet syndrome, and the frequency of  both the disease and the haplotype is high in Turkey, Japan,  and the Eastern Mediterranean countries. This distribution  appears correlated to the ancient “Silk Route” that extended  from China to Rome and was traveled by the Turks. Sexual  reproduction between immigrants and locals along the  route appears to have spread the genetic vulnerability. Inter-  estingly, when predisposed populations migrate to non-  endemic locations, the prevalence decreases, suggesting  environmental factors also are involved.    Behcet syndrome is uncommon in blacks and usually arises  in the third and fourth decades with the disease rarely pre-  senting before puberty or beyond the age of 50. Men exhibit  a slightly increased prevalence and tend to have a worse  clinical course.   Virtually all affected patients demonstrate oral ulcer-  ations that often herald the onset of the disease. Other less  frequently associated features in order of prevalence include  genital ulcerations, cutaneous lesions, arthritis, uveitis,  thrombophlebitis, gastrointestinal manifestations, and  central nervous system (CNS) involvement.   The oral lesions are similar to aphthous ulcerations  occurring in otherwise healthy individuals and demonstrate  the same duration and frequency. The individual lesions  vary in size and are surrounded by a larger zone of diffuse  erythema (Fig. 9-11). All three forms of oral aphthous sto-  matitis may be seen. Although the majority of affected  patients have lesions that resemble minor aphthous ulcer-  ations, some reports have documented a prevalence of major  aphthae that approaches 40% in patients affected with  Behcet syndrome. The herpetiform variant remains uncom-  mon and is noted in approximately 3%.   The genital lesions occur in 75% of the patients. In  males, approximately 90% of the lesions involve the  scrotum, whereas those in females are most frequent on the  vulva, vagina, or uterine cervix. Perineal, perianal, and groin  involvement is seen in both genders (Fig. 9-12). These  lesions recur less frequently than do the oral ulcerations, but  they are deeper and tend to heal with scarring.   Common cutaneous lesions include erythematous  papules, vesicles, pustules, pyoderma, folliculitis, acneiform  eruptions, and erythema nodosum—tlike lesions. In addition  to the typical distribution seen in adolescence, the acne-like  lesions also involve unusual sites, such as the extremities.  From a diagnostic standpoint, one of the most important  skin manifestations is the presence of positive “pathergy.”  One or 2 days after the oblique insertion of a 20-gauge or    @ Fig. 9-12 Behget Syndrome. Numerous irregular ulcerations of  the labia majora and perineum. (From Helm TN, Camisa C, Allen C,  et al: Clinical features of Behcet’s disease, Oral Surg Oral Med Oral  Pathol 72:30, 1991.)    ° Fig. 9-13 Behget Syndrome. Sterile pustule of the skin that devel-  oped 1 day after injection of saline. This reaction is termed cutaneous  pathergy.    smaller needle under sterile conditions, a tuberculin-like  skin reaction or sterile pustule develops (Fig. 9-13). Positive  pathergy is geographically variable with a prevalence of 60%  in Middle Eastern patients but seen in only approximately  3% of affected Caucasian patients.   Arthritis is one of the more common minor manifesta-  tions of the disease and is usually self-limiting and nonde-  forming. The knees, wrists, elbows, and ankles are affected  most frequently.   Ocular involvement occurs in up to 70% of the cases  and is more frequent and severe in males. The most common  findings are posterior uveitis, conjunctivitis, corneal ulcer-  ation, papilledema, and arteritis. The most common sec-  ondary ocular complications are cataracts, glaucoma,  and neovascularization of the iris and retina. Despite    ulcerations  Eye lesions Anterior or posterior  uveitis, cells in vitreous  on slit-lamp examination,  or retinal vasculitis  Skin lesions Erythema nodosum,    pseudofolliculitis or  papulopustular lesions,  or acneiform nodules  noted in postadolescent  patients not receiving  corticosteroids   Although the vascular disease may involve arteries, veins  are affected more frequently and present as superficial  and deep thrombophlebitis. The thrombi tend to be adher-  ent to the diseased veins without a tendency toward  embolism.   Gastrointestinal disease is variable and includes abdomi-  nal pain, anorexia, diarrhea, dyspepsia, and vomiting. CNS  involvement is not common but, when present, is associated  with a poor prognosis. From 10% to 25% of the patients  demonstrate CNS involvement, and the alterations pro-  duced result in a number of changes that include paralysis  and severe dementia.    No laboratory finding is diagnostic of Behcet syndrome. In  an attempt to standardize diagnoses, definitive criteria have  been developed. Table 9-1 delineates the requirements pro-  posed by the Behcet International Study Group.    The histopathologic features are not specific for Behcet syn-  drome and can be seen in many disorders, including aph-  thous stomatitis. The pattern most frequently seen is called  leukocytoclastic vasculitis. The ulceration is similar in appear-  ance to that seen in aphthous stomatitis, but the small blood  vessels classically demonstrate intramural invasion by neu-  trophils, karyorrhexis of neutrophils, extravasation of red  blood cells, and fibrinoid necrosis of the vessel wall.    Therapy is tailored to the disease severity and prognostic  factors. Many patients are treated symptomatically, with the  disease often going into remission as the patient ages.  Females and older patients have a better prognosis than  males or young patients. Ocular lesions and CNS involve-  ment are associated with significant morbidity and mandate  more aggressive therapy.   No single medication is universally effective with variable  responses seen in different groups of patients. Systemic medi-  cations include azathioprine, colchicine, corticosteroids,  cyclosporine, dapsone, interferon-O, methotrexate, pentoxi-  fylline, sulfasalazine, thalidomide, and anti- TNF-o medica-  tions (adalimumab, etanercept, and infliximab). The oral and  genital ulcerations typically respond well to potent topical or  intralesional corticosteroids or topical tacrolimus.   Behcet syndrome has a highly variable course. A relaps-  ing and remitting pattern is typical, with attacks becoming  more intermittent after 5 to 7 years. In the absence of CNS  disease or significant vascular complications, the prognosis  generally is good.    Sarcoidosis is a multisystem granulomatous disorder of  unknown cause. Jonathan Hutchinson initially described  the disease in 1875, but Boeck coined the term sarcoidosis  (Greek meaning “flesh-like condition”) 14 years later. The  evidence implicates improper degradation of antigenic  material with the formation of noncaseating granulomatous  inflammation. The nature of the antigen is unknown, and  probably several different antigens may be responsible. Pos-  sible involved antigens include infectious agents (e.g., myco-  bacterium, propionibacteria, Epstein-Barr virus, human  herpesvirus 8 [HHV-8]) and a number of environmental  factors (e.g., wood dust, pollen, clay, mold, and silica).  Several investigators have confirmed a genetic predisposition  and positive associations with certain HLA types.    Sarcoidosis has a worldwide distribution, tends to arise prior  to age 50, and exhibits an increased prevalence in females  and blacks. The disease may present acutely or demonstrate  a chronic course with periods of remission and exacerba-  tion. Acute cases often exhibit fever, fatigue, anorexia, or  weight loss combined with other manifestations, such as  respiratory symptoms, polyarthritis, visual problems, and  skin lesions. In chronic cases, pulmonary symptoms are  common and include dry cough, dyspnea, and chest dis-  comfort. Approximately 20% of patients have no symp-  toms, and the disease is discovered on routine chest  radiographs.   Although any organ may be affected, the lungs, lymph  nodes, skin, eyes, and salivary glands are the predominant  sites. Lymphoid tissue is involved in almost all cases. The    ® Fig. 9-14 Sarcoidosis. Violaceous indurated plaques of the right  malar area and bridge of nose. (Courtesy of Dr. George Blozis.)    mediastinal and paratracheal lymph nodes are involved  commonly, and chest radiographs frequently reveal bilateral  hilar lymphadenopathy. Approximately 90% of affected  patients will reveal an abnormal chest radiograph sometime  during the course of the disease. Cutaneous manifestations  occur about 25% of the time. These often appear as chronic,  violaceous, indurated lesions that are termed lupus pernio  and frequent the nose, ears, lips, and face (Fig. 9-14). Scat-  tered, nonspecific, tender erythematous nodules, known as  erythema nodosum, frequently occur on the lower legs.   Ocular involvement is noted in 25% of the cases and  most often appears as anterior uveitis. Lesions of the con-  junctiva and retina may occur. Involvement of the lacrimal  glands often produces keratoconjunctivitis sicca; the sali-  vary glands can be altered similarly, with resultant clinical  enlargement and xerostomia. The salivary gland enlarge-  ment, xerostomia, and keratoconjunctivitis sicca can  combine to mimic Sjégren syndrome (see page 434).   Although lymphoid, pulmonary, cutaneous, and ocular  lesions are most common, virtually any organ system may  be affected. Other potential sites include the endocrine  system, gastrointestinal tract, heart, kidneys, liver, nervous  system, and spleen. Intraosseous lesions may occur and  most commonly involve the phalanges, metacarpals, and  metatarsals. Less frequently, the skull, nasal bones, ribs, and  vertebrae are affected.   Two distinctive clinical syndromes are associated with  acute sarcoidosis. Lofgren syndrome consists of erythema  nodosum, bilateral hilar lymphadenopathy, and arthralgia.  Patients with Heerfordt syndrome (uveoparotid fever)  have parotid enlargement, anterior uveitis of the eye, facial  paralysis, and fever.   If salivary gland and lymph node involvement are  excluded, clinically evident oral manifestations in sarcoid-  osis are uncommon. Any oral mucosal site can be affected,  most often appearing as a submucosal mass, an isolated  papule, an area of granularity, or ulceration. The mucosal  lesions may be normal in color, brown-red, violaceous, or  hyperkeratotic (Figs. 9-15 and 9-16). The most frequently  affected intraoral soft tissue site is the buccal mucosa,    @ Fig. 9-15 Sarcoidosis. Multiple erythematous macules of the hard  palate. (Courtesy of Dr. George Blozis.)    ® Fig. 9-16 Sarcoidosis. Erythematous macules with central hyper-  keratosis of the lower labial mucosa.    followed by the gingiva, lips, tongue, and palate. Lesions of  the floor of the mouth occur but usually are secondary to  salivary gland involvement. Intraosseous lesions affect either  jaw and represent approximately one-fourth of all reported  intraoral cases. Of these cases, most appeared as ill-defined  radiolucencies that occasionally eroded the cortex but never  created expansion. In the previously reported intraoral  cases, the majority of patients demonstrated multisystem  involvement, but the oral lesion was the initial manifesta-  tion in two-thirds of the patients.    Microscopic examination of sarcoidosis exhibits a classic  picture of granulomatous inflammation. Tightly clustered  aggregates of epithelioid histiocytes are present, with a sur-  rounding rim of lymphocytes. Intermixed with the histio-  cytes are scattered Langhans’ or foreign body type giant cells  (Fig. 9-17). The granulomas often contain laminated. baso-  philic calcifications, known as Schaumann bodies (degen-  erated lysosomes), or stellate inclusions, known as asteroid  bodies (entrapped fragments of collagen) (Fig. 9-18). None  of these structures are specific for sarcoidosis. Special stains  for fungal and bacterial organisms are negative. No    ® Fig. 9-17 Sarcoidosis. Photomicrograph of a labial minor salivary  gland demonstrating granulomatous inflammation characterized by  circumscribed collections of histiocytes, lymphocytes, and multinucle-  ated giant cells.    The diagnosis is established by the clinical and radiographic  presentations, the histopathologic appearance, and the pres-  ence of negative findings with both special stains and cul-  tures for organisms. Elevated serum angiotensin-converting  enzyme (ACE) levels and appropriate documentation of  pulmonary involvement strongly support the diagnosis. In  spite of this, elevated ACE is reported in only 60% of  patients with sarcoidosis and in a minority of those with  oral involvement. Other laboratory abnormalities that may  be seen include eosinophilia; leukopenia; anemia; thrombo-  cytopenia; and elevation of the serum alkaline phosphatase  level, erythrocyte sedimentation rate, serum calcium con-  centration, and urinary calcium level.   In the past, a skin test for sarcoidosis, the Kveim test,  was performed by intradermal injection of a sterilized sus-  pension of human sarcoid tissue. However, this procedure  is no longer used because of difficulty in obtaining material    for the test, concern related to its accuracy, and the inability  to guarantee the absence of contamination (e.g., prions) in  this human tissue.   Minor salivary gland biopsy has been promoted as a  diagnostic aid in suspected cases of sarcoidosis (see Fig.  9-17) but is less effective than a parotid biopsy. Previously,  biopsy of the parotid was avoided because of the fear of  salivary fistula formation and damage to the facial nerve.  These concerns have been reduced through biopsy of the  posterior superficial lobe of the parotid gland, and confir-  mation of sarcoidosis has been reported in 93% of patients  from this procedure.    In approximately 60% of patients with sarcoidosis, the  symptoms resolve spontaneously within 2 years without  treatment. Most initial diagnoses are followed by a 3- to  12-month period of observation to define the general course  of the disease. Active intervention is recommended for pro-  gressive disease and patients with cardiac or neurologic  involvement, hypercalcemia, disfiguring skin disease, or  serious ocular lesions that do not respond to local therapy.  In patients requiring treatment, corticosteroids remain first-  line therapy, but resistance and relapses are common. Medi-  cations used in patients with refractory disease include    methotrexate, azathioprine, chlorambucil, chloroquine, and  cyclophosphamide. Several studies have shown promising  results with TNF-a antagonists such as etanercept, inflix-  imab, pentoxifylline, and thalidomide. In 10% to 20% of  those affected by sarcoidosis, resolution does not occur even  with treatment. Approximately 4% to 10% of patients die  of pulmonary, cardiac, or CNS complications.    Since Wiesenfeld introduced it 1985, orofacial granulo-  matosis has become a well-accepted and unifying term  encompassing a variety of clinical presentations that, on  biopsy, reveal the presence of nonspecific granulomatous  inflammation.   The disorder is idiopathic but appears to represent an  abnormal immune reaction to a variety of inciting agents.  In addition, similar lesions can be seen in association with  a number of systemic diseases. Table 9-2 delineates systemic  diseases that may mimic orofacial granulomatosis, and  Table 9-3 lists a number of additional possible triggers.    The clinical presentation of orofacial granulomatosis is  highly variable. The majority of patients are adults; however,    Neutrophil nitroblue tetrazolium reduction test (perform if medical history of chronic infections    Hematologic evaluation for evidence of gastrointestinal malabsorption (e.g., low albumin, calcium,    folate, iron, and red blood cell count; elevated erythrocyte sedimentation rate) or leukocyte  scintigraphy using °"Tc-HMPAO (hexamethyl propylene amine oxime); if initial screen is positive,  then recommend esophagogastroduodenoscopy, ileocolonoscopy, and small-bowel radiographs    Sarcoidosis Serum angiotensin—converting enzyme and chest radiograph (hilar lymphadenopathy)  Tuberculosis Skin test and chest radiograph (negative acid-fast bacteria [AFB] stain on biopsy specimen does  not rule out mycobacterial infection)  TABLE    The foreign debris noted in iatrogenic gingivitis is often subtle and difficult to associate    definitively with the diffuse inflammatory process. If lesions are nonmigrating and isolated to  gingiva, then response to local excision of a single focus should be evaluated.    chocolates, cinnamon, cocoa, dairy products, eggs, monosodium glutamate, peanuts, sun  yellow dye, and wheat) flavorings, oral hygiene products (e.g., toothpaste and mouth rinses),  and dental restorative metals have been implicated. Patch testing (i.e., contact dermatitis  standard series with oral battery) or elimination diet may discover the offending antigen.    e Fig. 9-19 Orofacial Granulomatosis (Cheilitis Granuloma-  tosa). Nontender, persistent enlargement of the upper lip. (From Allen  CM, Camisa C: Diseases of the mouth and lips. In Sams WM, Lynch  P, editors: Principles of dermatology, New York, 1990, Churchill  Livingstone.)    @ Fig. 9-20 Orofacial Granulomatosis (Melkersson-Rosenthal  Syndrome). Persistent enlargement of the lower lip. (Courtesy of  Dr. Richard Ziegler.)    the process may occur at any age. By far, the most frequent  site of involvement is the lips. The labial tissues demonstrate  a nontender, persistent swelling that may involve one or  both lips (Fig. 9-19). When these signs are combined with  facial paralysis and a fissured tongue, the clinical presenta-  tion is called Melkersson-Rosenthal syndrome (Figs. 9-20  and 9-21). Involvement of the lips alone is called cheilitis  granulomatosa (of Miescher). Neither of these two clinical  presentations represents a specific disease, and it appears  best to include both of these under the term orofacial  granulomatosis.   Intraoral sites also can be affected, and the predominant  lesions are edema, ulcers, and papules. The tongue may  develop fissures, edema, paresthesia, erosions, or taste altera-  tion. The gingiva can develop swelling, erythema, pain, or  erosions. The buccal mucosa often exhibits a cobblestone  appearance of edematous mucosa or focal areas of submu-  cosal enlargement. Linear hyperplastic folds may occur in  the sulcus, often with elongated ulcerations in the base of    Syndrome). Same patient as depicted in Fig. 9-20. Note numerous  furrows on the dorsal surface of the tongue. (Courtesy of Dr. Richard  Ziegler.)    ® Fig. 9-22 Orofacial Granulomatosis. Hyperplastic mucosa noted  bilaterally in the mandibular mucobuccal fold. (Courtesy of Dr. Steven  A. Anderson.)    these folds (Fig. 9-22). The palate may have papules or large  areas of hyperplastic tissue. Hyposalivation rarely is reported.    In classic cases of cheilitis granulomatosa, edema is present  in the superficial lamina propria with dilation of lymphatic  vessels and scattered lymphocytes seen diffusely and in clus-  ters. Fibrosis may be present in long-term lesions. Scattered  aggregates of noncaseating granulomatous inflammation,  consisting of lymphocytes and epithelioid histiocytes, are  present, with or without multinucleated giant cells. Typi-  cally, the granulomas appear to cluster around scattered    vessels and are not as well formed or discrete as those seen  in sarcoidosis (Fig. 9-23).   Special stains for fungal organisms and acid-fast bacteria  are negative. No dissolvable, pigmented, or polarizable  foreign material should be present. When the lesions are  confined to the gingiva, a thorough search should be made,  because many cases of granulomatous gingivitis are due to  subtle collections of foreign material (see page 146).    ‘The initial diagnosis of orofacial granulomatosis is made on  histopathologic demonstration of granulomatous inflam-  mation that is associated with negative special stains for  organisms and no foreign material. Because clinical and  histopathologic features of orofacial granulomatosis can be  produced by a variety of underlying causes, this diagnosis  is the beginning, not the end, of the patient’s evaluation.  Prior to administering any medication or considering surgi-  cal intervention, the patient should be evaluated for the  systemic diseases and local processes (see Tables 9-2 and  9-3) that may be responsible for similar oral lesions. If    ® Fig. 9-24 Orofacial Granulomatosis. A, Diffuse enlargement of the upper lip. B, Same patient after    features diagnostic of one of these more specific disorders  are discovered, then the oral lesions presumably would be  related to that disease. If a specific diagnosis cannot be  made, then potential foci of infection should be eliminated.  If no resolution is noted after reducing local inflammatory  factors, then referral of the patient for allergy testing should  be considered.   Patients ultimately discovered to have Crohn disease  often present at a younger age and have less lip swelling,  although lesions of the buccal vestibule are more likely.  Because gastrointestinal involvement has been discovered in  up to 60% of patients with orofacial granulomatosis who  have no intestinal symptoms, several investigators have sug-  gested thorough gastrointestinal evaluation of all children  and young adults presenting with orofacial granulomatosis.   The worldwide prevalence of allergy is estimated to be  22%, whereas the frequency noted in patients with orofacial  granulomatosis is well over 50% in several studies. Although  allergy testing has been useful in many patients, diet restric-  tion has been successful irrespective of patch test results in  occasional individuals. Several investigators have suggested  a cinnamon- and benzoate-free diet in all patients in whom  an obvious trigger cannot be found.    The first goal of management should be discovery of the  initiating cause, although this may be difficult because the  trigger often is elusive.   Oral lesions have been treated with a variety of interven-  tions, with variable results. Topical or intralesional cortico-  steroids, topical tacrolimus, radiotherapy, sulfasalazine,  hydroxychloroquine sulfate, azathioprine, cyclosporine A,  methotrexate, danazol, dapsone, TNF-o antagonists (inflix-  imab and thalidomide), clofazimine, metronidazole, and  numerous other antibiotics have been tried. Currently, most  investigators administer intralesional delayed-release high-  concentrate triamcinolone to control the progression of this  disease (Figs. 9-24 and 9-25). In the absence of a response  to other treatments, surgical recontouring has been used by    @ Fig. 9-25 Orofacial Granulomatosis. Same patient depicted in Fig. 9-24. A, Clinical appearance  before local therapy. B, Significant resolution after intralesional corticosteroid therapy.    some but carries a considerable risk of recurrence and rarely  appears to be warranted.   The prognosis is highly variable. No therapy has proved  to be the “silver bullet” in resolving the individual lesions.  In some cases, lesions resolve spontaneously, with or without  therapy; in others, they continue to progress in spite of a  myriad of therapeutic attempts to stop the progression.    Wegener granulomatosis is a well-recognized, although  uncommon, disease process of unknown cause. Initially  described in the German literature in 1936 by Friedrich  Wegener, the disorder includes necrotizing granulomatous  lesions of the respiratory tract, necrotizing glomerulone-  phritis, and systemic vasculitis of small arteries and veins.  The pathogenesis of the disease is thought to be due to an  abnormal immune reaction to an inhaled environmental  antigen or infectious agent. A possible hereditary predispo-  sition has been mentioned in some cases.    Wegener granulomatosis demonstrates a wide age range  from childhood to old age, with a mean of age of 41 years  and no sex predilection. Although most frequently present-  ing in adults, approximately 15% of the cases arise prior to  age 20. A prevalence of 3 out of 100,000 has been reported,  and 90% of the cases arise in Caucasians. The disease can    involve almost every organ system in the body. With classic  Wegener granulomatosis, patients initially show involve-  ment of the upper and lower respiratory tract; if the condi-  tion remains untreated, then renal involvement often  rapidly develops (generalized Wegener granulomatosis).   Limited Wegener granulomatosis is diagnosed when  there is involvement of the respiratory system without rapid  development of renal lesions. One subset of patients exhib-  its lesions primarily of the skin and mucosa, a condition  termed superficial Wegener granulomatosis. In this form  of the disease, systemic involvement develops slowly. These  three different clinical patterns highlight the variability of  the clinical aggressiveness that can occur in patients with  Wegener granulomatosis.   Purulent nasal drainage, chronic sinus pain, nasal ulcer-  ation, congestion, and fever are frequent findings from  upper respiratory tract involvement. Persistent otitis media,  sore throat, and epistaxis also are reported. With progres-  sion, destruction of the nasal septum can result in a saddle-  nose deformity. Patients with lower respiratory tract  involvement may be asymptomatic, or they may have dry  cough, hemoptysis, dyspnea, or chest pain. Renal involve-  ment usually occurs late in the disease process and is the  most frequent cause of death. The glomerulonephritis  results in proteinuria and red blood cell casts. Occasionally,  the eyes, ears, and skin also are involved.   The reported prevalence of oral lesions varies widely with  oral involvement representing the initial presentation in  2% of affected patients. The most characteristic oral    @ Fig. 9-26 Wegener Granulomatosis. Hemorrhagic and friable  gingiva (strawberry gingivitis). (Courtesy of Dr. Sam McKenna.)    @ Fig. 9-27 Wegener Granulomatosis. Hyperplastic and hemor-  rhagic mucosa of the facial mandibular gingiva on the left side. (Cour-  tesy of Dr. James Wilson.)    manifestation is strawberry gingivitis. This distinctive but  uncommon pattern of gingival alteration appears to be an  early manifestation of Wegener granulomatosis and has  been documented before renal involvement in most cases.  The affected gingiva demonstrates a florid and granular  hyperplasia. The surface forms numerous short bulbous  projections, which are hemorrhagic and friable; this red,  bumpy surface is responsible for the strawberry-like appear-  ance (Fig. 9-26 and 9-27). At the time of diagnosis, the  involvement may be localized or generalized to multiple  quadrants.   Oral ulceration also may be a manifestation of Wegener  granulomatosis. These lesions are clinically nonspecific and  may occur on any mucosal surface (Fig. 9-28). In contrast  to the gingival changes, the oral ulcerations are diagnosed  at a later stage of the disease, with more than 60% of the  affected patients demonstrating renal involvement. Other  less common orofacial manifestations include facial paraly-  sis, labial mucosal nodules, sinusitis-related toothache,  arthralgia of the temporomandibular joint (TMJ), jaw clau-  dication, palatal ulceration from nasal extension, oral-antral  fistulae, and poorly healing extraction sites.   Enlargement of one or more major salivary glands from  primary involvement of the granulomatous process also has  been reported. The glandular involvement also appears early    ® Fig. 9-28 Wegener Granulomatosis. Deep, irregular ulceration of  the hard palate on the left side. (From Allen CM, Camisa C, Salewski  C, et al: Wegener’s granulomatosis: report of three cases with oral  lesions, J Oral Maxillofac Surg 49:294-298, 1991.)   1? Tete 3 #3 we  Bat te as ei eek net Ae  © Fig. 9-29 Wegener Granulomatosis. Connective tissue contain-  ing proliferation of numerous vascular channels and a heavy inflamma-  tory infiltrate consisting of lymphocytes, neutrophils, eosinophils, and  multinucleated giant cells.    in the course of the disease and may lead to early diagnosis  and treatment.    Wegener granulomatosis appears as a pattern of mixed  inflammation centered around blood vessels. Involved  vessels demonstrate transmural inflammation, often with  areas of heavy neutrophilic infiltration, necrosis, and nuclear  dust (leukocytoclastic vasculitis). The connective tissue  adjacent to the vessel has an inflammatory cellular infiltrate,  which contains a variable mixture of histiocytes, lympho-  cytes, eosinophils, and multinucleated giant cells (Fig.  9-29). Special stains for organisms are negative, and no  foreign material can be found. In oral biopsy specimens, the  oral epithelium may demonstrate pseudoepitheliomatous  hyperplasia and subepithelial abscesses. Because of the  paucity of large vessels in many oral mucosal biopsies,  vasculitis may be difficult to demonstrate, and the histo-  pathologic presentation may be one of ill-defined collec-  tions of epithelioid histiocytes intermixed with eosinophils,    © Fig. 9-30 Wegener Granulomatosis. Gingival biopsy specimen  showing a mixed inflammatory cellular infiltrate obscured by extensive  extravasation of red blood cells.   e Abnormal urinary sediment (red blood cell casts or more than  five red blood cells/high power field)    lymphocytes, and multinucleated giant cells. In addition,  the lesions of strawberry gingivitis typically demonstrate  prominent vascularity with extensive red blood cell extrava-  sation (Fig. 9-30).    ‘The diagnosis of Wegener granulomatosis is made from the  combination of the clinical presentation and the micro-  scopic finding of necrotizing and granulomatous vasculitis.  The American College of Rheumatology proposed four  diagnostic criteria with a minimum of two required for a  diagnosis of Wegener granulomatosis (Box 9-2). Radio-  graphic evaluation of the chest and sinuses is recommended  to document possible involvement of these areas. The serum  creatinine and urinalysis results are used to rule out signifi-  cant renal alterations.   A laboratory marker for Wegener granulomatosis has  been identified. Indirect immunofluorescence for serum  antibodies directed against cytoplasmic components of neu-  trophils has been used to support a diagnosis of Wegener  granulomatosis. There are two reaction patterns of these  antineutrophil cytoplasm antibodies (ANCA). Antibodies  against proteinase-3, a component of neutrophilic azuro-  philic cytoplasmic granules, are designated PR3-ANCA  (previously termed c-ANCA). Likewise, antibodies against  myeloperoxidase, a neutrophilic lysosomal granule, are des-  ignated MPO-ANCA (previously termed p-ANCA).   PR3-ANCA is the most useful in the diagnosis of  Wegener granulomatosis and is seen in 90% to 95% of    generalized Wegener granulomatosis and 60% of the early  or localized cases. Immunofluorescence for PR3-ANCA  should be ordered along with the specific enzyme-linked  immunosorbent assay (ELISA) test for antibodies against  proteinase 3 (PR3). These combined tests are associated  with a sensitivity of 73% and a diagnostic specificity of 99%  for Wegener granulomatosis. False positives are uncommon  and may be associated with a variety of other diseases. In  contrast, MPO-ANCAs are detected in several vasculitides  that typically do not present in the oral cavity.    The mean survival of untreated patients with disseminated  classic Wegener granulomatosis is 5 months; 80% of the  patients are dead at 1 year and 90% within 2 years. The  prognosis is better for the limited and superficial forms  of the disease, although a proportion of patients with  localized disease eventually will develop classic Wegener  granulomatosis.   The first line of therapy is oral prednisone and cyclophos-  phamide. On remission, the prednisone is gradually discon-  tinued, with continuation of the cyclophosphamide for at  least 1 year. Although high response rates are noted, serious  side effects related to the therapy are not rare, especially  those related to the cyclophosphamide. Trimethoprim/  sulfamethoxazole has been used successfully in localized  cases. When added to the standard regimen, this antibiotic  combination seems to reduce associated infections and to  lower the relapse rate. Low-dose methotrexate and cortico-  steroids also have been used in patients whose disease is not  immediately life threatening or has not responded appro-  priately to cyclophosphamide. Alternatives for cyclophos-  phamide include cyclosporine, rituximab, and infliximab.  For maintenance therapy, cyclophosphamide often is  replaced with methotrexate or azathioprine.   Treatment has a profound effect on the progression of  the disease. With appropriate therapy, prolonged remission  is noted in up to 75% of affected patients; a cure often is  attainable when the disease is diagnosed and appropriately  treated while the involvement is localized. Because of a  relapse rate up to 30%, maintenance therapy is necessary in  many patients. The PR3-ANCA levels can be used to  monitor the disease activity. Patients appear less likely to  have relapses if their antineutrophilic antibodies disappear  during treatment; in contrast, patients whose levels of anti-  bodies persist are at greater risk for relapse.    The future of dentistry and medicine will involve a high  volume of patients suffering from adverse drug reactions.  By 2030, 20% of the population will be more than 65 years  old. As the population ages and those affected with chronic  diseases increase, patients taking multiple medications most  likely will escalate. In the United States during the year    2000, more than 2.8 billion prescriptions were filled,  enough to supply each inhabitant with ten prescriptions  annually. Although use of two medications is associated  with a 6% risk of an adverse reaction, the frequency rises  to 50% with five drugs and almost 100% when eight or  more medications are used simultaneously.   Two types of adverse drug reactions are seen. Type A (aug-  mented reactions) arise from an exaggerated but otherwise  expected pharmacologic action of the prescribed medication  (such as, bleeding associated with warfarin). Approximately  80% of the total adverse drug reactions are Type A. Type B  (bizarre reactions) are idiosyncratic reactions that are not  expected, the majority of which arise from immune-mediated  effects, such as hypersensitivity reactions.   Lists of medications related to several patterns of drug-  related mucosal alteration are provided. Because new drug  reactions are being reported on a regular basis and large  numbers of new medications continue to appear, these lists  should be considered incomplete and additional investiga-  tion is prudent. When presented with a patient with a  possible drug reaction, all utilized medications, both pre-  scribed and over-the-counter, that the patient is taking  should be researched with a reputable online pharmaceuti-  cal reference. This should include not only the information  within the drug insert but also the constantly updated  results of a complete search of the health care literature.   In addition to drug-related problems, such as angio-  edema (see page 326), medication-related osteonecrosis (see  page 271), cleft lip/palate (see page 1), erythema multi-  forme (see page 723), gingival hyperplasia (see page 148),  methemoglobinemia, mucosal discolorations (see page  290), burning mouth disorder (see page 807), tardive dys-  kinesia, taste disturbances (see page 809), sialorrhea (see  page 431), and xerostomia (see page 432), medications can  induce a wide variety of mucosal ulcerations and erosions.  A reaction of the oral mucosa to the systemic administration  ofa medication is called stomatitis medicamentosa. Several  different patterns of oral mucosal disease can be seen:   Anaphylactic stomatitis arises after the allergen enters the  circulation and binds to immunoglobulin E (IgE)—mast cell  complexes. Although systemic anaphylactic shock can  result, localized alterations also occur. Fixed drug eruptions  are inflammatory alterations of the mucosa or skin that  recur at the same site after the administration of any aller-  gen, often a medication. Medications reported to be associ-  ated with fixed drug eruptions are listed in Box 9-3,  lichenoid drug eruptions in Box 9-4, lupus erythematosus—  like drug eruptions in Box 9-5, pemphigus-like drug reac-  tions in Box 9-6, and mucosal pemphigoid—like eruptions  in Box 9-7. In addition, a long list of medications is known    Bismuth Penicillamine  Carbamazepine Phenindione  Carbimazole Phenothiazines  Chloral hydrate Phenylbutazone  Chlorpropamide Phenytoin  Cimetidine Prazosin  Clofibrate Procainamide  Colchicine Propylthiouracil  Cyanamide Protease inhibitors  Dapsone Protionamide  Dipyridamole Pyrimethamine  Ethionamide Pyritinol  Flunarizine Quinidine  Furosemide Rifampicin   Gold salts Spironolactone  Griseofulvin Streptomycin  Interferon-alpha Sulfonamides  Ketoconazole Sulfonylureas  Levamisole Tetracycline  Lincomycin Thiazide diuretics  Lithium Tocainide  Lorazepam Tolbutamide  Mepacrine Triprolidine  Metformin    to be associated with nonspecific erosive, ulcerative, or  aphthous-like lesions, but is not included due to its length.    The patterns of mucosal alterations associated with the sys-  temic administration of medications are varied, almost as  much as the number of drugs that result in these changes.  Anaphylactic stomatitis may occur alone or in conjunction  with urticarial skin lesions or other signs and symptoms of  anaphylaxis (e.g., hoarseness, respiratory distress, and vom-  iting). The affected mucosa may exhibit multiple zones of    Carbamazepine Lithium  Chlorpromazine Methyldopa  Etanercept Penicillamine  Ethosuximide Primidone  Gold Procainamide  Griseofulvin Quinidine  Hydantoins Reserpine  Hydralazine Streptomycin  Infliximab Thiouracil  Isoniazid Trimethadione    glycine Oxyphenbutazone  Ampicillin Penicillamine  Benzylpenicillin Phenobarbital  Captopril Phenylbutazone  Cefadroxil Piroxicam  Cephalexin Practolol  Diclofenac Probenecid  Ethambutol Procaine penicillin  Glibenclamide Propranolol  Gold Pyritinol chlorhydrate  Heroin Rifampin  Ibuprofen Thioproline  Interleukin-2   e Ibuprofen e Salicylic acid  e lsoniazid e Sulfonamides  e Mefenamic acid e Sulfasalazine  e Nadolol    erythema or numerous aphthous-like ulcerations. Mucosal  fixed drug eruptions appear as localized areas of erythema  and edema, which can develop into vesiculoerosive lesions  and are located most frequently on the labial mucosa.  Lichenoid, lupus-like, pemphigoid-like, and pemphigus-  like drug reactions resemble their namesakes clinically, his-  topathologically, and immunologically (Fig. 9-31). These  latter chronic drug reactions may involve any mucosal  surface, but the most common sites are the posterior buccal  mucosa and the lateral borders of the tongue (Figs. 9-32  and 9-33). Bilateral and symmetrical lesions are fairly  common.    ® Fig. 9-31 Allergic Mucosal Reaction to Systemic Drug Admin-  istration. A, Bilateral erosions of lower labial mucosa with intermixed  striae. Biopsy revealed lichenoid pattern of mucositis but with numer-  ous plasma cells intermixed with the lymphocytes. The erosions ulti-  mately were proven to be associated with simvastatin. B, Same patient  depicted in A after discontinuation of simvastatin.    @ Fig. 9-32 Lichenoid Drug Reaction to Allopurinol. Irregular area  of superficial erosion of the left buccal mucosa. Lesions were also  present on the contralateral buccal mucosa and bilaterally on the  lateral borders of the tongue.    Anaphylactic stomatitis typically reveals a nonspecific  pattern of subacute mucositis that contains lymphocytes  intermixed with eosinophils and neutrophils. Fixed drug  eruptions also reveal a mixed inflammatory cellular infiltrate    ® Fig. 9-33 Allergic Mucosal Reaction to Systemic Drug Admin-  istration. Large irregular erosion of the right ventral surface of the  tongue. The lesion arose secondary to use of oxaprozin, a nonsteroidal  antiinflammatory drug (NSAID).    that consists of lymphocytes, eosinophils, and neutrophils,  often combined with spongiosis and exocytosis of the epi-  thelium. Vacuolar change of the basal cell layer and indi-  vidual necrotic epithelial cells are occasionally noted. The  drug reactions that simulate lichen planus, lupus erythema-  tosus, and pemphigus resemble their namesakes. The histo-  pathologic and immunologic features of these chronic drug  reactions cannot be used reliably to separate them from  their associated primary immunologic disease.  Immunofluorescence has been used in an attempt to  separate drug reactions from primary vesiculoerosive disease.  In most instances, this technique has proven to be unsatis-  factory. In spite of these findings, a unique pattern of reac-  tion has been seen when indirect immunofluorescence for  IgG has been performed in patients with lichenoid drug  reactions. In many of these patients, a distinctive annular  fluorescent pattern, termed string of pearls, has been noted  along the cell membrane of the basal cell layer of stratified  squamous epithelium. The detected circulating antibody  has been termed basal cell cytoplasmic antibody. Although  further study is desirable, this technique may prove to be a  useful adjunct during evaluation of oral lichenoid lesions.    A detailed medical history must be obtained, and the patient  should be questioned closely concerning the use of both  prescription and over-the-counter medications. Once a  potentially offending medication is discovered, a temporal  relationship between the drug’s use and the mucosal altera-  tion must be established. The association may be acute and  obvious, or the onset of the oral lesions may be delayed. If  more than one medication is suspected, the most recently  administrated medication often is the culprit. If the last-to-  be-introduced drug does not appear responsible, serial  elimination of the medications can be performed in collabo-  ration with the patient's physician until the offending agent  is discovered.    In chronic drug reactions, definitive diagnosis can be  made if the mucosal alterations resolve after discontinuation  of the medication and recur on reintroduction of the agent.  Presumptive diagnosis usually is sufficient and justified  when the mucosal alterations clear after cessation of the  offending medication.   In possible lupus-like drug reactions, serum evaluation  for generic antinuclear antibodies (ANAs) and antibodies  against double-stranded DNA and histones often can be  beneficial. Lupus-like drug reactions typically are associated  with circulating generic ANAs and antibodies against his-  tones, whereas lupus erythematosus also reveals antibodies  to double-stranded DNA (a finding not typically noted in  drug reactions). This pattern does not hold true in reactions  associated with the TNF-o antagonists, infliximab and  etanercept, which simulate systemic lupus erythematosus  (SLE) very closely and are associated with antibodies to  double-stranded DNA.    The responsible medication should be discontinued and, if  necessary, replaced with another drug that provides a similar  therapeutic result. Localized acute reactions can be resolved  with topical corticosteroids. When systemic manifestations  are present, anaphylactic stomatitis often warrants systemic  administration of adrenaline (epinephrine), corticosteroids,  or antihistamines. Chronic oral lesions often resolve on  cessation of the offending drug, but topical corticosteroids  may sometimes be required for complete resolution.   If discontinuation of the medication is contraindicated,  palliative care can be provided; however, corticosteroids  often are ineffective as long as the offending medication is  continued.    The list of agents reported to cause allergic contact stoma-  titis reactions in the oral cavity is extremely diverse. Numer-  ous foods, food additives, chewing gums, candies, dentifrices,  mouthwashes, glove and rubber dam materials, topical anes-  thetics, restorative metals, acrylic denture materials, dental  impression materials, and denture adhesive preparations  have been mentioned. Two types of allergens, cinnamon (see  page 322) and dental restorative materials (see page 324),  demonstrate clinical and histopathologic patterns that are  sufficiently unique to justify separate descriptions.   Although the oral cavity is exposed to a wide variety of  antigens, the frequency of a true allergic reaction to any one  antigen from this contact appears to be rare. This was veri-  fied in a prospective study of 13,325 dental patients, in  which only seven acute and 15 chronic cases of adverse  effects were attributed to dental materials. The oral mucosa  is much less sensitive than the surface of the skin; this is  most likely because of the following:   ¢ The limited keratinization of oral mucosa makes hapten  binding more difficult, and the high vascularity tends to  remove any antigen quickly.   ¢ The allergen may not be recognized (because of the lower  density of Langerhans cells and T lymphocytes).   If the skin has been sensitized originally, the mucosa may  or may not demonstrate future clinical sensitization. In  contrast, if the mucosa is sensitized initially, then the skin  usually demonstrates similar changes with future exposure.  Long-term oral exposure may induce tolerance and reduce  the prevalence of cutaneous sensitivity in some instances.  For example, exposure to nickel-containing orthodontic  hardware has been associated with a reduced prevalence of  future cutaneous sensitivity to nickel jewelry.   In addition to oral lesions, allergic contact reactions may  produce exfoliative cheilitis (see page 278) or perioral der-  matitis (see next section). As mentioned in Chapter 8, most  cases of chronic cheilitis represent local irritation, usually  from chronic lip licking. In spite of this, investigation has  revealed that approximately 25% of affected cases are aller-  gic contact cheilitis from a variety of antigens that include  medications, lipsticks, sunscreens, toothpaste, dental floss,  nail polishes, and cosmetics.    Allergic contact stomatitis can be acute or chronic. Of those  cases diagnosed, there is a distinct female predominance in  both forms. After eliminating focal trauma, localized signs  and symptoms suggest mucositis from an isolated allergen  (e.g., dental metal); in contrast, widespread mouth pain  suggests an association with a more diffuse trigger, such as  food, drink, flavorings, or oral hygiene materials.   In patients with acute contact stomatitis, burning is the  most frequent symptom. The appearance of the affected  mucosa is variable, from a mild and barely visible redness  to a brilliantly erythematous lesion with or without edema.  Vesicles are rarely seen and, when present, rapidly rupture  to form areas of erosion (Fig. 9-34). Superficial ulcerations  that resemble aphthae occasionally arise. Itching, stinging,  tingling, and edema may be noted.   In chronic cases the affected mucosa is typically in  contact with the causative agent and may be erythematous  or white and hyperkeratotic. Periodically, erosions may  develop within the affected zones. Some allergens, especially  toothpastes, can cause widespread erythema, with desqua-  mation of the superficial layers of the epithelium (Fig.  9-35). Allergic contact cheilitis demonstrates clinical fea-  tures identical to those cases created through chronic irrita-  tion, and it most frequently appears as chronic dryness,  scaling, fissuring, or cracking of the vermilion border of the  lip. Rarely, symptoms identical to orolingual paresthesia can  be present without any clinically evident signs. One distinc-  tive pattern, plasma cell gingivitis, is discussed elsewhere    @ Fig. 9-34 Allergic Contact Stomatitis to Aluminum Chloride.  Mucosal erythema and vesicles of the lower labial mucosa caused by  use of aluminum chloride on gingival retraction cord.    ® Fig. 9-35 Allergic Contact Stomatitis to Toothpaste. Erythema-  tous mucosa with superficial epithelial desquamation.    Usually, the diagnosis of acute contact stomatitis is straight-  forward because of the temporal relationship between the  use of the agent and the resultant eruption. If an acute oral  or circumoral reaction is noted within 30 minutes of a  dental visit, then allergy to all used dental materials, local  anesthetics, and gloves should be investigated.   The diagnosis of chronic contact stomatitis is much more  difficult. Most investigators require good oral health, elimi-  nation of all other possible causes, and visible oral signs,  together with a positive history of allergy and a positive skin  test result to the suspected allergen. If allergic contact sto-  matitis is strongly suspected but skin test results are nega-  tive, then direct testing of the oral mucosa can be attempted.    The antigen can be placed on the mucosa in a mixture with  Orabase or in a rubber cup that is fixed to the mucosa.    In mild cases of acute contact stomatitis, removal of the  suspected allergen is all that is required. In more severe  cases, antihistamine therapy, which is combined with topical  anesthetics, usually is beneficial. Chronic reactions respond  to removal of the antigenic source and application of a  topical corticosteroid gel or oral suspension.   When attempting to discover the source of a diffuse  allergic mucositis, use of plain baking soda or toothpaste  that is free of flavoring or preservatives is recommended.  The patient also should be instructed to avoid mouthwash,  gum, mints, chocolate, cinnamon-containing products, car-  bonated drinks, and excessively salty, spicy, or acidic foods.  If an association cannot be found, then cutaneous patch  testing may provide helpful information.    Perioral dermatitis does not refer to every rash that occurs  around the mouth but is specific for a unique inflammatory  skin disease that involves the cutaneous surfaces surround-  ing the facial orifices. Because the disorder also often  involves the paranasal and periorbital skin, periorificial  dermatitis is the most appropriate designation. Although  the process is idiopathic, the dermatitis is associated strongly  with uncritical use of potent topical corticosteroids on the  facial skin. Fluorinated toothpaste and overuse of heavy  facial cosmetics, creams, and moisturizers also are impli-  cated in many patients. Weaker correlations have been seen  with systemic corticosteroids, corticosteroid inhalers, and  nasal corticosteroids. Heavy exposure to ultraviolet light,  heat, and wind appears to worsen the dermatitis. Some of  these substances may initially induce an irritant or allergic  contact dermatitis, whereas others are thought to produce  inappropriate occlusion of the skin surface with subsequent  proliferation of skin flora.    Perioral dermatitis appears with persistent erythematous  papules, papulovesicles, and papulopustules that involve the  skin surrounding the vermilion border of the upper and  lower lips. In addition, involvement of the perinasal skin is  seen in approximately 40% of affected patients, and 25%  have periorbital dermatitis (Fig. 9-36). Classically, there is  a zone of spared skin immediately adjacent to the vermilion  border. Pruritus and burning are variable. The vast majority  of the cases are diagnosed in women between the ages of 20  to 45 years, lending further support to the association with  cosmetic use. In spite of this, the process does occur in men  and in children of either sex.    @ Fig. 9-36 Perioral Dermatitis. Multiple erythematous papules of  the skin surrounding the vermilion border of the lips. Note similar  involvement around the nasal orifices (periorificial dermatitis). (Courtesy  of Dr. Billy Millay.)    Biopsy of perioral dermatitis demonstrates a variable  pattern. In many cases there is a chronic lymphohistiocytic  dermatitis that often exhibits spongiosis of the hair follicles.  In other patients a rosacea-like pattern is noted in which  there is perifollicular granulomatous inflammation. On  occasion, this histopathologic pattern has been misdiag-  nosed as sarcoidosis.    Most cases resolve with “zero therapy,” which includes dis-  continuation of corticosteroids, cosmetics, and facial creams.  Discontinuation of potent topical corticosteroid use often  is followed by a period of exacerbation, which can be mini-  mized by substitution of a less potent corticosteroid before  total cessation. Oral tetracycline is considered the therapeu-  tic gold standard for perioral dermatitis but must be avoided  during childhood and pregnancy. In addition, a shortage of  tetracycline in the United States has made its use problem-  atic. No strong evidence has been presented to demonstrate  that doxycycline or minocycline is equivalent or superior to  tetracycline. Luckily, perioral dermatitis also responds well  to topical pimecrolimus or topical erythromycin. Weaker  therapeutic recommendations include topical metronida-  zole, clindamycin, tacrolimus, tetracycline, adapalene, or  azelaic acid, plus systemic erythromycin or isotretinoin. The  pathosis typically demonstrates significant improvement  within several weeks and total resolution in a few months.  Recurrence is uncommon.    Mucosal abnormalities secondary to the use of artificially  flavored cinnamon products are fairly common, but the    range of changes was not recognized widely until the late  1980s. Cinnamon oil is used as a flavoring agent in confec-  tionery, ice cream, soft drinks, alcoholic beverages, pro-  cessed meats, gum, candy, toothpaste, breath fresheners,  mouthwashes, and even dental floss. Concentrations of the  flavoring are up to 100 times that in the natural spice. The  reactions are documented most commonly in those prod-  ucts associated with prolonged or frequent contact, such as  candy, chewing gum, and toothpaste. The anticalculus com-  ponents of tartar-control toothpastes have a strong bitter  flavor and require a significant concentration of flavoring  agents including cinnamon to hide the taste, resulting in a  greater chance these formulations will cause oral mucosal  lesions. Although much less common, reactions to cinna-  mon in its natural spice form have been documented.    ‘The clinical presentations of contact stomatitis vary some-  what, according to the medium of delivery. Toothpaste  results in a more diffuse pattern; the signs associated with  chewing gum and candy are more localized. Pain and  burning are common symptoms in all cases.   ‘The gingiva is the most frequent site affected by tooth-  paste, often resembling plasma cell gingivitis (see page  145); enlargement, edema, and erythema are common.  Sloughing of the superficial oral epithelium without cre-  ation of an erosion is seen commonly. Erythematous muco-  sitis, occasionally combined with erosion, has been reported  on the buccal mucosa and tongue. Exfoliative cheilitis and  circumoral dermatitis also may occur.   Reactions from chewing gum and candy are more local-  ized and typically do not affect the lip vermilion or perioral  skin. Most of the lesions appear on the buccal mucosa and  lateral borders of the tongue. Buccal mucosal lesions often  are oblong patches that are aligned along the occlusal plane  (Fig. 9-37). Individual lesions have an erythematous base  but often are predominantly white as a result of hyperkera-  tosis of the surface epithelium. Ulceration within the lesions  may occur. Hyperkeratotic examples often exhibit a ragged  surface and occasionally may resemble the pattern seen in  morsicatio (see page 259). Lingual involvement may become  extensive and spread to the dorsal surface (Fig. 9-38). Sig-  nificant thickening of the surface epithelium can occur and  may raise clinical concern for oral hairy leukoplakia (OHL)  (see page 242) or carcinoma (Fig. 9-39).    Usually, the epithelium in contact stomatitis from artificial  cinnamon flavoring is acanthotic, often with elongated rete  ridges and thinning of the suprapapillary plates. Hyperkera-  tosis and extensive neutrophilic exocytosis may be present.  The superficial lamina propria demonstrates a heavy inflam-  matory cell infiltrate that consists predominantly of lym-  phocytes that may be intermixed with plasma cells,  histiocytes, or eosinophils. This infiltrate often obscures the    ° Fig. 9-38 Contact Stomatitis from Cinnamon Flavoring. Sensi-  tive and thickened hyperkeratosis of the lateral and dorsal surface of  the tongue on the right side.    epithelium and connective tissue interface (Fig. 9-40). A  characteristic feature in localized cases caused by gum,  mints, or candies is the frequent presence of an obvious  perivascular inflammatory infiltrate that extends well below  the interface zone (Fig. 9-41).    vascular inflammatory infiltrate consisting predominantly of lympho-  cytes and plasma cells.    With a high index of suspicion and knowledge of the varia-  tions of the clinical pattern, the diagnosis of localized  contact stomatitis often can be made from the clinical  appearance and the history of cinnamon use. Often biopsies  are performed for atypical or extensive cases because of the  differential diagnosis, which includes several significant  vesiculoerosive and neoplastic conditions. The histopatho-  logic features are not specific, but they are sufficient to raise  a high index of suspicion in an oral and maxillofacial  pathologist who is familiar with the pattern. Use of  cinnamon-containing toothpaste should be investigated in  every patient with an atypical pattern of gingivitis. Diet-  related examples often are the most difficult to diagnose and  may necessitate cutaneous allergy patch testing or a diet  diary to isolate the cause.    Typically, the signs and symptoms disappear within 1 week  after the discontinuation of the cinnamon product. If the  patient resumes intake of the product, then the lesions    reappear, usually within 24 hours. On occasion, resolution  is more gradual and the patient may benefit from short-  term use of a topical corticosteroid.    Dental amalgam has been in active use for over 180 years  and has proven to be a durable and relatively inexpensive  material that remains one of the most commonly placed  dental restorations. Because of an associated low-level  release of mercury from these fillings (an amount signifi-  cantly less than the daily contribution from food and non-  dental sources), its use has been blamed for a wide variety  of health concerns. Due to the controversy, a number of  controlled studies were performed, showing no association  between the presence of dental amalgams and systemic  disease. Two oral pathoses, burning mouth syndrome and  orofacial granulomatosis, also have been correlated with  the presence of amalgams by some investigators, but no  conclusive evidence exists to associate these disorders with  the dental restorative material. The primary adverse effects  that are well documented include acute and chronic hyper-  sensitivity reactions.   Dental amalgams contain mercury, silver, tin, and copper,  with some variations also including zinc, indium, palla-  dium, or platinum. The vast majority of hypersensitivity  reactions to dental restorative materials are to dental  amalgam, usually associated with the mercury content.  Reactions have been seen much less frequently to other  dental restorations containing materials such as gold, beryl-  lium, chromium, cobalt, or composite resins.   Although rare acute reactions to mercury may be seen  following placement of amalgam, the vast majority of  adverse alterations represent chronic type IV hypersensitiv-  ity reactions that are seen most commonly associated with  older and corroded amalgams. It is believed the metal ions  released by corrosion haptenize with oral keratinocyte  surface proteins and initiate a cell-mediated autoimmune  response directed at the basal cell layer of the epithelium.  Some investigators have called these chronic alterations  “galvanic lesions,” but neither clinical nor experimental  studies support the electrogalvanic hypothesis of origin.   These chronic contact reactions appear clinically and  histopathologically similar to lichen planus (see page 729)  but demonstrate a different mucosal distribution. When  patients with true oral lichen planus are examined, the  lesions migrate and exhibit no direct correlation to contact  with dental materials. In addition, patients with lichen  planus do not demonstrate a significantly increased positive  patch testing to dental restorative materials and exhibit  minimal-to-no clinical improvement on removal of their  amalgams.   However, there is a subgroup of patients whose lichenoid  lesions do not migrate and usually involve only the mucosa  adjacent to a dental metal. On patch testing, the vast    majority of these patients react to the offending metal, and  the lesions resolve rapidly after removal of adjacent amal-  gams. Such lesions should be diagnosed as a lichenoid  contact reaction to a dental restorative material, not as true  lichen planus.    Acute reactions to dental amalgams are extremely rare and  related to an immediate hypersensitivity reaction to mercury.  ‘The signs tend to arise within hours after placement of an  amalgam and present with erythematous, pruritic, and urti-  carial lesions of the ipsilateral oral mucosa and facial skin.  In severe reactions, soft tissue edema, tachycardia, and  breathing difficulties also are seen.   The vast majority of lichenoid contact reactions affect  the posterior buccal mucosa and the ventral surface of the  lateral borders of the tongue. The lesions usually are con-  fined to the area of contact and may be white or erythema-  tous, with or without peripheral striae (Fig. 9-42). Most  patients have no symptoms, but periodic erosion may be  noted. In all likelihood, many of the lesions previously  reported as the so-called plaque type of lichen planus were,  in reality, lichenoid contact reactions.    The diagnosis of a lichenoid contact reaction is made from  the clinical appearance of the lesion, the lack of lesional  migration, and the correlation to adjacent dental metal  (Fig. 9-43). Although the histopathologic features may be  indistinguishable from lichen planus, biopsy occasionally is  performed to confirm the clinical impression and to rule  out other pathoses such as epithelial dysplasia. Although  patch testing is positive in up to 70% of patients with    contact reactions and similarly reactive in less than 4% of  patients with true lichen planus, the clinical presentation  has proven to be a more reliable diagnostic indicator than  patch testing.    Biopsy of allergic contact stomatitis from dental materials  exhibits numerous features of lichen planus. The surface  epithelium may be hyperkeratotic, atrophic, or ulcerated.  Areas of hydropic degeneration of the basal cell layer often  are present. The superficial lamina propria contains a dense  bandlike chronic inflammatory cellular infiltrate consisting  predominantly of lymphocytes, but there may be scattered  plasma cells. On occasion, deeper lymphoid aggregates may  be noted, often in a perivascular orientation.    ® Fig. 9-43 Oral Mucosal Contact Reaction to Dental Amalgam.  Radiating pattern of hyperkeratotic striae on the posterior buccal  mucosa that contacts a large distobuccal amalgam of the permanent  mandibular second molar.    © Fig. 9-42 Oral Mucosal Contact Reaction to Dental Amalgam. A, Hyperkeratotic lesion with a  peripheral radiating pattern on the lateral border of the tongue on the right side; the altered mucosa  contacted the amalgams of the adjacent mandibular molar teeth. The lesion remained in the same loca-  tion for 5 years and periodically became erosive and symptomatic. Smoothing and polishing of the  adjacent restorations had no effect. B, Appearance of previously altered area of the tongue 14 days after  removal of adjacent amalgams. Note total resolution of the mucosal alterations.    In patients with acute hypersensitivity reactions to the  mercury in an amalgam, the process usually is self-limiting  and resolves spontaneously within 2 to 3 days. In spite of  this, systemic symptoms, such as significant breathing difh-  culties, may necessitate removal of the newly placed amalgam.   For chronic lichenoid reactions, local measures, such as  improved oral hygiene, smoothing, polishing, and recon-  touring of the amalgam restoration, should be attempted  before more aggressive measures, because clinically similar  lesions have been noted as a result of surface plaque accu-  mulation. If this is unsuccessful, then the amalgam in ques-  tion should be replaced. Because patients rarely may exhibit  hypersensitivity to composite resins, use of inert materials  (such as, glass ionomer, porcelain, or porcelain-fused-to-  metal) is recommended. Like lichen planus, some investiga-  tors believe untreated lichenoid contact reactions rarely may  evolve into carcinoma, although the possibility that some  preneoplastic leukoplakias are mistaken for lichenoid  contact reactions cannot be ruled out. Although this asso-  ciation is far from proven, removal of amalgams adjacent to  possible lichenoid contact reactions appears prudent.  Lichenoid lesions that fail to resolve following removal of  the adjacent metal should be evaluated further.    Angioedema is a diffuse edematous swelling of the soft  tissues that most commonly involves the subcutaneous and  submucosal connective tissues but may affect the gastroin-  testinal or respiratory tract, occasionally with fatal results.  The disorder has been referred to as Quincke disease, after  the clinician who initially related the changes to an altera-  tion in vascular permeability. The outdated term angioneu-  rotic edema also has been used, because affected patients  often complained of a choking sensation and were labeled  neurotic.   The most common cause is mast cell degranulation,  which leads to histamine release and the typical clinical  alterations. IgE-mediated hypersensitivity reactions caused  by drugs, foods, plants, dust, and inhalants produce mast  cell degranulation and are fairly common. Contact allergic  reactions to foods, cosmetics, topical medications, and even  dental rubber dams also have been responsible. Mast cell  degranulation can even result from physical stimuli, such as  heat, cold, exercise, emotional stress, solar exposure, and  significant vibration.   An unusual pattern of drug reaction that can produce  severe forms of angioedema that are not mediated by IgE is  the type associated with use of drugs called angiotensin-  converting enzyme (ACE) inhibitors. These medications rep-  resent one of the most frequently prescribed drugs, with 35  to 40 million patients currently taking these antihyperten-  sives. Some of the most popular are captopril, enalapril, and    lisinopril. The swelling associated with these drugs does not  respond well to antihistamines and was thought to be the  result of excess bradykinin (ACE degrades bradykinin). In  an attempt to avoid this angioedema, a second generation  of medications called angiotensin II receptor blockers (e.g.,  losartan and valsartan) was developed specifically to avoid  any inhibition of bradykinin degradation. These newer  medications lower the frequency of angioedema but do not  eliminate the adverse reaction. The prevalence of this pattern  of angioedema is estimated to be 0.1% to 0.2% of those  who use ACE inhibitors. In the majority of affected patients,  the angioedema arises within hours of initial use of the  drug. In up to 30% of the cases, the angioedema is delayed,  with the longest reported interval between drug use initia-  tion and the initial attack being 10 years. Attacks precipi-  tated by dental procedures have been reported in long-term  users of ACE inhibitors. Many clinicians overlook the asso-  ciation between angioedema and ACE inhibitors, with  studies demonstrating continued administration of the  medication in more than 50% of affected patients.   Angioedema also can result from activation of the  complement pathway. This may be hereditary or acquired.  Two rare autosomal dominant hereditary forms are seen.  Type I, comprising 85% of the hereditary cases, is caused  by a quantitative reduction in the inhibitor that prevents  the transformation of Cl to Cl esterase. Without adequate  levels of Cl esterase inhibitor (C1-INH), Cl esterase  cleaves C4 and C2 and results in angioedema. Type II  exhibits normal levels of C1-INH, but the inhibitor is  dysfunctional.   The acquired type of C1-INH deficiency is seen in asso-  ciation with certain types of lymphoproliferative diseases  (Caldwell syndrome) or in patients who develop specific  autoantibodies. In lymphoproliferative diseases, monoclo-  nal antibodies directed against the tumor cells activate Cl  and lead to consumption of C1-INH. In the autoimmune  variant, the antibody attaches to the Cl receptor on the  C1-INH molecule, leading to dysfunctional C1-INH and  consumption of C1. In both the acquired and the heredi-  tary forms of abnormal C1-INH activity, minor trauma,  such as a dental procedure, can precipitate an attack.   Finally, angioedema has been seen in the presence of high  levels of antigen-antibody complexes (e.g., lupus erythema-  tosus and viral or bacterial infections) and in patients with  grossly elevated peripheral blood eosinophil counts.    Angioedema is characterized by the relatively rapid onset of  soft, nontender tissue swelling, which may be solitary or  multiple (Fig. 9-44). In the hereditary forms, the initial  onset typically is noted in childhood or adolescence. The  episodes are unpredictable and intermixed with edema-free  intervals. Recurrent skin swelling and abdominal pain are  the most frequent presentations. The extremities are the  most common cutaneous sites of involvement, although the  face, genitals, trunk, and neck also can be affected. Although    not individually frequent, edema of the larynx, pharynx,  uvula, or soft palate may be noted when patients are moni-  tored for extended periods (and may be associated with  respiratory distress). A deeper voice, hoarseness, aphonia,  and dyspnea are important warning signs. Recurrent  snoring-induced edema of the soft palate has been reported  and associated with severe dyspnea. Isolated tongue involve-  ment is uncommon. Involvement of the skin and mucous  membranes can cause enlargements that may measure up  to several centimeters in diameter (Fig. 9-45). Although  pain is unusual, itching is common and erythema may be    present. The enlargement typically resolves over 24 to 72  hours. In contrast to the hereditary variants, allergic,  acquired, and ACE inhibitor—associated angioedema dem-  onstrate significant involvement of the head and neck, such  as the face, lips, tongue, floor of mouth, pharynx, and  larynx. The risk of angioedema associated with ACE inhibi-  tors is significantly greater in blacks (three to four times that  of other races), and this pattern is the type most frequently  encountered by oral health practitioners.    In cases of allergic causation, the diagnosis of angioedema  often is made from the clinical presentation in conjunction  with the known antigenic stimulus. When multiple anti-  genic exposures occur, the diagnosis of the offending agent  can be difficult and involves dietary diaries and antigenic  testing.   Those patients whose conditions cannot be related to  antigenic exposure or medications should be evaluated for  the presence of adequate functional C1-INH. In the heredi-  tary types, both forms exhibit normal levels of C1 and  decreased levels of functional C1-INH. Type I demonstrates  a decreased quantity of C1-INH; type II exhibits normal  levels of the inhibitor, but it is dysfunctional. The acquired  type associated with lymphoproliferative diseases demon-  strates low C1 and low C1-INH, whereas the autoimmune  variant exhibits low C1 and dysfunctional C1-INH.    @ Fig. 9-45 Angioedema. A, Soft, nontender tissue swelling of the face arose relatively rapidly after  dental treatment. B, Facial appearance after resolution of edematous facial enlargement.    The treatment of allergic angioedema usually consists of oral  antihistamine therapy. If the attack is not controlled or if  laryngeal involvement is present, then intramuscular epi-  nephrine should be administered. If the epinephrine does  not stop the attack, then intravenous corticosteroids and  antihistamines should be given.   Cases of angioedema related to ACE inhibitors are not  IgE-mediated and often do not respond to antihistamines  and corticosteroids. In spite of this, some investigators  believe use of corticosteroids and histamine blockers short-  ens the time of intubation in patients who require airway  support. Although the mechanism is unclear, some patients  with ACE inhibitor—associated angioedema also have  responded to C1-INH concentrate. In many patients, no  form of pharmaceutical intervention is effective, and the  patients must be kept under close observation until the  airway is no longer at risk. Patients experiencing ACE  inhibitor—associated angioedema should avoid all medica-  tions in this class of drugs, and their physicians should  consider alternative hypertension management strategies.  Angiotensin II receptor blockers do not appear to be safe  alternatives.   Those cases related to C1-INH deficiency also do not  respond to antihistamine, corticosteroid, or adrenergic  therapy. Intubation and tracheostomy may be required for  laryngeal involvement. Fresh freeze-dried plasma has been  used; however, some investigators do not recommend its  use because there is a risk of transmitting infection, and  it replaces not only C1-INH but also potentially harmful  Cl esterase, Cl, C2, and C4. C1-INH concentrate and  esterase-inhibiting drugs (aprotinin or tranexamic acid) are  the treatments of choice for acute attacks. Because acute  attacks of hereditary angioedema are not only unpleasant  but also potentially life threatening, prevention is para-  mount. All patients should carry medical warning cards  that state the diagnosis and list elementary precautions.  Prophylaxis for C1-INH deficiency is recommended in  patients who have more than three attacks per year. Patients  should avoid violent physical activity and trauma. Medical  prophylaxis is recommended before any dental or surgical  procedure. In the hereditary types, such prophylaxis typi-  cally includes a combination of: 1) an attenuated andro-  gen, such as danazol or stanozolol (androgens induce  hepatic synthesis of C1-INH); 2) tranexamic acid or apro-  tinin; and 3) one or more infusions of C1-INH. The auto-  immune acquired type is best prevented through the use of  corticosteroids.   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Tosti A, Piraccini BM, Peluso AM: Contact and irritant stomatitis,  Semin Cutan Med Surg 16:314-319, 1997.   van Loon LAJ, Bos JD, Davidson CL: Clinical evaluation of fifty-six  patients referred with symptoms tentatively related to allergic  contact stomatitis, Oral Surg Oral Med Oral Pathol 74:572-575,  1992.   Boeck K, Abeck D, Werfel S, et al: Perioral dermatitis in children—  clinical presentation, pathogenesis-related factors and response to  topical metronidazole, Dermatology 195:235-238, 1997.   Hall CD, Reichenberg J: Evidence based review of perioral dermatitis  therapy, G Ital Dermatol Venereol 145:433-444, 2010.   Nguyen V, Eichenfield LF: Periorificial dermatitis in children and  adolescents, J Am Acad Dermatol 55:781—785, 2006.   Vanderweil SG, Levin NA: Perioral dermatitis: it’s not every rash that  occurs around the mouth, Dermatol Nurs 21:317-320, 353,  2009.    Cinnamon-Induced Contact Stomatitis  Allen CM, Blozis GG: Oral mucosal reactions to cinnamon-flavored  chewing gum, / Am Dent Assoc 116:664—-667, 1988.    Drake TE, Maibach HI: Allergic contact dermatitis and stomatitis  caused by a cinnamic aldehyde-flavored toothpaste, Arch Dermatol  112:202-203, 1976.   Endo H, Rees TD: Clinical features of cinnamon-induced contact  stomatitis, Compend Contin Educ Dent 27:403-409, 2006.   Lamey P-J, Ress TD, Forsyth A: Sensitivity reaction to the cinnam-  aldehyde component of toothpaste, Br Dent J 168:115-118,  1990.   Mihail RC: Oral leukoplakia caused by cinnamon food allergy,  J Otolaryngol 21:366-367, 1992.   Miller RL, Gould AR, Bernstein ML: Cinnamon-induced stomatitis  venenata: clinical and characteristic histopathologic features, Oral  Surg Oral Med Oral Pathol 73:708-7 16, 1992.   Holmstrup P: Reaction of the oral mucosa related to silver amalgam:  a review, J Oral Pathol Med 20:1-7, 1991.   Jameson MW, Kardos TB, Kirk EE, et al: Mucosal reactions to  amalgam restorations, / Oral Rehabil 17:293-301, 1990.   Kal BI, Evcin O, Dundar N, et al: An unusual case of immediate  hypersensitivity reaction associated with an amalgam restoration,  Br Dent J 205:547—550, 2008.   Larsson A, Warfvinge G: Oral lichenoid contact reactions may occa-  sionally transform into malignancy, Eur J Cancer Prev 14:525-  529, 2005.   Luiz AC, Hirota SK, Dal Vechio A, et al: Diagnosing oral lichenoid  contact reaction: clinical judgment versus skin-patch test, Minerva  Stomatol 61:311-317, 2012.   Mallo-Pérez L, Diaz-Donado C: Intraoral contact allergy to materials  used in dental practice: a critical review, Med Oral 8:334-347,  2003.    McCullough MJ, Tyas MJ: Local adverse effects of amalgam restora-  tions, /nt Dent J 58:3—9, 2008.   Thornhill MH, Pemberton MN, Simmons RK, et al: Amalgam-  contact hypersensitivity lesions and oral lichen planus, Oral Surg   Al-Khudari S, Loochtan MJ, Peterson E, et al: Management of  angiotensin-converting enzyme inhibitor-induced angioedema,  Laryngoscope 121:2327-2334, 2011.   Angostoni A, Cicardi M: Hereditary and acquired Cl-inhibitor defi-  ciency: biological and clinical characteristics in 235 patients,  Medicine 71:206-215, 1992.   Grant NN, Deeb ZE, Chia SH: Clinical experience with angiotensin-  converting enzyme inhibitor-induced angioedema, Otolaryngol  Head Neck Surg 137:931-935, 2007.   Greaves M, Lawlor F: Angioedema: manifestations and management,  J Am Acad Dermatol 25:155-165, 1991.   Hermans C, VanDer Vost S, Lambert C: Successful management of  hereditary angioedema during tonsillectomy: a case report, Blood  Coagul Fibrinolysis 23:155-157, 2012.   Nielsen EW, Gramstad S: Angioedema from angiotensin-converting  enzyme (ACE) inhibitor treated with complement 1 (C1) inhibi-  tor concentrate, Acta Anaesthesiol Scand 50:120-122, 2006.   Rees SR, Gibson J: Angioedema and swellings of the orofacial region,    Human papillomavirus (HPV) comprises a large group of  double-stranded DNA viruses, belonging to the family Pap-  illomaviridae. HPV exhibits tropism for squamous epithe-  lium and may infect skin or mucosa. Mucosal infection may  arise in the anogenital region, upper aerodigestive tract, and  other sites. More than 130 HPV types have been identified,  including more than 30 types known to infect the oral  mucosa in particular. Although HPV is associated with a  variety of benign, premalignant, and malignant epithelial  lesions, most infected individuals are asymptomatic and  lack clinically evident disease.   The reported prevalence of asymptomatic oral HPV  infection varies considerably (range 0% to 81%, mean  11%), likely due to differences in sampling techniques,  detection methods, and study cohorts. Many studies have  analyzed shed epithelial cells in oral rinses, although such  samples do not discriminate between oral and oropharyn-  geal infection. Notwithstanding, meta-analyses and system-  atic reviews of the literature suggest that oral HPV infection  is present in approximately 5% to 12% of normal, healthy  individuals. In the pediatric population, asymptomatic oral  HPV infection appears to be especially prevalent among  those under 1 year of age. Furthermore, a population-based  study conducted as part of the National Health and Nutri-  tion Examination Survey (NHANES) for 2009 to 2010  estimated the prevalence of oral HPV infection among indi-  viduals 14 to 69 years old in the United States to be about  7%. In this study, the age distribution exhibited a bimodal  pattern, with peaks at 30 to 34 years and 60 to 64 years.  Factors associated with an increased prevalence of oral HPV  infection in adolescence and adulthood include male gender,  an increased number of sexual partners, tobacco smoking,  and human immunodeficiency virus (HIV) infection.   Proposed modes of transmission for oral HPV infection  include sexual and nonsexual person-to-person contact, sali-  vary transfer, contaminated objects, autoinoculation, breast-  feeding, perinatal transmission, and, possibly, prenatal  transmission. The incubation period for benign HPV  disease is estimated to range from 3 weeks to 2 years.    The natural history of oral HPV infection is not well  characterized; however, it appears that in most people  the infection clears quickly, whereas in some individuals the  infection persists. Factors associated with persistent oral  infection include impaired immune function, older age,  smoking, presence of hand warts, and oral sex. Among  infants, persistence has been associated with parental oral  HPV infection and maternal hand warts. In normal-  appearing skin or mucosa, the virus may remain in a latent  state within the nuclei of basal epithelial cells; in such cases,  the viral DNA is present in episomal form (i.e., as an extra-  chromosomal circular molecule) in low copy numbers. In  contrast, in benign and low-grade premalignant HPV-  associated lesions, episomal HPV DNA typically is present  within the various epithelial cell layers in increased copy  numbers, with shedding of mature virions from the super-  ficial cells. With division of each infected basal epithelial  cell, one daughter cell remains in the basal layer to maintain  a viral reservoir; the other daughter cell migrates into the  suprabasal layers, interferes with cell cycle regulation, and  uses the host cell machinery to synthesize proteins needed  for viral replication. In the presence of high episomal  numbers, viral DNA may become integrated into the host  genome, leading to expression of oncoproteins and inactiva-  tion of tumor suppressor genes. Integrated HPV DNA  often is found in HPV-associated malignancies and high-  grade premalignant lesions, but it is not an absolute require-  ment for development of such lesions. Compared with  HPV infection, HPV-induced malignant transformation is  relatively rare. Based upon oncogenic potential, mucosal  HPV types are categorized as either low-risk (e.g., types 6,  11, 13, 32, 40, 42, 43, 44, 54, 55, 61, 62, 64, 67, 69, 70,  71, 72, and 81) or high-risk (e.g., types 16, 18, 31, 33, 35,  39, 45, 51, 52, 56; 58,59, 0G, G8, and 73),   In the United States, the Food and Drug Administration  has licensed two HPV vaccines (a quadrivalent vaccine  [Gardasil] targeting HPV types 6, 11, 16, and 18 and a  bivalent vaccine [Cervarix] targeting HPV types 16 and 18).  The Centers for Disease Control and Prevention recom-  mend routine HPV vaccination for females and males 11  to 12 years of age. Either quadrivalent or bivalent vaccine  is indicated for females for prevention of precancers and  cancers of the uterine cervix, vulva, and vagina; the quad-  rivalent vaccine is indicated for both genders for prevention    Oral squamous papilloma  Recurrent respiratory papillomatosis  Fungiform sinonasal papilloma  Inverted sinonasal papilloma    Focal epithelial hyperplasia 1, SZ 1, Gh Wal, WG, We, SS  Oropharyngeal squamous cell 16 1G, Ze GS, Si, AS, S2, ot  carcinoma  Conjunctival papilloma G, Ii, 1S  Skin Verruca vulgaris 2 1,446; % 1, 2s, 20, 22), 4h, Si, (SS, MSR  Verruca plana 6 10) 2, 5, 26-29, 38, 41, 49, 75, 76  Palmoplantar wart 1,4 2, 45, 57, 60, 63, 65, 66  Butcher's wart 2D, if 15 oh te 10, 23  Anogenital region Condyloma acuminatum Gril 2, 16, 18, 31, 33; 35, 39-45, 51-56, 538; 59;  66, 68, 70  Intraepithelial neoplasia Gy, ls WS, WE, Sil, GS AS}, Shs). EHS), sy, So, SZ, tisk lols), tote), Si), (6S),  (Gis), TAO), Mesh te  Cervical squamous cell carcinoma 16, 18 6, Vil, Sily 8, SS, BS), Hey, Sil, 2, SS), Sieh  59, 68    of genital warts. Furthermore, a recent large-scale study has  shown the bivalent vaccine to be more than 90% effective  in preventing oral HPV 16 and 18 infections among  women. A focus of ongoing investigation is the potential  for these vaccines to prevent oropharyngeal cancer and  other HPV-related lesions of the head and neck.   The following sections discuss benign HPV-associated  lesions of the oral cavity and other head and neck sites.  HPV-associated malignancies are addressed later in this  chapter. Examples of HPV-related lesions and their corre-  sponding virus types are listed in Table 10-1.    ‘The squamous papilloma is a benign, HPV-induced pro-  liferation of stratified squamous epithelium, resulting in a  papillary or verruciform mass. HPV types 6 and 11 are  identified most commonly, with an extremely low virulence  and infectivity rate.   The squamous papilloma occurs in one of every 250  adults and makes up approximately 3% of all oral lesions  submitted for biopsy. In addition, researchers have esti-  mated that squamous papillomas comprise 7% to 8% of all  oral masses or growths in children.    Most studies have reported either no significant gender  predilection or a slight male predominance. Some authors  have asserted that the oral squamous papilloma develops    ® Fig. 10-1 Squamous Papilloma. An exophytic lesion of the soft  palate with multiple short, white surface projections.    predominantly in children; however, epidemiologic studies  indicate that it can arise at any age and, in fact, is diagnosed  most often in persons 30 to 50 years old. Sites of predilec-  tion include the palate, tongue, and lips, but any oral  surface may be affected. This lesion is the most common  soft tissue mass arising from the soft palate.   The squamous papilloma is a soft, painless, usually  pedunculated, exophytic nodule with numerous fingerlike  surface projections that impart a “cauliflower” or wartlike  appearance (Fig. 10-1). Projections may be pointed or  blunted (Figs. 10-2 and 10-3), and the lesion may be white,  slightly red, or normal in color, depending on the amount  of surface keratinization. The papilloma is usually solitary    @ Fig. 10-2 Squamous Papilloma. A pedunculated lingual mass  with numerous long, pointed, and white surface projections. Note the  smaller projections around the base of the lesion.    © Fig. 10-3 Squamous Papilloma. A pedunculated mass of the  buccal commissure, exhibiting short or blunted surface projections and  minimal white coloration.    and enlarges rapidly to a maximum size of about 0.5 cm,  with little or no change thereafter. However, lesions as large  as 3.0 cm in greatest diameter have been reported.   It is sometimes difficult to distinguish this lesion clini-  cally from verruca vulgaris (see page 334), condyloma acu-  minatum (see page 335), verruciform xanthoma (see page  341), or multifocal epithelial hyperplasia (see page 336). In  addition, extensive coalescing papillary lesions (papilloma-  tosis) of the oral mucosa may be seen in several syndromes  and skin disorders, including nevus unius lateris, acanthosis  nigricans, focal dermal hypoplasia (Goltz-Gorlin) syn-  drome, and Down syndrome. Also attributed to HPV 6 and  11 infection, recurrent respiratory papillomatosis (RRP)  is a rare and potentially devastating disease of the respiratory  tract with a predilection for the larynx. RRP includes two  distinct types: (1) juvenile-onset and (2) adult-onset.  Hoarseness is the usual presenting feature, and rapidly pro-  liferating papillomas in the juvenile-onset type may obstruct  the airway. The strongest risk factor for juvenile-onset RRP  is a maternal history of genital warts during pregnancy;  HPV transmission via the birth canal, the placenta, or  amniotic fluid has been hypothesized.    ye.  as abe See a  @ Fig. 10-4 Squamous Papilloma. Low-power view showing a  pedunculated squamous epithelial proliferation. There are multiple  papillary projections with fibrovascular connective tissue cores.    The papilloma is characterized by a proliferation of keratin-  ized stratified squamous epithelium arranged in fingerlike  projections with fibrovascular connective tissue cores (Fig.  10-4). The connective tissue may show inflammation. The  keratin layer is thickened in lesions with a white clinical  appearance, and the epithelium typically exhibits a normal  maturation pattern. However, some papillomas demon-  strate basilar hyperplasia and mitotic activity, which can be  mistaken for mild epithelial dysplasia. Koilocytes (virus-  altered epithelial cells with crenated, pyknotic [small and  dark] nuclei surrounded by clear halos) sometimes are  evident high in the spinous cell layer.    Conservative surgical excision, including the base of the  lesion, is adequate treatment for the oral squamous papil-  loma, and recurrence is unlikely. Frequently, lesions have  been left untreated for years with no reported malignant  transformation, continuous enlargement, or dissemination  to other parts of the oral cavity.   Although spontaneous remission is possible, juvenile-  onset RRP tends to be continuously proliferative, some-  times leading to death by asphyxiation. Some investigators  have noted especially aggressive behavior among cases asso-  ciated with HPV 11 infection. The papillomatosis is treated  by repeated surgical debulking procedures to relieve airway  obstruction. Use of a microdebrider may decrease the risk  for postsurgical scarring and loss of vocal cord function.  Adjuvant therapy with interferon-alpha and cidofovir has  yielded variable results. Adult-onset RRP typically is less  aggressive and more localized. Conservative surgical removal  may be necessary to eliminate hoarseness from vocal cord  involvement. Transformation of RRP into squamous cell  carcinoma is rare and mainly occurs in patients with a  history of smoking or radiation exposure.    ® Fig. 10-5 Verruca Vulgaris. Several warts on the finger, exhibiting  a rough, papillary surface.    @ Fig. 10-6 Verruca Vulgaris. Nodular lesion of the skin exhibiting  numerous short papillary projections.    Verruca vulgaris is a focal, benign, HPV-induced hyper-  plasia of stratified squamous epithelium. HPV 2 is present  most often, although other HPV types may be found as well  (see Table 10-1). Verruca vulgaris is contagious and can  spread to other parts of a person’s skin or mucosa by auto-  inoculation. It infrequently develops on oral mucosa but is  extremely common on the skin.    Verruca vulgaris most often arises in children but occasion-  ally may develop even into middle age. The skin of the  hands is the most commonly involved site (Fig. 10-5). Oral  mucosal lesions usually are found on the vermilion border,  labial mucosa, or anterior tongue.   Typically, the verruca appears as a painless papule or  nodule with papillary projections or a rough, pebbly surface  (Figs. 10-6 and 10-7). It may be pedunculated or sessile.  Cutaneous lesions may be pink, yellow, or white; oral lesions  are almost always white. Verruca vulgaris enlarges rapidly to  its maximum size (usually <5 mm), and the size remains    @ Fig. 10-7 Verruca Vulgaris. Exophytic, white, papillary lesion of  the lateral soft palate.    constant for months or years thereafter unless the lesion is  irritated. Multiple or clustered lesions are common. On  occasion, extreme accumulation of compact keratin may  result in a hard surface projection, termed a cutaneous  horn or keratin horn. Other cutaneous lesions, including  seborrheic keratosis (see page 342), actinic keratosis (see  page 369), and squamous cell carcinoma, also may create a  cutaneous horn.    Verruca vulgaris is characterized by a proliferation of hyper-  keratotic stratified squamous epithelium arranged in finger-  like, pointed projections with connective tissue cores (Fig.  10-8). Chronic inflammatory cells often infiltrate the sup-  porting connective tissue. Elongated rete ridges tend to  converge toward the center of the lesion, producing a  “cupping” effect. A prominent granular cell layer (hyper-  granulosis) exhibits coarse, clumped keratohyaline granules.  Abundant koilocytes often are seen in the superficial spinous  layer. Koilocytes are HPV-altered epithelial cells with peri-  nuclear clearing and crenated, pyknotic nuclei. Eosinophilic  intranuclear viral inclusions sometimes are noted within the  cells of the granular layer.    Skin verrucae are treated effectively by topical salicylic acid,  topical lactic acid, or liquid nitrogen cryotherapy. Surgical  excision is indicated only for cases with an atypical clinical  presentation in which the diagnosis is uncertain. Skin  lesions that recur or are resistant to standard therapy may  be treated by alternative methods, such as intralesional bleo-  mycin, topical or intralesional 5-fluorouracil, cantharidin,  topical imiquimod, intralesional immunotherapy (with  Candida or mumps skin antigen), or photodynamic therapy.   Oral lesions usually are excised surgically, or they may be  destroyed by laser, cryotherapy, or electrosurgery. Cryother-  apy induces a subepithelial blister that lifts the infected  epithelium from the underlying connective tissue, allowing    i Ay |  ° Fig. 10-8 res ae A, Numerous papillary projections are  covered by hyperkeratotic stratified squamous epithelium. Elongated  rete ridges at the edge of the lesion converge toward the center.    B, High-power view showing clear koilocytes in the upper epithelial  layers.    it to slough away. All destructive or surgical treatments  should extend to the base of the lesion.   Recurrence is seen in a small proportion of treated cases.  Without treatment, verrucae do not transform into malig-  nancy, and two-thirds will disappear spontaneously within  2 years, especially in children.    Condyloma acuminatum is a HPV-induced proliferation  of stratified squamous epithelium of the anogenital region,  mouth, and larynx. Approximately 90% of cases are attrib-  uted to HPV 6 and 11; however, coinfection with various  other types—including the high-risk types 16 and 18—is  frequent (see Table 10-1).   Condyloma represents a common sexually transmitted  disease (STD), affecting about 1% of the sexually active  population. Between 500,000 and 1 million new cases are  diagnosed annually in the United States. However, since the  introduction of HPV vaccination, significant reductions in  incidence have been reported among adolescents and young  adults in many regions. Condyloma may be an indicator of    ® Fig. 10-9 Condyloma Acuminatum. Two lesions of the upper lip  mucosa exhibit short, blunted projections. (Courtesy of Dr. Brian  Blocher.)    sexual abuse when diagnosed in young children. In addi-  tion, studies of oral and pharyngeal HPV infection in  infants have suggested that vertical transmission from  mothers with genital HPV infection may occur perinatally  or perhaps in utero. Oral and anogenital condylomata may  be present concurrently. The incubation period is about 1  to 3 months, and autoinoculation of additional mucosal  sites is possible.    Condylomata usually are diagnosed in teenagers and young  adults, but people of all ages are susceptible. Oral lesions  most frequently occur on the labial mucosa and lingual  frenum; the soft palate often is involved as well. The typical  condyloma appears as a sessile, pink, well-demarcated, non-  tender, exophytic mass with short, blunted surface projec-  tions (Fig. 10-9). The condyloma tends to be larger than  the papilloma and characteristically is clustered with other  condylomata. The average size is 1.0 to 1.5 cm, but oral  lesions as large as 3 cm have been reported.    Condyloma acuminatum appears as a benign proliferation  of acanthotic stratified squamous epithelium with mildly  keratotic, papillary surface projections (Fig. 10-10). Thin  connective tissue cores support the papillary projections,  which are more blunted and broader than those of squa-  mous papilloma and verruca vulgaris. Keratin-filled crypts  often are seen between the papillary projections. In some  cases, lesions may extend from the surface mucosa to involve  the underlying salivary ductal epithelium; such lesions  should be distinguished from salivary ductal papillomas (see  page 452).   The surface epithelium is mature and differentiated, but  within the spinous cell layer, there are often koilocytes  (HPV-altered cells with pyknotic, crinkled [or “raisin-like”]  nuclei) (Fig. 10-11). Koilocytes may be less prominent in    @ Fig. 10-10 Condyloma Acuminatum. Medium-power photomi-  crograph showing acanthotic stratified squamous epithelium forming  a blunted projection.    ® Fig. 10-11 Condyloma Acuminatum. High-power photomicro-  graph demonstrating koilocytes (arrows) in the spinous layer.    oral lesions compared with genital lesions, in which case  distinction from squamous papilloma may be difficult.  Ultrastructural examination reveals virions within the cyto-  plasm or nuclei of koilocytes, and the virus also can be  demonstrated by immunohistochemical analysis, in situ  hybridization (ISH), and polymerase chain reaction (PCR).    Oral condylomata usually are treated by conservative surgi-  cal excision. Cryotherapy and laser ablation also may be  used. However, there is some concern regarding the poten-  tial for laser therapy to produce an infectious plume that  exposes the surgical team and patient to airborne HPV.  Patient-applied topical agents (such as, imiquimod, podo-  phyllotoxin, and sinecatechins) are becoming the mainstay  of treatment for anogenital condylomata, although such  treatments typically are not used for oral lesions. Additional  treatment options for anogenital lesions include trichloro-  acetic acid, systemic or intralesional interferon, and topical  cidofovir. Regardless of the method used, a condyloma  should be removed because it is contagious and can spread  by autoinoculation or to other persons    Anogenital condylomata infected with HPV 16 or 18 are  associated with an increased risk for malignant transforma-  tion to squamous cell carcinoma, but such transformation  has not been demonstrated in oral lesions. Interestingly, a  recent population-based study of Danish patients with  genital condylomata reported a long-term, increased risk for  not only anogenital but also head and neck cancer. Proposed  explanations for this observation include an immunologic  predisposition to persistent HPV infection (resulting in  increased risk for HPV-related head and neck cancer) and  behavioral cofactors (e.g., tobacco and alcohol consump-  tion, male homosexual behavior).   Two HPV vaccines (a quadrivalent vaccine [Gardasil]  targeting HPV 6, 11, 16, and 18 and a bivalent vaccine  [Cervarix] targeting HPV 16 and 18) are licensed in the  United States, with routine HPV vaccination recommended  for females and males 11 to 12 years of age. The quadrivalent  vaccine is indicated for prevention of genital warts; in addi-  tion, both vaccines are designed to reduce HPV transmission  rates and the risk of HPV-related anogenital cancers. Quad-  rivalent HPV vaccination would be expected to aid in pre-  venting oral condylomata as well, although the impact of  HPV vaccination on oral HPV-related disease requires study.    MULTIFOCAL EPITHELIAL HYPERPLASIA  (HECK DISEASE; MULTIFOCAL PAPILLOMA  VIRUS EPITHELIAL HYPERPLASIA; FOCAL  EPITHELIAL HYPERPLASIA)    Multifocal epithelial hyperplasia is a squamous epithelial  proliferation primarily attributed to HPV 13 and 32. The  condition initially was described in Native Americans and  Inuits but subsequently has been reported in many popula-  tions and ethnic groups. In some populations, as many as  40% of children are affected. Multifocal epithelial hyper-  plasia often affects multiple members of a given family; this  familial tendency may be related to either genetic suscepti-  bility or HPV transmission between family members. An  association with the HLA-DR4 (DRB1*0404) allele has  been described. Lower socioeconomic status, crowded living  conditions, poor hygiene, malnutrition, and HIV infection  appear to be additional risk factors. Although originally  reported as “focal epithelial hyperplasia,” the term multifocal  epithelial hyperplasia is preferred because patients usually  exhibit multiple lesions.    Multifocal epithelial hyperplasia predominantly arises in  children and adolescents, although adults also may be  affected. Studies have reported either a female predilection  or no significant gender bias. The most common sites of  involvement include the labial, buccal, and lingual mucosa,  but gingival, palatal, oral floor, and tonsillar lesions also are  possible. In addition, involvement of the conjunctiva has  been described very rarely.    @ Fig. 10-12 Multifocal Epithelial Hyperplasia. Multiple, flat-  topped papules and nodules of normal coloration are seen on the  lower lip of a child. (Courtesy of Dr. Mark Casafrancisco.)    @ Fig. 10-13 Multifocal Epithelial Hyperplasia. The lesions may  demonstrate a papillary surface change and paleness, as demon-  strated on this child’s tongue. (Courtesy of Dr. Roman Carlos.)    ‘There are two major clinical variants: papulonodular and  papillomatous. The more common papulonodular variant  is characterized by pink, smooth-surfaced papules and  nodules, with a predilection for the buccal mucosa, labial  mucosa, and commissure (Fig. 10-12). The papillomatous  variant appears as white to pale pink, pebbly nodules on the  tongue and attached gingiva (Fig. 10-13). In both variants,  the individual lesions are small (0.1 to 1.0 cm), discrete,  and well-demarcated, but they may coalesce to produce a  cobblestone or fissured appearance. According to some  authors, the lesions tend to be smaller, fewer in number,  and less exophytic among older patients compared to  younger patients; this observation may reflect spontaneous  regression over time.    The hallmark of focal epithelial hyperplasia is an abrupt and  sometimes considerable acanthosis of the surface epithelium  (Fig. 10-14). Because the thickened mucosa extends upward,    @ Fig. 10-14 Multifocal Epithelial Hyperplasia. Prominent acan-  thosis of the epithelium with broad and elongated rete ridges. The  slightly papillary surface alteration noted here may or may not be    (arrows) contain altered nuclei in this otherwise mature and well-  differentiated stratified squamous epithelium.    the lesional rete ridges are at the same depth as the adjacent,  normal rete ridges. The rete ridges are widened, often con-  fluent, and sometimes club-shaped. Some superficial kera-  tinocytes show koilocytic change similar to that seen in  other HPV infections. Others occasionally demonstrate an  altered nucleus that resembles a mitotic figure (mitosoid  cell) (Fig. 10-15). Viruslike particles have been noted ultra-  structurally within both the cytoplasm and the nuclei of  cells within the prickle cell layer, and the presence of HPV  has been demonstrated by DNA in situ hybridization,  immunohistochemistry, and polymerase chain reaction    Spontaneous regression has been reported after months or  years and is inferred from the rarity of the disease in adults.  Conservative surgical excision may be performed for diag-  nostic or aesthetic purposes or for lesions subject to recur-  rent trauma. Lesions also can be removed by cryotherapy,  carbon dioxide (CO,) laser, or electrocoagulation. A few    reported cases have been treated with topical interferon-  beta, systemic or intralesional interferon-alpha, or topical  imiquimod. Recurrence (after either treatment or spontane-  ous regression) is possible. There seems to be no malignant  transformation potential.    Sinonasal papillomas are benign, localized proliferations  of the sinonasal mucosa and include three histomorphologi-  cally distinct types:   Lesions exhibiting features of both the inverted and the  cylindrical cell types may be termed mixed or hybrid papil-  lomas. In addition, a keratinizing squamous papilloma,  similar to the oral squamous papilloma (see page 332),  rarely may occur in the nasal vestibule.   Collectively, sinonasal papillomas represent 10% to  25% of all sinonasal tumors. About half of sinonasal papil-  lomas arise from the lateral nasal wall; the remainder pre-  dominantly involves the maxillary and ethmoid sinuses and  the nasal septum. Multiple lesions may be present.   The etiopathogenesis of sinonasal papillomas remains  unclear. Historically, numerous contributory factors—such  as allergy, chronic sinusitis, nasal polyps, and tobacco smoke  or other airborne pollutants—have been proposed but  remain unsubstantiated. A variable association with HPV  infection has been reported, with the strongest association  noted for the fungiform type. According to a recent meta-  analysis of studies using various HPV detection methods,  approximately 39% of sinonasal papillomas are HPV-  positive, with HPV prevalence rates for the fungiform,  inverted, and cylindrical cell types of 65%, 38%, and 23%,  respectively.    The fungiform papilloma bears some similarity to the oral  squamous papilloma, although it has a somewhat more  aggressive biologic behavior and more varied epithelial  types. It represents 18% to 50% of all sinonasal papillomas  in various investigations. The majority of cases are positive  for HPV 6 or 11.    The fungiform papilloma arises almost exclusively on the  nasal septum and is more common in men than women (at  least 2: 1 male-to-female ratio). It occurs primarily in people  20 to 50 years of age. Typically, it causes unilateral nasal  obstruction or epistaxis and appears as a pink or tan, broad-  based nodule with papillary or warty surface projections  (Fig. 10-16). Most lesions measure less than 2 cm in  maximum diameter.    ® Fig. 10-16 Fungiform Papilloma. Erythematous, papillary growth  on the nasal septum.    The fungiform papilloma has a microscopic appearance  similar to that of the oral squamous papilloma, although  the stratified squamous epithelium covering the fingerlike  projections seldom is keratinized. Respiratory epithelium or  “transitional” epithelium (intermediate between squamous  and respiratory) may be seen in some lesions. Mucous  (goblet) cells and intraepithelial microcysts containing  mucus often are present. Mitoses are infrequent, and dys-  plasia is rare. The lamina propria consists of delicate fibrous  tissue with a minimal inflammatory component, unless it  is irritated.    Complete surgical excision is the treatment of choice for the  fungiform papilloma. Recurrence has been reported in  approximately 20% to 30% of cases; however, some of these  cases may reflect incomplete excision rather than true recur-  rence. Most authorities consider this lesion to have minimal  or no potential for malignant transformation.    The inverted papilloma is the most common sinonasal  papilloma variant, comprising approximately 50% to 78%  of cases. It is also the variant with the greatest potential for  local destruction and malignant transformation. Molecular  genetic investigations support that inverted papillomas rep-  resent true neoplasms of monoclonal origin (i.e., arising  from a single progenitor cell). Systematic reviews and meta-  analyses of the literature suggest that HPV is present in  approximately 24% to 38% of cases, with HPV 6, 11, 16,  and 18 representing the most prevalent types.    ® Fig. 10-17 Inverted Papilloma. Magnetic resonance image (MRI)  showing a tumor with a characteristic convoluted, cerebriform pattern.  (Courtesy of Dr. Zoran Rumboldt.)    The average age at presentation is 53 years, with a peak in  the fifth and sixth decades. There is a strong male predilec-  tion (3:1 to 5:1 male-to-female ratio). Inverted papillomas  arise predominantly from the lateral nasal wall or a parana-  sal sinus, usually the antrum. Typical signs and symptoms  include unilateral nasal obstruction, epistaxis, purulent dis-  charge, hyposmia, headache, or local deformity. The lesion  appears as a soft, pink or tan, polypoid or nodular growth.  Multiple lesions may be present. Bilateral involvement  occurs in only about 5% of cases. The lesion has significant  growth potential and, if neglected, may extend into the  nasopharynx, middle ear, orbit, or cranial base.   Pressure erosion of the underlying bone often is evident  radiographically. Primary sinus lesions may appear only as  a soft tissue radiodensity or mucosal thickening on radio-  graphs; sinus involvement generally represents extension  from the nasal cavity. Focal hyperostosis demonstrated by  computed tomography (CT) scan may indicate the site of  lesion attachment, which is important for surgical planning.  In addition, magnetic resonance imaging (MRI) can help  to identify the extent of the lesion and often reveals a con-  voluted, cerebriform pattern (Fig. 10-17).    The inverted papilloma microscopically exhibits downward  proliferation of squamous epithelium into the stroma (Fig.  10-18). The basement membrane remains intact, and the  epithelium appears to “push” into the underlying connective  tissue. Goblet (mucous) cells and mucin-filled microcysts   e Fig. 10-18 Inverted Papilloma. Low-power photomicrograph  showing a squamous epithelial proliferation, with multiple “inverting”  islands of epithelium extending into the underlying connective tissue.    frequently are noted within the epithelium. Keratin produc-  tion is uncommon, but thin surface keratinization may be  seen. Mitoses often are noted within the basilar or parabasi-  lar cells, and varying degrees of epithelial atypia may be  seen. Papillary surface projections separated by deep clefts  may be observed. The stroma consists of dense or myxoma-  tous connective tissue with or without inflammatory cells.  Destruction of underlying bone frequently is noted.   Marked surface keratinization and moderate to severe  dysplasia are worrisome histopathologic findings that  warrant careful microscopic examination to rule out malig-  nancy. Nonetheless, there are no histopathologic features  that are reliably predictive of malignant transformation in  inverted papillomas. A few studies suggest that increased  immunohistochemical expression of p53 and p21 (cell  cycle-related proteins), decreased immunohistochemical  expression of CD44 (a cell adhesion molecule), and the  presence of HPV 16 or 18 may be associated with an  increased risk for malignant transformation. Notably,  immunohistochemical expression of p16 in inverted papil-  lomas does not appear to be a reliable surrogate marker for  high-risk HPV infection.    Over the past few decades, the preferred treatment has  shifted from traditional open surgery (ie., medial maxil-  lectomy via a lateral rhinotomy or midfacial degloving  approach) to transnasal endoscopic surgery. Depending  upon the extent and accessibility of disease, endoscopic and  external surgical approaches may be combined. With  modern and aggressive surgical therapy, investigators have  reported recurrence rates of 13% to 17% or less. In contrast,  conservative surgical excision is associated with unaccept-  ably high recurrence rates (nearly 75% in some studies).  Recurrences usually are noted within 2 years of surgery but  can happen much later. Hence, long-term follow-up is  essential. Continued tobacco smoking is associated with an  increased risk for recurrence.    Approximately 3% to 24% of inverted papillomas trans-  form into malignancy (usually squamous cell carcinoma).  When malignancy is present, treatment typically consists of  radical surgery, with or without adjunctive radiotherapy.    The cylindrical cell papilloma accounts for less than 7%  of sinonasal papillomas. Some authorities consider this  lesion to be a variant of the inverted papilloma because of  the similarity in clinicopathologic features and a similarly  low frequency of HPV.    The cylindrical cell papilloma most often occurs in adults  older than 50 years. Most authors report either a male pre-  dominance or no significant gender bias. There is a predilec-  tion for the lateral nasal wall, maxillary antrum, and ethmoid  sinus. The most common presenting symptom is unilateral  nasal obstruction, and the lesion appears as a beefy-red or  brown mass with a multinodular surface.    Microscopically, the cylindrical cell papilloma demonstrates  both endophytic and exophytic growth. Surface papillary  projections have a fibrovascular connective tissue core and  are covered by a multilayered epithelium of tall columnar  cells with small, dark nuclei and eosinophilic, occasionally  granular cytoplasm. The lesional epithelial cell is similar to  an oncocyte. Cilia may be seen on the surface, and there  are numerous intraepithelial microcysts filled with mucin,  neutrophils, or both.    ‘The treatment and recurrence potential for cylindrical cell  papilloma and inverted papilloma (see previous topic) are  similar. Reported malignant transformation rates for cylin-  drical cell papilloma range from 4% to 17%.    Molluscum contagiosum is an epithelial lesion induced by  the molluscum contagiosum virus (MCV), a member of the  DNA poxvirus group. At least 6% of the population (more  in older age groups) has antibodies to this virus, although  few ever develop lesions. In adults and adolescents, MCV  typically is transmitted by sexual contact, whereas in chil-  dren it is transmitted mainly by nonsexual contact (e.g.,  wrestling, sharing clothing or towels). Warm, humid envi-  ronments, such as communal baths or swimming pools, also  may encourage disease spread. After an incubation period  of 14 to 50 days, multiple umbilicated papules may develop  on the skin or, rarely, mucous membranes. The lesions    usually remain small for months or years and then sponta-  neously involute.   The disease exhibits a predilection for warm portions of  the skin and sites of recent injury. Florid cases have been  reported in immunocompromised patients, and the preva-  lence of MCV coinfection among the HIV-positive patient  population is estimated to be 5% to 18% (see page 252).  Patients with atopic dermatitis and Darier disease also are  at risk for developing severe, prolonged disease.    Molluscum contagiosum mainly arises in children and  young adults. The lesions occur predominantly on the skin  of the neck, face (particularly eyelids), trunk, and genitalia.  Infrequently, oral involvement occurs, usually on the lips,  buccal mucosa, palate, or gingiva.   The lesions typically appear as multiple clustered, pink  or white, smooth-surfaced, sessile papules measuring 2 to  4 mm in diameter (Fig. 10-19). Many show a small central  indentation or plug from which a curd-like substance con-  taining viral particles can be expressed. Most lesions are  asymptomatic, although slight tenderness or pruritus is pos-  sible. Eczematous eruptions occasionally may develop in the  vicinity of molluscum contagiosum, particularly in patients  with atopic dermatitis.   In immunocompromised patients, the lesions may be  unusually large, verrucous, or markedly hyperkeratotic.    Molluscum contagiosum appears as a localized, lobular pro-  liferation of surface stratified squamous epithelium (Fig.  10-20). The central portion of each lobule is filled with  bloated keratinocytes that contain large, intranuclear, baso-  philic viral inclusions called molluscum bodies (or  Henderson-Paterson bodies) (Fig. 10-21). These bodies  begin as small, eosinophilic structures in cells just above the  basal layer and enlarge as they approach the surface. A    @ Fig. 10-19 Molluscum Contagiosum. Multiple, smooth-surfaced  papules, with several demonstrating small keratin-like plugs, are seen  on the neck of a child.    @ Fig. 10-20 Molluscum Contagiosum. Well-defined epidermal  proliferation demonstrating a central craterlike depression filled with  virally altered keratinocytes.    @ Fig. 10-21 Molluscum Contagiosum. Higher-power photomicro-  graph showing keratinocytes with large, basophilic viral inclusions  (molluscum bodies) being sloughed into the central crater (top).    central crater is formed at the surface as stratum corneum  cells disintegrate to release their molluscum bodies.    Most cases of molluscum contagiosum undergo spontane-  ous remission within 6 to 9 months. For immunocompe-  tent patients, there is ongoing debate as to whether the  disease should be treated or allowed to resolve on its own.  Treatment may be performed to decrease the risk of disease  transmission, prevent autoinoculation, provide symptom-  atic relief, or address cosmetic concerns.   Although there are few controlled studies of treatment  efficacy, the lesions most commonly are removed by    curettage or cryotherapy. Alternative treatment methods  include laser therapy, electrodessication, chemical destruc-  tive agents (e.g., salicylic acid, lactic acid, silver nitrate,  potassium hydroxide, podophyllotoxin, and cantharidin),  topical tretinoin, and topical imiquimod. In addition, a  limited number of cases have been treated by intralesional  injection of Candida antigen (which may stimulate a local  immune response and MCV clearance).   In immunosuppressed patients with recalcitrant lesions,  the antiviral agent cidofovir may be effective. Moreover, in  HIV-infected patients, combination antiretroviral therapy  indirectly counteracts MCV infection by increasing CD4+  T cell counts and improving the immune response.   Recurrence after initial clearing has been reported in up  to one-third of patients. There is no apparent malignant  transformation potential.    Verruciform xanthoma is a hyperplastic condition of the  epithelium, with a characteristic subepithelial accumula-  tion of lipid-laden histiocytes. It is primarily an oral disease,  but skin and genital lesions also are possible. The cause is  unknown. Although verruciform xanthoma is a papillary  lesion, HPV has been identified in only a small number of  cases, and no definitive pathogenetic role for this virus has  been established. The lesion probably represents an unusual  reaction or immune response to localized epithelial trauma  or damage. This hypothesis is supported by cases of verru-  ciform xanthoma that have developed in association with  disturbed epithelium (e.g., lichen planus, lupus erythema-  tosus, epidermolysis bullosa, epithelial dysplasia, squamous  cell carcinoma, pemphigus vulgaris, warty dyskeratoma,  graft-versus-host disease [GVHD]). The lesion is histo-  pathologically similar to other dermal xanthomas, but it is  not associated with diabetes or hyperlipidemia. Interest-  ingly, in a few cutaneous cases, investigators have identified  a somatic mutation in the gene encoding 3-beta-hydroxys-  teroid dehydrogenase (an enzyme essential for cholesterol  biosynthesis).    Verruciform xanthoma typically is seen in whites, 40 to 70  years of age, with a slight male predilection. Approximately  half of intraoral lesions occur on the gingiva and alveolar  mucosa, but any oral site may be involved.   The lesion appears as a well-demarcated, soft, painless,  sessile, slightly elevated mass with a white, yellow-white, or  red color and a papillary or roughened (verruciform) surface  (Figs. 10-22 and 10-23). Rarely, flat-topped nodules are  seen without surface projections. Most lesions are smaller  than 2 cm in greatest diameter; no oral lesion larger than  4 cm has been reported. Multiple lesions occasionally have  been described. Clinically, verruciform xanthoma may be  similar to squamous papilloma, condyloma acuminatum, or  early carcinoma.    © Fig. 10-22 Verruciform Xanthoma. A well-demarcated, slightly  elevated lesion of the hard palate that demonstrates a roughened or  papillary surface.    @ Fig. 10-23 Verruciform Xanthoma. A lesion of the ventral tongue  exhibits a biphasic appearance. The anterior aspect demonstrates  elongated white (well-keratinized) projections (large arrow). The pos-  terior aspect demonstrates a surface of yellow, blunted projections  (small arrow).    Verruciform xanthoma demonstrates papillary, acanthotic  surface epithelium covered by a thickened layer of parakera-  tin. On routine hematoxylin and eosin (H&E) staining, the  keratin layer often exhibits a distinctive orange color (Fig.  10-24). Clefts or crypts between the epithelial projections  are filled with parakeratin, and rete ridges are elongated to  a uniform depth. The most important diagnostic feature is  the accumulation of numerous large macrophages with  foamy cytoplasm, which typically are confined to the con-  nective tissue papillae. These foam cells, also known as  xanthoma cells, contain lipid and periodic acid-Schiff  (PAS)-positive, diastase-resistant granules. With immuno-  histochemical stains, the xanthoma cells are positive for    markers consistent with monocyte-macrophage lineage,  including CD68 (KP1) and cathepsin B.    ° ° Fig. 10-24 Vernucitormn Xanthoma. A, A slight papillary appear-  ance is produced by hyperparakeratosis, and the rete ridges are elon-  gated to a uniform depth. Note the parakeratin plugging between the  papillary projections. B, The connective tissue papillae are composed  almost exclusively of xanthoma cells—large macrophages with foamy  cytoplasm.    The verruciform xanthoma is treated with conservative sur-  gical excision. Recurrence after removal is rare, and no  malignant transformation has been reported. However,  there are two reported cases of verruciform xanthoma  arising in association with carcinoma in situ or squamous  cell carcinoma. This observation does not necessarily imply  that verruciform xanthoma is a potentially malignant lesion;  however, it may indicate that hyperkeratotic or dysplastic  oral lesions can undergo degenerative changes to form a  verruciform xanthoma.    Seborrheic keratosis is an extremely common skin lesion of  older people and represents an acquired, benign prolifera-  tion of epidermal basal cells. The cause is unknown, although  there is a positive correlation with chronic sun exposure,  sometimes with a hereditary (autosomal dominant) ten-  dency. In addition, somatic mutations in the fibroblast  growth factor receptor 3 (FGFR3) and phosphatidylinositol  3-kinase, catalytic subunit alpha (PIK3CA) genes may con-  tribute to the pathogenesis of these lesions. In some cases,    > . $i 4  a Ae Fa 4 Aid 4 Be }  ® Fig. 10-25 Seborrheic Keratosis. Multiple brown plaques on the  face of an older man exhibit a fissured surface. They had been slowly  enlarging for several years.    ® Fig. 10-26 Seborrheic Keratosis. Crusted and pigmented epi-  dermal plaque.    HPV DNA has been detected, but this finding may be coin-  cidental. Seborrheic keratosis does not occur in the mouth.    Seborrheic keratoses begin to develop on the skin of the  face, trunk, and extremities during the fourth decade of life,  and they become more prevalent with each passing decade.  Lesions are usually multiple, beginning as small, tan to  brown macules that are clinically indistinguishable from  actinic lentigines (see page 345). Subsequently, the lesions  gradually enlarge and elevate to form sharply demarcated  plaques, with finely fissured, pitted, verrucous, or smooth  surfaces (Figs. 10-25 and 10-26). The plaques appear “stuck  onto” the skin and are usually less than 2 cm in diameter.  Dermatosis papulosa nigra is a form of seborrheic kera-  tosis that occurs in approximately 30% to 77% of blacks  and frequently has an autosomal dominant inheritance  pattern. This condition typically appears as multiple small  (1 to 4 mm), dark-brown to black papules scattered about  the zygomatic and periorbital region (Fig. 10-27).  Moreover, the sudden appearance of numerous sebor-  theic keratoses with pruritus may be associated with internal    e Fig. 10-27 Dermatosis Papulosa Nigra. Multiple small pig-  mented papules of the malar area.    t ‘ Peis: LX a Pe +  ® Fig. 10-28 Seborrheic Keratosis. The acanthotic form demon-  strates considerable acanthosis, surface hyperkeratosis, and numer-  ous pseudocysts. The epidermal proliferation extends upward, above  the normal epidermal surface.    Seborrheic keratosis consists of an exophytic proliferation  of basilar epithelial cells that exhibit varying degrees of  surface keratinization, acanthosis, and papillomatosis (Fig.  10-28). Characteristically, the epithelial hyperplasia extends  upward, above the normal epidermal surface. The lesion  usually exhibits deep, keratin-filled invaginations that  appear cystic on cross-section; hence, they are called horn  cysts or pseudo-horn cysts (Fig. 10-29). Melanin pigmen-  tation often is seen within the basal layer.   Several histopathologic patterns may be seen in sebor-  theic keratoses. The most common is the acanthotic form,  which exhibits little papillomatosis and marked acanthosis  with minimal surface keratinization. The hyperkeratotic  form is characterized by prominent papillomatosis and  hyperkeratosis with minimal acanthosis. The adenoid form  consists of anastomosing trabeculae of lesional cells with  little hyperkeratosis or papillomatosis. The lesions of    e Fig. 10-29 Seborrheic Keratosis. Pseudocysts are actually  keratin-filled invaginations, as seen toward the left in this high-power  photomicrograph. The surrounding epithelial cells are basaloid in  appearance.    dermatosis papulosa nigra are predominantly of the adenoid  and acanthotic types.   Chronic trauma may alter these histopathologic features  to produce an irritated seborrheic keratosis (or inverted  follicular keratosis of Helwig). This lesion shows a mild  degree of proliferation into the connective tissue and an  associated chronic inflammatory cell infiltrate. Squamous  metaplasia of the lesional cells results in whorled epithelial  patterns called squamous eddies. Inflamed seborrheic kera-  tosis may exhibit enough nuclear atypia and mitotic activity  to cause confusion with squamous cell carcinoma, but  enough of the basic attributes of seborrheic keratosis typi-  cally remain to allow a proper diagnosis.    Except to address aesthetic concerns or secondary irritation,  seborrheic keratoses seldom are removed. Cryotherapy,  curettage, and shave excision are the most common methods  for removal. The lesion exhibits no appreciable malignant  potential. However, there are isolated reports of malignant  skin lesions developing within or adjacent to seborrheic  keratoses; it is unclear whether such cases are coincidental.  Rarely, melanomas may resemble seborrheic keratoses clini-  cally; thus it is important for a dermatologist or other quali-  fied clinician to determine whether it is most appropriate  to treat a lesion by cryotherapy or to excise and submit it  for histopathologic confirmation.    Sebaceous hyperplasia is a localized proliferation of seba-  ceous glands, with a predilection for the facial skin. The  exact cause is unknown, although investigators hypothesize  that hormonal and genetic factors may be important. In  addition, some reported cases have developed in association  with cyclosporine administration in transplant recipients or  with combination antiretroviral therapy for HIV-infected  patients. It is uncertain whether such cases result from    ® Fig. 10-30 Sebaceous Hyperplasia. Multiple soft papules of the  midface are umbilicated and small. Sebum can often be expressed  from the central depressed area.    immunosuppression or direct medication effects. Further-  more, sebaceous hyperplasia may arise in association with  Muir-Torre syndrome (a rare autosomal dominant disorder  characterized by visceral malignancies, sebaceous adenomas  and carcinomas, and keratoacanthomas). The major signifi-  cance of sebaceous hyperplasia is its clinical similarity to  more serious facial tumors, such as basal cell carcinoma.    Cutaneous sebaceous hyperplasia usually affects adults older  than 40 years. It occurs most commonly on the skin of the  face, especially the nose, cheeks, and forehead. Less com-  monly, lesions may involve the genital area, chest, and  areola. The condition is characterized by one or more soft,  nontender papules with white, yellow, or normal color (Fig.  10-30). Most lesions grow slowly and are smaller than  5 mm in greatest diameter. The lesions usually exhibit  central umbilication, representing the area where the ducts  of the involved sebaceous lobules terminate. The ability to  express sebum (the thick, yellow-white product of the seba-  ceous gland) from this small, central depression aids in  clinical distinction of sebaceous hyperplasia from basal cell  carcinoma.   An oral counterpart, which probably has no relation to  the skin lesion, appears as a white to yellow papule or  nodular mass with a “cauliflower” appearance, usually  involving the buccal mucosa or retromolar pad.    Histopathologically, sebaceous hyperplasia is characterized  by a collection of enlarged but otherwise normal sebaceous  gland lobules grouped around one or more centrally located  sebaceous ducts (Fig. 10-31).    No treatment is necessary for sebaceous hyperplasia except  for cosmetic reasons or unless basal cell carcinoma cannot    enlarged and more numerous than normal, but they demonstrate no  other pathologic changes.    be eliminated from the clinical differential diagnosis. Exci-  sional biopsy is curative. Cryosurgery, electrodessication,  laser therapy, photodynamic therapy, and isotretinoin are  alternative treatment methods.    An ephelis is a common, small, hyperpigmented macule of  the skin. The lesion results from increased melanin deposi-  tion in the epidermis, without an increase in the number  of melanocytes. Ephelides may become more pronounced  after sun exposure and are associated closely with a history  of painful sunburns in childhood. There is a genetic predi-  lection (autosomal dominant), and studies have demon-  strated a strong relationship with certain variants of the  melanocortin I receptor (MCIR) gene.    Ephelides arise most often on the face, arms, and back of  fair-skinned, blue-eyed, red- or blond-haired individuals.  ‘There is no gender predilection. The macules usually develop  during the first decade of life, seldom arise after the teenage  years, and become less prominent in adulthood.   Each lesion appears as a sharply demarcated, uniformly  light brown, round or oval macule, measuring less than  3 mm in diameter (Fig. 10-32). There is great variability in  the number of lesions present. Many individuals have less  than 10, whereas some have hundreds. The brown color is  not as dark as the lentigo simplex (see page 346), and there  is never elevation above the surface of the skin, as may occur  in a melanocytic nevus (see page 350).    The ephelis exhibits abundant melanin deposition in the  basal cell layer of the epidermis. Despite increased melanin,  the number of melanocytes is normal or slightly reduced.    @ Fig. 10-32 Ephelides. Multiple brown macules over the bridge of  the nose.    In contrast to lentigo simplex, there is no elongation of  rete ridges.    No treatment is necessary for ephelides. Cosmetically  unpleasing lesions may be treated by cryotherapy, hydroqui-  none, chemical peels, or laser therapy. Sunscreens can  prevent the appearance of new freckles and help prevent the  darkening of existing lesions.    ¢ ACTINIC LENTIGO (LENTIGO SOLARIS;  SOLAR LENTIGO; AGE SPOT; LIVER SPOT;  SENILE LENTIGO)    Actinic lentigo is a benign, brown macule that is consid-  ered a hallmark of photodamaged skin. The lesion is associ-  ated with both chronic and intermittent ultraviolet (UV)  light exposure. It frequently arises on the facial skin but does  not occur in the mouth. Actinic lentigo affects more than  90% of whites older than 70 years. The lesion rarely devel-  ops before age 40, although young adults with a history of  severe sunburns may develop multiple large actinic lentigi-  nes on the upper back. Persons who have facial ephelides  (freckles) in childhood are prone to developing actinic len-  tigines later in life.   Some authorities have proposed that actinic lentigo  represents a precursor to adenoid seborrheic keratosis (see  page 342). Interestingly, investigators have noted that at  least some cases of both actinic lentigo and seborrheic kera-  tosis exhibit mutations in the fbroblast growth factor receptor  3 (FGFR3) and phosphatidylinositol 3-kinase catalytic subunit  alpha (PIK3CA) genes.    Multiple lesions typically develop in older whites on sun-  exposed skin, especially on the face, dorsa of the hands,  forearms, shoulders, and upper back (Figs. 10-33 and   e Fig. 10-33 Actinic Lentigines. Multiple lesions on the sun-  exposed skin of the hand of an older adult. Lesions are brown macules  with irregular borders.    ba a  ® Fig. 10-34 Actinic Lentigo. Large, flat, evenly pigmented lesion  on the forehead of an older adult man.    10-34). The lesions may appear more prominent and at a  somewhat younger age among Asians compared to whites.  The individual lesions appear as uniformly pigmented,  brown to tan macules with well-demarcated but irregular  borders. Most examples are smaller than 5 mm in diameter,  although some lesions may measure more than 1 cm. Adja-  cent lesions may coalesce, and new ones continuously arise  with age. Unlike ephelides, no change in color intensity is  seen after UV light exposure.    ‘The rete ridges are elongated and club-shaped, with thin-  ning of the epithelium above the connective tissue papillae  (Fig. 10-35). The ridges sometimes coalesce with one  another. Within each rete ridge, melanin-laden basilar cells  are intermingled with excessive numbers of heavily pig-  mented melanocytes. Prominent solar elastosis typically is  seen within the dermis.    No treatment is required for actinic lentigo, except for  aesthetic reasons. Ablative treatment methods include cryo-    ® Fig. 10-35 Actinic Lentigo. Rete ridges are elongated and occa-  sionally intertwining. Pigmented melanocytes (with clear cytoplasm) are  excessive and commingled with melanin-laden basilar cells.    therapy, laser therapy, intense pulsed light, and chemical  peels. In addition, there is a wide range of topical therapies  available, including hydroquinone, tretinoin, tazarotene,  adapalene, and combined mequinol and tretinoin. Recent  small studies also have shown promising results with topical  undecylenoyl phenylalanine or combined L-ascorbic acid  and phytic acid. Generally, sunscreens are recommended as  preventive treatment and for maintenance of treatment  success. Lesions rarely recur after removal, although new  lesions may arise. Actinic lentigo does not undergo malig-  nant transformation; however, the lesion represents a clini-  cal marker of photodamage and may indicate an increased  risk for developing skin cancer.    Lentigo simplex is one of several forms of benign cutane-  ous melanocytic hyperplasia of unknown cause. In contrast  to the ephelis (see page 345), lentigo simplex typically is  found on skin that is not exposed to sunlight, appears  somewhat darker in color, does not darken with sun expo-  sure, and represents an increase in both local melanin pro-  duction and the number of melanocytes. Oral lesions have  been reported, but they are rare and may be examples of  the oral melanotic macule (see page 348).   Some investigators believe that lentigo simplex repre-  sents the earliest stage of another common skin lesion, the  melanocytic nevus (see page 350). However, according to  one recent study, lentigo simplex lacks BRAF gene muta-  tions that are commonly found in melanocytic nevi.    Lentigo simplex usually is seen in children, although it may  occur at any age. The typical lesion is a sharply demarcated,  uniformly tan to dark-brown macule smaller than 5 mm in  diameter (Fig. 10-36). It is usually solitary, although some  patients may have several lesions scattered on the skin of  the trunk and extremities. Lentigo simplex reaches its    @ Fig. 10-36 Lentigo Simplex. A sharply demarcated lesion of  uniform brown coloration is seen on the midface.    maximum size in a matter of months and may remain  unchanged indefinitely thereafter.   Clinically, individual lesions of lentigo simplex are indis-  tinguishable from the non-elevated melanocytic nevus. With  multiple lesions, conditions such as lentiginosis profusa,  Peutz-Jeghers syndrome (see page 701), and LEOPARD*  syndrome must be considered as diagnostic possibilities.    Lentigo simplex shows an increased number of benign  melanocytes within the basal layer of the epidermis. These  melanocytes often are clustered at the tips of slightly to  moderately elongated rete ridges. Abundant melanin is dis-  tributed among the melanocytes and basal keratinocytes, as  well as within the papillary dermis in association with mela-  nophages (melanin incontinence).    Lentigo simplex may fade spontaneously after many years,  but most lesions remain constant over time. Treatment is  not required, except for cosmetic reasons. Treatment  methods include conservative surgical excision, cryotherapy,  and laser therapy. No malignant transformation potential  has been documented.    Melasma is an acquired, symmetrical hyperpigmentation of  the sun-exposed skin of the face and neck. The exact cause  is unknown, but UV light exposure and hormonal influ-  ences appear to be important etiologic factors. Studies    *Lentigines (multiple), electrocardiographic abnormalities, ocular hyper-  telorism, pulmonary stenosis, abnormalities of genitalia, retardation of  growth, and deafness (sensorineural)    ® Fig. 10-37 Melasma. Diffuse hyperpigmentation of the facial skin  in a pregnant woman.    suggest that UV light stimulates production of dermal stem  cell factor and alpha-melanocyte stimulating hormone,  resulting in proliferation of melanocytes and increased  melanin production. Melasma classically is associated with  pregnancy. In addition, an association with oral contracep-  tives, hormone replacement therapy, thyroid disorders, pho-  totoxic medications, antiepileptic agents, and cosmetics has  been described. Several studies suggest a genetic predisposi-  tion. The condition most commonly affects medium- to  dark-complexioned persons—particularly Asian and His-  panic women. In the United States, melasma affects more  than 5 million individuals.    Melasma typically appears in adult women as bilateral  brown or grayish cutaneous macules that range from a few  millimeters to more than 2 cm in diameter (Fig. 10-37).  Lesions develop slowly with sun exposure and primarily  involve the skin of the midface, forehead, upper lip, chin,  mandibular ramus region, and (rarely) the arms. The pig-  mentation may remain faint or darken over time. Melasma  only rarely affects men.    Melasma is characterized by increased melanin deposition  and, possibly, an increased number of melanocytes in the  epidermis. The melanocytes typically are plump, full of  pigment, and highly dendritic. In addition, numerous  melanophages (melanin-laden macrophages) may be seen in  the dermis. Some authors have noted more severe solar  damage in lesional skin compared to adjacent normal-  appearing skin.    Melasma is difficult to treat. First-line therapy typically  consists of topical triple-combination cream (Tri-Luma)  containing 4% hydroquinone, 0.05% tretinoin, and 0.01%    fluocinolone acetonide. Dual-ingredient topical agents  (e.g., hydroquinone combined with glycolic acid or kojic  acid) or single topical agents (e.g., hydroquinone, retinoids,  and azelaic acid) are alternatives for patients who are sensi-  tive to triple-combination therapy. Variable results have  been reported with laser therapy, light therapy, or micro-  dermabrasion. Because sun exposure is an important etio-  logic factor, sun avoidance, protective clothing, and the use  of sunscreens containing zinc oxide or titanium dioxide are  crucial for effective management. ‘The lesions may resolve  after parturition or after discontinuing oral contraceptives.  There is no potential for malignant transformation.    The oral melanotic macule is a flat, brown, mucosal dis-  coloration produced by a focal increase in melanin deposi-  tion and, possibly, a concomitant increase in the number of  melanocytes. The cause remains unclear. Unlike the cutane-  ous ephelis (freckle), the melanotic macule is not dependent  on sun exposure. Some authorities have questioned the  purported lack of an association with actinic irradiation for  the melanotic macule located on the vermilion border and  prefer to consider it a distinct entity (labial melanotic  macule). In one study of more than 773 solitary oral mela-  nocytic lesions submitted to an oral pathology laboratory  for histopathologic examination, oral and labial melanotic  macules were the most common and comprised 86% of  cases; oral and labial melanotic macules were encountered  much more frequently than oral melanocytic nevi, melano-  acanthomas, and melanomas.    The oral melanotic macule occurs over a broad age range,  with an average age at diagnosis of 43 years and a 2:1  female-to-male ratio. The lower lip vermilion is the most  commonly involved site (33% of cases), followed by the  buccal mucosa, gingiva, and palate. Rare examples have  been reported on the tongue in newborns.   The typical lesion appears as a solitary (17% are multi-  ple), well-demarcated, uniformly tan to dark-brown, asymp-  tomatic, round or oval macule with a diameter of 7 mm or  less (Figs. 10-38 and 10-39). Occasional lesions may be blue  or black. The maximum dimension is achieved rather  rapidly and remains constant thereafter.    The oral melanotic macule is characterized by an increase  in melanin (and perhaps melanocytes) in the basal and  parabasal layers of an otherwise normal stratified squamous  epithelium (Fig. 10-40). Melanin also may be seen free  (melanin incontinence) or within melanophages in the  subepithelial connective tissue. Unlike actinic lentigo (see    ® Fig. 10-38 Oral Melanotic Macule. A single small, uniformly pig-  mented brown macule on the lower lip vermilion.    © Fig. 10-39 Oral Melanotic Macule. A well-demarcated brown  macule of the gingival mucosa.    page 345), the melanotic macule typically does not show  elongated rete ridges.    The oral melanotic macule generally is considered a benign  lesion with no malignant potential. However, a single case  of apparent malignant transformation of an oral melanotic  macule has been reported, and early melanoma can have a  similar clinical appearance. Therefore, all oral pigmented  macules of recent onset, large size, irregular pigmentation,  unknown duration, or recent enlargement should be sub-  mitted for microscopic examination. In addition, because  oral melanoma exhibits a predilection for the palatal and  maxillary alveolar mucosa, it is advisable to submit pig-  mented macules in these locations for histopathologic exam-  ination. Furthermore, removal may be desirable for melanotic  macules involving aesthetic areas. Excisional biopsy is the  preferred treatment method. Electrocautery, laser ablation,  or cryosurgery is effective, but no tissue remains for histo-  pathologic examination after these procedures.   On occasion, flat pigmented lesions that are clinically  and microscopically similar to the melanotic macule may  occur in association with a systemic disease, a genetic    increased melanin pigmentation distributed along basal epithelial layer.  B, High-power view showing granular brown melanin pigment in the  basilar cells.    disorder, or certain medications. A list of these conditions  is shown in Box 10-1.    Oral melanoacanthoma is an uncommon, benign, acquired  pigmentation of the oral mucosa characterized by dendritic  melanocytes dispersed throughout the epithelium. The  lesion appears to be a reactive process; in some cases an  association with trauma has been reported. Oral melanoac-  anthoma appears to be unrelated to the melanoacanthoma  of skin, which most authorities believe represents a variant  of seborrheic keratosis.    Oral melanoacanthoma is seen primarily in blacks, although  some cases also have been reported in Caucasians, Hispan-  ics, and Asians. The lesion exhibits a female predilection and  most commonly arises during the third and fourth decades  of life. The buccal mucosa is the most common site of  occurrence. The lips, palate, gingiva, and alveolar mucosa   e Yusho (chronic exposure to high levels of polychlorinated  biphenyls [PCBs])    also may be involved. Most patients exhibit solitary lesions,  although bilateral or multifocal involvement is possible.  Oral melanoacanthomas typically are asymptomatic;  however, pain, burning, and pruritus have been reported in  a few cases. The lesion appears smooth, flat or slightly  raised, and dark-brown to black (Fig. 10-41). Lesions often  rapidly increase in size, and they occasionally reach a diam-  eter of several centimeters within a few weeks.    The oral melanoacanthoma is characterized by numerous  benign dendritic melanocytes (cells that normally are con-  fined to the basal layer) scattered throughout the lesional  epithelium (Figs. 10-42 and 10-43). Basal layer melano-  cytes are also present in increased numbers. Spongiosis and  mild acanthosis typically are evident. In addition, the  underlying connective tissue often contains a mild to mod-  erate chronic inflammatory cell infiltrate that may include  eosinophils.    @ Fig. 10-41 Oral Melanoacanthoma. A, Smooth, darkly pig-  mented macule of the buccal mucosa in a young adult. B, Appearance  of the lesion 2 months later showing dramatic enlargement. C, Resolu-  tion of the lesion 3 months after incisional biopsy. (From Park SK,  Neville BW: AAOMP case challenge: rapidly enlarging pigmented  lesion of the buccal mucosa, J Contemp Dent Pract 3:69-73, 2002.)    Because of the alarming growth rate of oral melanoacan-  thoma, incisional biopsy usually is indicated to rule out  melanoma. Once the diagnosis has been established, no  further treatment is necessary. In several instances, lesions  have undergone spontaneous resolution after incisional  biopsy. Recurrence or development of additional lesions has  been reported only rarely. There is no potential for malig-  nant transformation.    @ Fig. 10-42 Oral Melanoacanthoma. Medium-power photomicro-  graph showing acanthosis of the epithelium. Spongiosis is demon-  strated by intercellular spaces between the keratinocytes.    The generic term nevus refers to congenital or developmen-  tal malformations of the skin (and mucosa). Nevi may arise  from the surface epithelium or underlying connective tissue.  The most commonly recognized nevus is the acquired  melanocytic nevus, or common mole—so much so that  the simple term nevus often is used synonymously for this  pigmented lesion. However, many other developmental  nevi also are recognized (Box 10-2).   The acquired melanocytic nevus represents a benign,  localized proliferation of nevus cells derived from the neural  crest. It is unclear whether these cells represent melanocytes  or merely “first cousins” of melanocytes. These melanocytic   Basal cell nevus (nevoid basal cell carcinoma) (see page 640)  White sponge nevus (See page 691)    cells migrate to the epidermis during development, and  lesions may appear shortly after birth.   The acquired melanocytic nevus is probably the most  common of all human “tumors,” with an average of 10 to  40 cutaneous nevi per white adult. Intraoral lesions are  uncommon.   Investigators have identified BRAF mutations in approxi-  mately 80% of acquired melanocytic nevi; such mutations  also are common in cutaneous melanomas. BRAF is a proto-  oncogene that encodes a serine/threonine kinase involved  in the mitogen-activated protein kinase (MAPK) signaling  pathway, which mediates cell proliferation and differentia-  tion. The life cycle of acquired melanocytic nevi includes  four stages: initiation (development of mutations in a pro-  genitor cell—possibly a melanocytic stem cell or differenti-  ated melanocyte), promotion (activation and proliferation  of the mutated progenitor cell), senescence (growth arrest),  and involution.    Acquired melanocytic nevi begin to develop on the skin  during childhood, and most cutaneous lesions are present  before 35 years of age. Women usually have a few more nevi  than men, and whites tend to have more than Asians or  blacks. Most lesions are distributed above the waist, and the  head and neck region commonly is involved.   Acquired melanocytic nevi evolve through several devel-  opmental stages: junctional, compound, and intradermal.  However, not all nevi pass through each stage. The junc-  tional nevus clinically appears as a sharply demarcated,  brown or black macule, typically less than 6 mm in diam-  eter. Although this early presentation may persist into adult-  hood, more often the nevus cells proliferate over a period  of years to produce a slightly elevated, soft papule with a  relatively smooth surface (compound nevus). The degree  of pigmentation becomes less; most lesions appear brown  or tan. As time passes, the nevus gradually loses its pigmen-  tation, the surface may become somewhat papillomatous,  and hairs may be seen growing from the center (intradermal  nevus) (Figs. 10-44 and 10-45). However, the nevus usually  remains less than 6 mm in diameter. Ulceration is not a  feature unless the lesion is traumatized. During the adult  years, many acquired melanocytic nevi involute and disap-  pear; therefore, fewer lesions are detected in older persons.   Intraoral melanocytic nevi are distinctly uncommon.  Most arise on the palate, mucobuccal fold, or gingiva,  although any oral mucosal site may be affected (Fig. 10-46).    i a 2 e2% ree setae  © Fig. 10-44 Melanocytic (Intradermal) Nevus. A brown nodule  on the facial skin with a papillomatous surface and protruding hairs.    hid ha Grimes au  ® Fig. 10-45 Melanocytic (Intradermal) Nevus. A well-demarcated,  lightly pigmented, dome-shaped papule is seen at the edge of the  vermilion border of the upper lip.    @ Fig. 10-46 Intramucosal Melanocytic Nevus. Pigmented lesion  of the anterior hard palate. (Courtesy of Dr. Lewis Claman.)    Intraoral melanocytic nevi have an evolution and appear-  ance similar to skin nevi, although mature lesions often  do not demonstrate a papillary surface. More than one in  five intraoral nevi lack clinical pigmentation (Fig. 10-47).  Approximately two-thirds of intraoral examples are found  in females; the average age at diagnosis is 35 years.    ® Fig. 10-47 Intramucosal Melanocytic Nevus. This intramucosal  nevus of the mandibular gingiva is nonpigmented. (Courtesy of  Dr. James Jacobs.)    @ Fig. 10-48 Junctional Nevus. Nests of melanocytic nevus cells  along the basal layer of the epithelium.    The acquired melanocytic nevus is characterized by a benign,  unencapsulated proliferation of nevus cells. Zones of dif-  ferentiation often are seen among the lesional cells. Super-  ficial nevus cells tend to be organized into small, round  aggregates (theques) and usually appear ovoid or epithelioid,  with abundant cytoplasm and frequent intracellular  melanin. Deeper nevus cells may have less cytoplasm, are  seldom pigmented, and appear much like lymphocytes. The  deepest nevus cells appear elongated and spindle-shaped,  much like Schwann cells or fibroblasts. Some authorities  classify these nevus cell variations as types A (epithelioid),  B (lymphocyte-like), and C (spindle-shaped). Nevus cells  typically lack the dendritic processes that melanocytes  possess.   Melanocytic nevi are classified histopathologically  according to their stage of development. The junctional  nevus represents an early stage, in which théques of nevus  cells are confined to the junction of the epithelium and  connective tissue (Fig. 10-48), especially at the tips of the  rete ridges. As the nevus cells proliferate, they begin to drop  off into the underlying dermis or lamina propria. When    nevus cells are present along the junctional area and within  the connective tissue, the lesion is called a compound  nevus (Fig. 10-49). In later stages, the nevus cells are found  only within the connective tissue. In the skin, this stage is  called an intradermal nevus; the intraoral counterpart is  called an intramucosal nevus (Fig. 10-50). Most intraoral  melanocytic nevi are classified microscopically as intramu-  cosal nevi. However, this finding probably reflects the age  (average, 35 years) at which most oral nevi undergo biopsy  and diagnosis, because these lesions would have evolved  earlier through junctional and compound stages.    No treatment is indicated for a cutaneous melanocytic  nevus unless it is cosmetically unacceptable, is chronically  irritated by clothing, or changes in size or color. By midlife,  cutaneous melanocytic nevi tend to regress; by age 90, very  few remain. If removal is elected, then conservative surgical  excision is the treatment of choice; recurrence is unlikely.    The risk of malignant transformation of an individual  acquired melanocytic nevus into cutaneous melanoma is  low (approximately one in 3,000 to 10,000). Nevertheless,  patients with a large number (>100) of cutaneous nevi are  at increased risk for developing melanoma and should be  monitored closely.   Current evidence does not suggest that oral melanocytic  nevi are a marker of increased risk for developing oral  mucosal melanoma. However, early oral mucosal melano-  mas may appear clinically similar to oral melanocytic nevi  or other benign pigmented lesions. Therefore, biopsy of all  unexplained pigmented oral lesions generally is advised.    The congenital melanocytic nevus affects approximately  1% of newborns in the United States. The trunk and  extremities are involved most commonly, although approxi-  mately 15% of lesions arise in the head and neck area.  Intraoral involvement is rare. Congenital melanocytic nevi  usually are classified according to projected adult size as  follows: small (<1.5 cm in diameter), medium (1.5 cm to  20 cm in diameter), or large (220 cm in diameter). Espe-  cially large lesions may be termed “giant.” Large congenital  melanocytic nevi often harbor NRAS mutations.    Small congenital melanocytic nevi may appear similar to  acquired melanocytic nevi. However, most lesions are  medium to large—appearing as light tan macules that over  time develop into dark brown to black, rough-surfaced  plaques or multinodular lesions (Figs. 10-51 and 10-52). A  common feature is hypertrichosis (excess hair) within the  lesion, which may become more prominent with age (giant  hairy nevus). A very large congenital nevus sometimes may  give the appearance that the patient is wearing an article of  clothing and, thus, may be termed a bathing trunk nevus  or garment nevus.    The histopathologic appearance of the congenital melano-  cytic nevus is similar to that of the acquired melanocytic  nevus, and some small congenital nevi cannot be distin-  guished microscopically from acquired nevi. Both congeni-  tal and acquired types are composed of nevus cells, which  may have a junctional, compound, or intradermal pattern.  The congenital nevus is usually of the compound or intra-  dermal type. In contrast to the acquired melanocytic nevus,  the congenital nevus often extends into deeper levels of the  dermis, with “infiltration” of nevus cells between collagen  bundles. In addition, congenital nevus cells often inter-  mingle with neurovascular bundles in the reticular dermis  and surround normal adnexal skin structures (e.g., hair    @ Fig. 10-51 Congenital Melanocytic Nevus. Pigmented lesion of  the skin showing hypertrichosis.    @ Fig. 10-52 Congenital Melanocytic Nevus. Deeply pigmented  lesion of the lingual mandibular gingiva in a 3-year-old child.    follicles, sebaceous glands). Large congenital melanocytic  nevi may extend into the subcutaneous fat.    Many congenital melanocytic nevi are excised for aesthetic  purposes. Systematic reviews of the literature suggest that  approximately 2% to 3% of large congenital nevi transform  into malignant melanoma. However, the efficacy of excision  in reducing this slightly elevated risk for melanoma is  unknown and remains controversial. Also, complete exci-  sion may not be feasible for large lesions. Alternative treat-  ment options include partial surgical removal, dermabrasion,  laser therapy, cryotherapy, and chemical peels. Close clinical  follow-up is recommended regardless of whether or not  treatment has been rendered.   Patients with giant or multiple congenital nevi also are  at risk for neurocutaneous melanosis. This rare and poten-  tially fatal congenital syndrome is characterized by congeni-  tal nevi in conjunction with melanotic neoplasms of the  central nervous system (CNS), including leptomeningeal  melanosis and melanoma.    ® Fig. 10-53 Halo Nevus. Elevated brown lesion of the skin showing  surrounding depigmentation.    The halo nevus is a melanocytic nevus with a hypopig-  mented border, apparently resulting from nevus cell and  melanocyte destruction by the immune system. The cause  of the immune attack is unknown, but regression of the  nevus usually results. Interestingly, multiple halo nevi may  develop in patients who have had a recent excision of a  melanoma. Infrequently, halo phenomena also may occur  in association with melanomas and basal cell carcinomas.    The halo nevus is typically an isolated finding that develops  from a preexisting acquired melanocytic nevus. It is most  common on the skin of the trunk during the second decade  of life. The lesion typically appears as a pigmented papule  or macule, surrounded by a hypopigmented zone measuring  2 to 3 mm or wider (Fig. 10-53).    Histopathologically, the halo nevus differs from the routine  acquired melanocytic nevus only in the presence of an  intense chronic inflammatory cell infiltrate.    Most halo nevi regress and do not require treatment. If  treatment is elected, then conservative surgical removal is  curative and recurrence is unlikely.    The Spitz nevus is an uncommon melanocytic nevus variant  that shares many histopathologic features with melanoma.    It was, in fact, first described as a juvenile melanoma.  However, this lesion’s distinctly benign biologic behavior  was emphasized by Spitz in 1948. Studies suggest that Spitz  nevi commonly harbor HRAS mutations, whereas conven-  tional melanocytic nevi and melanomas tend to exhibit  BRAF mutations. The first oral Spitz nevus was not reported  until 1990.    The Spitz nevus typically develops on the skin of the  extremities or the face during childhood. It usually appears  as a solitary, dome-shaped, pink to reddish-brown papule  smaller than 6 mm in greatest diameter. The young age at  presentation and relatively small size help distinguish the  Spitz nevus from melanoma.    Most Spitz nevi are compound in architecture, with zonal  differentiation from the superficial to deep aspects and good  symmetry. Lesional cells are either spindle-shaped or plump  (epithelioid), and the two types often are intermixed. The  epithelioid cells may be multinucleated and appear some-  what bizarre, often lacking cohesiveness. Solitary or coales-  cent eosinophilic globules (Kamino bodies) may be seen  within the epidermis or at the junction of the epidermis and  dermis. Ectatic blood vessels (imparting the reddish color  of some lesions) and normal mitotic figures may be present  in the superficial aspects of the lesion. Immunohistochem-  istry may show the lesional cells to be positive for various  melanocytic antigens, such as S-100, HMB-45, and melan-A  (MART-1).    Conservative surgical excision is the treatment of choice.  There is little chance of recurrence after removal.    The blue nevus is an uncommon, benign proliferation of  dermal melanocytes, usually deep within the connective  tissue. Two major types are recognized: 1) the common blue  nevus and 2) the cellular blue nevus. The common blue  nevus is the second most frequent melanocytic nevus  encountered in the mouth. The blue color of this melanin-  producing lesion can be explained by the Tyndall effect,  which relates to the interaction of light with particles in a  colloidal suspension. In the case of a blue nevus, the melanin  particles are deep to the surface, so that light reflected back  has to pass through the overlying tissue. Colors with long  wavelengths (reds and yellows) tend to be absorbed more  readily by the tissue; the shorter-wavelength blue light is  mote likely to be reflected back to the observer's eyes. Unlike  conventional acquired melanocytic nevi, blue nevi typically    @ Fig. 10-54 Blue Nevus. A well-circumscribed, deep-blue macular  lesion is seen on palatal mucosa.    exhibit mutations in the GNAQ gene (which encodes a  G-protein alpha subunit important for signal transduction  from cell-surface receptors) and only rarely harbor BRAF    The common blue nevus may affect any cutaneous or  mucosal site, but it has a predilection for the dorsa of the  hands and feet, the scalp, and the face. Mucosal lesions may  involve the oral mucosa, conjunctiva, and, rarely, sinonasal  mucosa. Oral lesions almost always are found on the palate.  The lesion usually occurs in children and young adults and  exhibits a female predilection. It appears as a macular or  dome-shaped, blue or blue-black lesion smaller than 1 cm  in diameter (Fig. 10-54).   The cellular blue nevus is much less common and usually  develops during the second to fourth decades of life, but it  may be congenital. More than 50% of cellular blue nevi  arise in the sacrococcygeal or buttock region, although they  may be seen on other cutaneous or mucosal surfaces. Clini-  cally, this nevus appears as a slow-growing, blue-black  papule or nodule that sometimes attains a size of 2 cm or  more. Occasional lesions remain macular.    Histopathologically, the common blue nevus consists of a  collection of elongated, slender melanocytes with dendritic  extensions and numerous melanin granules. These cells are  located deep within the dermis or lamina propria (Fig.  10-55) and usually align themselves parallel to the surface  epithelium. The cellular blue nevus appears as a well-  circumscribed, highly cellular aggregate of plump, melanin-  producing spindle cells within the dermis or submucosa.  Mote typical pigmented dendritic spindle cells are seen at  the periphery of the lesion. Occasionally, a blue nevus is  found in conjunction with an overlying melanocytic nevus,  in which case the term combined nevus is used.    propria and parallel to the surface epithelium. B, High-power view  showing heavily pigmented spindle-shaped cells.    If clinically indicated, conservative surgical excision is the  treatment of choice for cutaneous blue nevi. Recurrence is  minimal with this treatment. Malignant transformation to  melanoma is rare but has been reported.   Because an oral blue nevus clinically can mimic an early  melanoma, biopsy of intraoral pigmented lesions is usually  advisable.    As originally defined by the World Health Organization  (WHO), oral leukoplakia (/euko = white; plakia = patch)  represents “a white patch or plaque that cannot be charac-  terized clinically or pathologically as any other disease.” The  term is strictly a clinical one and does not imply a specific  histopathologic tissue alteration.   The definition of leukoplakia is unusual in that it makes  the diagnosis dependent not so much on definable appear-  ances as on the exclusion of other entities that appear as oral  white plaques. Such lesions as lichen planus, morsicatio  buccarum (chronic cheek nibbling), frictional keratosis,    e Precancerous lesion (precancer, premalignancy). A  benign, morphologically altered tissue that has a greater than  normal risk of malignant transformation.   e Precancerous condition. A disease or patient habit that  does not necessarily alter the clinical appearance of local  tissue but is associated with a greater than normal risk of  precancerous lesion or cancer development in that tissue.   initial diagnosis or in the future (usually expressed in  percentages). The potential for mucosa without precancerous  lesions or conditions is called normal.   e Relative risk. A specific epidemiologic measure of the  association between exposure to a particular factor and the  risk of acquiring a disease, expressed as a ratio of the  incidence or prevalence of a disease among those exposed  and those not exposed to the factor.    tobacco pouch keratosis, nicotine stomatitis, leukoedema,  and white sponge nevus must be ruled out before a clinical  diagnosis of leukoplakia can be made. As with most oral  white lesions, the clinical color results from a thickened  surface keratin layer, which appears white when wet, or a  thickened spinous layer, which masks the normal vascularity  (redness) of the underlying connective tissue.   Although leukoplakia does not constitute a specific his-  topathologic diagnosis, it is considered a precancerous or  premalignant lesion (see Box 10-3 for definitions of these  and other related terms). That is, the frequency of transfor-  mation into malignancy is greater than that for normal or  unaltered mucosa.    Leukoplakia is by far the most common oral precancer,  representing 85% of such lesions. In addition, more than  one-third of oral carcinomas exhibit leukoplakia in close  proximity. Based on pooled, weighted data from previously  reported studies, the worldwide prevalence of leukoplakia  has been estimated to fall within a range of 1.5% to 4.3%.  ‘There is a strong male predilection (70%), except in regional  populations in which women use tobacco products more  than men. A slight decrease in the proportion of affected  males, however, has been noted over the past half century.  The disease is diagnosed more frequently now than in the  past, probably because of an enhanced awareness among  health professionals (rather than because of a real increase  in frequency).    Among the various proposed contributory factors, tobacco  smoking appears to be the most closely associated with  leukoplakia. More than 80% of patients with leukoplakia  are smokers, and smokers are much more likely to have  leukoplakia than nonsmokers. Heavier smokers have greater  numbers of lesions and larger lesions than do light smokers,  especially after many years of tobacco use. In addition,  leukoplakias often disappear or become smaller within the  first year of smoking cessation.   Smokeless tobacco use often causes a clinically distinctive  white oral plaque called tobacco pouch keratosis (see page  364). This lesion probably is not a true leukoplakia. In  contrast, betel quid use (see page 366)—with or without  smokeless tobacco—is associated with true leukoplakia; this  habit is common in parts of Asia.    Alcohol exerts a strong synergistic effect with tobacco in oral  cancer development. Nevertheless, there is conflicting evi-  dence as to whether alcohol is associated independently  with leukoplakia. People who excessively use mouth rinses  with alcohol content greater than 25% may have grayish  buccal mucosal plaques, but these lesions are not considered  true leukoplakias.    Persons who use toothpaste or mouth rinses containing the  herbal extract, sanguinaria, may develop a true leukoplakia  called sanguinaria-associated keratosis. This lesion usually  arises in the maxillary vestibule or on the maxillary alveolar  mucosa (Fig. 10-56). More than 80% of individuals with  maxillary vestibular or alveolar leukoplakia have a history  of using products that contain sanguinaria, compared with  3% of the normal population.   ‘The affected epithelium may demonstrate dysplasia iden-  tical to that seen in other leukoplakias, although the poten-  tial for cancer development is uncertain. The white plaque  may persist for years even after the patient stops using the  product.    ® Fig. 10-57 Candidal Leukoplakia. A, Well-circumscribed red and  white plaque on the anterior floor of mouth, which showed candidal  infestation on cytology smears. B, After antifungal therapy, the ery-  thematous component resolved, resulting in a homogeneous white  plaque.    UV radiation is a causative factor for leukoplakia of the  lower lip vermilion. Such lesions typically represent actinic  cheiloses (see page 370). Immunocompromised persons,  such as transplant patients, are especially prone to develop-  ing leukoplakia and squamous cell carcinoma of the lower  lip vermilion.    Several microorganisms have been implicated in the etiol-  ogy of leukoplakia. Treponema pallidum, for example, pro-  duces glossitis in the late stage of syphilis, with or without  the arsenic therapy in popular use before the advent of  modern antibiotics. The tongue is stiff and frequently has  extensive dorsal leukoplakia.   Tertiary syphilis is rare today, but oral infection by  Candida albicans is not. C. albicans can colonize the keratin  layer of the oral mucosa, often producing a thick, granular,  red and white plaque (Fig. 10-57). The terms candidal leu-  koplakia and candidal hyperplasia have been used to  describe such a lesion, and biopsy may show epithelial dys-  plasia or hyperplasia. It is unknown whether this yeast pro-  duces dysplasia or secondarily infects previously altered  epithelium; however, some of these lesions disappear, shrink,    or become less severely dysplastic after antifungal therapy. In  some cases, tobacco smoking may cause the leukoplakia and  also may predispose the patient to develop candidiasis.   The potential role of HPV in the development of oral  leukoplakias remains uncertain. Investigators have detected  HPV DNA about two to four times more often in oral  leukoplakias than in clinically normal oral mucosa. Never-  theless, the presence of HPV DNA alone cannot exclude  the possibility of coincidental (or “bystander”) infection.  Low viral load and frequent absence of viral integration into  the host genome among many HPV-positive oral precancers  and cancers bring into question the biological relevance of  HPV infection in these lesions. Also problematic is the fact  that HPV is found more frequently in homogeneous leu-  koplakias than in non-homogeneous leukoplakias, whereas  non-homogeneous lesions are more likely to undergo malig-  nant transformation (see later).    Several keratotic lesions, which until recently had been  viewed as variants of leukoplakia, are now considered not  to be precancers. Nicotine stomatitis is a generalized white  palatal alteration that seems to be a hyperkeratotic response  to the heat generated by tobacco smoking (usually a pipe),  rather than a response to the carcinogens within the smoke  (see page 368). Its malignant transformation potential is so  low as to be about the same as that of normal palatal  mucosa.   In addition, chronic mechanical irritation can produce a  white lesion with a roughened keratotic surface, termed  frictional keratosis. Although this lesion clinically appears  similar to true leukoplakia, it is now thought to be no more  than a normal hyperplastic response (similar to a callus on  the skin). Keratoses of this type are readily reversible after  elimination of the trauma, and obviously traumatic  lesions—such as linea alba (see page 259), morsicatio (see  page 259), and toothbrush gingival “abrasion’—have not  been documented to transform into malignancy. In addi-  tion, the presence of dentures or broken and missing teeth  has not been shown to increase cancer risk. Alveolar ridge  keratoses (Fig. 10-58)—involving the retromolar pad or  crest of an edentulous alveolar ridge—represent another  form of frictional keratosis caused by masticatory function  or denture trauma. Frictional keratosis should be differenti-  ated from oral precancers.    Leukoplakia usually affects persons older than 40 years.  Prevalence increases rapidly with age, especially for males,  and as many as 8% of men older than 70 years are affected  (Fig. 10-59). The average age (60 years) is similar to that  for patients with oral cancer; however, in some studies,  leukoplakia has been found to occur about 5 years earlier  (on average) than oral squamous cell carcinoma.  Approximately 70% of oral leukoplakias are found on  the lip vermilion, buccal mucosa, and gingiva. Lesions on    ® Fig. 10-58 Frictional Keratosis. There is a rough, hyperkeratotic  change to the posterior mandibular alveolar ridge (“alveolar ridge kera-  tosis”), because this area is now edentulous and becomes traumatized  from mastication. Such frictional keratoses should resolve when the  source of irritation is eliminated and should not be mistaken for true    ® Fig. 10-59 Leukoplakia. Age-specific prevalence (number of new  cases per 1000 adults examined at various ages) for oral leukoplakia  demonstrates increasing prevalence with increasing age, especially for  men.    the tongue, lip vermilion, and oral floor, however, account  for more than 90% of those that show dysplasia or carci-  noma. Among betel quid users, the buccal mucosa and  commissure are the major sites for leukoplakia harboring  carcinoma.   Individual lesions may have a varied clinical appearance  and tend to change over time. Early, mild, or thin leuko-  plakia appears as a flat to slightly elevated, gray or white  plaque, which may be somewhat translucent, fissured, or  wrinkled. It is usually soft with sharply demarcated borders,  but occasionally it may blend gradually into normal mucosa.    © Fig. 10-60 Homogeneous or Thick Leukoplakia. A diffuse, cor-  rugated white patch on the right ventral surface of the tongue and floor  of mouth.    © Fig. 10-61 Homogeneous or Thick Leukoplakia. Extensive  buccal mucosal lesion with uneven whiteness and fissures. Moderate  epithelial dysplasia was noted on histopathologic evaluation, and  squamous cell carcinoma later developed in this area.    Thin leukoplakia may disappear or continue unchanged and  seldom shows dysplasia on biopsy. For tobacco smokers who  do not reduce their habit, as many as two-thirds of such  lesions enlarge and progress to a stage called homogeneous  or thick leukoplakia, characterized by a thickened, leath-  ery, distinctly white plaque with deepened fissures (Figs.  10-60 and 10-61). Most remain indefinitely at this stage.  However, as many as one-third regress or disappear. Some  lesions develop increased surface irregularities and are called  granular or nodular leukoplakia (Figs. 10-62). Lesions  with sharp or blunt, wartlike projections are called verru-  cous or verruciform leukoplakia.   A special high-risk form of leukoplakia, proliferative  verrucous leukoplakia (PVL), is characterized by the  development of multiple, slowly spreading, keratotic plaques  with rough surface projections (Figs. 10-63 and 10-64). The  relationship of PVL to cases described as verrucous leukopla-  kia is uncertain. The gingiva frequently is involved, but  other sites may be affected as well. Although the lesions  typically begin as simple, flat hyperkeratoses that are    @ Fig. 10-62 Granular Leukoplakia. Focal leukoplakic lesion with a  rough, granular surface on the posterior lateral border of the tongue.  Biopsy revealed early invasive squamous cell carcinoma.    e Fig. 10-63 Proliferative Verrucous Leukoplakia (PVL). A,  Diffuse, corrugated, white lesions of the buccal and palatal mucosa.  B, Thickened, corrugated, white lesion involving the palate, alveolar  ridge, and lingual marginal gingiva.    indistinguishable from ordinary leukoplakia, PVL exhibits  persistent growth, eventually becoming exophytic and ver-  rucous. As the lesions progress, they may go through a stage  indistinguishable from verrucous carcinoma (see page  389), but they later usually develop dysplasia and transform  into full-fledged squamous cell carcinoma (often within 8  years of initial PVL diagnosis). These lesions rarely regress    © Fig. 10-64 Proliferative Verrucous Leukoplakia (PVL). A, An  elderly white female developed extensive leukoplakia with rough  surface projections on the buccal mucosa and mandibular alveolar  ridge. B, After failing to comply with a recommendation for biopsy, the  same patient returned 2 years later with a verrucous carcinoma.    despite therapy. PVL is unusual among the leukoplakia  variants in having a strong female predilection (1:4 male-  to-female ratio) and minimal association with tobacco use.   Leukoplakia may become dysplastic or even malignant,  with no change in its clinical appearance. However, some  lesions eventually demonstrate scattered patches of redness,  called erythroplakia (see page 363). Such areas usually  represent sites in which epithelial cells are so immature or  atrophic that they can no longer produce keratin. This  intermixed red-and-white lesion, called erythroleukopla-  kia or speckled leukoplakia, frequently exhibits advanced  dysplasia on biopsy (Fig. 10-65).   Many leukoplakic lesions are a mixture of the previously  mentioned phases or subtypes. Figs. 10-66 and 10-67  provide a clinical and graphic representation of such a  lesion. Biopsies should be taken from areas of a lesion most  likely to harbor dysplasia or carcinoma (i.e., areas with a  clinical appearance similar to those toward the right in Fig.  10-67).   Over the years, several new techniques (such as vital dyes,  brush cytology, chemiluminescence, and autofluorescence)  have been proposed to aid in the identification or diagnosis  of premalignant and malignant oral lesions. However, there    is currently insufficient evidence to support the use of such  technologies in routine practice, and careful clinical evalu-  ation with directed conventional biopsy remains the gold  standard for assessment of oral leukoplakia (see Fig. 10-98).    Microscopically, leukoplakia is characterized by a thickened  keratin layer of the surface epithelium (hyperkeratosis),  with or without a thickened spinous layer (acanthosis).  Some leukoplakias demonstrate surface hyperkeratosis but  show atrophy or thinning of the underlying epithelium.  Frequently, variable numbers of chronic inflammatory cells  are noted within the subjacent connective tissue.    @ Fig. 10-65 Erythroleukoplakia. Red and white lesion of the lateral  border of the tongue. Biopsy revealed carcinoma in situ.    T  I  I  I  I  I  I  I  I  I  (mild/moderate) }  I  I  I  I  I  I  I  I  I    The keratin layer may consist of parakeratin (hyperpara-  keratosis), orthokeratin (hyperorthokeratosis), or a com-  bination of both (Fig. 10-68). With parakeratin, there is no  granular cell layer and the epithelial nuclei are retained in  the keratin layer. With orthokeratin, the epithelium dem-  onstrates a granular cell layer, and the nuclei are lost in the  keratin layer.   Verrucous leukoplakia has papillary or pointed surface  projections, varying keratin thickness, and broad, blunted  rete ridges. It may be difficult to differentiate from early  verrucous carcinoma.   The microscopic appearance of PVL varies by lesion  stage. Early PVL appears as a benign hyperkeratosis that is    @ Fig. 10-66 Leukoplakia. Extensive ventral and lateral tongue  lesion with areas representing various possible phases or clinical  appearances (compare with Fig. 10-67).    ¢ Bulbous and crowded rete pegs (on left)  ¢ Epithelial atrophy (on right)  ¢ Lymphocytes (moderate to numerous)    ® Fig. 10-67 Leukoplakia. Composite representation of the various phases or clinical appearances of  oral leukoplakia, with anticipated underlying histopathologic changes. Lesions have increasing malignant  transformation potentials as their appearances approach those toward the right. (From Bouquot JE,  Gnepp DR: Laryngeal precancer—a review of the literature, commentary and comparison with oral leu-  koplakia, Head Neck 13:488-497, 1991.)    See eaten a = A Sisyisir  © Fig. 10-68 Hyperorthokeratosis. This medium-power photomi-  crograph demonstrates hyperorthokeratosis with a well-defined granu-  lar cell layer on the left side. The right side shows normal parakeratinized  epithelium without a granular cell layer.    indistinguishable from conventional leukoplakia. With  time, the condition progresses to a papillary, exophytic pro-  liferation that is similar to localized lesions of verrucous  leukoplakia (or what is sometimes termed verrucous hyper-  plasia). In later stages, this papillary proliferation exhibits  downgrowth of well-differentiated squamous epithelium  with broad, blunt rete ridges and is indistinguishable from  verrucous carcinoma. In the final stages, the epithelium  becomes frankly invasive and less differentiated, transform-  ing into full-fledged squamous cell carcinoma. The diagno-  sis of PVL requires careful correlation of the variable clinical  and microscopic findings.   Epithelial dysplasia or carcinoma is found in only about  5% to 25% of oral leukoplakias. Dysplastic changes typi-  cally begin in the basilar and parabasilar portions of the  epithelium. The more dysplastic the epithelium becomes,  the more the atypical epithelial changes extend to involve the  entire thickness of the epithelium. The histopathologic alter-  ations of dysplastic epithelial cells are similar to those of  squamous cell carcinoma and may include the following:   ¢ Abnormal mitotic figures (tripolar or star-shaped mitoses  or mitotic figures above the basal layer)   In addition, histomorphologic alterations of dysplastic  epithelium are evident at low-power magnification, includ-  ing the following:  ¢ Bulbous or teardrop-shaped rete ridges  ¢ Loss of polarity (lack of progressive maturation toward    @ Fig. 10-69 Mild Epithelial Dysplasia. Hyperchromatic and slightly  pleomorphic nuclei are noted in the basal and parabasal cell layers of  this stratified squamous epithelium.    © Fig. 10-70 Moderate Epithelial Dysplasia. Dysplastic changes  extend to the midpoint of the epithelium and are characterized by  nuclear hyperchromatism, pleomorphism, and cellular crowding.    The grade of epithelial dysplasia refers to its “severity” or  intensity. Mild epithelial dysplasia refers to alterations  limited principally to the basal and parabasal layers (Fig.  10-69). Moderate epithelial dysplasia demonstrates  involvement from the basal layer to the midportion of the  spinous layer (Fig. 10-70). Severe epithelial dysplasia  demonstrates alterations from the basal layer to a level above  the midpoint of the epithelium (Fig. 10-71). Sometimes  dysplasia may extend down the duct of a minor salivary  gland, especially in lesions of the floor of the mouth (Fig.  10-72); such cases exhibit an increased risk for recurrence.   Carcinoma iz situ is defined as dysplasia involving the  entire thickness of the epithelium (i-e., extending from the  basal layer to the surface or “top-to-bottom” change) (Fig.  10-73). There may or may not be a thin layer of keratin on  the surface. The epithelium may be hyperplastic or atrophic.  Some authorities consider carcinoma in situ to be a precan-  cerous lesion, whereas others believe that it represents a  genuine malignancy discovered before invasion. Regardless,  an important feature of carcinoma in situ is absence of  invasion, and without invasion, metastasis cannot occur.    @ Fig. 10-71 Severe Epithelial Dysplasia. Epithelium exhibiting  marked pleomorphism, hyperchromatism, and scattered mitotic  figures. Atypical cells involve most of the epithelial thickness.    mous metaplasia and dysplasia that originated from an overlying  surface epithelial dysplasia.    In this light, keratin pearl formation is rare in carcinoma  in sits and may indicate focal invasive squamous cell  carcinoma.    Because leukoplakia represents a clinical term only, a biopsy  is required to obtain a histopathologic diagnosis and to  guide the appropriate management. Biopsies should be  taken from the clinically most “severe” areas (with features  toward the right of Fig. 10-67). Multiple biopsies may be  needed for large or multifocal lesions.   Leukoplakia exhibiting moderate epithelial dysplasia or  worse warrants complete destruction or removal, if feasible.  The management of leukoplakia exhibiting less severe  change is guided by the lesion size and the response to more  conservative measures, such as tobacco cessation. Some  smoking-related leukoplakias with no or minimal dysplasia  may disappear or diminish in size within 3 months after the  patient stops smoking.   Complete removal can be accomplished with equal effec-  tiveness by surgical excision, electrocautery, cryosurgery, or  laser ablation. An advantage of surgical excision is that it  allows for optimal tissue preservation for histopathologic  analysis, whereas the other methods may be preferable in  some cases for limiting procedure-related morbidity.   Even after removal, reported overall recurrence rates  range from 10% to 35%, and development of additional  leukoplakias is common. In particular, verruciform or gran-  ular leukoplakias exhibit an 83% recurrence rate and, thus,  often undergo additional removal or destruction. Neverthe-  less, it is unclear whether surgical excision of leukoplakia  significantly reduces the risk for developing malignancy.  Therefore, even after removal, long-term follow-up is  extremely important.   Although leukoplakia without dysplasia often is not  excised, clinical evaluation every 6 months is recommended  because of the possibility of disease progression. Additional  biopsies are recommended if smoking continues or if the  clinical changes increase in severity.   Reported malignant transformation rates for oral leuko-  plakia vary considerably across studies, although best esti-  mates suggest a malignant transformation rate of less than  2% per year. Some of this variation may be due to patient  selection bias, with lower rates typically reported among  community-based than hospital-based studies. Additional  confounding factors include variations in diagnostic defini-  tions, clinical management, and periods of observation.  Typically, the latter extend for 5 to 10 years, but several  studies have observed patients for more than 20 years. Car-  cinomatous transformation usually occurs 2 to 4 years after  leukoplakia onset, but it may occur within months or after  decades.   Each clinical phase of leukoplakia has a different malig-  nant transformation potential. Thin leukoplakia seldom  becomes malignant without demonstrating a clinical  change. In contrast, malignant transformation occurs in    approximately 1% to 7% of homogeneous, thick leukopla-  kias and 4% to 15% of granular or verruciform leukopla-  kias. Erythroleukoplakia carries an average transformation  potential of 28%, but reported rates vary from 18%  to 47%.   The transformation potential of the different phases of  leukoplakia is related closely to the degree of dysplasia  present. Lesions with moderate and severe dysplasia report-  edly have malignant transformation potentials of 4% to  11% and 20% to 43%, respectively.   Additional factors associated with an increased risk for  malignant transformation of leukoplakia include female  gender, older age, nonsmoking status, lesion persistence for  several years, extensive lesion size, and involvement of the  ventrolateral tongue or floor of mouth. In particular, leu-  koplakia of the ventrolateral tongue and oral floor exhibits  malignant transformation in 16% to 39% of cases and 47%  of those occurring in females.   There is much interest in the identification of chromo-  somal, genetic, and molecular alterations that may aid in  predicting the risk of malignant transformation for oral  leukoplakia. Cytogenetic studies have suggested that loss  of heterozygosity (LOH) of chromosome arms 3p and 9p  is associated with increased risk of malignant transforma-  tion, and additional LOH at 4q, 8p, 11q, 13q, and 17p  further increases this risk. Additional alterations—such as  microsatellite instability (insertion or deletion of base pairs  in repetitive stretches of short DNA sequences), increased  telomerase activity (important for cellular longevity), and  changes in expression of various molecular markers (e.g.,  p53, survivin, and other regulators of apoptosis; p16  and other markers of cell cycle regulation; epidermal  growth factor receptor [EGFR]; matrix metalloproteinases;  vascular endothelial growth factor)—have exhibited a vari-  able association with histopathologic progression in oral  premalignant lesions. Despite these interesting observa-  tions, histopathologic grading of dysplasia remains the  standard method for predicting the risk of progression to  malignancy.   Chemoprevention for oral leukoplakia has been  attempted but remains experimental. Retinoid-based thera-  pies (e.g., 13-cis-retinoic acid; vitamin A alone or in com-  bination with beta-carotene) have reduced or eliminated  some leukoplakic lesions in short-term studies. Toxic reac-  tions to systemic retinoids are frequent, however, as is lesion  recurrence after the conclusion of therapy. Additional  potential chemopreventive agents of interest include lyco-  pene, cyclooxgenase-2 (COX-2) inhibitors, epidermal  growth factor receptor (EGFR) inhibitors, green tea poly-  phenols, peroxisome proliferator activator (PPAR)-gamma  agonists (traditionally used as oral hypoglycemics for diabe-  tes management), and ONYX-015 (an attenuated adenovi-  rus with selectivity for cells harboring 7P53 mutations).  However, to date there is insufficient evidence to support  the effectiveness of such medical therapies in preventing the  progression of oral premalignant lesions to squamous cell  carcinoma.    Similar to leukoplakia, erythroplakia is defined as a red  patch or plaque that cannot be clinically or pathologically  diagnosed as any other condition. Queyrat originally used  the term erythroplasia to describe a precancerous red lesion  on the penis. Oral erythroplakia is clinically and histo-  pathologically similar to the genital process. Almost all true  erythroplakias demonstrate significant epithelial dysplasia,  carcinoma in situ, or invasive squamous cell carcinoma.  The causes of erythroplakia are presumed to be the same as  those associated with oral squamous cell carcinoma (see  page 375).   The estimated point prevalence rate (number of persons  with active lesions at a given point in time) of oral eryth-  roplakia is 1 per 2500 adults. The reported prevalence  among several large-scale epidemiologic surveys—many of  which were conducted in Asia and the United States—  ranges from 0.01% to 0.83%. The incidence is unknown,  but the estimated annual incidence for microscopically  proven oral carcinoma in situ, which represents the great  majority of erythroplakias, is 1.2 per 100,000 population  in the United States.   Erythroplakia also may occur in conjunction with leu-  koplakia (see page 355) and has been found concurrently  with a large proportion of early invasive oral carcinomas.  Although erythroplakia is less common than leukoplakia, it  has a much greater potential to be severely dysplastic at the  time of biopsy or to develop malignancy later.    Erythroplakia is predominantly a disease of middle-aged to  older adults with no significant gender predilection. In the  United States, a peak prevalence of 65 to 74 years has been  reported. In India, the peak prevalence is in a somewhat  younger age range of 45 to 54 years. The floor of mouth,  tongue, and soft palate are the most common sites of  involvement, and multiple lesions may be present.   The lesion appears as a well-demarcated, erythematous  patch or plaque with a soft, velvety texture (Figs. 10-74 and  10-75). It is usually asymptomatic and may be associated  with an adjacent leukoplakia (erythroleukoplakia) (sce  Fig. 10-65). Biopsy typically is required to distinguish  erythroplakia from other conditions with a similar clinical  appearance, such as nonspecific mucositis, candidiasis, pso-  riasis, or vascular lesions.    According to one large clinicopathologic investigation, 90%  of erythroplakic lesions histopathologically represent severe  epithelial dysplasia (see page 361), carcinoma in situ (see  page 361), or superficially invasive squamous cell carcinoma  (see page 385). The epithelium lacks keratin production and   @ Fig. 10-74 Erythroplakia. Erythematous macule on the right  floor of the mouth. Biopsy showed early invasive squamous cell  carcinoma.    @ Fig. 10-75 Erythroplakia. Well-circumscribed red patch on the  posterior lateral hard and soft palate. (From Neville BW, Chi AC, Jeter  M: Diagnostic challenge: a red lesion on the palate, J Am Dent Assoc  137:1537-1538, 2006.)    often is atrophic, thereby allowing the underlying microvas-  culature to show through and produce a red appearance.  The underlying connective tissue frequently demonstrates  chronic inflammation.    Red lesions of the oral mucosa, especially those of the oral  floor and ventrolateral tongue, should be viewed with sus-  picion, and a biopsy should be performed. If a source of  irritation can be identified and removed, then biopsy may  be delayed for 2 weeks to allow a clinically similar inflam-  matory lesion time to regress.   As with leukoplakia, the treatment of erythroplakia is  guided by the histopathologic diagnosis. Moderate dysplasia  or worse typically warrants complete excision or destruction  (see treatment methods for leukoplakia on page 362). Exci-  sion often is preferred, because it allows for microscopic  examination to rule out invasive carcinoma. Recurrence and  multifocal involvement are common; hence, long-term  follow-up is suggested.    * SMOKELESS TOBACCO USE AND  SMOKELESS TOBACCO KERATOSIS  (SNUFF POUCH; SNUFF DIPPER’S LESION;  TOBACCO POUCH KERATOSIS; SPIT  TOBACCO KERATOSIS)    The three main types of smokeless tobacco used in the  United States include chewing tobacco, dry snuff, and moist  snuff. The latter is most popular, with increasing sales  over the past few decades due in part to the convenience  of small, inconspicuous, prepackaged pouches. Chewing  tobacco often is used by men in conjunction with outdoor  activities, and dry snuff is used primarily by women in the  southern United States. Smokeless tobacco use also has been  referred to as spit tobacco use—a term preferred by the US  federal government in its attempt to diminish the appeal  of the habit.   In the United States, according to the 2011 National  Survey on Drug Use and Health, approximately 3.2% of  people (or 8.2 million individuals) 12 years and older use  smokeless tobacco. The highest prevalence rates are seen in  some Southeastern and Midwestern states. The habit is  especially common among young individuals, with approxi-  mately 13% of male high school students reporting current  smokeless tobacco use. The habit typically is started at  around 8 to 14 years of age, and rarely is initiated after 20  years of age. Another national survey detected smokeless  tobacco lesions of all types in 1.5% (2.9% in males, 0.1%  in females) of US adolescents and teenagers. As part of its  Healthy People 2020 objectives, the US Department of  Health and Human Services has set a goal to reduce the  national prevalence of smokeless tobacco use from 2.3% to  0.3% among adults and from 8.9% to 6.9% among  adolescents.   In India and other Asian countries, smokeless tobacco  may be combined in a quid with betel leaves, areca nuts,  and slaked lime. Oral lesions associated with betel quid use  are described separately (see page 366).    Several health and addiction hazards may be associated with  smokeless tobacco use because of the ready absorption of  nicotine and other molecules through the oral mucosa. A  variety of local oral alterations also are found in chronic  users. One of the most common local changes is painless  gingival recession in the area of tobacco contact (Fig. 10-76),  at times accompanied by destruction of the underlying  facial alveolar bone. The severity of the defect correlates  with the quantity and duration of smokeless tobacco use.  Although the association between smokeless tobacco and  gingival recession is well known, there is some variability  across studies regarding the association between smokeless  tobacco and periodontal bone loss. Researchers have sug-  gested that this variability may be related to the specific type    @ Fig. 10-76 Smokeless Tobacco-related Gingival Recession.  Extensive recession of the anterior mandibular facial gingiva.   Dental caries also has been reported to be more prevalent  in smokeless tobacco users, perhaps because of the high  sugar content of some brands; other reports dispute caries  susceptibility. Long-term use may lead to localized or gen-  eralized wear of occlusal and incisal surfaces, especially in  those using the product in dusty environments. A brown-  black extrinsic tobacco stain typically is found on the tooth  surfaces adjacent to the tobacco. In addition, halitosis is a  frequent finding.   Smokeless tobacco keratosis represents a characteristic  white or gray plaque involving the mucosa in direct contact  with snuff or chewing tobacco. In Western cultures, it  affects 15% of chewing tobacco users and 60% of snuff  users, if mild examples are included. Lesion development is  influenced most strongly by habit duration and also by the  brand of tobacco used, early onset of smokeless tobacco use,  total hours of daily use, amount of tobacco consumed daily,  and number of sites routinely used for tobacco placement.  In Western populations, smokeless tobacco keratosis most  often is noted in young adult men and men older than 65  years of age; however, in some subpopulations the preva-  lence is greatest among older women. Individual lesions  begin to develop shortly after heavy tobacco use begins, and  new lesions seldom arise in persons with a long history  of use.   The altered mucosa typically is thin and almost translu-  cent, with an indistinct border (Fig. 10-77). Sometimes  mild peripheral erythema is present. Upon palpation, the  lesion may feel soft and velvety. Stretching of the mucosa  often reveals a distinct “pouch” (snuff pouch, tobacco  pouch) caused by flaccidity in the area of chronic tobacco  placement. The mucosa appears fissured or rippled, in a  fashion resembling the sand on a beach after an ebbing tide.  Similar alterations can occur when other bulky materials  (e.g., hard candy, sunflower seeds, and beef jerky) are held  chronically in the vestibule. Induration, ulceration, and  pain are not associated with this lesion.    @ Fig. 10-77 Tobacco Pouch Keratosis, Mild. A soft, fissured,  gray-white lesion of the lower labial mucosa located in the area of  chronic snuff placement. The gingival melanosis is racial pigmentation  and not associated with the keratosis.    © Fig. 10-78 Tobacco Pouch Keratosis, Severe. A somewhat  leathery, white, fissured plaque of the right mandibular vestibule, which  was located in the area of chronic chewing tobacco placement.    Smokeless tobacco keratosis usually takes 1 to 5 years to  develop. Once it occurs, however, the keratosis typically  remains unchanged indefinitely unless the daily tobacco  contact time is altered. In some cases, the lesion gradually  becomes thickened to the point of appearing leathery or  nodular (Fig. 10-78).    The histopathologic appearance of smokeless tobacco kera-  tosis is not specific. The squamous epithelium is hyperkera-  totic and acanthotic, with or without intracellular  vacuolization or “edema” of glycogen-rich superficial cells.  Parakeratin chevrons may be seen as pointed projections  above or within superficial epithelial layers (Fig. 10-79).  Increased subepithelial vascularity and vessel engorgement  often are observed. In some cases, an unusual deposition of  amorphous eosinophilic material is noted within the subja-  cent connective tissue and salivary glands (Fig. 10-80).  Epithelial dysplasia is uncommon in smokeless tobacco  keratosis and, when present, is typically mild. Occasionally,    showing mild hyperkeratosis and acanthosis. Note linear deposition of  amorphous, eosinophilic material in the lamina propria above the minor  salivary glands. B, Higher-power view of the amorphous material.    Chronic use of smokeless tobacco in the United States is  considered to be carcinogenic, although the risk is less than  that associated with cigarette smoking and alcohol abuse.  Fortunately, the clinical appearance of smokeless tobacco  keratosis is distinct enough and the malignant transforma-  tion potential is low enough that biopsy is needed for only  severe or atypical lesions (i.e., those demonstrating an  intense whiteness, a granular or verruciform clinical appear-  ance, ulceration, mass formation, induration, or hemor-  rhage). Treatment depends on the histopathologic diagnosis.  Keratoses without dysplasia or malignancy may require only  continued monitoring and encouraged tobacco cessation.  Alternating the tobacco-chewing sites between the left and  right sides will eliminate or reduce the keratotic lesion but  may result in epithelial alteration or gingival and periodon-  tal difficulties in two sites rather than one.   Squamous cell carcinoma (see page 376) related to  smokeless tobacco use typically develops after a latency  period of several decades. Most such cases represent con-  ventional squamous cell carcinoma, although an uncom-  mon low-grade variant known as verrucous carcinoma  (“snuff dipper’s” cancer) (see page 389) also is possible. In  a review of case control studies performed in the United  States and Western Europe, the reported relative risk of  developing oral cancer from chronic smokeless tobacco use  ranged from less than 2 to 26, with lower risk associated  with chewing tobacco and moist snuff and higher risk asso-  ciated with dry snuff. Recent studies from Sweden, however,  have failed to show an increased risk for users of Swedish  moist snuff (also known as sus). Many of the early reports  of malignant transformation described lesions among  female dry snuff users in the southern United States. Only  recently have epidemiologic studies tried to separate the  various types of smokeless tobacco with respect to their  carcinogenic potential.   Significantly, habit cessation leads to a normal mucosal  appearance (usually within 2 weeks) in 98% of smokeless  tobacco keratoses that are not intensely white (Fig. 10-81).  A lesion that remains after 6 weeks without smokeless  tobacco contact should be considered a true leukoplakia  and should be biopsied and managed accordingly (see  page 362).    Oral submucous fibrosis is a high-risk, precancerous con-  dition characterized by chronic, progressive scarring of the  oral mucosa. It is seen primarily in the Indian subcontinent,  Southeast Asia, Taiwan, southern China, Polynesia, and  Micronesia. The condition affects more than 5 million  people in India alone. Cases among Asian communities in  North America, Europe, and Africa also have been reported.    @ Fig. 10-81 Tobacco Pouch Keratosis. A, Moderately severe lesion of the lower anterior vestibule  and lip in a 15-year-old male. There is a gray-white, fissured surface. The patient had placed snuff in the  area for several years. B, Two weeks after cessation of the tobacco habit, the mucosa returned to an    ‘The etiology is linked to the use of betel quid (paan) and  related products—a habit among up to 20% of the world’s  population. The quid consists of a betel leaf wrapped around  a mixture of areca nut (from the Areca catechu palm tree),  slaked lime, possibly tobacco, and sometimes sweeteners  and spices. The slaked lime releases alkaloids from the areca  nut to produce a feeling of euphoria in the user. Villagers  habitually chew betel quid from an early age, frequently for  16 to 24 hours daily.   The incidence of oral submucous fibrosis has been  increasing—especially among young persons—due to the  growing popularity of commercially freeze-dried betel quid  substitutes (such as, pan masala, gutkha, and mawa), con-  veniently packaged in portable sachets. These products  contain a higher concentration of areca nut and may cause  oral submucous fibrosis more rapidly than conventionally  prepared betel quid.   The fibrosis appears to be induced by areca nut, whereas  the epithelial alterations and carcinogenesis appear to result  mainly from tobacco. However, several studies suggest that  even betel quid without tobacco may be carcinogenic, albeit  probably less so than when combined with tobacco. Nutri-  tional deficiency increases the risk and severity of fibrosis.  Furthermore, based upon human leukocyte antigen [HLA]  associations and circulating immune complexes and auto-  antibodies, a possible underlying autoimmune mechanism  with a genetic predisposition has been proposed in some  cases.   The pathogenesis of oral submucous fibrosis is hypoth-  esized to involve the disruption of collagen metabolism by  components of the areca nut. Alkaloids stimulate fibroblasts  to produce collagen, whereas flavonoids inhibit collagenase  (an enzyme that catalyzes collagen breakdown). In addition,  there are considerable amounts of copper in areca nut prod-  ucts. Copper upregulates lysyl oxidase, which is an enzyme  involved in collagen cross-linking; this process renders col-  lagen fibrils resistant to degradation by collagenase. Further-  more, cytokines and growth factors produced by activated    @ Fig. 10-82 Oral Submucous Fibrosis. Pallor and fibrosis of the  soft palate in a betel quid chewer. The uvula has retained its normal  color.    inflammatory cells may promote fibrosis by inducing fibro-  blast proliferation, upregulating collagen synthesis, and  downregulating collagenase production.    Oral submucous fibrosis often manifests in young adult  betel quid users. Reported gender predilection varies by  population. Typical chief complaints include an inability to  open the mouth (trismus) and a generalized oral burning  sensation (stomatopyrosis) with intolerance to spicy foods.  An interincisal distance of less than 20 mm is considered  severe; in advanced cases, the jaws may be inseparable.  Vesicles, petechiae, melanosis, xerostomia, and stomato-  pyrosis are usually the first signs and symptoms. The buccal  mucosa, retromolar area, and soft palate are the most com-  monly affected sites. Subsequently, the mucosa develops a  blotchy, marblelike pallor and progressive stiffness (Fig.  10-82). The tongue may become immobile, diminished in  size, and devoid of papillae. Submucosal fibrous bands are  palpable on the buccal mucosa, soft palate, and labial   ® Fig. 10-83 Oral Submucous Fibrosis. Mucosal biopsy exhibiting  hyperparakeratosis, basilar hyperplasia, and fibrosis in the lamina  propria.    mucosa of fully developed cases. Involvement may extend  to include the pharynx and upper esophagus. Leukoplakia  of the surface mucosa often is noted as well (see page 355).   Betel quid chewers also may exhibit a brown-red discol-  oration of the mucosa with an irregular surface that tends  to desquamate. This particular change, known as betel  chewer’s mucosa, is not believed to be precancerous. In  addition, some authors have reported betel quid lichenoid  lesions, characterized by white, parallel, wavy striae resem-  bling oral lichen planus (see page 729). Other possible  sequelae include tooth staining, attrition, and periodontal  disease.    Oral submucous fibrosis is characterized by juxtaepithelial  and submucosal deposition of densely collagenized, hypo-  vascular connective tissue with variable numbers of chronic  inflammatory cells (Fig. 10-83). Epithelial changes include  subepithelial vesicles in early lesions and hyperkeratosis  with marked epithelial atrophy in older lesions. Epithelial  dysplasia is found in 10% to 15% of cases submitted for  biopsy, and carcinoma is found in at least 6% of sampled  cases.   Betel chewer’s mucosa appears histopathologically similar  to morsicatio buccarum (see page 259), except the ragged  keratinaceous surface is covered by encrusted betel quid  ingredients.    Unlike tobacco pouch keratosis, oral submucous fibrosis  does not regress with habit cessation. Mild cases may be  treated with intralesional corticosteroids to reduce symp-  toms and limit progression. Moderate to severe cases may  require surgical splitting or excision of the fibrous bands  followed by lifelong physiotherapy; however, relapse is    treatments, such as intralesional injection of interferon-  gamma; topical or intralesional proteolytics (e.g., collage-  nase, hyaluronidase, chymotrypsin, and human placental  extract); vitamins and minerals; antioxidants (e.g., lyco-  pene); pentoxifylline; and ayurvedic remedies (e.g.,  turmeric).   Frequent evaluation for development of oral squamous  cell carcinoma is essential because a 17-year malignant  transformation rate of 8% has been determined for betel  quid users in India. Overall, persons with oral submucous  fibrosis are at least 19 times more likely to develop oral  cancer than persons without the disease.    Once a common mucosal change of the hard palate, nico-  tine stomatitis has become less common because cigar and  pipe smoking have lost popularity. Although this hyperkera-  totic lesion is associated with tobacco smoking, it does not  appear to have a premalignant nature, perhaps because it  develops in response to heat rather than the chemicals in  tobacco smoke. In particular, pipe smoking appears to gen-  erate more heat on the palate than other forms of smoking.  Similar changes also can be produced by the long-term use  of extremely hot beverages.   In some South American and Southeast Asian cultures,  hand-rolled cigarettes and cigars are smoked with the lit end  held within the mouth. This “reverse smoking” habit pro-  duces a pronounced palatal keratosis, or reverse smoker’s  palate, which has a significant potential to develop dyspla-  sia or carcinoma.    Nicotine stomatitis most commonly affects men older than  45 years. With long-term exposure to heat, the palatal  mucosa becomes diffusely gray or white; numerous slightly  elevated papules are noted, usually with punctate red centers  (Figs. 10-84 and 10-85). Such papules represent inflamed  minor salivary glands and their ductal orifices.   The palatal keratin may become so thickened that a fis-  sured or “dried mud” appearance is imparted. The whiteness  also may involve the marginal gingiva and interdental papil-  lae, and hyperkeratosis of the buccal mucosa occasionally is  seen. A heavy brown or black tobacco stain may be present  on the teeth.    Nicotine stomatitis is characterized by hyperkeratosis and  acanthosis of the palatal epithelium and mild, patchy, chronic  inflammation of subepithelial connective tissue and mucous  glands (Fig. 10-86). Squamous metaplasia of the excretory  ducts is usually seen, and an inflammatory exudate may be  noted within the duct lumina. In cases with papular    ® Fig. 10-84 Nicotine Stomatitis. This extensive leathery, white  change of the hard palate in a pipe smoker is sprinkled throughout  with numerous red papules, which represent inflamed salivary duct  openings. The gingival mucosa also is keratotic.    ® Fig. 10-85 Nicotine Stomatitis. Close-up of the inflamed ductal  openings of involved salivary glands of the hard palate. Note the white  keratotic ring at the lip of many of the inflamed ducts.    ® Fig. 10-86 Nicotine Stomatitis. There is hyperkeratosis and  acanthosis of the palatal epithelium. Note the squamous metaplasia  of the minor salivary gland ducts.    elevation, hyperplastic ductal epithelium may be seen near  the orifice. The degree of epithelial hyperplasia and hyper-  keratosis appears to correlate positively with the duration and  the level of heat exposure. Epithelial dysplasia rarely is seen.    Nicotine stomatitis is completely reversible, even when it  has been present for many decades. The palate usually  returns to normal within 1 to 2 weeks of smoking cessation.  Although this lesion is not precancerous and does not  require treatment, the patient nevertheless should be  encouraged to stop smoking (and other high-risk areas  should be examined closely). Any white lesion of the palatal  mucosa that persists after 1 month of habit cessation should  be considered a true leukoplakia and managed accordingly  (see page 362).    Actinic keratosis is a common, cutaneous premalignant  lesion that is caused by chronic, high-level exposure to UV  radiation. A similar phenomenon, actinic cheilosis, is asso-  ciated with sun damage to the lower lip vermilion (see page  370). UV light exposure can produce mutations in various  genes, such as the tumor suppressor gene 7P53. Additional  risk factors for actinic keratosis include fair skin, old age,  immunosuppression, arsenic exposure, and certain genetic  abnormalities (e.g., albinism, Rothmund-Thompson syn-  drome, Cockayne syndrome, xeroderma pigmentosum [see  page 696], and Bloom syndrome). Furthermore, recent  studies suggest that HPV infection may be a cofactor in  some cases, especially those arising in immunosuppressed  individuals.   Actinic keratosis affects more than 50% of white adults  with significant lifetime sun exposure. In the United States,  reported prevalence rates range from 14% to 27% for men  and 6% to 10% for women. According to the National  Ambulatory Medical Care Survey, more than 47 million  physician office visits were conducted in the United States  over a 10-year period for the diagnosis of actinic keratosis.  Another study reported that actinic keratosis accounts for  more than 5 million physician office visits per year in the  United States.    Actinic keratosis seldom occurs in persons younger than 40  years. Common sites of involvement include the face, neck,  dorsum of the hands, forearms, and balding scalp. The  lesions most often occur in clusters (apparently due to  UV-induced field cancerization [see page 389]), although  solitary lesions also are possible. The lesions appear as irreg-  ular, scaly plaques, which range in color from normal to  white, gray, or brown, and may be superimposed on an    (es. : er eg yrs  ® Fig. 10-87 Actinic Keratosis. A plaque of the skin of the face with  a rough, sandpaper-like surface.    erythematous background (Fig. 10-87). The keratotic scale  peels off with varying degrees of difficulty. Palpation reveals  a rough, “sandpaper-like” texture, and some lesions can be  felt more easily than they can be seen. Each lesion typically  is smaller than 7 mm in diameter, but some lesions may  reach a size of 2 cm or more. Most lesions are minimally  elevated above the skin surface, although occasional lesions  produce so much keratin that a central “horn” may be  evident. Other skin lesions, such as verruca vulgaris or  seborrheic keratosis, also may produce keratin or cutane-  ous horns.    Histopathologically, actinic keratosis is characterized by  hyperparakeratosis and acanthosis (Fig. 10-88). The epithe-  lium often exhibits teardrop-shaped rete ridges, and by defi-  nition, some degree of epithelial dysplasia is present. When  full-thickness dysplasia is noted, this is termed bowenoid  actinic keratosis. Suprabasilar acantholysis may be seen, as  well as melanosis and a lichenoid inflammatory infiltrate.  The dermis exhibits a pale, basophilic band of sun-damaged  collagen and elastic fibers (solar elastosis). In this band of  sun-damaged connective tissue, there is a fourfold increase  in the amount of elastic fibers, and band thickness increases  with further exposure to actinic rays. Variable numbers of  chronic inflammatory cells are typically present.    Preventive measures include avoiding sun exposure, wearing  protective clothing, and using sunscreen. Because of its  precancerous nature, actinic keratosis should be treated. For  solitary lesions, the most common treatment is cryotherapy;  additional treatment options include curettage, electrodes-  iccation, and surgical excision. In contrast, multifocal  lesions or sun-damaged skin fields at risk for lesion develop-  ment may be treated with topical agents (e.g., 5-fluorouracil,  imiquimod, diclofenac, tretinoin, and ingenol mebutate),  chemical peels, laser therapy, or photodynamic therapy.    of parakeratin is noted on the epidermal surface. B, High-power view  showing hyperchromatism and pleomorphism of the epidermal cells.    Alternatively, cryotherapy may be combined with broader  application of topical agents. Recurrence is rare, but addi-  tional lesions frequently arise in adjacent sun-damaged skin.  Long-term follow-up, therefore, is recommended.   ‘The estimated malignant transformation rate for an indi-  vidual lesion varies considerably (0.025% to 16% per year)  but generally is considered low. However, the risk increases  significantly for a patient with a large number of lesions  over an extended period. The average person initially pres-  ents to a dermatologist with six to eight actinic keratoses; a  person with this many lesions is estimated to have a 6% to  10% risk of progression to squamous cell carcinoma over a  10-year period. Longitudinal studies suggest that malig-  nancy most often develops within 2 years, and spontaneous  regression may occur in up to 26% of cases within 12  months of reduced sun exposure.    Actinic cheilosis is a common premalignant alteration of  the lower lip vermilion that results from chronic UV light  exposure. Its etiopathogenesis is similar to that of actinic  keratosis of the skin (see previous topic). The incidence of    ® Fig. 10-89 Actinic Cheilosis. Diffuse, irregular white plaque at the  wet line of the lower lip vermilion.    actinic cheilosis increases with proximity to the equator, and  there is a predilection among middle-aged to elderly, fair-  complexioned men. Outdoor occupations are associated  with this condition, leading to popular terms, such as farm-  ers lip and sailors lip. In addition, there is increased suscep-  tibility among patients with certain genetic disorders (e.g.,  xeroderma pigmentosum, albinism, and porphyria cutanea  tarda). Furthermore, cofactors—such as immunosuppres-  sion and tobacco smoking—may increase the likelihood of  progression to squamous cell carcinoma.    Actinic cheilosis seldom occurs in persons younger than 45  years. There is a strong male predilection (reported male-to-  female ratio as high as 10:1), which may reflect more  outdoor occupational activity and less frequent use of lip  protective agents among men compared to women.   The lesion develops so slowly that patients often are  unaware of a change. Early clinical findings include atrophy  (characterized by smooth, blotchy, pale areas), dryness, and  fissures of the lower lip vermilion, with blurring of the  margin between the vermilion and the adjacent skin. As the  lesion progresses, rough, scaly areas develop on the drier  portions of the vermilion. These areas may thicken to form  leukoplakic lesions, especially when they extend near the  wet line of the lip (Fig. 10-89). The patient may peel off  the scale with some difficulty, only to see it reform within  a few days.   Eventually, chronic ulceration may develop (Fig. 10-90).  Such ulcerations may last for months and suggest progres-  sion to squamous cell carcinoma (Fig. 10-91).    ‘The surface epithelium exhibits varying degrees of dysplasia.  There is usually hyperkeratosis, and the epithelium may be  either atrophic or acanthotic. The underlying connective  tissue invariably demonstrates a band of amorphous, acel-  lular, basophilic change known as solar elastosis, an UV    GS Oe te a ea ae ll  ® Fig. 10-90 Actinic Cheilosis. Crusted and ulcerated lesions of the  lower lip vermilion.    © Fig. 10-91 Squamous Cell Carcinoma Arising in Actinic Chei-  losis. Patient with actinic cheilosis of the lower lip, who developed a  small, chronic ulceration. Biopsy revealed early invasive squamous cell  carcinoma.    light-induced alteration of collagen and elastic fibers (Fig.  10-92). A chronic inflammatory cell infiltrate and dilated  blood vessels may be present as well.    Many of the changes associated with actinic cheilosis are  probably irreversible, but patients should be encouraged to  reduce sun exposure, wear a wide-brimmed hat, and use  sunscreen to prevent further damage. Areas of induration,  thickening, ulceration, or leukoplakia should be submitted  for biopsy to rule out carcinoma. In clinically severe cases  without obvious malignant transformation, a lip shave pro-  cedure (vermilionectomy) may be performed. The vermil-  ion mucosa is removed, and either a portion of the intraoral  labial mucosa is pulled forward or the wound is allowed to  heal by secondary intention. The advantage of this tech-  nique is that it provides tissue for histopathologic examina-  tion should areas of superficially invasive squamous cell  carcinoma be present. Alternative treatments include CO,  or erbium:YAG (Er:YAG) laser ablation, electrodesiccation,    ® Fig. 10-92 Actinic Cheilosis. Hyperorthokeratosis and epithelial  atrophy. Note the striking underlying solar elastosis.    cryotherapy, 5-fluorouracil, topical imiquimod, and photo-  dynamic therapy. Long-term follow-up is recommended.  Of course, if a squamous cell carcinoma is identified, then  the involved lip is treated accordingly.   Actinic cheilosis more than doubles an individual’s risk  for developing squamous cell carcinoma of the lip. Also, the  risk of malignant transformation is approximately 2.5 times  greater for actinic cheilosis compared to actinic keratosis.  However, it typically takes several decades for actinic chei-  losis to transform into squamous cell carcinoma, and the  resulting carcinoma usually is histopathologically well dif  ferentiated. Metastasis, if it occurs, is generally a late event.    Keratoacanthoma is a self-limiting, epithelial proliferation  with a strong clinical and histopathologic similarity to well-  differentiated squamous cell carcinoma. Indeed, many  dermatopathologists consider it to represent an extremely  well-differentiated squamous cell carcinoma. Cutaneous  lesions presumably arise from the infundibulum of hair  follicles. Intraoral lesions have been reported, but they are  rare; in fact, some authorities do not accept keratoacan-  thoma as an intraoral disease.   The exact cause is unknown. An association with sun  damage is suggested by the fact that most solitary lesions are  found on sun-exposed skin in older adults. Additional poten-  tial contributing factors include tar exposure, HPV, immu-  nosuppression, certain drugs (such as, BRAF inhibitors and  tyrosine kinase inhibitors), tattooing, and burns or other  trauma. Keratoacanthoma-like lesions have been produced  in animals by the cutaneous application of carcinogens.   There appears to be a hereditary predisposition for mul-  tiple lesions, and the lesions occur with increased frequency    e Fig. 10-93 Keratoacanthoma. A nontender, well-demarcated  nodule of the skin of the nose in an older woman. The nodule dem-  onstrates a central keratin plug.    ita | ,  ® Fig. 10-94 Keratoacanthoma. This lesion, which is located at the    outer edge of the vermilion border of the lip, demonstrates a prominent  core or plug of keratin.    in certain heritable conditions attributed to defects in DNA  repair, including Muir-Torre syndrome (sebaceous neo-  plasms, keratoacanthomas, and gastrointestinal carcinomas)  and xeroderma pigmentosum (see page 696).   Comparative genomic hybridization has shown that  keratoacanthomas and squamous cell carcinomas typically  exhibit distinct genetic profiles, which suggest different  underlying pathogenetic mechanisms.    Keratoacanthoma shows a male predilection and rarely  occurs before 45 years of age. Almost 95% of solitary lesions  involve sun-exposed skin, and 8% of all cases involve the  outer edge of the vermilion border of the lips, with equal  frequency on the upper and lower lips.   Keratoacanthoma appears as a firm, well-demarcated,  sessile, dome-shaped nodule with a central plug of keratin  (Figs. 10-93 and 10-94), although lesions reported as intra-  oral keratoacanthoma usually have lacked a central plug.  The outer portion of the nodule typically has a normal  texture and color but may be erythematous. The central    ® Fig. 10-95 Keratoacanthoma. A, Appearance on initial presenta-  tion. Note small, central keratin-filled invagination. B, Same lesion 1  week later showing slight enlargement. C, Same lesion showing further  growth 3 weeks after initial presentation. All three photographs were  taken at the same magnification. (Courtesy of Dr. John Lovas.)    keratin plug is yellowish, brown, or black and has an irregu-  lar, crusted, often verruciform surface. Most lesions are  asymptomatic, although pruritus and mild tenderness are  possible.   The evolution of keratoacanthoma can be divided into  three phases: 1) growth phase, 2) stationary phase, and 3)  involution phase. During the growth phase, rapid enlarge-  ment is typical, with the lesion usually attaining a diameter  of 1 to 2 cm within 6 weeks (Fig. 10-95). This critical  feature helps to distinguish it from the more slowly enlarg-  ing squamous cell carcinoma. The lesion stabilizes during    the stationary phase, which usually is of similar duration as  the growth phase. Most lesions regress spontaneously within  6 to 12 months of onset, frequently leaving behind a  depressed scar. The regression of keratoacanthomas is a  curious phenomenon, which some investigators have theo-  rized is related to a cytotoxic immune response to the tumor  or mechanisms similar to those controlling normal cycling  of hair follicles. Some authors also have described a subset  of lesions (termed abortive keratoacanthoma) that involute  after only 4 to 6 weeks.   Several other variants exist, including giant keratoacan-  thoma (greater than 2 to 3 cm in diameter), keratoacan-  thoma centrifugum marginatum (characterized by continuous  peripheral growth and central scarring), subungual keratoac-  anthoma (involving the nail bed), and mucosal keratoacan-  thoma (involving the oral, nasal, genital, ocular, or other  regions). These variants often do not regress.   In addition, early onset of multiple keratoacanthomas  has been described in association with two rare, heritable  conditions: Ferguson-Smith syndrome and Witten-Zak  syndrome. The former is characterized by nodular lesions  and primarily affects patients of Scottish descent; the latter  typically exhibits a mixture of variably sized lesions. In  contrast, Grzybowski syndrome manifests later in life as  hundreds or thousands of small papules of the skin and  upper digestive tract and may be associated with internal  malignancy.    Because the overall architectural pattern is crucial for the  diagnosis of keratoacanthoma, excisional or large incisional  biopsy with inclusion of adjacent, clinically normal epithe-  lium is necessary for proper histopathologic interpretation.  The tumor cells appear mature, although considerable dys-  keratosis (abnormal keratin production) typically is seen in  the form of deeply located individually keratinizing cells  and keratin pearls similar to those found in well-differentiated  squamous cell carcinoma.   ‘The surface epithelium at the edge of the tumor appears  normal; at the lip of the central crater, however, a charac-  teristic acute angle (or “buttress”) is formed between the  overlying epithelium and the lesion. The crater is filled with  keratin, and the epithelium at the base of the crater prolifer-  ates downward (Fig. 10-96), often with a pronounced  chronic inflammatory cell response. Downward prolifera-  tion typically does not extend below the sweat glands in  skin lesions or into underlying muscle in vermilion lesions.  Late-stage lesions show considerably more keratinization in  the deeper aspects of the tumor than do early lesions. Peri-  neural and vascular invasion have been reported rarely;  although worrisome, such features do not necessarily indi-  cate a worse prognosis. Migration of eosinophils or neutro-  phils into the epithelium with resultant microabscess  formation is a frequent finding. Regressing lesions tend  to flatten, hollow out, and exhibit an underlying band    e Fig. 10-96 Keratoacanthoma. Low-power microscopic view  showing extensive epidermal proliferation with a central keratin plug.    Numerous immunohistochemical studies comparing  keratoacanthoma and squamous cell carcinoma have been  reported, but no reliable marker for discernment between  these two lesions has been identified    Because of the difficulty in clinically and histopathologically  distinguishing between keratoacanthoma and squamous cell  carcinoma, many authorities advocate excision without  waiting for spontaneous regression. Also, early treatment  may prevent significant scarring. Approximately 4% to 8%  of lesions recur after excision. Although conventional surgi-  cal excision is preferred, alternative therapies include cryo-  surgery (reserved for small early lesions), electrodessication  and curettage, Mohs micrographic surgery (especially for  lesions of the central face), laser therapy, intralesional injec-  tion of chemotherapeutic agents (such as, 5-fluorouracil,  bleomycin, methotrexate, or interferon alpha), and topical  agents (such as, imiquimod or 5-fluorouracil). Systemic reti-  noids may be used alone or in combination with local treat-  ment for patients with multiple or especially large lesions.   Aggressive behavior and transformation into carci-  noma have been reported in a small proportion of  keratoacanthomas—particularly those occurring in the  setting of immunosuppression. However, the close histo-  pathologic similarities between this lesion and squamous  cell carcinoma sometimes make it difficult to rule out the  possibility of microscopic misinterpretation.    In the United States, approximately one of every two men  and one of every three women will develop a malignancy  (other than nonmelanoma skin cancer) at some point. It is  estimated that in the United States in 2013, more than 1.6  million new cancer cases will be diagnosed, in addition to  around 3.5 million nonmelanoma skin cancers. Although  the relative 5-year cancer survival rate is approximately  68%, cancer still causes more than 580,000 deaths each year    in the United States and accounts for more than 20% of all  deaths. From 1930 to 1991, the annual cancer death rate  (excluding nonmelanoma skin cancer) increased and reached  a peak of 215 per 100,000 population. This trend reflected  an increase in the incidence of lung cancer as well as a  decrease in mortality at an early age from other common  disorders, such as cardiovascular disease and infection. Since  1991, however, the annual cancer death rate has declined  to about 173 per 100,000 population. In part, this decline  is related to a decrease in tobacco use and lung cancer  deaths; in addition, improvements in detection and treat-  ment have resulted in declines in breast, colorectal, and  prostate cancer deaths.   Squamous cell carcinoma accounts for more than 90%  of oral malignancies. Statistics for oral cancer can be difh-  cult to review, because cancer registries and investigators  often report oral and pharyngeal cancers in aggregate. Also,  a distinction between intraoral and lip vermilion cancers is  not always made. With that said, in the United States oral  cancer accounts for less than 2% of all cancers (excluding  nonmelanoma skin cancers and in situ carcinomas for all  sites but urinary bladder). It represents the eleventh most  common cancer in males and the sixteenth most common  in females. Around 27,000 new cases of oral cancer are  diagnosed annually, and approximately 5,500 individuals  die of this disease each year.   The risk for oral and pharyngeal cancer increases with  age, especially among males. In the United States, according  to the Surveillance, Epidemiology, and End Results (SEER)  Program, the age-adjusted incidence rate for oral and pha-  ryngeal cancer from 2005 to 2009 was 60 per 100,000 for  males aged 65 years and older, compared to 10 per 100,000  for males younger than 65 years. Among those 65 years and  older, the incidence was somewhat higher for white males  (62 per 100,000) than black males (52 per 100,000),  whereas similar incidence rates were seen for black and  white males under 65 years. Notably, there was a marked  disparity in age-adjusted mortality rates between black and  white males (5.7 versus 3.6 per 100,000, respectively) with  oral and pharyngeal cancer. This disparity traditionally has  been explained by socioeconomic factors and differences in  access to quality health care. However, recent studies suggest  that patient outcomes actually are similar between races for  oral and other non-oropharyngeal head and neck cancers;  instead much of this disparity may be due to racial differ-  ences in oropharyngeal cancers. Specifically, white patients  are more likely to have HPV-positive oropharyngeal tumors  compared to black patients, and these HPV-positive tumors  are associated with a better response to treatment and pro-  longed survival. It is unknown why racial differences exist  in the prevalence of HPV-positive oropharyngeal carcino-  mas, although some investigators have hypothesized that  differences in behavior, oral HPV acquisition rates, and/or  viral clearance may play a role.   In the United States, females overall have a much lower  incidence of oral and pharyngeal cancer than males, with a  male-to-female ratio of approximately 2.5:1. However,    among young adults and pediatric patients, recently reported  incidence rates for oral and pharyngeal cancers in females  have been similar or even slightly higher than that in males.  Interestingly, over the past several decades, a significant  increase in the incidence of oral tongue cancer has been  noted among young individuals, especially white women  aged 18 to 44 years. The underlying cause for this trend is  uncertain. Such cases often are not associated with the  traditional risk factors of tobacco and alcohol use, and the  oral tongue—unlike the base of tongue—is an infrequent  site for HPV-positive carcinomas.   Carcinoma of the lip vermilion is somewhat different  from intraoral carcinoma. It has a pathophysiology more  akin to squamous cell carcinoma of sun-exposed. skin.  According to recent SEER data, the overall age-adjusted  annual incidence rate for lip cancer in the United States is  0.7 per 100,000 population. However, the incidence  increases with age, with annual rates among those 75 years  and older of approximately 7 per 100,000 for males and 3  per 100,000 for females. White males are affected most  commonly, although there has been a considerable decrease  in the incidence of lip cancer in this group over the last  several decades; this trend may be related to a decline in the  number of white males engaged in outdoor occupations.  Among women and nonwhite men, lip carcinoma is very  infrequent. The low incidence among women may be  related to little outdoor occupational activity and prevalent  use of lip protective agents. In nonwhites, racial pigmenta-  tion may provide protection against sun exposure.   The worldwide incidence of oral cancer is approximately  263,000 cases per year, with an especially high incidence  reported in the Indian subcontinent, Taiwan, Hungary,  France, Brazil, and parts of southern Africa. Exceptionally  wide variations in oral cancer incidence and mortality across  regions likely results from differences in population habits,  life expectancies, preventive education, and accuracy of  disease reporting. Despite the difficulties involved in inter-  preting such data, these findings have been helpful in iden-  tifying potential causative factors.    The cause of oral squamous cell carcinoma is multifactorial.  No single causative agent or factor (carcinogen) has been  clearly defined or accepted, but both extrinsic and intrinsic  factors may be involved. It is likely that more than a single  factor is needed to produce such a malignancy (cocarcino-  genesis). Extrinsic factors include tobacco smoke, alcohol,  and (for vermilion cancers only) sunlight. Intrinsic factors  include systemic or generalized states, such as malnutrition  or iron-deficiency anemia. Heredity does not appear to play  a major causative role, although a few heritable conditions  (e.g., dyskeratosis congenita [see page 695], Fanconi anemia)  have been associated with an increased risk for oral squa-  mous cell carcinoma. Many oral squamous cell carcinomas  have been documented to be associated with or preceded by  a precancerous lesion, especially leukoplakia (Table 10-2).    Precancerous Lesions of the Oral,  Pharyngeal, and Laryngeal Mucosa  (Clinical Terms Only)    Proliferative verrucous leukoplakia FOO KI  (PVL)*  Nicotine palatinus in reverse smokers! kkk  Erythroplakia 0.0. 0.9.4  Oral submucous fibrosis KaAKK  Erythroleukoplakia tk  Granular leukoplakia kkk  Laryngeal keratosis kkk  Actinic cheilosis kr  Smooth, thick leukoplakia kk  Smooth, red tongue of Plummer- kk  Vinson syndrome  Smokeless tobacco keratosis *  Lichen planus (erosive forms)* *?  Smooth, thin leukoplakia +/-    From Speight PM, Farthing PM, Bouquot JE: The pathology of oral  cancer and precancer, Curr Diag Pathol 3:165-176, 1997.   *PVL: High-risk, high-recurrence form of oral leukoplakia affecting mul-  tiple sites.    Tobacco smoking reached its greatest popularity in the  United States during the 1940s, when at least 65% of white  men smoked and other population subgroups were begin-  ning to smoke in large numbers. Today less than 20% of  US adults, men and women alike, smoke cigarettes.  Although an overall decrease in smoking prevalence has  been observed over the past decade, intensive efforts will be  required to meet the US Department of Health and Human  Services’ Healthy People objective to reduce smoking preva-  lence by the year 2020 to 12% or less.   Tobacco smoke contains more than 70 carcinogens,  including nitrosamines, arsenic, benzo[a]pyrene, and  benzene. In addition, smoking produces free radicals and  oxidants that promote the destruction and counteract the  protective effects of endogenous antioxidants (such as,  glutathione-S-transferase, glutathione reductase, and super-  oxide dismutase).   Much indirect clinical evidence implicates tobacco  smoking in the development of oral squamous cell carci-  noma. The proportion of smokers (80%) among patients  with oral carcinoma is about four times greater than that    among the general population. For patients who quit  smoking, the risk for developing oral cancer declines over  time; approximately 10 years after cessation, the incidence  of oral cancer approaches that of individuals who have never  smoked. The risk for a second primary carcinoma of the  upper aerodigestive tract is two to six times greater for  treated patients with oral cancer who continue to smoke  than for those who quit after diagnosis.   According to a meta-analysis of observational studies on  tobacco smoking and cancer in various regions of the world,  the pooled risk for oral cancer is approximately three times  greater among smokers than nonsmokers. Moreover, the  relative risk (smoker’s risk for oral cancer compared with  that of a nonsmoker) is dose-dependent. It is at least five  for persons who smoke 40 cigarettes daily, but increases to  as much as 17 for persons who smoke 80 or more cigarettes  daily. The risk also increases the longer a person smokes.  Furthermore, studies suggest that cigar or pipe smoking is  associated with a similar or greater risk for oral cancer com-  pared to cigarette smoking.   In India it is common to smoke bidi (small, hand-rolled  cigarettes consisting of flaked tobacco rolled in a temburni  or tendu leaf), and bidi smoking is associated with an  approximately threefold greater risk of oral cancer com-  pared to cigarette smoking. The highest risk of all probably  is found in certain Indian and South American cultures in  which the practice of reverse smoking is popular, especially  among women. In reverse smoking, the burning end of a  handmade cigar or cigarette is held inside the mouth. Where  reverse smoking is practiced, as many as 50% of all oral  malignancies are found on the hard palate, a site usually  spared by this disease.    Smokeless tobacco use in Western cultures may increase a  chronic user’s risk for oral carcinoma by a factor ranging  from less than two to as high as 26. This variation in  reported relative risk may be influenced by the type of  smokeless tobacco used, with some studies suggesting a  lower risk associated with moist snuff and chewing tobacco  and a higher risk associated with dry snuff. This apparent  increased risk is supported by clinicopathologic investiga-  tions that have found an abnormal male-to-female ratio for  oral carcinoma (>1.0:1.5) in geographic areas where the  habit is more popular among women than among men.  These geographic areas are typically in the southeastern  United States, where women use dry snuff. In addition,  approximately 50% of all oral cancers in smokeless tobacco  users occur at the site where the tobacco is habitually placed.    Betel quid (or paan) is a combination of natural substances  (ie., areca palm nuts, betel leaf, slaked lime, and perhaps  tobacco leaf) chewed for their psychostimulating effects.  The carcinogenicity of betel quid traditionally has been  attributed to tobacco, although areca nut alone also appears  to be carcinogenic. In addition, commercially freeze-dried    betel quid substitutes (e.g., pan masala and gutkha) pack-  aged in convenient sachets have become increasingly  popular. Among betel quid users in Asia, the lifetime risk  of developing oral cancer is a remarkable 8%. This habit  also is associated with development of precancers, such as  leukoplakia. As many as 600 million persons worldwide  chew these quids on a regular basis.    It is well established that alcohol in combination with  tobacco is a significant risk factor for oral cancer develop-  ment, with a reported relative risk of 15 or more among  heavy users of both substances. Furthermore, even after  controlling for tobacco use, epidemiologic studies have  reported a twofold to fourteenfold increased risk for oral  cancer among heavy drinkers (often defined as individuals  who consume more than four alcoholic beverages or 60 g  of alcohol per day). The risk generally appears to be dose-  dependent and time-dependent, although a few studies have  suggested that light or moderate drinking may exhibit a  protective effect, especially among females. Nevertheless,  the lowest annual oral cancer incidence rate in the United  States is found in Utah, where 75% of the population  follows Mormon doctrines that forbid tobacco and alcohol  use.   Indirect evidence for alcohol’s role in oral cancer devel-  opment includes the fact that approximately one-third of  male patients with oral cancer are heavy alcohol users,  whereas less than 10% of the general population can be  classified as such. Likewise, cirrhosis of the liver is found in  at least 20% of male patients with oral cancer.   The exact role of alcohol in oral carcinogenesis is not well  understood, although several mechanisms have been pro-  posed. Ethanol in alcoholic beverages is metabolized into  acetaldehyde, which is a known carcinogen. In addition,  carcinogenic impurities—such as, polycyclic aromatic  hydrocarbons and nitrosamines—may be present in some  alcoholic beverages. Moreover, alcohol may help solubilize  other carcinogenic compounds and may increase the perme-  ability of oral epithelium to these compounds. Nutritional  deficiencies associated with heavy alcohol consumption also  may be a contributory factor.   There is much debate in the literature regarding the  potential for alcohol-containing mouthwashes to increase  the risk for oral cancer. High-quality epidemiologic studies  are limited, and inconsistent findings across studies have    Some studies have reported an increased oral cancer risk for  workers in the wood products industry chronically exposed  to certain chemicals, such as phenoxyacetic acids. Such  workers also are at increased risk for nasal and nasopharyn-  geal carcinoma. In addition, there is limited and inconsis-  tent evidence for elevated oral cancer risk among metal  workers, electrical workers, plumbers, machinists, painters,    and other individuals with occupational exposure to sol-  vents or metal dust.   In regions of Taiwan with a particularly high incidence  of oral cancer, investigators have reported elevated levels of  heavy metal pollutants (e.g., nickel, chromium, and arsenic)  in farm soil and increased blood concentrations of some of  these metals in affected patients.    The effects of UV radiation on the lips are discussed else-  where (actinic cheilosis, see page 370). Interestingly, a recent  large-scale retrospective study has suggested that certain  antihypertensive medications (e.g., hydrochlorothiazide,  hydrochlorothiazide-triamterene, and nifedipine) may act  as photosensitizers and may potentiate the development of  UV-induced lip cancer. However, further studies are needed  to confirm these findings and to establish direct causality.   In addition, it is well known that x-irradiation decreases  immune reactivity and produces chromosomal abnormali-  ties. Indeed, radiotherapy to the head and neck area increases  the risk for later development of a new primary oral malig-  nancy, either a carcinoma or sarcoma. ‘This effect is dose-  dependent, but even low-dose radiotherapy for benign  entities may increase the local risk somewhat. Although  there has been controversy regarding whether dental radi-  ography may pose an increased risk for developing various  tumors, dental imaging has not been associated with oral  carcinoma.    Iron deficiency, especially the severe, chronic form known  as the Plummer-Vinson or Paterson-Kelly syndrome (see  page 772), is associated with an elevated risk for squamous  cell carcinoma of the esophagus, oropharynx, and posterior  mouth. Malignancies develop at an earlier age than in  patients without iron deficiency anemia. Iron deficiency  may cause impaired cell-mediated immunity. In addition,  because the epithelium of the upper digestive tract has a  relatively high turnover rate, rapid loss of iron-dependent  enzymes may lead to degenerative changes, including  mucosal atrophy and esophageal webs (intertwining fibrous  bands of scar tissue), with heightened susceptibility to  malignant transformation.   Vitamin-A deficiency produces excessive keratinization  of the skin and mucous membranes, and researchers have  suggested that this vitamin may help to prevent oral pre-  cancer and cancer. Some believe that blood levels of retinol  and the amount of dietary betacarotene ingested are inversely  proportional to the risk of oral squamous cell carcinoma  and leukoplakia. Long-term therapy with retinoic acids and  betacarotene also has been associated with regression of at  least some leukoplakic lesions and a concomitant reduction  in the severity of dysplasia within such lesions.   Several epidemiologic studies suggest that high intake of  fruits and vegetables decreases the risk for numerous cancer  types, including oral cancer. This finding may be related to  the protective effects of not only vitamin A but also various    other substances (e.g., vitamins C and E, folate, flavonoids,  fiber, lycopene, and phytosterols) present within plant  foods. However, tobacco and alcohol may represent con-  founding factors, because heavy tobacco and alcohol users  often consume small amounts of fruits and vegetables. Also,  some studies suggest that animal fats and processed or salted  meat may increase the risk for oral cancer.   A few studies have reported an increased risk for oral  cancer in association with drinking hot maté (an herbal tea  mainly consumed in parts of South and Central America).  Furthermore, there has been interest in the potential protec-  tive effects of green tea, coffee, and their associated poly-  phenols. However, further studies are needed to confirm  and explain the carcinogenic or protective properties of such  beverages.    The potential for microflora of the oral cavity to contribute  to carcinogenesis represents a growing area of scientific  investigation. Studies suggest that oral bacteria may interact  with tobacco and alcohol. Ethanol is metabolized into the  carcinogen acetaldehyde by not only hepatocytes and oral  epithelial cells but also bacteria. In particular, high levels of  acetaldehyde production have been associated with certain  Streptococcus species, Neisseria species, and other bacteria;  overgrowth of such bacteria has been described in smokers  and heavy drinkers. In addition to bacteria, Candida may  contribute to acetaldehyde production.   Furthermore, some investigators hypothesize that peri-  odontal disease-causing bacteria may induce production of  proinflammatory cytokines. These cytokines may enhance  cell proliferation and inhibit apoptosis, thereby producing  a microenvironment favorable for carcinogenesis. However,  epidemiological studies of associations between poor oral  hygiene, poor dental status, and oral cancer have yielded  variable results. Some of this variation may be due to dif-  ficulty in controlling for confounding factors, such as  tobacco use, alcohol consumption, nutrition, and socioeco-  nomic status.   Although rarely seen today, tertiary syphilis has been  associated with a fourfold increased risk for development of  dorsal tongue carcinoma. This risk may be due to the car-  cinogenic properties of the arsenical agents and other heavy  metals that were used to treat syphilis before the advent of  modern antibiotic therapy.    Hyperplastic candidiasis (see page 195) frequently is cited  as an oral precancerous condition. Because this lesion  appears as a white plaque that cannot be rubbed off, it  also has been called candidal leukoplakia. Unfortunately,  it is difficult both clinically and histopathologically to  distinguish between a true hyperplastic candidiasis and  a preexisting leukoplakia with superimposed candidiasis.  Experimentally, some strains of Candida albicans have pro-  duced hyperkeratotic lesions of the dorsal rat tongue without  any other contributing factors. Other studies have    demonstrated that certain strains may produce nitrosamines  (carcinogens that can activate certain proto-oncogenes) or  may convert ethanol into the carcinogen acetaldehyde.  However, the evidence for the promotion of oral carcino-  genesis by Candida is largely circumstantial.    Oncogenic (tumor producing) viruses may play a major role  in a wide variety of cancers. Viral integration into the host’s  genetic material may result in abnormal cell growth and  proliferation. The oncogenic viruses may immortalize the  host cell, thereby facilitating malignant transformation. In  the past, adenoviruses, Epstein-Barr virus (EBV), herpes  simplex virus (HSV), human papillomavirus (HPV), and  retroviruses (e.g., human immunodefiency virus [HIV]) all  have been suggested to play a role in the development of  oral carcinoma. However, HPV and HIV are the only ones  still implicated. HPV is discussed here; oral squamous cell  carcinoma in the setting of HIV infection is discussed in  the following section on immunosuppression and also  on page 252.   HPV actually is best known for its role in the develop-  ment of cancers of the anogenital region (especially the  uterine cervix but also the anus, vulva, vagina, and penis).  In addition, over the past decade, a strong link between  HPV and oropharyngeal carcinoma has been established. In  contrast, only a small subset of oral carcinomas has been  attributed to HPV infection.   The high-risk HPV types (see page 331) are most closely  associated with dysplasia and squamous cell carcinoma. In  particular, detection of HPV 16 in exfoliated oral epithelial  cells is associated with a nearly fourfold increased risk for  oral cancer and a more than fourteenfold increased risk for  oropharyngeal cancer. Investigators have proposed that per-  sistent oral infection with HPV 16 and other high-risk  HPV types increases the risk for eventual development of  oropharyngeal cancer. HPV 16 has been identified in more  than 90% of HPV-positive oropharyngeal squamous cell  carcinomas. Similarly, in HPV-positive oral squamous cell  carcinomas, HPV 16 appears to be the most common type,  although some authors have reported a greater diversity of  high-risk HPV types in oral carcinomas compared to oro-  pharyngeal carcinomas.   In the United States, based upon data from the SEER  Program, investigators have estimated that from 1988 to  2004 the incidence of HPV-positive oropharyngeal cancers  increased by 225% (from 0.8 to 2.6 per 100,000 popula-  tion) and the incidence of HPV-negative oropharyngeal  cancers decreased by 50%. If this trend were to continue,  by the year 2020, the annual number of HPV-positive  oropharyngeal cancers would be expected to surpass the  annual number of cervical cancers. This epidemiologic shift  has been hypothesized to result from an increase in oral  sexual behavior and a decline in tobacco use. Significant  increases in HPV-positive oropharyngeal cancer incidence  also have been reported in Sweden, Australia, Canada, and  other countries. In North America since the year 2000, the    proportion of oropharyngeal cancers attributable to HPV  infection has been estimated to be approximately 70%.   On the other hand, the proportion of oral carcinomas  caused by HPV infection appears to be small. Various  reviews of the literature have estimated the prevalence of  HPV DNA in oral squamous cell carcinomas as determined  by PCR to range from 20% to 40%; nonetheless, the pres-  ence of HPV DNA is not indicative of transcriptionally  active HPV infection and cannot discriminate between bio-  logically relevant versus bystander infection. Instead, quan-  titative reverse transcriptase polymerase chain reaction  (qRI-PCR) for detection of high-risk HPV £6 and £7  oncogene expression is considered the gold standard for  evidence of HPV infection as a likely cause of tumor devel-  opment. The primary mechanisms by which HPV is believed  to contribute to carcinogenesis are linked to the products  of these viral oncogenes: 1) E6 protein promotes degrada-  tion of the tumor suppressor protein p53 and 2) E7 protein  leads to inactivation of the tumor suppressor protein pRb.  Using qRI-PCR, one multi-center retrospective study  reported that only 6% of oral squamous cell carcinomas  analyzed could be attributed to HPV infection.   The characteristic risk profile for patients with HPV-  positive head and neck squamous cell carcinoma differs  from that for patients with HPV-negative disease. In both  patient groups, there is a male predilection, although the  average age is approximately 10 years younger among the  HPV-positive group. Unlike HPV-negative lesions, HPV-  positive lesions tend to affect individuals of higher socio-  economic status. The proportion of HPV-positive cases  affecting blacks is much smaller than that affecting whites  (4% versus 34%, respectively). Compared to HPV-negative  cases, HPV-positive cases are more strongly associated with  certain parameters of sexual behavior (e.g., increased  number of lifetime sexual or oral sexual partners, early age  at sexual debut). In addition, HPV-positive lesions are less  likely to occur in patients with an extensive history of  tobacco and alcohol history. Nevertheless, patients with  HPV-positive tumors often have some history of tobacco  and alcohol use, and there are conflicting reports regarding  potential interactions between HPV, tobacco, and alcohol  in promoting head and neck cancer development. Further-  more, studies assessing a possible association between mari-  juana use and HPV-positive head and neck carcinomas have  yielded variable results.    Immunosuppression may play a role in the development of  at least some malignancies of the upper aerodigestive tract.  Without effective immunologic surveillance and attack, it  is thought that malignant cells cannot be recognized and  destroyed at an early stage. Persons with HIV infection and  those who are undergoing immunosuppressive therapy for  malignancy or organ transplantation are at increased risk  for oral squamous cell carcinoma and other head and neck  malignancies, especially when tobacco smoking and alcohol  abuse are present.    The molecular basis of carcinogenesis involves an accumula-  tion of mutations or epigenetic changes in two broad classes  of genes: proto-oncogenes and tumor suppressor genes.  Proto-oncogenes may be transformed into activated onco-  genes by environmental agents (e.g., viruses, irradiation,  and chemical carcinogens) or inherited changes. Activated  oncogenes promote uncontrolled cell division and are  involved in the initiation and progression of a wide variety  of malignancies. Tumor suppressor genes, on the other  hand, inhibit cell division and indirectly allow tumor pro-  duction when they become inactivated or mutated. Most  authorities propose that an accumulation of several genetic  aberrations is necessary before the affected cell expresses a  malignant phenotype.   Genetic aberrations commonly identified in oral squa-  mous cell carcinomas include abnormalities of the ras, myc,  and epidermal growth factor receptor (EGFR; also known  as c-erbB1) oncogenes, and the 7P53, pRb, p16, and  E-cadherin tumor suppressor genes. Head and neck squa-  mous cell carcinomas associated with tobacco and alcohol  use often exhibit mutated 7P53, pRb overexpression, and  decreased p16 expression. In contrast, HPV-associated cases  typically express wild-type 753, low levels of pRb, and    Persons with oral squamous cell carcinoma are most often  older men who have been aware of an alteration for 4 to 8  months before seeking professional help (8 to 24 months  among lower socioeconomic groups). There is minimal pain  during the early growth phase, which may explain the delay  in seeking professional care. If the health care professional  does not have a high index of suspicion, then additional  weeks or months may elapse before a biopsy is performed.   Oral squamous cell carcinoma has a varied clinical pre-  sentation, including the following:  ¢ Exophytic (mass-forming; fungating, papillary, and   * Leukoplakic (white patch) (Fig. 10-97)  e Erythroplakic (red patch)  ¢ Erythroleukoplakic (combined red-and-white patch)   The /ewkoplakic and erythroplakic examples are probably  early cases that have not yet produced a mass or ulceration,  and the clinical features are identical to those described for  premalignant leukoplakia and erythroplakia (see pages 355  and 363).   An exophytic lesion typically has a surface that is irregular,  fungating, papillary, or verruciform, and its color may vary  from normal to white or red, depending on the amount of  keratin and vascularity (Figs. 10-99 and 10-100). The  surface is often ulcerated, and the tumor feels hard (indu-  rated) on palpation (Fig. 10-101).    © Fig. 10-97 Squamous Cell Carcinoma. Leukoplakic lesion with  a granular surface on the left ventrolateral tongue. (Courtesy of Dr.  Larry Cunningham.)    @ Fig. 10-98 Squamous Cell Carcinoma. Speckled erythroplakia  of the left posterior buccal mucosa. Brush sampling had been reported  to be negative for epithelial abnormality, but incisional biopsy revealed  invasive squamous cell carcinoma. (From Chi AC, Ravenel MC:  AAOMP case challenge: a “speckled” lesion, J Contemp Dent Pract  6:168-172, 2005.)    © Fig. 10-99 Squamous Cell Carcinoma. An exophytic lesion of  the posterior lateral tongue demonstrates surface nodularity and  minimal surface keratin production. It is painless and indurated.    ® Fig. 10-100 Squamous Cell Carcinoma. An exophytic buccal  lesion shows a roughened and irregular surface with areas of erythema  admixed with small areas of white keratosis. Surface ulceration is  evident.    lesion on the right ventral surface of the tongue. The rolled anterior  margin felt indurated on palpation.    The endophytic growth pattern has a central, depressed,  irregularly shaped ulcer with a surrounding “rolled” border  of pink, red, or white mucosa (Fig. 10-102). The rolled  border results from invasion of the tumor downward and  laterally under adjacent epithelium. Traumatic granulomas,  deep fungal infections, tuberculosis, tertiary syphilis, and  oral lesions of Wegener granulomatosis or Crohn's disease  may exhibit a similar clinical appearance.   Destruction of underlying bone, when present, may be  painful or completely painless; it appears on radiographs as  a “moth-eaten” radiolucency with ill-defined or ragged  margins (an appearance similar to osteomyelitis) (Fig.  10-103). Perineural invasion may cause paresthesia.    Carcinoma of the lip vermilion typically is found in light-  skinned persons with chronic exposure to UV radiation  from sunlight. Seventy percent of affected individuals have  outdoor occupations. It usually is associated with actinic  cheilosis (see page 370) and may arise at the site where the    © Fig. 10-102 Squamous Cell Carcinoma. An ulcerated or endo-  phytic lesion of the hard palate demonstrates rolled borders and a    necrotic ulcer bed. This cancer was painless, although it had partially  destroyed underlying palatal bone.    patient holds a cigarette, cigar, or pipe. Almost 90% of  lesions are located on the lower lip.   The typical vermilion carcinoma is a crusted, oozing,  nontender, indurated ulceration that is usually less than  1 cm in greatest diameter when discovered (Figs. 10-104  and 10-105). The tumor usually grows slowly, and most  patients are aware of a “problem” in the area for 12 to 16  months before diagnosis. Metastasis is a late event; at diag-  nosis, fewer than 10% of patients have lymph node metas-  tasis, usually in the submental region. Perineural invasion  may result in extension of the tumor into the mandible  through the mental foramen. Although this tumor typically  is diagnosed and treated at an early stage, patient neglect  can result in considerable destruction of normal tissue (Fig.  10-106).    In the United States, the most common sites for intraoral  carcinoma are the tongue (usually the posterior lateral and  ventral surfaces) and floor of mouth. Other sites of    © Fig. 10-104 Squamous Cell Carcinoma. Crusted, ulcerated  nodule of the lower lip vermilion. Risk factors in this patient included  chronic sun exposure as well as immunosuppression due to bone  marrow transplantation.    © Fig. 10-105 Squamous Cell Carcinoma. Ulcerated mass of the  lower lip vermilion.    the lip vermilion. This ulcerating lesion of the lower lip had been present  for more than 1 year before diagnosis.    ® Fig. 10-107 Squamous Cell Carcinoma. Diffuse, red and white  lesion of the posterior lateral border of the tongue.    © Fig. 10-108 Squamous Cell Carcinoma. Granular red and white  lesion in the anterior floor of mouth.    involvement (in descending order of frequency) are the  gingiva, buccal mucosa, labial mucosa, and hard palate.   Carcinoma of the tongue accounts for more than 50%  of intraoral cancers in the United States (Figs. 10-107).  Two-thirds of lingual carcinomas appear as painless, indu-  rated masses or ulcers of the posterior lateral border; 20%  occur on anterior lateral or ventral surfaces, and only 4%  occur on the dorsum. For unknown reasons, the oral tongue  represents an increasingly common site of involvement in  young patients.   Of all intraoral carcinomas, floor of mouth lesions are  the most likely to arise from a preexisting leukoplakia or  erythroplakia (Fig. 10-108). The floor of mouth also repre-  sents the oral cancer site most often associated with the  development of a second primary malignancy, either else-  where in the aerodigestive tract or in a distant organ. Floor  of mouth carcinomas most often arise in the midline region  near the frenum.   Gingival and alveolar carcinomas are usually painless and  most frequently arise from keratinized, posterior mandibu-  lar mucosa (Fig. 10-109). Interestingly, among intraoral  carcinomas, gingival lesions are least associated with tobacco  smoking and have the greatest predilection for females.    ® Fig. 10-109 Squamous Cell Carcinoma. Red and white granular  lesion of the posterior lingual mandibular gingiva.    Gingival and alveolar carcinomas have a special propensity  to mimic common, benign inflammatory and reactive  lesions, such as the pyogenic granuloma, gingivitis (Fig.  10-110), and periodontal disease. Gingival tumors often  destroy the underlying bone and cause tooth mobility. The  lesion may go unrecognized until after tooth extraction,  when it proliferates out of the socket to mimic the hyper-  plastic granulation tissue of an epulis granulomatosa (see  page 484). Cancers that develop in an edentulous area may  “wrap around” a denture flange and superficially resemble  inflammatory fibrous hyperplasia (epulis fissuratum) (Fig.  10-111). Tumors of the maxillary alveolar ridge may extend  onto the hard palate. Recent studies suggest that carcinomas  involving the maxillary mucosa may be more aggressive  than previously thought, with nearly 30% of cases harbor-  ing occult cervical lymph node metastasis.   Similarly, recent evidence suggests that carcinomas of the  buccal mucosa may be more aggressive than previously sus-  pected, with reported locoregional recurrence rates ranging  from 30% to 80%. The buccal mucosa is an especially  common site for oral carcinoma in regions of the world  where betel quid use is prevalent.   Carcinomas of the retromolar trigone may spread to  numerous adjacent structures, including the oropharynx,    © Fig. 10-111 Squamous Cell Carcinoma. An exophytic lesion  with an irregular and pebbled surface. There is a linear indentation  along the facial aspect resulting from pressure from the patient’s lower  denture. The underlying alveolar bone was destroyed.    @ Fig. 10-112 Squamous Cell Carcinoma. Carcinoma of the ret-  romolar trigone with extension into the oropharynx (including the soft  palate and anterior faucial pillar). Associated leukoplakia also extends  anteriorly along the buccal mucosa.    buccal mucosa, alveolar ridge, and pterygomandibular  raphe (Fig. 10-112). Invasion of the pterygomandibular  raphe may lead to involvement of the skull base, masticator  space, and floor of mouth.    Subsites for oropharyngeal carcinoma include the soft palate,  base of tongue, tonsillar region (i.e., tonsil, tonsillar fossa, and  pillars), and posterior pharyngeal wall. Among these subsites,  the tonsillar region accounts for the majority (approximately  70% to 80%) of cases. Indeed, the tonsillar region is a favored  site for HPV-associated carcinomas, and the majority of oro-  pharyngeal carcinomas in the United States currently are  attributed to HPV infection (Fig. 10-113).   Oropharyngeal carcinomas exhibit the same basic clini-  cal appearance as more anterior carcinomas; however, in this  posterior location, lesions often go unrecognized for long  periods. By the time of diagnosis, tumor size is typically  greater than that of oral carcinomas, and the proportion of  cases with cervical and distant metastasis is higher. Common  presenting symptoms for oropharyngeal carcinoma include    © Fig. 10-113 Squamous Cell Carcinoma, Oropharyngeal. A,  Large, erythroplakic lesion involving the left soft palate and tonsillar  region. B, Immunohistochemical staining showed the tumor to be  positive for p16, which is a surrogate marker for transcriptionally active,  high-risk human papilloma virus (HPV) infection among oropharyngeal  squamous cell carcinomas. C, /n situ hybridization (ISH) demonstrated  the presence of intranuclear HPV 16 DNA.    persistent sore throat, difficulty in swallowing (dysphagia),  and pain on swallowing (odynophagia). The pain may be  dull or sharp and frequently is referred to the ear.    Metastasis of oral squamous cell carcinoma occurs largely  via the lymphatics to the ipsilateral cervical lymph nodes  (Fig. 10-114). A cervical lymph node that contains meta-  static carcinoma is usually firm to stony hard, nontender,    © Fig. 10-114 Squamous Cell Carcinoma, Metastatic Spread.  Diagram demonstrating potential sites for metastatic spread of oral  carcinoma to regional lymph nodes.    ® Fig. 10-115 Squamous Cell Carcinoma. Metastatic deposits  within cervical lymph nodes present as firm, painless enlargements as  seen in this patient with metastasis to a superior jugular node from a  posterior lateral tongue carcinoma.    and enlarged (Fig. 10-115). If the malignant cells have  perforated the capsule of the node and invaded into sur-  rounding tissues, then the node will feel “fixed,” or not  easily movable. Extracapsular spread (extension of meta-  static deposits outside of the lymph node capsule) is a  microscopic feature associated with poor prognosis, includ-  ing increased risk for locoregional recurrence, distant metas-  tasis, and shortened survival.   Occasionally, contralateral or bilateral metastatic depos-  its are seen, and at least 2% of patients have distant (“below  the clavicles”) metastasis at diagnosis; in some studies this  figure is as high as 22%. The most common sites of distant  metastasis are the lungs, liver, and bones, but any part of  the body may be affected.   Carcinoma of the lower lip and oral floor tends to travel  to the submental nodes; tumors from the posterior portions  of the mouth typically travel to the superior jugular and    digastric nodes. Metastatic deposits from oropharyngeal  carcinoma usually are found in the jugulodigastric or retro-  pharyngeal nodes.   Metastasis is not an early event for carcinomas of the oral  cavity proper. However, because of delay in diagnosis,  approximately 21% of patients have cervical metastases at  diagnosis (60% in reports from tertiary care medical  centers). In contrast, oropharyngeal tumors are prone to  early metastasis, with more than 50% of affected persons    exhibiting cervical lymph node metastasis and 10% exhibit-  ing distant metastasis at diagnosis.    Tumor size and the extent of metastatic spread are the best  prognostic indicators for oral squamous cell carcinoma.  Quantifying these clinical parameters is called staging.  Table 10-3 summarizes the tumor-node-metastasis (TINM)    {2 Tumor more than 2 cm but not more than 4 cm in greatest dimension    is Tumor more than 4 cm in greatest dimension or extension to lingual surface of epiglottis    (Lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face, that is, chin or nose    (Oral cavity) Tumor invades adjacent structures only (e.g., through cortical bone [mandible or maxilla] into deep [extrinsic]  muscle of tongue [genioglossus, hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of face)    (Oropharynx) Tumor invades the larynx, extrinsic muscles of tongue, medial pterygoid, hard palate, or mandible  (Note: Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does    Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base, or encases carotid artery    N1 Metastasis in a single ipsilateral node 3 cm or less in greatest dimension    N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in  multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph    N2a Metastasis in a single ipsilateral node more than 3 cm but not greater than 6 cm in greatest dimension    N2b Metastasis in multiple ipsilateral nodes, none more than 6 cm in greatest dimension    N2c Metastasis in bilateral or contralateral nodes, none more than 6 cm in greatest dimension    N3 Metastasis in a node more than 6 cm in greatest dimension    *Note: Metastases at level VII are considered regional lymph node metastases.    From Lip and Oral Cavity. In Edge SB, Byrd DR, Compton CC, et al, editors, AJCC Cancer Staging Manual, ed 7, New York, 2010, Springer, pp 29-40; Pharynx.  In Edge SB, Byrd DR, Compton CC, et al, editors, AJCC Cancer Staging Manual, ed 7, New York, 2010, Springer, pp 41-56.    svN=j8-3 Tumor-node-metastasis (TNM) Clinical Staging Categories for Oral and Oropharyngeal Squamous Cell    Stage 0 Tis NO MO  Stage | T1 NO MO 12% 96% 56%**  Stage I T2 NO MO 58% 83% 58%*  Stage Ill T3 NO MO 45% 57% 55%**  T3 NO MO  T1 N1 MO  T2 N1 MO  T3 N1 MO  Stage IV 382% 48% 43%*  IVA T4a NO MO  T4a N1 MO  T1 N2 MO  T2 N2 MO  T3 N2 MO  T4a N2 MO  VB Any T N3 MO  T4b Any N MO  IVC Any T Any N M1    *From Lip and Oral Cavity. In Edge SB, Byrd DR, Compton CC, et al, editors, AJCC Cancer Staging Manual, ed 7, New York, 2010, Springer, pp 29-40.  ‘Based on SEER data for patients treated from 1988 to 2001. Source: American Cancer Society. Oral cavity and oropharyngeal cancer. http://www.cancer.org/  cancer/oralcavityandoropharyngealcancer/detailedguide/oral-cavity-and-oropharyngeal-pdf. Accessed August 29, 2013.   #Due to the increasing incidence in HPV-related oropharyngeal carcinoma, recent studies have shown a significant improvement in survival over  that reflected in the SEER data from 1998-2001. Some centers have reported an overall 5-year survival rate of 54%-89% for HPV oropharyngeal  carcinoma, whereas the 5-year survival rate for HPV tumors ranges from 33%-65%.    system for staging oral and oropharyngeal carcinoma. ‘This  staging protocol depends on three basic clinical features:  1. T—Size of the primary tumor, in centimeters  2. N—Regional lymph node involvement  3. M—Distant metastasis   These three parameters are tallied together to determine  the stage (Table 10-4). In general, the higher the stage, the  worse the prognosis. In other words, a stage IV lesion is  associated with a much worse prognosis than a stage I  lesion. However, for oropharyngeal carcinoma, survival  rates are similar for patients with stage I, H, and III disease  (see Table 10-4); instead, HPV status appears to be the most  important prognostic factor for patients with oropharyngeal  carcinoma (see later).    Squamous cell carcinoma arises from dysplastic surface epi-  thelium and is characterized histopathologically by invasive  islands and cords of malignant squamous epithelial cells. At  the earliest moment of invasion, the adjectives superficially  invasive or microinvasive often are used. The features of  epithelial dysplasia are discussed in more detail in the  section on leukoplakia (see page 360).   Invasion is represented by irregular extension of lesional  epithelium through the basement membrane and into sub-  epithelial connective tissue. Individual squamous cells and    sheets or islands of cells proliferate within the connective  tissue, without attachment to the surface epithelium. The  invading tumor destroys normal tissue and may extend  deeply into underlying adipose tissue, muscle, or bone.  Lesional cells may breach the perineurium that encases  nerve bundles (perineural invasion) or may invade the  lumina of veins or lymphatics (vascular invasion) (Fig.  10-116). There is often a strong inflammatory or immune  cell response to invading epithelium, and necrosis may be  present. The tumor may induce dense fibrosis (desmoplasia  or scitrhous change) and the formation of new blood  vessels (angiogenesis).   The lesional cells generally show abundant eosinophilic  cytoplasm with large, often darkly staining (hyperchro-  matic) nuclei and an increased nuclear-to-cytoplasmic ratio.  Varying degrees of cellular and nuclear pleomorphism are  seen. The normal product of squamous epithelium is keratin,  and keratin pearls (a round focus of concentrically layered,  keratinized cells) may be produced within lesional epithe-  lium. Individual cells also may undergo keratinization.   Histopathologic grading of squamous cell carcinoma is  based upon the degree of resemblance to normal squamous  epithelium and the amount of keratin production. Lesions  are graded on a three-point (grades I to III) or a four-point  (grades I to IV) scale. The less differentiated tumors receive  the higher numerals. The histopathologic grade of a tumor is  related somewhat to its biologic behavior. In other words, a    © Fig. 10-116 Squamous Cell Carcinoma. A, Perineural invasion.  Tumor has breached the perineurium encasing this nerve fiber.  B, Angioinvasion. Tumor is present within the lumen of this vessel.    tumor that is mature enough to closely resemble its tissue of  origin often grows at a slightly slower pace and metastasizes  later in its course. Such a tumor is called low-grade, grade [,  or well-differentiated (Fig. 10-117). In contrast, a tumor with  marked pleomorphism and little or no keratin production  may be so immature that it becomes difficult to identify the  tissue of origin. In such cases, immunohistochemical studies  (e.g., for cytokeratins or p63) may be needed to support an  epithelial origin. Such tumors often enlarge rapidly, metasta-  size early, and are termed high-grade, grade III/IV, poorly dif-  ferentiated, or anaplastic (Fig. 10-118). A tumor with a  microscopic appearance somewhere between these two  extremes is called moderately differentiated (Fig. 10-119).  Grading is a somewhat subjective process, depending on  the area of the tumor sampled and the individual patholo-  gist’s criteria for evaluation. Moreover, clinical staging cor-  relates much better with the prognosis than microscopic  grading. Over the past several decades, investigators have  proposed various multi-parameter histopathologic assess-  ment systems in an attempt to provide more objective cri-  teria that correlate with prognosis. Variables such as pattern  of invasion, tumor thickness, degree of keratinization,  nuclear pleomorphism, lymphocytic response, and mitotic  rate have been included in such grading systems. However,    A, Low-power photomicrograph showing islands of malignant squa-  mous epithelium invading into the lamina propria. B, High-power view  showing dysplastic epithelial cells with keratin pearl formation.    @ Fig. 10-118 Poorly Differentiated Squamous Cell Carcinoma.  The numerous pleomorphic cells within the lamina propria represent  anaplastic carcinoma.   For oropharyngeal squamous cell carcinoma, detection  of transcriptionally active HPV infection is especially  important in determining prognosis. HPV-positive oropha-  ryngeal squamous cell carcinomas often are poorly differen-  tiated and nonkeratinizing with basaloid cytologic features;  in addition, the majority of cases are diagnosed at an    @ Fig. 10-119 Moderately Differentiated Squamous Cell Carci-  noma. Although no keratinization is seen in this medium-power view,  these malignant cells are still easily recognizable as being of squamous  epithelial origin.    advanced clinical stage. Despite these features, HPV-positive  oropharyngeal squamous cell carcinomas typically exhibit  better treatment outcomes compared to HPV-negative  cases. The gold standard for determining whether a carci-  noma likely was caused by HPV is high-risk HPV E6 and  E7 oncogene expression analysis by quantitative reverse  transcriptase polymerase chain reaction (qRT-PCR).  However, this method is best suited for fresh frozen tissue  and is technically demanding. In comparison, detection of  p16 by immunohistochemistry is more widely available, is  readily performed on formalin-fixed paraffin-embedded  tissue, and is considered a highly sensitive (albeit not highly  specific) surrogate for transcriptionally active, high-risk  HPV infection in oropharyngeal carcinomas (see Fig.  10-113, B). (Ihe molecular basis for this finding is that  overexpression of p16 results from inactivation of the tumor  suppressor pRB [retinoblastoma protein] by the HPV onco-  protein E7.) Also, in the case of a cervical lymph node with  metastatic carcinoma of unknown origin, some studies  suggest that p16 immunoreactivity may be useful in direct-  ing the search for the primary tumor to the oropharynx.  Furthermore, investigators have found that in situ hybrid-  ization (ISH) for HPV 16 exhibits strong agreement with  p16 immunohistochemistry, although it may fail to detect  the minority of oropharyngeal tumors caused by other HPV  types (see Fig. 10-113, C). In particular, the recent develop-  ment of RNA ISH probes complementary to E6 and E7  mRNA allows for detection of transcriptionally active HPV  in routinely processed tissue. Also, there is currently much  interest in evaluating liquid-phase hybridization assays for  detection of HPV in cytologic preparations from head and  neck squamous cell carcinomas. Importantly, widely  accepted testing algorithms, validated commercially avail-  able assays, and standardized reporting criteria for determi-  nation of HPV status in oropharyngeal and other head and  neck tumors still need to be established.   In contrast to oropharyngeal squamous cell carcinomas,  p16 immunohistochemistry performed on oral squamous  cell carcinomas exhibits low positive predictive value for    transcriptionally active HPV infection and is not useful for  prognostication. Furthermore, there is only limited data  regarding qRT-PCR analysis of high-risk HPV E6 and E7  expression in oral squamous cell carcinoma, with no signifi-  cant correlation with prognosis demonstrated thus far.    Clinical staging guides the treatment of squamous cell car-  cinoma. Most lip vermilion carcinomas are detected at an  early stage and treated by surgical excision (typically a wedge  resection) with excellent results. In contrast, advanced cases  may be treated by definitive radiation therapy or combined  chemoradiation therapy. At diagnosis, less than 10% of all  lip vermilion carcinomas have metastasized; therefore, neck  dissection seldom is indicated. However, a notable excep-  tion is squamous cell carcinoma of the upper lip vermilion,  which exhibits a high risk for regional lymph node metas-  tasis (apparently related to the extensive lymphatic network  in this location). Fortunately, squamous cell carcinoma only  rarely occurs in the upper lip.   For intraoral squamous cell carcinoma, early-stage lesions  usually are treated with surgery; definitive radiation therapy  may be an alternative for patients unable to tolerate surgery.  Moderately advanced tumors typically are treated with  surgery followed by either radiation therapy or concurrent  chemoradiation therapy. Very advanced disease or cases in  which surgery would result in unacceptable functional out-  comes may be treated with radiation therapy and/or  chemotherapy.   In addition to advanced stage, indications for postopera-  tive (adjuvant) radiation or chemoradiation therapy in the  treatment of intraoral carcinoma may include close or posi-  tive resection margins, high-grade histopathologic features,  extracapsular spread, and perineural or angiolymphatic  invasion. ILntensity-modulated radiation therapy (IMRT)  often is used to target the treatment area while minimizing  damage to neighboring tissue. Brachytherapy (placement of  tiny, radioactive seeds) may be used for select applications  (e.g., definitive treatment of small intraoral tumors or as an  adjunct with IMRT to deliver an additional radiation dose).   In patients with intraoral carcinoma, cervical lymph  node involvement is evident at presentation in approxi-  mately 30% of cases and occult (or subclinical) in about  10% to 40% of cases. However, the risk for regional metas-  tasis varies considerably by subsite. In the past, radical neck  dissection (e7 bloc removal of the lymphatics of the lateral  triangle of the neck along with associated nonlymphatic  structures, including the internal jugular vein, submandibu-  lar gland, sternocleidomastoid muscle, and spinal accessory  nerve) was standard treatment for clinically evident or sus-  pected cervical lymph node metastasis. However, over the  past several decades, modified radical neck dissection  (similar to radical neck dissection but with preservation of  nonlymphatic structures) and selective neck dissection  (removal of only select cervical lymph node groups) have  gained favor; these techniques are associated with decreased    morbidity and, depending upon the extent of disease, often  allow for disease control comparable to that of classical  radical neck dissection. Histopathologic findings (e.g.,  number of positive nodes and presence of extracapsular  spread) in a selective neck dissection may aid in determining  the need for postoperative radiation or chemoradiation  therapy.   The depth of invasion or tumor thickness may help predict  occult cervical lymph node metastasis despite early T-stage  and may be used to determine the need for elective selective  neck dissection. Although some investigators have used  these terms interchangeably, depth of invasion represents  the distance from the basement membrane to the deepest  portion of the tumor, whereas tumor thickness is the dis-  tance from the tumor surface to the deepest portion of the  tumor. Many studies suggest a significantly increased risk  for nodal metastasis with a depth of invasion or tumor  thickness greater than about 3 to 5 mm; however, suggested  cutoffs vary considerably by tumor subsite and study meth-  odology. In addition, sentinel-node biopsy (biopsy of the  first lymph node in the lymphatic basin to receive drainage  from the tumor) has shown promise in identifying patients  with occult neck metastasis, but this technique remains  investigational for patients with oral cancer.   Chemotherapeutic agents commonly used for treating  intraoral carcinoma include platinum-containing com-  pounds (e.g., cisplatin and carboplatin), 5-fluorouracil, and  taxanes (e.g., paclitaxel and docetaxel). Induction or neoad-  juvant chemotherapy may be administered initially to shrink  a tumor prior to additional therapy and has been advocated  by some investigators to decrease the risk for distant metas-  tasis; however, studies suggest this approach may yield either  no or minimal improvement in locoregional disease control  and patient survival. In contrast, for patients with locally  advanced (stage III, IVa, or IVb) disease, current evidence  supports postoperative concurrent chemoradiation therapy  (especially incorporating cisplatin) for optimal locoregional  control and disease-free survival. For intraoral carcinomas  with distant metastasis (stage Vc), single- or multi-agent  chemotherapy may be administered.   In addition, there are several promising targeted therapies,  including monoclonal antibodies (e.g., cetuximab and pani-  tumumab) or small molecule tyrosine kinase inhibitors (e.g.,  erlotinib) directed against epidermal growth factor receptor  (EGFR); anti-vascular endothelial growth factor (VEGF)  antibodies; and mammalian target of rapamycin (mTOR)  inhibitors. In particular, cetuximab has been approved by the  United States Food and Drug Administration for treatment  of head and neck squamous cell carcinoma and typically is  combined with radiation and/or chemotherapy. Molecular-  based targeted therapies are anticipated to become increas-  ingly important treatment strategies in the future.   For oropharyngeal squamous cell carcinoma, early-  stage disease may be treated by either definitive radiation  therapy or surgery; however, most cases are diagnosed at  an advanced stage and require multimodal therapy involv-  ing various combinations of surgery, radiation therapy, or    sy\:ja-3 Overall 5-year Relative Survival Estimates for  Oral and Pharyngeal Cancers*    Oral cavity and pharynx 65%  (combined)  Lip 88%  Tongue 65%  Floor of mouth 54%  Oropharynx 65%!    *Based upon Surveillance Epidemiology and End Results (GEER) 9 data for  patients diagnosed in 2006. Source: Surveillance Research Program,  National Cancer Institute. Fast Stats: An interactive tool for access to SEER  cancer statistics, http://seer.cancer.gov/faststats. Accessed April 9, 2015.  Survival of oropharyngeal carcinoma is related to HPV status of the tumor.  Some centers have reported overall 5-year survival rates of 54%-89% for  HPV oropharyngeal carcinomas and 33%-65% for HPV tumors.    chemotherapy. Oncologists traditionally have preferred  radiation or concurrent chemoradiation therapy over  surgery in this anatomic location; however, recent advances  in surgical techniques have led some to reconsider this view.  Based upon available data for patients recently diagnosed  in the United States, the estimated 5-year relative survival rate  for oral and pharyngeal cancers combined is approximately  64%. Although some patients die of their disease as many as  10 years after initial treatment, the great majority of deaths  occur within the first 5 years. The prognosis varies consider-  ably by tumor stage and subsite (Tables 10-4 and 10-5).  Because most lip vermilion carcinomas are diagnosed at an  early stage, the overall 5-year relative survival rate is excellent  (approximately 95%). In contrast, intraoral and oropharyn-  geal carcinomas often are diagnosed at later stages, with sig-  nificantly lower 5-year relative survival rates (e.g., 51% for  floor of mouth lesions and 65% for oropharyngeal lesions).  For both intraoral and lip vermilion carcinomas, tumor  stage is the best prognostic indicator. However, for oropha-  ryngeal carcinoma, HPV tumor status (i.e., presence or  absence of transcriptionally active HPV [see page 378]) is  considered the most important prognostic factor, followed  by tobacco exposure and tumor stage. Compared to patients  with HPV-negative tumors, those with HPV-positive tumors  typically exhibit a better response to chemotherapy and/or  radiation therapy, with an approximately 60% reduction in  risk of death and 30% greater 5-year absolute survival rate.  Improved survival may reflect the unique biology of HPV-  positive carcinomas as well as the low rate of comorbidity  among the relatively young age group typically affected.  Possible biologic reasons for favorable prognosis include an  intact p53-mediated apoptotic response to radiation and a  lack of field cancerization (see next section). Investigations  of targeted therapies and less intensive treatment regimens  for HPV-positive oropharyngeal tumors are ongoing.  Various molecular markers associated with oral squamous  cell carcinoma, such as 7P53 mutations, have shown    equivocal results as prognostic indicators. Several investiga-  tors have reported that overexpression of survivin (a member  of the inhibitor of apoptosis protein family) is associated  with poor prognosis, but the clinical utility of this finding  requires further study. Moreover, unlike oropharyngeal  carcinoma (see later), there is no clear correlation between  HPV tumor status and prognosis for oral squamous cell  carcinomas.   In the United States, deaths from oral and pharyngeal  cancers have been decreasing over the past several decades.  The age-adjusted death rate for oral and pharyngeal cancers  combined decreased from 4.3 per 100,000 population in  1975 to 2.5 per 100,000 population in 2010. From 2000  to 2010, the mortality rate decreased by approximately  1.3% annually. In particular, for oropharyngeal cancers,  5-year relative survival rates have improved—from approx-  imately 51% to 59% for those diagnosed from 1995  through 2001 to approximately 65% for those diagnosed  from 2002 through 2005. (This trend is reflected in the  difference between oropharyngeal survival rates shown in  Tables 10-4 and 10-5). Areas of investigational interest for  continuing declines in oral and pharyngeal cancer mortal-  ity include improvements in prevention, early diagnosis,  and treatment.    Patients with one carcinoma of the mouth or throat are at  increased risk for additional concurrent (synchronous) or,  more commonly, later (metachronous) primary surface epi-  thelial malignancies of the upper aerodigestive tract,  stomach, lungs, and other sites. This risk has been estimated  to be as low as 6% and as high as 44%; the highest figures  are associated with male patients who continue to smoke  and abuse alcohol after therapy. Overall, 9% to 25% of  patients with oral carcinoma develop additional mouth or  throat malignancies.   This tendency for the development of multiple mucosal  cancers is hypothesized to result from field cancerization—a  process whereby exposure to carcinogens, such as tobacco  and alcohol, creates a diffuse field of altered epithelial cells  with increased potential for malignant transformation.  Molecular analyses of various markers, including loss of  heterozygosity (LOH), microsatellite alterations, 7P53  tumor suppressor gene mutations, and X-chromosome  inactivation, have identified genetic alterations shared  between tumor tissue and adjacent clinically normal-  appearing tissue in one-third to one-half of cases examined.  In addition, investigators have shown that a significant pro-  portion of second primary tumors develop from the same  preneoplastic precursor lesion or “field,” with the remaining  cases representing tumors that develop independently. Fur-  thermore, researchers have proposed that patches of clonal  cells can progress to develop additional mutations and give  rise to subclones in a process known as clonal divergence,  which would account for the genetic heterogeneity typically  seen among these tumors. Interestingly, field cancerization    does not appear to be associated with malignancies attrib-  uted to HPV infection.    Verrucous carcinoma is a low-grade variant of oral squa-  mous cell carcinoma. In 1948, Ackerman described this  lesion in detail, although the term verrucous carcinoma had  been used in 1944 in a series of cases reported by Burford,  Ackerman, and Robinson. Ackerman postulated that some  of these lesions might be associated with smokeless tobacco  use, because 11 of his 31 patients were “tobacco chewers.”  However, there was no mention of the type of smokeless  tobacco used and no mention of whether any of these  patients also had smoked tobacco. In addition to the oral  mucosa, verrucous carcinoma has been identified at several  extraoral sites, including laryngeal, vulvovaginal, penile,  anorectal, sinonasal, and esophageal mucosa, as well as the  skin of the breast, axilla, ear canal, and soles of the feet.  Extraoral cases are unrelated to tobacco use. Several inves-  tigators have identified DNA from HPV types 6, 11, 16,  and 18 ina minority of oral verrucous carcinomas, although  the possibility that these cases represent coincidental HPV  infection cannot be excluded.   Verrucous carcinoma represents less than 1% to 16% of  all oral squamous cell carcinomas, depending on the local  popularity of smokeless tobacco use. The only epidemio-  logic assessment of this tumor in a Western culture reported  an average annual incidence rate of one to three oral lesions  per 1 million population each year. Among 411,534 cases  of head and neck carcinoma recorded in the National  Cancer Database from 1985 to 1996, only 0.6% of cases  were diagnosed as verrucous carcinoma.   Some oral verrucous carcinomas arise in people who  chronically use chewing tobacco or snuff. Cases also occur  in those who combine habits (i.e., smokeless tobacco,  smoking, and alcohol), exclusively smoke tobacco, or have  no identifiable risk factors. However, exact figures are dif-  ficult to assess because patients often deny their habits.  Nevertheless, among smokeless tobacco users, conventional  squamous cell carcinoma is much more likely to develop  than this low-grade variant.    Verrucous carcinoma is found predominantly in men older  than 55 years (average age: 65 to 70 years). In areas where  women frequently use dry snuff, however, older females  may predominate. The most common sites of oral mucosal  involvement include the mandibular vestibule, buccal  mucosa, gingiva, tongue, and hard palate. The involved area  often corresponds to the site of chronic tobacco placement.  In cultural groups who keep the tobacco in the maxillary  vestibule or under the tongue, these locations are involved  most commonly.    @ Fig. 10-120 Verrucous Carcinoma. Extensive papillary, white  lesion of the maxillary vestibule.    @ Fig. 10-121 Verrucous Carcinoma. Large, exophytic, papillary  mass of the maxillary alveolar ridge.    Oral verrucous carcinoma is usually extensive by the time  of diagnosis, and it is not unusual for a tumor to be present  for 2 to 3 years before definitive diagnosis. The lesion appears  as a diffuse, well-demarcated, painless, thick plaque with  papillary or verruciform surface projections (Figs. 10-120  and 10-121). Lesions are typically white but also may appear  erythematous or pink. The color depends on the amount of  keratin produced and the degree of host inflammatory  response to the tumor. When left untreated, the lesions may  destroy underlying structures, such as bone, cartilage, muscle,  and salivary glands. Enlarged cervical lymph nodes in patients  with verrucous carcinoma usually represent inflammatory  reactive changes rather than nodal metastasis.   Leukoplakia or tobacco pouch keratosis may be seen  on adjacent mucosal surfaces, and verrucous carcinoma is a  lesion that may develop from the high-risk precancer, pro-  liferative verrucous leukoplakia (PVL) (see page 358). PVL  and verrucous carcinoma may have been reported in the  past by the name oral florid papillomatosis.    Verrucous carcinoma has a deceptively benign microscopic  appearance; it is characterized by wide and elongated rete  ridges that appear to “push” into the underlying connective    @ Fig. 10-122 Verrucous Carcinoma. A, Low-power photomicro-  graph showing marked epithelial hyperplasia with a rough, papillary  surface and keratin plugging. B, High-power view showing bulbous  rete ridges without significant dysplasia.    tissue (Fig. 10-122). Lesions usually show abundant keratin  (usually parakeratin) production and a papillary or verruci-  form surface. Parakeratin typically fills the depressions  (parakeratin clefts) between the surface projections. These  projections may be long and pointed or short and blunted.  The lesional epithelial cells generally show no significant  cytologic atypia. There is frequently an intense inflamma-  tory cell infiltrate in the subjacent connective tissue.   The histopathologic diagnosis of verrucous carcinoma  requires an adequate incisional biopsy. Because the indi-  vidual cells are not very dysplastic, the pathologist must  evaluate the overall histomorphologic configuration of the  lesion to make the diagnosis. Adequate sampling also is  important because conventional squamous cell carcinoma  develops concurrently within up to 20% of verrucous  carcinomas.    The treatment of choice is surgical excision. The surgery  generally need not be as extensive as that required for con-  ventional squamous cell carcinoma of a similar size. If cervi-  cal lymph node enlargement is clinically evident, then a  selective neck dissection may be performed, although most  such cases turn out to represent reactive lymphadenopathy  rather than metastasis. Approximately 90% of patients are  disease free 5 years after surgery, but some patients will  require at least one additional surgical procedure during    that time. The treatment failures usually occur in patients  with the most extensive involvement or in those unable to  tolerate extensive surgery because of unrelated systemic dis-  eases. An additional cause of treatment failure is the initial  inability to identify focal, concurrent conventional squa-  mous cell carcinoma; such cases should be treated as con-  ventional squamous cell carcinomas.   Radiotherapy is an alternative primary treatment modal-  ity but provides poorer local control and, thus, is considered  less effective than surgery. In addition, radiotherapy has  been unpopular because of published reports of poorly dif  ferentiated or anaplastic carcinoma developing within the  lesion after treatment. However, more recent analysis sug-  gests that this threat is overexaggerated. In a limited number  of cases, tumor regression after chemotherapy, radiochemo-  therapy, or photodynamic therapy has been reported,  although these treatment alternatives require further study.    ¢ SPINDLE CELL CARCINOMA  (SARCOMATOID SQUAMOUS CELL  CARCINOMA; POLYPOID SQUAMOUS  CELL CARCINOMA; CARCINOSARCOMA;  PSEUDOSARCOMA)    Spindle cell carcinoma is a rare variant of squamous cell  carcinoma characterized by dysplastic surface epithelium in  conjunction with an invasive spindle cell element. With  routine light microscopy, it may be indistinguishable from  connective tissue sarcomas or other spindle cell malignan-  cies. Spindle cell carcinoma of the upper aerodigestive tract  is closely associated with tobacco and alcohol use. Some  cases develop after radiotherapy for a more differentiated  squamous cell carcinoma, a phenomenon known as dedif-  ferentiation. Transcriptionally active HPV appears to be  exceptionally rare in this variant.   In the past, this biphasic lesion was thought to be a “col-  lision” tumor between a carcinoma and sarcoma, but most  authorities now consider the spindle cells to represent ana-  plastic carcinoma cells. Electron microscopy and immuno-  histochemical analysis support the concept that these  lesional cells are of epithelial origin, with the ability to  produce mesenchymal intermediate filaments. Based on  immunohistochemical studies, some investigators have  hypothesized that a dysfunctional cadherin-catenin complex  important for intercellular adhesion causes the tumor cells  to shift from a squamous to a spindled type, with increased  infiltrative behavior.    Spindle cell carcinoma may arise anywhere within the upper  aerodigestive tract, with a predilection for the larynx and  oral cavity. In the mouth, the alveolar mucosa, tongue,  buccal mucosa, and lower lip are common sites, but other  areas may be involved. Males are affected more often than  females. According to the largest reported series restricted    - cas  © Fig. 10-123 Spindle Cell Carcinoma. Large polypoid mass  arising from the right lateral tongue.    to oral cases, the mean age at diagnosis is 57 years (range:  29 to 93 years).   In contrast to other oral cancers, spindle cell carcinoma  typically appears as a pedunculated, polypoid mass, but  occasionally it may appear as a sessile, nodular or fungating  mass (Fig. 10-123). The surface often is ulcerated. Pain and  paresthesia are prominent features. The tumor grows rapidly,  tends to metastasize early, and typically is diagnosed at a  late stage. Lower lip lesions seem to have a special propen-  sity to travel along nerves through the mental foramen and  into the mandibular canal.    Spindle cell carcinoma is composed predominantly of fas-  cicles of anaplastic, spindle-shaped cells (Fig. 10-124). Some  spindle cells may appear as obvious epithelial elements, but  others strongly resemble atypical mesenchymal cells. On  tare occasions, bone, cartilage, or muscle differentiation  may be seen. Numerous mitotic figures often are present.  The overall picture is similar to that of an anaplastic fibro-  sarcoma (see page 516), except for the often-inconspicuous  squamous element.    ‘The squamous component usually consists of dysplasia or  carcinoma in situ of the overlying surface epithelium but may  appear as islands of atypical squamous epithelium among the  spindle cells. Direct transition between the two cell types  may be seen. Because of frequent surface ulceration, a neo-  plastic surface component may be difficult to discern. Meta-  static lesions may show only spindle cells, only squamous  cells, or a combination of spindle and squamous cells.   Serial sections may be needed to find areas of unequivo-  cal squamous cell carcinoma, and immunohistochemical  techniques can be particularly useful in distinguishing this  tumor from mesenchymal spindle cell malignancies. Most  mesenchymal tumors express vimentin but not epithelial  markers. In contrast, approximately 65% to 80% of spindle  cell carcinomas react with antibodies directed against at  least one epithelial marker, such as cytokeratin, epithelial  membrane antigen (EMA), or p63. Nearly all cases express  vimentin; immunoreactivity for other mesenchymal markers    The treatment of choice for oral spindle cell carcinoma is  radical surgery, with neck dissection when clinically positive  nodes are present. Most authors agree that radiotherapy and  chemotherapy are ineffective. However, adjuvant radiation  therapy may be of benefit when surgical margins are positive  for tumor. The 5-year disease-free survival rate is approxi-  mately 30% for oral lesions, with most deaths occurring  within 1 year of diagnosis. The prognosis for oral spindle  cell carcinoma is somewhat worse than that for spindle cell  carcinoma arising in other anatomic sites, but it is similar  to the prognosis for high-grade, conventional oral squa-  mous cell carcinoma. Surprisingly, tumor size seems to have  little effect on the prognosis. Negative prognostic factors  include endophytic (rather than polypoid) growth and an    Adenosquamous carcinoma is a rare squamous cell carci-  noma variant that is characterized histopathologically by a  combination of adenocarcinoma and squamous cell carci-  noma. The adenoid (glandular) pattern, which includes  mucus production, has been demonstrated clearly in meta-  static deposits. Some authorities consider this carcinoma to  be merely a high-grade mucoepidermoid carcinoma (see  page 454). In some cases, tobacco and alcohol use have been  implicated as causative factors. In addition, transcription-  ally active HPV has been identified in a few cases involving  the oropharynx and nasal cavity.    Adenosquamous carcinoma may involve the tongue, oral  floor, and other mucosal surfaces, usually in older adults.  There is a male predilection. The tumor typically presents    as a nodular, broad-based, variably painful mass with or  without surface ulceration. The majority of patients have  cervical lymph node metastasis at diagnosis.    Adenosquamous carcinoma appears as an admixture of a  surface squamous cell carcinoma and an underlying adeno-  carcinoma. The glandular component tends to be most  prominent in deeper portions of the tumor. Mucicarmine  staining demonstrates intracytoplasmic mucin in most  cases, making differentiation from mucoepidermoid carci-  noma difficult but helping to distinguish adenosquamous  carcinoma from forms of squamous cell carcinoma that  exhibit a pseudoglandular pattern of degeneration. Both  squamous and glandular components immunoreact with  antibodies directed against high molecular—weight cytokera-  tins (KL1).    Adenosquamous carcinoma typically is treated with radical  surgical excision, at times supplemented with radiation or  chemoradiation therapy. The prognosis is poor; for upper  aerodigestive tract lesions, the overall 5-year survival rate is  approximately 13%, with about 42% of patients dying of  disease within 2 years of diagnosis. Among previously  reported head and neck cases, local recurrence has devel-  oped in approximately 32%; cervical lymph node metastasis  in approximately 46%; and distant metastasis in approxi-  mately 29%, with the lung being the most common site of  dissemination.    Basaloid squamous carcinoma is a recently described  squamous cell carcinoma variant that arises primarily in the  upper aerodigestive tract, with a predilection for the larynx,  hypopharynx, and tongue base. More than 100 oral cases  also have been reported. Heavy tobacco and alcohol use  appear to represent major risk factors. In addition, recent  studies suggest that HPV may play an important role in the  etiopathogenesis of a distinct subset of oropharyngeal basa-  loid squamous cell carcinomas—particularly those arising  in the palatine and lingual tonsils.    Basaloid squamous carcinoma tends to occur in persons 40  to 85 years of age and arises more commonly in males than  females. The lesion clinically appears as a fungating mass or  ulcer and may be painful or interfere with swallowing (dys-  phagia). Approximately two-thirds of cases are diagnosed  at an advanced clinical stage.    ® Fig. 10-125 Basaloid Squamous Carcinoma. Sheets of basaloid  squamous epithelium exhibiting a high mitotic index and tumor  necrosis.    As its name connotes, basaloid squamous carcinoma has  two microscopic components. The first is a superficial, well-  differentiated or moderately differentiated squamous cell  carcinoma, often with surface ulceration, multifocal origin,  and areas of carcinoma in situ. The second, deeper compo-  nent is an invasive basaloid epithelium arranged in islands,  cords, and glandlike lobules. This deeper tumor often shows  palisading of peripheral cells, central necrosis, and occa-  sional squamous differentiation (Fig. 10-125). This compo-  nent appears similar to basal cell carcinoma, adenoid cystic  carcinoma, basal cell adenocarcinoma, or neuroendocrine  carcinoma. The interface between the two components is  typically sharp and distinct, but gradual transition from  squamous to basaloid cells may be seen occasionally. The  tumor islands often are surrounded by mucoid stroma  (basal lamina material). Microcystic spaces filled with PAS-  positive basal lamina material may be interspersed among  the tumor islands as well.    Treatment typically consists of surgery, often followed by  radiation or chemoradiation therapy. Basaloid squamous  carcinoma generally is considered a highly aggressive malig-  nancy, with a mean survival of only 23 months. However,  several authors have suggested that basaloid squamous cell  carcinoma may have a similar outcome compared with con-  ventional squamous cell carcinoma when cases are matched  by clinical stage and anatomic location. Therefore, the poor  prognosis for basaloid squamous cell carcinoma simply  might reflect a tendency for these patients to be diagnosed  with late-stage disease. Furthermore, recent evidence sug-  gests that HPV status has a major impact on the prognosis  of oropharyngeal basaloid squamous cell carcinomas, with  significantly improved survival among HPV-positive cases  compared to HPV-negative cases. Therefore, conflicting  reports in the literature regarding prognosis may reflect    differences in subsite distribution and HPV tumor status  among study cohorts.    Carcinoma of the maxillary sinus or antrum is an uncom-  mon malignancy of largely unknown cause. It does not  appear to be related to sinusitis or nasal polyps. Unlike  squamous cell carcinomas in other head and neck sites,  squamous cell carcinomas of the paranasal sinuses have been  associated only weakly with tobacco use. A strong causal  relationship to occupational wood and leather dust expo-  sure has been established for the rarely occurring sinonasal  intestinal type of adenocarcinoma. In addition, emerging  evidence suggests that HPV may be an etiologic factor in  some cases, with one large series detecting transcriptionally  active high-risk HPV in approximately 20% of sinonasal  carcinomas examined.   Maxillary sinus carcinomas comprise only 3% of all head  and neck carcinomas; however, among paranasal sinus car-  cinomas, the maxillary sinus is the most common site  (accounting for 80% of lesions). Most lesions remain  asymptomatic or mimic sinusitis for long periods while the  tumor grows to fill the sinus. Therefore, the diagnosis may  not be made until the lesion has perforated through the  surrounding bone.   The majority of maxillary sinus carcinomas represent  squamous cell carcinomas. However, additional carcinomas  that may arise in this location include sinonasal adenocar-  cinoma, sinonasal undifferentiated carcinoma (SNUC)  (see next section), neuroendocrine (small cell undifferenti-  ated) carcinoma, and salivary gland-type adenocarcinoma.    Carcinoma of the maxillary sinus mainly affects older  adults, with a slight male predilection. More than 80% of  cases are advanced (stage III or IV) at the time of diagnosis.  Patients generally complain of chronic unilateral nasal stuff-  iness or notice an ulceration or mass of the hard palate or  alveolar bone (Fig. 10-126). When the second division of  the trigeminal nerve is involved, intense pain or paresthesia  of the midface or maxilla may occur, perhaps simulating a  toothache. Adjacent teeth may become loose, and dental  radiographs often reveal a “moth-eaten” destruction of the  lamina dura and surrounding bone. A panoramic radio-  graph shows a cloudy sinus with destruction of its bony  wall; however, the extent of the tumor is best visualized by  CT or MRI.   If the tumor perforates the lateral wall of the sinus, uni-  lateral facial swelling and pain are usually present. With  medial extension, nasal obstruction and hemorrhage are  common. Superior extension results in displacement or pro-  trusion of the eyeball. Approximately 9% to 14% of patients    ® Fig. 10-126 Carcinoma of the Maxillary Sinus. The tumor has  produced a bulge of the posterior maxillary alveolar ridge and is begin-  ning to ulcerate through the surface mucosa.    have cervical or submandibular lymph node metastasis at  the time of diagnosis. Distant metastasis is uncommon until  late in the progression of disease.    Although the antrum is lined by respiratory epithelium,  the great majority of maxillary sinus carcinomas are squa-  mous cell carcinomas, usually moderately or poorly  differentiated.    Carcinoma confined within the maxillary sinus usually is  treated by hemimaxillectomy. Resectable tumors that have  perforated through the surrounding bone are treated by  surgery combined with radiotherapy and/or chemotherapy.  Despite radical treatment, the prognosis generally is poor,  with a 5-year survival rate of approximately 40%. Regional  lymph node metastasis or involvement of the pterygopala-  tine fossa reduces the survival rate to less than 8%. Death  usually occurs from local destruction and the inability to  control the primary disease. Recent analysis suggests that  HPV-positive sinonasal carcinomas may exhibit improved  clinical outcomes compared to HPV-negative cases;  however, additional studies are needed to confirm this    Sinonasal undifferentiated carcinoma (SNUC) is a rare,  highly aggressive, and clinicopathologically distinctive neo-  plasm of the nasal cavity and paranasal sinuses. The tumor  initially was described in 1986, and since then more than  200 cases have been reported. In the earlier literature, these  tumors probably were classified as anaplastic carcinomas or  high-grade olfactory neuroblastomas.    @ Fig. 10-127 Sinonasal Undifferentiated Carcinoma (SNUC).  T1-weighted magnetic resonance image (MRI) showing a large  destructive mass filling the right maxillary sinus with extension into the  orbital region and nasal cavity. (Courtesy of Dr. Zoran Rumboldt.)    The histogenesis and pathogenesis are poorly under-  stood. Some investigators have theorized that the cell of  origin may be related to the Schneiderian membrane or  olfactory epithelium. There is only a weak association  with tobacco smoking or Epstein-Barr virus (EBV). In  some instances, patients have developed SNUC secondary  to radiation therapy for nasopharyngeal carcinoma or  retinoblastoma.    SNUC occurs over a broad age range (third through ninth  decades), with a median age at presentation in the sixth  decade. The male-to-female ratio is approximately 2:1  to 3:1.   The tumor is well known for rapid development of  locally extensive disease. It typically appears as a large mass  that can involve multiple regions of the sinonasal tract,  including the nasal cavity, maxillary sinus, and ethmoid  sinuses. In addition, extension into contiguous sites—such  as, the nasopharynx, orbit, and cranial cavity—is common.  Inferior penetration into the oral cavity is possible as well.  There is often rapid development of multiple sinonasal  symptoms, including nasal obstruction or discharge, epi-  staxis, swelling, and pain. Orbital involvement may lead to  proptosis, periorbital swelling, diplopia, and vision loss.  Cranial nerve palsies are common as well.   Tumor extent is best assessed by CT or MRI, which  typically reveals a large, expansile sinonasal mass with  bony destruction and invasion of adjacent structures (Fig.  10-127).    SNUC is characterized by trabeculae, ribbons, sheets, and  nests of polygonal cells with minimal cytoplasm and pleo-  morphic, hyperchromatic to vesicular nuclei. No squamous  or glandular differentiation should be observed. Mitotic  figures are numerous. Tumor necrosis, apoptosis, and lym-  phovascular invasion usually are prominent. The surface  epithelium overlying the tumor may exhibit dysplasia or  carcinoma in situ. Immunohistochemical staining for cyto-  keratin or epithelial membrane antigen (EMA) typically is  positive. Careful histopathologic examination and a broad  immunohistochemical panel typically are needed to rule  out other entities, such as poorly differentiated squamous  cell carcinoma, olfactory neuroblastoma, undifferentiated  nasopharyngeal carcinoma, neuroendocrine carcinoma,  melanoma, lymphoma, and nuclear protein in testis (NUT)  midline carcinoma. (The latter is a recently described,  highly lethal malignancy defined by balanced transloca-  tions involving the NUT gene on chromosome 15q14.)    Most patients present with locally advanced disease. In such  cases, the standard approach is aggressive multimodal  therapy, including surgical resection followed by adjuvant  radiation and/or chemotherapy. Unresectable disease is  treated by definitive chemoradiation therapy. When resect-  ability is questionable, some authorities advocate induction  chemotherapy in order to shrink the tumor prior to addi-  tional treatment and, possibly, to decrease the risk for distant  metastasis. However, this approach is somewhat controver-  sial and is associated with significant toxicity. The prognosis  is generally poor, although several centers have reported  improved outcomes with modern treatment approaches.  Overall 5-year survival rates in the recent literature range  from 20% to 74%. Local recurrence is common and is  the major cause of morbidity and mortality. Metastasis is  possible, usually to cervical lymph nodes, bone, liver,  or brain.    Nasopharyngeal carcinoma represents a group of malig-  nancies that arise from the lining epithelium of the lym-  phoid tissue-rich nasopharynx; similar tumors are found in  the palatine tonsil and base of tongue. These three anatomic  sites are collectively called Waldeyer tonsillar tissue or  Waldeyer ring.   Nasopharyngeal carcinoma is rare in most areas of the  world. The average annual incidence rate in the United  States is less than 1 per 100,000 persons. In southern  Chinese men, however, the rate is a startling 20 to 55 per  100,000. Among southern Chinese men who migrate to the  United States, the rate is intermediate, which suggests an  environmental causative agent. Intermediate rates also are  observed among many indigenous people of Southeast Asia    (including Thais, Vietnamese, Malays, and Filipinos), Inuits  of Alaska and Greenland, and Arabs of North Africa.   Infection with Epstein-Barr virus (EBV), diets deficient  in vitamin C, and consumption of salt fish containing  carcinogenic N-nitrosamines have been implicated as con-  tributory factors. Tobacco also has been implicated as a risk  factor; however, the risk for carcinoma development for a  given level of tobacco exposure is lower in the nasopharynx  than in other parts of the upper aerodigestive tract. In addi-  tion, recent studies have detected high-risk HPV in a small  subset of nasopharyngeal carcinomas with a predilection for  white individuals.    Nasopharyngeal carcinoma occurs in all age groups but  most commonly affects those who are 40 to 60 years old.  It also occurs three times more commonly in men than in  women. The primary lesion, which usually arises from the  lateral nasopharyngeal wall, often is small and difficult to  detect, even by endoscopy. The first sign of disease for 50%  to 60% of patients is an enlarged, firm to hard, cervical  lymph node, which represents metastatic tumor (Fig.  10-128). Symptoms related to the ear are described by  slightly less than half of patients. If the tumor obstructs the  eustachian tube, then unilateral serous otitis media, otalgia,  or hearing loss may be the presenting complaint.    © Fig. 10-128 Nasopharyngeal Carcinoma. This patient initially  appeared with metastatic carcinoma in the left lateral neck. Further  evaluation revealed a primary tumor of the nasopharynx. (Courtesy of  Dr. D. E. Kenady.)    Epistaxis, nasal obstruction, and pharyngeal pain may be  present. The tumor may invade through the foramen  lacerum into the brain, producing CNS symptoms, or it  may involve cranial nerves in the area, causing specific  symptoms related to those nerves. Involvement of the ptery-  goid muscles can produce facial pain with limited jaw  movement, thereby mimicking a temporomandibular joint  disorder. Significantly, 5% to 10% of patients also have  distant metastasis at the time of diagnosis.   geal mucosa may be necessary for tumor identification and  diagnosis. Nasopharyngeal carcinoma mainly includes the  following histopathologic types:   3. Undifferentiated nonkeratinizing carcinoma (poorly dif-  ferentiated carcinoma, anaplastic carcinoma, and  lymphoepithelioma)   When more than one histopathologic type is present, the  tumor is classified according to the predominant type.   The histopathologic features of keratinizing squamous  cell carcinoma are identical to those of squamous cell car-  cinoma of other head and neck regions (see page 385).  Keratinization must be evident at the light microscopic level.   The lesional cells of differentiated nonkeratinizing car-  cinoma are relatively mature and somewhat squamous in  nature, but they produce no keratin. Broad interconnecting  bands of oval or round cells are organized in plexiform and  papillary patterns.   Undifferentiated nonkeratinizing carcinoma consists  of sheets of undifferentiated cells with indistinct margins,  very little cytoplasm, and large, vesicular nuclei (Fig.  10-129). These tumor cells are often intermixed with the  lymphoid cells normally found at this anatomic site. The    ® Fig. 10-129 Nasopharyngeal Carcinoma. Poorly differentiated  tumor exhibiting sheets of rounded tumor cells.    term lymphoepithelioma has been used to describe this  lesion because it was once thought to be a malignancy that  originated from both epithelial and lymphoid tissues. This  terminology should be discouraged, however, because the  lymphoid tissue is not part of the neoplastic process. Such  undifferentiated tumors may be difficult to distinguish from  lymphoma by routine light microscopic examination, and  immunohistochemical studies often are used to demon-  strate cytokeratins within the carcinoma cells. Occasional  cases show neuroendocrine differentiation.   The undifferentiated lesions tend to occur in younger  individuals and account for virtually all nasopharyngeal  carcinomas in people younger than 40 years. Among south-  ern Chinese patients, the vast majority (95%) of cases are  classified as undifferentiated nonkeratinizing carcinomas,  whereas in nonendemic areas, 25% to 50% of cases are  keratinizing squamous cell carcinomas.   The differentiated and undifferentiated nonkeratinizing  types are very closely associated with EBV, which is best  demonstrated by in situ hybridization for EBV-encoded  early RNA (EBER). In contrast, EBV status is highly  variable in the keratinizing type, with EBV most often  detected among cases in endemic areas. Among the small  subset of HPV-positive cases, the nonkeratinizing types  predominate.    Because of the inaccessibility of the nasopharynx and the  keen radiosensitivity of nasopharyngeal carcinoma, radio-  therapy is the mainstay of treatment. Early-stage disease  typically is managed by radiotherapy alone. However, most  patients present with advanced locoregional disease, for  which current evidence supports concurrent platinum-  based chemotherapy and radiation therapy. Targeted thera-  pies (e.g., inhibitors of epidermal growth factor receptor  [EGFR] and angiogenesis) and immunotherapy directed  against EBV antigens are currently under investigation.   In the United States, the relative 5-year survival rates for  patients with stage I, II, IH, and IV disease are 72%, 64%,  62%, and 38%, respectively. For all stages combined, the  relative 5-year survival rate is 59%. When treated with  radiation therapy, the differentiated and undifferentiated  nonkeratinizing types exhibit a higher local control rate but  a greater risk for distant metastasis compared with the kera-  tinizing type. In the United States, higher survival rates have  been observed among Chinese-American patients compared  with other ethnic groups. This trend traditionally has been  attributed to the prevalence of the more radiosensitive  undifferentiated nonkeratinizing type among Chinese-  American patients; however, for unknown reasons, Chinese  ethnicity is a favorable prognostic factor even independent  of histopathologic type. Additional favorable prognostic  factors include age under 40 years, female gender, and low  titers of circulating EBV DNA (determined pre-treatment  and post-treatment by real-time PCR). The prognostic sig-  nificance of HPV-positivity currently is unclear. Persons  treated for nasopharyngeal carcinoma are also at increased    risk for developing a second primary malignancy of the  head and neck mucosa.    Basal cell carcinoma represents the most common skin  cancer, as well as the most common of all cancers. It is a  locally invasive, slowly spreading, epithelial malignancy that  arises from the basal cell layer of the skin and its append-  ages. About 80% are found on the skin of the head  and neck.   The incidence is difficult to determine because basal cell  carcinoma typically is not reported to cancer registries.  However, researchers estimate that 2.8 million basal cell  carcinomas were treated in the United States in 2006.  Moreover, according to one study, as of 2007 there were  about 13 million non-Hispanic whites in the United States  with a personal history of at least one nonmelanoma skin  cancer, with the majority (80%) of these cases representing  basal cell carcinomas. The worldwide incidence of basal cell  carcinoma varies considerably by region, with the highest  rates (>2000 per 100,000 person-years) reported in parts of  Australia. The risk generally increases with age, proximity  to the equator, and lighter skin pigmentation. Furthermore,  the incidence in North America and Europe has increased  sharply over the past several decades; in part, this trend may  be due to aging populations, although some investigators  have reported a disproportionate increase among young  adults (particularly women) as well.   This cancer mainly results from cumulative (including  chronic and intermittent) UV radiation exposure. Frequent  sunburns and tendency for freckling in childhood are associ-  ated with an increased risk. Additional risk factors include  outdoor occupational activity, psoralen and ultraviolet A  (PUVA) treatment (often used for psoriasis), tanning device  use, ionizing radiation exposure, immunosuppression, and  arsenic ingestion. Allelic variations in genes related to DNA  repair or pigmentation (e.g., the melanocortin I receptor  [MCIR] gene) also may confer increased susceptibility. Fur-  thermore, several genodermatoses are associated with basal  cell carcinoma, including the nevoid basal cell carcinoma  syndrome (see page 640), xeroderma pigmentosum (see page  696), albinism, Rasmussen syndrome, Rombo syndrome,  Bazex-Christol-Dupré syndrome, and the Dowling-Meara  subtype of epidermolysis bullosa simplex (see page 708).   Molecular genetic studies have shown that dysregulation  of the hedgehog signaling pathway is a critical early event  in the development of basal cell carcinoma. Inactivating  mutations in the patched (PTCH) gene on chromosome  9q22 have been identified in both sporadic cases and  patients with the nevoid basal cell carcinoma syndrome.  Mutations in other genes participating in this pathway (e.g.,  smoothened [SMOJ) occasionally may be found in sporadic  cases as well. These mutations lead to constitutive activation  of hedgehog signaling and enhanced cellular proliferation.  In addition, 753 mutations are found in more than 50%    of sporadic basal cell carcinomas and may represent a later  event in tumor development.   Well-documented reports of oral basal cell carcinoma  are rare. Many of the cases described in the literature  actually represent misdiagnosed salivary or odontogenic  neoplasms.    Basal cell carcinoma most often affects white adults, espe-  cially those with fair complexions. Although most patients  are older than 40 years at diagnosis, some lesions are detected  as early as the second decade of life, particularly in patients  with red or blonde hair and blue or green eyes. Males are  affected about twice as often as females; however, among  young patients, there is a female predilection (possibly due  to tanning bed use). Approximately 80% of lesions occur  on the head and neck, with the remainder involving the  trunk and limbs.   The most common clinicopathologic variant, nodular  (noduloulcerative) basal cell carcinoma, begins as a firm,  painless papule that slowly enlarges and develops a central  depression or umbilication. Telangiectatic blood vessels  usually are evident within the rolled border surrounding the  central depression (Figs. 10-130 and 10-131). When the  lesion is pressed, a characteristic pearly opalescent quality is  discerned. Expanding ulceration often develops in the  central depression, and the patient may report intermittent  bleeding followed by healing. Untreated lesions continue to  enlarge slowly, with ulceration and destruction of underly-  ing structures—hence the term rodent ulcer (Fig. 10-132).  Destruction of underlying bone or cartilage may occur, but  metastasis is extremely rare.   Several other variants have been described. Pigmented  basal cell carcinoma represents a noduloulcerative tumor  colonized by benign melanocytes (Fig. 10-133). The melanin  production imparts a tan, brown, black, or even bluish  color, and usually the pigment is not distributed uniformly,  as it would be in a melanocytic nevus (see page 350).    @ Fig. 10-130 Basal Cell Carcinoma. Early noduloulcerative basal  cell carcinoma of the forehead showing raised, rolled borders and focal  ulceration. Fine, telangiectatic blood vessels can be seen on the  surface.    ® Fig. 10-131 Basal Cell Carcinoma. Noduloulcerative lesion of the  upper lip demonstrating telangiectasia and small ulceration.    @ Fig. 10-132 Basal Cell Carcinoma. This tumor was neglected for  many years and became exceptionally large. (Courtesy of Dr. Terry  Day.)    @ Fig. 10-133 Basal Cell Carcinoma. Pigmented basal cell carci-  noma of the cheek.    Sclerosing (morpheaform) basal cell carcinoma is an  insidious lesion that often mimics scar tissue. The overlying  skin appears pale and atrophic, and the lesion is firm to  palpation with poorly demarcated borders. A slight eleva-  tion may be noted at the tumor edges. Often a great deal  of invasion has occurred before the patient becomes aware  of a problem.    showing ulceration of the epidermal surface associated with an invad-  ing tumor of hyperchromatic epithelial cells. Inset demonstrates islands  of basophilic epithelium with peripheral palisading.    Superficial basal cell carcinoma occurs primarily on the  skin of the trunk. Often, lesions are multiple and appear as  well-demarcated, erythematous, scaly patches that may be  mistaken clinically for psoriasis or eczema. A fine, elevated,  “threadlike” border is seen at the margins.   Some investigators believe that basal cell carcinomas  associated with the nevoid basal cell carcinoma syndrome  (see page 640) should be placed in a separate category. These  lesions develop in both sun-exposed and protected areas of  the skin and may number in the hundreds on a single  patient. The tumors associated with this syndrome usually  do not produce significant tissue destruction.    Basal cell carcinoma displays considerable histopathologic  diversity and includes the following microscopic patterns:  noduloulcerative (nodulocystic), pigmented, keratotic,  adenoid, superficial, infiltrative, sclerosing (morpheaform),  and micronodular. The noduloulcerative, pigmented, and  syndrome-related basal cell carcinomas are comprised of  uniform, ovoid, dark-staining basaloid cells with medium-  sized nuclei and little cytoplasm (Fig. 10-134). The cells are  arranged in well-demarcated islands and strands, which  appear to arise from the basal cell layer of the overlying  epidermis and invade the underlying connective tissue. Epi-  thelial islands typically demonstrate palisading of the  peripheral cells; frequently, artifactual retraction is seen  between the epithelial islands and the connective tissue.  Although most of these neoplasms show no differentiation,  some exhibit areas of keratin production, sebaceous differ-  entiation, or interlacing strands of lesional cells that resem-  ble duct formation (“adenoid”). Necrosis of epithelial  islands may produce a cystic appearance. Actinic damage in  the form of solar elastosis almost always is seen in adjacent  stroma.   Pigmented basal cell carcinoma demonstrates dendritic  melanocytes within tumor islands, and melanophages may    be seen in the surrounding stroma. Both the infiltrative and  sclerosing types exhibit infiltrating thin strands of basaloid  tumor cells; the latter type also shows a densely collagenous  background. Superficial basal cell carcinoma includes  lobules of tumor cells that drop from the epidermis in a  multifocal pattern. Micronodular basal cell carcinoma  exhibits small, round tumor nests less than 0.15 mm in  diameter (or about the size of a hair follicle bulb). Occasion-  ally, basal cell carcinoma is admixed with an independent  primary squamous cell carcinoma of the skin. The resulting  “collision” tumor is called basosquamous carcinoma.  Some authorities consider basosquamous carcinoma to be  a simple basal cell carcinoma with abundant squamous  metaplasia.   Some studies suggest that immunohistochemical expres-  sion of Ber-EP4 (a cell surface glycoprotein preferentially  expressed in cutaneous basal cell carcinoma) may help to  distinguish extremely rare cases of intraoral basal cell carci-  noma from peripheral ameloblastoma.    The following features are associated with increased risk for  recurrence among cutaneous basal cell carcinomas of the  head and neck:   e Lesions of 6 mm or more in the so-called “mask area” of  the face (i.e., skin of the central face/nose, ocular region,  temples, auricular region, and_ perioral/mandibular  region)   ¢ Lesions arising in immunosuppressed individuals or in a  prior site of radiotherapy  Lesions with low risk for recurrence typically are treated   tage, with 3- to 5-mm margins of clinically normal-  appearing skin beyond the visible lesion. These methods  result in a cure rate of 95% to 98%. Head and neck lesions  with a high risk for recurrence often are treated by Mohs  micrographic surgery. This technique uses intraoperative,  frozen-section evaluation of specially mapped and marked  surgical specimens to ensure complete tumor removal.   Alternative treatments—such as topical 5-fluorouracil,  topical imiquimod, photodynamic therapy, or vigorous  cryotherapy—may be effective for low-risk, superficial basal  cell carcinomas. However, such alternatives are associated  with suboptimal cure rates and, thus, typically are reserved  for cases in which surgery and radiation are contraindicated  or impractical. Recently, the United States Food and Drug  Administration approved vismodegib (a small-molecule  inhibitor of the hedgehog signaling pathway) for the    treatment of recurrent, advanced basal cell carcinomas or  lesions in patients unable to tolerate surgery or radiation.  Several other targeted agents are under development.   Recurrence of a properly treated basal cell carcinoma is  uncommon, and metastasis is exceptionally rare. In patients  with uncontrollable disease, death usually results from local  invasion into vital structures. However, with early detection  and the advent of Mohs surgery, such an outcome is unusual  today.   Patients with a history of basal cell carcinoma must be  evaluated periodically. There is an estimated 44% chance of  a second basal cell carcinoma and 6% chance of a cutaneous  squamous cell carcinoma developing within 3 years of treat-  ment of the initial tumor.    ¢ MERKEL CELL CARCINOMA (MERKEL  CELL TUMOR; NEUROENDOCRINE  CARCINOMA OF SKIN; SMALL CELL  CARCINOMA OF SKIN; TRABECULAR  CARCINOMA OF SKIN)    Merkel cell carcinoma is a rare, aggressive malignancy with  neuroendocrine features. It most often occurs on the skin  of the head and neck region. As with other skin malignan-  cies, UV light exposure and old age are major risk factors.  In addition, there is an increased frequency among immu-  nocompromised individuals, including transplant recipi-  ents, patients receiving immunosuppressive therapy for  autoimmune diseases, patients with other underlying malig-  nancies (especially chronic lymphocytic leukemia), and  patients with HIV infection. Recently, investigators have  detected DNA from the novel Merkel cell polyomavirus  (MCPyV) in up to 80% of cases.   Based upon the identification of cytoplasmic neurosecre-  tory granules by electron microscopy and neuroendocrine  markers by immunohistochemistry, this neoplasm tradi-  tionally was thought to arise from Merkel cells (mechano-  receptor cells found primarily in skin, but also found at  other sites, including keratinized oral mucosa). However,  because of the presence of nonendocrine epithelial and sar-  comatous elements in some cases, many authorities cur-  rently favor an origin from pluripotent epidermal or dermal  stem cells. These hypotheses may be reconciled by the recent  discovery that Merkel cells are derived from epidermal  stem cells.   Intraoral and lip vermilion cases have been reported  rarely. However, some oral neuroendocrine malignancies  previously reported as Merkel cell carcinomas actually may  be more akin to high-grade small cell neuroendocrine car-  cinomas of the upper aerodigestive tract mucosa. The latter  tumor type is closely associated with tobacco and alcohol  abuse, is not associated with UV light exposure or MCPyV,  exhibits microscopic features similar to small cell carcinoma  of the lung, and may behave even more aggressively than  Merkel cell carcinoma.    @ Fig. 10-135 Merkel Cell Carcinoma. Red nodule on the vermilion  border of the upper lip. (From Chang JYF, Stewart JM, Cheng YSL,  et al: Upper lip nodule, Oral Surg Oral Med Oral Pathol Oral Radiol  Endod 105:549-553, 2008.)    More than 70% of Merkel cell carcinomas arise in indi-  viduals 70 years or older. The tumor mainly affects whites  (95% of cases) and exhibits a male predominance. It occurs  primarily on sun-exposed areas of fair-skinned individuals,  with a predilection for the skin of the face, upper limbs,  and shoulders. The lip vermilion is also susceptible (Fig.  10-135). Extracutaneous lesions are rare and most often  affect the salivary glands, although involvement of the  oral, nasal, pharyngeal, laryngeal, esophageal, and genital  mucosa also are possible. The tumor usually appears as an  asymptomatic, rapidly enlarging, smooth, dome-shaped  nodule with prominent surface vessels (telangiectasias).  Some authors have used the acronym AEIOU (Asymptom-  atic, Expanding rapidly, Immunosuppression, Old age,  Ultraviolet-exposed fair skin) to summarize the salient clin-  ical findings. The lesion typically is red, violaceous, or pink  and ranges in size from 0.5 to 5.0 cm. An often innocuous  clinical appearance may cause delay in diagnosis. Approxi-  mately 27% of cases demonstrate regional lymph node  metastasis at diagnosis. In about 14% of cases, there is  nodal disease of unknown primary origin, presumably due  to regression of the primary tumor.    Merkel cell carcinoma consists of sheets and anastomosing  strands of small to moderately sized, round, basophilic cells,  which infiltrate the dermis and subcutaneous fat (Fig.  10-136). Epidermal involvement is present in only a small  proportion of cases. Pseudoglandular, trabecular, cribriform  (“Swiss cheese”), and sheetlike patterns may be seen. The  tumor cells typically exhibit overlapping nuclei, finely gran-  ular chromatin, scant cytoplasm, indistinct cell borders, and  brisk mitotic activity. MCPyV-positive lesions tend to have  uniformly round nuclei, whereas MCPyV-negative cases  often exhibit irregular nuclei. Intracytoplasmic argyrophilic    granules may be demonstrated by the Grimelius stain, and  immunohistochemical staining for cytokeratin 20 (CK20)  usually shows a “perinuclear dot” pattern. Immunopositiv-  ity for neuroendocrine markers (e.g., chromogranin A, syn-  aptophysin, neuron-specific enolase, and CD56) and  neurofilament also may be helpful in establishing the diag-  nosis. In approximately 70% to 80% of cases, MCPyV  DNA is detectable by polymerase chain reaction (PCR).  Lack of immunoreactivity for thyroid transcription factor 1  (TTF-1) may help to exclude metastatic small cell carci-  noma of the lung, which may have similar histomorpho-  logic features. The microscopic differential diagnosis also  may include amelanotic melanoma, metastatic esthesioneu-  roblastoma, lymphoma, and other “round-cell” malignan-  cies. Immunohistochemical studies and thorough physical  examination may aid in excluding these other entities. Fur-  thermore, Merkel cell carcinomas may occur in combina-  tion with other neoplasms, especially actinic keratosis and  invasive or in situ squamous cell carcinoma.    Surgery (i.e., wide local excision or Mohs micrographic  surgery) is the mainstay of treatment and often is combined  with adjuvant radiotherapy. Lymph node dissection is per-  formed when clinically palpable nodes are found. Sentinel  lymph node biopsy typically is used to determine whether  regional lymph node dissection and/or radiation are indi-  cated in patients with clinically negative nodes. Chemo-  therapy is reserved for cases with distant metastasis. Immune  reconstitution by combination antiretroviral therapy is  important for controlling Merkel cell carcinoma in patients  with HIV infection. Also, in some cases, tumor regression  has been reported after cessation of immunosuppressive  therapy.   Recurrence develops in 55% of cases, most commonly  within the draining lymph nodes. ‘The relative 10-year sur-  vival rates for patients with localized, regional, and distant  disease are 71%, 48%, and 20%, respectively. The overall  10-year survival rate is approximately 57%. Female sex,    upper limb involvement, and age under 70 years are positive  predictors of survival. Primary mucosal lesions exhibit a  worse prognosis than the more common, primary cutane-  ous lesions. Similarly, lip lesions may have a worse prognosis  than those arising in more frequently involved head and  neck sites. There is some controversy regarding whether  tumor positivity for MCPyV represents a favorable prog-  nostic factor.   Approximately 25% of patients with Merkel cell carci-  noma develop additional malignancies (e.g., squamous cell  carcinomas of the skin, hematologic malignancies, or ade-  nocarcinomas of the breast or ovary). Thus these patients  should be monitored closely.    Melanoma is a malignant neoplasm of melanocytic origin;  it may arise de novo or from a preexisting benign melano-  cytic lesion. Most cases occur on the skin, although mucosal  lesions also are possible. UV radiation exposure from sun-  light is a major etiologic factor, with increased incidence of  melanoma among white populations as they approach the  equator. Acute sun damage may be of greater causative  importance than chronic exposure. Oral mucosal lesions, of  course, are not related to sun exposure.   Risk factors for melanoma include a fair complexion,  light-colored hair and eyes, a tendency to sunburn or freckle  easily, a history of painful or blistering sunburns in child-  hood, an indoor occupation with outdoor recreational  habits, a personal or family history of melanoma, a personal  history of dysplastic or congenital nevus, and a personal  history of excessive (>100) common nevi. Potential associa-  tions with tanning device use, immunosuppressive therapy  for organ transplantation, and various childhood malignan-  cies also have been proposed. Furthermore, among some  melanoma-prone kindreds, investigators have identified  mutations (e.g., in the cyclin-dependent kinase inhibitor 2A  [CDKN2A] and cyclin-dependent kinase 4 [CDK4] genes)  that confer a high risk for melanoma development. More-  over, recent genomic studies have identified numerous  genetic loci associated with a slightly- to moderately-  increased risk for melanoma (e.g., allelic variants in the key  pigmentation gene, melanocortin I receptor [MCIR)).   Melanoma represents the third most common skin  cancer. It accounts for less than 5% of total skin cancer cases  but 75% of skin cancer deaths. In the United States for the  year 2013, the American Cancer Society estimates that  76,690 new cases of cutaneous melanoma will be diagnosed  and 9,480 people will die of the disease. According to the  most recent estimate by the SEER Program, 1 in 50 persons  in the United States will be diagnosed with cutaneous mela-  noma during his or her lifetime. For 2009, the age-adjusted  annual incidence rates for skin melanoma were approxi-  mately 29 per 100,000 men and 18 per 100,000 women.  Over the past several decades, dramatic increases in the    incidence of melanoma have been reported worldwide.  Some investigators contend that this trend reflects increased  numbers of skin biopsies and improved diagnosis of early-  stage disease. However, others have demonstrated increased  frequency of both early- and late-stage disease and, thus,  propose that there is a true increase in disease rate. Despite  increasing incidence, the mortality rate for cutaneous mela-  noma has remained relatively constant since the late 1980s,  apparently because a large proportion of cases are diagnosed  at an early stage.   According to the National Cancer Database Report on  Cutaneous and Noncutaneous Melanoma, 91.2% of all mela-  nomas arise on the skin, whereas ocular, mucosal, and  unknown primaries account for 5.2%, 1.3%, and 2.2% of  cases, respectively. Almost 25% of cutaneous melanomas  arise in the head and neck area, 40% on the extremities,  and the rest on the trunk. More than half of mucosal mela-  nomas occur in the head and neck (including the oral and  sinonasal regions), with the remainder primarily involving  the urogenital and anorectal mucosa. Importantly, mucosal  melanoma is much more aggressive than its cutaneous  counterpart.   Oral mucosal melanoma is rare in the United States,  where it occurs in only 1.2 per 10 million population annu-  ally and comprises much less than 1% of all melanomas.  An analysis of various worldwide cancer registries has shown  similarly low incidence rates, with primary oral melanoma  accounting for only 0.26% of all oral cavity cancers. Several  reports suggest that mucosal melanoma is more frequent in  certain countries, such as Japan and Uganda; however, other  investigators have suggested that the true incidence of  mucosal melanoma is not greater in these countries but only  appears so because of the comparatively low incidence of  cutaneous melanoma in these racial groups.   In recent years, there have been many discoveries  regarding recurrent genetic alterations in melanomas,  including those involving the Ras/Raf/MEK/mitogen-  activating protein kinase (MAPK) and phosphatidylinositol  3-kinase (PI3K)/AKT signaling pathways. In particular,  approximately 50% of melanomas possess mutations in the  gene encoding BRAE£ a protein kinase involved in the Ras/  Raf/MEK/MAPK pathway. Among mucosal melanomas,  frequent alterations have been identified in the KIT gene,  which encodes a receptor tyrosine kinase that interacts  with Ras.    Cutaneous melanomas most commonly develop in white  adults. Although the lesion occurs over a broad age range,  most cases arise in individuals 45 through 84 years old, with  a median age at diagnosis of 61 years. There is a female  predilection among patients younger than 40 years (possibly  related to tanning bed use); in contrast, a male predilection  is seen among older patients. The most frequent primary  site in men is the back, whereas in women the lower extrem-  ities are affected most commonly. Because many clinical    Asymmetry (because of its uncontrolled growth pattern)  Border irregularity (often with notching)   Color variegation (which varies from shades of brown to  black, white, red, and blue, depending on the amount and  depth of melanin pigmentation)   Diameter greater than 6 mm (which is the diameter of a  pencil eraser)   Evolving (lesions that have changed with respect to size,  shape, color, surface, or symptoms over time)    similarities exist between cutaneous melanoma and its  benign counterpart, the melanocytic nevus, an “ABCDE”  clinical evaluation system has been developed to help dis-  tinguish between these two entities (Box 10-4).   The following major clinicopathologic types of mela-  noma are described below:  1. Superficial spreading melanoma  2. Nodular melanoma  3. Lentigo maligna melanoma  4, Acral lentiginous melanoma   Melanomas tend to exhibit two directional patterns of  growth: 1) the radial growth phase and 2) the vertical  growth phase. In the early stages, the radial growth phase  tends to predominate in lentigo maligna melanoma, super-  ficial spreading melanoma, and acral lentiginous melanoma.  In these lesions, the malignant melanocytes have a propen-  sity to spread horizontally through the basal layer of the  epidermis. Eventually, however, the malignant cells begin to  invade the underlying connective tissue, thus initiating the  vertical growth phase. In nodular melanoma, the radial  growth phase is very short or nonexistent, and the vertical  growth phase predominates.    Superficial spreading melanoma is the most common  form of melanoma, representing 70% of cutaneous lesions  (Fig. 10-137). The most common sites of origin are the  interscapular area of males and the back of the legs of  females. The lesion appears as a macule or plaque with a  variety of potential colors (i.e., tan, brown, gray, black, blue,  white, and pink). Typically, the lesion is smaller than 3 cm  in greatest diameter at diagnosis, but it may be several times  that size. Clinically, invasion is indicated by the appearance  of surface nodules or induration, and usually occurs within  1 year of discovery of the precursor macule. Satellites may  develop around the primary lesion.    Nodular melanoma represents 15% of cutaneous melano-  mas, and one-third of such lesions develop in the head and  neck. Nodular melanoma is thought to begin almost  immediately in the vertical growth phase; therefore, it typi-  cally appears as a nodular elevation that rapidly invades  the connective tissue. Nodular melanoma is usually    @ Fig. 10-137 Superficial Spreading Melanoma. This lesion on  the neck demonstrates the ABCDE warning signs of melanoma:  Asymmetry, Border irregularity, Color variegation, Diameter larger than  apencil eraser, and Evolving larger size. (Courtesy of Dr. Mark Bowden.)    ® Fig. 10-138 Lentigo Maligna Melanoma. A slowly evolving pig-  mented lesion of the facial skin in an older adult man.    deeply pigmented, although sometimes the melanoma  cells are so poorly differentiated that they no longer can  produce melanin, resulting in a nonpigmented amelanotic  melanoma.    Lentigo maligna melanoma, which accounts for 5% to  10% of cutaneous melanomas, develops from a precursor  lesion called lentigo maligna (Hutchinson freckle).  Lentigo maligna occurs almost exclusively on the sun-  exposed skin of fair-complexioned older adults, particularly  in the midfacial region, and represents a melanoma in situ  in a purely radial growth phase.   The lesion appears as a large, slowly expanding macule  with irregular borders and a variety of colors, including tan,  brown, black, and even white (Fig. 10-138). Patients usually  indicate that the lesion has been present and has slowly  expanded laterally for years. The average duration of the  radial growth phase is 15 years. The appearance of nodular-  ity within a lentigo maligna signals the onset of the invasive  or vertical growth phase and the transition to lentigo  maligna melanoma.    @ Fig. 10-139 Oral Melanoma. This discrete area of pigmentation,  measuring approximately 5 mm in diameter, was discovered on the  posterior hard palate of a middle-aged woman during a routine oral  examination. Biopsy revealed melanoma in situ.    Acral lentiginous melanoma is the most common form of  melanoma in blacks, and it is also the most common form  of oral melanoma. It typically develops on the palms of the  hands, soles of the feet, subungual area, and mucous mem-  branes. It begins as a dark, irregularly marginated macule,  which later develops a nodular invasive growth phase. Some  authorities have separated this lesion into two entities: 1)  acral lentiginous melanoma and 2) mucosal lentiginous  melanoma.   Oral melanoma is often nodular at the time of diagnosis,  but early lesions may be flat. There is a male predilection,  and affected persons are usually in their fifth through  seventh decades of life. Approximately 70% to 80% of oral  melanomas are found on the hard palate or maxillary alveo-  lus. At least one in three patients with oral melanoma has  a history of a pigmented macule in the tumor region for  some time before melanoma diagnosis. The lesion typically  begins as a brown to black macule with irregular borders  (Figs. 10-139 and 10-140). However, some lesions contain  little pigment and exhibit either a normal mucosal tint or  a vascular appearance. The macule extends laterally, and a  lobulated, exophytic mass develops once vertical growth is  initiated (Fig. 10-141). Ulceration may develop early, but  many lesions are not ulcerated at the time of diagnosis. Pain  is uncommon except in ulcerated lesions, and most lesions  remain relatively soft to palpation. Adjacent bone may show  radiographic evidence of irregular or “moth-eaten” destruc-  tion. Cervical lymph node metastasis often is evident at  initial presentation. In addition, melanoma occasionally  affects the parotid gland, usually as a metastatic deposit  from a scalp, conjunctival, or paranasal tumor.    With cutaneous and oral melanomas, atypical melanocytes  initially are seen at the epithelial and connective tissue    @ Fig. 10-140 Oral Melanoma. Diffuse, splotchy area of pigmenta-  tion of the lateral hard palate. (Courtesy of Dr. Len Morrow.)    junction. From here, they have the potential to proliferate  throughout the epithelium, laterally along the basal cell  layer, and downward into the connective tissue. In early  stages, atypical melanocytes are seen either scattered singly  among the basal epithelial cells or as nests within the basal  cell layer. The atypical melanocytes are enlarged, with varying  degrees of nuclear pleomorphism and hyperchromatism.   In superficial spreading melanoma, there is often pagetoid  spread (i.e., single tumor cells infiltrating into the upper  layers of the surface epithelium) (Fig. 10-142). This micro-  scopic pattern resembles an intraepithelial adenocarcinoma  known as Paget’s disease of skin.   The spread of the lesional cells along the basal layer of  the surface epithelium constitutes the radial growth phase.  Appreciable lateral spread prior to invasion of the underly-  ing connective tissue is characteristic of superficial spreading  melanoma, lentigo maligna melanoma, and acral lentigi-  nous melanoma. In acral lentiginous melanoma, many of  the melanocytes have prominent dendritic processes (Fig.  10-143).   The vertical growth phase is characterized by malignant  melanocytes invading the connective tissue. In nodular    ® Fig. 10-142  phase is characterized by the spread of atypical melanocytes along  the basilar portion of the epidermis. Also note the presence of indi-  vidual melanocytes invading the higher levels of the epithelium.    @ Fig. 10-143 Acral Lentiginous Melanoma. This palatal mela-  noma demonstrates numerous atypical melanocytes in the basilar  portion of the epithelium with invasion into the superficial lamina  propria. This represents the biopsy specimen from Fig. 10-140.    melanoma, this vertical growth phase occurs early in the  disease course. No radial growth can be observed in the  overlying epithelium beyond the edge of the invasive tumor  (Fig. 10-144). The tumor usually appears as pleomorphic,  spindle-shaped or epithelioid cells arranged in loosely aggre-  gated cords or sheets. Oral lesions show invasion of  lymphatic and blood vessels more often than skin  lesions. Several mucosal melanomas have been reported to  contain unequivocal bone and cartilage, a feature that may  cause diagnostic confusion with pleomorphic adenoma,  sarcomatoid carcinoma, osteosarcoma, and mesenchymal  chondrosarcoma.   Approximately 10% of oral melanomas are amelanotic.  A lack of melanin production may cause diagnostic confu-  sion with various other undifferentiated tumors at the light  microscopic level. Immunohistochemical studies showing  reactivity for S-100 protein, HMB-45, MART-1 (Melan-  A), and microphthalmia-associated transcription factor  (Mitf) may aid in diagnosis.    NaN - a LIF oer  @ Fig. 10-144 Nodular Melanoma. A, Low-power photomicrograph  showing a nodular mass of malignant melanocytes invading into the  dermis. Note the lack of radial growth in the adjacent overlying epider-  mis. B, Higher-power photomicrograph showing atypical spindle-  shaped melanocytes.    Depth of invasion is an important prognostic factor for  cutaneous melanoma. The Clark system assigns a “level”  corresponding to the deepest region that has been invaded  by tumor cells (Table 10-6). The more recent Breslow clas-  sification, however, correlates more accurately with progno-  sis and is based on measurement of the distance from the  top of the granular cell layer to the deepest identifiable point  of tumor invasion.   Clinical staging for cutaneous melanoma is performed  using a TNM classification system that takes into account  Breslow tumor thickness, ulceration, regional metastasis,  and distant metastasis (Table 10-7). In addition, mitotic  activity is considered in subclassifiying T1 (or “thin”) mela-  nomas, and the serum level of lactate dehydrogenase (LDH)  considered in subclassifying cases with distant metastasis.   Surgical excision is the mainstay of treatment. Current  evidence indicates that a 1-cm margin is adequate for cuta-  neous tumors with a thickness of 1 mm or less. For more  deeply invasive tumors, wide surgical excision with at least  2-cm margins typically is recommended. However, in aes-  thetically sensitive areas, 1-cm margins may be acceptable  for lesions thinner than 2 mm.    ES Clark's Classification for Cutaneous Lymph node dissection usually is performed on patients  Melanoma with clinically evident regional metastasis in the absence of    distant metastasis. Elective lymph node dissection for  patients with intermediate thickness (1 to 4 mm) lesions in  the absence of clinically palpable nodes is somewhat con-  troversial. The rationale for this procedure is that these  patients have a high probability of occult regional nodal  disease and low probability of distant metastasis. However,  Cells filling papillary dermis Level Ill the reported survival benefit of this strategy is variable, and  significant morbidity can be associated with lymph node  dissection. To address this problem, sentinel-node biopsy  Cells invading subcutaneous fat Level V (biopsy of the first lymph node in the lymphatic basin to    10-7 Tumor-node-metastasis (TNM) Classification System and Stage Groupings for Cutaneous Melanoma    TX NA (Primary tumor cannot be assessed [e.g.,  curettaged or severely regressed melanoma))  TO No evidence of primary tumor  Tis Melanoma in situ  T1 Melanomas 1.0 mm or less in thickness a: w/o ulceration and mitosis <1/mm?  b: With ulceration or mitoses =1/mm?  2 Melanomas 1.01-2.0 mm a: w/o ulceration  b: With ulceration  Ts Melanomas 2.01-4.0 mm a: w/o ulceration  b: With ulceration  T4 Melanomas more than 4.0 mm a: w/o ulceration  b: With ulceration    NX Patients in whom the regional lymph nodes cannot be  assessed (@.g., previously removed for another reason)    NO No regional metastases detected  N41 1 node a: Micrometastasis*  b: Macrometastasis'  N2 2-3 nodes a: Micrometastasis*  b: Macrometastasis'  c: In transit met(s)/satellite(s) without  metastatic nodes  N38 4 or more metastatic nodes, or matted nodes, or in    Stage O Tis NO MO  Stage IA T1a NO MO 97%  Stage IB T1b NO MO 94%  T2a NO MO 91%  Stage IIA T2b NO MO 82%  T3a NO MO 79%  Stage IIB T3b NO MO 68%  T4a NO MO 71%  Stage IIC T4b NO MO 53%  Stage Ill Any T = N1 MO 40% to 78%  Stage IV Any T Any N M1 about 15% to 20%    From Melanoma of the skin. In Edge SB, Byrd DR, Compton CC, et al, editors, AJCC cancer staging manual, ed 7, New York, 2010, Springer, pp 325-344.  *Micrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed).  tMacrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross    In transit metastases defined arbitrarily as clinically evident cutaneous and/or subcutaneous metastases identified at a distance greater than 2 cm from the  primary melanoma in the region between the primary and the first echelon of regional lymph nodes.  Satellite metastases defined arbitrarily as grossly visible cutaneous and/or subcutaneous metastases occurring within 2 cm of the primary melanoma.    alternative to elective lymph node dissection to identify  patients with occult nodal metastases who would benefit  from total lymphadenectomy.   Most patients with early-stage lesions are cured by  surgery alone. However, adjuvant radiation therapy or  immunotherapy (often with interferon-alpha) may be con-  sidered for certain subsets of patients at high risk for recur-  rence. For patients with distant metastasis, various agents  (e.g., high-dose interleukin-2 [IL-2], dacarbazine, imatinib,  and paclitaxel) have been tried with limited success. Notably,  in 2011 the United States Food and Drug Administration  approved two novel treatments for metastatic melanoma:  vemurafenib (a BRAF inhibitor) and ipilimumab (a mono-  clonal antibody that promotes T-cell antitumoral activity by  blocking cytotoxic T-lymphocyte-associated antigen 4  [CTLA-4]). These recent developments in genotype-  directed and immunotherapy have led to prolonged survival  for patients with advanced disease and likely will form the  foundation for the next generation of therapies for meta-  static melanoma.   The 5-year survival rates for patients with cutaneous  melanomas that are thin and confined to the skin exceed  90%, whereas patients with regional or distant metastasis  exhibit 5-year survival rates of approximately 40% to 78%    and 15 to 20%, respectively (see Table 10-7). Primarily as  a result of public education efforts, the clinical features of  cutaneous melanoma are so widely known that the majority  of lesions are discovered and treated at an early stage.   Other factors may influence outcome besides the depth  of invasion. For reasons that are unclear, cutaneous mela-  nomas on the trunk, head, and neck carry a worse prognosis  than those on the extremities. In particular, among head  and neck lesions, those arising on the scalp and neck are  associated with decreased survival rates. In contrast, positive  prognostic factors include age younger than 50 years and  female gender. Follow-up after treatment is important not  only to monitor for metastatic disease but also because, in  3% to 5% of these patients, a second primary melanoma  eventually will develop.   For mucosal melanomas of the head and neck, TNM  classification takes into account the anatomic extent of the  primary tumor (ie., confined to mucosa or invading adja-  cent structures), regional lymph node metastasis, and distant  metastasis (Table 10-8). Because head and neck mucosal  lesions typically exhibit aggressive behavior, they are classi-  fied at a minimum as stage III. For patients with stage III  or IVb disease, radical surgery is indicated and often is  combined with adjunctive radiation therapy. Patients with    i7\=j8=) Tumor-node-metastasis (TNM) Classification System and Stage Groupings for Mucosal Melanoma  ules of the Head and Neck    T4a Moderately advanced disease  Tumor involving deep soft tissue, cartilage, bone, or overlying skin    T4b Very advanced disease  Tumor involving brain, dura, skull base, lower cranial nerves (IX, X, Xl, and XIl),  masticator space, carotid artery, prevertebral space, or mediastinal structures    NX Regional lymph nodes cannot be assessed  NO No regional lymph node metastases  N41 Regional lymph node metastases present  MO No distant metastasis  M1 Distant metastasis present  Stage Ill T3 NO MO  Stage IVA T4a NO MO  T3-4a N1 MO  Stage IVB T4b any N MO  Stage IVC Any T Any N M1    From Mucosal melanoma of the head and neck. In Edge SB, Byrd DR, Compton CC, et al, editors: AJCC cancer staging manual, ed 7, New York, 2010,    stage [Vb or IVc disease should strongly consider clinical  trial participation. Because KJT mutations often are present  in mucosal melanomas, clinical trials evaluating tyrosine  kinase inhibitors (such as, imatinib) are of particular  interest.   The prognosis for oral melanoma is extremely poor. Most  authors report 5-year survival rates in the range of only 10%  to 25%. Death usually results from distant metastasis rather  than lack of local control. The poor prognosis for oral mela-  noma appears to be related to difficulty in achieving wide  resection and a tendency for early metastasis. Younger  patients exhibit better survival than older ones, and patients  with amelanotic lesions appear to have a particularly poor  prognosis. There is generally a marked deterioration in  prognosis among patients with oral mucosal melanomas  exceeding a depth of 0.5 mm, although depth of invasion  and presence of ulceration are not so closely correlated with  prognosis of mucosal melanomas compared to cutaneous  melanomas.   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The  condition may occur alone, although agenesis of the glands  is often a component of one of several syndromes, including  mandibulofacial dysostosis (Treacher Collins syndrome; see  page 41), hemifacial microsomia, and lacrimo-auriculo-  dento-digital (LADD) syndrome.    Salivary gland aplasia has been reported more frequently in  males than females by a 2:1 ratio. Some individuals are  affected by agenesis of all four of the largest glands (both  parotids and submandibular glands), but others may be  missing only one to three of the four glands. In spite of the  absence of the glands, the face still has a normal appearance  because the sites are filled in by fat or connective tissue.  Intraorally, the orifices of the missing glands are absent.  Some patients also may exhibit absence of the lacrimal  glands or lacrimal puncta.   As would be anticipated, the most significant symptom  associated with salivary gland aplasia is severe xerostomia  with its attendant problems (see page 432). The tongue may  appear leathery, and the patient is at greater risk for develop-  ing dental caries and erosion (Fig. 11-1). However, some  degree of moisture still may be present because of the con-  tinued activity of the minor salivary glands. Absence of the  major glands can be confirmed by technetium-99m pertech-  netate scintiscan, computed tomography (CT), magnetic  resonance imaging (MRI), or ultrasonography.   LADD syndrome is an autosomal dominant disorder  that is caused by mutations in the fibroblast growth factor  10 (FGF1O) gene. It is characterized by aplasia or hypoplasia  of the lacrimal and salivary glands, cup-shaped ears, hearing  loss, and dental and digital anomalies. Dental features may  include hypodontia, microdontia, and mild enamel  hypoplasia.    Patient management is directed toward compensating for  the saliva deficiency, and saliva substitutes are often    necessary. If any residual functional salivary gland tissue is  present, then sialagogue medications (such as, pilocarpine  or cevimeline) may be used to increase saliva production.  Salivary flow also may be stimulated via the use of sugarless  gum or sour candy. Regular preventive dental care is im-  portant to avoid xerostomia-related caries and enamel    The mucocele is a common lesion of the oral mucosa that  results from rupture of a salivary gland duct and spillage of  mucin into the surrounding soft tissues. This spillage is  often the result of local trauma, although there is no known  history of trauma in many cases. Unlike the salivary duct  cyst (see page 425), the mucocele is not a true cyst because  it lacks an epithelial lining. Some authors, however, have  included true salivary duct cysts in their reported series of  mucoceles, sometimes under the classification of retention  mucocele or mucus retention cyst. Because these two entities  exhibit distinctly different clinical and histopathologic fea-  tures, they are discussed as separate topics in this chapter.    Mucoceles typically appear as dome-shaped mucosal swell-  ings that can range from | or 2 mm to several centimeters  in size (Figs. 11-2 to 11-4). They are most common in  children and young adults, perhaps because younger people  are more likely to experience trauma that induces mucin  spillage. However, mucoceles have been reported in patients  of all ages, including infants and older adults. The spilled  mucin below the mucosal surface often imparts a bluish  translucent hue to the swelling, although deeper mucoceles  may be normal in color. The lesion characteristically is  fluctuant, but some mucoceles feel firmer to palpation. The  reported duration of the lesion can vary from a few days to  several years; most patients report that the lesion has been  present for several weeks. Many patients relate a history of  a recurrent swelling that periodically may rupture and  release its fluid contents.    ® Fig. 11-1 Salivary Gland Aplasia. Dry, leathery tongue and diffuse  enamel erosion in a child with aplasia of the major salivary glands.    The lower lip is by far the most common site for the  mucocele; a recent large study of 1715 cases found that  81.9% occurred at this one site (Table 11-1). Lower lip  mucoceles usually are found lateral to the midline. Less  common sites include the floor of mouth (ranulas: 5.8%),  anterior ventral tongue (from the glands of Blandin-Nuhn:  5.0%), buccal mucosa (4.8%), palate (1.3%), and retro-  molar pad (0.5%). Mucoceles rarely develop on the upper  lip. In the large series summarized in Table 11-1, not a  single example was identified from the upper lip. This is  in contrast to salivary gland tumors, which are not unusual  in the upper lip but are distinctly uncommon in the  lower lip.   As noted, the soft palate and retromolar area are uncom-  mon sites for mucoceles. However, one interesting variant,  the superficial mucocele, does develop in these areas and  along the posterior buccal mucosa. Superficial mucoceles  present as single or multiple tense vesicles that measure 1  to 4 mm in diameter (Fig. 11-5). The lesions often burst,  leaving shallow, painful ulcers that heal within a few days.  Repeated episodes at the same location are not unusual.  Some patients relate the development of the lesions to  mealtimes. Superficial mucoceles also have been reported to    Data from Chi AC, Lambert PR 3rd, Richardson MS, et al: Oral muco-  celes: a clinicopathologic review of 1,824 cases, including unusual vari-  ants, J Oral Maxillofac Surg 69:1086-1098, 2011.    @ Fig. 11-5 Superficial Mucocele. Vesicle-like lesion on the soft  palate.    occur in association with lichenoid disorders, such as lichen  planus, lichenoid drug eruptions, and chronic graft-versus-  host disease (GVHD). The vesicular appearance is created  by the superficial nature of the mucin spillage, which causes  a separation of the epithelium from the connective tissue.  The pathologist must be aware of this lesion and should not  mistake it microscopically for a vesiculobullous disorder,  especially mucous membrane pemphigoid.    On microscopic examination, the mucocele shows an area  of spilled mucin surrounded by a granulation tissue response  (Figs. 11-6 and 11-7). The inflammation usually includes  numerous foamy histiocytes (macrophages). In some cases,  a ruptured salivary duct may be identified feeding into the  area. The adjacent minor salivary glands often contain a  chronic inflammatory cell infiltrate and dilated ducts.    Some mucoceles are short-lived lesions that rupture and  heal by themselves. Many lesions, however, are chronic in  nature, and local surgical excision is necessary. To minimize  the risk of recurrence, the surgeon should remove any adja-  cent minor salivary glands that may be feeding into the  lesion when the area is excised. The excised tissue should be  submitted for microscopic examination to confirm the diag-  nosis and rule out the possibility of a salivary gland tumor.  The prognosis is excellent, although occasional mucoceles  will recur, necessitating reexcision, especially if the feeding  glands are not removed.    Ranula is a term used for mucoceles that occur in the floor  of the mouth, arising from the sublingual gland. The name  is derived from the Latin word rana, which means “frog,”  because the swelling may resemble a frog’s translucent  underbelly. The term ranula also has been used to describe    e Fig. 11-6 Mucocele. Mucin-filled cystlike cavity beneath the  mucosal surface. Minor salivary glands are present below and lateral  to the spilled mucin.    @ Fig. 11-7 Mucocele. High-power view showing spilled mucin that  is associated with granulation tissue containing foamy histiocytes.    other similar swellings in the floor of the mouth, including  true salivary duct cysts, dermoid cysts, and cystic hygromas.  However, the term is best used for mucus escape reactions  (mucoceles).   The sublingual gland has a complex anatomy. ‘The lesser  sublingual gland actually consists of 15 to 30 smaller glands,  each secreting through a short duct of Rivinus to the sub-  lingual plica. Some individuals also have a greater sublin-  gual gland with an excretory duct (Bartholin duct) that  either joins with Wharton duct or opens next to it at the  sublingual caruncle. Unlike the submandibular gland, the  sublingual gland produces a continuous flow of mucus even  in the absence of neural stimulation, which accounts for its    e Fig. 11-8 Ranula. Blue-pigmented swelling in the left floor of the  mouth.    ability to produce a ranula after rupture of one of its mul-  tiple ducts.    The ranula usually appears as a blue, dome-shaped, fluctu-  ant swelling in the floor of the mouth (Fig. 11-8), but  deeper lesions may be normal in color. Ranulas are seen  most frequently in children and young adults. They tend to  be larger than mucoceles in other oral locations, often devel-  oping into large masses that fill the floor of the mouth and  elevate the tongue. The ranula usually is located lateral to  the midline, a feature that may help to distinguish it from  a midline dermoid cyst (see page 30). Like other mucoceles,  ranulas may rupture and release their mucin contents, only  to re-form.   An unusual clinical variant, the plunging or cervical  ranula, occurs when the spilled mucin dissects through the  mylohyoid muscle and produces swelling within the neck  (Fig. 11-9). A concomitant swelling in the floor of the  mouth may or may not be present. If no lesion is produced  in the mouth, then the clinical diagnosis of ranula may not  be suspected. Imaging studies can be helpful in supporting  a diagnosis of plunging ranula and in determining the origin  of the lesion. CT and MRI images of plunging ranulas from  the sublingual gland often exhibit a slight extension of the  lesion into the sublingual space, known as a “tail sign.”    The microscopic appearance of a ranula is similar to that of  a mucocele in other locations. The spilled mucin elicits a  granulation tissue response that typically contains foamy  histiocytes.    Treatment of the ranula consists of removal of the feeding  sublingual gland and/or marsupialization. Marsupialization    (exteriorization) entails removal of the roof of the intraoral  lesion, which often can be successful for small, superficial  ranulas. However, marsupialization is often unsuccessful for  larger ranulas, and most authors emphasize that removal of  the offending gland is the most important consideration in  preventing a recurrence of the lesion. If the gland is removed,  then meticulous dissection of the lining of the lesion may  not be necessary for the lesion to resolve, even for the plung-  ing ranula. If the specific portion of the sublingual gland  giving rise to the lesion can be identified, then partial exci-  sion of the gland may be successful.    ¢ SALIVARY DUCT CYST (MUCUS  RETENTION CYST; MUCUS DUCT  CYST; SIALOCYST)    The salivary duct cyst is an epithelium-lined cavity that  arises from salivary gland tissue. Unlike the more common  mucocele (see page 422), it is a true developmental cyst  that is lined by epithelium that is separate from the adja-  cent normal salivary ducts. The cause of such cysts is  uncertain.   Cystlike dilatation of salivary ducts also may develop  secondary to ductal obstruction (e.g., mucus plug), which  creates increased intraluminal pressure. Although some  authors refer to such lesions as mucus retention cysts, such  lesions probably represent salivary ductal ectasia rather than  a true cyst.    Salivary duct cysts usually occur in adults and can arise  within either the major or minor glands. Cysts of the major  glands are most common within the parotid gland, present-  ing as slowly growing, asymptomatic swellings. Intraoral  cysts can occur at any minor gland site, but most frequently  they develop in the floor of the mouth, buccal mucosa, and  lips (Fig. 11-10). They often look like mucoceles and are  characterized by a soft, fluctuant swelling that may appear  bluish, depending on the depth of the cyst below the  surface. Some cysts may feel relatively firm to palpation.  Cysts in the floor of the mouth often arise adjacent to the  submandibular duct and sometimes have an amber color.  On rare occasions, patients have been observed to  develop prominent ectasia of the excretory ducts of many  of the minor salivary glands throughout the mouth. Such  lesions have been termed “mucus retention cysts,” although  they probably represent multifocal ductal dilatation. The    e Fig. 11-10 Salivary Duct Cyst. Nodular swelling overlying  Wharton duct.    individual lesions often present as painful nodules that  demonstrate dilated ductal orifices on the mucosal surface.  Mucus or pus may be expressed from these dilated ducts.    The lining of the salivary duct cyst is variable and may  consist of cuboidal, columnar, or atrophic squamous epi-  thelium surrounding thin or mucoid secretions in the  lumen (Fig. 11-11). In contrast, ductal ectasia secondary to  salivary obstruction is characterized by oncocytic metaplasia  of the epithelial lining. This epithelium often demonstrates  papillary folds into the cystic lumen, somewhat reminiscent  of a small Warthin tumor (see page 449) but without the  prominent lymphoid stroma (Fig. 11-12). If this prolifera-  tion is extensive enough, then these lesions sometimes are  diagnosed as papillary cystadenoma, although it seems  likely that most are not true neoplasms. The individual    @ Fig. 11-12 Oncocytic Salivary Ductal Ectasia. This dilated duct  is lined by columnar eosinophilic oncocytes that exhibit papillary folds  into the ductal lumen. Such lesions may develop secondary to ductal    @ Fig. 11-11 Salivary Duct Cyst. A, Low-power photomicrograph showing a cyst below the mucosal  surface. B, High-power view of cystic cavity (top) lined by thin cuboidal epithelium. Adjacent to the cyst  is an excretory salivary gland duct lined by columnar epithelium (bottom).    Isolated salivary duct cysts are treated by conservative surgi-  cal excision. For cysts in the major glands, partial or total  removal of the gland may be necessary. The lesion should  not recur.   For rare patients who develop multifocal salivary ductal  ectasia (“mucus retention cysts”), local excision may be per-  formed for the more problematic swellings; however, surgi-  cal management does not appear feasible or advisable for all  of the lesions, which may number as many as 100. In one  reported case, systemic erythromycin and chlorhexidine  mouth rinses were helpful in relieving pain and reducing  drainage of pus. Sialagogue medications also may be helpful  in stimulating salivary flow, thereby preventing the accumu-  lation of inspissated mucus within the dilated excretory  ducts.    Sialoliths are calcified structures that develop within the  salivary ductal system. Researchers believe that they arise  from deposition of calcium salts around a nidus of debris  within the duct lumen. This debris may include inspis-  sated mucus, bacteria, ductal epithelial cells, or foreign  bodies. The cause of sialoliths is unclear, but their forma-  tion can be promoted by chronic sialadenitis and partial  obstruction. Their development typically is not related to  any systemic derangement in calcium and phosphorus  metabolism.    Sialoliths most often develop within the ductal system of  the submandibular gland, which accounts for about 80%  of cases; the formation of stones within the parotid gland  system is distinctly less frequent. The long, tortuous, upward  path of the submandibular (Wharton) duct and the thicker,  mucoid secretions of this gland may be responsible for its  greater tendency to form salivary calculi. Sialoliths also can  form within the minor salivary glands, most often within  the glands of the upper lip or buccal mucosa. Salivary stones  can occur at almost any age, but they are most common in  young and middle-aged adults.   Major gland sialoliths most frequently cause episodic  pain or swelling of the affected gland, especially at meal-  time. The severity of the symptoms varies, depending on  the degree of obstruction and the amount of resultant back-  pressure produced within the gland. If the stone is located  toward the terminal portion of the duct, then a hard mass  may be palpated beneath the mucosa (Fig. 11-13).    e Fig. 11-13 Sialolithiasis. Hard mass at the orifice of Wharton  duct.    e Fig. 11-14 Sialolithiasis. Radiopaque mass located at the left  angle of the mandible. (Courtesy of Dr. Roger Bryant.)    Sialoliths typically appear as radiopaque masses on radio-  graphic examination. However, not all stones are visible  on standard radiographs (perhaps because of the degree of  calcification of some lesions). They may be discovered  anywhere along the length of the duct or within the gland  itself (Fig. 11-14). Stones in the terminal portion of the  submandibular duct are best demonstrated with an occlusal  radiograph. On panoramic or periapical radiographs, the  calcification may appear superimposed on the mandible and  care must be exercised not to confuse it with an intrabony  lesion (Fig. 11-15). Multiple parotid stones radiographically  can mimic calcified parotid lymph nodes, such as might  occur in tuberculosis. Sialography, ultrasound, and CT  scanning may be helpful additional imaging studies for  sialoliths. Diagnostic sialendoscopy also can be a valuable  tool in the evaluation and diagnosis of ductal obstructions.  In this technique, a miniaturized endoscope is inserted into  the duct orifice, allowing visualization of the ductal system  for any stones, strictures, or adhesions.   Minor gland sialoliths often are asymptomatic but may  produce local swelling or tenderness of the affected gland  (Fig. 11-16). A small radiopacity often can be demonstrated  with a soft tissue radiograph.    On gross examination, sialoliths appear as hard masses that  are round, oval, or cylindrical. They are typically yellow,    @ Fig. 11-15 Sialolithiasis. A, Periapical film showing discrete radi-  opacity (arrow) superimposed on the body of the mandible. Care must  be taken not to confuse such lesions with intrabony pathosis.  B, Occlusal radiograph of same patient demonstrating radiopaque  stone in Wharton duct.    although they may be a white or yellow-brown color. Sub-  mandibular stones tend to be larger than those of the  parotid or minor glands. Sialoliths are usually solitary,  although occasionally two or more stones may be discovered  at surgery.   Microscopically, the calcified mass exhibits concentric  laminations that may surround a nidus of amorphous debris  (Fig. 11-17). If the associated duct also is removed, then it    ® Fig. 11-16 Sialolithiasis. A, Minor salivary gland sialolith present-  ing as a hard nodule in the upper lip. B, A soft tissue radiograph of  the same lesion revealed a laminated calcified mass.    @ Fig. 11-17 Sialolithiasis. Intraductal calcified mass showing con-  centric laminations. The duct exhibits squamous metaplasia.    often demonstrates squamous, oncocytic, or mucous cell  metaplasia. Periductal inflammation is also evident. The  ductal obstruction frequently is associated with an acute or  chronic sialadenitis of the feeding gland.    Small sialoliths of the major glands sometimes can be  treated conservatively by gentle massage of the gland in an    effort to milk the stone toward the duct orifice. Sialagogues  (drugs that stimulate salivary flow), moist heat, and increased  fluid intake also may promote passage of the stone. Larger  sialoliths usually need to be removed surgically. If significant  inflammatory damage has occurred within the feeding  gland, then the gland may need to be removed. Minor gland  sialoliths are best treated by surgical removal, including the  associated gland.   Extracorporeal shock wave lithotripsy and interventional  sialendoscopy with basket retrieval are newer techniques  that can be effective in the removal of sialoliths from the  major glands. These minimally invasive techniques have low  morbidity and may preclude the necessity of gland removal.    Inflammation of the salivary glands (sialadenitis) can arise  from various infectious and noninfectious causes. The most  common viral infection is mumps (see page 238), although  a number of other viruses also can involve the salivary  glands, including Coxsackie A, ECHO, choriomeningitis,  parainfluenza, human immunodeficiency virus (HIV), and  cytomegalovirus (CMY) (in neonates). Most bacterial infec-  tions arise as a result of ductal obstruction or decreased sali-  vary flow, allowing retrograde spread of bacteria throughout  the ductal system. Blockage of the duct can be caused by  sialolithiasis (see page 427), congenital strictures, or com-  pression by an adjacent tumor. Decreased flow can result  from dehydration, debilitation, or medications that inhibit  secretions.   One of the more common causes of sialadenitis is recent  surgery (especially abdominal surgery), after which an acute  parotitis (surgical mumps) may arise because the patient has  been kept without food or fluids (NPO) and has received  atropine during the surgical procedure. Other medications  that produce xerostomia as a side effect also can predispose  patients to such an infection. Most community-acquired  cases of acute bacterial sialadenitis are caused by Staphylococ-  cus aureus or streptococcal species. Hospital-acquired infec-  tions are also most frequently associated with S. aureus, but  they also may be caused by a variety of other species, includ-  ing Eikenella corrodens, Escherichia coli, Fusobacterium, Hae-  mophilus influenzae, Klebsiella, Prevotella, Proteus, and  Pseudomonas. Noninfectious causes of salivary inflamma-  tion include Sjégren syndrome (see page 434), sarcoidosis  (see page 310), radiation therapy (see page 266), and various  allergens.    Acute bacterial sialadenitis is most common in the parotid  gland and is bilateral in 10% to 25% of cases. The affected  gland is swollen and painful, and the overlying skin may be  warm and erythematous (Fig. 11-18). An associated low-  grade fever and trismus may be present. A purulent dis-  charge often is observed from the duct orifice when the  gland is massaged (Fig. 11-19).    @ Fig. 11-19 Sialadenitis. A purulent exudate can be seen arising  from Stensen duct when the parotid gland is massaged.    Recurrent or persistent ductal obstruction (most com-  monly caused by sialoliths) can lead to a chronic sialadeni-  tis. Periodic swelling and pain occur within the affected  gland, usually developing at mealtime when salivary flow  is stimulated. Sialography often demonstrates sialectasia  (ductal dilatation) proximal to the area of obstruction (Fig.  11-20). In chronic parotitis, Stensen duct may show a char-  acteristic sialographic pattern known as “sausaging,” which  reflects a combination of dilatation plus ductal strictures  from scar formation. Chronic sialadenitis also can occur in  the minor glands, possibly as a result of blockage of ductal  flow or local trauma.   Juvenile recurrent parotitis is the most common  inflammatory salivary disorder of children in the United  States and the second most common such disorder world-  wide (following mumps). It is characterized by recurring  episodes of unilateral or bilateral, non-suppurative parotid  swelling, usually beginning between the ages of 3 and 6  years. The exact cause is unknown, although congenital  duct malformations, genetic factors, immunologic disor-  ders, and dental malocclusion have been suggested as pos-  sible contributing factors. Although multiple recurrences  often develop, the condition usually resolves around the  time of puberty.    @ Fig. 11-20 Chronic Sialadenitis. Parotid sialogram demonstrat-  ing ductal dilatation proximal to an area of obstruction. (Courtesy of  Dr. George Blozis.)    Subacute necrotizing sialadenitis is a form of salivary  inflammation that occurs most commonly in teenagers and  young adults. The lesion usually involves the minor salivary  glands of the hard or soft palate, presenting as a painful  nodule that is covered by intact, erythematous mucosa.  Unlike necrotizing sialometaplasia (see page 439), the lesion  does not ulcerate or slough necrotic tissue. An infectious or  allergic cause has been hypothesized.    In patients with acute sialadenitis, accumulation of neutro-  phils is observed within the ductal system and acini. Chronic  sialadenitis is characterized by scattered or patchy infiltra-  tion of the salivary parenchyma by lymphocytes and plasma  cells. Atrophy of the acini is common, as is ductal dilatation.  If associated fibrosis is present, then the term chronic scle-  rosing sialadenitis is used (Fig. 11-21).   Subacute necrotizing sialadenitis is characterized by a  heavy mixed inflammatory infiltrate consisting of neu-  trophils, lymphocytes, histiocytes, and eosinophils. There  is loss of most of the acinar cells, and many of the  remaining ones exhibit necrosis. The ducts tend to be  atrophic and do not show hyperplasia or squamous  metaplasia.    Patients with sialadenitis should have a screening panoramic  radiograph to investigate for the presence of a sialolith.  Additional imaging studies, such as CT or MRI scans, may  also be warranted. If purulence is noted at the duct orifice,  then bacterial culture and sensitivity studies should be  performed.   The treatment of acute sialadenitis includes appropriate  antibiotic therapy and rehydration of the patient to stimu-  late salivary flow. Surgical drainage may be needed if there  is abscess formation. Although this regimen is usually suf  ficient, a 20% to 50% mortality rate has been reported in    @ Fig. 11-21 Chronic Sclerosing Sialadenitis. Chronic inflamma-  tory infiltrate with associated acinar atrophy, ductal dilatation, and  fibrosis.    debilitated patients because of the spread of the infection  and sepsis.   The management of chronic sialadenitis depends on the  severity of the condition and ranges from conservative  therapy to surgical intervention. Initial management often  includes antibiotics, analgesics, short-term corticosteroids,  sialagogues, and glandular massage. Early cases that develop  secondary to ductal blockage may respond to removal of the  sialolith or other obstruction. However, if sialectasia is  present, then the dilated ducts can lead to stasis of secretions  and predispose the gland to further sialolith formation.  Sialoendoscopy and ductal irrigation often are employed to  dilate ductal strictures and to eliminate sialoliths and mucus  plugs. If necessary, a period of ductal stenting can also be  performed. If conservative methods cannot control chronic  sialadenitis, then surgical removal of the affected gland may  be necessary.   Sialoendoscopy with saline irrigation also has proven to  be a useful technique for patients with juvenile recurrent  parotitis, often greatly reducing the number of recurring  episodes until the disorder resolves at puberty. Subacute  necrotizing sialadenitis is a self-limiting condition that  usually resolves within 2 weeks of diagnosis without  treatment.    Cheilitis glandularis is a rare inflammatory condition of  the minor salivary glands. The cause is uncertain, although  several etiologic factors have been suggested, including  actinic damage, tobacco, poor hygiene, and heredity.    Cheilitis glandularis characteristically occurs on the lower  lip vermilion, although cases also have been reported to  involve the upper lip and palate. Affected individuals expe-  rience swelling and eversion of the lower lip as a result of  hypertrophy and inflammation of the glands (Fig. 11-22).    © Fig. 11-22 Cheilitis Glandularis. Prominent lower lip with inflamed  openings of the minor salivary gland ducts. An early squamous cell  carcinoma has developed on the patient’s left side just lateral to the  midline (arrow). (Courtesy of Dr. George Blozis.)    ‘The openings of the minor salivary ducts are inflamed and  dilated, and pressure on the glands may produce mucopu-  rulent secretions from the ductal openings. The condition  most often has been reported in middle-aged and older  men, although cases also have been described in women and  children. However, some of the childhood cases may repre-  sent other entities, such as exfoliative cheilitis (see page  278). Examples also have been described in albino patients,  presumably secondary to sun sensitivity.  Historically, cheilitis glandularis has been classified into  three types, based on the severity of the disease:  1. Simple  2. Superficial suppurative (Baelz disease)  3. Deep suppurative (cheilitis glandularis apostematosa)  ‘The latter two types represent progressive stages of the  disease with bacterial involvement; they are characterized by  increasing inflammation, suppuration, ulceration, and    ‘The microscopic findings of cheilitis glandularis may include  chronic sialadenitis, ductal dilatation with mucin accumula-  tion, and oncocytic ductal metaplasia. Concomitant dys-  plastic changes may be observed in the overlying surface  epithelium in some cases.    The treatment of choice for most cases of persistent  cheilitis glandularis associated with actinic damage is ver-  milionectomy (lip shave), which usually produces a satisfac-  tory cosmetic result. It has been noted that some cases have  been associated with the development of squamous cell  carcinoma of the overlying epithelium of the lip. Because  actinic damage has been implicated in many cases of chei-  litis glandularis, it is likely that this same solar radiation is  responsible for the malignant degeneration.    Sialorrhea, or excessive salivation, is an uncommon condi-  tion that has various causes. Minor sialorrhea may result  from local irritations, such as aphthous ulcers or ill-fitting  dentures. Patients with new dentures often experience excess  saliva production until they become accustomed to the  prosthesis. Episodic hypersecretion of saliva, or “water  brash,” may occur as a protective buffering system to neu-  tralize stomach acid in individuals with gastroesophageal  reflux disease. Sialorrhea is a well-known clinical feature of  rabies and heavy-metal poisoning (see page 286). It also  may occur as a consequence of certain medications, such as  antipsychotic agents, especially clozapine, and cholinergic  agonists used to treat dementia of the Alzheimer type and  myasthenia gravis.   Drooling can be a problem for patients who are intel-  lectually disabled, who have undergone surgical resection of  the mandible, or who have various neurologic disorders  such as cerebral palsy, Parkinson disease, amyotrophic lateral  sclerosis (ALS), or stroke. In these instances, the drooling  is probably not caused by overproduction of saliva but by  poor neuromuscular control.   In addition, there is a second group of patients who  report complaints of drooling; however, no obvious clinical  evidence of excessive saliva production is observed, and they  do not have any of the recognized causes for sialorrhea.  Personality analysis has suggested that the complaint of  drooling in such otherwise healthy patients does not have  an organic basis but may be associated with high levels of  neuroticism and a tendency to dissimulate.    Excess saliva production typically produces drooling and  choking, which may cause social embarrassment. In chil-  dren with intellectual disability or cerebral palsy, uncon-  trolled salivary flow may lead to macerated sores around the  mouth, chin, and neck that can become secondarily infected.  The constant soiling of clothes and bed linens can be a  significant problem for the parents and caretakers of these  patients.   An interesting type of supersalivation of unknown cause  has been termed idiopathic paroxysmal sialorrhea. Indi-  viduals with this condition experience short episodes of  excessive salivation lasting from 2 to 5 minutes. These  episodes are associated with a prodrome of nausea or  epigastric pain.    Some causes of sialorrhea are transitory or mild, and no  treatment is needed. For individuals with increased saliva-  tion associated with gastroesophageal reflux disease, medical  management of their reflux problem may be beneficial.  For persistent severe drooling, therapeutic intervention  may be indicated. Speech therapy can be used to improve    neuromuscular control, but patient cooperation is neces-  sary. Anticholinergic medications can decrease saliva  production but may produce unacceptable side effects.  ‘Transdermal scopolamine has been tried with some success,  but it should not be used in children younger than age 10.  Intraglandular injection of botulinum toxin has been shown  to be successful in reducing salivary secretions, with dura-  tion of action that varies from 6 weeks to 6 months.  Several surgical techniques have been used successfully  to control severe drooling in individuals with poor neuro-  muscular control:  ¢ Relocation of the submandibular ducts (sometimes along  with excision of the sublingual glands)  ¢ Relocation of the parotid ducts  e Submandibular gland excision plus parotid duct  ligation  ¢ Ligation of the parotid and submandibular ducts  ¢ Bilateral tympanic neurectomy with sectioning of the  chorda tympani  In ductal relocation, the ducts are repositioned posteri-  orly to the tonsillar fossa, thereby redirecting salivary flow  and minimizing drooling. The use of bilateral tympanic  neurectomy and sectioning of the chorda tympani destroys  parasympathetic innervation to the glands, reducing sali-  vary secretions and possibly inducing xerostomia. However,  this procedure, which results in a loss of taste to the anterior  two-thirds of the tongue, is rarely performed today.    Xerostomia refers to a subjective sensation of a dry mouth;  it is frequently, but not always, associated with salivary  gland hypofunction. A number of factors may play a role  in the cause of xerostomia, and these are listed in Box 11-1.  Xerostomia is a common problem that has been reported  in 25% of older adults. In the past, complaints of dry  mouth in older patients often were ascribed to the predict-  able result of aging. However, it is now generally thought  that any reductions in salivary function associated with age  are modest and probably are not associated with any signifi-  cant reduction in salivary function. Instead, xerostomia in  older adults is more likely to be the result of other factors,  especially medications. More than 500 drugs have been  reported to produce xerostomia as a side effect, including  63% of the 200 most frequently prescribed medicines in  the United States. A list of the most common and signifi-  cant drugs associated with xerostomia is provided in Table  11-2. Not only are specific drugs known to produce dry  mouth, but the prevalence of xerostomia also increases in  relation to the total number of drugs that a person takes,  regardless of whether the individual medications are xero-  genic or not.    Examination of the patient typically demonstrates a reduc-  tion in salivary secretions, and the residual saliva appears  either foamy or thick and “ropey.” The mucosa appears dry,    and the clinician may notice that the examining gloves stick  to the mucosal surfaces. The dorsal tongue often is fissured  with atrophy of the filiform papillae (see Fig. 11-1). The  patient may complain of difficulty with mastication and  swallowing, and they may even indicate that food adheres  to the oral membranes during eating. The clinical findings,  however, do not always correspond to the patient’s symp-  toms. Some patients who complain of dry mouth may  appear to have adequate salivary flow and oral moistness.  Conversely, some patients who clinically appear to have a  dry mouth have no complaints. The degree of saliva produc-  tion can be assessed by measuring both resting and stimu-  lated salivary flow.   There is an increased prevalence of oral candidiasis in  patients with xerostomia because of the reduction in the  cleansing and antimicrobial activity normally provided by  saliva. In addition, these patients are more prone to dental  decay, especially cervical and root caries. This problem  has been associated more often with radiation therapy, and  it is sometimes called radiation-induced caries but more  appropriately should be called xerostomia-related caries  (see page 268).    The treatment of xerostomia is difficult and often unsatis-  factory. Artificial salivas are available and may help make  the patient more comfortable, as may continuous sips of  water throughout the day. In addition, sugarless candy can  be used in an effort to stimulate salivary flow. One of the  better patient-accepted management approaches includes  the use of oral hygiene products that contain lactoperoxi-  dase, lysozyme, and lactoferrin (e.g., Biotene toothpaste and  mouth rinse, and Oralbalance gel). If the dryness is second-  ary to the patient’s medication, then discontinuation or  dose modification in consultation with the patient’s physi-  cian may be considered; a substitute drug can also be tried.   Systemic pilocarpine is a parasympathomimetic agonist  that can be used as a sialagogue. At doses of 5 to 10 mg,  three to four times daily, it can be an effective promoter of  salivary secretion. Excess sweating is a common side effect,  but more serious problems, such as increased heart rate and  blood pressure, are uncommon. Cevimeline hydrochloride,  a cholinergic agonist with affinity for muscarinic M; recep-  tors, also has been proven to be an effective sialagogue. Both  pilocarpine and cevimeline are contraindicated in patients  with narrow-angle glaucoma.   Because of the increased potential for dental caries in  patients with xerostomia, frequent dental visits are recom-  mended. Office and daily home fluoride applications can  be used to help prevent decay, and chlorhexidine mouth  rinses minimize plaque buildup.    In the late 1800s, Johann von Mikulicz-Radecki described  a patient with an unusual bilateral painless swelling of the  lacrimal glands and all of the salivary glands, which was    caused by an intense chronic inflammatory infiltrate. This  clinical presentation became known as Mikulicz disease.  Similar cases of parotid and lacrimal enlargement caused by  other diseases (e.g., tuberculosis, sarcoidosis, and lym-  phoma) were considered to be different from Mikulicz  disease and were termed Mikulicz syndrome. However,  these two terms have become so confusing and ambiguous  that they should no longer be used.   Although the true nature of his original patient’s condi-  tion is uncertain, some examples of so-called Mikulicz  disease likely have been benign lymphoepithelial lesions  associated with Sjogren syndrome (see page 434). However,  it is thought that other examples would be classified today  as IgG4-related disease, a newly described fibroinflamma-  tory disorder.   IgG4-related disease was first recognized as a sclerosing  inflammatory process of the pancreas under the designation  “autoimmune pancreatitis.” This condition later was linked  to elevated serum levels of IgG4, as well as the presence of  IgG4-positive plasma cells within pancreatic tissues. The  systemic nature of IgG4-related disease was established  when it was recognized that a variety of inflammatory  lesions in other organs, including the salivary and lacrimal  glands, represent the same disease process. Serum concen-  trations of polyclonal IgG4 can measure up to 25 times  greater than normal levels, although 20% to 40% of patients  will have IgG4 levels within normal limits. Allergic disor-  ders such as asthma, allergic rhinitis, and atopic dermatitis  are common.    IgG4-related disease typically occurs in middle-aged and  older adults, with a mean age of approximately 60 years.  Men are affected equally or slightly more often than women,  although reports from Japan have shown a female predilec-  tion. Following the pancreas, the head and neck region is  the second most common site affected by this condition.  IgG4-related sialadenitis occurs most frequently in the sub-  mandibular gland and only rarely involves the parotid gland  and minor salivary glands. Patients present with unilateral  or bilateral submandibular gland swelling ranging from  1.5 cm to 5 cm in diameter, which often mimics a neoplas-  tic process.   Because IgG4-related disease can affect almost any tissue  or organ within the body, the severity and course of the  disorder depend on the specific site of involvement. Pancre-  atitis can lead to obstructive jaundice, weight loss, and  abdominal discomfort. Sclerosing cholangitis can result in  hepatic failure. Other complications include abdominal  aortitis with aneurysm formation, inflammatory pseudotu-  mors of the kidney, thyroid inflammation (Riedel thyroid-  itis), and lymphadenopathy.    Microscopic examination reveals chronic sclerosing sialad-  enitis, which is characterized by a heavy lymphoplasmacytic    infiltrate, hyperplastic lymphoid follicles, and acinar  atrophy. Prominent interlobular fibrosis results in a stori-  form pattern when the gland is viewed at low power.  Another common finding is obliterative phlebitis, which  can be highlighted with an elastic stain. This overall pattern  has sometimes been termed a Kiittner tumor.    IgG4-related disease often requires immediate, aggressive  treatment with systemic corticosteroids to prevent signifi-  cant organ damage and failure. Glucocorticoid-sparing  agents, such as azathioprine, mycophenolate mofetil, and  methotrexate, also can be used. Most patients show a rapid  response to immunosuppressive therapy and have a favor-  able prognosis. For patients with recurrent disease, B-cell  depletion with rituximab can be effective.    Sjégren syndrome is a chronic, systemic autoimmune dis-  order that principally involves the salivary and lacrimal  glands, resulting in xerostomia (dry mouth) and xerophthal-  mia (dry eyes). The effects on the eye often are called kera-  toconjunctivitis sicca (sicca means “dry”), and the clinical  presentation of both xerostomia and xerophthalmia is also  sometimes called the sicca syndrome. Traditionally, two  forms of the disease are recognized:   1. Primary Sjégren syndrome (sicca syndrome alone; no  other autoimmune disorder is present)   2. Secondary Sjégren syndrome (the patient manifests sicca  syndrome in addition to another associated autoimmune  disease)   However, some authors have suggested that the distinc-  tion between primary and secondary Sjogren syndrome may  now be obsolete.   The cause of Sjégren syndrome is unknown. Although it  is not a hereditary disease per se, there is evidence of a  genetic influence. Examples of Sjégren syndrome have been  reported in twins or in two or more members of the same  family. Relatives of affected patients have an increased fre-  quency of other autoimmune diseases. In addition, certain  histocompatibility antigens (HLAs) are found with greater  frequency in patients with Sjogren syndrome. HLA-DRw52  is associated with both forms of the disease; HLA-B8 and  HLA-DR3 are seen with increased frequency in the primary  form of the disease. Researchers have suggested that viruses,  such as Epstein-Barr virus (EBV) or human T-cell lympho-  tropic virus, may play a pathogenetic role in Sjogren syn-  drome, but evidence for this is still speculative.    Sjégren syndrome is not a rare condition. Although the  exact prevalence depends on the clinical criteria used,  current estimates place the population prevalence at 0.5%,  with a 9:1 female-to-male ratio. It is seen predominantly    in middle-aged adults, but rare examples have been described  in children. The classification criteria suggested by the  American-European Consensus Group are shown in Box  11-2. More recently, the American College of Rheumatol-  ogy has proposed new classification criteria based on three  objective features, as presented in Box 11-3.   When the condition is associated with another connec-  tive tissue disease, it is called secondary Sjogren syndrome. It  can be associated with almost any other autoimmune  disease, but the most common associated disorder is rheu-  matoid arthritis. About 15% of patients with rheumatoid  arthritis have Sjogren syndrome. In addition, secondary  Sjégren syndrome may develop in 30% of patients with  systemic lupus erythematosus (SLE).   The principal oral symptom is xerostomia, which is  caused by decreased salivary secretions; however, the severity  of this dryness can vary widely from patient to patient. The  saliva may appear frothy, with a lack of the usual pooling  saliva in the floor of the mouth. Affected patients may  complain of difficulty in swallowing, altered taste, or diffi-  culty in wearing dentures. The tongue often becomes fis-  sured and exhibits atrophy of the papillae (Fig. 11-23). The  oral mucosa may be red and tender, usually as a result of  secondary candidiasis. Related denture sore mouth and  angular cheilitis are common. The lack of salivary cleansing  action predisposes the patient to dental decay, especially  cervical caries.   From one-third to one-half of patients have diffuse, firm  enlargement of the major salivary glands during the course  of their disease (Fig. 11-24). This swelling is usually bilat-  eral, may be nonpainful or slightly tender, and may be  intermittent or persistent in nature. The greater the severity  of the disease, the greater the likelihood of this salivary  enlargement. In addition, the reduced salivary flow places  these individuals at increased risk for retrograde bacterial  sialadenitis.   Although it is not diagnostic, sialographic examination  often reveals punctate sialectasia and lack of normal arbo-  rization of the ductal system, typically demonstrating a  “fruit-laden, branchless tree” pattern (Fig. 11-25). Scintig-  raphy with radioactive technetium-99m pertechnetate char-  acteristically shows decreased uptake and delayed emptying  of the isotope.   The term keratoconjunctivitis sicca describes not only  the reduced tear production by the lacrimal glands but also  the pathologic effect on the epithelial cells of the ocular  surface. As in xerostomia, the severity of xerophthalmia can  vary widely from one patient to the next. The lacrimal  inflammation causes a decrease of the aqueous layer of the  tear film; however, mucin production is normal and may  result in a mucoid discharge. Patients often complain of a  scratchy, gritty sensation or the perceived presence of a  foreign body in the eye. Defects of the ocular surface epi-  thelium develop, which may result in blurred vision and,  sometimes, an aching pain. The ocular manifestations are  least severe in the morning on wakening and become more  pronounced as the day progresses.    . Ocular symptoms: A positive response to at least one of the   A. Have you had daily, persistent, troublesome dry eyes for  more than 3 months?   B. Do you have a recurrent sensation of sand or gravel in  the eyes?   C. Do you use tear substitutes more than three times  a day?   . Oral symptoms: A positive response to at least one of the   A. Have you had a daily feeling of dry mouth for more than  3 months?   B. Have you had recurrently or persistently swollen salivary  glands as an adult?   C. Do you frequently drink liquids to aid in swallowing dry  food?   defined as a positive result for at least one of the following   A. Schirmer | test, performed without anesthesia (<5 mm in  5 minutes)   B. Rose bengal score or other ocular dye score (<4  according to van Bijsterveld’s scoring system)   IV. Histopathology: In minor salivary glands (obtained through  normal-appearing mucosa) focal lymphocytic sialadenitis,  evaluated by an expert histopathologist, with a focus score  >1, defined as a number of lymphocytic foci (which are  adjacent to normal-appearing mucous acini and contain  more than 50 lymphocytes) per 4 mm? of glandular tissue   gland involvement defined by a positive result for at least one    Patients must have at least two of the following three objective   1. Positive autoantibodies to Ro(SS-A) and/or La(SS-B)  antigens, or positive rheumatoid factor (RF) and antinuclear  antibody (ANA) titer 21 :320   2. Labial salivary gland biopsy exhibiting focal lymphocytic  sialadenitis with a focus score >1 focus/4 mm?   8. Keratoconjunctivitis sicca with ocular staining score =3  (assuming the patient is not currently using daily eye drops  for glaucoma and has not had corneal surgery or cosmetic  eyelid surgery in the last 5 years)    *Exclusion criteria are similar to the Revised International Classification Criteria  in Box 11-2.    A simple means to confirm the decreased tear secretion  is the Schirmer test. A standardized strip of sterile filter  paper is placed over the margin of the lower eyelid, so that  the tabbed end rests just inside the lower lid. By measuring  the length of wetting of the filter paper, tear production can  be assessed. Values less than 5 mm (after a 5-minute period)    B. Parotid sialography showing the presence of diffuse  sialectasia (punctate, cavitary, or destructive pattern),  without evidence of obstruction in the major ducts   C. Salivary scintigraphy showing delayed uptake,  reduced concentration, and/or delayed excretion of  tracer   . Presence of any four of the six items is indicative of primary  Sjégren syndrome, as long as either item IV (histopathology)  or VI (Serology) is positive   |. Presence of any three of the four objective criteria items  (items Ill, IV, V, and VI)   n patients with a potentially associated disease (e.g., another  well-defined connective tissue disease), presence of item | or  item Il plus any two from among items Ill, IV, and V is  considered indicative of secondary Sjégren syndrome.    @ Fig. 11-23 Sjégren Syndrome. Dry and fissured tongue. (Cour-  tesy of Dr. David Schaffner.)    are considered abnormal. In addition, the possibility of  damage to the corneal and conjunctival surfaces can be  assessed. by slit lamp examination after rose bengal and lis-  samine green staining.   Sjégren syndrome is a systemic disease, and the inflam-  matory process also can affect various other body tissues.  ‘The skin is often dry, as are the nasal and vaginal mucosae.    RAA OS :  @ Fig. 11-24 Sjégren Syndrome. Benign lymphoepithelial lesion of  the parotid gland. (Courtesy of Dr. David Schaffner.)    Fatigue is fairly common, and depression sometimes can  occur. Other possible associated problems include lymph-  adenopathy, primary biliary cirrhosis, Raynaud phenome-  non, interstitial nephritis, interstitial lung fibrosis, vasculitis,  and peripheral neuropathies.    In patients with Sjogren syndrome, the erythrocyte sedi-  mentation rate is high and serum immunoglobulin (Ig)  levels, especially IgG, typically are elevated. A variety of  autoantibodies can be produced, and although none of  these is specifically diagnostic, their presence can be another    drome. Lymphocytic infiltrate of the parotid gland with an associated  epimyoepithelial island.    helpful clue to the diagnosis. A positive rheumatoid factor  (RF) is found in approximately 60% of cases, regardless of  whether the patient has rheumatoid arthritis. Antinuclear  antibodies (ANAs) are also present in 75% to 85% of  patients. Two particular nuclear autoantibodies—anti-SS-A  (anti-Ro) and anti-SS-B (anti-La)—may be found, espe-  cially in patients with primary Sjogren syndrome. Anti-SS-  A antibodies have been detected in approximately 50% to  76% of patients, whereas anti-SS-B antibodies have been  discovered in 30% to 60% of these individuals. Occasion-  ally, salivary duct autoantibodies also can be demonstrated,  usually in secondary Sjégren syndrome. However, because  these are infrequent in primary cases, they are believed to  occur as a secondary phenomenon (rather than playing a  primary role in pathogenesis).    The basic microscopic finding in Sjogren syndrome is a  lymphocytic infiltration of the salivary glands, which leads  to destruction of the acinar units. More advanced lesions  result in a pattern known as a benign lymphoepithelial  lesion (myoepithelial sialadenitis). Although the acini are  destroyed, the ductal epithelium persists. The ductal cells  and surrounding myoepithelial cells become hyperplastic,  forming highly characteristic groups of cells, known as epi-  myoepithelial islands, throughout the lymphoid proliferation  (Fig. 11-26). Germinal centers may or may not be seen.  Lymphocytic infiltration of the minor glands also occurs,  although epimyoepithelial islands are rarely seen in this  location.   Biopsy of the minor salivary glands of the lower lip some-  times is used as a diagnostic test for Sjogren syndrome. A  1.5- to 2.0-cm incision is made on clinically normal lower  labial mucosa, parallel to the vermilion border and lateral to  the midline, allowing the harvest of five or more accessory  glands. These glands then can be examined histopathologi-  cally for the presence of focal chronic inflammatory aggre-  gates composed of 50 or more lymphocytes and plasma cells.  The aggregates should be adjacent to normal-appearing    acini and should be found consistently in most of the  glands in the specimen. The following formula has been  suggested:    The focus score calculates the number of inflammatory  aggregates per 4-mm/” area of salivary gland tissue. A focus  score 2 1 (ie., one or more foci of 50 or more cells per  4-mm/ area of glandular tissue) is considered supportive of  the diagnosis of Sjogren syndrome (Fig. 11-27). The greater  the number of foci (up to 12 or confluent foci) is, the  greater is the correlation with this diagnosis. The focal  nature of this chronic inflammation among otherwise  normal acini is a highly suggestive pattern; in contrast, the  finding of scattered inflammation with ductal dilatation and  fibrosis (chronic sclerosing sialadenitis) does not support the  diagnosis of Sjégren syndrome.   Although labial salivary gland biopsy has become a  widely used test in the diagnosis of Sjégren syndrome, it is  not 100% reliable. Some patients diagnosed with Sjogren  syndrome will show no significant labial gland inflamma-  tion; conversely, examination of labial glands removed inci-  dentally from non-Sjégren patients sometimes will show  focal lymphocytic infiltrates. Sjégren syndrome patients  who smoke have been shown to have a significantly lower  frequency of abnormal lymphocytic foci scores in their  labial gland specimens. It also is important that a patholo-  gist experienced in the analysis of these specimens examines  the labial gland biopsies. One study showed that slightly  more than half of labial gland specimens required a revised  diagnosis after being reviewed by a second pathologist.   Other authors have advocated incisional biopsy of the  parotid gland through a posterior auricular approach instead  of a labial salivary gland biopsy. One study has shown this  technique to be more sensitive in demonstrating inflamma-  tory changes that support the diagnosis of Sjogren syn-  drome; however, other authors think that this technique  confers no increased benefit over labial gland biopsy. Parotid    biopsy may enable the clinician to evaluate an enlarged  gland for the development of lymphoma and rule out the  possibility of sialadenosis or sarcoidosis.    The treatment of the patient with Sjogren syndrome is  mostly supportive. The dry eyes are best managed by peri-  odic use of artificial tears. In addition, attempts can be made  to conserve the tear film through the use of sealed glasses  to prevent evaporation. Sealing the lacrimal punctum at the  inner margin of the eyelids also can be helpful by blocking  the normal drainage of any lacrimal secretions into the nose.   Artificial salivas are available for the treatment of xero-  stomia; sugarless candy or gum can help to keep the mouth  moist. Symptoms often can be relieved by the use of oral  hygiene products that contain lactoperoxidase, lysozyme,  and lactoferrin (e.g., Biotene toothpaste and mouth rinse,  and Oralbalance gel). Sialagogue medications, such as pilo-  carpine and cevimeline, can be useful to stimulate salivary  flow if enough functional salivary tissue still remains. Medi-  cations known to diminish secretions should be avoided, if  at all possible. Because of the increased risk of dental caries,  daily fluoride applications may be indicated in dentulous  patients. Antifungal therapy often is needed to treat second-  ary candidiasis.   Patients with Sjogren syndrome have a lifetime risk  for lymphoma of 5% to 15%, which is estimated to be  about 20 times greater than the general population. These  tumors may arise initially within the salivary glands or  within lymph nodes. With the advent of modern molecular  pathology techniques to detect B-cell monoclonality (e.g.,  in situ hybridization, polymerase chain reaction [PCR]),  many salivary gland infiltrates formerly thought to rep-  resent benign lymphoepithelial lesions are now being  diagnosed as lymphomas. These tumors are predominantly  low-grade non-Hodgkin B-cell lymphomas of the mucosa-  associated lymphoid tissue (ie, MALT lymphomas,  extranodal marginal zone B-cell lymphomas), although  occasionally, high-grade lymphomas can develop that dem-  onstrate more aggressive behavior. Prognostic risk factors  for lymphoma development include persistent parotid  gland enlargement, lymphadenopathy, splenomegaly, neu-  tropenia, low C4 complement levels, cryoglobulinemia,  and palpable purpura. The detection of immunoglobulin  gene rearrangements in labial salivary gland biopsies may  prove to be a useful marker for predicting the develop-  ment of lymphoma.    Sialadenosis is an unusual noninflammatory disorder char-  acterized by salivary gland enlargement, particularly involv-  ing the parotid glands. The condition frequently is associated  with an underlying systemic problem, which may be endo-  crine, nutritional, or neurogenic in origin (Box 11-4). The  best known of these conditions include diabetes mellitus,  general malnutrition, alcoholism, and bulimia.    These conditions are believed to result in dysregulation  of the autonomic innervation of the salivary acini, causing  an aberrant intracellular secretory cycle. This leads to exces-  sive accumulation of secretory granules, with marked  enlargement of the acinar cells. In addition, reduced inner-  vation of myoepithelial cells may lead to atrophy of the  supporting myofilaments around the acinar cells.    Sialadenosis usually appears as a slowly evolving swelling of  the parotid glands, which may or may not be painful (Fig.  11-28). The condition is usually bilateral, but it also can be  unilateral. In some patients, the submandibular glands may  be affected, but involvement of minor salivary glands is  distinctly rare. Decreased salivary secretion may occur. Sia-  lography demonstrates a “leafless tree” pattern, which is  thought to be caused by compression of the finer ducts by  hypertrophic acinar cells.    Microscopic examination reveals hypertrophy of the acinar  cells, sometimes two to three times greater than normal size.  The nuclei are displaced to the cell base, and the cytoplasm  is engorged with zymogen granules. In cases associated with  long-standing diabetes or alcoholism, there may be acinar  atrophy and fatty infiltration. Significant inflammation is  not observed.    The clinical management of sialadenosis is often unsatisfac-  tory because it is closely related to the control of the under-  lying cause. Mild examples may cause few problems. If the    @ Fig. 11-28 Sialadenosis. Enlargement of the parotid and subman-  dibular glands secondary to alcoholism. (Courtesy of Dr. George  Blozis.)    swelling becomes a cosmetic concern, then partial paroti-  dectomy can be performed. Pilocarpine has been reported  to be beneficial in reducing salivary gland enlargement in  bulimic patients.    Adenomatoid hyperplasia is a rare lesion of the minor  salivary glands characterized by localized swelling that  mimics a neoplasm. This pseudotumor most often occurs  on the hard or soft palate, although it also has been reported  in other oral minor salivary gland sites. The pathogenesis of  adenomatoid hyperplasia is uncertain, but it has been spec-  ulated that local trauma may play a role. It is most common  in the fourth to sixth decades of life. Most examples present  as sessile, painless masses that may be soft or firm to palpa-  tion. They usually are normal in color, although a few  lesions are red or bluish.    Microscopic examination demonstrates lobular aggregates  of relatively normal-appearing mucous acini that are greater  in number than normally would be found in the area. These  glands also sometimes appear to be increased in size. In    some instances, the glands are situated close to the mucosal  surface. Chronic inflammation occasionally is seen, but it  usually is mild and localized.    Because the clinical presentation ofadenomatoid hyperplasia  mimics a tumor, biopsy is necessary to establish the diagno-  sis. Once the diagnosis has been established, no further  treatment is indicated and the lesion should not recur.   The pathologist should be wary of making a diagnosis of  adenomatoid hyperplasia without good clinical correlation.  On occasion, attempted biopsy of a true salivary gland  tumor may harvest only adjacent normal salivary tissue,  which might be misinterpreted as adenomatoid hyperplasia.  Good communication between the clinician and patholo-  gist is important.    Necrotizing sialometaplasia is an uncommon, locally  destructive inflammatory condition of the salivary glands.  Although the cause is uncertain, most authors believe it is  the result of ischemia of the salivary tissue that leads to local  infarction. The importance of this lesion rests in the fact  that it mimics a malignant process, both clinically and  microscopically.   A number of potential predisposing factors have been  suggested, including the following:  ¢ Traumatic injuries  ¢ Dental injections  e Ill-fitting dentures  ¢ Upper respiratory infections  e Adjacent tumors  ° Previous surgery  e Eating disorders with binge-purging   Researchers have suggested that these factors may play a  role in compromising the blood supply to the involved  glands, resulting in ischemic necrosis. However, many cases  occur without any known predisposing factors.    Necrotizing sialometaplasia most frequently develops in the  palatal salivary glands; more than 75% of all cases occur on  the posterior palate. The hard palate is affected more often  than the soft palate. About two-thirds of palatal cases are  unilateral, with the rest being bilateral or midline in loca-  tion. Necrotizing sialometaplasia also has been reported in  other minor salivary gland sites and, occasionally, in the  parotid gland. The submandibular and sublingual glands are  rarely affected. Although it can occur at almost any age,  necrotizing sialometaplasia is most common in adults; the  mean age of onset is 46 years. Males are affected nearly twice  as often as females.   The condition appears initially as a nonulcerated swell-  ing, often associated with pain or paresthesia (Fig. 11-29).    @ Fig. 11-29 Necrotizing Sialometaplasia. Early lesion demon-  strating swelling of the posterior lateral hard palate. (From Allen CM,  Camisa C: Diseases of the mouth and lips. In Sams WM, Lynch P,  editors: Principles of dermatology, New York, 1990, Churchill  Livingstone.)    e Fig. 11-30 Necrotizing Sialometaplasia. Later-stage lesion  showing craterlike defect of the posterior palate.    Within 2 to 3 weeks, necrotic tissue sloughs out, leaving a  craterlike ulcer that can range from less than 1 cm to more  than 5 cm in diameter (Fig. 11-30). The patient may report  that “a part of my palate fell out.” At this point, the pain  often subsides. In rare instances, there can be destruction  of the underlying palatal bone.    The microscopic appearance of necrotizing sialometaplasia  is characterized by acinar necrosis in early lesions, followed  by associated squamous metaplasia of the salivary ducts  (Fig. 11-31). Although the mucous acinar cells are necrotic,  the overall lobular architecture of the involved glands is still  preserved—a helpful histopathologic clue. There may be  liberation of mucin, with an associated inflammatory  response. The squamous metaplasia of the salivary ducts can  be striking and produce a pattern that is easily misdiagnosed  as squamous cell carcinoma or mucoepidermoid carcinoma.  The frequent association of pseudoepitheliomatous hyper-  plasia of the overlying epithelium may further compound    @ Fig. 11-31 Necrotizing Sialometaplasia. Necrotic mucous acini  (left) and adjacent ductal squamous metaplasia (right).    this mistaken impression. In most cases, however, the squa-  mous proliferation has a bland cytologic appearance. In  examples that are difficult to distinguish from carcinoma,  low immunoreactivity for p53 protein and Ki-67 may help  to support a diagnosis of necrotizing sialometaplasia.    Because of the worrisome clinical presentation of necrotiz-  ing sialometaplasia, biopsy usually is indicated to rule out  the possibility of malignant disease. Once the diagnosis has  been established, no specific treatment is indicated or neces-  sary. The lesion typically resolves on its own accord, with  an average healing time of 5 to 6 weeks.    Tumors of the salivary glands constitute an important area  in the field of oral and maxillofacial pathology. Although  such tumors are uncommon, they are by no means rare. The  annual incidence of salivary gland tumors around the world  ranges from about 1.0 to 6.5 cases per 100,000 people.  Although soft tissue neoplasms (e.g., hemangioma), lym-  phoma, and metastatic tumors can occur within the salivary  glands, the discussion in this chapter is limited to primary  epithelial neoplasms.   An often-bewildering array of salivary tumors has been  identified and categorized. In addition, the classification  scheme is a dynamic one that changes as clinicians learn  more about these lesions. As an example, since the last  edition of this text, mammary analogue secretory carcinoma  has been newly recognized as an important low-grade sali-  vary malignancy that may occur in both major and minor  glands. Box 11-5 includes most of the currently recognized  tumors. Some of the tumors on this list are not specifically  discussed because their rarity places them outside the scope  of this text.   Polymorphous low-grade adenocarcinoma  Basal cell adenocarcinoma  Epithelial-myoepithelial carcinoma  Mammary analogue secretory carcinoma  Salivary duct carcinoma    A number of investigators have published their findings  on salivary gland neoplasia, but a comparison of these  studies is often difficult. Some studies have been limited to  only the major glands or have not included all the minor  salivary gland sites. In addition, the ever-evolving classifica-  tion system makes an evaluation of some older studies dif-  ficult, especially when researchers attempt to compare them  with more recent analyses. Notwithstanding these difficul-  ties, it is still helpful to compare these studies because they  provide a good overview of salivary neoplasia in general. An  evaluation of various studies shows fairly consistent trends  (with minor variations) with regard to salivary gland tumors.   Tables 11-3 and 11-4 summarize five large series of  primary epithelial salivary gland tumors, analyzed by sites  of occurrence and frequency of malignancy, respectively.  Some variations between studies may represent differences  in diagnostic criteria, geographic differences, or referral bias    in the cases seen. (Some centers may tend to see more  malignant tumors on referral from other sources.)   The most common site for salivary gland tumors is the  parotid gland, accounting for 61% to 80% of all cases.  Fortunately, a relatively low percentage of parotid tumors  are malignant, ranging from 15% to 32%. Overall, it can  be stated that two-thirds to three-quarters of all salivary  tumors occur in the parotid gland, and two-thirds to three-  quarters of these parotid tumors are benign.   Table 11-5 summarizes four large series of parotid neo-  plasms. The pleomorphic adenoma is overwhelmingly the  most common tumor (50% to 77% of all cases in the  parotid gland). Warthin tumors are also fairly common;  they account for 5% to 22% of cases. A variety of malig-  nant tumors occur, with the mucoepidermoid carcinoma  appearing to be the most frequent overall. Although previ-  ous studies suggested that the United Kingdom may have  a lower frequency of this tumor, a more recent series showed  prevalence numbers equivalent to other countries.   From 8% to 11% of all salivary tumors occur in the  submandibular gland, but the frequency of malignancy in  this gland is much greater than that of the parotid gland,  ranging from 26% to 45%. However, as shown in ‘Table  11-6, the pleomorphic adenoma is still the most common  tumor and makes up 53% to 72% of all neoplasms. Unlike  its occurrence in the parotid gland, the Warthin tumor is  unusual in the submandibular gland, making up no more  than 1% to 2% of all tumors. Adenoid cystic carcinoma is    the most common malignancy, ranging from 11% to 17%  of all cases.   Tumors of the sublingual gland are rare, comprising no  more than 1% of all salivary neoplasms. However, 70% to  95% of sublingual tumors are malignant.   Tumors of the various smaller minor salivary glands  make up 9% to 28% of all tumors, which makes this group  the second most common site for salivary neoplasia. Table  11-7 summarizes the findings of five large surveys of minor  gland tumors. Unfortunately, relatively high proportions  (38% to 49%) of these have been malignant in most studies.  Excluding rare sublingual tumors, it can be stated that the  smaller the gland is, the greater is the likelihood of malig-  nancy for a salivary gland tumor.   As observed in the major glands, the pleomorphic  adenoma is the most common minor gland tumor and  accounts for about 40% of all cases. Mucoepidermoid car-  cinoma is the most frequent malignancy of minor gland  origin, comprising 13% to 23% of all tumors. Adenoid  cystic carcinoma and polymorphous low-grade adenocarci-  noma are also recognized as relatively common malignant  tumors arising from the minor salivary glands.   The palate is the most frequent site for minor salivary  gland tumors, with 42% to 54% of all cases found there  (Table 11-8). Most of these occur on the posterior lateral  hard or soft palate, which have the greatest concentration  of glands. Table 11-9 shows the relative prevalence of various  tumors on the palate. The lips are the second most common   Pleomorphic adenoma 49.9% 53.0% 63.3% 76.8%  Warthin tumor 22.4% 7.7% 14.0% 4.7%  Oncocytoma 0.5% 1.9% 0.9% 1.0%  Basal cell adenoma 5.8% 1.4% — =  Other benign tumors 3.4% 3.7% Tale © _  Total 82.1% 67.7% 85.3% 82.5%  Malignant Tumors   Mucoepidermoid carcinoma 4.3% 9.6% 1.5% 4.1%  Acinic cell carcinoma 3.2% 8.6% 2.5% 3.1%  Adenoid cystic carcinoma 1.8% 2.0% 2.0% 2.3%  Malignant mixed tumor 2.3% 2.5% 3.2% 1.5%  Squamous cell carcinoma 0.7% Palo 1.1% 0.3%  Other malignant tumors 5.6% 7.5% 4.4% 6.3%  Total 17.9% 32.3% 14.7% 17.5%   Pleomorphic adenoma 122% SS) 59.5% 60.0%  Warthin tumor 0.6% 1.3% 0.8% 2.4%  Oncocytoma 0.2% 1.5% 0.4% 0.6%  Basal cell adenoma 0.3% 1.0% = =  Other benign tumors 0.6% 1.7% 1.9% * —  Total 73.9% 58.8% 62.6% 62.9%  Malignant Tumors   Mucoepidermoid carcinoma 4.2% 9.1% 1.6% 3.5%  Acinic cell carcinoma 1.1% Zathyo) 0.4% 0.6%  Adenoid cystic carcinoma WW2% W1.0% 16.8% 15.3%  Malignant mixed tumor 4.1% 3.5% 7.8% 1.8%  Squamous cell carcinoma 1.1% 3.4% 1.9% 7.1%  Other malignant tumors 4.5% 10.8% 8.9% 8.8%  Total 26.1% 41.2% 37.4% 37.1%    Total number of cases 455 380 546 3355 426  Benign Tumors  Pleomorphic adenoma 40.4% 39.2% 83:29 38.1% 40.8%  “Monomorphic” adenoma 15.2% 7.6% 9.2% 4.5% 10.8%  (canalicular and basal  cell adenoma)  Other benign tumors 6.6% 12.1% 13.5% 8.8% 5.9%  Total 62.2% 58.9% 55.9% 51.3% 57.5%  Malignant Tumors  Mucoepidermoid 13.0% 21.8% 22.9% 21.5% 15.3%  carcinoma  Acinic cell carcinoma* 1.3% 1.6% 3.8% 3.5% 3.5%  Adenoid cystic carcinoma 11.4% 6.3% 6.4% 7.7% 9.4%  Malignant mixed tumor 2.4% 0.5% 0.4% 1.7% 1.4%  Polymorphous low-grade 6.2% 7.1% 5.1% 2.2% 11.0%  adenocarcinoma  Other malignant tumors 3.5% 3.7% 5.5% 121% 1.9%  Total 37.8% 41.1% 44.1% 48.7% 42.5%  ee numbers for acinic cell carcinoma are probably high because they predate recognition of mammary analogue secretory carcinoma, which has similar  eatures.  beter a] Location of Minor Salivary Gland Tumors    Waldron et al. (1988) 426 42% 22% 15% 5% 5% 1% 9%  Ellis et al. (1991) 3355 44% 21% 12% 2% 3% 5% 12%  Buchner et al. (2007) 380 54% 22% 14% 5% 3% 1% 0%  Jones et al. (2008) 455 51% 24% 12% 2% 2% 2% 8%    location for minor gland tumors (21% to 24% of cases),  followed by the buccal mucosa (12% to 15% of cases).  Labial tumors are significantly more common in the upper  lip, which accounts for 74% to 87% of all lip tumors (Table  11-10). Although mucoceles are commonly found on the  lower lip, this is a surprisingly rare site for salivary gland  tumors.   Significant differences in the percentage of malignancies  and the relative frequency of various tumors can be noted  for different minor salivary gland sites. As shown in Table  11-11, 41% to 47% of palatal tumors and 30% to 50% of    buccal mucosa tumors are malignant, similar to the overall  prevalence of malignancy in all minor salivary gland sites  combined. In the upper lip, however, only 9% to 25% of  tumors are malignant because of the high prevalence of the  canalicular adenoma, which has a special affinity for this  location. In contrast, although lower lip tumors are uncom-  mon, 43% to 86% are malignant (mostly mucoepidermoid  carcinomas). Up to 95% of retromolar tumors are malig-  nant, also because of a predominance of mucoepidermoid  carcinomas. Unfortunately, most tumors in the floor of the  mouth and tongue are also malignant.    *Incidence numbers for acinic cell carcinoma are probably high because they predate recognition of mammary analogue secretory carcinoma, which has similar  features.    The pleomorphic adenoma, or benign mixed tumor, is  easily the most common salivary neoplasm. It accounts for    Waldron et al. 93 85% 15% 50% to 77% of parotid tumors, 53% to 72% of subman-  (1988) dibular tumors, and 33% to 41% of minor gland tumors.  Neate 103 84% 16% Pleomorphic adenomas are derived from a mixture of  (1988) ductal and myoepithelial elements. A remarkable micro-  Elis et al. (1991) 536 77% 53%) scopic diversity can exist from one tumor to the next, as  well as in different areas of the same tumor. The terms    atypia is acceptable.) Likewise, although the tumor often  has a prominent mesenchyme-appearing “stromal” compo-  nent, it is not truly a mixed neoplasm that is derived from  more than one germ layer. Cytogenetic analysis has shown   Eveson & Cawson 47% 25% 50% 50% 60% = 92%  (1985)   Waldron et al. (1988) 42% 14% 86% 46% 91% 80% 75%   Ellis et al. (1991) 47% 22% 60% 50% 90% 88% 86%   Buchner et al. (2007) 43% 9% 56% 37% 95% 69% 60%   Jones et al. (2008) 41% 15% 43% 30% 88% 75% 71%    @ Fig. 11-32 Pleomorphic Adenoma. Small, firm nodule located  below the left ear in the parotid gland. (Courtesy of Dr. Mike Hansen.)    @ Fig. 11-33 Pleomorphic adenoma. Slowly growing tumor of the  parotid gland.    translocations in approximately 70% of pleomorphic ade-  nomas, primarily involving pleomorphic adenoma gene I  (PLAG1) located at chromosome region 8q12.    Regardless of the site of origin, the pleomorphic adenoma  typically appears as a painless, slowly growing, firm mass    © Fig. 11-34 Pleomorphic Adenoma. Tumor of the submandibular  gland. (Courtesy of Dr. Roman Carlos.)    (Figs. 11-32 to 11-34). The patient may be aware of the  lesion for many months or years before seeking a diagnosis.  The tumor can occur at any age but is most common in  young and middle-aged adults between the ages of 30 and  60. Pleomorphic adenoma is also the most common primary  salivary gland tumor to develop during childhood. There is  a slight female predilection.   Most pleomorphic adenomas of the parotid gland occur  in the superficial lobe and present as a swelling overlying  the mandibular ramus in front of the ear. Facial nerve palsy  and pain are rare. Initially, the tumor is movable but  becomes less mobile as it grows larger. If neglected, then the  lesion can grow to grotesque proportions. About 10% of  parotid mixed tumors develop within the deep lobe of the  gland beneath the facial nerve (Fig. 11-35). Sometimes  these lesions grow in a medial direction between the ascend-  ing ramus and stylomandibular ligament, resulting in a  dumbbell-shaped tumor that appears as a mass of the lateral  pharyngeal wall or soft palate. On rare occasions, bilateral  pleomorphic adenomas of the parotid glands have been  reported, developing in either a synchronous or metachro-  nous fashion.    e Fig. 11-35 Pleomorphic Adenoma. A, Large tumor from the  deep lobe of the parotid gland, which has resulted in a firm mass of  the lateral soft palate. B, Contrast-enhanced axial magnetic resonance  image (MRI) of a tumor of the deep lobe of the parotid gland. (Courtesy  of Dr. Terry Day.)    The palate is the most common site for minor gland  mixed tumors, accounting for approximately 50% to 65%  of intraoral examples. This is followed by the upper lip  (19% to 27%) and buccal mucosa (13% to 17%). Palatal  tumors almost always are found on the posterior lateral  aspect of the palate, presenting as smooth-surfaced, dome-  shaped masses (Figs. 11-36 and 11-37). If the tumor is  traumatized, then secondary ulceration may occur. Because  of the tightly bound nature of the hard palate mucosa,  tumors in this location are not movable, although those in  the lip or buccal mucosa frequently are mobile.    The pleomorphic adenoma is typically a well-circumscribed,  encapsulated tumor (Fig. 11-38). However, the capsule may  be incomplete or show infiltration by tumor cells. This lack  of complete encapsulation is more common for minor  gland tumors, especially along the superficial aspect of  palatal tumors beneath the epithelial surface.    ® Fig. 11-36 Pleomorphic Adenoma. Firm mass of the hard palate  lateral to the midline.    @ Fig. 11-38 Pleomorphic Adenoma. Low-power view showing a  well-circumscribed, encapsulated tumor mass. Even at this power, the  variable microscopic pattern of the tumor is evident.    The tumor is composed of a mixture of glandular epi-  thelium and myoepithelial cells within a mesenchyme-like  background. The ratio of the epithelial elements and the  mesenchyme-like component is highly variable among dif-  ferent tumors. Some tumors may consist almost entirely of  background “stroma.” Others are highly cellular with little  background alteration.    The epithelium often forms ducts and cystic structures  or may occur as islands or sheets of cells. Keratinizing squa-  mous cells and mucus-producing cells also can be seen.  Myoepithelial cells often make up a large percentage of the  tumor cells and have a variable morphology, sometimes  appearing angular or spindled. Some myoepithelial cells are  rounded and demonstrate an eccentric nucleus and eosino-  philic hyalinized cytoplasm, thus resembling plasma cells  (Fig. 11-39). These characteristic plasmacytoid myoepithe-  lial cells are more prominent in tumors arising in the minor  glands.   The highly characteristic “stromal” changes are believed  to be produced by the myoepithelial cells. Extensive accu-  mulation of mucoid material may occur between the tumor  cells, resulting in a myxomatous background (Fig. 11-40).  Vacuolar degeneration of cells in these areas can produce a  chondroid appearance (Fig. 11-41). In many tumors, the  stroma exhibits areas of an eosinophilic, hyalinized change  (Fig. 11-42). At times, fat or osteoid also is seen.   Occasionally, salivary tumors are seen that are composed  almost entirely of myoepithelial cells with no ductal ele-  ments. Such tumors often are called myoepitheliomas,    @ Fig. 11-40 Pleomorphic Adenoma. Ductal structures (left) with  associated myxomatous background (right).    although they probably represent one end of the spectrum  of mixed tumors.    Pleomorphic adenomas are best treated by surgical excision.  For lesions in the superficial lobe of the parotid gland,  superficial parotidectomy with identification and preserva-  tion of the facial nerve is recommended. Local enucleation  should be avoided because the entire tumor may not be  removed or the capsule may be violated, resulting in seeding  of the tumor bed. For tumors of the deep lobe of the  parotid, total parotidectomy is usually necessary, also with  preservation of the facial nerve, if possible. Submandibular  tumors are best treated by total removal of the gland with  the tumor. Tumors of the hard palate usually are excised  down to periosteum, including the overlying mucosa. In  other oral sites the lesion often enucleates easily through the  incision site.   With adequate surgery the prognosis is excellent, with a  cure rate of more than 95%. The risk of recurrence appears  to be lower for tumors of the minor glands. Conservative    @ Fig. 11-41 Pleomorphic Adenoma. Chondroid material (right)  with adjacent ductal epithelium and myoepithelial cells.    © Fig. 11-42 Pleomorphic Adenoma. Many of the ducts and myo-  epithelial cells are surrounded by a hyalinized, eosinophilic background  alteration.    enucleation of parotid tumors often results in recurrence,  with management of these cases made difficult as a result  of multifocal seeding of the primary tumor bed. In such  cases, multiple recurrences are not unusual and may neces-  sitate adjuvant radiation therapy. Tumors with a predomi-  nantly myxoid appearance are more susceptible to recur  than those with other microscopic patterns.   Malignant degeneration is a potential complication,  resulting in a carcinoma ex pleomorphic adenoma (see  page 460). The risk of malignant transformation is probably  small, but it may occur in as many as 3% to 4% of all cases.  This risk increases with the duration of the tumor.    The oncocytoma is a benign salivary gland tumor com-  posed. of large epithelial cells known as oncocytes. The  prefix onco- is derived from the Greek word onkoustai,  which means zo swell. The swollen granular cytoplasm of  oncocytes is due to excessive accumulation of mitochondria.  Focal oncocytic metaplasia of salivary ductal and acinar cells  is a common finding that is related to patient age; oncocytes  are uncommon in persons younger than 50, but they can  be found in almost all individuals by age 70. In addition to  salivary glands, oncocytes have been identified in a number  of other organs, especially the thyroid, parathyroid, and  kidney. The oncocytoma is a rare neoplasm, representing  approximately 1% of all salivary tumors.    ‘The oncocytoma is predominantly a tumor of older adults,  with peak prevalence in the sixth to eighth decades of life.  No significant sex predilection has been observed. Oncocy-  tomas occur primarily in the major salivary glands, espe-  cially the parotid gland, which accounts for about 85% to  90% of all cases. Oncocytomas of the minor salivary glands  are exceedingly rare.   The tumor appears as a firm, slowly growing, painless  mass that rarely exceeds 4 cm in diameter. Parotid oncocy-  tomas usually are found in the superficial lobe and are  clinically indistinguishable from other benign tumors. On  occasion, bilateral tumors can occur, although these may  represent examples of oncocytosis (multinodular onco-  cytic hyperplasia) (see next topic).    The oncocytoma is usually a well-circumscribed tumor that  is composed of sheets of large polyhedral cells (oncocytes),  with abundant granular, eosinophilic cytoplasm (Fig.  11-43). Sometimes these cells form an alveolar or glandular  pattern. The cells have centrally located nuclei that can  vary from small and hyperchromatic to large and vesicular.  Little stroma is present, usually in the form of thin fibro-  vascular septa. An associated lymphocytic infiltrate may be  noted.    The granularity of the cells corresponds to an overabun-  dance of mitochondria, which can be demonstrated by elec-  tron microscopy. These granules also can be identified on  light microscopic examination with a phosphotungstic acid  hematoxylin (PTAH) stain. The cells also contain glycogen,  as evidenced by their positive staining with the periodic  acid-Schiff (PAS) technique but by negative PAS staining  after digestion with diastase.   Oncocytomas may contain variable numbers of cells  with a clear cytoplasm. In rare instances, these clear cells  may compose most of the lesion and create difficulty in  distinguishing the tumor from low-grade salivary clear cell  adenocarcinoma or metastatic renal cell carcinoma.    Oncocytomas are best treated by surgical excision. In the  parotid gland, this usually entails partial parotidectomy  (lobectomy) to avoid violation of the tumor capsule. The  facial nerve should be preserved whenever possible. For  tumors in the submandibular gland, treatment consists of  total removal of the gland. Oncocytomas of the oral minor  salivary glands should be removed with a small margin of  normal surrounding tissue.   ‘The prognosis after removal is good, with a low rate of  recurrence. However, oncocytomas of the sinonasal glands  can be locally aggressive and have been considered to be  low-grade malignancies. Rare examples of histopathologi-  cally malignant oncocytomas (oncocytic carcinoma) also  have been reported. These carcinomas have a relatively poor  prognosis.    Oncocytic metaplasia is the transformation of ductal and  acinar cells to oncocytes. Such cells are uncommon before  the age of 50; however, as people get older, occasional onco-  cytes are common findings in the salivary glands. Focal    oncocytic metaplasia also may be a feature of other salivary  gland tumors. Oncocytosis refers to both the proliferation  and the accumulation of oncocytes within salivary gland  tissue. It may mimic a tumor, both clinically and micro-  scopically, but it also is considered to be a metaplastic  process rather than a neoplastic one.    Oncocytosis is found primarily in the parotid gland;  however, in rare instances, it may involve the subman-  dibular or minor salivary glands. It can be an incidental  finding in otherwise normal salivary gland tissue, but it  may be extensive enough to produce clinical swelling.  Usually the proliferation is multifocal and nodular, but  sometimes the entire gland can be replaced by oncocytes  (diffuse hyperplastic oncocytosis). As with other onco-  cytic proliferations, oncocytosis occurs most frequently in  older adults.    Microscopic examination usually reveals focal nodular col-  lections of oncocytes within the salivary gland tissue. These  enlarged cells are polyhedral and demonstrate abundant  granular, eosinophilic cytoplasm as a result of the prolifera-  tion of mitochondria. On occasion, these cells may have a  clear cytoplasm from the accumulation of glycogen (Fig.  11-44). The multifocal nature of the proliferation may be  confused with that of a metastatic tumor, especially when  the oncocytes are clear in appearance.    Oncocytosis is a benign condition and often is discovered  only as an incidental finding. No further treatment is neces-  sary, and the prognosis is excellent.    @ Fig. 11-44 Oncocytosis. Multifocal collections of clear oncocytes  (arrows) in the parotid gland.    Warthin tumor is a benign neoplasm that occurs almost  exclusively in the parotid gland. Although it is much less  common than the pleomorphic adenoma, it represents the  second most common benign parotid tumor, accounting for  5% to 22% of all parotid neoplasms. The name adenolym-  phoma also has been used for this tumor, but this term  should be avoided because it overemphasizes the lymphoid  component and may give the mistaken impression that the  lesion is a type of lymphoma. Analyses of the epithelial and  lymphoid components of the Warthin tumor usually have  shown both to be polyclonal; this suggests that this lesion  may not represent a neoplasm but would be better classified  as a tumorlike process. However, a small percentage of  Warthin tumors have been shown to demonstrate a chro-  mosomal translocation and fusion gene transcript similar to  that seen in mucoepidermoid carcinoma. ‘This finding may  indicate that subsets of these tumors are true neoplasms,  although such examples also could represent evidence of  an early mucoepidermoid carcinoma developing within a  Warthin tumor.   The pathogenesis of Warthin tumor is uncertain. The  traditional hypothesis suggests that it arises from hetero-  topic salivary gland tissue found within parotid lymph  nodes. However, researchers have also suggested that these  tumors may develop from a proliferation of salivary gland  ductal epithelium that is associated with secondary forma-  tion of lymphoid tissue. A number of studies have demon-  strated a strong association between the development of this  tumor and smoking. Smokers have an eightfold greater risk  for Warthin tumor than do nonsmokers.    The Warthin tumor usually appears as a slowly growing,  painless, nodular mass of the parotid gland (Fig. 11-45). It  may be firm or fluctuant to palpation. The tumor most  frequently occurs in the tail of the parotid near the angle of  the mandible, and it may be noted for many months before  the patient seeks a diagnosis. One unique feature is the  tendency of Warthin tumor to occur bilaterally, which has  been noted in 5% to 17% of reported cases. Most of these  bilateral tumors do not occur simultaneously but are meta-  chronous (occurring at different times).   In rare instances, the Warthin tumor has been reported  within the submandibular gland or minor salivary glands.  However, because the lymphoid component is often less  pronounced in these extraparotid sites, the pathologist  should exercise caution to avoid overdiagnosis of a lesion  better classified as a papillary cystadenoma or a salivary duct  cyst with oncocytic ductal metaplasia.   Warthin tumor most often occurs in older adults, with  peak prevalence in the sixth and seventh decades of life. The  observed frequency of this tumor is much lower in blacks    © Fig. 11-45 Warthin Tumor. Mass in the tail of the parotid gland.  (Courtesy of Dr. George Blozis.)    than in whites. Most studies show a decided male predilec-  tion, with some early studies demonstrating a male-to-  female ratio up to 10: 1. However, more recent investigations  show a more balanced sex ratio. Because Warthin tumors  have been associated with cigarette smoking, this changing  sex ratio may be a reflection of a more equal prevalence of  smoking in women over the past few decades. This associa-  tion with smoking also may help explain the frequent bilat-  erality of the tumor, because any tumorigenic effects of  smoking would be manifested in both parotids.    The Warthin tumor has one of the most distinctive histo-  pathologic patterns of any tumor in the body. Although the  term papillary cystadenoma lymphomatosum is cumber-  some, it accurately describes the salient microscopic  features.   ‘The tumor is composed of a mixture of ductal epithelium  and a lymphoid stroma (Figs. 11-46 and 11-47). The epi-  thelium is oncocytic in nature, forming uniform rows of  cells surrounding cystic spaces. The cells have abundant,  finely granular eosinophilic cytoplasm and are arranged in  two layers. The inner luminal layer consists of tall columnar  cells with centrally placed, palisaded, and slightly hyper-  chromatic nuclei. Beneath this is a second layer of cuboidal  or polygonal cells with more vesicular nuclei. The lining  epithelium demonstrates multiple papillary infoldings that  protrude into the cystic spaces. Focal areas of squamous    metaplasia or mucous cell prosoplasia may be seen. The  epithelium is supported by a lymphoid stroma that fre-  quently shows germinal center formation.    Surgical removal is the treatment of choice for most patients  with Warthin tumor. The procedure usually is easily accom-  plished because of the superficial location of the tumor.  Some surgeons prefer local resection with minimal sur-  rounding tissue; others opt for superficial parotidectomy to  avoid violating the tumor capsule and because a tentative  diagnosis may not be known preoperatively. If a confident  diagnosis of Warthin tumor can be made by fine-needle  aspiration cytology of a non-suspicious parotid growth,  some clinicians will elect to manage the patient conserva-  tively with regular follow-up visits rather than surgery.   A 2% to 6% recurrence rate has been reported following  surgery. Many authors, however, believe that the tumor is  frequently multicentric in nature; therefore, it is difficult to  determine whether these are true recurrences or secondary  tumor sites. Malignant Warthin tumors (carcinoma ex  papillary cystadenoma lymphomatosum) have been  reported but are exceedingly rare.    The term monomorphic adenoma originally was used to  describe a group of benign salivary gland tumors demon-  strating a more uniform histopathologic pattern than the  common pleomorphic adenoma. In some classification  schemes, a variety of tumors were included under the broad  heading of monomorphic adenoma, including Warthin  tumor, oncocytoma, basal cell adenoma, and canalicular  adenoma. Other authors have used this term more specifi-  cally as a synonym just for the basal cell adenoma or cana-  licular adenoma. Because of its ambiguous nature, the term  monomorphic adenoma probably should be avoided, and  each of the tumors mentioned should be referred to by its  more specific name.    The canalicular adenoma is an uncommon tumor that  occurs almost exclusively in the minor salivary glands.  Because of its uniform microscopic pattern, the canalicular  adenoma also has been called a monomorphic adenoma.  However, because this term also has been applied to other  tumors, its use probably should be discontinued. Likewise,  the term basal cell adenoma sometimes has been used  synonymously for this tumor but should be avoided because  it refers to a separate tumor with different clinical features  (see next topic).    The canalicular adenoma shows a striking predilection for  the upper lip, with nearly 75% occurring in this location.  It represents the first or second most common tumor (along  with pleomorphic adenoma) of the upper lip. The buccal  mucosa is the second most common site. Occurrence in  other minor salivary glands is uncommon, and canalicular  adenomas of the parotid gland are rare.   The tumor nearly always occurs in older adults, with  peak prevalence in the seventh decade of life. There is a  definite female predominance, ranging from 1.2 to 1.8  females for each male.   The canalicular adenoma appears as a slowly growing,  painless mass that usually ranges from several millimeters to  2 cm (Fig. 11-48). It may be firm or somewhat fluctuant  to palpation. The overlying mucosa may be normal in color  or bluish and can be mistaken for a mucocele. However,  mucoceles of the upper lip are rare. In some instances, the  lesion has been noted to be multifocal, with multiple sepa-  rate tumors discovered in the upper lip or buccal mucosa.    The microscopic pattern of canalicular adenoma is mono-  morphic in nature. This pattern is characterized by single-  layered cords of columnar or cuboidal epithelial cells  with deeply basophilic nuclei (Fig. 11-49). In some areas,    © Fig. 11-48 Canalicular Adenoma. Mass in the upper lip. (Cour-  tesy of Dr. John Fantasia.)    @ Fig. 11-49 Canalicular Adenoma. Uniform columnar cells forming  canal-like ductal structures.    adjacent parallel rows of cells may be seen, resulting in a  bilayered appearance of the tumor cords. These cells enclose  ductal structures, sometimes in the form of long canals.  Larger cystic spaces often are created, and the epithelium  may demonstrate papillary projections into the cystic  lumina. The tumor cells are supported by a loose connective  tissue stroma with prominent vascularity. Unlike the appear-  ance in pleomorphic adenomas, stromal alterations, such as  chondroid metaplasia, do not occur. A thin, fibrous capsule  often surrounds the tumor, although satellite islands are  observed in the surrounding salivary gland tissue in approxi-  mately 22% to 24% of cases, which explains the tendency  for multifocal tumors.    The canalicular adenoma is best treated by local surgical  excision. Recurrence is uncommon and actually may repre-  sent cases that are multifocal in nature.    The basal cell adenoma is a benign salivary tumor that  derives its name from the basaloid appearance of the tumor    cells. It isan uncommon neoplasm that represents only 1%  to 4% of all salivary tumors. Because of its uniform histo-  pathologic appearance, it often has been classified as one of  the monomorphic adenomas. However, as mentioned pre-  viously, this term probably should be avoided because of its  imprecise and frequently confusing definition. In addition,  ultrastructural and immunohistochemical studies have  shown that basal cell adenomas are not necessarily com-  posed of only one cell type but sometimes of a combination  of salivary ductal epithelium and myoepithelial cells. The  basal cell adenoma shows some histopathologic similarity  to the canalicular adenoma; in the past, these two terms  have been used synonymously. However, histopathologic  and clinical differences warrant that they be considered as  distinct entities.    Unlike the canalicular adenoma, the basal cell adenoma is  primarily a tumor of the parotid gland, with around 75%  of all cases occurring there. However, the minor glands  represent the second most common site, specifically the  glands of the upper lip and buccal mucosa. The tumor can  occur at any age but is most common in middle-aged and  older adults, with peak prevalence in the seventh decade of  life. The tumor appears to be more common in women,  with some studies showing as high as a 2: 1 female-to-male  ratio.   Clinically, the basal cell adenoma appears as a slowly  growing, freely movable mass similar to a pleomorphic  adenoma. Most tumors are less than 3 cm in diameter.  Parotid tumors usually are located within the superficial  lobe of the gland.   One subtype, the membranous basal cell adenoma,  deserves separate mention. This form of the tumor appears  to be hereditary, often occurring in combination with skin  appendage tumors, such as dermal cylindromas and  trichoepitheliomas. Multiple bilateral tumors may develop  within the parotids. Because these tumors often bear a  histopathologic resemblance to the skin tumors, they also  have been called dermal analogue tumors.    The basal cell adenoma is usually encapsulated or well cir-  cumscribed. The most common subtype is the solid variant,  which consists of multiple islands and cords of epithelial  cells that are supported by a small amount of fibrous stroma.  The peripheral cells of these islands are palisaded and cuboi-  dal to columnar in shape, similar to the microscopic appear-  ance of basal cell carcinoma. These peripheral cells are  frequently hyperchromatic; the central cells of the islands  tend to have paler staining nuclei. The central cells occa-  sionally form eddies or keratin pearls.   The trabecular subtype demonstrates narrow cordlike  epithelial strands (Fig. 11-50). The tubular subtype is char-  acterized by the formation of small, round, ductlike    structures. Some basal cell adenomas demonstrate zones  with a cribriform pattern that can mimic adenoid cystic  carcinoma. Frequently, a mixture of histopathologic sub-  types is seen.   The membranous basal cell adenoma exhibits multiple  large lobular islands of tumor that are molded together in  a jigsaw puzzle fashion. These islands are surrounded by a  thick layer of hyaline material, which represents redupli-  cated basement membrane. Similar hyaline droplets also are  often found among the epithelial cells. The microscopic  appearance is similar to that of a dermal cylindroma, one  of the skin tumors with which it is often associated.    The treatment of basal cell adenoma is similar to that of  pleomorphic adenoma and consists of complete surgical  removal. Recurrence is rare for most histopathologic sub-  types. However, the membranous subtype has a 25% to  37% recurrence rate, possibly related to its multifocal  nature.   The malignant counterpart of the basal cell adenoma is  the basal cell adenocarcinoma. Most basal cell adenocar-  cinomas arise de novo, but some examples develop from  malignant degeneration of a preexisting basal cell adenoma.  Fortunately, these tumors have a relatively good prognosis;  although local recurrence is common, the tumor rarely  metastasizes or results in death.    A number of salivary gland tumors can be characterized  microscopically by a papillomatous pattern, the most  common being Warthin tumor (papillary cystadenoma  lymphomatosum). The sialadenoma papilliferum, intra-  ductal papilloma, and inverted ductal papilloma are    three rare salivary tumors that also show unique papilloma-  tous features.   It also should be mentioned that, on occasion, the  common squamous papilloma (see page 332) of the oral  mucosa will arise at the site where a minor salivary gland  duct merges with the surface epithelium. Because of this  location, such squamous papillomas may contain scattered  mucous cells within the exophytic papillary growth, and  these lesions have sometimes been called ductal papillomas.  However, it should be emphasized that these lesions are  surface papillomas and not primary salivary gland tumors.    The sialadenoma papilliferum most commonly arises from  the minor salivary glands, especially on the palate, although  it also has been reported in the parotid gland. It usually is  seen in older adults and has a 1.5:1.0 male-to-female ratio.  The tumor appears as an exophytic, papillary surface growth  that is clinically similar to the common squamous papil-  loma (Fig. 11-51).   The intraductal papilloma is an ill-defined lesion that  often has been confused with other salivary gland lesions,  such as the papillary cystadenoma. It usually occurs in  adults and is most common in the minor salivary glands,  where it appears as a submucosal swelling.   The inverted ductal papilloma is a rare tumor that has  been described only in the minor salivary glands of adults.  The lower lip and mandibular vestibule are the most  common locations. The lesion usually appears as an asymp-  tomatic nodule, which sometimes may show a pit or inden-  tation in the overlying surface mucosa (Fig. 11-52).    At low-power magnification, the sialadenoma papilliferum  is somewhat similar to the squamous papilloma, exhibiting  multiple exophytic papillary projections that are covered by  stratified squamous epithelium. This epithelium is contigu-  ous with a proliferation of papillomatous ductal epithelium    @ Fig. 11-51 Sialadenoma Papilliferum. Exophytic papillary mass  on the palate. (Courtesy of Dr. Peter Lyu.)    found below the surface and extending downward into the  deeper connective tissues (Fig. 11-53). Multiple ductal  lumina are formed, which characteristically are lined by a  double-rowed layer of cells consisting of a luminal layer of  tall columnar cells and a basilar layer of smaller cuboidal  cells. These ductal cells often have an oncocytic appearance.  An inflammatory infiltrate of plasma cells, lymphocytes,    ie. “ a = | .  e Fig. 11-52 Inverted Ductal Papilloma. Exophytic mass with  central papillary projections on the lower labial mucosa. (Courtesy of  Dr. Amy Bogardus.)    showing a papillary surface tumor with associated ductal structures in  the superficial lamina propria. B, High-power view of cystic areas lined  by papillary, oncocytic epithelium.    @ Fig. 11-54 Inverted Ductal Papilloma. Papillary intraductal pro-  liferation located beneath the mucosal surface. Higher-power view  shows both squamous cells and mucous cells (inset). (Courtesy of Dr.  Dean K. White.)    and neutrophils is characteristically present. Because of their  microscopic similarity, this tumor has been considered to  be an analogue of the cutaneous syringocystadenoma  papilliferum.   The intraductal papilloma exhibits a dilated, unicystic  structure that is located below the mucosal surface. It is  lined by a single or double row of cuboidal or columnar  epithelium, which has multiple arborizing papillary projec-  tions into the cystic lumen. In contrast, the inverted ductal  papilloma is composed primarily of a proliferation of squa-  moid epithelium with multiple thick, bulbous papillary  projections that fill the ductal lumen (Fig. 11-54). This  epithelium may be contiguous with the overlying mucosal  epithelium, communicating with the surface through a  small pore-like opening. Although the tumor is primarily  squamous in nature, the luminal lining cells of the papillary  projections are often cuboidal or columnar in shape, with  scattered mucus-producing cells. Jn situ hybridization anal-  ysis has shown positivity for human papillomavirus (HPV)  types 6 and 11 in both the surface and inverted epithelium  of some inverted ductal papillomas.    All three forms of ductal papilloma are best treated by con-  servative surgical excision. Recurrence is rare.    Mucoepidermoid carcinoma is the most common salivary  gland malignancy. Because of its highly variable biologic    @ Fig. 11-55 Mucoepidermoid Carcinoma. Blue-pigmented mass  of the posterior lateral hard palate. (Courtesy of Dr. James F.  Drummond.)    potential, it was originally called mucoepidermoid tumor.  The term recognized one subset that acted in a malignant  fashion and a second group that appeared to behave in a  benign fashion with favorable prognosis. However, research-  ers later recognized that even low-grade tumors occasionally  will exhibit malignant behavior; therefore, the term muco-  epidermoid carcinoma is the preferred designation.   The pathogenesis of this tumor is uncertain, although  radiation exposure may be one risk factor. Published series  have reported that 38% to 82% of mucoepidermoid carci-  nomas will show a t(11;19) reciprocal translocation, which  results in the production of the CRT'C1-MAML2 fusion  oncogene. This translocation is identified more frequently  in low- and intermediate-grade tumors.    Most large series show mucoepidermoid carcinoma to be  the most common malignant salivary gland neoplasm, com-  prising 4% to 10% of all major gland tumors and 13% to  23% of minor gland tumors. The tumor occurs fairly evenly  over a wide age range, extending from the second to seventh  decades of life. Rarely is it seen in the first decade of life.  However, mucoepidermoid carcinoma is the most common  malignant salivary gland tumor in children.   The mucoepidermoid carcinoma is most common in  the parotid gland and usually appears as an asymptomatic  swelling. Most patients are aware of the lesion for 1 year  or less, although some report a mass of many years’ dura-  tion. Pain or facial nerve palsy may develop, usually in  association with high-grade tumors. The minor glands con-  stitute the second most common site, especially the palate  (Fig. 11-55). Minor gland tumors also typically appear as  asymptomatic swellings, which are sometimes fluctuant and  have a blue or red color that can be mistaken clinically  for a mucocele. Although the lower lip, floor of mouth,  tongue, and retromolar pad areas are uncommon locations  for salivary gland neoplasia, the mucoepidermoid carci-  noma is the most common salivary tumor in each of these    sites (Fig. 11-56). Intraosseous tumors also may develop  in the jaws (see page 457).    As its name implies, the mucoepidermoid carcinoma is com-  posed of a mixture of mucus-producing cells and squamous  (epidermoid) cells (Figs. 11-57 to 11-59). The mucous cells  vary in shape but contain abundant foamy cytoplasm that  stains positively with mucin stains. The epidermoid cells are  characterized by squamoid features, often demonstrating a  polygonal shape, intercellular bridges, and, rarely, keratini-  zation. In addition, a third type of cell—the intermediate  cell—is typically present and is believed to be a progenitor  of both the mucous and the epidermoid cells. Intermediate  cells vary in appearance from small, basaloid (“maternal”)  cells to slightly larger ovoid cells with scant, pale eosino-  philic cytoplasm. Some tumors also show variable numbers  of clear cells, which sometimes can predominate the micro-  scopic picture (Fig. 11-60). An associated lymphoid    infiltrate is not unusual and may be so prominent in some  cases that the lesion can be mistaken for a metastatic tumor  within a lymph node. Other variants of mucoepidermoid  carcinoma can demonstrate numerous oncocytes or promi-  nent sclerosis of the tumor stroma.    @ Fig. 11-58 Mucoepidermoid Carcinoma. This low-grade tumor  shows numerous large mucous cells surrounding a cystic space.    showing a sheet of squamous cells with focal mucus-producing cells  (left).    moderately well-differentiated tumor showing ductal and cystic spaces  surrounded by mucous and squamous cells.    e Fig. 11-61 Mucoepidermoid Carcinoma. High-power view  showing a sheet of pleomorphic squamous epithelial cells intermixed  with mucous and intermediate cells.    Traditionally, mucoepidermoid carcinomas have been  categorized into one of three histopathologic grades based  on the following:   Low-grade tumors show prominent cyst formation,  minimal cellular atypia, and a relatively high proportion of  mucous cells. High-grade tumors consist of solid islands of  squamous and intermediate cells, which can demonstrate  considerable pleomorphism and mitotic activity (Fig.  11-61). Mucus-producing cells may be infrequent, and the  tumor sometimes can be difficult to distinguish from squa-  mous cell carcinoma.   Intermediate-grade tumors show features that fall  between those of the low-grade and high-grade neoplasms.  Cyst formation occurs but is less prominent than that  observed in low-grade tumors. All three major cell types are  present, but the intermediate cells usually predominate.  Cellular atypia may or may not be observed.   However, some authors have found that the relative pro-  portion of the three different cell types does not necessarily  correlate with prognosis. To overcome this, two expert  groups have proposed evaluation schemes based on signifi-  cant microscopic parameters, to which relative point values  have been assigned to determine the grade of the tumor  (Table 11-12).    The treatment of mucoepidermoid carcinoma is predicated  by the location, histopathologic grade, and clinical stage of  the tumor. Early-stage tumors of the parotid often can be  treated by subtotal parotidectomy with preservation of the  facial nerve. Advanced tumors may necessitate total removal    From Auclair PL, Goode RK, Ellis GL: Mucoepidermoid carcinoma of  intraoral salivary glands: evaluation and application of grading criteria in  143 cases, Cancer 69:2021-2030, 1992; Brandwein MS, Ivanov kK,  Wallace DI, et al: Mucoepidermoid carcinoma: a clinicopathologic study  of 80 patients with special reference to histological grading, Am J Surg  Pathol 25:835-845, 2001.    of the parotid gland, with sacrifice of the facial nerve. Sub-  mandibular gland tumors are treated by total removal of the  gland. Mucoepidermoid carcinomas of the minor glands  usually are treated by assured surgical excision. For low-  grade neoplasms, only a modest margin of surrounding  normal tissue may need to be removed, but high-grade or  large tumors warrant wider resection, similar to that required  for squamous cell carcinomas. If there is underlying bone  destruction, then the involved bone must be excised.    Neck dissection is indicated for patients with clinical  evidence of metastatic disease and also may be considered  for patients with larger or high-grade tumors. Postoperative  radiation therapy also may be used for more aggressive  tumors.   The prognosis depends on the grade and stage of the  tumor. Patients with low-grade tumors generally have a  good prognosis. For most primary sites, local recurrences or  regional metastases are uncommon, and around 90% to  98% of patients are cured. The prognosis for those with  intermediate-grade tumors is slightly worse than that for  low-grade tumors. The outlook for patients with high-grade  tumors is more guarded, with only 30% to 54% of patients  surviving. Tumors that exhibit the t(11;19) translocation  and CRTC1-MAML2 fusion gene transcript have a better  prognosis than tumors without this translocation.   For unknown reasons, submandibular gland tumors are  associated with a poorer outlook than those in the parotid  gland. Mucoepidermoid carcinomas of the oral minor sali-  vary glands generally have a good prognosis, probably  because they are mostly low- to intermediate-grade tumors.  However, tumors of the tongue and floor of the mouth are  less predictable and may exhibit more aggressive behavior.    On rare occasions, salivary gland tumors arise centrally  within the jaws. The most common and best-recognized  intrabony salivary tumor is the intraosseous mucoepider-  moid carcinoma. However, other salivary tumors have  been reported to develop within the jaws, including adenoid  cystic carcinoma, benign and malignant mixed tumors,  adenocarcinoma, acinic cell adenocarcinoma, epithelial-  myoepithelial carcinoma, and monomorphic adenoma.   Several hypotheses have been proposed to explain the  pathogenesis of intraosseous salivary tumors. One theory  suggests that they may arise from ectopic salivary gland  tissue that was developmentally entrapped within the jaws.  However, the discovery of ectopic salivary tissue is uncom-  mon in biopsy specimens from the jaws; therefore, this  seems an unlikely source for most intrabony salivary tumors.  Some maxillary tumors may arise from glands of the sinus  lining, but this is often difficult to prove or disprove. The  most likely source for most intraosseous tumors is odonto-  genic epithelium. Mucus-producing cells are common in  odontogenic cyst linings, especially dentigerous cysts (see  page 632). In addition, many intraosseous mucoepidermoid  carcinomas develop in association with impacted teeth or  odontogenic cysts.    Intraosseous mucoepidermoid carcinomas are most common  in middle-aged adults and demonstrate a slight female    @ Fig. 11-62 Intraosseous Mucoepidermoid Carcinoma. Multi-  locular lesion of the posterior mandible. (Courtesy of Dr. Joseph F.  Finelli.)    predilection. They are more common in the mandible than  in the maxilla and are most often seen in the molar-ramus  area. The most frequent presenting symptom is cortical  swelling, although some lesions may be discovered as inci-  dental findings on radiographs. Pain, trismus, and paresthe-  sia are reported less frequently.   Radiographs usually reveal either a unilocular or multi-  locular radiolucency with well-defined borders (Fig. 11-62).  However, some examples are characterized by a more irregu-  lar and ill-defined area of bone destruction. Some cases are  associated with an unerupted tooth and, therefore, clinically  may suggest an odontogenic cyst or tumor.    The microscopic appearance of intraosseous mucoepider-  moid carcinoma is similar to that of its soft tissue counter-  part. Most tumors are low-grade lesions, although high-grade  mucoepidermoid carcinomas also have been reported within  the jaws.    The primary treatment modality for patients with intraos-  seous mucoepidermoid carcinoma is surgery; adjunctive  radiation therapy also sometimes is used. Radical surgical  resection offers a better chance for cure than do more con-  servative procedures, such as enucleation or curettage. The  local recurrence rate with conservative treatment is 40%, in  contrast to 13% for more radical treatment. Metastasis has  been reported in about 12% of cases. The overall prognosis  is fairly good; around 10% of patients die, usually as a result  of local recurrence of the tumor.    The acinic cell carcinoma is a salivary gland malignancy  with cells that show serous acinar differentiation. Because    many of these tumors act in a nonaggressive fashion and are  associated with a good prognosis, this neoplasm formerly  was called acinic cell tumor, a nonspecific designation  that did not indicate whether the lesion was benign or  malignant. However, because some of these tumors do  metastasize or recur and cause death, it is generally agreed  today that acinic cell carcinoma should be considered a  low-grade malignancy.   Many cases previously reported as acinic cell carcinoma,  but which are poor in zymogen granules, would be reclas-  sified today as examples of a newly delineated salivary  neoplasm—mammary analogue secretory carcinoma (see  next topic). This is especially true for purported acinic cell  carcinomas in non-parotid sites. Therefore, evaluation of  the literature and data on acinic cell carcinoma prior to  2010 is made more difficult.    Around 85% to 90% of all acinic cell carcinomas occur in  the parotid gland, a logical finding because this is the largest  gland and one that is composed entirely of serous elements  (Fig. 11-63). Most surveys have shown that this neoplasm  makes up 2% to 3% of all parotid tumors, although one  study showed it represented 8.6% of all parotid tumors (see  Table 11-4). It is much less common in the submandibular  gland, which is the site for only 2.7% to 5% of these  tumors. About 9% of all acinic cell carcinomas reportedly  develop in the oral minor salivary glands, with the buccal  mucosa, lips, and palate being the most common sites.  Overall, around 1.3% to 3.8% of all minor salivary gland  tumors have been reported to be acinic cell carcinomas,  although it is likely that many of these cases would be reclas-  sified today as mammary analogue secretory carcinoma.  The tumor occurs over a broad age range, with a rela-  tively even peak prevalence stretching from the second to  the seventh decades of life; the mean age is in the middle  40s to early 50s. The tumor usually appears as a slowly  growing mass, and the lesion often is present for many  months or years before a diagnosis is made. The tumor may    @ Fig. 11-63 Acinic Cell Carcinoma. Large, firm mass of the right  parotid gland.    be otherwise asymptomatic, although associated pain or  tenderness sometimes is reported. Facial nerve paralysis is  an infrequent but ominous sign for parotid tumors.    Acinic cell carcinomas are highly variable in their micro-  scopic appearance. The tumor often is well circumscribed  and sometimes may even appear encapsulated; however,  some tumors exhibit an infiltrative growth pattern. The  most characteristic cell is one with features of the serous  acinar cell, with abundant granular basophilic cytoplasm  and a round, darkly stained eccentric nucleus. These cells  are fairly uniform in appearance, and mitotic activity is  uncommon. Other cells may resemble intercalated duct  cells, and some tumors also have cells with a clear, vacuo-  lated cytoplasm. On rare occasions, the tumor may demon-  strate high-grade features, including pleomorphism,  increased mitotic activity, and necrosis.   Several growth patterns have been described. The solid  variety consists of numerous well-differentiated acinar cells  arranged in a pattern that resembles normal parotid gland  tissue (Figs. 11-64 and 11-65). In the microcystic variety,  multiple small cystic spaces are created that may contain  some mucinous or eosinophilic material. In the papillary-  cystic variety, larger cystic areas are formed that are lined  by epithelium having papillary projections into the cystic  spaces. The follicular variety has an appearance similar to  that of thyroid tissue. A lymphoid infiltrate, sometimes with  germinal center formation, is not unusual.    Acinic cell carcinomas confined to the superficial lobe of  the parotid gland are best treated by lobectomy; for those  in the deep lobe, total parotidectomy is usually necessary.  The facial nerve may need to be sacrificed if it is involved  by tumor. Submandibular tumors are managed by total  removal of the gland, and minor gland tumors are treated  with assured surgical excision. Lymph node dissection is not    @ Fig. 11-64 Acinic Cell Carcinoma. Parotid tumor demonstrating  sheet of granular, basophilic serous acinar cells.    @ Fig. 11-65 Acinic Cell Carcinoma. High-power view of serous  cells with basophilic, granular cytoplasm.    indicated unless there is clinical evidence of metastatic  disease. Adjunctive radiation therapy may be considered for  uncontrolled local disease.   The acinic cell carcinoma is associated with one of the  better prognoses of any of the malignant salivary gland  tumors. Approximately 10% to 20% of patients have recur-  rences locally, and metastases develop in 8% to 11% of  patients. About 10% of patients will die of their disease,  with high-grade tumors showing a much worse prognosis  than that for low-grade tumors. The outcome for minor  gland tumors is better than that for tumors arising in the  major glands.    Mammary analogue secretory carcinoma is a newly rec-  ognized salivary gland malignancy with histopathologic and  molecular features that are similar to secretory carcinoma  of the breast. Both of these tumors harbor a balanced chro-  mosomal translocation, t(12;15)(p13;q25), which results in  the formation of an ETV6-NTRK3 fusion gene. Prior to  its recognition in 2010, many examples of mammary ana-  logue secretory carcinoma probably were diagnosed as  acinic cell carcinoma, which has overlapping light micro-  scopic features (see legend for Fig. 11-66).    The most common site of origin for the mammary analogue  secretory carcinoma is the parotid gland, which accounts  for 58% of reported cases. The minor salivary glands (31%)  and submandibular gland (9%) are less frequent sites. The  lips, soft palate, and buccal mucosa are the most common  intraoral subsites (Fig. 11-66). The mean age is 47 years,  and the tumor has been reported to occur slightly more  often in males than in females. The lesion usually presents  as a slowly growing, painless mass, which the patient may    © Fig. 11-66 Mammary Analogue Secretory Carcinoma. Bluish  swelling of the anterior buccal mucosa, which could be mistaken clini-  cally for a mucocele. (This tumor originally was diagnosed as acinic  cell carcinoma before mammary analogue secretory carcinoma was  recognized as a distinct entity. This same image was used to illustrate  an acinic cell carcinoma in the previous edition of this text!)    ® Fig. 11-67 Mammary Analogue Secretory Carcinoma. Medium-  power view showing papillary-cystic spaces and small solid islands.    have noticed for months or many years. Occasional exam-  ples have been associated with some degree of discomfort.    Mammary analogue secretory carcinoma shows microscopic  features that are similar to those of secretory carcinoma of  the breast. The tumor cells exhibit bland, vesicular nuclei  surrounded by slightly granular or vacuolated cytoplasm.  These cells are variably arranged as solid, tubular, microcys-  tic, or macrocystic structures. Larger cystic spaces may  exhibit papillary infolding of tumor cells with a “hobnail”  appearance (Fig. 11-67). Mitotic figures are rare.   The tumor cells show diffuse immunoreactivity for S-100  protein, vimentin, and mammaglobin. The chromosomal  translocation can be confirmed via fluorescent in situ    hybridization (FISH) using the ETV6 break-apart probe,  or by detection of the ETV6-NTRK3 fusion gene by reverse  transcription-polymerase chain reaction (RT-PCR).    Although data on treatment and outcome are limited,  mammary analogue secretory carcinoma appears to be a  low-grade malignancy with a generally favorable prognosis.  However, local tumor recurrence and metastases occasion-  ally have been documented, including several patients who  died of tumor. Treatment most often has consisted of surgi-  cal resection, sometimes supplemented by adjuvant radia-  tion therapy.    * MALIGNANT MIXED TUMORS  (CARCINOMA EX PLEOMORPHIC  ADENOMA; CARCINOMA EX MIXED  TUMOR; CARCINOSARCOMA;  METASTASIZING MIXED TUMOR)    Malignant mixed tumors represent malignant counter-  parts to the benign mixed tumor or pleomorphic adenoma.  These uncommon neoplasms constitute 2% to 4% of all  salivary tumors and can be divided into three categories:  1. Carcinoma ex pleomorphic adenoma (carcinoma ex   The most common of these is the carcinoma ex pleo-  morphic adenoma, which is characterized by malignant  transformation of the epithelial component of a previously  benign pleomorphic adenoma. The carcinosarcoma is a  rare “mixed” tumor in which both carcinomatous and sar-  comatous elements are present. The metastasizing mixed  tumor has histopathologic features that are identical to the  common pleomorphic adenoma (mixed tumor). In spite of  its benign appearance, however, the lesion metastasizes. The  metastatic tumor also has a benign microscopic appearance,  usually similar to that of the primary lesion.    There is fairly convincing evidence that the carcinoma ex  pleomorphic adenoma represents a malignant transforma-  tion within what was previously a benign neoplasm. First  of all, the mean age of patients with this tumor is about  15 years older than that for the benign pleomorphic  adenoma. It is most common in middle-aged and older  adults, with peak prevalence in the sixth to eighth decades  of life. In addition, patients may report that a mass has  been present for many years, sometimes undergoing a recent  rapid growth with associated pain or ulceration. However,  some tumors may have a short duration. The histopatho-  logic features, which are discussed later, also support    malignant transformation of a benign pleomorphic  adenoma. It has been noted that the risk for malignant  change in a pleomorphic adenoma increases with the dura-  tion of the tumor.   More than 80% of cases of carcinoma ex pleomorphic  adenoma are seen within the major glands, primarily the  parotid gland (Fig. 11-68). Nearly two-thirds of minor sali-  vary gland cases occur on the palate (Fig. 11-69). Although  pain or recent rapid growth is not unusual, many cases  present as a painless mass that is indistinguishable from a  benign tumor. Parotid tumors may produce facial nerve    © Fig. 11-68 Carcinoma Ex Pleomorphic Adenoma. Mass of the  parotid gland.    e Fig. 11-69 Carcinoma Ex Pleomorphic Adenoma. Granular  exophytic and ulcerated mass filling the vault of the palate.    The carcinosarcoma is an extremely rare tumor. Most cases  have been reported in the parotid gland, but the lesion also  has been seen in the submandibular gland and minor sali-  vary glands. The clinical signs and symptoms are similar to  those of the carcinoma ex pleomorphic adenoma. Some  patients have a previous history of a benign pleomorphic  adenoma, although other cases appear to arise de novo.    The metastasizing mixed tumor is also quite rare. As with  other malignant mixed tumors, most cases originate in  the parotid gland, but the primary tumor also may occur  in the submandibular gland or minor salivary glands.  Metastases have been found most frequently in the bones  or lung, but they also can occur in other sites, such as  regional lymph nodes, skin, or the liver. Most patients  have a history of a benign mixed tumor, which may have  been excised many years earlier. Many times the primary  tumor exhibits multiple recurrences before metastasis  occurs.    The carcinoma ex pleomorphic adenoma shows a variable  microscopic appearance. Areas of typical benign pleomor-  phic adenoma usually can be found and may constitute  most or only a small portion of the lesion. However, exten-  sive sampling may be required to identify the benign com-  ponent in some cases. Within the tumor are areas of  malignant degeneration of the epithelial component, char-  acterized by cellular pleomorphism and abnormal mitotic  activity (Fig. 11-70). This change is most often in the form  of a poorly differentiated adenocarcinoma (such as, salivary  duct carcinoma), but other patterns also can develop,  including myoepithelial carcinoma, polymorphous low-  grade adenocarcinoma, mucoepidermoid carcinoma, and  adenoid cystic carcinoma.    Based on the pattern of growth, carcinoma ex pleomor-  phic adenoma can be divided into three subcategories: inva-  sive, minimally invasive, or noninvasive. Invasive carcinoma  ex pleomorphic adenoma shows malignant cells penetrating  greater than 1.5 mm from the tumor capsule into adjacent  tissues. Minimally invasive tumors show extracapsular inva-  sion that measures 1.5 mm or less. Noninvasive tumors may  be discovered as a small malignant focus within the center  of an encapsulated pleomorphic adenoma but without vio-  lation of the tumor capsule. Because such tumors have a  markedly better prognosis than invasive tumors, they also  have been designated as carcinoma in situ ex mixed tumor  or intracapsular carcinoma ex pleomorphic adenoma.    The carcinosarcoma is a biphasic tumor, demonstrating  both carcinomatous and sarcomatous areas. The epithelial  component usually consists of a poorly differentiated  adenocarcinoma or an undifferentiated carcinoma. The sar-  comatous portion often predominates the tumor and is  usually in the form of chondrosarcoma but also may show  characteristics of osteosarcoma, fibrosarcoma, liposarcoma,  rhabdomyosarcoma, or malignant fibrous histiocytoma.  Some lesions have evidence of an origin from a benign  mixed tumor.    ‘The metastasizing mixed tumor has microscopic features of  a benign pleomorphic adenoma, within both the primary  and the metastatic sites. Malignant histopathologic changes  are not observed.    Invasive carcinoma ex pleomorphic adenoma usually is best  treated by wide excision, possibly in conjunction with local  lymph node dissection and adjunctive radiation therapy.  The prognosis is guarded; the overall 5-year survival rate  ranges from 25% to 65%, but this rate drops to 10% to    @ Fig. 11-70 Carcinoma Ex Pleomorphic Adenoma. A, Medium-power view of the benign portion  of the tumor showing sheets of plasmacytoid myoepithelial cells within a myxoid background. B, Malignant  portion of the tumor showing epithelial cells with pleomorphic nuclei.    35% at 15 years. The prognosis is related to the histopatho-  logic subtype of the malignant component. One study  showed that well-differentiated carcinomas, such as poly-  morphous low-grade adenocarcinoma, have nearly a 90%  5-year survival rate. However, the outlook is much worse  for patients with tumors that are poorly differentiated or  that have invaded more than 8 mm beyond the residual  capsule or benign residual tumor. In contrast, the prognosis  for noninvasive or minimally invasive carcinoma ex pleo-  morphic adenoma approaches that for benign mixed tumor.  However, rare examples of metastasis or tumor death have  been documented in these latter groups.    Carcinosarcomas are treated by radical surgical excision,  which may be combined with radiation therapy and che-  motherapy. The prognosis is poor, with around 75% of  patients either dying from their disease or developing recur-  rent local tumor or metastases.    The treatment for a metastasizing mixed tumor consists of  surgical excision of both the primary tumor and the meta-  static sites. A mortality rate of 40% has been reported.    The adenoid cystic carcinoma is one of the more common  and best-recognized salivary malignancies. Because of its  distinctive histopathologic features, it was originally called  a cylindroma, and this term still is heard sometimes as a  synonym for this neoplasm. However, use of the term cyl-  indroma should be avoided because it does not convey the  malignant nature of the tumor, and also because this same  term is used for a skin adnexal tumor that has a markedly  different clinical presentation and prognosis.    The adenoid cystic carcinoma can occur in any salivary  gland site, but approximately 40% to 45% develop within  the minor salivary glands. The palate is the most common  site for minor gland tumors (Fig. 11-71). The remaining  tumors are found mostly in the parotid and submandibular  glands, with a fairly even distribution between these two  sites. On an individual basis, however, a striking difference  can be seen among the various glands. In the parotid gland,  the adenoid cystic carcinoma is relatively rare, constituting  only 2% of all tumors. In the submandibular gland, this  tumor accounts for 11% to 17% of all tumors and is the  most common malignancy. It is also relatively common  among palatal salivary neoplasms; it represents 8% to 15%  of all such tumors. The lesion is most common in middle-  aged adults and is rare in people younger than age 20.  Surveillance, Epidemiology, and End Results (SEER) data  from 1973 to 2007 in the United States showed a  male:female ratio of 1: 1.4.    © Fig. 11-71 Adenoid Cystic Carcinoma. Painful mass of the hard  palate and maxillary alveolar ridge. (Courtesy of Dr. George Blozis.)    © Fig. 11-72 Adenoid Cystic Carcinoma. Computed tomography  (CT) scan of this massive palatal tumor shows extensive destruction  of the hard palate with extension of the tumor into the nasal cavity and  both maxillary sinuses. (Courtesy of Dr. Kevin Riker.)    The adenoid cystic carcinoma usually appears as a slowly  growing mass. Pain is a common and important finding,  occasionally occurring early in the course of the disease  before there is a noticeable swelling. Patients often complain  ofaconstant, low-grade, dull ache, which gradually increases  in intensity. Facial nerve paralysis may develop with parotid  tumors. Palatal tumors can be smooth surfaced or ulcerated.  Tumors arising in the palate or maxillary sinus often show  radiographic evidence of bone destruction (Fig. 11-72).    The adenoid cystic carcinoma is composed of a mixture of  myoepithelial cells and ductal cells that can have a varied  arrangement (Fig. 11-73). Three major patterns are recog-  nized: 1) cribriform, 2) tubular, and 3) solid. Usually a  combination of these is seen, and the tumor is classified  based on the predominant pattern.   The cribriform pattern is the most classic and best-  recognized appearance, characterized by islands of basaloid  epithelial cells that contain multiple cylindrical, cystlike  spaces resembling Swiss cheese. These spaces often contain  a mildly basophilic mucoid material, a hyalinized eosino-  philic product, or a combined mucoid-hyalinized appear-  ance. Sometimes the hyalinized material also surrounds  these cribriform islands (Fig. 11-74), or small strands of  tumor are found embedded within this hyalinized “stroma.”  The tumor cells are small and cuboidal, exhibiting deeply  basophilic nuclei and little cytoplasm. These cells are fairly  uniform in appearance, and mitotic activity is rarely seen.  The pathologist should be mindful that other salivary  tumors, especially polymorphous low-grade adenocarci-  noma, also may exhibit areas with a cribriform pattern.    e Fig. 11-73 Adenoid Cystic Carcinoma. Islands of hyperchro-  matic cells forming cribriform and tubular structures. inset shows a  high-power view of a small cribriform island.    © Fig. 11-74 Adenoid Cystic Carcinoma. The tumor cells are sur-  rounded by hyalinized material.    In the tubular pattern, the tumor cells are similar but  occur as multiple small ducts or tubules within a hyalinized  stroma. The tubular lumina can be lined by one to several  layers of cells, and sometimes both a layer of ductal cells  and myoepithelial cells can be discerned.   ‘The solid variant consists of larger islands or sheets of  tumor cells that demonstrate little tendency toward duct or  cyst formation. Unlike the cribriform and tubular patterns,  cellular pleomorphism and mitotic activity, as well as focal  necrosis in the center of the tumor islands, may be observed.   A highly characteristic feature of adenoid cystic carci-  noma is its tendency to show perineural invasion (Fig.  11-75), which probably corresponds to the common clini-  cal finding of pain in these patients. Sometimes the cells  appear to have a swirling arrangement around nerve bundles.  However, perineural invasion is not pathognomonic for  adenoid cystic carcinoma; it also may be seen in other sali-  vary malignancies, especially polymorphous low-grade  adenocarcinomas.   Positive immunostaining reactions for CD43 and c-kit  (CD117) in adenoid cystic carcinoma have been reported  to be useful diagnostic features that can help to distinguish  this tumor from polymorphous low-grade adenocarcinoma,  basal cell adenoma, and canalicular adenoma. In addition,  the patterns of expression of a variety of other immunohis-  tochemical markers have been suggested to be diagnostically  relevant, including stains for vimentin, collagen IV, laminin,  integrins, Ki-G7, smooth muscle actin, and various  cytokeratins.    Adenoid cystic carcinoma is a relentless tumor that is prone  to local recurrence and eventual distant metastasis. Surgical  resection is usually the treatment of choice. Adjuvant radia-  tion therapy may slightly improve patient survival in some  cases, although recent SEER data suggest that radiation  therapy does little to improve prognosis overall. Because  metastasis to regional lymph nodes is uncommon (6% to  10% of cases), neck dissection usually is not indicated.    Because the tumor is prone to late recurrence and metas-  tasis, the 5-year survival rate has limited significance and  does not equate to a cure. The 5-year survival rate may  be as high as 77% to 82%, but this rate continues to  decrease over time. The 10-year survival currently ranges  from 60% to 68%, and by 20 years, only 35% to 52%  of patients are still alive. Tumors with a solid histopatho-  logic pattern are associated with a worse outlook than those  with a cribriform or tubular arrangement. With respect to  site, the prognosis is poorest for tumors arising in the  maxillary sinus and submandibular gland. Better survival  is observed in females, younger patients, and patients with  localized disease at the time of diagnosis. Most studies have  shown that microscopic identification of perineural inva-  sion has little effect on the prognosis. Tumor DNA ploidy  analysis may help to predict the prognosis of adenoid cystic  carcinoma; patients with diploid tumors have been shown  to have a significantly better outcome than patients with  aneuploid tumors.   Death usually results from local recurrence or distant  metastases. Tumors of the palate or maxillary sinus eventu-  ally may invade upward to the base of the brain. Metastases  occur in approximately 35% of patients, most frequently  involving the lungs, bone, and brain.    The polymorphous low-grade adenocarcinoma is a more  recently recognized type of salivary malignancy that was first  described in 1983. Before its identification as a distinct  entity, examples of this tumor were categorized as pleomor-  phic adenoma, an unspecified form of adenocarcinoma, or  sometimes as adenoid cystic carcinoma. Once recognized as  a specific entity, however, it was realized that this tumor  possesses distinct clinicopathologic features and is one of  the more common minor salivary gland malignancies.    The polymorphous low-grade adenocarcinoma is almost  exclusively a tumor of the minor salivary glands. However,  rare examples also have been reported in the major glands,  either arising de novo or as the malignant component of a  carcinoma ex pleomorphic adenoma. Sixty-five percent  occur on the hard or soft palate (Fig. 11-76), with the upper  lip and buccal mucosa being the next most common loca-  tions. It is most common in older adults, having peak  prevalence in the sixth to eighth decades of life. Two-thirds  of all cases occur in females.   The tumor most often appears as a painless mass that  may have been present for a long time with slow growth.  Occasionally, it is associated with bleeding or discomfort.  Tumor can erode or infiltrate the underlying bone.    e Fig. 11-76 Polymorphous Low-Grade Adenocarcinoma.  Slow-growing, firm mass of the right posterior lateral hard palate.  (Courtesy of Dr. Kevin Riker.)    medium-power view shows a cribriform arrangement of uniform tumor  cells with pale-staining nuclei.    The tumor cells of polymorphous low-grade adenocarcino-  mas have a deceptively uniform appearance. They are round  to polygonal in shape, with indistinct cell borders and pale  to eosinophilic cytoplasm. The nuclei may be round, ovoid,  or spindled; these nuclei usually are pale staining, although  they can be more basophilic in some areas. The cells can  exhibit different growth patterns, hence, the polymorphous  term. The cells may grow in a solid pattern or form cords,  ducts, or larger cystic spaces. In some tumors, a cribriform  pattern can be produced that mimics adenoid cystic carci-  noma (Fig. 11-77). Mitotic figures are uncommon.   At low power, the tumor sometimes appears well circum-  scribed. However, the peripheral cells are usually infiltrative,  invading the adjacent tissue in a single-file fashion (Fig.  11-78). Extension into underlying bone or skeletal muscle  may be observed. The stroma is often mucoid in nature, or  it may demonstrate hyalinization. Perineural invasion is    common—another feature that may cause the tumor to  be mistaken for adenoid cystic carcinoma (Fig. 11-79).  However, a distinction between these two tumors is impor-  tant because of their vastly different prognoses.   Immunohistochemical staining can be helpful in distin-  guishing polymorphous low-grade adenocarcinoma from  other salivary gland tumors that it may mimic. When com-  pared with adenoid cystic carcinoma, polymorphous low-  grade adenocarcinoma exhibits significantly weaker  expression of CD43 and c-kit (CD117). Likewise, lack of  staining for glial fibrillary acidic protein (GFAP) can help  to differentiate this tumor from pleomorphic adenoma,  which is almost always strongly positive for GFAP.    The polymorphous low-grade adenocarcinoma is best  treated by wide surgical excision, sometimes including  resection of the underlying bone. Metastasis to regional  lymph nodes is relatively uncommon, occurring in 9% to  17% of patients. Therefore, neck dissection seems    unwarranted in most cases unless there is clinical evidence  of cervical metastases. However, tumors arising at the base  of the tongue show a greater risk of regional metastasis.  Distant metastasis is rare.   The overall prognosis is relatively good. Recurrent disease  has been reported in 9% to 29% of all patients, but this  usually can be controlled with reexcision. Death from  tumor is rare but may occur secondary to direct extension  into vital structures. Microscopic identification of perineu-  ral invasion does not appear to affect the prognosis.    In spite of the wide variety of salivary gland malignancies  that have been specifically identified and categorized, some  tumors still defy the existing classification schemes. These  tumors usually are designated as salivary adenocarcino-  mas, not otherwise specified (NOS).    Because these adenocarcinomas represent such a diverse  group of neoplasms, it is difficult to generalize about their  clinical and microscopic features. Like most salivary tumors,  they appear to be most common in the parotid gland, fol-  lowed by the minor glands and the submandibular gland  (Figs. 11-80 and 11-81). They may present as asymptomatic  masses or cause pain or facial nerve paralysis. The micro-  scopic appearance is highly variable but demonstrates fea-  tures of a glandular malignancy with evidence of cellular  pleomorphism, an infiltrative growth pattern, or both.  These tumors exhibit a wide spectrum of differentiation,  ranging from well-differentiated, low-grade neoplasms to  poorly differentiated, high-grade malignancies.    As these tumors are studied more, it should be possible  to classify some of them into separate, specific categories  and allow more definitive analyses of their clinical and  microscopic features.    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Spiro RH, Huvos AG, Strong EW: Adenocarcinoma of salivary origin:  clinicopathologic study of 204 patients, Am J Surg 144:423-431,  1982.   Stene T, Koppang HS: Intraoral adenocarcinomas, / Oral Pathol  10:216-225, 1981.   Wahlberg P, Anderson H, Bidrklund A, et al: Carcinoma of the  parotid and submandibular glands—a study of survival in 2465  patients, Oral Oncol 38:706-713, 2002.    ¢ FIBROMA (IRRITATION FIBROMA;  TRAUMATIC FIBROMA; FOCAL FIBROUS  HYPERPLASIA; FIBROUS NODULE)    The fibroma is the most common “tumor” of the oral  cavity. However, it is doubtful that it represents a true neo-  plasm in most instances; rather, it is a reactive hyperplasia  of fibrous connective tissue in response to local irritation or  trauma.    Although the irritation fibroma can occur anywhere in the  mouth, the most common location is the buccal mucosa  along the bite line. Presumably, this is a consequence of  trauma from biting the cheek (Figs. 12-1 and 12-2). The  labial mucosa, tongue, and gingiva also are common sites  (Figs. 12-3 and 12-4). It is likely that many gingival fibro-  mas represent fibrous maturation of a preexisting pyogenic  granuloma. The lesion typically appears as a smooth-  surfaced pink nodule that is similar in color to the sur-  rounding mucosa. In black patients, the mass may  demonstrate gray-brown pigmentation. In some cases the  surface may appear white as a result of hyperkeratosis from  continued irritation. Most fibromas are sessile, although  some are pedunculated. They range in size from tiny lesions  that are only a couple of millimeters in diameter to large  masses that are several centimeters across; however, most  fibromas are 1.5 cm or less in diameter. The lesion usually  produces no symptoms, unless secondary traumatic ulcer-  ation of the surface has occurred. Irritation fibromas are  most common in the fourth to sixth decades of life, and the  male-to-female ratio is almost 1:2 for cases submitted for  biopsy.   ‘The frenal tag is a commonly observed type of fibrous  hyperplasia, which most frequently occurs on the maxillary  labial frenum. Such lesions present as small, asymptomatic,  exophytic growths attached to the thin frenum surface  (Fig. 12-5).    Microscopic examination of the irritation fibroma shows a  nodular mass of fibrous connective tissue covered by strati-  fied squamous epithelium (Figs. 12-6 and 12-7). This con-  nective tissue is usually dense and collagenized, although in  some cases, it is looser in nature. The lesion is not encapsu-  lated; the fibrous tissue instead blends gradually into the  surrounding connective tissues. The collagen bundles may  be arranged in a radiating, circular, or haphazard fashion.  The covering epithelium often demonstrates atrophy of the  rete ridges because of the underlying fibrous mass. However,  the surface may exhibit hyperkeratosis from secondary  trauma. Scattered inflammation may be seen, most often  beneath the epithelial surface. Usually this inflammation is  chronic and consists mostly of lymphocytes and plasma cells.    The irritation fibroma is treated by conservative surgical  excision; recurrence is extremely rare. However, it is impor-  tant to submit the excised tissue for microscopic examina-  tion because other benign or malignant tumors may mimic  the clinical appearance of a fibroma.   Because frenal tags are small, innocuous growths that  are easily diagnosed clinically, no treatment is usually  necessary.    ‘The giant cell fibroma is a fibrous tumor with distinctive  clinicopathologic features. Unlike the traumatic fibroma, it  does not appear to be associated with chronic irritation. The  giant cell fibroma represents approximately 2% to 5% of all  oral fibrous proliferations submitted for biopsy.    The giant cell fibroma is typically an asymptomatic sessile  or pedunculated nodule, usually less than 1 cm in size    @ Fig. 12-1 Fibroma. Pink nodule of the posterior buccal mucosa  near the level of the occlusal plane.    @ Fig. 12-2 Fibroma. Black patient with a smooth-surfaced pig-  mented nodule on the buccal mucosa near the commissure.    ® Fig. 12-3 Fibroma. Lesion on the lateral border of the tongue.    (Fig. 12-8). The surface of the mass often appears papillary;  therefore, the lesion may be clinically mistaken for a papil-  loma (Fig. 12-9). Compared with the common irritation  fibroma, the lesion usually occurs at a younger age. In about  60% of cases, the lesion is diagnosed during the first three  decades of life. Some studies have suggested a slight female    @ Fig. 12-4 Fibroma. Smooth-surfaced, pink nodular mass of the  palatal gingiva between the cuspid and first bicuspid.    @ Fig. 12-6 Fibroma. Low-power view showing an exophytic nodular  mass of dense fibrous connective tissue.    predilection. Approximately 50% of all cases occur on the  gingiva. The mandibular gingiva is affected twice as often  as the maxillary gingiva. The tongue and palate also are  common sites.   The retrocuspid papilla is a microscopically similar  developmental lesion that occurs on the gingiva lingual to    ® Fig. 12-8 Giant Cell Fibroma. Exophytic nodule on the dorsum  of the tongue.    @ Fig. 12-9 Giant Cell Fibroma. Papillary growth on the lingual  mandibular gingiva. Because of the rough surface, this lesion would  be easily mistaken for a papilloma.    @ Fig. 12-10 Retrocuspid Papilla. Bilateral papular lesions on the  gingiva lingual to the mandibular canines (arrows).    the mandibular cuspid. It is frequently bilateral and typi-  cally appears as a small, pink papule that measures less than  5 mm in diameter (Fig. 12-10). Retrocuspid papillae are  quite common, having been reported in 25% to 99% of  children and young adults. The prevalence in older adults  drops to 6% to 19%, suggesting that the retrocuspid papilla  represents a normal anatomic variation that disappears  with age.    Microscopic examination of the giant cell fibroma reveals a  mass of vascular fibrous connective tissue, which is usually  loosely arranged (Fig. 12-11). The hallmark is the presence  of numerous large, stellate fibroblasts within the superficial  connective tissue. These cells may contain several nuclei.  Frequently, the surface of the lesion is pebbly. The covering  epithelium often is thin and atrophic, although the rete  tidges may appear narrow and elongated.    The giant cell fibroma is treated by conservative surgical  excision. Recurrence is rare. Because of their characteristic  appearance, retrocuspid papillae should be recognized clini-  cally and do not need to be excised.    ¢ EPULIS FISSURATUM (INFLAMMATORY  FIBROUS HYPERPLASIA; DENTURE  INJURY TUMOR; DENTURE EPULIS)    ‘The epulis fissuratum is a tumorlike hyperplasia of fibrous  connective tissue that develops in association with the flange  of an ill-fitting complete or partial denture. Although the  simple term epulis sometimes is used synonymously for  epulis fissuratum, epudis is actually a generic term that can  be applied to any tumor of the gingiva or alveolar mucosa.  Therefore, some authors have advocated not using this term,    © Fig. 12-11 Giant Cell Fibroma. A, Low-power view showing a  nodular mass of fibrous connective tissue covered by stratified squa-  mous epithelium. Note the elongation of the rete ridges. B, High-power  view showing multiple large stellate-shaped and multinucleated  fibroblasts.    preferring to call these lesions inflammatory fibrous hyperpla-  sia or other descriptive names. However, the term epulis  fissuratum is still widely used today and is well understood  by virtually all clinicians. Other examples of epulides  include the giant cell epulis (peripheral giant cell granu-  loma) (see page 485), ossifying fibroid epulis (peripheral  ossifying fibroma) (see page 487), and congenital epulis  (see page 503).    ‘The epulis fissuratum typically appears as a single or mul-  tiple fold or folds of hyperplastic tissue in the alveolar ves-  tibule (Figs. 12-12 and 12-13). Most often, there are two  folds of tissue, and the flange of the associated denture fits  conveniently into the fissure between the folds. The redun-  dant tissue is usually firm and fibrous, although some lesions  appear erythematous and ulcerated, similar to the appear-  ance of a pyogenic granuloma. Occasional examples of  epulis fissuratum demonstrate surface areas of inflammatory  papillary hyperplasia (see page 478). The size of the lesion  can vary from localized hyperplasias less than 1 cm in size  to massive lesions that involve most of the length of the    @ Fig. 12-12 Epulis Fissuratum. Hyperplastic folds of tissue in the  anterior maxillary vestibule.    @ Fig. 12-13 Epulis Fissuratum. A, Several folds of hyperplastic  tissue in the maxillary vestibule. B, An ill-fitting denture fits into the  fissure between two of the folds. (Courtesy of Dr. William Bruce.)    vestibule. The epulis fissuratum usually develops on the  facial aspect of the alveolar ridge, although occasional  lesions are seen lingual to the mandibular alveolar ridge  (Fig. 12-14).   The epulis fissuratum most often occurs in middle-aged  and older adults, as would be expected with a denture-  related lesion. It may occur on either the maxilla or man-  dible. The anterior portion of the jaws is affected much    @ Fig. 12-14 Epulis Fissuratum. Redundant folds of tissue arising  in the floor of the mouth in association with a mandibular denture.    more often than the posterior areas. There is a pronounced  female predilection; most studies show that two-thirds to  three-fourths of all cases submitted for biopsy occur in  women.   Another similar but less common fibrous hyperplasia,  often called a fibroepithelial polyp or leaflike denture  fibroma, occurs on the hard palate beneath a maxillary  denture. This characteristic lesion is a flattened pink mass  that is attached to the palate by a narrow stalk (Fig. 12-15).  Usually, the flattened mass is closely applied to the palate  and sits in a slightly cupped-out depression. However, it is  easily lifted up with a probe, which demonstrates its pedun-  culated nature. The edge of the lesion often is serrated and  resembles a leaf.    Microscopic examination of the epulis fissuratum reveals  hyperplasia of the fibrous connective tissue. Often multiple  folds and grooves occur where the denture impinges on the  tissue (Fig. |    12-16). The overlying epithelium is frequently  hyperparakeratotic and demonstrates irregular hyperplasia  of the rete ridges. In some instances, the epithelium shows  inflammatory papillary hyperplasia (see page 478) or pseu-  doepitheliomatous (pseudocarcinomatous) hyperplasia.  Focal areas of ulceration are not unusual, especially at the  base of the grooves between the folds. A variable chronic  inflammatory infiltrate is present; sometimes, it may include  eosinophils or show lymphoid follicles. If minor salivary  glands are included in the specimen, then they usually show  chronic sialadenitis.   In rare instances, the formation of osteoid or chondroid  is observed. This unusual-appearing product, known as  osseous and chondromatous metaplasia, is a reactive phe-  nomenon caused by chronic irritation by the ill-fitting  denture (see page 292). The irregular nature of this bone or  cartilage can be microscopically disturbing, and the pathol-  ogist should not mistake it for a sarcoma.   The denture-related fibroepithelial polyp has a narrow  core of dense fibrous connective tissue covered by stratified    @ Fig. 12-15 Fibroepithelial Polyp. Flattened mass of tissue arising  on the hard palate beneath a maxillary denture; note its pedunculated  nature. Because of its serrated edge, this lesion also is Known as a  leaflike denture fibroma. Associated inflammatory papillary hyperplasia  is visible in the palatal midline.    e Fig. 12-16 Epulis Fissuratum. Low-power photomicrograph  demonstrating folds of hyperplastic fibrovascular connective tissue  covered by stratified squamous epithelium.    squamous epithelium. Like the epulis fissuratum, the over-  lying epithelium may be hyperplastic.  Treatment and Prognosis    The treatment of the epulis fissuratum or fibroepithelial  polyp consists of surgical removal, with microscopic    examination of the excised tissue. The ill-fitting denture  should be remade or relined to prevent a recurrence of the  lesion.    Inflammatory papillary hyperplasia is a reactive tissue  growth that usually, although not always, develops beneath  a denture. Some investigators classify this lesion as part of  the spectrum of denture stomatitis (see page 194). Although  the exact pathogenesis is unknown, the condition most  often appears to be related to the following:  * An ill-fitting denture  ¢ Poor denture hygiene  e Wearing the denture 24 hours a day   Approximately 20% of patients who wear their dentures  24 hours a day have inflammatory papillary hyperplasia.  Candida organisms also have been suggested as a cause, but  any possible role appears uncertain.    Inflammatory papillary hyperplasia usually occurs on the  hard palate beneath a denture base (Figs. 12-17 and 12-18).  Early lesions may involve only the palatal vault, although  advanced cases cover most of the palate. Less frequently, this  hyperplasia develops on the edentulous mandibular alveolar  ridge or on the surface of an epulis fissuratum. On rare  occasions, the condition occurs on the palate of a patient  without a denture, especially in people who habitually  breathe through their mouth or have a high palatal vault.  Candida-associated palatal papillary hyperplasia also has  been reported in dentate patients with human immunode-  ficiency virus (HIV) infection.   Inflammatory papillary hyperplasia is usually asymptom-  atic. The mucosa is erythematous and has a pebbly or    @ Fig. 12-18 Inflammatory Papillary Hyperplasia. An advanced  case exhibiting more pronounced papular lesions of the hard palate.    @ Fig. 12-19 Inflammatory Papillary Hyperplasia. Medium-power  view showing fibrous and epithelial hyperplasia resulting in papillary  surface projections. Heavy chronic inflammation is present.    The mucosa in inflammatory papillary hyperplasia exhibits  numerous papillary growths on the surface that are covered  by hyperplastic, stratified squamous epithelium (Fig. 12-19).  In advanced cases, this hyperplasia is pseudoepithelioma-  tous in appearance, and the pathologist should not mistake  it for carcinoma (Fig. 12-20). The connective tissue can vary  from loose and edematous to densely collagenized. A  chronic inflammatory cell infiltrate is usually seen, which  consists of lymphocytes and plasma cells. Less frequently,  polymorphonuclear leukocytes are also present. If underly-  ing salivary glands are present, then they often show scleros-  ing sialadenitis.    For very early lesions of inflammatory papillary hyperplasia,  removal of the denture may allow the erythema and edema    ° ON a Es <e = SR Saute Pr  @ Fig. 12-20 Inflammatory Papillary Hyperplasia. Higher-power  view showing pseudoepitheliomatous hyperplasia of the epithelium.  This epithelium has a bland appearance that should not be mistaken  for carcinoma.    to subside, and the tissues may resume a more normal  appearance. The condition also may show improvement  after topical or systemic antifungal therapy. For more  advanced and collagenized lesions, many clinicians prefer to  excise the hyperplastic tissue before fabricating a new  denture. Various surgical methods have been used, includ-  ing the following:  e Partial-thickness or  excision  * Curettage  e Electrosurgery  ° Cryosurgery  ¢ Laser surgery  After surgery, the existing denture can be lined with a  temporary tissue conditioner that acts as a palatal dressing  and promotes greater comfort. After healing, the patient  should be encouraged to leave the new denture out at night  and to keep it clean.    Fibrous histiocytomas are a diverse group of tumors that  exhibit fibroblastic and histiocytic differentiation, although  the cell of origin is uncertain. Because of the variable nature  of these lesions, an array of terms has been used for them,  including dermatofibroma, sclerosing hemangioma,  fibroxanthoma, and nodular subepidermal fibrosis.  Unlike other fibrous growths discussed previously in this  chapter, the fibrous histiocytoma is generally considered to  represent a true neoplasm.    The fibrous histiocytoma can develop almost anywhere in  the body. The most common site is the skin of the extremi-  ties, where the lesion is called a dermatofibroma. Tumors of  the oral and perioral region are rare, and it is likely that  many previously reported examples would be reclassified    @ Fig. 12-21 Fibrous Histiocytoma. Nodular mass on the dorsum  of the tongue.    today as solitary fibrous tumors (see next topic). Rare intra-  bony lesions of the jaws also have been reported. Oral  fibrous histiocytomas tend to occur in middle-aged and  older adults; cutaneous examples are most frequent in  young adults. The tumor is usually a painless nodular mass  and can vary in size from a few millimeters to several cen-  timeters in diameter (Fig. 12-21). Deeper tumors tend to  be larger.    Microscopically, the fibrous histiocytoma is characterized by  a cellular proliferation of spindle-shaped fibroblastic cells  with vesicular nuclei (Figs. 12-22 and 12-23). The margins  of the tumor often are not sharply defined. The tumor cells  are arranged in short, intersecting fascicles, known as a  storiform pattern because of its resemblance to the irregular,  whorled appearance of a straw mat. Rounded histiocyte-like  cells, lipid-containing xanthoma cells, or multinucleated  giant cells can be seen occasionally, as may scattered lym-  phocytes. The stroma may demonstrate areas of myxoid  change or focal hyalinization.    Local surgical excision is the treatment of choice. Recur-  rence is uncommon, especially for superficial tumors. Larger  lesions of the deeper soft tissues have a greater potential to  recur.    ‘The solitary fibrous tumor was initially described as a  pleural neoplasm that was believed to arise from either  mesothelial cells or submesothelial fibroblasts. However,  examples of this tumor were later identified in a number of  other anatomic sites, including the head and neck region.  ‘The term hemangiopericytoma was originally used for a  rare soft tissue neoplasm that presumably was derived from  pericytes (i.e., cells with processes that encircled endothelial  cells of capillaries). However, a pericytic origin appears  doubtful, and there is a growing consensus that most  so-called hemangiopericytomas represent cellular variants  within the spectrum of solitary fibrous tumor.   In addition, a neoplasm microscopically similar to the  hemangiopericytoma has been recognized in the sinonasal  tract. This tumor does show myoid, pericyte-like differen-  tiation and is thought to represent a separate entity known  as a sinonasal-type hemangiopericytoma (glomangio-  pericytoma; myopericytoma).    Solitary fibrous tumors have been reported primarily in  adults and are rare in children. The tumor often is described  as a slow-growing, painless, submucosal, or deep soft tissue  mass that is easily removed from the surrounding tissues.  Solitary fibrous tumors of the head and neck region are  most common in the buccal mucosa, which accounts for  approximately one-third of such cases.    Sinonasal-type hemangiopericytoma occurs primarily in  middle-aged and older adults. Common presenting symp-  toms include nasal obstruction and epistaxis.    Solitary fibrous tumors are usually well-circumscribed  lesions that exhibit a variable microscopic appearance. At  one end of the spectrum, the lesional cells appear as tightly  packed cells and surround endothelium-lined vascular  channels—hence, the concept of hemangiopericytoma. The  cells are haphazardly arranged and demonstrate round to  ovoid nuclei and indistinct cytoplasmic borders. The blood  vessels often show irregular branching, which results in a  characteristic “staghorn” and “antlerlike” appearance (Fig.  12-24, A).   At the other end of the spectrum, the cells are more  spindled and arranged in either short fascicles or in a dis-  organized fashion (“patternless pattern”) (see Fig. 12-24, B).  The tumor often demonstrates alternating hypercellular and  hypocellular zones with a variable degree of myxoid back-  ground change. Prominent hyalinized collagen bundles are  characteristically observed in the hypocellular areas. Immu-  nohistochemical studies show the lesional cells to be posi-  tive for CD34 and bcl-2 in nearly all cases.    The identification of four or more mitoses per ten high-  power fields suggests a rapidly growing tumor that is capable  of metastasis. The presence of necrosis also suggests malig-  nancy. However, it is difficult to predict microscopically  whether a particular tumor will act in a benign or malignant  fashion.   Sinonasal-type hemangiopericytomas have a more prom-  inent spindle cell pattern, with the cells arranged in a more  orderly fashion. Mitotic figures are rare or absent. The vas-  cular component is less intricate, and less interstitial colla-  gen is found among the tumor cells. Most examples will  express myogenic markers, such as smooth muscle actin  (92%) and muscle-specific actin (77%), but, in contrast to  solitary fibrous tumor, the cells are usually negative for    For solitary fibrous tumors with a benign histopathologic  appearance, local excision is the treatment of choice. More  extensive surgery is required for tumors with malignant  characteristics. Oral examples usually behave in a benign  fashion, although approximately 10% of extrapleural soli-  tary fibrous tumors have been reported to show malignant  behavior. Therefore, long-term follow-up of patients with  this tumor is recommended.   The sinonasal-type hemangiopericytoma usually has a  favorable prognosis with a recurrence rate of approximately  17%. Rare examples of locally aggressive or metastatic  tumors have been reported.    The fibromatoses are a broad group of fibrous prolifera-  tions that have a biologic behavior and histopathologic  pattern that is intermediate between those of benign fibrous  lesions and fibrosarcoma. A number of different forms of  fibromatosis are recognized throughout the body, and they  often are named based on their particular clinicopathologic  features. In the soft tissues of the head and neck, these  lesions are frequently called juvenile aggressive fibromato-  ses or extraabdominal desmoids. Similar lesions within  the bone have been called desmoplastic fibromas (see page  613). Individuals with familial adenomatous polyposis and  Gardner syndrome (see page 606) have a greatly increased  risk for developing aggressive fibromatosis.    Soft tissue fibromatosis of the head and neck is a firm, pain-  less mass, which may exhibit rapid or insidious growth (Fig.  12-25). The lesion most frequently occurs in children or  young adults; hence, the term juvenile fibromatosis.  However, cases also have been seen in middle-aged adults.  The most common oral site is the paramandibular soft tissue  region, although the lesion can occur almost anywhere. The  tumor can grow to considerable size, resulting in significant    @ Fig. 12-25 Fibromatosis. Locally aggressive proliferation of fibrous  connective tissue of the lingual mandibular gingival mucosa.    ® Fig. 12-26 Fibromatosis. Streaming fascicles of fibroblastic cells  that demonstrate little pleomorphism.    facial disfigurement. Destruction of adjacent bone may be  observed on radiographs and other imaging studies.    Soft tissue fibromatosis is characterized by a cellular pro-  liferation of spindle-shaped cells that are arranged in  streaming fascicles and are associated with a variable  amount of collagen (Fig. 12-26). The lesion is usually  poorly circumscribed and infiltrates the adjacent tissues.  Hyperchromatism and pleomorphism of the cells should  not be observed.    Because of its locally aggressive nature, the preferred treat-  ment for soft tissue fibromatosis is wide excision that  includes a generous margin of adjacent normal tissues.  Adjuvant chemotherapy or radiation therapy sometimes has  been used for incompletely resected or recurrent tumors. A  30% recurrence rate has been reported for aggressive fibro-  matosis of the head and neck. Metastasis does not occur.    e Fig. 12-27 Myofibroma. Computed tomography (CT) scan  showing an expansile lytic mass of the posterior mandible on the left  side of the illustration. (Courtesy of Dr. Timothy Armanini.)    Myofibroma is a rare spindle cell neoplasm that consists of  myofibroblasts (i.e., cells with both smooth muscle and  fibroblastic features). Such cells are not specific for this  lesion, however, because they also can be identified in other  fibrous proliferations. Most myofibromas occur as solitary  lesions, but some patients develop a multicentric tumor  process known as myofibromatosis.    Although myofibromas are rare neoplasms, they demon-  strate a predilection for the head and neck region. Solitary  tumors develop most frequently in the first four decades of  life, with a mean age of 22 years. The most common oral  location is the mandible, followed by the tongue and buccal  mucosa. The tumor is typically a painless mass that some-  times exhibits rapid enlargement. Intrabony tumors create  radiolucent defects that usually tend to be poorly defined,  although some may be well defined or multilocular (Fig.  12-27). Multicentric myofibromatosis primarily affects neo-  nates and infants who may have tumors of the skin, subcu-  taneous tissue, muscle, bone, and viscera. The number of  tumors can vary from several to more than 100.    Myofibromas are composed of interlacing bundles of  spindle cells with tapered or blunt-ended nuclei and eosin-  ophilic cytoplasm (Fig. 12-28). Nodular fascicles may    alternate with more cellular zones, imparting a biphasic  appearance to the tumor. Scattered mitoses are not uncom-  mon. Centrally, the lesion is often more vascular with a  hemangiopericytoma-like appearance. The tumor cells are  positive for smooth muscle actin and muscle-specific actin  with immunohistochemistry, but they are negative for  desmin.    Solitary myofibromas are usually treated by surgical exci-  sion. A small percentage of tumors will recur after treat-  ment, but typically, these can be controlled with reexcision.  Multifocal tumors arising in soft tissues and bone rarely  recur after surgical removal. Spontaneous regression may  occur in some cases. However, myofibromatosis involving  the viscera or vital organs in infants can act more aggres-  sively and sometimes proves to be fatal within a few days    Oral focal mucinosis is an uncommon tumorlike mass that  is believed to represent the oral counterpart of cutaneous  focal mucinosis or a cutaneous myxoid cyst. The cause is  unknown, although the lesion may result from overproduc-  tion of hyaluronic acid by fibroblasts.    Oral focal mucinosis is most common in young adults and  shows a 2:1 female-to-male predilection. The gingiva is  the most common site; two-thirds to three-fourths of all  cases are found there. The hard palate is the second most  common location. The mass rarely appears at other oral  sites. The lesion usually presents as a sessile or peduncu-  lated, painless nodular mass that is the same color as the  surrounding mucosa (Fig. 12-29). The surface is typically  smooth and nonulcerated, although occasional cases exhibit    © Fig. 12-29 Oral Focal Mucinosis. Nodular mass arising from the  gingiva between the mandibular first and second molars.    @ Fig. 12-30 Oral Focal Mucinosis. Low-power view showing a  nodular mass of loose, myxomatous connective tissue.    a lobulated appearance. The size varies from a few milli-  meters up to 2 cm in diameter. The patient often has been  aware of the mass for many months or years before the  diagnosis is made.    Microscopic examination of oral focal mucinosis shows a  well-localized but nonencapsulated area of loose, myxoma-  tous connective tissue surrounded by denser, normal col-  lagenous connective tissue (Figs. 12-30 and 12-31). The  lesion is usually found just beneath the surface epithelium  and often causes flattening of the rete ridges. The fibroblasts  within the mucinous area can be ovoid, fusiform, or stellate,  and they may demonstrate delicate, fibrillar processes. Few  capillaries are seen within the lesion, especially compared  with the surrounding denser collagen. Similarly, no signifi-  cant inflammation is observed, although a perivascular lym-  phocytic infiltrate often is noted within the surrounding  collagenous connective tissue. No appreciable reticulin is  evident within the lesion, and special stains suggest that the  mucinous product is hyaluronic acid.    ® Fig. 12-31 Oral Focal Mucinosis. High-power view demonstrat-  ing the myxomatous change.    Oral focal mucinosis is treated by surgical excision and does  not tend to recur.    ‘The pyogenic granuloma is a common tumorlike growth  of the oral cavity that traditionally has been considered to  be nonneoplastic in nature.* Although it was originally  thought to be caused by pyogenic organisms, it is now  believed to be unrelated to infection. Instead, the pyogenic  granuloma is thought to represent an exuberant tissue  response to local irritation or trauma. In spite of its name,  it is not a true granuloma.    ‘The pyogenic granuloma is a smooth or lobulated mass that  is usually pedunculated, although some lesions are sessile  (Figs. 12-32 to 12-34). The surface is characteristically ulcer-  ated and ranges from pink to red to purple, depending on  the age of the lesion. Young pyogenic granulomas are highly  vascular in appearance; older lesions tend to become more  collagenized and pink. They vary from small growths only a  few millimeters in size to larger lesions that may measure  several centimeters in diameter. Typically, the mass is pain-  less, although it often bleeds easily because of its extreme  vascularity. Pyogenic granulomas may exhibit rapid growth,  which may create alarm for both the patient and the clini-  cian, who may fear that the lesion might be malignant.  Oral pyogenic granulomas show a striking predilection  for the gingiva, which accounts for approximately 75% to    *However, some pyogenic granulomas (also known as lobular capillary  hemangiomas) currently are categorized as vascular tumors under the clas-  sification scheme of the International Society for the Study of Vascular  Anomalies (see Box 12-2, page 504).    ® Fig. 12-32 Pyogenic Granuloma. Erythematous, hemorrhagic  mass arising from the maxillary anterior gingiva.    ® Fig. 12-33 Pyogenic Granuloma. Ulcerated and lobulated mass  on the dorsum of the tongue.    @ Fig. 12-34 Pyogenic Granuloma. Unusually large lesion arising  from the palatal gingiva in association with an orthodontic band. The  patient was pregnant.    85% of all cases. Gingival irritation and inflammation that  result from poor oral hygiene may be a precipitating factor  in many patients. The lips, tongue, and buccal mucosa are  the next most common sites. A history of trauma before the  development of the lesion is not unusual, especially for    @ Fig. 12-35 Pyogenic Granuloma. A, Large gingival mass in a  pregnant woman just before childbirth. B, The mass has decreased in  size and undergone fibrous maturation 3 months after childbirth.  (Courtesy of Dr. George Blozis.)    extragingival pyogenic granulomas. Lesions are slightly  more common on the maxillary gingiva than the mandibu-  lar gingiva; anterior areas are more frequently affected than  posterior areas. These lesions are much more common on  the facial aspect of the gingiva than the lingual aspect; some  extend between the teeth and involve both the facial and  the lingual gingiva.   Although the pyogenic granuloma can develop at any  age, it is most common in children and young adults. Most  studies also demonstrate a definite female predilection, pos-  sibly because of the vascular effects of female hormones.  Pyogenic granulomas of the gingiva frequently develop in  pregnant women, so much so that the terms pregnancy  tumor or granuloma gravidarum often are used. Such lesions  may begin to develop during the first trimester, and their  prevalence increases up through the seventh month of preg-  nancy. The gradual rise in development of these lesions  throughout pregnancy may be related to the increasing  levels of estrogen and progesterone as the pregnancy pro-  gresses. After pregnancy and the return of normal hormone  levels, some of these pyogenic granulomas resolve without  treatment or undergo fibrous maturation and resemble a  fibroma (Fig. 12-35).   Epulis granulomatosa is a term used to describe hyper-  plastic growths of granulation tissue that sometimes arise in    @ Fig. 12-36 Epulis Granulomatosa. Nodular mass of granulation  tissue that developed in a recent extraction site.    ® Fig. 12-37 Pyogenic Granuloma. Low-power view showing an  exophytic mass of granulation-like tissue with an ulcerated surface.  Note the lobular endothelial proliferation in the deeper connective  tissue.    healing extraction sockets (Fig. 12-36). These lesions resem-  ble pyogenic granulomas and usually represent a granula-  tion tissue reaction to bony sequestra in the socket.    Microscopic examination of pyogenic granulomas shows a  highly vascular proliferation that resembles granulation  tissue (Figs. 12-37 and 12-38). Numerous small and larger  endothelium-lined channels are formed that are engorged  with red blood cells. These vessels sometimes are organized  in lobular aggregates—hence, the term /obular capillary  hemangioma. the surface is usually ulcerated and replaced  by a thick fibrinopurulent membrane. A mixed inflamma-  tory cell infiltrate of neutrophils, plasma cells, and lympho-  cytes is evident. Neutrophils are most prevalent near the  ulcerated surface; chronic inflammatory cells are found  deeper in the specimen. Older lesions may have areas with  a more fibrous appearance. In fact, many gingival fibromas  probably represent pyogenic granulomas that have under-  gone fibrous maturation.    ‘The treatment of patients with pyogenic granuloma consists  of conservative surgical excision, which is usually curative.  ‘The specimen should be submitted for microscopic exami-  nation to rule out other more serious diagnoses. For gingival  lesions, the excision should extend down to periosteum and  the adjacent teeth should be thoroughly scaled to remove  any source of continuing irritation. A recurrence rate of 3%  to 15% has been reported in most studies. In rare instances,  multiple recurrences have been noted.   For lesions that develop during pregnancy, usually treat-  ment should be deferred unless significant functional or  aesthetic problems develop. The recurrence rate is higher for  pyogenic granulomas removed during pregnancy, and some  lesions will resolve spontaneously after parturition.    ‘The peripheral giant cell granuloma is a relatively common  tumorlike growth of the oral cavity. It probably does not  represent a true neoplasm but rather is a reactive lesion  caused by local irritation or trauma. In the past, it often was  called a peripheral giant cell reparative granuloma, but any  reparative nature appears doubtful. Some investigators  believe that the giant cells show immunohistochemical fea-  tures of osteoclasts, whereas other authors have suggested  that the lesion is formed by cells from the mononuclear  phagocyte system. The peripheral giant cell granuloma bears  a close microscopic resemblance to the central giant cell  granuloma (see page 584), and some pathologists believe  that it may represent a soft tissue counterpart of this intraos-  seous lesion.    ‘The peripheral giant cell granuloma occurs exclusively on  the gingiva or edentulous alveolar ridge, presenting as a red  or red-blue nodular mass (Figs. 12-39 and 12-40). Most    e Fig. 12-39 Peripheral Giant Cell Granuloma. Nodular blue-  purple mass of the mandibular gingiva.    @ Fig. 12-40 Peripheral Giant Cell Granuloma. Ulcerated mass of  the mandibular gingiva.    lesions are smaller than 2 cm in diameter, although larger  ones are seen occasionally. The lesion can be sessile or  pedunculated and may or may not be ulcerated. The clinical  appearance is similar to the more common pyogenic granu-  loma of the gingiva (see page 483), although the peripheral  giant cell granuloma often is more blue-purple compared  with the bright red of a typical pyogenic granuloma.   Peripheral giant cell granulomas can develop at almost  any age, especially during the first through sixth decades of  life. The mean age in several large series ranges from 31 to  46 years. Approximately 52% to 60% of cases occur in  females. It may develop in either the anterior or posterior  regions of the gingiva or alveolar mucosa, and the mandible  is affected slightly more often than the maxilla. Although  the peripheral giant cell granuloma develops within soft  tissue, “cupping” resorption of the underlying alveolar bone  sometimes is seen. On occasion, it may be difficult to deter-  mine whether the mass arose as a peripheral lesion or as a  central giant cell granuloma that eroded through the corti-  cal plate into the gingival soft tissues.    Microscopic examination of a peripheral giant cell granu-  loma shows a proliferation of multinucleated giant cells    @ Fig. 12-41 Peripheral Giant Cell Granuloma. Low-power view  showing a nodular proliferation of multinucleated giant cells within the  gingiva.    alg a cs, EE OS ae  @ Fig. 12-42 Peripheral Giant Cell Granuloma. High-power view  showing scattered multinucleated giant cells within a hemorrhagic  background of ovoid and spindle-shaped mesenchymal cells.    within a background of plump ovoid and spindle-shaped  mesenchymal cells (Figs. 12-41 and 12-42). The giant cells  may contain only a few nuclei or up to several dozen. Some  of these cells may have large, vesicular nuclei; others dem-  onstrate small, pyknotic nuclei. Mitotic figures are fairly  common in the background mesenchymal cells. Abundant  hemorrhage is characteristically found throughout the mass,  which often results in deposits of hemosiderin pigment,  especially at the periphery of the lesion.   ‘The overlying mucosal surface is ulcerated in about 50%  of cases. A zone of dense fibrous connective tissue usually  separates the giant cell proliferation from the mucosal  surface. Adjacent acute and chronic inflammatory cells are  frequently present. Areas of reactive bone formation or dys-  trophic calcifications are not unusual.    ‘The treatment of the peripheral giant cell granuloma con-  sists of local surgical excision down to the underlying bone.  The adjacent teeth should be carefully scaled to remove any  source of irritation and to minimize the risk of recurrence.  Approximately 10% to 18% of lesions are reported to recur,    and reexcision must be performed. On rare occasions,  lesions indistinguishable from peripheral giant cell granulo-  mas have been seen in patients with hyperparathyroidism  (see page 781). They apparently represent the so-called  osteoclastic brown tumors associated with this endocrine  disorder. However, the brown tumors of hyperparathyroid-  ism are much more likely to be intraosseous in location and  mimic a central giant cell granuloma.    ¢ PERIPHERAL OSSIFYING FIBROMA  (OSSIFYING FIBROID EPULIS;  PERIPHERAL FIBROMA WITH  CALCIFICATION; CALCIFYING  FIBROBLASTIC GRANULOMA)    The peripheral ossifying fibroma is a relatively common  gingival growth that is considered to be reactive rather than  neoplastic in nature. The pathogenesis of this lesion is  uncertain. Because of their clinical and histopathologic  similarities, researchers believe that some peripheral ossify-  ing fibromas develop initially as pyogenic granulomas that  undergo fibrous maturation and subsequent calcification.  However, not all peripheral ossifying fbromas may develop  in this manner. The mineralized product probably has  its origin from cells of the periosteum or periodontal  ligament.   Considerable confusion has existed over the nomencla-  ture of this lesion, and several terms have been used to  describe its variable histopathologic features. In the past, the  terms peripheral odontogenic fibroma (see page 678) and  peripheral ossifying fibroma often were used synonymously,  but the peripheral odontogenic fibroma is now considered  to be a distinct and separate entity. In addition, in spite of  the similarity in names, the peripheral ossifying fibroma  does not represent the soft tissue counterpart of the central  ossifying fibroma (see page 602).    The peripheral ossifying fibroma occurs exclusively on the  gingiva. It appears as a nodular mass, either pedunculated  or sessile, that usually emanates from the interdental papilla  (Figs. 12-43 and 12-44). The color ranges from red to pink,  and the surface is frequently, but not always, ulcerated. The  growth probably begins as an ulcerated lesion; older ones  are more likely to demonstrate healing of the ulcer and an  intact surface. Red, ulcerated lesions often are mistaken for  pyogenic granulomas; the pink, nonulcerated ones are clini-  cally similar to irritation fibromas. Most lesions are less than  2 cm in size, although larger ones occasionally occur. The  lesion often has been present for many weeks or months  before the diagnosis is made.   The peripheral ossifying fibroma is predominantly a  lesion of teenagers and young adults, with peak prevalence  between the ages of 10 and 19. Almost two-thirds of all  cases occur in females. There is a slight predilection for the    © Fig. 12-43 Peripheral Ossifying Fibroma. This red, ulcerated  mass of the maxillary gingiva has recurred twice. Such ulcerated  lesions are easily mistaken for a pyogenic granuloma.    © Fig. 12-44 Peripheral Ossifying Fibroma. Pink, nonulcerated  mass arising from the maxillary gingiva. The remaining roots of the first  molar are present.    maxillary arch, and more than 50% of all cases occur in the  incisor-cuspid region. Usually, the teeth are unaffected;  rarely, there can be migration and loosening of adjacent  teeth.    The basic microscopic pattern of the peripheral ossifying  fibroma is one of a fibrous proliferation associated with the  formation of a mineralized product (Figs. 12-45 and 12-  46). If the epithelium is ulcerated, then the surface is  covered by a fibrinopurulent membrane with a subjacent  zone of granulation tissue. The deeper fibroblastic compo-  nent often is cellular, especially in areas of mineralization.  In some cases, the fibroblastic proliferation and associated  mineralization is only a small component of a larger mass  that resembles a fibroma or pyogenic granuloma.   The type of mineralized component is variable and may  consist of bone, cementum-like material, or dystrophic cal-  cifications. Frequently, a combination of products is formed.  Usually, the bone is woven and trabecular in type, although  older lesions may demonstrate mature lamellar bone. Tra-  beculae of unmineralized osteoid are not unusual. Less    fibrous mass of the gingiva showing central bone formation. B, Higher-  power view showing trabeculae of bone with adjacent fibrous connec-  tive tissue.    frequently, ovoid droplets of basophilic cementum-like  material are formed. Dystrophic calcifications are character-  ized by multiple granules, tiny globules, or large, irregular  masses of basophilic mineralized material. Such dystrophic  calcifications are more common in early, ulcerated lesions;  older, nonulcerated examples are more likely to demonstrate  well-formed bone or cementum. In some cases, multinucle-  ated giant cells may be found, usually in association with  the mineralized product.    @ Fig. 12-47 Lipoma. Soft, yellow nodular mass in the floor of the  mouth. (Courtesy of Dr. Michael Tabor.)    The treatment of choice for the peripheral ossifying fibroma  is local surgical excision with submission of the specimen  for histopathologic examination. The mass should be excised  down to periosteum because recurrence is more likely if the  base of the lesion is allowed to remain. In addition, the  adjacent teeth should be thoroughly scaled to eliminate any  possible irritants. Periodontal surgical techniques, such as  repositioned flaps or connective tissue grafts, may be neces-  sary to repair the gingival defect in an aesthetic manner.  Although excision is usually curative, a recurrence rate of  8% to 16% has been reported.    ‘The lipoma is a benign tumor of fat. Although it represents  by far the most common mesenchymal neoplasm, most  examples occur on the trunk and proximal portions of the  extremities. Lipomas of the oral and maxillofacial region are  much less frequent, accounting for only 1% to 4% of all  such tumors. The pathogenesis of lipomas is uncertain, but  they appear to be more common in obese people. However,  the metabolism of lipomas is completely independent of the  normal body fat. If the caloric intake is reduced, then  lipomas do not decrease in size, although normal body fat  may be lost.    Oral lipomas are usually soft, smooth-surfaced nodular  masses that can be sessile or pedunculated (Figs. 12-47 and  12-48). Typically, the tumor is asymptomatic and often has  been noted for many months or years before diagnosis.  Most are less than 3 cm in size, but occasional lesions can  become much larger. Although a subtle or more obvious  yellow hue often is detected clinically, deeper examples may  appear pink. The buccal mucosa and buccal vestibule are  the most common intraoral sites and account for nearly  50% of all cases. Some buccal cases may not represent true    ® Fig. 12-48 Lipoma. Nodular mass of the posterior buccal mucosa.    tumors, but rather herniation of the buccal fat pad through  the buccinator muscle, which may occur after local trauma  in young children or subsequent to surgical removal of third  molars in older patients. Less common sites include the  tongue, floor of the mouth, and lips. Most patients are 40  years of age or older; lipomas are uncommon in children.  Lipomas of the oral and maxillofacial region have shown a  fairly balanced sex distribution in most studies.    Most oral lipomas are composed of mature fat cells that  differ little in microscopic appearance from the surrounding  normal fat (Figs. 12-49 and 12-50). The tumor is usually  well circumscribed and may demonstrate a thin fibrous  capsule. A distinct lobular arrangement of the cells often is  seen. On rare occasions, central cartilaginous or osseous  metaplasia may occur within an otherwise typical lipoma.  A number of microscopic variants have been described.  The most common of these is the fibrolipoma, which is  characterized by a significant fibrous component intermixed  with the lobules of fat cells. The remaining variants are rare.  ‘The angiolipoma consists of an admixture of mature fat  and numerous small blood vessels. The spindle cell lipoma    @ Fig. 12-50 Lipoma. High-power view showing the similarity of the  tumor cells to normal fat.    demonstrates variable amounts of uniform-appearing  spindle cells in conjunction with a more typical lipomatous  component. Some spindle cell lipomas exhibit a mucoid  background (myxoid lipoma) and may be confused with  myxoid liposarcomas. Pleomorphic lipomas are character-  ized by the presence of spindle cells plus bizarre, hyperchro-  matic giant cells; they can be difficult to distinguish from a  pleomorphic liposarcoma. Intramuscular (infiltrating)  lipomas often are more deeply situated and have an infiltra-  tive growth pattern that extends between skeletal muscle  bundles. The term sialolipoma was coined to describe  tumors that secondarily entrap salivary gland tissue.    Lipomas are treated by conservative local excision, and  recurrence is rare. Most microscopic variants do not affect  the prognosis. Intramuscular lipomas have a higher recur-  rence rate because of their infiltrative growth pattern, but  this variant is rare in the oral and maxillofacial region.    The traumatic neuroma is not a true neoplasm but a reac-  tive proliferation of neural tissue after transection or other  damage of a nerve bundle. After a nerve has been damaged  or severed, the proximal portion attempts to regenerate and  reestablish innervation of the distal segment by the growth  of axons through tubes of proliferating Schwann cells. If  these regenerating elements encounter scar tissue or other-  wise cannot reestablish innervation, then a tumorlike mass  may develop at the site of injury.    Traumatic neuromas of the oral mucosa are typically  smooth-surfaced, nonulcerated nodules. They can develop    @ Fig. 12-51 Traumatic Neuroma. Painful nodule of the mental  nerve as it exits the mental foramen (arrow).    ® Fig. 12-52 Traumatic Neuroma. Note the irregular nodular prolif-  eration along the mental nerve that is being exposed at the time of  surgery.    at any location but are most common in the mental  foramen area, tongue, and lower lip (Figs. 12-51 and  12-52). A history of trauma often can be elicited; some  lesions arise subsequent to tooth extraction or other surgical  procedures. Intraosseous traumatic neuromas may demon-  strate a radiolucent defect on oral radiographs. Examples  also may occur at other head and neck sites; it has  been estimated that traumatic neuromas of the greater  auricular nerve develop in 5% to 10% of patients under-  going surgery for pleomorphic adenomas of the parotid  gland.   Traumatic neuromas can occur at any age, but they are  diagnosed most often in middle-aged adults. They appear  to be slightly more common in women. Many traumatic  neuromas are associated with altered nerve sensations that  can range from anesthesia to dysesthesia to overt pain.  Although pain has been traditionally considered a hallmark  of this lesion, studies indicate that only one-fourth to one-  third of oral traumatic neuromas are painful. This pain can  be intermittent or constant and ranges from mild tender-  ness or burning to severe radiating pain. Neuromas of the    haphazard arrangement of nerve bundles within the background  fibrous connective tissue.    @ Fig. 12-54 Traumatic Neuroma. High-power view showing cross-  sectioned nerve bundles within dense fibrous connective tissue.    mental nerve are frequently painful, especially when  impinged on by a denture or palpated.    Microscopic examination of traumatic neuromas shows a  haphazard proliferation of mature, myelinated and unmy-  elinated nerve bundles within a fibrous connective tissue  stroma that ranges from densely collagenized to myxoma-  tous in nature (Figs. 12-53 and 12-54). An associated mild  chronic inflammatory cell infiltrate may be present. Trau-  matic neuromas with inflammation are more likely to be  painful than those without significant inflammation.    The treatment of choice for the patient with a traumatic  neuroma is surgical excision, including a small portion of  the involved proximal nerve bundle. Most lesions do not  recur; in some cases, however, the pain persists or returns  at a later date.    @ Fig. 12-55 Palisaded Encapsulated Neuroma. Small, painless  nodule of the lateral hard palate.    The palisaded encapsulated neuroma is a benign neural  tumor with distinctive clinical and histopathologic features.  It represents one of the more common superficial nerve  tumors, especially in the head and neck region. The cause  is uncertain, but some authors have speculated that trauma  may play an etiologic role; the tumor is generally consid-  ered to represent a reactive lesion rather than a true  neoplasm.    ‘The palisaded encapsulated neuroma shows a striking pre-  dilection for the face, which accounts for approximately  90% of reported cases. The nose and cheek are the most  common specific sites. The lesion is most frequently diag-  nosed between the fifth and seventh decades of life, although  the tumor often has been present for many months or years.  It is a smooth-surfaced, painless, dome-shaped papule or  nodule that is usually less than 1 cm in diameter.   Oral palisaded encapsulated neuromas are not uncom-  mon, although many are probably diagnosed microscopi-  cally as neurofibromas or schwannomas. The lesion appears  most frequently on the hard palate (Fig. 12-55), gingiva,  and labial mucosa, although it also may occur in other oral  locations.    Palisaded encapsulated neuromas appear well circumscribed  and often encapsulated (Fig. 12-56), although this capsule  may be incomplete, especially along the superficial aspect  of the tumor. Some lesions have a lobulated appearance.  The tumor consists of moderately cellular interlacing fas-  cicles of spindle cells that are consistent with Schwann cells.  The nuclei are characteristically wavy and pointed, with no  significant pleomorphism or mitotic activity. Although the    1 mye , 4  Vt et Ii  @ Fig. 12-56 Palisaded Encapsulated Neuroma. A, Low-power  view showing a well-circumscribed, nodular proliferation of neural  tissue. B, Higher-power view demonstrating spindle cells with wavy  nuclei.    © Fig. 12-57 Palisaded Encapsulated Neuroma. Immunohisto-  chemical reaction demonstrating spindle-shaped cells that are strongly  positive for S-100 protein.    nuclei show a similar parallel orientation within the fasci-  cles, the more definite palisading and Verocay bodies typical  of the Antoni A tissue of a schwannoma are usually not  seen. Special stains reveal the presence of numerous axons  within the tumor (a feature not seen in schwannoma) and  the cells show a positive immunohistochemical reaction for  S-100 protein (Fig. 12-57). Negative immunoreactivity for    glial fibrillary acidic protein (GFAP) may be helpful in  distinguishing the palisaded encapsulated neuroma from  other neural tumors. Because the tumor is not always encap-  sulated and the cells are usually not truly palisaded, some  pathologists prefer solitary circumscribed neuroma as a  better descriptive term for this lesion.    The treatment for the palisaded encapsulated neuroma con-  sists of conservative local surgical excision. Recurrence is  rare. However, specific recognition of this lesion is impor-  tant because it is not associated with neurofibromatosis or  multiple endocrine neoplasia (MEN) type 2B.    The schwannoma is a benign neural neoplasm of Schwann  cell origin. It is relatively uncommon, although 25% to  48% of all cases occur in the head and neck region. Bilateral  schwannomas of the auditory-vestibular nerve are a charac-  teristic feature of the hereditary condition, neurofibroma-  tosis type II (NF2). Multiple schwannomas also occur in    The solitary schwannoma is a slow-growing, encapsulated  tumor that typically arises in association with a nerve trunk.  As it grows, it pushes the nerve aside. Usually, the mass is  asymptomatic, although tenderness or pain may occur in  some instances. The lesion is most common in young and  middle-aged adults and can range from a few millimeters  to several centimeters in size.   The tongue is the most common location for oral  schwannomas, although the tumor can occur almost any-  where in the mouth (Fig. 12-58). On occasion, the tumor  arises centrally within bone and may produce bony    @ Fig. 12-58 Schwannoma. Nodular mass in the floor of the mouth.  (Courtesy of Dr. Art A. Gonty.)    expansion. Intraosseous examples are most common in the  posterior mandible and usually appear as either unilocular  or multilocular radiolucencies on radiographs. Pain and  paresthesia are not unusual for intrabony tumors.   NF2 is an autosomal dominant condition caused by a  mutation of a tumor suppressor gene (NF2) on chromo-  some 22, which codes for a protein known as merlin. In  addition to bilateral schwannomas (“acoustic neuromas”) of  the vestibular nerve, patients also develop schwannomas of  peripheral nerves, plus meningiomas and gliomas of the  central nervous system (CNS). On occasion, neurofibromas  and café au lait skin pigmentation may be observed. Char-  acteristic symptoms include progressive sensorineural deaf-  ness, dizziness, and tinnitus.   Schwannomatosis is related to a mutation of the  SMARCB1 gene on chromosome 22. Patients develop mul-  tiple painful schwannomas at various sites but without  involvement of the auditory-vestibular nerve.    The schwannoma is usually an encapsulated tumor that  demonstrates two microscopic patterns in varying amounts:  1) Antoni A and 2) Antoni B. Streaming fascicles of  spindle-shaped Schwann cells characterize Antoni A tissue.  These cells often form a palisaded arrangement around  central acellular, eosinophilic areas known as Verocay  bodies (Fig. 12-59). These Verocay bodies consist of redu-  plicated basement membrane and cytoplasmic processes.  Antoni B tissue is less cellular and less organized; the  spindle cells are randomly arranged within a loose, myxo-  matous stroma. Typically, neurites cannot be demonstrated  within the tumor mass. The tumor cells will show a  diffuse, positive immunohistochemical reaction for S-100  protein.   Degenerative changes can be seen in some older tumors  (ancient schwannomas). These changes consist of hemor-  rhage, hemosiderin deposits, inflammation, fibrosis, and  nuclear atypia. However, these tumors are still benign, and  the pathologist must be careful not to mistake these altera-  tions for evidence of a sarcoma. Another rare variant is the  plexiform schwannoma, which is characterized grossly  and microscopically by a multinodular, plexiform growth  pattern. Such tumors occasionally are associated with NF2  or schwannomatosis.    The solitary schwannoma is treated by surgical excision, and  the lesion should not recur. Malignant transformation does  not occur or is extremely rare.   Vestibular schwannomas in patients with NF2 are diffi-  cult to manage. Surgical removal is indicated for large symp-  tomatic tumors, but this often results in deafness and risks  facial nerve damage. Stereotactic radiosurgery may be con-  sidered for older adult or frail patients, as well as for indi-  viduals who decline traditional surgery.    organized Antoni A tissue (right) with adjacent myxoid and less orga-  nized Antoni B tissue (left). B, The Schwann cells of the Antoni A tissue  form a palisaded arrangement around acellular zones known as  Verocay bodies.    The neurofibroma is the most common type of peripheral  nerve neoplasm. It arises from a mixture of cell types,  including Schwann cells and perineural fibroblasts.    Neurofibromas can arise as solitary tumors or be a compo-  nent of neurofibromatosis (see page 495). Solitary tumors  are most common in young adults and present as slow-  growing, soft, painless lesions that vary in size from small  nodules to larger masses. The skin is the most frequent loca-  tion for neurofibromas, but lesions of the oral cavity are not  uncommon (Fig. 12-60). The tongue and buccal mucosa  are the most common intraoral sites. On rare occasions, the  tumor can arise centrally within bone, where it may produce  a well-demarcated or poorly defined unilocular or multi-  locular radiolucency (Fig. 12-61).    ® Fig. 12-60 Neurofibroma. Smooth-surfaced, nodular mass of the  maxillary gingiva and alveolar mucosa. (Courtesy of Dr. Neal  Lemmerman.)    ® Fig. 12-61 Neurofibroma. Intraosseous tumor filling the right man-  dibular ramus. (Courtesy of Dr. Paul Allen.)    The solitary neurofibroma often is well circumscribed, espe-  cially when the proliferation occurs within the perineurium  of the involved nerve. Tumors that proliferate outside the  perineurium may not appear well demarcated and tend to  blend with the adjacent connective tissues.   The tumor is composed of interlacing bundles of spindle-  shaped cells that often exhibit wavy nuclei (Figs. 12-62 and  12-63). These cells are associated with delicate collagen  bundles and variable amounts of myxoid matrix. Mast cells  tend to be numerous and can be a helpful diagnostic feature.  Sparsely distributed small axons usually can be demon-  strated within the tumor tissue by using silver stains. Immu-  nohistochemically, the tumor cells show a scattered, positive  reaction for S-100 protein.    The treatment for solitary neurofibromas is local surgical  excision, and recurrence is rare. Any patient with a lesion  that is diagnosed as a neurofibroma should be evaluated    clinically for the possibility of neurofibromatosis (see next  topic). Malignant transformation of solitary neurofibromas  can occur, although the risk appears to be remote, especially  compared with that in patients with neurofibromatosis.    Neurofibromatosis type I is a relatively common heredi-  tary condition that is estimated to occur in one of every  2,500 to 3,000 births (see Table 12-1, page 493). At least  eight forms of neurofibromatosis have been recognized, but  the most common form is neurofibromatosis type I  (NF1), which is discussed here. This form of the disease,  also known as von Recklinghausen disease of the skin,  accounts for 85% to 97% of neurofibromatosis cases and is  inherited as an autosomal dominant trait (although 50% of  all patients have no family history and apparently represent  new mutations). It is caused by a variety of mutations of  the NFI gene, which is located on chromosome region  17q11.2 and is responsible for a tumor suppressor protein  product known as neurofibromin.    The diagnostic criteria are met if a patient has two or more of  the following features:   1. Six or more café au lait macules more than 5 mm in greatest  diameter in prepubertal persons and more than 15 mm in  greatest diameter in postpubertal persons   Two or more neurofibromas of any type or one plexiform  neurofibroma   A distinctive osseous lesion such as sphenoid dysplasia or  thinning of long bone cortex with or without pseudoarthrosis  A first-degree relative (parent, sibling, or offspring) with NF1,  based on the previously mentioned criteria    The diagnostic criteria for NF1 are summarized in Box  12-1. Patients have multiple neurofibromas that can occur  anywhere in the body but are most common on the skin.  The clinical appearance can vary from small papules to  larger soft nodules to massive baggy, pendulous masses  (elephantiasis neuromatosa) on the skin (Figs. 12-64 and  12-65). The plexiform variant of neurofibroma, which feels  like a “bag of worms,” is considered pathognomonic for  NF1. The tumors may be present at birth, but they often  begin to appear during puberty and may continue to  develop slowly throughout adulthood. Accelerated growth  may be seen during pregnancy. There is a wide variability  in the expression of the disease. Some patients have only a  few neurofibromas; others have literally hundreds or thou-  sands of tumors. However, two-thirds of patients have rela-  tively mild disease.   Another highly characteristic feature is the presence of  café au lait (coffee with milk) pigmentation on the skin  (Fig. 12-66). These spots occur as yellow-tan to dark-brown    @ Fig. 12-66 Neurofibromatosis Type I. Same patient as depicted  in Fig. 12-64. Note the café au /ait pigmentation on the arm.    macules that vary in diameter from 1 to 2 mm to several  centimeters. In NF1, this pigmentation typically has a  smooth edge (“coast of California’), in contrast to the irreg-  ular border (“coast of Maine”) of the café au lait spots that  may occur with polyostotic fibrous dysplasia (see page 593).  The pigmentation usually is present at birth or it may  develop during the first year of life. Freckling of the axilla  (Crowe sign) or of other intertriginous zones is also a  highly suggestive sign.   Lisch nodules, translucent brown-pigmented spots on  the iris, are found in nearly all affected individuals. The  most common general medical problem is hypertension,  which may develop secondary to coarctation of the aorta,  pheochromocytoma, or renal artery stenosis. Other possible  abnormalities include CNS tumors, macrocephaly, mental  deficiency, seizures, short stature, and scoliosis.   Studies indicate that oral manifestations may occur in as  many as 72% to 92% of cases, especially if a detailed clinical  and radiographic examination is performed. The most com-  monly described finding is enlargement of the fungiform  papillae, which has been reported in up to 50% of patients;  however, the specificity of this finding for neurofibromatosis  is unknown. Only about 25% to 37% of patients will    e Fig. 12-67 Neurofibromatosis Type I. Diffuse neurofibroma  resulting in unilateral enlargement of the tongue.    develop actual intraoral neurofibromas (Fig. 12-67). Radio-  graphic findings may include enlargement of the mandibu-  lar foramen, enlargement or branching of the mandibular  canal, increased bone density, concavity of the medial  surface of the ramus, and increase in dimension of the coro-  noid notch. Cephalometric analysis often shows a short  length of the mandible, maxilla, and cranial base.   Several unusual clinical variants of NF1 have been  described. On occasion, the condition can include unilat-  eral enlargement that mimics hemifacial hyperplasia (see  page 35). In addition, several patients with NF1 have been  described with associated Noonan syndrome or with central  giant cell granulomas of the jaw.    There is no specific therapy for NF1, and treatment often  is directed toward prevention or management of complica-  tions. Facial neurofibromas can be removed for cosmetic  purposes. Carbon dioxide (CO ) laser and dermabrasion  have been used successfully for extensive lesions. NF1  patients with prominent hemifacial enlargement may  require more significant cosmetic remodeling surgery.   One of the most feared complications is the development  of cancer, most often a malignant peripheral nerve sheath  tumor (neurofibrosarcoma; malignant schwannoma),  which has been reported to occur in about 5% of cases.  These tumors are most common on the trunk and extremi-  ties, although head and neck involvement is occasionally  seen (Figs. 12-68 to 12-70). The 5-year survival rate for  malignant peripheral nerve sheath tumors associated with  NF1 is 35% to 54%. Other malignancies also have been  associated with NF1, including CNS tumors, pheochromo-  cytoma, leukemia, rhabdomyosarcoma, and Wilms tumor.  The average lifespan of individuals with NF1 is 8 to 15 years    @ Fig. 12-68 Neurofibromatosis Type I. Malignant peripheral nerve  sheath tumor of the left cheek in a patient with type | neurofibromato-  sis. (From Neville BW, Hann J, Narang R, et al: Oral neurofibrosarcoma  associated with neurofibromatosis type |, Oral Surg Oral Med Oral  Pathol 72:456-461, 1991.)    ® Fig. 12-69 Neurofibromatosis Type I. Same patient as depicted  in Fig. 12-68. Note the intraoral appearance of malignant peripheral  nerve sheath tumor of the mandibular buccal vestibule. The patient  eventually died of this tumor. (From Neville BW, Hann J, Narang R,  et al: Oral neurofibrosarcoma associated with neurofibromatosis type  |, Oral Surg Oral Med Oral Pathol 72:456-461, 1991.)    less than the general population, mostly related to vascular  disease and malignant neoplasms.   In recent years, there has been considerable interest in  Joseph (not John) Merrick, the so-called Elephant Man.  Although Merrick once was mistakenly considered to have  NF1, it is now generally accepted that his horribly disfig-  ured appearance was not because of neurofibromatosis, but    @ Fig. 12-70 Malignant Peripheral Nerve Sheath Tumor. High-  power view of an intraoral tumor that developed in a patient with  neurofibromatosis type |. There is a cellular spindle cell proliferation  with numerous mitotic figures.    that he most likely had a rare condition known as Proteus  syndrome. Because patients with NF1 may fear acquiring  a similar clinical appearance, they should be reassured that  they have a different condition. The phrase “Elephant Man  disease” is incorrect and misleading, and it should be  avoided. Genetic counseling is extremely important for all  patients with neurofibromatosis.    The multiple endocrine neoplasia (MEN) syndromes are  a group of rare autosomal dominant conditions character-  ized by tumors or hyperplasias of the neuroendocrine tissues  (see Table 12-1, page 493). MEN type 1 is caused by muta-  tions of the MENI gene located on chromosome 11.  Affected individuals can develop a variety of tumors of the  parathyroid glands, pancreatic islets, anterior pituitary  gland, and adrenal cortex. MEN type 2 encompasses a  family of disorders (familial medullary thyroid carcinoma  [MTC] syndrome, MEN type 2A, and MEN type 2B) that  are characterized by the development of MTC. These three  conditions are caused by mutations at various sites of the  RET proto-oncogene on chromosome 10. Patients with  familial MTC syndrome develop MTC but are not at  increased risk for other neuroendocrine tumors. Patients  with MEN type 2A are at increased risk for MTC (over  95% of patients), adrenal pheochromocytomas (50% of  patients), and primary hyperparathyroidism (20% to 30%  of patients).   Over 95% of cases of MEN type 2B are caused by a  germline mutation at codon 918 (M918T) of the RET  proto-oncogene, although a few examples have been  described with a mutation at codon 883 (A883F). In addi-  tion to MTC and pheochromocytomas, patients develop  mucosal neuromas that especially involve the oral mucous  membranes. Because oral manifestations are prominent    @ Fig. 12-71 Multiple Endocrine Neoplasia (MEN) Type 2B. Note  the narrow face and eversion of the upper eyelids.    only in MEN type 2B, the remainder of the discussion is  limited to this condition.    Patients with MEN type 2B usually have a marfanoid body  build characterized by thin, elongated limbs with muscle  wasting. The face is narrow, but the lips are characteristically  thick and protuberant because of the diffuse proliferation  of nerve bundles. The upper eyelid sometimes is everted  because of thickening of the tarsal plate (Fig. 12-71). Small,  pedunculated neuromas may be observable on the conjunc-  tiva, eyelid margin, or cornea.   Oral mucosal neuromas are usually the first sign of the  condition and may be detectable during infancy. These neu-  romas appear as soft, painless papules or nodules that prin-  cipally affect the lips and anterior tongue but also may be  seen on the buccal mucosa, gingiva, and palate (Fig. 12-72).  Bilateral neuromas of the commissural mucosa are highly  characteristic.   Pheochromocytomas of the adrenal glands develop in at  least 50% of all patients and become more prevalent with  increasing age. These neuroendocrine tumors are frequently  bilateral or multifocal. The tumor cells secrete catechol-  amines, which result in symptoms such as profuse sweating,  intractable diarrhea, headaches, flushing, heart palpitations,  and severe hypertension. Also, approximately 40% of  patients with MEN type 2B will develop ganglioneuroma-  tosis of the gastrointestinal tract, which can result in    @ Fig. 12-72 Multiple Endocrine Neoplasia (MEN) Type 2B. Mul-  tiple neuromas along the anterior margin of the tongue and bilaterally  at the commissures. (Courtesy of Dr. Emmitt Costich.)   The most significant aspect of this condition is the devel-  opment of MTC, which occurs in virtually all cases. This  aggressive tumor arises from the parafollicular cells (C cells)  of the thyroid gland, which are responsible for calcitonin  production. MTC silently develops early in life and, without  prophylactic thyroidectomy before 1 year of age, most  patients will develop metastatic tumor during childhood or  adolescence.    If MTC is present, then serum or urinary levels of calcitonin  are elevated. An increase in calcitonin levels may herald  the onset of the tumor, and calcitonin also can be moni-  tored to detect local recurrences or metastases after treat-  ment. Pheochromocytomas may result in increased levels  of urinary vanillylmandelic acid (VMA) and increased  epinephrine-to-norepinephrine ratios.    The mucosal neuromas are characterized by marked hyper-  plasia of nerve bundles in an otherwise normal or loose  connective tissue background (Figs. 12-73 and 12-74).  Prominent thickening of the perineurium is typically seen.    The prognosis for patients with MEN type 2B centers on  early recognition of the oral features. Because of the  extremely poor prognosis for MTC, the thyroid gland  should be removed as soon as possible—preferably within  the first year of life. The average age of death from this  neoplasm is 21 years. It has been suggested that patients  with the A883F mutation of the RET proto-oncogene may  develop a less aggressive form of MTC than patients with  the M918T mutation. Patients also should be observed for  the development of pheochromocytomas because they may    @ Fig. 12-73 Multiple Endocrine Neoplasia (MEN) Type 2B. Low-  power view of an oral mucosal neuroma showing marked hyperplasia  of nerve bundles.    ae Je Dy ie]  @ Fig. 12-74 Multiple Endocrine Neoplasia (MEN) Type 2B. High-  power view of the same neuroma as depicted in Fig. 12-73. Note the  prominent thickening of the perineurium.    result in a life-threatening hypertensive crisis, especially if  surgery with general anesthesia is performed.    The melanotic neuroectodermal tumor of infancy is a  rare pigmented neoplasm that usually occurs during the first  year of life. It is generally accepted that this lesion is of  neural crest origin. In the past, however, a number of tissues  were suggested as possible sources of this tumor. These  included odontogenic epithelium and retina, which resulted  in various older terms for this entity, such as pigmented  ameloblastoma, retinal anlage tumor, and melanotic  progonoma. Because these names are inaccurate, however,  they should no longer be used.    Melanotic neuroectodermal tumor of infancy almost always  develops in young children during the first year of life; only    @ Fig. 12-75 Melanotic Neuroectodermal Tumor of Infancy.  Infant with an expansile mass of the anterior maxilla. (From Steinberg  B, Shuler C, Wilson S: Melanotic neuroectodermal tumor of infancy:  evidence for multicentricity, Oral Surg Oral Med Oral Pathol 66:666-  669, 1988.)    © Fig. 12-76 Melanotic Neuroectodermal Tumor of Infancy.  Radiolucent destruction of the anterior maxilla associated with dis-  placement of the developing teeth. (Courtesy of Dr. Len Morrow.)    9% of cases are diagnosed after the age of 12 months. There  is a striking predilection for the maxilla, which accounts for  69% of reported cases. Less frequently reported sites include  the skull (11%), epididymis and testis (9%), mandible  (6%), and brain (4%). A slight male predilection has been  noted.   The lesion is most common in the anterior region of the  maxilla, where it classically appears as a rapidly expanding  mass that is frequently blue or black (Fig. 12-75). The  tumor often destroys the underlying bone and may be asso-  ciated with displacement of the developing teeth (Fig.  12-76). In some instances, there may be an associated osteo-  genic reaction, which exhibits a “sun ray” radiographic  pattern that can be mistaken for osteosarcoma.    High urinary levels of vanillylmandelic acid (VMA) often  are found in patients with melanotic neuroectodermal  tumor of infancy. These levels may return to normal once    © Fig. 12-78 Melanotic Neuroectodermal Tumor of Infancy.  High-power view of a tumor nest demonstrating two cell types: 1)  small, hyperchromatic round cells and 2) larger epithelioid cells with  vesicular nuclei. Some stippled melanin pigment is also present.    the tumor has been resected. This finding supports the  hypothesis of neural crest origin because other tumors from  this tissue (e.g., pheochromocytoma and neuroblastoma)  often secrete norepinephrine-like hormones that are metab-  olized to VMA and excreted in the urine.    The tumor consists of a biphasic population of cells that  form nests, tubules, or alveolar structures within a dense,  collagenous stroma (Figs. 12-77 and 12-78). The alveolar  and tubular structures are lined by cuboidal epithelioid cells  that demonstrate vesicular nuclei and granules of dark-  brown melanin pigment. The second cell type is neuroblas-  tic in appearance and consists of small, round cells with  hyperchromatic nuclei and little cytoplasm. These cells grow  in loose nests and are frequently surrounded by the larger  pigment-producing cells. Mitotic figures are rare.   Because of the tumor’s characteristic microscopic fea-  tures, immunohistochemistry usually is not essential to  establish the diagnosis. However, the larger epithelioid cells    typically are positive for cytokeratin, HMB-45, and neuron-  specific enolase. In addition, the smaller cells usually are  positive for neuron-specific enolase and CD56, and some-  times they will express other neuroendocrine markers such  as synaptophysin.    Despite their rapid growth and potential to destroy bone,  most melanotic neuroectodermal tumors of infancy are  benign. The lesion is best treated by surgical removal. Some  clinicians prefer simple curettage, although others advocate  that a 5-mm margin of normal tissue be included with the  specimen. Recurrence of the tumor has been reported in  about 20% of cases. In addition, about 7% of reported cases,  mostly from the brain or skull, have acted in a malignant  fashion, resulting in metastasis and death. Although this  estimation of 7% is probably high (because unusual malig-  nant cases are more likely to be reported), it underscores the  potentially serious nature of this tumor and the need for  careful clinical evaluation and follow-up of affected patients.    ¢ PARAGANGLIOMA (CAROTID BODY  TUMOR; CHEMODECTOMA; GLOMUS  JUGULARE TUMOR; GLOMUS  TYMPANICUM TUMOR)    The paraganglia are specialized tissues of neural crest origin  that are associated with the autonomic nerves and ganglia  throughout the body. Some of these cells act as chemorecep-  tors, such as the carotid body (located at the carotid bifurca-  tion), which can detect changes in blood pH or oxygen  tension and subsequently cause changes in respiration and  heart rate. Tumors that arise from these structures are col-  lectively known as paragangliomas, with the term prefer-  ably preceded by the anatomic site at which they are located.  Therefore, tumors of the carotid body are appropriately  known as carotid body paragangliomas (carotid body  tumors). Other examples in the head and neck include  jugular paragangliomas (glomus jugulare tumors), tym-  panic paragangliomas (glomus tympanicum tumors),  and vagal paragangliomas.   Most head and neck paragangliomas occur as sporadic  tumors, although 30% of cases are associated with heritable  germline mutations of genes that encode for subunits  or cofactors of succinate dehydrogenase (mitochondrial  complex II). Four hereditary paraganglioma syndromes  (PGL1-4) have been recognized, all of which show an  autosomal dominant inheritance pattern. However, PGL1  and PGL2 exhibit an unusual “parent-of-origin—dependent  effect” consistent with maternal imprinting of the disease  gene. Although the gene can be inherited from either the  father or mother, only paternal transmission will result in  development of tumors in the offspring. Therefore, the trait  may appear to skip generations within a family. Develop-  ment of head and neck paragangliomas also has been    ® Fig. 12-79 Carotid Body Paraganglioma. Large tumor in the left  neck producing a visible external swelling. (Courtesy of Dr. Terry Day.)    described rarely in several other genetic conditions, such as  neurofibromatosis type 1, multiple endocrine neoplasia type  2, and von Hippel-Lindau syndrome.    Although paragangliomas are rare, the head and neck area  is the most common site for these lesions. Isolated, mutation-  negative tumors show a 4:1 female: male ratio, whereas  mutation-positive examples have an equal sex distribution.  The tumor usually occurs in middle-aged adults (mean age  of 41 to 47 years), although inherited cases tend to develop  in patients over a decade younger. Hereditary cases have a  greater chance of being multicentric; about 37% of such  patients will develop more than one tumor.   The most common type is the carotid body paragangli-  oma, which develops at the bifurcation of the internal and  external carotid arteries (Figs. 12-79 and 12-80). Most often  it is a slowly enlarging, painless mass of the upper lateral  neck below the angle of the jaw. It is seen more frequently  in patients who live at high altitudes, indicating that some  cases may arise from chronic hyperplasia of the carotid body  in response to lower oxygen levels. Angiography can help  to localize the tumor and demonstrate its characteristic  vascular nature.   Jugular and tympanic paragangliomas are the next most  common types of these tumors. The most common symp-  toms include dizziness, tinnitus (a ringing or other noise in  the ear), hearing loss, and cranial nerve palsies.    The paraganglioma is characterized by round or polygonal  epithelioid cells that are organized into nests or zellballen  (Fig. 12-81). The overall architecture is similar to that of the  normal paraganglia, except the ze//ballen are usually larger  and more irregular in shape. These nests consist primarily of  chief cells, which demonstrate centrally located, vesicular  nuclei and somewhat granular, eosinophilic cytoplasm.  These cells are positive for neuroendocrine markers, such as    e Fig. 12-80 Carotid Body Paraganglioma. Same patient as  depicted in Fig. 12-79. The magnetic resonance image (MRI) shows  a tumor mass at the carotid bifurcation. Arrows indicate the external  and internal branches of the carotid artery. (Courtesy of Dr. Terry Day.)    chromogranin and synaptophysin. The chief cells are sur-  rounded by a flattened layer of sustentacular cells that are  immunoreactive for S-100 protein. The tumor is typically  vascular and may be surrounded by a thin fibrous capsule.    The treatment of paragangliomas may include surgery, radi-  ation therapy, or both, depending on the extent and loca-  tion of the tumor. Localized carotid body paragangliomas  often can be treated by surgical excision with maintenance  of the vascular tree. If the carotid artery is encased by tumor,  it also may need to be resected, followed by vascular graft-  ing. Although most carotid body paragangliomas can be  controlled with surgery, vascular complications can lead to  considerable surgical morbidity, such as intraoperative hem-  orrthage, stroke, and blood pressure instability. Radiation    therapy may be used for unresectable tumors or as adjunc-  tive treatment.   Because of their location near the base of the brain,  jugular and tympanic paragangliomas are more difficult to  manage. Hearing loss and other cranial nerve deficits are  common postsurgical complications of jugular paraganglio-  mas. Radiation therapy may be used in conjunction with  surgery or as a primary treatment for unresectable tumors.  Stereotactic radiosurgery (gamma knife treatment) has  shown promise in the management of primary or recurrent  jugular paragangliomas in patients who are poor surgical  candidates. Tympanic paragangliomas are associated with a  much lower risk of postsurgical problems.   Approximately 6% of paragangliomas will metastasize,  either to regional lymph nodes or distant sites. Unfortu-  nately, it is difficult to predict which tumors will act in a  malignant fashion based on their microscopic features.  However, the risk is much greater for patients with SDHB  mutations (paraganglioma syndrome 4), where the rate of  malignancy ranges from 13% to 23%.    The granular cell tumor is an uncommon benign soft  tissue neoplasm that shows a predilection for the oral cavity.  The histogenesis of this lesion continues to be debated.  Originally, it was believed to be of skeletal muscle origin  and was called the granular cell myoblastoma. However,  more recent investigations point to a derivation from  Schwann cells (granular cell schwannoma/neurofibroma).  At present, it seems best to use the noncommittal term  granular cell tumor for this lesion.    Granular cell tumors are most common in the oral cavity  and on the skin. The single most common site is the tongue,  which accounts for one-third to half of all reported cases.  Tongue lesions most often occur on the dorsal surface. The  buccal mucosa is the second most common intraoral loca-  tion. The tumor most frequently occurs in the fourth to  sixth decades of life and is rare in children. There is a 2:1  female predilection.   The granular cell tumor is typically an asymptomatic  sessile nodule that is usually 2 cm or less in size (Figs. 12-82  and 12-83). The lesion often has been noted for many  months or years, although sometimes the patient is unaware  of its presence. The mass is typically pink, but some granular  cell tumors appear yellow. The granular cell tumor is usually  solitary, although multiple, separate tumors sometimes  occur, especially in black patients.    The granular cell tumor is composed of large, polygonal  cells with abundant pale eosinophilic, granular cytoplasm  and either dark or vesicular nuclei (Fig. 12-84). The cells    e Fig. 12-82 Granular Cell Tumor. Submucosal nodule on the  dorsum of the tongue.    e Fig. 12-83 Granular Cell Tumor. Nodular mass of the buccal  mucosa near the commissure.    e Fig. 12-84 Granular Cell Tumor. Medium-high-power view  showing polygonal cells with abundant granular cytoplasm.    are usually arranged in sheets, but they also may be found  in cords and nests. The cell borders often are indistinct,  which results in a syncytial appearance. The lesion is not  encapsulated and often intermingles with the adjacent con-  nective tissues. Often, there appears to be a transition from  normal adjacent skeletal muscle fibers to granular tumor    : su :  @ Fig. 12-85 Granular Cell Tumor. Marked pseudoepitheliomatous  hyperplasia overlying a granular cell tumor. Such cases may easily be  mistaken for squamous Cell carcinoma.    cells; this finding led earlier investigators to suggest a muscle  origin for this tumor. Less frequently, one may see groups  of granular cells that envelop small nerve bundles. Immu-  nohistochemical analysis reveals positivity for S-100 protein  within the cells—a finding that is supportive, but not diag-  nostic, of neural origin. The lesional cells also are positive  for CD-68, calretinin, and neuron-specific enolase.   An unusual and significant microscopic finding is the  presence of acanthosis or pseudoepitheliomatous (pseudo-  carcinomatous) hyperplasia of the overlying epithelium,  which has been reported in up to 50% of all cases (Fig.  12-85). Although this hyperplasia is usually minor in  degree, in some cases it may be so striking that it results in  a mistaken diagnosis of squamous cell carcinoma and sub-  sequent unnecessary cancer surgery. The pathologist must  be aware of this possibility, especially when dealing with a  superficial biopsy sample or a specimen from the dorsum  of the tongue—an unusual location for oral cancer.    The granular cell tumor is best treated by conservative local  excision, and recurrence is uncommon, even when the  lesion is not entirely removed. Extremely rare examples of  malignant granular cell tumor have been reported.    ¢ CONGENITAL EPULIS (CONGENITAL  EPULIS OF THE NEWBORN; CONGENITAL  GRANULAR CELL LESION)    The congenital epulis is an uncommon soft tissue tumor  that occurs almost exclusively on the alveolar ridges of new-  borns. It is often known by the redundant term, congenital  epulis of the newborn. Rare examples also have been  described on the tongue; therefore, some authors prefer  using the term congenital granular cell lesion, because not    °® Fig. 12-86 Congenital Epulis. Polypoid mass of the anterior max-  illary alveolar ridge in a newborn.    all cases present as an epulis on the alveolar ridge. It also has  been called gingival granular cell tumor of the newborn,  but this term should be avoided. Although it bears a slight  microscopic resemblance to the granular cell tumor  (discussed previously), it exhibits ultrastructural and immu-  nohistochemical differences that warrant its classification as  a distinct and separate entity. However, the histogenesis of  this tumor is still uncertain.    The congenital epulis typically appears as a pink-to-red,  smooth-surfaced, polypoid mass on the alveolar ridge of a  newborn (Fig. 12-86). Most examples are 2 cm or less in  size, although lesions as large as 7.5 cm have been reported.  On occasion, the tumor has been detected in utero via  ultrasound examination. Multiple tumors develop in 10%  of cases. A few rare examples on the tongue have been  described in infants who also had alveolar tumors.   The tumor is two to three times more common on the  maxillary ridge than on the mandibular ridge. It most fre-  quently occurs lateral to the midline in the area of the  developing lateral incisor and canine teeth. The congenital  epulis shows a striking predilection for females, which sug-  gests a hormonal influence in its development, although  estrogen and progesterone receptors have not been detected.  Nearly 90% of cases occur in females.    The congenital epulis is characterized by large, rounded cells  with abundant granular, eosinophilic cytoplasm and round  to oval, lightly basophilic nuclei (Figs. 12-87 and 12-88). In  older tumors, these cells may become elongated and sepa-  rated by fibrous connective tissue. In contrast to the granular  cell tumor, the overlying epithelium never shows pseudoepi-  theliomatous hyperplasia but typically demonstrates atrophy  of the rete ridges. In addition, in contradistinction to the  granular cell tumor, immunohistochemical analysis shows  the tumor cells to be negative for S-100 protein.    ‘The congenital epulis is usually treated by surgical excision.  The lesion never has been reported to recur, even with  incomplete removal.   After birth, the tumor appears to stop growing and may  even diminish in size. Eventual complete regression has    been reported in a few patients, even without treatment  (Fig. 12-89).    In recent years, great progress has been made in the classi-  fication and understanding of tumors and tumorlike prolif  erations of vascular origin. A modified classification scheme  for these vascular anomalies is presented in Box 12-2.   The term hemangioma traditionally has been used to  describe a variety of developmental vascular anomalies. Cur-  rently, hemangiomas are considered to be benign tumors of  infancy that display a rapid growth phase with endothelial  cell proliferation, followed by gradual involution. Most  hemangiomas cannot be recognized at birth, but arise sub-  sequently during the first 8 weeks of life. On the other    Hemangiomas of infancy  Superficial  Deep  Mixed  Congenital hemangiomas  Noninvoluting congenital hemangioma (NICH)  Rapidly involuting congenital hemangioma (RICH)  Kaposiform hemangioendothelioma  Tufted angioma  Pyogenic granuloma (lobular capillary hemangioma)    Vascular Malformations  Simple  Capillary malformation  Venous malformation  Lymphatic malformation  Arteriovenous malformation  Combined malformations    ® Fig. 12-89 Congenital Epulis. A, Nodular mass on the maxillary alveolar ridge. Instead of being  excised, the lesion was monitored clinically. B, Clinical appearance of the child at 1 year of age. The mass  has disappeared without treatment. (Courtesy of Dr. Erwin Turner.)    hand, vascular malformations are structural anomalies of  blood vessels with normal endothelial cell turnover. By defi-  nition, vascular malformations are present at birth and  persist throughout life. They can be categorized according  to the type of vessel involved (capillary, venous, or arterio-  venous) and according to hemodynamic features (low flow    Hemangiomas are the most common tumors of infancy,  occurring in 4% to 5% of 1-year-old children. They are  much more common in females than in males (ratio of 3:1  to 5:1), and they occur more frequently in whites than in  other racial groups. The most common location is the head  and neck, which accounts for 60% of all cases. Eighty  percent of hemangiomas occur as single lesions, but 20%  of affected patients will have multiple tumors.   Infantile hemangiomas are rarely present at birth,  although a pale macule with threadlike telangiectasias may  be noted on the skin. During the first few weeks of life, the  tumor will demonstrate rapid development that occurs at a  faster pace than the infant’s overall growth. Superficial  tumors of the skin appear raised and bosselated with a  bright-red color (“strawberry” hemangioma) (Fig. 12-90).  They are firm and rubbery to palpation, and the blood  cannot be evacuated by applying pressure. Deeper tumors  may appear only slightly raised with a bluish hue.   The initial proliferative phase usually lasts for 6 to 12  months, after which the tumor grows proportionately with  the child, followed by slow involution. The color gradually  changes to a dull-purple hue, and the lesion feels less firm  to palpation. By age 5, most of the red color is usually gone.  About half of all hemangiomas will show complete resolu-  tion by 5 years of age, with 90% resolving by age 9. After  tumor regression is complete, normal skin will be restored  in about 50% of patients; however, up to 40% of affected  individuals will show permanent changes such as atrophy,  scarring, wrinkling, or telangiectasias.   Congenital hemangiomas, which are fully developed at  birth, occur in two varieties. Rapidly involuting congenital    hemangioma (RICH) shows early regression, with full invo-  lution by 9 to 14 months of age. Noninvoluting congenital  hemangioma (NICH) grows proportionately with the child  and does not undergo involution.   Complications occur in about 20% of hemangiomas.  The most common problem is ulceration, which may occur  with or without secondary infection. Although hemorrhage  may be noted, significant blood loss does not usually occur.  Hemangiomas that occur in crucial areas can be associated  with significant morbidity. Periocular tumors often result in  amblyopia (dimness of vision), strabismus, or astigmatism.  Patients with multiple cutaneous hemangiomas or large  facial hemangiomas are at increased risk for concomitant  visceral hemangiomas. Tumors in the neck and laryngeal  region can lead to airway obstruction.   Large, segmental cervicofacial hemangioma can be a  component of a well-recognized hemangioma syndrome—  PHACE(S) syndrome. This acronym stands for the  following:  ¢ Posterior fossa brain anomalies (usually Dandy-Walker   malformation)  ¢ Hemangioma (usually cervical segmental hemangioma)  e Arterial anomalies  ¢ Cardiac defects and Coarctation of the aorta  e Eye anomalies  ¢ Sternal cleft or Supraumbilical raphe   Kasabach-Merritt phenomenon is a serious coagulopa-  thy that has been associated with two rare vascular tumors  known as tufted hemangioma and kaposiform hemangioendo-  thelioma. This disorder is characterized by severe thrombocy-  topenia and hemorrhage because of platelet trapping within  the tumor. The mortality rate is as high as 20% to 30%.    In contrast to hemangiomas, vascular malformations are  present at birth and persist throughout life. Port wine stains  are relatively common capillary malformations that occur  in 0.3% of newborns and have been associated with somatic  mutations in the GNAQ gene. They are most common on  the face, particularly along the distribution of the trigeminal  nerve. In Sturge-Weber syndrome, associated intracranial  lesions are present (see page 508). Port wine stains are typi-  cally pink or purple macular lesions that grow commensu-  rately with the patient. As the patient gets older, the lesion  often darkens and becomes nodular because of vascular  ectasia.   Low-flow venous malformations encompass a wide  spectrum of lesions, from small isolated ectasias to complex  growths that involve multiple tissues and organs. They are  present at birth, although they may not always be immedi-  ately apparent. Typically, venous malformations are blue  and are easily compressible (Fig. 12-91). They often grow  proportionately with the patient, but they may swell when  dependent or with increased venous pressure. Secondary  thrombosis and phlebolith formation can occur.   Arteriovenous malformations are high-flow lesions  that result from persistent direct arterial and venous    communication. Although they are present from birth, they  may not become noticeable until later in childhood or adult-  hood. Because of the fast vascular flow through these lesions,  a palpable thrill or bruit often is noticeable. The overlying  skin typically feels warmer to touch. Presenting symptoms  may include pain, bleeding, and skin ulceration.    Intrabony “hemangiomas” also may occur and usually rep-  resent either venous or arteriovenous malformations. In the  jaws, such lesions are detected most often during the first  three decades of life. They are slightly more common in  females than in males and occur three times more often in  the mandible than the maxilla. The lesion may be com-  pletely asymptomatic, although some examples are associ-  ated with pain and swelling. Mobility of teeth or bleeding  from the gingival sulcus may occur. A bruit or pulsation  may be apparent on auscultation and palpation.   The radiographic appearance of intrabony vascular mal-  formations is variable. Most commonly, the lesion shows a  multilocular radiolucent defect. The individual loculations  may be small (honeycomb appearance) or large (soap bubble  appearance). In other cases the lesion may present as an  ill-defined radiolucent area or a well-defined, cystlike radio-  lucency (Fig. 12-92). Large malformations may cause corti-  cal expansion, and occasionally a “sunburst” radiographic  pattern is produced (Fig. 12-93). Angiography can be  helpful in demonstrating the vascular nature of the lesion  (Fig. 12-94).    Early hemangiomas of infancy are characterized by numer-  ous plump endothelial cells and often-indistinct vascular  lumina (Figs. 12-95 and 12-96). At this stage, such lesions  often are known microscopically as juvenile or cellular  hemangiomas. Because of their cellular nature, these  lesions also have been called juvenile hemangioendothe-  lioma, although this term should be avoided because    @ Fig. 12-92 Intrabony Venous Malformation. Well-circumscribed  radiolucency that contains fine trabeculations.    @ Fig. 12-94 Intrabony Arteriovenous Malformation. A, Periapi-  cal radiograph showing an expansile, mottled radiolucency in the  mandibular incisor region. Pulsatile hemorrhage was encountered  when a biopsy of this lesion was attempted. B, Angiogram demon-  strating a vascular proliferation between the mandibular incisors.  (Courtesy of Dr. Larry Cunningham and Dr. Jason Ford.)    @ Fig. 12-95 Juvenile (Cellular) Hemangioma. Low-power photo-  micrograph showing a circumscribed cellular mass of vascular endo-  thelial cells arranged in lobular aggregates.    showing a highly cellular endothelial proliferation forming occasional  indistinct vascular lumina.    hemangioendothelioma also is used to designate other vas-  cular tumors of intermediate malignant potential. As the  lesion matures, the endothelial cells become flattened, and  the small, capillary-sized vascular spaces become more  evident (Fig. 12-97). As the hemangioma undergoes involu-  tion, the vascular spaces become less prominent and are  replaced by fibrofatty connective tissue.   Vascular malformations do not show active endothelial  cell proliferation, and the channels resemble the vessels of  origin. Therefore, capillary malformations may be similar to  the capillary stage of hemangioma, whereas venous malfor-  mations may show more dilated vessels (Fig. 12-98). Because  of their similar features, many vascular malformations  are incorrectly categorized as hemangiomas. Arteriovenous    @ Fig. 12-97 Capillary Hemangioma. High-power photomicro-  graph demonstrating well-formed capillary-sized vessels.    @ Fig. 12-98 Venous Malformation. Low-power photomicrograph  showing multiple large, dilated blood vessels.    malformations demonstrate a mixture of thick-walled arter-  ies and veins, along with capillary vessels.   GLUT1 is an immunohistochemical marker that is con-  sistently positive in the hemangioma of infancy. In contrast,  this marker is negative in other developmental vascular  tumors and anomalies listed in Box 12-2 (RICH, NICH,  tufted angioma, kaposiform hemangioendothelioma, pyo-  genic granuloma, and vascular malformations).    Because most hemangiomas of infancy undergo involution,  management often consists of “watchful neglect.” It is  important to educate parents that although rapid growth  may be seen, regression will occur. For problematic or life-  threatening hemangiomas, pharmacologic therapy with the  beta blocker propranolol has become the first-line treatment  in recent years. Systemic corticosteroids also may help to  reduce the size of the lesion, but this approach is associated  with a greater risk potential than propranolol therapy. Intra-  lesional and topical corticosteroids sometimes have been  used for smaller localized, problematic lesions. Intravenous  (IV) vincristine may be considered for complicated tumors    that are unresponsive to other therapies. Interferon 0t-2a is  no longer widely used because of the reported risk of per-  manent spastic diplegia.   Surgical removal rarely is warranted for infantile heman-  gioma, although excision may be effective for localized,  pedunculated tumors that demonstrate ulceration or recur-  rent bleeding. Surgical management early in childhood also  might be a consideration in situations where eventual surgi-  cal repair would be required anyway and the scar can be  easily hidden. Upper eyelid tumors that can affect vision  also may be candidates for surgery.   Flashlamp pulsed dye lasers can be effective in the treat-  ment of port wine stains. The management of venous mal-  formations depends on the size, location, and associated  complications of the lesion. Small, stable malformations  may not require treatment. Larger, problematic lesions may  be treated with a combination of sclerotherapy and surgical  excision. Sclerotherapy involves the injection of sclerosing  agents, such as 95% ethanol or sodium tetradecyl sulfate,  directly into the lesion to induce fibrosis. Sclerotherapy  alone may be sufficient for smaller lesions; for larger lesions,  subsequent surgical resection can be accomplished with less  risk of bleeding after sclerotherapy.   The treatment of arteriovenous malformations is more  challenging and also depends on the size of the lesion and  degree of involvement of vital structures. For cases that  require resection, radiographic embolization often is  performed 24 to 48 hours before surgery to minimize  blood loss.   Vascular malformations of the jaws are potentially dan-  gerous lesions because of the risk of severe bleeding, which  may occur spontaneously or during surgical manipulation.  Needle aspiration of any undiagnosed intrabony lesion  before biopsy is a wise precaution to rule out the possibility  of a vascular malformation. Severe and even fatal hemor-  rhages have occurred after incisional biopsy or extraction of  teeth in the area of such lesions.    Sturge-Weber syndrome is a rare, nonhereditary develop-  mental condition that is characterized by a hamartomatous  vascular proliferation involving the tissues of the brain and  face. This condition recently was shown to be related to a  somatic activating mutation of the GNAQ gene on chromo-  some 9q21. It has been suggested that this embryologic  mutation results in failure of the primitive cephalic venous  plexus to regress and mature properly during the first tri-  mester of pregnancy.    Patients with Sturge-Weber syndrome are born with a  dermal capillary vascular malformation of the face known    @ Fig. 12-99 Port Wine Stain. Nevus flammeus of the malar area in  a patient without Sturge-Weber syndrome. Unless the vascular lesion  includes the region innervated by the ophthalmic branch of the trigemi-  nal nerve, usually the patient does not have central nervous system  (CNS) involvement.    as a port wine stain or nevus flammeus because of its  deep-purple color. This port wine stain usually has a unilat-  eral distribution along one or more segments of the trigemi-  nal nerve. Occasionally, patients have bilateral involvement  or additional port wine lesions elsewhere on the body. Only  8% to 10% patients with facial port wine nevi will have  Sturge-Weber syndrome. Risk for the condition occurs pri-  marily in patients with involvement along the distribution  of the ophthalmic branch of the trigeminal nerve (V1)  (Figs. 12-99 and 12-100). If the port-wine stain involves  the entire distribution of V1, the risk for neurologic and  ocular involvement is 78%.   In addition to the facial port wine nevus, individuals  with Sturge-Weber syndrome have leptomeningeal angio-  mas that overlie the ipsilateral cerebral cortex. This menin-  geal angiomatosis usually is associated with a convulsive  disorder and often results in intellectual disability or con-  tralateral hemiplegia. Other potential problems include  migraine headaches, stroke-like episodes, growth hormone  deficiency, and central hypothyroidism. Imaging studies of  the brain may reveal gyriform “tramline” calcifications on  the affected side (Fig. 12-101). Ocular involvement may be  manifested by glaucoma and vascular malformations of the  conjunctiva, episclera, choroid, and retina.   Intraoral involvement in Sturge-Weber syndrome is  common, resulting in hypervascular changes to the ipsilat-  eral mucosa (Fig. 12-102). The gingiva may exhibit slight  vascular hyperplasia or a more massive hemangiomatous  proliferation that can resemble a pyogenic granuloma. Such  gingival hyperplasia may be attributable to the increased  vascular component, anticonvulsant therapy used to control  the epileptic seizures, or both. Destruction of the underly-  ing alveolar bone has been reported in rare instances.    of dilated blood vessels in the middle and deep dermis. The    aN . vy  @ Fig. 12-100 Sturge-Weber Syndrome. Port wine stain of the left  face, including involvement along the ophthalmic branch of the trigemi-  nal nerve. The patient also was intellectually disabled and had a seizure  disorder.    intraoral lesions show a similar vascular dilatation. Prolifera-  tive gingival lesions may resemble a pyogenic granuloma.    The treatment and prognosis of Sturge-Weber syndrome  depend on the nature and severity of the possible clinical  features. Usually, facial port wine nevi can be improved  by using flashlamp pulsed dye lasers. Cortical excision  of angiomatous meningeal lesions may be necessary in  some cases. Patients with intractable epilepsy and progres-  sive intellectual disability eventually may require more    e Fig. 12-102 Sturge-Weber Syndrome. Unilateral vascular  involvement of the soft palate.   Port wine nevi that affect the gingiva can make flossing  and dental prophylaxis difficult. Great care must be taken  when performing surgical procedures in affected areas of the  mouth because significant hemorrhage may be encoun-  tered. Lasers also may be helpful in the removal of hyper-  plastic oral lesions.    The nasopharyngeal angiofibroma is a rare vascular and  fibrous tumorlike lesion that occurs only in the nasophar-  ynx. Although microscopically benign, it frequently exhibits  locally destructive and aggressive behavior. It may represent  a vascular malformation rather than a true neoplasm.    Nasopharyngeal angiofibromas occur almost exclusively in  males. The tumor is exceedingly rare in females—so much  so that the diagnosis in a female patient should be viewed  with skepticism and closely scrutinized. The lesion also  shows a striking predilection for adolescents between the  ages of 10 and 17 and often has been called the juvenile  nasopharyngeal angiofibroma. However, rare examples also  have been reported in slightly younger and older patients.  Because of its almost exclusive occurrence in adolescent  boys, a hormonal influence seems likely, although no endo-  crine abnormalities have been detected.   Nasal obstruction and epistaxis are common early symp-  toms. The lesion is currently presumed to arise in the ptery-  gopalatine fossa and expands medially into the nasal cavity  via the sphenopalatine foramen. Some cases show extension  into the paranasal sinuses, orbits, or middle cranial fossa.  Invasion into the oral cavity or cheek rarely has been  reported. Computed tomography (CT) scans and magnetic  resonance imaging (MRI) studies are helpful adjuncts in  visualizing the extent of the lesion and degree of adjacent  tissue destruction. Anterior bowing of the posterior wall of  the maxillary sinus is a characteristic feature (Fig. 12-103).    @ Fig. 12-103 Nasopharyngeal Angiofibroma. A contrasted com-  puted tomography (CT) scan showing a tumor of the nasopharynx and  pterygopalatine fossa, with characteristic anterior bowing of the pos-  terior wall of the right maxillary sinus (arrow). (Courtesy of Dr. Pamela  Van Tassel.)    © Fig. 12-104 Nasopharyngeal Angiofibroma. A digital subtrac-  tion angiogram of the external carotid artery showing the intense  vascular blush of the tumor. (Courtesy of Dr. Pamela Van Tassel.)    Angiograms can be used to confirm the vascular nature of  the lesion (Fig. 12-104).    ‘The nasopharyngeal angiofibroma consists of dense fibrous  connective tissue that contains numerous dilated, thin-    ® Fig. 12-105 Nasopharyngeal Angiofibroma. Moderately cellular  fibrous connective tissue with prominent blood vessels.    walled blood vessels of variable size (Fig. 12-105). Typically,  the vascular component is more prominent at the periphery  of the tumor, especially in lesions from younger patients.    The primary treatment of nasopharyngeal angiofibroma  usually consists of surgical excision. Depending on the  extent of the lesion, this may be accomplished via endo-  scopic surgery, lateral rhinotomy, midfacial degloving  procedure, infratemporal fossa approach, or combined cra-  niofacial resection. Preoperative embolization of the tumor  is helpful in controlling blood loss. Radiation therapy  usually is reserved for recurrent lesions and extensive tumors  with unusual vascular supplies or intracranial extension.   The recurrence rate varies from 20% to 40% in most  studies. Such recurrences usually are retreated with further  surgery or radiation therapy. Malignant transformation into  fibrosarcoma rarely has been reported and probably is asso-  ciated with prior radiation therapy.    Lymphatic malformations are benign, hamartomatous  tumorlike growths of lymphatic vessels. Like other vascular  malformations, it is doubtful that they are true neoplasms;  instead, they most likely represent developmental anomalies  that arise from sequestrations of lymphatic tissue that do not  communicate normally with the rest of the lymphatic system.  Lymphatic malformations can be classified into three  types:  1. Macrocystic—composed of cystlike spaces measuring  2 cm or greater in diameter  2. Microcystic—composed of smaller vascular channels  measuring less than 2 cm in diameter  3. Mixed—composed of a combination of macrocystic and  microcystic spaces  The subtypes are probably variants of the same patho-  logic process, and the size of the vessels may depend on the    ® Fig. 12-106 Lymphatic Malformation. Young boy with a cystic  hygroma primarily involving the right side of the face. (Courtesy of Dr.  Frank Kendrick.)    nature of the surrounding tissues. Macrocystic lymphatic  malformations (“cystic hygroma”) often occur in the neck,  where the loose adjacent connective tissues allow for more  expansion of the vessels. Microcystic lesions are more fre-  quent in the mouth, where the denser surrounding connec-  tive tissue and skeletal muscle limit vessel expansion.    Lymphatic malformations have a marked predilection for  the head and neck, which accounts for 50% to 75% of all  cases (Fig. 12-106). About half of all lesions are noted at  birth, and around 90% develop by 2 years of age.  Cervical lymphatic malformations are more common in  the posterior triangle and are typically soft, fluctuant masses.  They occur less frequently in the anterior triangle, although  lesions in this location are more likely to result in respiratory  difficulties or dysphagia if they grow large. Occasionally,  cervical lesions will extend into the mediastinum or upward  into the oral cavity. Such growths can become massive and  can measure 15 cm or greater in size. Rapid enlargement  may occur secondary to an upper respiratory tract infection,  presumably because of increased lymph production, blocked  lymphatic drainage, or secondary infection of the tumor.  Oral lymphatic malformations may occur at various sites  but are most frequent on the anterior two thirds of the  tongue, where they often result in macroglossia (Figs.  12-107 and 12-108). Usually, the lesion is superficial in    e@ Fig. 12-107 Lymphatic Malformation. Pebbly, vesicle-like  appearance of a tumor of the right lateral tongue.    @ Fig. 12-108 Lymphatic Malformation. Dorsal tongue lesion dem-  onstrating a purple color, which can be caused by secondary hemor-  rhage or an associated hemangiomatous component.    location and demonstrates a pebbly surface that resembles  a cluster of translucent vesicles. The surface has been likened  to the appearance of frog eggs or tapioca pudding. Second-  ary hemorrhage into the lymphatic spaces may cause some  of these “vesicles” to become purple. Deeper tumors present  as soft, ill-defined masses.   Small lymphatic anomalies less than 1 cm in size occur  on the alveolar ridge in around 4% of black neonates. These  lesions often occur bilaterally on the mandibular ridge and  show a 2:1 male-to-female distribution. Most of these  alveolar lymphangiomas apparently resolve spontaneously  because they are not observed in older people.    Lymphatic malformations are composed of lymphatic  vessels that may show mild dilatation (microcystic) (Figs.  12-109 and 12-110) or macroscopic cystlike structures  (macrocystic) (Fig. 12-111). The vessels often diffusely infil-  trate the adjacent soft tissues and may demonstrate lym-  phoid aggregates in their walls. The lining endothelium is  typically thin, and the spaces contain proteinaceous fluid  and occasional lymphocytes. Some channels also may    ® Fig. 12-109 Microcystic Lymphatic Malformation. Lesion of the  tongue showing dilated lymphatic vessels beneath the epithelium and  in the deeper connective tissues.    @ Fig. 12-110 Microcystic Lymphatic Malformation. High-power  photomicrograph showing dilated, lymph-filled vessels immediately  below the atrophic surface epithelium.    ® Fig. 12-111 Macrocystic Lymphatic Malformation. Lesion from  the neck showing markedly dilated lymphatic vessels.    contain red blood cells, which creates uncertainty as to  whether they are lymphatic or blood vessels. Although  many of these likely represent secondary hemorrhage into  a lymphatic vessel, some actually may be examples of mixed  vascular malformations composed of both lymphatic and  blood vessels.    In intraoral tumors, the lymphatic vessels are character-  istically located just beneath the epithelial surface and often  replace the connective tissue papillae. This superficial loca-  tion results in the translucent, vesicle-like clinical appear-  ance. However, extension of these vessels into the deeper  connective tissue and skeletal muscle also may be seen.    ‘The treatment of lymphatic malformations of the head and  neck depends on the size, location, and subtype of the  anomaly. Smaller lesions not associated with significant  functional or cosmetic problems may be managed best by  observation alone. For example, some clinicians do not  recommend treatment for nonenlarging lesions of the  tongue because of the difficulty in removal and high  recurrence rate. Spontaneous regression of lymphatic mal-  formations is rare but has been reported in about 3% of  cases.   When required, treatment usually consists of either sur-  gical excision or percutaneous sclerotherapy. Total surgical  removal may not be possible in all cases because of large size  or involvement of vital structures. Recurrence after surgery  is common, especially for microcystic lymphatic malforma-  tions of the oral cavity, because of their infiltrative nature.  Macrocystic lesions of the cervical region are often well  circumscribed and have a lower rate of recurrence.   In recent years, percutaneous sclerotherapy has proven  to be a successful alternative to surgery for many lymphatic  malformations. In the United States, the most widely used  sclerosant currently is doxycycline. Other sclerosing agents  that have been utilized include bleomycin, ethanol, acetic  acid, sodium tetradecyl sulfate, and OK-432 (outside of the  United States). Sclerotherapy is most successful in the man-  agement of macrocystic lesions, with most patients showing  75% to 100% clinical resolution. A lower success rate is  achieved in mixed and microcystic subtypes.   ‘The prognosis is good for most patients, although large  tumors of the neck or tongue may result in airway obstruc-  tion and death.   skin. Leiomyomas of the oral cavity are rare. Most of these   probably have their origin from vascular smooth muscle.  The three types are as follows:   Almost all oral leiomyomas are either solid or vascular in  type; angiomyomas account for nearly 75% of all oral cases.  Rare examples of developmental hamartomas composed  primarily of smooth muscle (leiomyomatous hamartoma)  also have been described in the oral cavity.    @ Fig. 12-112 Leiomyoma. Small, pink-red nodule on the posterior  hard palate lateral to the midline.    . a AES  @ Fig. 12-113 Leiomyoma. Low-power view showing a well-  circumscribed cellular mass of spindle-shaped smooth muscle cells.    The oral leiomyoma can occur at any age and is usually a  slow-growing, firm, mucosal nodule (Fig. 12-112). Most  lesions are asymptomatic, although occasional tumors can  be painful. Solid leiomyomas are typically normal in color,  although angiomyomas may exhibit a bluish hue. The most  common sites are the lips, tongue, palate, and cheek, which  together account for 80% of cases. Extremely rare intraos-  seous examples may present as unilocular radiolucencies of  the jaws.    Solid leiomyomas are well-circumscribed tumors that  consist of interlacing bundles of spindle-shaped smooth  muscle cells (Figs. 12-113 and 12-114). The nuclei are  elongated, pale staining, and blunt ended. Mitotic figures  are uncommon. Angiomyomas also are well-circumscribed  lesions that demonstrate multiple tortuous blood vessels  with thickened walls caused by hyperplasia of their smooth  muscle coats (Fig. 12-115). Intertwining bundles of smooth  muscle may be found between the vessels, sometimes  with intermixed adipose tissue. As its name implies, the    shaped cells with blunt-ended nuclei. Immunohistochemical analysis  shows strong positivity for smooth muscle actin (inset).    @ Fig. 12-115 Angiomyoma. Well-circumscribed tumor exhibiting  prominent blood vessels surrounded by smooth muscle.    epithelioid leiomyoma is composed primarily of epithelioid  cells rather than spindle cells.   Special stains and immunohistochemistry may be helpful  to confirm the smooth muscle origin if the diagnosis is in  doubt. The smooth muscle stains bright red with the  Masson trichrome stain (Fig. 12-116). Immunohistochemical    @ Fig. 12-117 Adult Rhabdomyoma. Nodular mass (arrow) in the  left cheek. (Courtesy of Dr. Craig Little.)    analysis usually reveals the tumor cells to be positive for  vimentin, smooth muscle actin, and muscle-specific actin;  desmin positivity also may be seen.    Oral leiomyomas are treated by local surgical excision. The  lesion should not recur.    Benign neoplasms of skeletal muscle are called rhabdomyo-  mas. The term rhabdomyoma also is used to describe a  hamartomatous lesion of the heart that often is associated  with tuberous sclerosis (see page 705). Despite the great  amount of skeletal muscle throughout the body, benign  skeletal muscle tumors are extremely rare. However, these  extracardiac rhabdomyomas show a striking predilection for  the head and neck. Rhabdomyomas of the head and neck  can be subclassified into two major categories: 1) adult  thabdomyomas and 2) fetal rhabdomyomas.    Adult rhabdomyomas of the head and neck occur primarily  in middle-aged and older patients, with about 75% of cases  found in men. The most frequent sites are the pharynx, oral  cavity, and larynx; intraoral lesions are most common in the  floor of the mouth, soft palate, and base of tongue. The  tumor appears as a nodule or mass that can grow many  centimeters before discovery (Figs. 12-117 and 12-118).  Laryngeal and pharyngeal lesions often lead to airway  obstruction. Sometimes, the tumor is multinodular in  nature, with two or more discrete nodules found in the same  anatomic location. From 3% to 10% of adult rhabdomyo-  mas are multicentric, with separate, distinct tumors at dif-  ferent sites.    Fetal rhabdomyomas usually occur in young children,  although some also develop in adults. A similar male    @ Fig. 12-118 Adult Rhabdomyoma. Computed tomography (CT)  scan of the same tumor depicted in Fig. 12-117. Note the mass (arrow)  lateral to the left body of the mandible. (Courtesy of Dr. Craig Little.)    a uniform tumor composed of rounded and polygonal cells with focal  vacuolization.    predilection is noted. The most common locations are the  face and periauricular region.    The adult rhabdomyoma is composed of well-circumscribed  lobules of large, polygonal cells, which exhibit abundant  granular, eosinophilic cytoplasm (Fig. 12-119). These cells  often demonstrate peripheral vacuolization that results in  a “spider web” appearance of the cytoplasm. Focal cells  with cross striations can be identified in most cases (Fig.  12-120). Although rarely necessary for the diagnosis,  immunohistochemical examination will show the tumor  cells to be positive for myoglobin, desmin, and muscle-  specific actin.    ® Fig. 12-120 Adult Rhabdomyoma. Phosphotungstic acid hema-  toxylin (PTAH) stain that demonstrates focal cross striations in some  cells (arrow).    The fetal rhabdomyoma has a less mature appearance and  consists of a haphazard arrangement of spindle-shaped  muscle cells that sometimes are found within a myxoid  stroma. Some tumors may show considerable cellularity and  mild pleomorphism, which makes them easily mistaken for  thabdomyosarcomas.    The treatment of both variants of rhabdomyoma consists of  local surgical excision. Recurrence has been reported in  10% to 42% of cases, but this largely may be due to incom-  plete removal.    A choristoma is a tumorlike growth of microscopically  normal tissue in an abnormal location. Several different  tissue types may occur in the mouth as choristomas. These  include gastric mucosa, glial tissue, and tumorlike masses  of sebaceous glands. However, the most frequently observed  choristomas of the oral cavity are those that consist of bone,  cartilage, or both. These lesions sometimes have been called  soft tissue osteomas or soft tissue chondromas, but cho-  ristoma is a better term because they do not appear to be  true neoplasms.    Osseous and cartilaginous choristomas show a striking pre-  dilection for the tongue, which accounts for 85% of cases.  The most common location is the posterior tongue near the  foramen cecum, although rare examples also have been  reported elsewhere on the tongue and at other oral loca-  tions. The lesion is usually a firm, smooth-surfaced, sessile  or pedunculated nodule between 0.5 and 2.0 cm in    ® Fig. 12-121 Osseous Choristoma. Hard pedunculated nodule on  the posterior dorsum of the tongue. (Courtesy of Dr. Michael  Meyrowitz.)    @ Fig. 12-122 Osseous Choristoma. Mass of dense lamellar bone  beneath the surface epithelium.    diameter (Fig. 12-121). Many patients are unaware of the  lesion, although some complain of gagging or dysphagia.    Microscopic examination of choristomas shows a well-  circumscribed mass of dense lamellar bone or mature carti-  lage that is surrounded by dense fibrous connective tissue  (Fig. 12-122). Sometimes a combination of bone and car-  tilage is formed. The bone has a well-developed Haversian  canal system and occasionally demonstrates central fatty or  hematopoietic marrow.    Osseous and cartilaginous choristomas are best treated by  local surgical excision. Recurrence has not been reported.    Fortunately, soft tissue sarcomas are rare in the oral and  maxillofacial region and account for less than 1% of the  cancers in this area. Because of their relative rarity, it is  beyond the scope of this book to give a complete, detailed  discussion of each of these tumors. However, a review of  these entities is included in the following section.    ‘The fibrosarcoma is a malignant tumor of fibroblasts. At  one time, it was considered one of the most common soft  tissue sarcomas. However, the diagnosis of fibrosarcoma is  made much less frequently today because of the recognition  and separate classification of other spindle cell lesions that  have similar microscopic features. The tumor is most  common in the extremities; only 10% to 19% occur in the  head and neck region.    Fibrosarcomas most often present as slow-growing masses  that may reach considerable size before they produce pain  (Fig. 12-123). They can develop at any age and occur any-  where in the head and neck region. A number of cases have  been reported in the nose and paranasal sinuses, where they  often result in obstructive symptoms.    Fibrosarcoma is often a diagnosis of exclusion, which is used  for spindle cell sarcomas that do not fit microscopically into  other recognized categories. Well-differentiated examples  consist of fascicles of spindle-shaped cells that classically  form a “herringbone” pattern (Fig. 12-124). The cells often  show little variation in size and shape, although variable  numbers of mitotic figures can usually be identified. In  more poorly differentiated tumors, the cells are less  organized and may appear rounder or ovoid. Mild    @ Fig. 12-123 Fibrosarcoma. Child with a large mass of the hard  palate and maxillary alveolar ridge. (Courtesy of Dr. John McDonald.)    pleomorphism along with more frequent mitotic activity  may be seen. Higher grade tumors tend to produce less  collagen than do well-differentiated tumors. Immunohisto-  chemical markers should be negative except for vimentin  and minimal smooth muscle actin.    ‘The treatment of choice is usually surgical excision, includ-  ing a wide margin of adjacent normal tissue. Recurrence is  noted in about half of cases, and 5-year survival rates range  from 40% to 70%.    ‘The term malignant fibrous histiocytoma was introduced  in the 1960s to describe a group of sarcomas that were  considered to show both fibroblastic and histiocytic fea-  tures. This concept rapidly gained acceptance and malig-  nant fibrous histiocytoma soon became the most commonly  diagnosed soft tissue sarcoma in adults. However, experts  today have questioned this concept because, with the help  of immunohistochemistry and other ancillary studies, most  tumors formerly diagnosed as malignant fibrous histiocy-  toma can now be reclassified into other categories, such as  liposarcoma, leiomyosarcoma, rhabdomyosarcoma, myxofi-  brosarcoma, melanoma, and anaplastic carcinoma. However,  there still remains a heterogeneous group of tumors from  this former family, whose line of differentiation cannot  be determined. The term undifferentiated pleomorphic  sarcoma is now recommended for these lesions.    Undifferentiated pleomorphic sarcomas occur primarily in  older age groups. The most common complaint is an  expanding mass that may or may not be painful or ulcer-  ated. The deep tissues of the trunk and extremities are the    Me .  ® Fig. 12-125 Undifferentiated Pleomorphic Sarcoma. Spindle  cell neoplasm demonstrating marked pleomorphism and scattered  mitoses.    most frequent locations. Tumors of the nasal cavity and  paranasal sinuses produce obstructive symptoms.    Several histopathologic patterns have been described. The  most classic variety is the storiform-pleomorphic type,  which is characterized by short fascicles of plump spindle  cells arranged in a storiform pattern, admixed with areas of  pleomorphic giant cells (Fig. 12-125).    Undifferentiated pleomorphic sarcoma is considered to be  an aggressive tumor that is usually treated by radical surgical  resection. Approximately 40% of patients with head and  neck tumors will have local recurrence, and almost 30% will  develop metastases. The overall 5-year survival rate is 52%    The liposarcoma is a malignant neoplasm of fatty origin.  It currently is considered to be the most common soft tissue  sarcoma and accounts for 17% to 30% of all soft tissue  malignancies in adults. The most common sites are the  thigh, retroperitoneum, and inguinal region. Liposarcomas  of the head and neck are rare, comprising only 3% of all  such tumors.    Liposarcomas are seen primarily in adults; the mean age for  head and neck tumors is 57 years. The tumor is typically a  soft, slow-growing, ill-defined mass that may appear normal  in color or yellow. Pain or tenderness is uncommon; when  present, it is usually a late feature. The neck is the most  common site for liposarcomas of the head and neck region.  The most frequent intraoral locations are the tongue and    ® Fig. 12-126 Liposarcoma. High-power view showing vacuolated  lipoblasts with pleomorphic nuclei.   The most common of these variants in the oral cavity is  the well-differentiated liposarcoma, which accounts for  55% to 90% of all cases. These tumors resemble benign  lipomas but demonstrate scattered lipoblasts and atypical,  hyperchromatic stromal cells (Fig. 12-126).   Myxoid liposarcomas demonstrate proliferating lipo-  blasts within a myxoid stroma that contains a rich capillary  network. The round cell liposarcoma is a more aggressive  form of myxoid liposarcoma with less differentiated,  rounded cells.   Pleomorphic liposarcomas exhibit extreme cellular  pleomorphism and bizarre giant cells. Dedifferentiated  liposarcomas are characterized by the combination of well-  differentiated liposarcoma with poorly differentiated, non-  lipogenic sarcomatous changes. These features may coexist  in the same neoplasm, or the dedifferentiated changes may  develop in a recurrent tumor or metastasis.    Radical excision is the treatment of choice for most liposar-  comas throughout the body. In spite of this, around 50%  of all tumors recur. The overall 5-year survival rate ranges  from 59% to 70%. There is a 10-year survival rate  of approximately 50%. The histopathologic subtype is  extremely important in predicting the prognosis; the  outlook for pleomorphic liposarcomas is much worse than  for myxoid and well-differentiated tumors.   In contrast, the prognosis for oral liposarcoma is more  favorable because of the predominance of well-differentiated  subtypes and because most tumors are small when    diagnosed. Local recurrence has been reported in 15% to  20% of cases, but metastasis and death as a result of tumor  is rare.    @ MALIGNANT PERIPHERAL NERVE  SHEATH TUMOR (MALIGNANT  SCHWANNOMA; NEUROFIBROSARCOMA;  NEUROGENIC SARCOMA)    The principal malignancy of peripheral nerve origin is pref  erably called a malignant peripheral nerve sheath tumor.  These tumors account for 3% to 10% of all soft tissue sar-  comas, with nearly half of such cases occurring in patients  with neurofibromatosis type I (see page 495). The lesion is  most common on the proximal portions of the extremities  and the trunk; 14% to 19% of cases occur in the head  and neck.    Malignant peripheral nerve sheath tumors are most common  in young adults. The mean age in patients with neurofibro-  matosis (29 to 36 years) is about one decade younger than  in those without this condition (40 to 46 years). The tumor  is an enlarging mass that sometimes exhibits rapid growth.  Associated pain or a nerve deficit is common.   Oral tumors may occur anywhere, but the most common  sites are the mandible, lips, and buccal mucosa (see Figs.  12-68 and 12-69, page 497). Radiographic examination of  intraosseous tumors of the mandible may reveal widening  of the mandibular canal or the mental foramen, with or  without irregular destruction of the surrounding bone.    The malignant peripheral nerve sheath tumor shows  fascicles of atypical spindle-shaped cells, which often resem-  ble the cells of fibrosarcoma (see Fig. 12-70, page 516).  However, these cells frequently are more irregular in shape  with wavy or comma-shaped nuclei. In addition to stream-  ing fascicles, less cellular myxoid areas also may be present.  With some tumors, there can be heterologous elements,  which include skeletal muscle differentiation (malignant  Triton tumor), cartilage, bone, or glandular structures.   A definitive diagnosis of neural origin often is difficult,  especially in the absence of neurofibromatosis. Positive  immunostaining for S-100 protein can be a helpful clue, but  this is found in only about 50% of all cases and may be focal.    The treatment of malignant peripheral nerve sheath tumors  consists primarily of radical surgical excision, possibly along  with adjuvant radiation therapy and chemotherapy. The  prognosis is generally poor, with disease-specific survival  ranging from 39% to 60% at 5 years, and 26% to 45% at    10 years. A number of studies have suggested that patients  with neurofibromatosis type I have a worse prognosis than  sporadic cases, although other studies have shown no sig-  nificant difference between these two groups. One recent  study reported that tumors negative for S-100 protein were  associated with a significantly worse prognosis.    The olfactory neuroblastoma is a rare neuroectodermal  neoplasm of the upper nasal vault that shows some similari-  ties to neuroblastomas seen elsewhere in the body. It is  believed to arise from sensory olfactory neuroepithelial cells.    Unlike the usual neuroblastoma, the olfactory neuroblas-  toma is rare in patients younger than the age of 10 years.  Instead, it is more common in adults, with a mean age at  diagnosis of 45 to 56 years. The tumor arises high in the  nasal cavity close to the cribriform plate. From there it may  extend into the adjacent paranasal sinuses (especially the  ethmoid sinus), the orbit, and the anterior cranial fossa (Fig.  12-127). The most common symptoms are nasal obstruc-  tion, epistaxis, pain, and anosmia.    Olfactory neuroblastomas consist of small, round to ovoid  basophilic cells that are arranged in sheets and lobules    @ Fig. 12-127 Olfactory Neuroblastoma. A T1-weighted sagittal  magnetic resonance image (MRI) showing a tumor filling the superior  nasal cavity and ethmoid sinus, with extension into the anterior cranial  fossa (arrows). (Courtesy of Dr. Pamela Van Tassel.)    ® Fig. 12-128 Olfactory Neuroblastoma. Sheet of small, basophilic  cells adjacent to the sinonasal epithelium (top).    (Fig. 12-128). Rosette and pseudorosette formation and  areas of delicate neurofibrillary material may be seen.    ‘The treatment of olfactory neuroblastoma consists of surgi-  cal excision, often with adjuvant radiation therapy. A com-  bined craniofacial surgical approach frequently is used.  Chemotherapy also has been administered, especially in  advanced cases.   The prognosis depends on the stage of the disease. For  patients with stage A lesions (tumor confined to the nasal  cavity), the 5-year survival rate ranges from 75% to 91%.  ‘The 5-year survival rate drops to 68% to 71% for stage B  disease (tumor extending into the paranasal sinuses). For  stage C disease (tumor extending beyond the nasal cavity  and sinuses), the 5-year survival rate ranges from 41% to  47%, Death is usually a result of local recurrence; metastasis  occurs in approximately 20% to 37% of cases.    Angiosarcoma is a rare malignancy of vascular endothe-  lium, which may arise from either blood or lymphatic  vessels. More than 50% of all cases occur in the head and  neck region, with the scalp and forehead being the most  common sites. Oral lesions are quite rare.   The term hemangioendothelioma is used to describe  vascular tumors with microscopic features intermediate  between those of hemangiomas and angiosarcomas. Such  tumors also are rare and are considered to be of intermediate  malignancy.    Cutaneous angiosarcomas of the head and neck are most  common in older adult patients. Early lesions often resem-  ble a simple bruise, which may lead to a delay in diagnosis.  However, the lesion continues to enlarge, which results in  an elevated, nodular, or ulcerated surface (Fig. 12-129).    @ Fig. 12-129 Angiosarcoma. Slightly elevated, bluish purple lesion  on the scalp. (Courtesy of Dr. Terry Day.)    ® Fig. 12-130 Angiosarcoma. Sinusoidal vascular spaces lined by  pleomorphic endothelial cells.    Many examples appear multifocal in nature. Oral angiosar-  comas have been reported in various locations; the tongue  and mandible are two of the more common sites.    Angiosarcoma is characterized by an infiltrative prolifera-  tion of endothelium-lined blood vessels that form an anas-  tomosing network (Fig. 12-130). The endothelial cells  appear hyperchromatic and atypical; they often tend to pile  up within the vascular lumina. Increased mitotic activity  may be seen. Immunohistochemical studies show the tumor  cells to be positive for CD31 and factor VIH-related antigen  in most cases, whereas CD34 positivity is observed less  consistently.    Treatment usually consists of radical surgical excision, radia-  tion therapy, or both. The prognosis for angiosarcoma of  the face and scalp is poor, with a reported 10-year survival  rate of only 14% to 21%. However, angiosarcomas of the  oral cavity and salivary glands appear to have a better    @ Fig. 12-131 Kaposi Sarcoma. Classic Kaposi sarcoma in an  older man presenting as multiple purple macules and plaques on the  lower leg.    outcome. One study showed 11 of 14 patients with oral  and salivary angiosarcoma to be free of tumor on follow-up  (mean follow-up period of 8.6 years).    Kaposi sarcoma is an unusual vascular neoplasm that was  first described in 1872 by Moritz Kaposi, a Hungarian  dermatologist. Before the advent of the acquired immuno-  deficiency syndrome (AIDS) epidemic, it was a rare tumor;  however, beginning in the early 1980s, Kaposi sarcoma  became quite common because of its propensity to develop  in individuals infected by HIV. Since the introduction of  combination antiretroviral therapy (CART) in the mid- to  late 1990s, the prevalence of AIDS-related Kaposi sarcoma  in the Western world has declined.   Kaposi sarcoma is caused by infection with human her-  pesvirus 8 (HHV-8; Kaposi sarcoma-associated herpesvirus  [KSHV]). The lesion most likely arises from endothelial  cells, which may express markers for both lymphatic and  blood vessel differentiation. Four clinical presentations are  recognized:   The first three forms are discussed here; AIDS-related  Kaposi sarcoma is covered in the section on HIV disease  (see page 244).    Classic (chronic) Kaposi sarcoma is primarily a disease of  late adult life, and 70% to 95% of cases occur in men. It  mostly affects individuals of Italian, Jewish, or Slavic ances-  try. Multiple blue-purple macules and plaques are present  on the skin of the lower extremities (Fig. 12-131). These  lesions grow slowly over many years and develop into pain-  less tumor nodules. Oral lesions are rare and most    frequently involve the palate. Some studies have suggested  that patients with classic Kaposi sarcoma have an increased  prevalence of lymphoreticular malignancies, but other  reports have questioned any significant association.    Prior to the advent of HIV/AIDS, endemic Kaposi sarcoma  was already recognized as a relatively common neoplasm of  younger adults and children in sub-Saharan Africa. The  course of the disease can vary widely; some patients develop  indolent skin lesions similar to the pattern observed in  classic Kaposi sarcoma, whereas others exhibit more aggres-  sive tumors that involve deeper tissues, bone, and viscera.  A particularly aggressive lymphadenopathic form also is  recognized in young children, which is characterized by  rapidly growing tumors of the lymph nodes, occasional  visceral organ lesions, and sparse skin involvement. Although  endemic Kaposi sarcoma used to be the most common form  of the disease seen in Africa, epidemic (AIDS-related)  Kaposi sarcoma is seen more frequently now.    Iatrogenic (transplant-associated) Kaposi sarcoma occurs  in recipients of solid organ transplants. It affects 0.5% of  renal transplant patients, usually several months to a few  years after the transplant. It is probably related to the loss  of cellular immunity from immunosuppressive therapy  given to prevent organ rejection. Like classic Kaposi sarcoma,  iatrogenic cases are more common in individuals of Italian,  Jewish, and Slavic ancestry; however, the disease may run a  more aggressive course.   A proliferation of miniature vessels characterizes the  patch stage. This results in an irregular, jagged vascular  network that surrounds preexisting vessels. Sometimes  normal structures, such as hair follicles or preexisting blood  vessels, may appear to protrude into these new vessels  (promontory sign). The lesional endothelial cells have a  bland appearance and may be associated with scattered lym-  phocytes and plasma cells.   The plaque stage demonstrates further proliferation of  these vascular channels along with the development of a  significant spindle cell component.   In the nodular stage, the spindle cells increase to form  a nodular tumorlike mass that may resemble a fibrosarcoma  or other spindle cell sarcomas (Figs. 12-132 and 12-133).  However, numerous extravasated erythrocytes are present,  and slitlike vascular spaces may be discerned.   Other microscopic variants of Kaposi sarcoma include  lymphangioma-like, telangiectatic, desmoplastic, lymphan-  giectatic, ecchymotic, and anaplastic subtypes.    e Fig. 12-132 Kaposi Sarcoma. Low-power photomicrograph  showing a cellular spindle cell tumor within the connective tissue.    The treatment of Kaposi sarcoma depends on the clinical  subtype and stage of the disease. For skin lesions in the  classic form of the disease, radiation therapy (especially  electron beam) often is used. Radiation therapy for oral  lesions must be approached with caution, because an unusu-  ally severe mucositis can develop. Surgical excision can be  performed for the control of individual lesions of the skin  or mucosa. Systemic chemotherapy also may be helpful.  Intralesional injection of vinblastine is used to control indi-  vidual lesions.   ‘The prognosis is variable, depending on the form of the  disease and the patient’s immune status. The classic form of  the disease is slowly progressive; only 10% to 20% of  patients develop disseminated lesions. The mean survival  time is 10 to 15 years, and patients often die from unrelated  causes. Some patients with the endemic form of the disease  develop indolent lesions similar in behavior to classic non-  African Kaposi sarcoma. However, the other endemic  African forms are more aggressive and the prognosis is  poorer. The lymphadenopathic form runs a particularly ful-  minant course, usually resulting in the death of the patient  within 2 to 3 years. In transplant patients, the disease also    @ Fig. 12-134 Leiomyosarcoma. Ulcerated mass of the anterior  maxillary alveolar ridge. (Courtesy of Dr. Jim Weir.)    may be somewhat more aggressive, although the tumors  may regress if immunosuppressive therapy is discontinued  or reduced.    The leiomyosarcoma is a malignant neoplasm of smooth  muscle differentiation, which accounts for 7% of all soft  tissue sarcomas. The most common sites are the uterine wall  and gastrointestinal tract. Leiomyosarcomas of the oral  cavity are rare.    In general, leiomyosarcomas are most common in middle-  aged and older adults. However, tumors in the oral and  maxillofacial region occur over a wide age range without a  predilection for any age group. They have been reported  at various sites, but half of all oral cases occur in the jaw-  bones. The clinical appearance is nonspecific; there is  usually an enlarging mass that may or may not be painful  (Fig. 12-134). Secondary ulceration of the mucosal surface  may occur.    The microscopic examination of a leiomyosarcoma shows  fascicles of spindle-shaped cells with abundant eosinophilic  cytoplasm and blunt-ended, cigar-shaped nuclei (Fig.  12-135). Some tumors may be composed primarily of  rounded epithelioid cells that have either eosinophilic or  clear cytoplasm (epithelioid leiomyosarcoma). The degree  of pleomorphism varies from one tumor to the next, but  smooth muscle tumors with the presence of five or more  mitoses per ten high-power fields should be considered  malignant. Glycogen usually can be demonstrated within  the cells with a periodic acid-Schiff (PAS) stain, and the cell  cytoplasm appears bright red with a Masson trichrome  stain. Immunohistochemical analysis usually reveals the  presence of one or more of the following myogenic markers:    desmin, muscle-specific actin (HHF 35), smooth muscle  myosin (SMMS), and smooth muscle actin.    The treatment of leiomyosarcoma primarily consists of  radical surgical excision, sometimes with adjunctive chemo-  therapy or radiation therapy. The prognosis for oral tumors  is guarded, with the potential for local recurrence and  distant metastasis. Although few cases are available for anal-  ysis, a 5-year survival rate of 55% has been estimated.    Rhabdomyosarcoma is a malignant neoplasm that is char-  acterized by skeletal muscle differentiation. These tumors  are much more common in young children, accounting for  50% of soft tissue sarcomas in childhood. In contrast, rhab-  domyosarcoma comprises only 2% to 5% of soft tissue  sarcomas in adults. The most frequent site is the head and  neck, which accounts for 35% of all cases. The genitouri-  nary tract is the second most common location. Several    @ Fig. 12-135 Leiomyosarcoma. Medium-high-power view of a  pleomorphic spindle cell proliferation.    microscopic patterns of pediatric rhabdomyosarcoma are  recognized (Table 12-2), although discussion here will be  limited primarily to the embryonal and alveolar subtypes.    Rhabdomyosarcoma primarily occurs during the first decade  of life but also may occur in teenagers and young adults. It  is rare in people older than 45 years, and approximately  60% of all cases occur in males. Embryonal rhabdomyosar-  comas are most common in the first 10 years of life and  account for about 60% of all cases. Alveolar rhabdomyosar-  comas occur most often in persons between 10 and 25 years  of age; they account for 20% to 30% of all tumors. Pleo-  morphic rhabdomyosarcomas represent less than 5% of all  cases and show peak prevalence in patients older than 40  years of age. Most head and neck lesions are embryonal or  alveolar types; pleomorphic rhabdomyosarcomas primarily  occur on the extremities.   The tumor is most often a painless, infiltrative mass that  may grow rapidly (Figs. 12-136 and 12-137). In the head  and neck region, the face and orbit are the most frequent    @ Fig. 12-136 Embryonal Rhabdomyosarcoma. Young child with  a mass of the right maxilla. (Courtesy of Dr. Robert Achterberg.)   Spindle 38% 88% Excellent  Alveolar rhabdomyosarcoma 31% 53% Poor  Undifferentiated sarcoma 38% 44% Poor  Anaplastic rhabdomyosarcoma 2% 45% Poor    Adapted from Hicks J, Flaitz C: Rhabdomyosarcoma of the head and neck in children, Oral Oncol 38:450-459, 2002.    e Fig. 12-137 Embryonal Rhabdomyosarcoma. Computed  tomography (CT) scan of patient from Fig. 12-136 showing expansile  lytic lesion of the maxilla. (Courtesy of Dr. Robert Achterberg.)    locations, followed by the nasal cavity. The palate is the  most frequent intraoral site, and some lesions may appear  to arise in the maxillary sinus and break through into the  oral cavity. Some embryonal rhabdomyosarcomas that arise  within a cavity, such as the vagina or oropharynx, demon-  strate an exophytic, polypoid growth pattern that resembles  a cluster of grapes. The term botryoid (grapelike) rhabdomyo-  sarcoma has been used for these lesions.    The embryonal rhabdomyosarcoma resembles various stages  in the embryogenesis of skeletal muscle. Poorly differenti-  ated examples may be difficult to diagnose and consist of  small round or oval cells with hyperchromatic nuclei and  indistinct cytoplasm (Fig. 12-138). Alternating hypercel-  lular and myxoid zones may be seen. Better-differentiated  lesions show round to ovoid rhabdomyoblasts with dis-  tinctly eosinophilic cytoplasm and fibrillar material around  the nucleus. Some tumors contain elongated, strap-shaped  thabdomyoblasts, but cross striations rarely are found  (Fig. 12-139).   The botryoid subtype of embryonal rhabdomyosarcoma  is sparsely cellular and has a pronounced myxoid stroma.  Increased cellularity, or a so-called cambium layer, is usually  seen just beneath the mucosal surface.   Immunohistochemical analysis for the presence of  desmin, myogenin, and muscle-specific actin can be helpful  in supporting the muscular nature of the tumor. However,  the intensity of the immunostaining can vary depending on  the degree of rhabdomyoblastic differentiation.    Both classic and solid variants of alveolar rhabdomyosar-  coma are recognized. The classic pattern is characterized by  aggregates of poorly differentiated round to oval cells sepa-  rated by fibrous septa. These cells demonstrate a central loss  of cohesiveness, which results in an alveolar pattern. The  peripheral cells of these aggregates adhere to the septal walls    @ Fig. 12-139 Embryonal Rhabdomyosarcoma. This tumor shows  strap-shaped rhabdomyoblasts that are positive for desmin with  immunohistochemical staining. Note the cross striations.    in a single layer. The central cells appear to float freely  within the alveolar spaces. Mitoses are common, and mul-  tinucleated giant cells also may be seen. In contrast, solid  alveolar rhabdomyosarcoma demonstrates cellular fields of  small round basophilic cells without fibrovascular septa.   Cytogenetic and molecular studies play an important  role in the diagnosis of rhabdomyosarcoma. Two distinct  chromosomal translocations have been identified in alveo-  lar rhabdomyosarcoma: PAX3-FKHR (FOXO1) and PAX7-  FKHR (FOXO1). Embryonal rhabdomyosarcoma usually is  characterized by loss of heterozygosity with loss of imprint-  ing at chromosome 11p15.5.    Before 1960 the prognosis for a patient with rhabdomyo-  sarcoma was extremely poor, with more than 90% of  patients dying. With the advent of multimodal therapy, the  prognosis has improved dramatically.   Treatment typically consists of local surgical excision fol-  lowed by multiagent chemotherapy (vincristine, actinomy-  cin D, and cyclophosphamide). Postoperative radiation  therapy also is used, except for localized tumors that have    been completely resected at initial surgery. The 5-year sur-  vival rate for embryonal rhabdomyosarcoma (not otherwise  specified [NOS]) of the head and neck is around 66% to  72%, although the figures for botryoid (95%) and spindle  cell variants (88%) are much better. The 5-year survival rate  for alveolar rhabdomyosarcoma is only 44% to 53%.    Synovial sarcoma is an uncommon malignancy that repre-  sents 5% to 10% of all soft tissue sarcomas. The tumor  occurs primarily near large joints and bursae, especially in  the extremities, but authorities now agree that this lesion  probably does not arise from the synovium. Although it is  often para-articular in location, the tumor rarely occurs  within the joint capsule. In some instances, it arises in areas  without any obvious relationship to synovial structures.  Synovial sarcomas of the head and neck are rare (only 1.9%  to 3.7% of all cases), and many of these are unrelated to  joint areas.   Over 90% of synovial sarcomas exhibit a specific bal-  anced reciprocal translocation between the X chromosome  and chromosome 18: t(X;18)(p11.2;q11.2), which results  in an SS18-SSX fusion gene. Detection of this translocation  can be helpful in making the diagnosis and confirming the  presence of metastatic disease.    Synovial sarcomas most frequently occur in teenagers and  young adults, and there is a slight male predilection. The  most common presentation is a gradually enlarging mass  that often is associated with pain or tenderness. Tumors in  the head and neck region are most common in the paraver-  tebral and parapharyngeal areas. Often, they produce symp-  toms of dysphagia, dyspnea, or hoarseness. One recent  series of head and neck synovial sarcomas showed a predilec-  tion for the parotid and temporal regions. Oral tumors most  often have been reported in the tongue and cheek.    Classic synovial sarcoma is a biphasic tumor that consists  of a combination of spindle cells and epithelial cells (Fig.  12-140). The spindle cells usually predominate and produce  a pattern that is similar to fibrosarcoma. Within this spindle  cell background are groups of cuboidal to columnar epi-  thelial cells that surround glandlike spaces or form nests,  cords, or whorls. Calcifications are seen in around 30% of  cases.   Frequently the tumor is monophasic and consists pri-  marily or entirely of spindle cells. The diagnosis of these  tumors is difficult, but most lesions demonstrate at least  focal positive immunostaining of spindle cells for cytokera-  tin or epithelial membrane antigen. Molecular genetic  testing for the SS18-SSX fusion gene transcript is especially  helpful in confirming the diagnosis. Rare examples of    @ Fig. 12-140 Synovial Sarcoma. Biphasic tumor consisting of  spindle cells intermixed with cuboidal to columnar epithelial cells that  line glandlike spaces.    Treatment of synovial sarcoma usually consists of radical  surgical excision, possibly with adjunctive radiation therapy  or chemotherapy. The prognosis is poor because the tumor  has a high rate of recurrence and metastasis. The reported  5-year survival rate ranges from 36% to 64%. However, the  10-year survival rate drops to 20% to 38% because of the  high rate of late metastases.    The alveolar soft-part sarcoma is a rare neoplasm of uncer-  tain histogenesis, which accounts for 0.5% to 1% of all  soft tissue sarcomas. About 5% to 12% of all cases occur  in the head and neck. Molecular analysis of this tumor  shows a characteristic genetic translocation, der(17)t(X;17)  (p11.2;q25), which results in an ASPL-7TFE3 fusion gene.    The alveolar soft-part sarcoma is usually a slow-growing,  painless mass that is most common in young adults and  children. The lower extremity is the most frequent location.  The orbit and tongue are the most common head and neck  sites, and the median age for lingual tumors is only 5 to 8  years. During the first two decades of life, the tumor shows  nearly a 2:1 female predilection. However, cases that  develop after the age of 30 are more common in men.    Alveolar soft-part sarcomas are composed of groups of large,  polygonal cells that are arranged around central alveolar    spaces (Fig. 12-141). These cells have abundant granular,  eosinophilic cytoplasm and one to several vesicular nuclei.  Mitoses are rare. Special stains will reveal PAS-positive,  diastase-resistant crystals that are highly characteristic for  this tumor. Under the electron microscope, these crystals  appear as rhomboid, polygonal, or rod-shaped structures  with a regular latticework pattern.   Immunohistochemical analysis will demonstrate strong  positivity for TFE3 transcription factor in the tumor nuclei.  The diagnosis can be confirmed by identification of the  ASPL-TFE3 fusion gene with reverse-transcription poly-  merase chain reaction (RT-PCR).    Most patients with alveolar soft-part sarcomas are treated  by radical surgical excision, possibly in conjunction with  radiation therapy and chemotherapy. The prognosis is gen-  erally poor, often as a result of late metastasis. One study  reported a 5-year survival rate of 60%, but the 20-year  survival rate dropped to only 15%. Another series showed  a 5-year disease-free survival of 71% for patients with local-  ized disease, compared with only 20% for patients who  presented with metastatic disease. However, the prognosis  for children appears to be better than for adults. Lingual  and orbital tumors have much higher survival rates, possibly  because of smaller tumor size at diagnosis and younger  patient age.    Metastatic tumors to the oral cavity are uncommon and  represent approximately 1% of all oral malignancies. Such  metastases can occur to bone (see page 622) or to the oral  soft tissues. The mechanism by which tumors can spread to  the oral cavity is poorly understood. Primary malignancies  from immediately adjacent tissues might be able to spread  by a lymphatic route; however, such a mechanism cannot    @ Fig. 12-143 Metastatic Renal Carcinoma. Nodular mass of the  left lateral border of the tongue. (Courtesy of Dr. Mark Bowden.)    explain metastases from tumors from lower parts of the  body, which are almost certainly blood-borne and should  be filtered out by the lungs. One possible explanation for  blood-borne metastases to the head and neck, especially in  the absence of pulmonary metastases, is Batson plexus, a  valveless vertebral venous plexus that might allow retrograde  spread of tumor cells, bypassing filtration through the lungs.    The most common site for oral soft tissue metastases is the  gingiva, which accounts for 54% of all cases. The next most  common site is the tongue, which accounts for 22.5% of  cases. The lesion usually appears as a nodular mass that  often resembles a hyperplastic or reactive growth, such as a  pyogenic granuloma (Figs. 12-142 to 12-144). Occasion-  ally, the lesion appears as a surface ulceration. Adjacent  teeth may become loosened by an underlying destruction  of the alveolar bone. The presence of teeth may play an  important role in the preference of metastases for the  gingiva. Once malignant cells reach the oral cavity, the rich  vascular network of inflamed gingival tissues may serve as a  fertile site for further growth.    @ Fig. 12-144 Metastatic Adenocarcinoma of the Colon. A, Focal swelling of the left retromolar pad  area. B, Same patient 4 weeks later. Note the marked enlargement of the lesion. (Courtesy of Dr. George    Oral soft tissue metastases are more common in males  and are seen most frequently in middle-aged and older  adults. Almost any malignancy from any body site is capable  of metastasis to the oral cavity, and a wide variety of tumors  have been reported to spread to the mouth. (However, there  is probably a bias in the literature toward reporting more  unusual cases.) In the cases reported, lung cancer is respon-  sible for nearly one-third of all oral soft tissue metastases in  men, followed by renal carcinoma and melanoma. Although  prostate cancer is common in men, metastases from these  tumors have an affinity for bone and rarely occur in soft  tissues. For women, breast cancer accounts for almost 25%  of all cases, followed by malignancies of the genital organs,  kidney, lung, and bone.   In most cases the primary tumor already is known when  the metastatic lesion is discovered. In 25% of patients,  however, the oral lesion is the first sign of the malignant  disease.    The microscopic appearance of the metastatic neoplasm  should resemble the tumor of origin (Fig. 12-145). Most    cases represent carcinomas; metastatic sarcomas to the oral  region are rare.    ‘The prognosis for patients with metastatic tumors is gener-  ally poor because other metastatic sites also are frequently  present. Management of the oral lesion is usually palliative  and should be coordinated with the patient’s overall  treatment.   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The lymphoid tissue of the body plays an important role in  the recognition and processing of foreign antigens, such as  viruses, fungi, and bacteria. In addition, the lymphoid tissue  has a protective function through a variety of direct and  indirect mechanisms. In responding to antigenic challenges,  lymphoid cells proliferate, thus increasing their numbers, to  combat the offending agent more effectively. This prolifera-  tion results in enlargement of the lymphoid tissue, which is  seen clinically as lymphoid hyperplasia.    Lymphoid hyperplasia may affect the lymph nodes, the  lymphoid tissue of Waldeyer ring, or the aggregates of lym-  phoid tissue that are normally scattered throughout the  oral cavity, particularly in the oropharynx, the soft palate,  the lateral tongue, and the floor of the mouth. When lym-  phoid hyperplasia affects the lymph nodes, usually the site  that the lymph node drains can be identified as a source  of active or recent infection. In the head and neck region,  the anterior cervical chain of lymph nodes is most com-  monly involved, although any lymph node in the area may  be affected.   With acute infections, the lymphadenopathy appears as  enlarged, tender, relatively soft, freely movable nodules.  Chronic inflammatory conditions produce enlarged,  rubbery firm, nontender, freely movable nodes. Sometimes  these chronic hyperplastic lymph nodes may be difficult to  distinguish clinically from lymphoma, and a history of a  preceding inflammatory process and lack of progressive  enlargement are helpful clues that are consistent with a  reactive process. Another condition, however, that should  be considered in the differential diagnosis of multiple, per-  sistently enlarged, nontender lymph nodes is human immu-  nodeficiency virus (HIV) infection (see page 245).   Tonsillar size is variable from one person to the next,  but lymphoid tissue is normally more prominent in younger  individuals, usually reaching its peak early during the  second decade of life and gradually diminishing thereafter.  Some patients have such large tonsils that it seems as if    they would occlude the airway (so-called kissing tonsils).  Often, however, these patients have no symptoms and are  unaware of a problem. As long as the large tonsils are sym-  metrical and asymptomatic (Fig. 13-1), it is likely that they  are normal for that particular patient. Tonsillar asymmetry  is a potentially serious sign that should be evaluated further  to rule out the presence of a metastatic tumor or  lymphoma.   Hyperplastic intraoral lymphoid aggregates appear as  discrete, nontender, submucosal swellings, usually less than  1 cm in diameter, which may appear normal or dark pink  in color if the aggregate is deeper; they may have a creamy  yellow-orange to amber hue if the collection of lymphocytes  is closer to the surface (Figs. 13-2 and 13-3). Lymphoid  hyperplasia commonly involves the posterior lateral tongue,  where it may appear somewhat ominous. The enlargement  is usually bilaterally symmetrical, however, which helps to  distinguish the condition from a malignancy. The buccal  lymph node may also become hyperplastic and appear as a  nontender, solitary, freely movable nodule, usually less than  1 cm in diameter, within the substance of the cheek. Infre-  quently, a more diffuse lymphoid hyperplasia involves the  posterior hard palate, producing a slowly growing, non-  tender, boggy swelling with an intact mucosal surface and  little color change. These palatal lesions may be clinically  impossible to distinguish from extranodal lymphoma and  would, therefore, necessitate biopsy.    The microscopic features of lymphoid hyperplasia include  sheets of small, well-differentiated lymphocytes with numer-  ous interspersed, sharply demarcated collections of reactive  lymphoblasts called germinal centers. The cells that com-  prise the germinal centers are primarily transformed B  lymphocytes that may demonstrate numerous mitoses.  Macrophages can also be identified by the presence of  phagocytized material (tingible bodies) in their cytoplasm  as they engulf nuclear debris from the proliferating lympho-  cytes. In some instances, immunohistochemical studies and  clonality assays must be performed to rule out the possibil-  ity of follicular lymphoma.    Once the diagnosis of lymphoid hyperplasia is confirmed,  no treatment is usually required because it is a completely  benign process. For those patients with palatal lymphoid  hyperplasia that may interfere with a dental prosthesis,  complete excision of the lesion is recommended.    o ee _— —  @ Fig. 13-1 Lymphoid Hyperplasia. The large tonsil observed in this  patient represents a benign hyperplasia of the lymphoid cells. If signifi-  cant asymmetry is observed, further investigation may be warranted  to rule out the possibility of lymphoma.    paw A. 2 5 sn iw ae  @ Fig. 13-2 Lymphoid Hyperplasia. The smooth-surfaced papule  of the posterior lateral tongue represents an enlarged lymphoid aggre-  gate. The lesion exhibits a lighter color as a result of the accumulation  of lymphocytes, which are white blood cells. (Courtesy of Dr. Dean  White.)    Hemophilia (emo = blood; philia = loving) represents a  variety of bleeding disorders associated with a genetic defi-  ciency of any one of the clotting factors of the blood (Table  13-1). This condition was common in certain European  royal families, with the initial mutation of the gene for  factor IX affecting Queen Victoria of England, who then  passed it on to her descendants. DNA analysis of the  remains of the Russian royal family (Tsarina Alexandra was  a granddaughter of Queen Victoria) confirmed a factor IX  gene mutation that resulted in hemophilia B. Because this  is an X-linked hereditary condition, a significant proportion  of the male members of these families had hemophilia.   In the days before blood transfusions and clotting factor  replacement therapy, many of these patients died as a direct  result of, or from the complications of, uncontrolled hemor-  rhage. Because hemophilia A (factor VII deficiency) is the  most significant and widely recognized form of hemophilia  and accounts for 80% to 85% of the bleeding diatheses  associated with a specific clotting factor deficiency, most of  this discussion centers on that entity. Its estimated preva-  lence in the United States is 1 in 10,000 persons (or 1 in  5000 males).   As previously mentioned, a deficiency of factor IX or  hemophilia B (Christmas disease) also may be encoun-  tered. Hemophilia B is similar to hemophilia A in its    i -  @ Fig. 13-3 Lymphoid Hyperplasia. Multiple prominent lymphoid  aggregates in the floor of the mouth.    Type Defect Inheritance Findings  Hemophilia A (classic hemophilia) Factor VII| deficiency X-linked recessive Abnormal PTT  Hemophilia B (Christmas disease) Factor IX deficiency X-linked recessive Abnormal PTT    PFA, Platelet function assay (replaces bleeding time test); PTT, partial thromboplastin time.    presentation, being transmitted in an X-linked fashion.  Hemophilia B is much less common than hemophilia A,  occurring with a prevalence of 1 in 60,000 (or 1 in 30,000  males). The term Christmas disease was obtained from the  surname of the first person, a Canadian boy, who was iden-  tified as having hemophilia B in 1952.   Another clotting disorder that is sometimes seen, von  Willebrand disease, is the result of a genetic deficiency of  a plasma glycoprotein called von Willebrand factor. This  glycoprotein aids in the adhesion of platelets at a site of  bleeding, and it also binds to factor VIII, acting as a trans-  port molecule. Von Willebrand disease is a genetically het-  erogeneous condition, with several subtypes currently  identified, and it may be transmitted in an autosomal domi-  nant or recessive pattern. It is the most common of the  inherited bleeding disorders, affecting an estimated 1 in 800  to 1000 persons. However, many cases of von Willebrand  disease are mild and may be clinically insignificant.    Hemophilia A is an X-linked disorder. Females typically  carry the trait, but it is expressed primarily in males.  Approximately 1 in 5000 males is born with this genetic  disease, with about 30% of the cases representing new  mutations. Failure of normal hemostasis after circumcision  is typically one of the first signs that a bleeding disorder is  present.   ‘The severity of the bleeding disorder depends on the  extent of the clotting factor deficiency. Hemophilia A is a  heterogeneous disorder that is caused by any one of a variety  of mutations associated with the gene for factor VII.  Because the mutations occur at different sites in the factor  VIII gene (more than 900 different mutations have been  identified), a clinical spectrum of deficiency of factor VIII  is seen. This results in varying degrees of disease expression,  with those mutations affecting more significant or larger  portions of the factor VIII gene causing more severe clinical  disease. Not all patients have an absolute lack of the par-  ticular clotting factor; rather, the deficiency may be a per-  centage of the normal value in a given patient. For example,  a patient with only 25% of normal factor VIII levels may  be able to function normally under most circumstances; one  with less than 5% commonly manifests a marked tendency  to bruise with only minor trauma.   In infants, oral lacerations and ecchymoses that involve  the lips and tongue are a frequent occurrence as a result of  the common falls and bumps experienced by this age group.  If not treated appropriately, then such lacerations may result  in significant blood loss in more severely affected patients.  Sometimes deep hemorrhage occurs during normal activity  and may involve the muscles, soft tissues, and weight-  bearing joints (hemarthrosis), especially the knees (Fig.  13-4). The result of such uncontrolled bleeding is the for-  mation of scar tissue as the body removes the extravasated  blood. This often causes a crippling deformity of the knee  joints secondary to arthritis and ankylosis. Sometimes the    @ Fig. 13-4 Hemophilia. The enlargement of the knees of this patient  with factor VIII deficiency is due to repeated episodes of bleeding into  the joints (hemarthrosis). Inflammation and scarring have resulted.    @ Fig. 13-5 Hemophilia. Hemorrhage in a patient with factor IX  deficiency occurred after routine periodontal curettage.    tissue hemorrhage results in the formation of a tumorlike  mass, which has been called pseudotumor of hemophilia.  Such lesions have been reported in the oral regions.   An increased coagulation time (delay in blood clotting),  of course, is the hallmark feature of this group of condi-  tions. Uncontrollable or delayed hemorrhage may result  from any laceration; this includes surgical incisions, dental  extractions, and periodontal curettage (Fig. 13-5). Measure-  ments of the platelet count, platelet function assay (PFA—  an in vitro test of platelet function that has replaced the  bleeding time test), prothrombin time (PT), and partial  thromboplastin time (PTT) should be ordered as screening  tests for any patient with a possible bleeding disorder.    ‘The treatment of clotting factor deficiencies essentially con-  sists of replacement therapy with the appropriate clotting  factor. Whether treatment is instituted depends on the  severity of the clotting factor deficiency.   Patients who have greater than 25% of normal values of  factor VII may function normally. For patients with mild  hemophilia (5% to 40% of normal levels of factor VIII),    no special treatment is typically required for normal activi-  ties. If surgery is to be performed, then clotting factor  replacement therapy may be indicated.   For patients with severe deficiencies (less than 1% of  normal levels of factor VIII), injections with the clotting  factor must be performed as soon as a hemorrhagic episode  occurs to prevent such complications as the crippling joint  deformities of the knees.   The use of aspirin is strictly contraindicated because of  its adverse effect on blood platelet function. Severe hemor-  rhage may result if these patients use aspirin-containing  medications.   Genetic counseling should be provided to these patients  and their families to help them understand the mechanism  of inheritance. Using molecular techniques, women who are  carriers can be confirmed. In addition, affected male fetuses  can now be identified, and the severity of the factor VIII  mutation can be assessed.   Optimal dental care is strongly encouraged for these  patients to prevent oral problems that might require surgery.  If oral or periodontal surgery is necessary, then consultation  with the patient's physician is mandatory. The patient is  usually prepared for the procedure by the administration of  clotting factor just before the surgery. With an extensive  surgical procedure, additional doses of clotting factor may  be needed subsequently. In addition, epsilon-aminocaproic  acid (EACA), an antifibrinolytic agent that inhibits clot  degradation, should be given 1 day before the surgery and  continued for 7 to 10 days afterward. Alternative therapy  for patients who have levels of factor VIII greater than 5%  of normal is desmopressin (1-deamino-8-D-arginine;  DDAVP), which can be given just before surgery, either  intravenously, subcutaneously, or intranasally. This drug  causes the release of bound factor VIH, producing a tem-  porary increase in the plasma levels of the clotting factor.  Desmopressin may also be used to manage most patients  affected by type 1 von Willebrand disease, which represents  approximately 70% to 80% of the cases of that disorder.   Although it saved many lives, clotting factor replacement  therapy has also resulted in a tragic complication for many  of these patients. Cryoprecipitation, the traditional method  of concentrating clotting factors from the plasma, also  resulted in the concentration of several viruses, including the  hepatitis viruses and HIV. More than 40% of hemophilia A  and B patients in the United States were estimated to be  infected with hepatitis C virus. In addition, as many as 80%  to 90% of hemophiliac patients treated with multiple doses  of factor VIII cryoprecipitate were infected with HIV, and  many of these patients eventually developed acquired immu-  nodeficiency syndrome (AIDS). The methods of preparing  the clotting factors from pooled human plasma have been  modified to eliminate or inactivate HIV; hepatitis A, B, and  C; and parvovirus. Recombinant DNA technology also now  provides a source of factor VII that is manufactured by  inserting the human factor VIII gene into bacteria that then  synthesize the protein. Therefore, this product can now be  manufactured without contamination by any viral    organisms. Young people affected by hemophilia currently  have minimal risk of contracting these infections as a result  of their clotting factor replacement therapy.   Other problems must occasionally be confronted,  however. Approximately 25% to 30% of patients with  severe hemophilia A may develop antibodies directed against  factor VIII, and this is a very serious complication. Because  the antibodies react with the factor VIII molecule, the result  is an inhibition of the activity of the clotting factor, and  these patients are once more faced with the prospect of  uncontrolled bleeding. Patients with factor IX deficiency  can develop similar inhibitory antibodies to factor IX, but  this appears to occur much less frequently. Attempts to  induce immune tolerance may help some individuals,  although more immediate care has generally centered on  bypassing the factor VIII-related portion of the clotting  cascade by administration of recombinant factor VIIa or  activated prothrombin complex. Research has shown this  approach to be effective, although costly.    Plasminogen deficiency is a rare autosomal recessive condi-  tion that is caused by any one of several mutations of the gene  responsible for the production of plasminogen, the precursor  to plasmin. In the clotting cascade, factors are activated that  lead to the development of a clot; however, simultaneously  serum proteins such as plasminogen are converted to plasmin,  which is responsible for degrading the clot. Without the  formation of plasmin, the clot tends to grow and persist  despite having performed its original hemostatic function.  The result of plasminogen deficiency is a buildup of fibrin,  deposited as irregular plaques and nodules that primarily  affect mucosal surfaces. Involvement of the conjunctival  mucosa is characterized by the formation of thick, firm  plaques, for which the term /igneous conjunctivitis has been  used (digneous means “woodlike”). Even though this condi-  tion was initially described in the nineteenth century, it was  during the late 1990s that an explanation for the majority of  these cases was provided. Similar lesions have been produced  in mice that have been genetically manipulated to create  knock-out mutations of the plasminogen gene.    The most striking aspect of plasminogen deficiency is the  development of thick, creamy yellow to erythematous, firm  plaques and nodules involving primarily the conjunctival  mucosa of the upper eyelid. Typically the condition is  detected during the first decade of life, but lesions can  develop later as well. Even though this is an autosomal  recessive condition, there is a tendency for the disease to  present more often in women, although the reason for this  is unknown.    @ Fig. 13-6 Plasminogen Deficiency. The ulcerated plaques and  papules seen on the gingiva of this patient with plasminogen deficiency  represent accumulations of fibrin. (Courtesy of Dr. Kenneth  Rasenberger.)    In addition to the conjunctival lesions, other mucosal  surfaces can be affected, including the oral mucosa, laryn-  geal mucosa, and vaginal mucosa. In a recent series of 50  patients with this condition, ocular lesions were docu-  mented in 80%, gingival lesions in 34%, respiratory tract  lesions in 16%, and vaginal lesions in 8%. Laryngeal  mucosal involvement often includes the vocal cords, which  typically results in a raspy, hoarse voice. Occlusion of the  airway by a fibrin mass has been described rarely.   Oral lesions of plasminogen deficiency primarily involve  the gingivae, presenting as patchy ulcerated papules and  nodules with a very irregular surface (Fig. 13-6). These  lesions may be few in number or distributed diffusely in all  quadrants, and they tend to wax and wane in severity.    The microscopic features of the lesions associated with this  condition can be very confusing for the pathologist who is  not familiar with the disease. The accumulation of fibrin  appears as diffuse sheets of acellular eosinophilic material  that bears a close resemblance to amyloid (Fig. 13-7).  Special stains for amyloid (such as, Congo red) are negative,  however, because this material represents fibrin. Confirma-  tion that the eosinophilic material is fibrin can be done  using the Fraser-Lendrum histochemical staining method.  Variable numbers of inflammatory cells are seen, and granu-  lation tissue is usually seen adjacent to the fibrin deposits.    Treatment of plasminogen deficiency remains a problem.  Damage to the mucosal tissues, including surgical trauma,  should be minimized to reduce the likelihood of fibrin accu-  mulation. Careful, thorough oral hygiene practices should  be encouraged to diminish the effect of local inflammation.  Sporadic reports describe resolution of the conjunctival  lesions with either topical or systemic plasminogen; however,    @ Fig. 13-7 Plasminogen Deficiency. This high-power photomicro-  graph shows attenuated surface epithelium and a collection of rela-  tively acellular eosinophilic material that superficially resembles amyloid,  but is actually fibrin.    this agent is not available commercially. Some patients have  experienced spontaneous regression of their lesions over  time. Topical heparin combined with prednisone has helped  control the gingival lesions in some patients. Alternatively,  surgical excision of the gingival nodules, followed by low-  dose systemic doxycycline, topical chlorhexidine mouth  rinse, and systemic warfarin has also reportedly been effec-  tive in managing the lesions. These may be the two most  reasonable approaches for treating the oral lesions until  replacement plasminogen is marketed or gene therapy is  feasible. Interestingly, these patients do not have any unusual  problems with intravascular thrombus formation, and their  lifespan does not appear to be shortened.    Anemia is a general term for either a decrease in the volume  of red blood cells (hematocrit) or in the concentration of  hemoglobin. This problem can result from a number of  factors, including a decreased production of erythrocytes or  an increased destruction or loss of erythrocytes. Laboratory  studies, such as the red blood cell (RBC) count, hematocrit,  hemoglobin concentration, mean corpuscular volume  (MCV), mean corpuscular hemoglobin (MCH), and mean  corpuscular hemoglobin concentration (MCHC), can help  indicate the probable cause of the anemia.   Rather than being a disease itself, anemia is often a sign  of an underlying disease, such as renal failure, liver disease,  chronic inflammatory conditions, malignancies, or vitamin  or mineral deficiencies. The diverse causes and complexity  of the problem of anemia are presented in Box 13-1.    e Anemia of chronic infection (infective endocarditis,  tuberculosis, osteomyelitis, lung abscess, and pyelonephritis)  e Anemia of inflammatory connective tissue disorders  (rheumatoid arthritis, lupus erythematosus, sarcoidosis,  temporal arteritis, and regional enteritis)  e Anemia associated with malignancy  e Secondary to chronic bleeding  e Myelophthisic anemia  Anemia of uremia  Anemia of endocrine failure  Anemia of liver disease    e Extrinsic causes  e Splenomegaly  e Red cell antibodies  e Trauma in the circulation  e Direct toxic effects (various microorganisms, copper salts,  and venom of certain snakes)  e Membrane abnormalities  e Spur cell anemia  e Paroxysmal nocturnal hemoglobinuria  e Hereditary spherocytosis  e Hereditary elliptocytosis  e Disorders of the interior of the red cell  e Defects in the Embden-Meyerhof pathway  e Defects in the hexose monophosphate shunt    The symptoms of anemia are typically related to the reduced  oxygen-carrying capacity of the blood, which is a result of  the reduced numbers of erythrocytes. Symptoms such as  tiredness, headache, shortness of breath, or lightheadedness  are often present.   Pallor of the mucous membranes may be observed in  severe cases of anemia. The palpebral conjunctiva is often  the site where this paleness is most easily appreciated, but  the oral mucosa may show similar signs.    The treatment of anemia depends on determining the  underlying cause of the anemia and correcting that problem,  if possible.    Sickle cell anemia is one of the more severe genetic disor-  ders of hemoglobin synthesis (hemoglobinopathies).  Because of the mutational substitution of a thymine mol-  ecule for an adenine in DNA, the codon is altered to code  for the amino acid valine rather than glutamic acid in the  B-globin chain of hemoglobin. This results in a hemoglobin  molecule that, in the deoxygenated state, is prone to molec-  ular aggregation and polymerization. Consequently, the red  blood cells (RBCs) of patients with sickle cell anemia have  a marked tendency to undergo deformation from the  normal biconcave disk shape to a rigid-and-curved (sickle)  shape. Because the genes for hemoglobin synthesis are  codominant, if only one allele is affected, then only 40% to  50% of that patient's hemoglobin will be abnormal. Such a  patient is simply a carrier and is said to have sickle cell  trait, a condition that has no significant clinical manifesta-  tions in most everyday circumstances. Some sickling may  be precipitated under certain conditions, such as dehydra-  tion or low-oxygen tensions related to either exercise or high  altitudes.   This abnormal gene has persisted in the human race  perhaps because it confers a degree of resistance to the  malarial organism. As a result, the gene is seen most fre-  quently in populations, such as African, Mediterranean, and  Asian, who reside in areas where malaria is endemic. In the  United States, nearly 2.5 million people (approximately 8%  of the black population) carry this trait.   Unfortunately, in patients who inherit two alleles that  code for sickle hemoglobin, the RBCs contain primarily  sickle hemoglobin, which results in the condition called  sickle cell disease. In the United States, about 1 of every  350 to 400 blacks is born with this disease. Such patients  are often susceptible to the problems associated with abnor-  mal RBC morphology. The sickled erythrocytes are more  fragile than normal, lasting only 12 to 16 days in the cir-  culation (about one-tenth of the lifespan of a normal RBC),  and they tend to block the capillaries because of their shape  and adherence properties. As a result, these patients have a  chronic hemolytic anemia and many difficulties related to  reduced blood flow to organs and tissues, which produces  ischemia, infarction, and tissue death.    Virtually any tissue or organ may be affected in sickle cell  disease. The clinical spectrum of involvement can vary tre-  mendously, with approximately one-third of patients exhib-  iting severe manifestations. Perhaps the most dramatic sign  of this disease is the sickle cell crisis, a situation in which  the sickling of the erythrocytes becomes severe. Hypoxia,  infection, hypothermia, or dehydration may precipitate a  crisis; however, for most crises there is no identifiable pre-  disposing factor. Patients who experience a crisis suffer  extreme pain from ischemia and infarction of the affected  tissue. The long bones, lungs, and abdomen are among the  most commonly affected sites, and each episode lasts 3 to    @ Fig. 13-8 Sickle Cell Anemia. Lateral skull radiograph reveals an  altered trabecular pattern, including a slight degree of “hair-on-end”  appearance of the cranial bones. (Courtesy of Dr. Reg Munden.)    10 days. Pulmonary involvement, known as acute chest  syndrome, is particularly serious, and one large study indi-  cated that this is frequently precipitated by fat embolism or  community-acquired pneumonia. Some patients may expe-  rience such crises monthly; others may go for 1 year or  longer without problems. Often fever accompanies the  crisis; therefore, infection must be considered in the dif-  ferential diagnosis.   Patients with sickle cell disease are susceptible to infec-  tions, especially those caused by Streptococcus pneumoniae,  probably because of the destruction of the spleen at an early  age by repeated infarctions. Such infections are the most  common cause of death among children affected by sickle  cell disease in the United States.   Other problems include delayed growth and develop-  ment in most patients. Impaired kidney function and ocular  abnormalities develop secondary to the damage caused by  vaso-occlusive episodes in the capillary networks of those  organs. If the patient lives long enough, then renal failure  may eventually develop. In addition, approximately 5% to  8% of these patients will experience central nervous system  (CNS) damage in the form of a stroke, which occurs at an  average age of about 8 years.   The oral radiographic features of sickle cell disease are  relatively nonspecific. They consist of a reduced trabecular  pattern of the mandible because of increased hematopoiesis  occurring in the marrow spaces. Occasionally, a “hair-on-  end” appearance is seen on the skull radiograph, although  this is less prominent than that seen in thalassemia (Fig.  13-8). Other oral problems that have been reported include  an increased prevalence of osteomyelitis of the mandible,  mandibular bone infarction, prolonged paresthesia of the  mandibular nerve, and asymptomatic pulpal necrosis.    In homozygous sickle cell disease, a peripheral blood smear  shows a peculiar curved distortion of the erythrocytes,  resembling a sickle or boomerang shape.    The patient experiencing a sickle cell crisis should be  managed with supportive care, including fluids, rest, and  appropriate analgesic therapy (usually narcotic prepara-  tions). It is important, but often difficult, to rule out the  possibility of infection. Acute chest syndrome or cerebral  infarct may require treatment with RBC transfusions.   All 50 states now screen for this hemoglobin disorder as  part of their newborn infant health care system to identify  affected individuals as soon as possible so that appropriate  therapy can be instituted. For children with a diagnosis of  sickle cell disease, continuous prophylactic penicillin  therapy is indicated until at least 5 years of age. In addition,  the child should be given polyvalent pneumococcal vaccina-  tions. Situations that might precipitate a crisis, such as  strenuous exercise, dehydration, or exposure to cold, should  be avoided. For adults with relatively severe disease, hydroxy-  urea has been approved for treatment. This drug increases  the fetal form of hemoglobin (hemoglobin F), which may  inhibit polymerization of hemoglobin S and may also  reduce the adherence of erythrocytes to the vessel walls.  Unfortunately, hydroxyurea has a number of potential side  effects and should be used judiciously. Bone marrow trans-  plantation is curative, but this is a procedure with multiple  potential complications and is used primarily for severely  affected patients having a histocompatibility antigen (HLA)-  matched donor sibling. Only about 1% of sickle cell anemia  patients currently meet these criteria.   When surgery is necessary, local anesthesia, if possible,  is usually preferred. If general anesthesia is indicated, then  precautions should be taken to avoid conditions that might  induce a crisis, such as hypoxia, vascular stasis, acidosis,  infection, reduced body temperature, or dehydration.   For patients who have the sickle cell trait or the disease,  genetic counseling is appropriate. DNA diagnostic tech-  niques have been used for several years to assess whether a  fetus is affected by sickle cell disease, permitting consider-  ation of termination of the pregnancy. Molecular evaluation  of the DNA from a single cell obtained from an embryo  that was fertilized in vitro has allowed selection of a nonaf-  fected embryo for uterine implantation. For parents who  are carriers of the sickle cell trait, this is one method to  ensure that their offspring do not have sickle cell disease.   Although the mortality rate for sickle cell disease in  developed countries has improved dramatically over the past  few years, the prognosis is variable because of the wide  spectrum of disease activity. Those who are severely affected,  however, often are quite disabled because of the many com-  plications of the disease and have a decreased life span.    Thalassemia represents a group of disorders of hemoglobin  synthesis that are characterized by reduced synthesis of  either the o-globin or B-globin chains of the hemoglobin  molecule. As in those with sickle cell trait, people who carry  the trait for one of the forms of thalassemia seem to be more    resistant to infection by the malarial organism; an increased  frequency of these genes is seen in Mediterranean, African,  Indian, and Southeast Asian populations. Because the origi-  nal cases were reported from the region of the Mediterra-  nean Sea, the name thalassemia was given, derived from the  Greek word thalassa, meaning “sea.” The thalassemias are  considered to be among the most common inherited condi-  tions that affect humans.   An understanding of the structure and synthesis of  hemoglobin is helpful in explaining the pathophysiology of  these conditions. The hemoglobin molecule is a tetramer  that is composed of two & chains and two f chains; if one  of the chains is not being made in adequate quantities, then  the normal amount of hemoglobin cannot be made. Fur-  thermore, the excess globin chains accumulate within the  erythrocyte, further compromising the structure and func-  tion of the cell. These abnormal erythrocytes are recognized  by the spleen and selected for destruction (hemolysis). In  addition, there is evidence of ineffective erythropoiesis  caused by premature cell death of erythrocyte precursors in  the bone marrow because of activation of apoptotic mecha-  nisms. The net result is that the patient has hypochromic,  microcytic anemia.   Because two genes code for the B chain and four genes  code for the o chain, the degree of clinical severity in these  conditions can vary considerably. The severity depends on  which specific genetic alteration is present and whether it  is heterozygous or homozygous. In the heterozygous state,  an adequate amount of normal hemoglobin can be made  and the affected patient experiences few signs or symptoms.  In the homozygous state, however, the problems are often  severe or even fatal. In addition, variations in the severity  of the clinical presentation may be a reflection of the specific  alteration in the genetic code, because more than 200 dif-  ferent mutations have been documented for B-thalassemia  alone.    If only one defective gene for the B-globin molecule is  inherited (thalassemia minor), no significant clinical man-  ifestations are usually present.   When two defective genes for the B-globin molecule are  inherited, the patient typically is affected with thalassemia  major, also called Cooley anemia or Mediterranean  anemia. The disease is usually detected during the first year  of life because a severe microcytic, hypochromic anemia  develops when fetal hemoglobin synthesis ceases after 3 to  4 months of age. The red blood cells (RBCs) that are pro-  duced are extremely fragile and survive for only a few days  in the peripheral circulation.   In an attempt to maintain adequate oxygenation, the rate  of hematopoiesis (despite being ineffective) is greatly  increased (up to 30 times normal), resulting in massive bone  marrow hyperplasia, as well as hepatosplenomegaly and  lymphadenopathy because of extramedullary hematopoie-  sis. The bone marrow hyperplasia may affect the jaws    @ Fig. 13-9 Thalassemia. Periapical radiographs of the anterior  mandible showing reduced trabeculation because of increased hema-  topoiesis. (Courtesy of Dr. José Luis Tapia.)    especially, producing an altered trabecular pattern and  marked, painless enlargement of the mandible and maxilla  (Fig. 13-9). This results in a characteristic “chipmunk” facies  and causes reduced size or obliteration of the paranasal  sinuses. Frontal bossing is also present, and a skull radio-  graph may show a prominent “hair-on-end” appearance of  the calvaria (Fig. 13-10). Generalized maturational delay of  the patient is typically seen. Delayed development of the  dentition also has been described, with the teeth showing a  mean delay of approximately 1 year compared with a  matched population.   Without therapy, tissue hypoxia worsens and serious  bacterial infections with pneumococcal organisms often  develop. Eventually, high-output cardiac failure occurs;  many patients die by 1 year of age as a result of infection  or heart problems.    Because four ot-globin genes may be affected, O-thalassemia  has a broader spectrum of involvement than does  B-thalassemia. The condition is caused by deletion at the  a-globin gene locus.   When only one deleted gene is inherited, no disease can  be detected. With the inheritance of two deleted genes, the  condition is known as Ot-thalassemia trait. These patients  have a mild degree of anemia and microcytosis that is    usually not clinically significant. With three deleted genes,  the term hemoglobin H (HbH) disease is applied. Patients  have problems with hemolytic anemia and splenomegaly.  For patients with severe hemolysis, splenectomy may be  indicated.   The homozygous state, in which all four genes are  deleted, causes severe generalized fetal edema, a condition  that has been termed hydrops fetalis. Hydrops fetalis is not  specific for O&-thalassemia and can be seen as a manifestation  of other diseases, such as severe Rh incompatibility. Infants  with o-thalassemia who are affected by this problem typi-  cally die within a few hours of birth.    Thalassemia major is treated today primarily by means of  blood transfusions. These should be administered every 2  to 3 weeks to simulate the normal hematologic state. Unfor-  tunately, with repeated blood transfusions, iron overload  inevitably develops because of the constant infusion of  exogenous RBCs. This is a serious problem, and often death  is due to hemochromatosis, an abnormal deposition of  iron throughout the tissues of the body. The heart, liver, and  endocrine glands are particularly affected by the toxic accu-  mulation of iron. To combat this problem, an iron-chelating  agent, deferoxamine (also known as desferrioxamine), must  be given. If such therapy is used steadfastly, patients with  B-thalassemia may have a relatively normal life span;  however, problems may arise with patient compliance  because this medication must be infused parenterally over  several hours for at least 250 nights each year. Two oral iron  chelators, deferiprone and deferasirox, are now available and  appear to be good therapeutic additions. Deferiprone used  alone is not as effective as deferoxamine, but the number of  weekly infusions of the latter drug can be reduced when  combined with deferiprone. Hematologic studies are done  weekly due to agranulocytosis developing in 1% of patients  taking deferiprone. Deferasirox does not seem to have sig-  nificant side effects. All of these iron chelators are expensive,  although the oral medications are more cost effective because  patient compliance is better and infusion-related costs are  eliminated. Hematopoietic stem cell transplantation has  also been used with considerable success for individuals who  are relatively young, have little organ damage, and have an  HLA-matched donor.   Clinicians can now identify o-thalassemia, with its atten-  dant hydrops fetalis (historically considered a fatal condi-  tion), im utero by molecular testing, and the fetus can be  given intrauterine umbilical vein transfusions. An 80% sur-  vival rate has been reported for these infants, although they  will require either lifelong transfusion therapy or hemato-  poietic stem cell transplantation. Prenatal diagnosis is also  available for B-thalassemia.   For patients who have developed an abnormal facial  appearance caused by thalassemia, surgical correction can  be performed in many cases. Prevention of thalassemia also  is desirable, either by screening for carriers of the genetic    Aplastic anemia is a rare, life-threatening hematologic dis-  order that is characterized by failure of the hematopoietic  precursor cells in the bone marrow to produce adequate  numbers of all types of blood cells (pancytopenia). A sig-  nificant amount of evidence supports the concept that most  cases of aplastic anemia represent an immune-mediated  disease caused by cytotoxic T lymphocytes that target dif  ferentiating hematopoietic cells in the marrow. As a result,  the hematopoietic stem cells do not seem to undergo normal  maturation despite normal or increased levels of cytokines,  such as granulocyte-macrophage colony-stimulating factor  (GM-CSF), which normally induce the production and  maturation of several types of white blood cells.   Although the underlying trigger for the immune-  mediated destruction of the hematopoietic cells is unknown,  some cases of aplastic anemia are associated with exposure  to certain environmental toxins (e.g., benzene), treatment  with certain drugs (especially the antibiotic chlorampheni-  col), or infection with certain viruses (particularly non-A,  non-B, non-C, or non-G hepatitis). It is possible that the  abnormal immune response is perhaps initiated by such  exogenous stimuli in certain instances. A few genetic disor-  ders, such as Fanconi anemia and dyskeratosis congenita  (see page 695), also are associated with an increased fre-  quency of aplastic anemia.    Because all of the formed elements of the blood are decreased  in patients with aplastic anemia, the initial symptoms may  be related to any one or several of the deficiencies. The  erythrocyte deficiency produces signs and symptoms related  to a decreased oxygen-carrying capacity of the blood; there-  fore, patients may experience fatigue, lightheadedness,  tachycardia, or weakness. The platelet deficiency (thrombo-  cytopenia) is seen as a marked tendency for bruising and  bleeding, which affects a variety of sites. Retinal and cere-  bral hemorrhages are some of the more devastating mani-  festations of this bleeding tendency. Deficiency of white  blood cells (neutropenia, leukopenia, or granulocytopenia)  is the most significant complication of this disease, predis-  posing the patient to bacterial and fungal infections that  often are the cause of death.   The oral findings related to thrombocytopenia include  gingival hemorrhage (Fig. 13-11), oral mucosal petechiae,  purpura, and ecchymoses. The oral mucosa may appear pale  because of the decreased numbers of red blood cells (RBCs).  Oral ulcerations associated with infection due to neutrope-  nia, particularly those that involve the gingival tissues, may  be present. Minimal erythema is usually associated with the  periphery of the ulcers. Gingival hyperplasia has also been  reported in association with aplastic anemia.    A bone marrow biopsy specimen usually demonstrates a  relatively acellular marrow with extensive fatty infiltration.  The histopathologic features of an oral ulceration in a  patient with aplastic anemia show numerous microorgan-  isms in addition to a remarkable lack of inflammatory cells  in the ulcer bed.    The diagnosis of aplastic anemia is usually established by  laboratory studies. A pancytopenia is characterized by at  least two of the following findings:    The course for patients with aplastic anemia is unpredict-  able. For the milder forms of the disease, spontaneous  recovery of the marrow may occur in some instances; pro-  gression to severe aplastic anemia may be seen in others.  Generally, in severe cases, the chances of spontaneous recov-  ery are slim. If a particular environmental toxin or drug is  associated with the process, then withdrawal of the offend-  ing agent may sometimes result in recovery.   The treatment is initially supportive. Appropriate antibi-  otics are given for the infections that develop, and transfu-  sions of packed RBCs or platelets are administered for  symptomatic treatment of anemia and bleeding problems,  respectively.   Definitive therapy for aplastic anemia is to replace the  defective marrow with normal marrow, either by bone  marrow transplantation or peripheral blood stem cell trans-  plantation from a matched donor. Patients must be carefully  selected; patients younger than 50 years of age and those  with an HLA-matched donor (usually a sibling) have the  best prognosis, but unfortunately only about 30% of  patients meet these criteria.    For those patients who would not be a good prospect for  bone marrow transplantation because of their advanced age  or no matched donor, immunosuppressive therapy is recom-  mended. Antithymocyte globulin combined with cyclospo-  rine produces a response in the majority of these patients.  Compared with treatment results from only 25 years ago,  the prognosis for this condition has markedly improved. In  the past, for patients with severe aplastic anemia treated with  only antibiotics and transfusions, the mortality rate was  greater than 80% in the first year after the diagnosis. Cur-  rently, an overall long-term survival of 75% of these patients  can be achieved with either bone marrow transplant or  immunosuppressive therapy. However, even if the disease is  controlled, then these patients remain at risk for recurrent  marrow aplasia and are at increased risk for acute leukemia.    Neutropenia refers to a decrease in the number of the  circulating neutrophils below 1500/mm? in an adult. It is  often associated with an increased susceptibility of the  patient to bacterial infections. Clinicians must be aware of  this disorder because infection of the oral mucosa may be  the initial sign of the disease. Interestingly, several ethnic  groups, including patients of African and Middle Eastern  background, will consistently have neutrophil counts that  would qualify as neutropenia (as low as 1200/mm’), yet  these individuals are otherwise healthy. This finding has  been termed benign ethnic neutropenia, and it appears to  have no effect on the health of the patient because neutro-  phil counts respond to bacterial challenge.   A decrease in neutrophils may be precipitated by several  mechanisms, most of which involve decreased production  or increased destruction of these important inflammatory  cells. When infections are noted in infancy and neutrope-  nia is detected, the problem is usually the result of a  congenital or genetic abnormality, such as Schwachman-  Diamond syndrome, dyskeratosis congenita (see page  695), cartilage-hair syndrome, or severe congenital neu-  tropenia. If the neutropenia is detected later in life, it  usually represents one of the acquired forms. Many acquired  neutropenia conditions have an unknown cause; however,  others are clearly associated with various causes. A decreased  production of neutrophils and the other formed elements  of the blood may result from the destruction of the bone  marrow by malignancies, such as leukemia (see page 547),  or by metabolic diseases, such as Gaucher disease (see page  763), and osteopetrosis (see page 574).   Many drugs may affect neutrophil production, either  through direct toxic effects on the bone marrow progenitor  cells or by unknown idiosyncratic mechanisms. These drugs  include the following:   e Anticancer chemotherapeutic agents (e.g., nitrogen  mustard, busulfan, chlorambucil, and cyclophospha-  mide)   Neutropenia can also be a late manifestation of ritux-  imab therapy, occurring 4 to 5 weeks after treatment on  average. Nutritional deficiencies of vitamin B,, or folate,  which may be a consequence of malabsorption syndromes,  can inhibit neutrophil production as well.   A variety of viral and bacterial infections not only may  reduce production of neutrophils but also seem to increase  their destruction, typically at the sites of infection. Viral  infections that have been implicated include the following:  ¢ Hepatitis A and B  ¢ Rubella  ¢ Measles  e Respiratory syncytial virus  ¢ Varicella  e HIV   Numerous bacterial infections, such as typhoid, tuber-  culosis, brucellosis, and tularemia, may also cause neutro-  penia. The increased destruction of neutrophils by an  autoimmune mechanism also occurs in such disorders as  systemic lupus erythematosus (SLE), in which autoantibod-  ies directed against the neutrophil are produced.    Most patients with neutropenia have some form of bacterial  infection rather than a viral or fungal infection, particularly  if the other elements of the immune system (lymphocytes,  plasma cells, and monocytes) are still intact. Staphylococcus  aureus and gram-negative organisms seem to cause the most  problems for patients with neutropenia. The suppuration  and abscess formation normally associated with such infec-  tions may be markedly reduced because of the lack of neu-  trophils. The most common sites of infection include the  middle ear, the oral cavity, and the perirectal area. When  neutrophil counts drop below 500/mm’, however, pulmo-  nary infections often develop.   The oral lesions of neutropenia consist of ulcerations that  usually involve the gingival mucosa, probably because of the  heavy bacterial colonization of this area and the chronic  trauma that it receives. These ulcers characteristically lack  an erythematous periphery, although this finding has been  variable. Premature periodontal bone loss with exfoliation  of the deciduous dentition has been described.    A biopsy specimen of neutropenic ulceration usually shows  a reduced number or the absence of neutrophils. Bacterial  invasion of the host tissue may be apparent in some  instances.    Infections related to neutropenia are managed with appro-  priate antibiotic therapy. The patient should be encouraged    to maintain optimal oral hygiene to decrease the bacterial  load in the oral cavity. Studies using recombinant human  granulocyte colony-stimulating factor (G-CSF; filgrastim;  pegfilgrastim), a cytokine that promotes the growth and  differentiation of neutrophils, have shown remarkable  results. Patients with severe neutropenia have a significant  increase in neutrophil counts and resolution of infections  after treatment with this agent. Prophylactic use of filgras-  tim or pegfilgrastim reduces the risk of febrile neutropenia  in patients who are receiving certain antineoplastic chemo-  therapeutic regimens. Patients who do not respond to  G-CSF may have to be considered for hematopoietic stem  cell transplantation, depending on the severity of the neu-  tropenia and subsequent infections.    Agranulocytosis is a condition in which the cells of the  granulocytic series, particularly neutrophils, are absent. As  in other disorders of the formed elements of the blood,  agranulocytosis may occur as a result of decreased  production or increased destruction or use of these cells.  Although some cases are idiopathic, most are induced by  exposure to one of several drugs. Some drugs, such as the  anticancer chemotherapeutic agents, induce agranulocytosis  by inhibiting the normal mitotic division and maturation  of the hematopoietic stem cells. In other instances, the  drugs trigger an immunologic reaction that results in the  destruction of granulocytes. Rarely, agranulocytosis may  be a congenital syndrome (congenital agranulocytosis,  Kostmann syndrome) that results from a decreased level  of the cytokine granulocyte colony-stimulating factor    Agranulocytosis typically develops within a few days after a  person ingests the offending drug. Because of the lack of  granulocytes (especially neutrophils), bacterial infections  often develop and patients may show signs and symptoms  of malaise, sore throat, swelling, fever, chills, bone pain,  pneumonia, and shock. The erythrocyte and platelet counts  are usually normal or only slightly depressed.   Oral lesions are common and include necrotizing, deep,  punched-out ulcerations of the buccal mucosa, tongue, and  palate. The gingivae are especially susceptible to infection,  often resembling the pattern of necrotizing ulcerative gin-  givitis (NUG) (see page 143).    Microscopic examination of a biopsy specimen from one of  the oral ulcerations in agranulocytosis characteristically  shows abundant bacterial organisms, both on the surface  and within the tissue. The host inflammatory response is  relatively sparse, with few granulocytes, particularly neutro-  phils, seen in the ulcer bed.    If the clinician believes that a particular drug has caused the  agranulocytosis, the medication should be discontinued as  soon as is reasonably possible. In many instances, the granu-  locyte count returns to normal within 10 to 14 days after  cessation of the offending agent. For patients who have  agranulocytosis secondary to cancer chemotherapy, oral  hygiene should be meticulous to foster an immaculate oral  environment. In addition, the use of chlorhexidine-  containing mouth rinses seems to reduce the severity of the  oral lesions. Active infections are treated with appropriate  antibiotic medications.   If the agranulocytosis is related to cancer treatment, the  white blood cell count usually returns to normal after a  period of weeks. For patients whose granulocyte counts do  not recover, administration of G-CSF or granulocyte-  macrophage colony-stimulating factor (GM-CSF) may be  beneficial. The overall mortality rate for this condition in  the past was 20% to 30%, although cytokine therapy and  the newer broad-spectrum antibiotics have improved the  outlook for these patients.    Cyclic neutropenia is a rare idiopathic hematologic disor-  der that is characterized by regular periodic reductions in  the neutrophil population of the affected patient. The  underlying cause seems to be a mutation of the neutrophil  elastase (ELA-2 or ELAINE) gene, resulting in arrested devel-  opment of neutrophils at the promyelocyte stage within the  marrow. This mutation is also associated with premature  apoptosis of these myeloid precursor cells. The best esti-  mated frequency of this disease in the population is about  1 in 1 million. Although an autosomal dominant pattern  of inheritance has been described in a few cases, most exam-  ples of cyclic neutropenia are isolated.   Symptoms usually begin in childhood and tend to cor-  relate with the neutrophil counts. When the neutrophil  count is at its nadir (i.e., lowest point), the patient experi-  ences problems with infection. As the neutrophil count rises  toward normal, the signs and symptoms abate. Very low  neutrophil counts usually are present for 3 to 6 days, and  blood monocyte and eosinophil levels are typically increased  when the neutrophil count is depressed. Even when the  neutrophil count is at its peak, the levels are often less than  normal.    The signs and symptoms of cyclic neutropenia occur in  rather uniformly spaced episodes, which usually have a  21-day cycle. Patients typically complain of recurrent  episodes of fever, anorexia, cervical lymphadenopathy,  malaise, pharyngitis, and oral mucosal ulcerations. Other    @ Fig. 13-12 Cyclic Neutropenia. Ulceration of the lateral tongue is  typical of the lesions associated with cyclic neutropenia. (From Allen  CM, Camisa C: Diseases of the mouth and lips. In Sams WM, Lynch  P, editors: Principles and practice of dermatology, ed 2, New York,  1996, Churchill Livingstone.)    @ Fig. 13-13 Cyclic Neutropenia. Cyclic neutropenia is one of  several conditions that may produce premature bone loss, as shown  in the interradicular regions of the mandibular deciduous molar teeth.    gastrointestinal mucosal areas, including the colon, rectum,  and anus, may be affected by recurrent ulcerations.   The oral ulcerations develop on any oral mucosal surface  that is exposed to even minor trauma, particularly the lips,  tongue, buccal mucosa, and oropharynx (Fig. 13-12). An  erythematous halo is variably present at the periphery of the  ulcers. The gingiva is the most severely affected region of  the oral cavity. Severe periodontal bone loss with marked  gingival recession and tooth mobility also is characteristic    The diagnosis of cyclic neutropenia should be established  by sequential complete blood counts (typically three times  per week for 6 to 8 weeks) to determine whether cycling of  the neutrophil levels occurs. The neutrophil count should  be less than 500/mm’ for 3 to 5 days during each of at least  three successive cycles to make this diagnosis.    The histopathologic features of cyclic neutropenia are  similar to those of the other neutropenic and granulocyto-  penic ulcerations if the biopsy is performed during the nadir  of the neutrophil count.    Supportive care for the patient with cyclic neutropenia  includes antibiotic therapy for significant infections that  might occur while the neutrophil count is at its lowest.  Unfortunately, this approach cannot be considered a per-  manent treatment. Other methods that have been used  with marginal success include splenectomy, corticosteroid  therapy, and nutritional supplementation. Administration  of the cytokine granulocyte colony-stimulating factor  (G-CSF) several times weekly seems to correct the lack of  production of neutrophils. This treatment results in a  decrease in the time of neutropenia from 5 days to 1 day,  which improves the clinical course of the disease. The cycles  are reduced from 18 to 21 days to 11 to 13 days, and the  severity of mucositis and infection are reduced.   Supportive care in the form of optimal oral hygiene  should be maintained to reduce the number and severity of  oral infections and improve the prognosis of the periodontal  structures. Fortunately, for many of these patients, the  severity of symptoms related to cyclic neutropenia seems to  diminish after the second decade of life, despite the fact that  the cycling of the neutrophils continues.    Thrombocytopenia is a hematologic disorder that is char-  acterized by a markedly decreased number of circulating  blood platelets (formed elements derived from megakaryo-  cyte precursors in the bone marrow). Platelets are necessary  for hemostasis and clot formation. A platelet count  of 200,000 to 400,000/mm? is considered normal. The  decrease in platelets may be the result of the following:    Reduced production of platelets may be the result of various  causes, such as infiltration of the bone marrow by malignant  cells or the toxic effects of cancer chemotherapeutic drugs.  In such instances, decreases in the other formed elements  of the blood are also seen.    Increased destruction of platelets may be caused by an  immunologic reaction, which is often precipitated by any  one of more than 100 different drugs; heparin is one of the    most common offending agents. This type of reaction is  typically idiosyncratic and, therefore, not related to the dose  of the drug. Similarly, autoantibodies directed against plate-  lets, specifically certain surface glycoproteins, may on rare  occasions be induced by viral infection or vaccination. In  addition, certain systemic diseases may have thrombocyto-  penia as a component, such as systemic lupus erythematosus  (SLE) and HIV infection. Increased destruction may  also occur because of increased consumption of platelets  associated with abnormal blood clot formation. This occurs  in patients with conditions, such as thrombotic thrombo-  cytopenic purpura (TTP). This serious disorder of coagu-  lation is caused by a deficiency of a von Willebrand  factor-cleaving metalloprotease (ADAMTS13), which trig-  gers the formation of numerous thrombi within the small  blood vessels of the body. The condition is usually caused  by antibodies directed against ADAMTS13, but TTP can  also rarely be inherited as an autosomal recessive condition  when mutations of the ADAMTS13 gene are present.    Under normal conditions, one-third of the platelet popula-  tion is sequestered in the spleen. Consequently, conditions  that cause splenomegaly (e.g., portal hypertension second-  ary to liver disease, splenic enlargement secondary to tumor  infiltration, and splenomegaly associated with Gaucher  disease) also cause larger numbers of platelets to be taken  out of circulation. Regardless of the cause, the result for the  patient is a bleeding problem because normal numbers of  platelets are not available for proper hemostasis.    Clinical evidence of thrombocytopenia is not usually seen  until the platelet levels drop below 100,000/mm°. The  severity of involvement is directly related to the extent of  platelet reduction. The condition often is initially detected  because of the presence of oral lesions. Minor traumatic  events are continuously inflicted on the oral mucosa during  chewing and swallowing of food. The small capillaries that  are damaged during this process are normally sealed off with  microscopic thrombi. In a patient with thrombocytopenia,  however, the thrombi do not form properly. This results in  a leakage of blood from the small vessels. Clinically, this  usually produces pinpoint hemorrhagic lesions known as  petechiae. Ifa larger quantity of blood is extravasated, then  an ecchymosis or bruise results (Fig. 13-14). With even  larger amounts of extravasated blood, a hematoma (hemat  = blood; oma = tumor) will develop (Fig. 13-15). Spontane-  ous gingival hemorrhage often occurs in these patients, as  does bleeding from sites of minor trauma.   Similar hemorrhagic events occur throughout the body.  With severe thrombocytopenia (<10,000 platelets/mm’),  massive bleeding from the gastrointestinal or urinary tract  may be fatal. Epistaxis is often present in these patients, and  hemoptysis indicates significant pulmonary hemorrhage.    @ Fig. 13-14 Thrombocytopenia. The bruising (purpura) seen on  this patient’s forearm is a result of reduced platelet count secondary  to myelodysplasia, a preleukemic bone marrow disorder.    ® Fig. 13-15 Thrombocytopenia. This dark palatal lesion represents  a hematoma caused by a lack of normal coagulation, characteristic of  thrombocytopenia.    Intracranial hemorrhage is also a potentially fatal complica-  tion of severe thrombocytopenia.   Immune thrombocytopenic purpura (ITP), which  used to be known as idiopathic thrombocytopenic purpura,  can present as either an acute or chronic process. Acute ITP  usually occurs during childhood, classically after a nonspe-  cific viral infection. The symptoms of thrombocytopenia  appear quickly and may be severe. Most cases, however,  resolve spontaneously within 4 to 6 weeks, and 90% of  patients recover by 3 to 6 months. Chronic ITP most fre-  quently affects women between 20 and 40 years. Autoanti-  bodies directed against antigens on the platelet surface result  in sequestration and destruction of the platelets in the  spleen. Consequently many of these patients may respond  to splenectomy.    Gingival biopsy may be performed for diagnostic purposes  in patients with suspected TTP. Approximately 30% to    40% of such biopsy specimens show the presence of fibrin  deposits in the small vessels. These deposits are more readily  appreciated after staining the tissue section using the peri-    If the clinician believes the thrombocytopenia to be drug-  related, the drug should be discontinued immediately. In  most instances, the platelet count returns to normal after  several days. Platelet transfusions and corticosteroid therapy  may be necessary if life-threatening hemorrhage occurs. As  mentioned earlier, ITP often resolves spontaneously, but  those cases that are more severe may require corticosteroid  therapy or intravenous immunoglobulin (IVIG) therapy.  Refractory ITP has been treated with splenectomy, but  newer medical treatments, such as rituximab (targeting B  lymphocytes) and thrombopoietin-receptor agonists, are  now available. For some forms of thrombocytopenia, such  as TTP, the patient’s prognosis is relatively guarded. In the  past, the condition was almost uniformly fatal, although the  outlook has greatly improved since therapy with plasma  exchange transfusions, combined with corticosteroids or  rituximab, became available. More than 70% of these  patients now survive with proper treatment.    ¢ POLYCYTHEMIA VERA (PRIMARY  POLYCYTHEMIA; POLYCYTHEMIA RUBRA  VERA; PRIMARY ACQUIRED  ERYTHROCYTOSIS)    Polycythemia vera is a rare idiopathic hematologic disorder  that is best thought of as an increase in the mass of the red  blood cells (RBCs). Uncontrolled production of platelets  and granulocytes, however, is often seen concurrently, and  most authorities feel that this condition represents a rela-  tively nonaggressive myeloproliferative disorder. Research-  ers believe the overproduction is related to the abnormal  behavior of a single progenitor marrow stem cell, which  begins multiplying without regard to the normal regulatory  hormones, such as erythropoietin. This gives rise to a group  or clone of unregulated cells that then produce the excess  numbers of these formed elements of the blood at two to  three times the normal rate. These cells generally function  in a normal fashion.    Polycythemia vera typically affects older adults. The median  age at diagnosis is 60 years. Only 5% of cases are diagnosed  before the age of 40 years. No sex predilection is seen, and  the annual incidence in the United States is estimated to be  approximately 20 cases per million population. An acquired  mutation of one of the tyrosine kinase genes, Janus kinase  2 (JAK2), plays a significant role in the development of this    disorder, and more than 95% of patients with polycythemia  vera have been shown to have this mutation.   The initial symptoms of the disease are nonspecific and  include the following:  ¢ Headache  e Weakness  ¢ Dizziness  ¢ Drowsiness  ¢ Visual disturbances  ° Sweating  ¢ Weight loss  ¢ Dyspnea  ¢ Epigastric pain   A ruddy complexion may be evident on physical exami-  nation. One relatively characteristic complaint, described in  about 40% of affected patients, is that of generalized pru-  ritus (itching), particularly after bathing, without evidence  of a rash.   The problems caused by thrombus formation, which  would be expected with the increased viscosity of the blood  and the increased platelet numbers, include transient isch-  emic attacks, cerebrovascular accidents, and myocardial  infarctions. Hypertension and splenomegaly are also  common.   A peculiar peripheral vascular event called erythrome-  lalgia affects the hands and feet. Patients experience a  painful burning sensation accompanied by erythema and  warmth. This may eventually lead to thrombotic occlusion  of the vessels that supply the digits. Digital gangrene and  necrosis may result. Erythromelalgia is probably caused by  excessive platelets, and its onset seems to be precipitated by  exercise, standing, or warm temperatures.   Strangely enough, these patients may also have problems  with excess hemorrhage. Epistaxis and ecchymoses are  sometimes a problem, and gingival hemorrhage has been    With the initial diagnosis of polycythemia vera, an immedi-  ate attempt is made to reduce the RBC mass. The first  treatment is usually phlebotomy, with as much as 500 mL  of blood removed every other day until a hematocrit of less  than 45% is achieved. If thrombotic events are an immedi-  ate problem, then treatment with low-dose aspirin should  be started. To control the platelet levels, anagrelide hydro-  chloride, a selective inhibitor of megakaryocyte maturation  and platelet production, may be prescribed. Antihistamines  are used to help control the symptoms of pruritus.  Long-term management may include intermittent phle-  botomy, although myelosuppressive therapy has also been  advocated. An increased risk of leukemia is associated with  some chemotherapeutic drugs. Hydroxyurea is one chemo-  therapeutic agent that may not pose an increased risk of  leukemia, however, because it acts as an antimetabolite  and does not appear to have any mutagenic properties.    Nevertheless, in 2% to 10% of patients with polycythemia  vera, acute leukemia ultimately develops.   Overall, the prognosis is fair; patients with polycythemia  vera survive an average of 10 to 12 years after the diagnosis,  if treated. Given the fact that the median age at diagnosis  is 60 years, the majority of affected patients do not seem to  have a markedly higher death rate compared with their  unaffected peers.    Leukemia represents several types of malignancies of hema-  topoietic stem cell derivation. The disease begins with the  malignant transformation of one of the stem cells, which  initially proliferates in the bone marrow and eventually  overflows into the peripheral blood of the affected patient.  Problems arise when the leukemic cells crowd out the  normal defense cell and erythrocyte precursors. In the  United States, approximately 2.9% of all cancers are leuke-  mia, and 4.1% of deaths from cancer can be attributed to  this disease.   Leukemias are usually classified according to their histo-  genesis and clinical behavior. Therefore, the broad catego-  ries would be acute or chronic (referring to the clinical  course) and myeloid or lymphocytic/lymphoblastic (refer-  ring to the histogenetic origin). Myeloid leukemias can  differentiate along several different pathways; thus they  produce malignant cells that usually show features of granu-  locytes or monocytes, and less frequently, erythrocytes or  megakaryocytes.   Acute leukemias, if untreated, run an aggressive course  and often result in the death of the patient within a few  months. Chronic leukemias tend to follow a more indolent  course, although the end result is the same. One of the  greatest successes in cancer treatment has been achieved in  acute lymphoblastic leukemia of childhood, a condition  that used to be uniformly fatal but now is often capable of  being controlled.   Leukemias are probably the result of a combination of  environmental and genetic factors. Certain syndromes are  associated with an increased risk. These genetic disorders  include the following:  ¢ Down syndrome  ¢ Bloom syndrome  ¢ Neurofibromatosis type I  ¢ Schwachman syndrome  e Ataxia-telangiectasia syndrome  ¢ Klinefelter syndrome  ¢ Fanconi anemia  e Wiskott-Aldrich syndrome   In addition, certain types of leukemia show specific chro-  mosomal abnormalities. The first chromosomal abnormal-  ity to be detected was found in patients with chronic  myeloid leukemia, and this malignancy was characterized  by a genetic alteration called the Philadelphia chromo-  some. This abnormality represents a translocation of the    chromosomal material between the long arms of chromo-  somes 22 and 9. This rearrangement of the genetic material  occurs in such a fashion as to fuse the breakpoint cluster  region (BCR) gene with the Abelson (ABL) oncogene, pro-  ducing an entirely new gene: BCR-ABL. ‘This gene is con-  tinuously transcribed, and the resulting protein product, a  tyrosine kinase, causes the uncontrolled proliferation of the  leukemic cells. Identifying such pathogenetic mechanisms  has opened up an entirely new field of chemotherapy that  targets specific molecular mechanisms of carcinogenesis. A  variety of other genetic alterations in the bone marrow stem  cells has been associated with the myelodysplasia syn-  dromes, a group of disorders that appear to represent early  stages in the evolution of acute myeloid leukemia. As the  genetic alterations accumulate in the stem cells, the chances  of the patient developing leukemia increase.   Some environmental agents are associated with an  increased risk of leukemia, but their overall contribution to  the leukemia problem is thought to be less than 5%. Expo-  sure to pesticides, benzene, and benzene-like chemicals has  been associated with an increased risk of developing leuke-  mia. Ionizing radiation has also been implicated; this was  documented by the increased frequency of chronic myeloid  leukemia in the survivors of the atomic bomb blasts at Hiro-  shima and Nagasaki during World War II. Viruses have also  been shown to produce leukemia, although this is not a  common finding. The most thoroughly studied is the retro-  virus known as human T-cell leukemia/lymphoma virus type I  (HTLV-1), which is transmitted by contaminated blood  from infected to uninfected individuals. This virus can cause  a relatively rare form of malignancy of T lymphocytes, which  may present as a leukemia or non-Hodgkin lymphoma (see  page 555). Most cases have been identified in parts of the  Caribbean, central Africa, and southwestern Japan.   As knowledge about this group of diseases increases, the  fact that the leukemias are diverse and complex cannot be  overlooked. For example, at least eight distinct subtypes of  acute myeloid leukemia have now been identified, and each  subtype has a different treatment approach and prognosis.  Because of the complexity of this area, the discussion is  limited to those aspects of leukemia that are more directly  related to the oral or head and neck region.    If all types of leukemia are considered, this condition occurs  at a rate of 13 cases per 100,000 population annually.  Slightly more males than females are affected. The myeloid  leukemias generally affect an adult population; acute  myeloid leukemia affects a broader age range, which  includes children. Chronic myeloid leukemia shows peak  prevalence during the third and fourth decades of life.  Acute lymphoblastic leukemia, in contrast, occurs pre-  dominantly in children and represents one of the more  common childhood malignancies. Chronic lymphocytic  leukemia, the most common type of leukemia, primarily    Many of the clinical signs and symptoms of leukemia are  related to the marked reduction in the numbers of normal  white and red blood cells, a phenomenon that results from  the crowding out of the normal hematopoietic stem cells  by the malignant proliferation (myelophthisic anemia).  Because of the reduced red blood cell (RBC) count and  subsequent reduction in oxygen-carrying capacity of the  blood, patients complain of fatigue, easy tiring, and dyspnea  on mild exertion. The malignant cells may also infiltrate  other organs and often cause splenomegaly, hepatomegaly,  and lymphadenopathy.   Leukemic patients may also complain of easy bruising  and bleeding, problems that are caused by a lack of blood  platelets (thrombocytopenia), the result of megakaryocytes  being crowded out of the marrow. Petechial hemorrhages of  the posterior hard palate and the soft palate may be observed,  and these may be accompanied by spontaneous gingival  hemorrhage, especially with platelet counts less than 10,000  to 20,000/mm?. Because disturbances in stem cell differen-  tiation accompany the myelodysplasia syndromes, throm-  bocytopenia is often present in these patients, and gingival  hemorrhage has been reported in this setting. Serious hem-  orrhagic complications may result from bleeding into the  CNS or the lungs.   A fever associated with infection may be the initial sign  of the leukemic process. Perirectal infections, pneumonia,  urinary tract infections, and septicemia are common infec-  tious complications. The microorganisms that are typically  involved include gram-negative bacteria, gram-positive  cocci, and certain Candida species.   Ulceration of the oral mucosa is often present as a result  of the impaired ability of the host to combat the normal  microbial flora. Usually, the gingival mucosa is the most  severely affected because of the abundant bacteria normally  present around the teeth. The neutropenic ulcers that are  produced are typically deep, punched-out lesions with a  gray-white necrotic base. Oral candidiasis is often a com-  plication of leukemia, involving the oral mucosa diffusely.  Herpetic infections are the most common viral lesions, and  these may involve any area of the oral mucosa rather than  being confined to the keratinized mucosa, as in immuno-  competent patients.   Occasionally, the leukemic cells infiltrate the oral soft  tissues and produce a diffuse, boggy, nontender swelling  that may or may not be ulcerated. This occurs most fre-  quently with the myelomonocytic types of leukemia, and it  may result in diffuse gingival enlargement (Figs. 13-16  and 13-17) or a prominent tumorlike growth (Fig. 13-18).  The tumorlike collection of leukemic cells is known as  myeloid sarcoma, a designation that has replaced the older  terms, granulocytic sarcoma and extramedullary myeloid  tumor. Historically the proliferation of leukemic cells was  called chloroma because it is often greenish (chlor = green;  oma = tumor) on fresh-cut sections. Other oral manifesta-  tions include infiltration of the periapical tissues, simulating  periapical inflammatory disease both clinically and  radiographically.    ® Fig. 13-16 Leukemia. Diffuse gingival enlargement, as depicted in  this photograph, may occur in leukemic patients, particularly in those  with monocytic leukemia. This older man had a history of myelodys-  plasia for several years before the development of leukemia.    @ Fig. 13-17 Leukemia. Extensive hemorrhagic enlargement of the  maxillary and mandibular gingivae. (Courtesy of Dr. Michael Tabor.)    @ Fig. 13-18 Leukemia. The ulcerated soft tissue nodule of the hard  palate represents leukemic cells that have proliferated in this area.    Microscopic examination of leukemia-affected tissue shows  diffuse infiltration and destruction of the normal host tissue  by sheets of poorly differentiated cells with either myelo-  monocytic characteristics or lymphoid features.    The diagnosis is usually established by confirming the pres-  ence of poorly differentiated leukemic cells in the peripheral  blood and bone marrow. Bone marrow biopsy is normally  performed in conjunction with the peripheral blood studies  because some patients may go through an aleukemic phase  in which the atypical cells are absent from the circulation.  Classifying the type of leukemia requires establishing the  immunophenotype by using immunohistochemical markers  to identify cell surface antigens expressed by the tumor cells.  Immunohistochemical confirmation of certain characteris-  tic enzymes (e.g., myeloperoxidase and lysozyme) is neces-  sary to identify and classify the myeloid leukemias. In  addition, cytogenetic and molecular characterization of the  lesional cells is typically necessary. In many cases, the results  of these various studies will be significant because the  patient’s prognosis is directly affected.    The treatment of a patient with leukemia consists of various  forms of chemotherapy; the type of leukemia dictates the  chemotherapeutic regimen. In most cases the purpose of  chemotherapy is to destroy as many of the atypical cells as  possible in a short time, thus inducing a remission. For this  reason, this technique has been termed induction chemo-  therapy. Usually, this phase of chemotherapy requires high  doses of toxic chemotherapeutic agents; often, the patient  experiences a number of unpleasant side effects during treat-  ment. Once remission has been induced, this state must be  maintained. This is the purpose of maintenance chemo-  therapy, which typically requires lower doses of chemo-  therapeutic drugs given over a longer period.   If the BCR-ABL fusion is identified in the leukemic cells  of a patient with chronic myeloid leukemia, then treatment  with a tyrosine kinase inhibitor is appropriate. The first  tyrosine kinase inhibitor to be developed and marketed was  imatinib mesylate, and at least half of these patients will  respond dramatically to this therapy. Imatinib must be  taken continuously, because relapses develop quickly if the  drug is stopped. Unfortunately over 100 different muta-  tions have been identified in this fused gene; consequently,  33% of chronic myelogenous leukemia patients will be  resistant to imatinib. More potent BCR-ABL tyrosine  kinase inhibitors, such as dasatinib and nilotinib, have now  been developed and can be used as first- or second-line  therapy. Chronic lymphocytic leukemia is considered  curable only by treatment with allogeneic hematopoietic  stem cell transplantation, a procedure that has its own risks  and can be considered in patients less than 60 years of age.  Most patients achieve a significant response when treated  with traditional chemotherapeutic agents that are combined  with monoclonal antibodies directed against one of the  B-lymphocyte cell surface antigens. Rituximab, which is a  CD20 antibody, has been effective in managing this disease;  however, other monoclonal B-cell surface antibodies are    being investigated. Drug therapy may be combined with  radiation therapy to the CNS because the chemotherapeutic  drugs often do not cross the blood-brain barrier effectively.  Therefore, the leukemic cells may survive in this site and  cause a relapse of the leukemia. Direct intrathecal infusion  of the chemotherapeutic agent may be performed to cir-  cumvent the problem of the blood-brain barrier. If this  strategy succeeds in inducing a remission, then a bone  marrow transplant may be considered as a therapeutic  option, particularly for the types of leukemia that tend to  relapse. This option often is reserved for patients younger  than 45 years of age because the success rate is less favorable  in older patients.   Supportive care is often necessary if these patients are to  survive their leukemia. For patients with bleeding problems,  transfusions with platelets may be necessary. If severe anemia  is present, packed RBCs may be required. Infections, of  course, should be evaluated with respect to the causative  organism, and appropriate antibiotics must be prescribed.  Support must be maintained from an oral perspective  because many of these patients experience infections of the  oral mucosa during the course of their disease. Optimal oral  hygiene should be encouraged, and aggressive investigation  of any oral complaint should be performed as soon as  possible to prevent potentially serious oral infectious  complications.   The prognosis of a particular patient depends on a  number of variables, including the type of leukemia, the age  of the patient, and the cytogenetic alterations associated  with the disease. In children with acute lymphoblastic  leukemia, nearly 90% of these patients are now considered  to be cured after appropriate treatment. In an adult with  the same diagnosis, even though the rate of initial remission  induction is 80%, the 5-year survival rate is generally much  lower in most reported series.   Patients younger than 60 years of age with acute myeloid  leukemia have a 5-year survival rate of approximately 40%  today. This form of leukemia in a patient older than 60  years, however, has a much poorer prognosis, with less than  a 10% chance of survival seen in that population. Similarly,  patients with a previous history of myelodysplasia have an  unfavorable prognosis.   Even though an indolent period is experienced with  chronic myeloid leukemia, eventually the neoplastic cells  undergo a process known as blast transformation, in which  they become less differentiated, proliferate wildly, and cause  the patient’s death within 3 to 6 months. In the past, the  5-year survival rate for chronic myeloid leukemia was in the  20% range. Today, most centers are reporting 5-year sur-  vival rates of approximately 80%, a dramatic improvement  presumably because of the effect of tyrosine kinase inhibitor  therapy. Additional factors that may play a role in improved  survival include diagnosis of the disease at an earlier stage  and the availability of better supportive care. Attempts  to control chronic myeloid leukemia by bone marrow  transplantation from an HLA-matched donor have  resulted in 5-year survival rates of 60% to 70% in younger    patients with this disease. This may be an option for those  patients who do not respond to tyrosine kinase inhibitor  therapy.   Chronic lymphocytic leukemia is considered to be  incurable, but its course is highly variable and depends on  the stage of the disease. Patients with limited disease  have an average survival time of more than 10 years. Those  with more advanced disease survive an average of only 2  years.    @ LANGERHANS CELL HISTIOCYTOSIS  (HISTIOCYTOSIS X; LANGERHANS CELL  DISEASE; IDIOPATHIC HISTIOCYTOSIS;  EOSINOPHILIC GRANULOMA;  LANGERHANS CELL GRANULOMA;  LANGERHANS CELL GRANULOMATOSIS)    The term /istiocytosis X was introduced as a collective des-  ignation for a spectrum of rare clinicopathologic disorders  characterized by proliferation of histiocyte-like cells that are  accompanied by varying numbers of eosinophils, lympho-  cytes, plasma cells, and multinucleated giant cells. The dis-  tinctive histiocytic cells present in this lesion have been  identified as Langerhans cells, and the condition is now  designated as Langerhans cell histiocytosis. Estimates of  its incidence in the general population range from 1 to 4  cases per million annually.   Langerhans cells are dendritic mononuclear cells nor-  mally found in the epidermis, mucosa, lymph nodes, and  bone marrow. ‘These cells process and present antigens to T  lymphocytes. For many years, researchers have debated  whether Langerhans cell histiocytosis represents a nonneo-  plastic condition or a true neoplasm. Studies examining the  clonality of the lesional cells of this condition have shown  this to be a monoclonal proliferation, a finding that is more  consistent with a neoplastic process. BRAF mutations  have been identified in 40% to 60% of Langerhans cell  histiocytosis lesions, and this oncogene has been implicated  in uncontrolled cell division related to several other  neoplasms.   ¢ Monostotic or polyostotic eosinophilic granuloma of  bone—solitary or multiple bone lesions without visceral  involvement   ¢ Chronic disseminated histiocytosis—a disease involving  bone, skin, and viscera (Hand-Schiiller-Christian  disease)   ¢ Acute disseminated histiocytosis—a disease with promi-  nent cutaneous, visceral, and bone marrow involvement  occurring mainly in infants (Letterer-Siwe disease)    It is difficult to categorize many patients into one of  these classic designations because of overlapping clinical  features. The often-cited Hand-Schiiller-Christian triad—  bone lesions, exophthalmos, and diabetes insipidus—is  present in only a few patients with chronic disseminated  disease. It is widely believed that the traditional designations  of Hand-Schiiller-Christian and Letterer-Siwe disease serve  no useful purpose and should be discontinued. Many cases  reported as Letterer-Siwe disease in the older literature  probably included obscure infections, immunodeficiency  syndromes, and malignant histiocytic lesions. Pulmonary  Langerhans cell histiocytosis has also been described, but  this probably is unrelated to the condition that affects the  jaws. Patients who develop pulmonary Langerhans cell his-  tiocytosis are usually adults with a history of smoking, and  clonality studies suggest that this is probably a reactive  process. The Histiocyte Society, in order to better define  prognostic categories of Langerhans cell histiocytosis, has  proposed the following classification:   ¢ Low-risk (skin, bone, lymph nodes, and/or pitu-  itary gland)  ¢ High-risk (lung, liver, spleen, and/or bone marrow)   Although Langerhans cell histiocytosis may be encoun-  tered in patients over a wide age range, more than 50% of  all cases are seen in patients younger than age 15. Although  some series have reported a male predilection, overall the  sexes appear to be equally affected. Bone lesions, either soli-  tary or multiple, are the most common clinical presenta-  tion. Lesions may be found in almost any bone, but the  skull, ribs, vertebrae, and mandible are among the most  frequent sites. Children younger than age 10 most often  have skull and femoral lesions; patients older than age 20  more often have lesions in the ribs, shoulder girdle, and  mandible. Adult patients with solitary or multiple bone  lesions may have lymphadenopathy but usually do not have  significant visceral involvement.   ‘The jaws are affected in 10% to 20% of all cases. Dull  pain and tenderness often accompany bone lesions. Radio-  graphically, the lesions often appear as sharply punched-out  radiolucencies without a corticated rim, but occasionally an  ill-defined radiolucency is seen. Bone involvement in the  mandible usually occurs in the posterior areas, and a char-  acteristic “scooped out” appearance may be evident when  the superficial alveolar bone is destroyed. The resulting bone  destruction and loosening of the teeth clinically may resem-  ble severe periodontitis (Fig. 13-19). Extensive alveolar  involvement causes the teeth to appear as if they are “float-  ing in air” (Fig. 13-20).   Ulcerative or proliferative mucosal lesions or a prolifera-  tive gingival mass may develop if the disease breaks out of  bone (Fig. 13-21). Occasionally, this process may involve    @ Fig. 13-19 Langerhans Cell Histiocytosis. Severe bone loss in  the mandibular molar regions that resembles advanced periodontitis.  (Courtesy of Dr. James White.)    only the oral soft tissues. Lesions also can occur within the  body of the mandible or maxilla, where they may simulate  a periapical inflammatory condition.    The bone lesions of patients with Langerhans cell histiocy-  tosis show a diffuse infiltration of large, pale-staining mono-  nuclear cells that resemble histiocytes. These cells have  indistinct cytoplasmic borders and rounded or indented  vesicular nuclei. Varying numbers of eosinophils are typi-  cally interspersed among the histiocyte-like cells (Fig.  13-22). Plasma cells, lymphocytes, and multinucleated  giant cells are often seen, and areas of necrosis and hemor-  rhage may be present.   The identification of lesional Langerhans cells is neces-  sary to confirm the diagnosis. Because Langerhans cells  cannot be differentiated from other histiocytes by routine  histologic staining, additional diagnostic methods are  required. Electron microscopic evaluation of lesional tissue  was the gold standard for many years because, ultrastructur-  ally, Langerhans cells contain rod-shaped cytoplasmic struc-  tures known as Birbeck granules, which differentiate them  from other mononuclear phagocytes (Fig. 13-23). Immu-  nohistochemical procedures are now used to identify the  lesional Langerhans cells because of their immunoreactivity  with antibodies directed against either CD-1a or CD-207  (langerin), and both markers are specific for Langerhans cell  histiocytosis when seen in the correct clinical setting.    Because this condition is relatively rare, treatment recom-  mendations are often based on anecdotal experience, rather  than randomized controlled trials. Most patients with oral  involvement have single organ disease affecting the jaws,  although other skeletal lesions may be present. Accessible  bone lesions, such as those in the maxilla and mandible, are  usually treated by curettage. Low doses of radiation may be    ® Fig. 13-20 Langerhans Cell Histiocytosis. Periapical radiograph  showing marked bone loss involving the mandibular teeth in a young  girl, resulting in a “floating-in-air” appearance of the teeth.    @ Fig. 13-21 Langerhans Cell Histiocytosis. Clinical photograph  of the same patient shown in Fig. 13-20. The lesion has broken out  of bone and produced this soft tissue mass.    used for less accessible bone lesions, although the potential  for induction of malignancy secondary to this treatment is  a concern in younger patients. Intralesional injection with  corticosteroid agents has also been reported to be effective  in some patients with localized bone lesions. Infrequently,  the apparent spontaneous regression of localized Langer-  hans cell histiocytosis has been reported. The prognosis for  bone lesions in the absence of significant visceral involve-  ment is generally good; however, progression or dissemina-  tion of the disease may occur, particularly for patients who  have three or more bones affected.   When multiple organs are involved, the low-risk pattern  is often associated with considerable morbidity, but the  mortality is considerably less than that of patients with    ae Se AA | AS a  ® Fig. 13-22 Langerhans Cell Histiocytosis. There is a diffuse  infiltrate of pale-staining Langerhans cells intermixed with numerous    ® Fig. 13-23 Langerhans Cell Histiocytosis. Electron micrograph  showing rod-shaped Birbeck bodies (black arrows) in the cytoplasm  of a Langerhans cell. (Courtesy of Richard Geissler.)    high-risk organ involvement. Because of the relative rarity  of disseminated cases, the ideal treatment has yet to be  identified. Single-agent chemotherapy using prednisolone,  etoposide, vincristine, or cyclosporine has produced a good  response in a significant percentage of such patients,  although recurrence is typically seen in over half of the cases.  A combination of vincristine and prednisone seems to  reduce this risk of recurrence, particularly in children.  Lesions in adults, however, respond much better to low-  dose cytosine arabinoside (ARA-C), which is also less toxic.  Multiple high-risk organ involvement seen in infants and  young children may not respond to these more conservative  approaches, and multiple chemotherapeutic agents are  given in that situation. Patients who improve significantly  with induction chemotherapy during the first 6 weeks have  a much better prognosis (nearly 90% survival) compared to  those who do not respond. In that group, only 20% to 35%  survive. In general, the prognosis is poorer for patients in  whom the first sign of the disease develops at a very young  age and somewhat better for patients who are older at the  time of onset.    Hodgkin lymphoma represents a malignant lymphoprolif-  erative disorder, although for many years the exact nature  of the process was poorly understood. The difficulty in  comprehending the character of the condition is reflected  in the relatively noncommittal term Hodgkin disease, which  was used for decades and still may be heard today. Perhaps  one reason why Hodgkin lymphoma was not easily under-  stood is that, unlike most malignancies, the neoplastic cells  (Reed-Sternberg cells) make up only about 0.1% to 2%  of the cells in the enlarged lymph nodes that characterize  this condition. Current evidence regarding the histogenesis  of the Reed-Sternberg cell points to a B-lymphocyte origin.  Certainly, the disease can cause death if appropriate therapy  is not instituted, although the treatment of this malignancy  is one of the few major success stories in cancer therapy  during the past 30 years. In the United States, Hodgkin  lymphoma is about one sixth as common as non-Hodgkin  lymphoma; approximately 9000 cases are diagnosed annu-  ally. Although the cause of this disease is unknown, epide-  miologic and molecular studies have linked Epstein-Barr  virus (EBV) infection to a significant percentage of these  lesions.    Hodgkin lymphoma almost always begins in the lymph  nodes, and any lymph node group is susceptible. The most  common sites of initial presentation are the cervical and  supraclavicular nodes (70% to 75%) or the axillary and  mediastinal nodes (5% to 10% each). The disease initially  appears less than 5% of the time in the abdominal and  inguinal lymph nodes.   Overall, a male predilection is observed, and a bimodal  pattern is noted with respect to the patient's age at diagno-  sis. One peak is observed between 15 and 35 years of age;  another peak is seen after the age of 50.   The usual presenting sign is the identification by the  patient of a persistently enlarging, nontender, discrete mass  or masses in one lymph node region (Fig. 13-24). In the  early stages, the involved lymph nodes are often rather  movable; as the condition progresses, the nodes become  more matted and fixed to the surrounding tissues. If it is  untreated, then the condition spreads to other lymph node  groups and eventually involves the spleen and other extra-  lymphatic tissues, such as bone, liver, and lung. Oral  involvement has been reported, but it is rare. In about 30%  to 40% of patients with Hodgkin disease, other systemic  signs and symptoms may be present, such as weight loss,  fever, night sweats, and generalized pruritus (itching).  ‘The absence of these systemic signs and symptoms is con-  sidered to be better in terms of the patient’s prognosis, and  this information is used in staging the disease. Patients who    have no systemic signs are assigned to category A and those  with systemic signs to category B.   The staging of Hodgkin lymphoma is important for  planning treatment and estimating the prognosis for a given  patient. The staging procedure typically includes confirma-  tion of the pathologic diagnosis, careful history and physical  examination, abdominal and thoracic computed tomogra-  phy (CT) scans or magnetic resonance imaging (MRI)  studies, chest radiographs, and routine hematologic studies  (e.g., complete blood count, serum chemistries, and eryth-  rocyte sedimentation rate). Evaluation of the extent of  disease involvement using positron emission tomography  (PET) scans is becoming part of the standard protocol,  particularly at large institutions. Lymphangiography,  gallium scan, bone marrow biopsy, exploratory laparotomy,  and splenectomy may be necessary if the information that  they would provide might have an effect on staging or treat-  ment. A summary of the staging system for Hodgkin lym-  phoma is presented in Table 13-2.    Hodgkin lymphoma is recognized to comprise two main  forms, 1) nodular lymphocyte—predominant Hodgkin lym-  phoma and 2) classical Hodgkin lymphoma, the latter of  which is divided into five subtypes. Although this group of  diseases has certain features in common, current immuno-  histochemical and molecular biologic techniques have    Involvement of a single lymph node region (I)  or a single extralymphatic organ or site (I)    Il Involvement of two or more lymph node  regions on the same side of the diaphragm  (Il) or one or more lymph node regions with  an extralymphatic site (Ilz)    Ill Involvement of lymph node regions on both  sides of the diaphragm (Ill), possibly with  an extralymphatic organ or site (Ill-), the  spleen (lls), or both (IIlge)    IV Diffuse or disseminated involvement of one or  more extralymphatic organs (identified by  symbols), with or without associated lymph  node involvement   B: Presence of fever, night sweats, and/or  unexplained loss of 10% or more of body  weight during the 6-month period before  diagnosis    Adapted from Gobbi PG, Ferreri AJM, Ponzoni M, et al: Hodgkin lym-  phoma, Crit Rev Oncol Hematol 85:216-237, 2013.    @ Fig. 13-25 Hodgkin Lymphoma. This high-power photomicro-  graph shows the characteristic Reed-Sternberg cell (arrow) of Hodgkin  lymphoma, identified by its “owl-eye” nucleus.    allowed distinctions to be made among the various types.  The common features include effacement of the normal  nodal architecture by a diffuse, often mixed, infiltrate of  inflammatory cells that is interspersed with large, atypical  neoplastic lymphoid cells. In the case of classical Hodgkin  lymphoma, this atypical cell is known as a Reed-Sternberg  cell (Fig. 13-25). The Reed-Sternberg cell is typically binu-  cleated (“owl-eye” nuclei), although it may be multinucle-  ated (“pennies on a plate”), with prominent nucleoli.  The malignant cell in nodular lymphocyte—predominant  Hodgkin lymphoma is the “popcorn cell,” which is so-named  because of the resemblance of the nucleus to a kernel of   These names describe the most prominent histopatho-  logic feature of each type, and specific epidemiologic and  prognostic characteristics are associated with each type.   Nodular lymphocyte—predominant Hodgkin lym-  phoma constitutes 4% to 5% of all cases of Hodgkin lym-  phoma in the United States. In the past, this form was  probably combined with the lymphocyte-rich subtype, but  the presence of the characteristic popcorn cells is a signifi-  cant clue to the diagnosis.   Lymphocyte-rich classical Hodgkin lymphoma repre-  sents about 6% of all cases. Sheets of small lymphocytes  with few Reed-Sternberg cells characterize this form.   The nodular sclerosis subtype makes up 60% to 80%  of cases and occurs more frequently in females during the  second decade of life. This type gets its name from the broad  fibrotic bands that extend from the lymph node capsule into  the lesional tissue. Reed-Sternberg cells in the nodular scle-  rosis form appear to reside in clear spaces and, therefore, are  referred to as lacunar cells.   The mixed cellularity form accounts for about 15% to  30% of the cases and is characterized by a mixture of small  lymphocytes, plasma cells, eosinophils, and histiocytes with  abundant Reed-Sternberg cells.   The lymphocyte depletion subtype, the most aggressive  type, makes up less than 1% of the cases in recent reports.  Before modern immunohistochemical techniques, many  examples of large cell lymphoma or anaplastic T-cell lym-  phoma were undoubtedly included in this category. In this  form of Hodgkin lymphoma, numerous bizarre giant Reed-  Sternberg cells are present, with few lymphocytes.   Occasionally, examples of Hodgkin lymphoma are  encountered that really do not fit the criteria for any of  the known subtypes, and these are designated as  unclassifiable.    The treatment of Hodgkin lymphoma depends on the stage  of involvement. In the past, patients who had limited  disease (stages I and II) often were managed by local radia-  tion therapy alone. Recent treatment trends, however,    combine less extensive radiotherapy fields with milder mul-  tiagent chemotherapy regimens to maximize disease control  and minimize long-term complications of therapy. Patients  with stage II] or IV disease require chemotherapy; radiation  therapy is used conjointly if significant mediastinal involve-  ment or residual disease is detected. For many years a  regimen known as MOPP (mechlorethamine, Oncovin,  procarbazine, prednisone) was widely used to treat Hodgkin  lymphoma. Because significant long-term side effects can be  associated with this chemotherapy, another regimen known  as ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine  [DTIC]) is now used most often because it has fewer  complications.   Before modern cancer therapy was developed for  Hodgkin lymphoma, the 5-year survival rate was only 5%.  The prognosis for this disease is fairly good today; the best  treatment results occur in those who present in the early  stages. Patients with stage I and II disease often have an  80% to 90% relapse-free 10-year survival rate; those with  stage III and IV disease have a 55% to 75% 10-year survival  rate.   The histopathologic subtype of Hodgkin lymphoma  appears to have minimal impact on the response to therapy.  In the past, researchers believed that the lymphocyte deple-  tion form had a poorer prognosis than the other subtypes.  However, with newer immunohistochemical studies, clini-  cians now realize that many of these cases were misdiag-  nosed. In most instances, the stage of disease now plays a  more important role in determining the patient’s prognosis  than does the histopathologic subtype.   After 15 years posttreatment, patient mortality is due  more often to the complications of therapy: either second-  ary malignancy or cardiovascular disease. Currently, research  is focused on the development of treatment regimens that  continue to have a superior cure rate, while simultaneously  decreasing the risk of treatment-related complications.    The non-Hodgkin lymphomas include a diverse and  complex group of malignancies of lymphoreticular histo-  genesis and differentiation. In most instances, they initially  arise within lymph nodes and tend to grow as solid masses.  This is in contrast to lymphocytic leukemias (see page 547),  which begin in the bone marrow and are characterized by  a large proportion of malignant cells that circulate in the  peripheral blood. The non-Hodgkin lymphomas most com-  monly originate from cells of the B-lymphocyte series,  with an estimated 85% of European and American lym-  phoid neoplasms having this derivation. Tumors with a  T-lymphocyte derivation are less common, whereas true  histiocyte-derived lymphomas are even rarer.   The microscopic appearance of the lesional cells was used  in the past to classify the tumors as either lymphocytic or  histiocytic. With the development of modern immunologic  techniques, however, it is now known that many of the  lesions that had been classified as histiocytic were in fact    neoplasms composed of transformed B lymphocytes. In the  early 1980s, a group of American pathologists devised a  classification scheme, known as the Working Formulation for  Clinical Use, which may still be referred to in the United  States. Based on this classification, lymphomas were broadly  grouped into three categories:   Unfortunately, the Working Formulation has been  shown to be somewhat limited in its utility and accuracy.  Many lesions that have been recently defined are not  included in this classification. For these reasons, an inter-  national study group in the early 1990s devised a new  method of categorizing the lymphomas, known as the REAL  (revised European-American lymphoma) classification. With  this system, a combination of histopathologic features,  immunologic cell surface markers, and gene rearrangement  studies are used to organize this group of neoplasms. Further  revisions to the World Health Organization (WHO) lym-  phoma classification system appear periodically as knowl-  edge about this challenging area of pathology accumulates  (Box 13-2). This classification is more precise than the  Working Formulation, and currently most pathologists in  the United States categorize lymphomas according to the  modified REAL system, although some of the more sophis-  ticated molecular studies may not be available at smaller  laboratories.   Approximately 70,000 cases of non-Hodgkin lymphoma  are diagnosed in the United States annually; approximately  one-third of this number will die of the disease each year.  For reasons that are currently unclear, the incidence of this  malignancy seems to be rising in the United States. The  prevalence of lymphoma is increased in patients who have  immunologic problems, such as congenital immunodefi-  ciencies (e.g., Bloom syndrome, Wiskott-Aldrich syndrome,  and common variable immunodeficiency), AIDS, organ  transplantation, and autoimmune disease (e.g., Sjogren syn-  drome, systemic lupus erythematosus (SLE), and rheuma-  toid arthritis).   Viruses may play a role in the pathogenesis of at least  some of these lesions. For example, Epstein-Barr virus  (EBV) has been implicated, but not proven, to be an etio-  pathogenic agent in Burkitt lymphoma (see page 560), a  type of high-grade, small, noncleaved B-cell lymphoma.  EBV is more convincingly related to the development of  various lymphoproliferative conditions (known as EBV-  associated lymphoproliferative disorders) that range from  benign, reactive processes through overt malignancies.  Some of these occur in the setting of immune senescence  (decreased function of the immune system with aging),  whereas others are related to immunosuppressive medica-  tions (Fig. 13-26), immunosuppression after solid organ or  bone marrow transplant, or in association with AIDS (see  page 245). Human herpesvirus 8 (HHV-8) has not only  been associated with Kaposi sarcoma but also with primary  body cavity lymphoma and some cases of plasmablastic    * BOX 13-2 Classification of Hematopoietic and  Lymphoid Neoplasms, Modified from   . Follicular lymphoma  Extranodal marginal zone B-cell lymphoma of MALT type   . Splenic marginal zone lymphoma (+ villous lymphocytes)  Hairy cell leukemia  Plasmacytoma/plasma cell myeloma   . Extranodal T-/NK-cell lymphoma, nasal type  Enteropathy-type intestinal T-cell lymphoma  Adult T-cell lymphoma/leukemia (HTLV 1+)   . Anaplastic large cell lymphoma, primary systemic type  Anaplastic large cell lymphoma, primary cutaneous type    HTLV, Human T-lymphotropic virus; LBL, lymphoblastic lymphoma; MALT,  mucosa-associated lymphoid tissue; NK, natural killer.    lymphoma. The blood-borne human retrovirus, human  T-cell leukemia/lymphoma virus type I (HTLV-1), has been  shown to cause an aggressive form of peripheral T-cell lym-  phoma among certain populations in the Caribbean, central  Africa, and southwest Japan.   Even bacteria have been shown to induce the formation  of so-called mucosa-associated lymphoid tissue (MALT)  lymphoma of the stomach. Antibiotic treatment of Helico-  bacter pylori infection of the stomach lining often results in  complete regression of this low-grade lymphoma.    Non-Hodgkin lymphoma occurs primarily in adults,  although children may be affected, particularly by the more    @ Fig. 13-26 Epstein-Barr Virus (EBV)-Associated Lymphopro-  liferative Disorder. A, This 42-year-old woman, treated for autoim-  mune hepatitis with mycophenolate mofetil, developed painful gingival  ulcers. B, Resolution of the lesion after immune suppression was  stopped and rituximab therapy was initiated.    aggressive intermediate- and high-grade lymphomas. The  condition most commonly develops in the lymph nodes,  but so-called extranodal lymphomas are also found. In the  United States, approximately 20% to 40% of lymphomas  develop in an extranodal site, but in Asian countries such  as Korea and Japan, nearly half of all lymphomas are  extranodal.   With a nodal presentation, the patient usually is aware  of a nontender mass that has been slowly enlarging for  months. The lesion typically involves a local lymph node  collection, such as the cervical, axillary, or inguinal nodes;  one or two freely movable nodules are noticed initially. As  the malignancy progresses, the nodes become more numer-  ous and are fixed to adjacent structures or matted together  (Fig. 13-27). Gradually, the process involves other lymph  node groups, and invasion of adjoining normal tissues  occurs.   In the oral cavity, lymphoma usually appears as extra-  nodal disease. Although the oral lesions of lymphoma are  often a component of more widely disseminated disease, at  times the lymphoma begins in the oral tissues and has not  spread to other sites. The malignancy may develop in the  oral soft tissues or centrally within the jaws. Soft tissue  lesions appear as nontender, diffuse swellings; they most    @ Fig. 13-27 Non-Hodgkin Lymphoma. The matted, nontender  lymph node enlargement in the lateral cervical region represents a  common presentation of lymphoma.    ® Fig. 13-28 Non-Hodgkin Lymphoma. One of the frequent loca-  tions of extranodal lymphoma in the head and neck area is the palate,  where the tumor appears as a nontender, boggy swelling. Note the  overlying telangiectatic blood vessels, a feature often seen with  malignancy.    commonly affect the buccal vestibule, posterior hard palate,  or gingiva (Figs. 13-28 and 13-29). Such swellings charac-  teristically have a boggy consistency. The lesion may appear  erythematous or purplish, and it may or may not be ulcer-  ated. Patients who wear a denture that contacts the lesional  site often complain that their denture does not fit because  it feels too tight.   Lymphoma of bone may cause vague pain or discomfort,  which might be mistaken for a toothache. The patient may    @ Fig. 13-29 Non-Hodgkin Lymphoma. Ulcerated mass of the left  posterior maxilla.    complain of paresthesia, particularly with a mandibular  lesion (so-called numb chin syndrome). Radiographs usually  show an ill-defined or ragged radiolucency, although in the  early stages, the radiographic changes may be subtle or  nonexistent. If untreated, then the process typically causes  expansion of the bone, eventually perforating the cortical  plate and producing a soft tissue swelling. Such lesions have  been mistaken for a dental abscess, although a significant  amount of pain is not present in most cases.   Clinical staging to determine the extent to which the  disease has spread is an important factor in assessing the  prognosis for a particular patient. The staging evaluation  should include a history, physical examination, complete  blood count, liver function studies, CT scans of the tho-  racic, pelvic and abdominal regions, and bone marrow  biopsy. Because of the information obtained with CT  imaging, studies such as chest radiographs, lymphangiogra-  phy and staging laparotomy are not routinely performed.  PET scans are also useful in staging, but this technique may  not be available at all medical centers. In some cases it is  employed to assess response to treatment, rather than for  staging. The staging system for Hodgkin lymphoma (see  Table 13-2) has been widely adopted for use with the non-  Hodgkin lymphomas.    Non-Hodgkin lymphomas are histopathologically charac-  terized by a proliferation of lymphocytic-appearing cells  that may show varying degrees of differentiation, depending  on the type of lymphoma. Low-grade lesions consist of  well-differentiated small lymphocytes. High-grade lesions  tend to be composed of less differentiated cells. All lympho-  mas grow as infiltrative, broad sheets of relatively uniform  neoplastic cells that usually show little or no evidence of  lesional tissue necrosis (Figs. 13-30 and 13-31). In some  lesions, particularly those of B-lymphocyte origin, a vague  semblance of germinal center formation may be seen (i.e.,  a nodular or follicular pattern). Other lymphomas show no  evidence of such differentiation, and this pattern is termed    @ Fig. 13-30 Non-Hodgkin Lymphoma. This low-power photomi-  crograph shows a diffuse infiltration of the subepithelial connective  tissue by lymphoma.    @ Fig. 13-31 Non-Hodgkin Lymphoma. This high-power photomi-  crograph shows lesional cells of lymphoma, consisting of a population  of poorly differentiated cells of the lymphocytic series with minimal  cytoplasm.    diffuse. If the lymphoma arises in a lymph node, then the  tumor destroys the normal architecture of the node. An  extranodal lymphoma destroys the normal adjacent host  tissue by infiltrating throughout the area. In the oral cavity,  diffuse large B-cell lymphoma, which is considered to be a  high-grade lymphoma, is the most common diagnosis,  comprising approximately 60% of the cases.   Standard of care demands that appropriate immunohis-  tochemical and cytogenetic studies be performed for a  tumor diagnosed as lymphoma. In general, these studies can  become quite involved and, therefore, are beyond the scope  of this text.    ‘The treatment of a patient with non-Hodgkin lymphoma  is based on several factors, including the stage and grade of  the lymphoma, the overall health of the patient, and the  patient’s pertinent past medical history. The patient’s health  must be considered because many of the chemotherapeutic  regimens are quite debilitating. Surgical management is not  usually indicated.    Because most non-Hodgkin lymphomas are of B-cell dif-  ferentiation, many treatment strategies now incorporate  monoclonal antibodies directed against CD20, a B-cell  surface antigen, as part of the chemotherapeutic regimen for  both low-grade and high-grade lymphomas. Rituximab is  one of the more commonly used agents (see Fig. 13-26),  although others are now available. Novel monoclonal anti-  bodies to CD20 and other lymphoid cell surface antigens are  continually being developed and examined in clinical trials.   Low-grade (indolent) lymphomas are perhaps the most  controversial in terms of treatment. Some authorities recom-  mend no particular treatment because these tumors are slow  growing and tend to recur despite chemotherapy. Given the  fact that low-grade lymphomas arise in older adults and the  median survival without treatment is 8 to 10 years, many  oncologists opt for a “watch and wait” strategy, treating the  patient only if symptoms develop. Unfortunately, approxi-  mately 40% of low-grade lymphomas eventually transform  to a high-grade lymphoma, leading to the patient’s demise.  Because these low-grade lymphomas have been considered  “incurable,” new treatments are being investigated.   For high-grade (aggressive) lymphomas, the treatment  of localized disease consists of radiation plus chemotherapy.  With more advanced and disseminated disease, chemo-  therapy alone usually is implemented. Multiagent chemo-  therapy is used routinely, and new combinations are  being evaluated continuously. Unfortunately, although the  response rate of many lesions is good and much progress  has been made in this area, the cure rate is not high. High-  grade lymphomas are associated with a 60% mortality rate  at 5 years after diagnosis and treatment.    From its name, one might think that mycosis fungoides is  a fungal infection. The early dermatologists who first rec-  ognized mycosis fungoides knew that this was not the case;  however, they still thought the disease resembled a fungal  condition. Thus this term has persisted. This condition, in  fact, represents a lymphoma that is derived from T lympho-  cytes, specifically the T-helper (CD4+) lymphocyte. With  modern diagnostic techniques, clinicians now know that  there are several types of cutaneous lymphomas, each having  specific T-lymphocyte or B-lymphocyte differentiation pat-  terns. Even though mycosis fungoides is the most common  of these cutaneous lymphomas, it is still a relatively rare  malignancy; only about 1,200 new cases are diagnosed in  the United States annually. This condition exhibits a pecu-  liar property called epidermotropism (i.ec., a propensity to  invade the epidermis of the skin). Oral involvement,  although infrequent, may also be present.    Mycosis fungoides is a condition that usually affects middle-  aged adult men; there is a 2:1 male-to-female ratio and a    ® Fig. 13-32 Mycosis Fungoides. In the tumor stage of the disease,  patients with mycosis fungoides have ulcerated nodules of the skin.  (From Damm DD, White DK, Cibull ML, et al: Mycosis fungoides: initial  diagnosis via palatal biopsy with discussion of diagnostic advantages  of plastic embedding, Ora! Surg Oral Med Oral Pathol 58:413-419,  1984.)    mean age at diagnosis of 55 to 60 years. African-Americans  appear to be affected approximately 1.5 times more fre-  quently than other ethnic groups. The disease progresses  through three stages, usually over the course of several years.   ‘The first stage, known as the eczematous (erythema-  tous) stage, is often mistaken for psoriasis of the skin  because of the well-demarcated, scaly, erythematous patches  that characterize these lesions. Patients may complain of  pruritus. With time, the erythematous patches evolve into  slightly elevated, red lesions (plaque stage). These plaques  tend to grow and become distinct papules and nodules. At  this time, the disease has entered the tumor stage (Fig.  13-32). Visceral involvement is also seen at this point.   Approximately 35 cases of mycosis fungoides with oral  involvement have been reported. The most commonly  affected sites are the tongue, palate, and gingiva (Fig. 13-33).  The buccal mucosa, tonsils, lips, sinuses, and nasopharynx  may also be affected. The oral lesions present as erythema-  tous, indurated plaques or nodules that are typically ulcer-  ated. Generally, these lesions appear late in the course of the  disease and develop after the cutaneous lesions.   Sézary syndrome is an aggressive expression of mycosis  fungoides that essentially represents a dermatopathic T-cell  leukemia. The patient has a generalized exfoliative erythro-  derma, as well as lymphadenopathy, hepatomegaly, and  splenomegaly. The lung, kidneys, and CNS can also be  involved. This condition follows a fulminant course and  typically results in the patient’s death within a short period  of time; the median survival for this form of the disease is  2 to 3 years.    ‘The early stages of mycosis fungoides may be difficult to  diagnose histopathologically because of the subtle changes  that characterize the initial lesions. A psoriasiform pattern  of epithelial alteration is seen, with parakeratin production  and elongation of the epithelial rete ridges. Scattered,    e Fig. 13-33 Mycosis Fungoides. The ulcerated palatal lesions  represent a rare example of oral mucosal involvement by mycosis  fungoides.    slightly atypical lymphocytic cells may be seen in the con-  nective tissue papillae, but such features are often mistaken  for an inflammatory process.    With the development of the plaque stage, a more readily  identifiable microscopic pattern emerges. Examination  of the surface epithelium reveals infiltration by atypical  lymphocytic cells, which are sometimes referred to as  mycosis cells or Sézary cells. These atypical lymphocytes  classically form small intraepithelial aggregates termed  Pautrier microabscesses (Fig. 13-34). The lesional cells have  an extremely unusual nucleus because of the marked infold-  ing of the nuclear membrane, which results in what is  termed a cerebriform nucleus. This feature can best be appre-  ciated when viewed in special semithin, plastic-embedded  microscopic sections (Fig. 13-35). The diagnosis of mycosis  fungoides can be confirmed by demonstrating positivity for  CD4 (a cell surface marker for T-helper cells) in the lesional  cell population. In addition, T-cell receptor gene rearrange-  ment analysis should identify a monoclonal population  of T lymphocytes. A mixed infiltrate of eosinophils, histio-  cytes, and plasma cells may be observed in the subepithelial  connective tissue.    As the condition progresses to the tumor stage, the diffuse  infiltration of the dermis and epidermis by atypical lympho-  cytic cells makes it easier to identify as a malignant process.  Other types of lymphoma would enter into the histopatho-  logic differential diagnosis.   Immunohistochemical studies demonstrating a T-helper  phenotype, combined with the T-cell receptor gene rear-  rangement studies, would help to distinguish the malignant  infiltrate from other lymphomas and establish the diagnosis  of mycosis fungoides. Examination of the peripheral blood  of a patient with Sézary syndrome shows circulating atypical  lymphoid cells.    @ Fig. 13-34 Mycosis Fungoides. This medium-power photomicro-  graph of a cutaneous lesion of mycosis fungoides shows infiltration  of the epithelium by the malignant infiltrate that forms Pautrier  microabscesses.    ® Fig. 13-35 Mycosis Fungoides. This high-power photomicro-  graph of an oral biopsy specimen reveals the atypical, malignant lym-  phoid cells of mycosis fungoides that exhibit cerebriform morphology  (inset).    Topical nitrogen mustard, topical carmustine, superpotent  topical corticosteroids, topical bexarotene (a synthetic reti-  noid), electron beam therapy, or photochemotherapy (PUVA  [8-methoxy-psoralen + ultraviolet A]) are effective in control-  ling mycosis fungoides during the early stages. Ultimately, the  topical forms of therapy fail, and aggressive chemotherapy is  necessary, particularly if there is visceral involvement. Newer  agents that may be added to the chemotherapy regimen  include monoclonal antibodies directed against the cell surface  marker CD52, certain retinoid compounds (including sys-  temic bexarotene), and specific interferon compounds.  Another new agent that may be used for advanced disease is  known as denileukin diftitox, which is derived from diphtheria  toxin and targets the interleukin-2 receptor on the neoplastic  lymphocytes. If Sézary syndrome develops, then extracorpo-  real photopheresis or chemotherapy is used as a treatment  modality. Extracorporeal photopheresis involves removing of  a small amount of the patient’s blood and separating the red  and white blood cells. The red blood cells are returned to the  patient immediately. The white blood cells are mixed with the    photoactive drug 8-methoxypsoralen, and are irradiated  outside the body (extracorporeal) with ultraviolet A. These  altered white cells are then infused back into the patient.  Many of the altered white cells undergo apoptosis, but the  procedure also may help generate an immunologic response  to the patient’s own abnormal lymphocytes.   Although mycosis fungoides is not considered to be  curable, the disease is usually slowly progressive. As a result,  there is a median survival time of 8 to 10 years, and patients  may die of causes unrelated to their lymphoma. Once the  disease progresses beyond the cutaneous involvement, the  course becomes much worse. The patient usually dies of  organ failure or sepsis within 1 year.    Burkitt lymphoma is a malignancy of B-lymphocyte origin  that represents an undifferentiated lymphoma. It was named  after the missionary doctor, Denis Burkitt, who first docu-  mented the process. In the original report, this type of lym-  phoma was described in young African children, and it seemed  to have a predilection for the jaws. Because it was seen fre-  quently in sub-Saharan Africa, the term African Burkitt  lymphoma has been applied to the disease. It is now known  to have increased prevalence in areas of the world where  malaria is also seen, such as northeastern Brazil and New  Guinea, and some investigators now refer to such tumors  arising in these areas of increased prevalence as endemic  Burkitt lymphoma. Examination of tumor tissue from the  African cases led to the discovery of Epstein-Barr virus (EBV)  by virologists in 1964. Although the mechanism is unknown,  the pathogenesis of endemic Burkitt lymphoma is undoubt-  edly related to EBV because more than 90% of the tumor cells  show expression of EBV nuclear antigen, and affected patients  have elevated antibody titers to EBV. Malarial infection  somehow plays a role in endemic Burkitt lymphoma as well,  because patients with the highest antibody titers to Plasmo-  dium falciparum, the causative organism of malaria, are most  likely to develop the malignancy. Characteristic cytogenetic  chromosomal translocations, which may also be responsible  for neoplastic transformation, have also been described.  Tumors with a similar histomorphology, commonly referred  to as sporadic or American Burkitt lymphoma, have been  observed in other countries, where the neoplasm is usually  first detected as an abdominal mass. EBV is much less fre-  quently identified in the sporadic tumors, however. Some  HIV-related lymphomas may also have the microscopic fea-  tures of Burkitt lymphoma, and these lesions have been des-  ignated immunodeficiency-associated Burkitt lymphoma.  Similar tumors have been reported in other immunodefi-  ciency settings, such as in patients who have received allografts  or have a congenital immunodeficiency syndrome.    As many as 50% to 70% of the cases of endemic Burkitt  lymphoma present in the jaws. The malignancy usually    e Fig. 13-36 Burkitt Lymphoma. This patient had documented  American Burkitt lymphoma involving the abdominal region. The retro-  molar swelling represents oral involvement with the malignancy.    affects children (peak prevalence, about 7 years of age) who  live in Central Africa, and a male predilection is usually  reported. The posterior segments of the jaws are more com-  monly affected, and the maxilla is involved more often than  the mandible (a 2:1 ratio). Sometimes all four quadrants  of the jaws show tumor involvement.   The tendency for jaw involvement seems to be age  related; nearly 90% of 3-year-old patients have jaw lesions,  in contrast to only 25% of patients older than age 15.  Sporadic Burkitt lymphoma tends to affect patients over a  greater age range than is noted for the African tumor.  Although the abdominal region is typically affected, jaw  lesions have been reported in sporadic Burkitt lymphoma  (Fig. 13-36).   ‘The growth of the tumor mass may produce facial swell-  ing and proptosis. Pain, tenderness, and paresthesia are  usually minimal, although marked tooth mobility may be  present because of the aggressive destruction of the alveolar  bone. Premature exfoliation of deciduous teeth and enlarge-  ment of the gingiva or alveolar process may also be seen.   The radiographic features are consistent with a malignant  process and include a radiolucent destruction of the bone  with ragged, ill-defined margins (Fig. 13-37). This process  may begin as several smaller sites, which eventually enlarge  and coalesce. Patchy loss of the lamina dura has been men-  tioned as an early sign of Burkitt lymphoma.    Burkitt lymphoma histopathologically represents an undif-  ferentiated, small, noncleaved B-cell lymphoma. The lesion  invades as broad sheets of tumor cells that exhibit round  nuclei with minimal cytoplasm. Each tumor nucleus often  has several prominent nucleoli, and numerous mitoses are  seen. Immunohistochemical studies using markers that  identify proliferating cells (e.g., Ki-67) typically indicate  that almost 100% of the tumor cells are in the process of  replicating. On viewing the lesion on low-power magnifica-  tion, a classic “starry-sky” pattern is often appreciated—a    @ Fig. 13-37 Burkitt Lymphoma. This 4-year-old child had evidence  of bone destruction with tooth mobility in all four quadrants of his jaws.  Note the patchy, ill-defined loss of bone. (Courtesy of Dr. Gregory  Anderson.)    phenomenon that is caused by the presence of macrophages  within the tumor tissue (Fig. 13-38). These macrophages  have abundant cytoplasm, which microscopically appears  less intensely stained in comparison with the surrounding  process. Thus these cells tend to stand out as “stars” set  against the “night sky” of deeply hyperchromatic neoplastic  lymphoid cells (Fig. 13-39).   Because the histopathologic features of Burkitt lym-  phoma can appear similar to some cases of diffuse large  B-cell lymphoma, standard of care now dictates that, in  addition to immunohistochemical studies, molecular  genetic analysis of the tumor tissue should be performed.  This distinction is important because these two malignan-  cies are treated differently. Burkitt lymphoma is character-  ized by one of several specific translocations, the most  common being t(8;14)(q24;q32), that results in overexpres-  sion of the oncogene c-myc, an event that presumably drives  the neoplastic proliferation.    @ Fig. 13-39 Burkitt Lymphoma. This high-power photomicrograph  demonstrates the undifferentiated, small, dark lesional cells with  numerous histiocytes.    Burkitt lymphoma is an aggressive malignancy that usually  results in the death of the patient within 4 to 6 months after  diagnosis if it is not treated. Treatment generally consists of  an intensive chemotherapeutic regimen, which emphasizes  the use of high doses of cyclophosphamide. More than 90%  of the patients respond to this treatment.   The prognosis for Burkitt lymphoma in the past was  poor, with a median survival time of only 10'/, months.  More recent trials with more intensive, multi-agent chemo-  therapeutic protocols have shown an 85% to 95% event-  free (no evidence of recurrence) survival rate 3 to 5 years  after treatment for patients with stage I or II disease. Even  for advanced stage (II and IV) Burkitt lymphoma, the  event-free survival has improved to 75% to 85%.    * EXTRANODAL NK/T-CELL LYMPHOMA,  NASAL-TYPE (ANGIOCENTRIC T-CELL  LYMPHOMA; MIDLINE LETHAL  GRANULOMA; IDIOPATHIC MIDLINE  DESTRUCTIVE DISEASE; POLYMORPHIC  RETICULOSIS; MIDLINE MALIGNANT  RETICULOSIS; ANGIOCENTRIC  IMMUNOPROLIFERATIVE LESION)    Extranodal NK/T-cell lymphoma, nasal-type is a rare  malignancy that is characterized clinically by aggressive,  non-relenting destruction of the midline structures of the  palate and nasal fossa. For many decades, the nature of this  process was controversial, a fact that can readily be appreci-  ated by the wide variety of terms by which it has been called.  In actuality, many of the cases reported as “midline lethal  granuloma” in the past represented a wide variety of immu-  nologic (e.g., Wegener granulomatosis) and infectious  (e.g., tertiary syphilis) diseases. The term midline lethal    granuloma should be used only as a descriptive designation  of a destructive midline condition, and thorough diagnostic  evaluation, including biopsy and culture, is necessary to  make a definitive diagnosis. Once the other causes of  midline destruction have been eliminated, in most cases this  disorder can be identified as a natural killer (NK)/T-cell  lymphoma, based on modern cytogenetic, immunologic,  and molecular studies. Epstein-Barr virus (EBV) is thought  to play a significant role in the pathogenesis of this malig-  nancy, and by the WHO criteria, iz situ evidence of EBV  in the lesional cells is necessary to make this diagnosis. The  difficulty in distinguishing among these destructive disor-  ders can be appreciated by the fact that lymphomatoid  granulomatosis, which had been considered part of this  T-cell lymphoma spectrum, is now known to be an EBV-  driven proliferation of B lymphocytes.   Even though extranodal NK/T-cell lymphoma often  does not have the classic histopathologic features of lym-  phoma microscopically, it behaves in a malignant fashion  and responds to the same treatments to which lymphomas  respond. For reasons that are unclear, this condition is seen  with greater frequency in Asian, Guatemalan, and Peruvian  populations.    Extranodal NK/T-cell lymphoma is typically observed in  adults, and a male predilection is noted in most case series.  The initial signs and symptoms are often localized to the  nasal region and include nasal stuffiness or epistaxis. Pain  may accompany the nasal symptoms. Swelling of the soft  palate or posterior hard palate may precede the formation  of a deep, necrotic ulceration, which usually occupies a  midline position. This ulceration enlarges and destroys the  palatal tissues, which typically creates an oronasal fistula  (Fig. 13-40). Secondary infection may complicate the  course of the disease, and life-threatening hemorrhage is a  potential problem in some instances.    Histopathologic examination of one of these lesions shows  a mixed infiltrate of a variety of inflammatory cells, often  arranged around blood vessels (angiocentric) (Fig. 13-41).  The lesional process appears to invade and destroy the  normal tissue in the area. Necrosis is often present in some  areas of the lesion, presumably secondary to infiltration of  the blood vessels by the tumor cells. Medium to large,  angular, lymphocytic cells with an atypical appearance are  usually identified as a component of the cellular infiltrate.  Immunohistochemical evaluation of this infiltrate shows  that the atypical cells mark with antibodies directed against  either NK-cell antigens (such as CD56) or T-lymphocyte  antigens (such as CD3). Probes for EBV-encoded RNA  (EBER) should label nearly all of the tumor cells as well.  Molecular genetic studies may show monoclonal gene rear-  rangements of the T-lymphocyte receptor, consistent with    ° Fig. 13-40 Extranodal NK/T-Cell Lymphoma, Nasal-Type. A, This 62-year-old man had a destruc-  tive palatal lesion that proved to be a T-cell lymphoma, and evaluation showed cervical lymph node  involvement as well. B, Resolution of the lesion 1 month later, after multiagent chemotherapy.    © Fig. 13-41 Extranodal NK/T-Cell Lymphoma, Nasal-Type. This  medium-power photomicrograph shows atypical lymphoid cells infil-  trating the wall and filling the lumen of a blood vessel. Such a pattern  is termed angiocentric (i.¢., around blood vessels).    a lymphoreticular malignancy, in those tumors that have  T-cell, rather than NK-cell, differentiation.    Without treatment, extranodal NK/T-cell lymphoma is a  relentlessly progressive, highly destructive process that ulti-  mately leads to the patient’s death by secondary infection,  massive hemorrhage, or infiltration of vital structures in the  area. Lesions that are localized usually respond to radiation  therapy, a feature that is similar to that of T-cell lymphomas  of other sites. Treatment with 40 to 50 Gy will appear to  control the disease, although dissemination of the lesion  develops in approximately 30% of these patients. Concur-  rent or sequential treatment with a multidrug chemothera-  peutic regimen is now recommended. Five-year survival  rates are usually reported to be in the range of 70% to 80%.  For patients with more disseminated disease, combination  chemotherapy is indicated, and a less favorable prognosis  can be expected, with 30% to 50% 5-year survival generally  reported.    Multiple myeloma is a relatively uncommon malignancy  of plasma cell origin that often appears to have a multicen-  tric origin within bone. The cause of the condition is  unknown, although sometimes a plasmacytoma (see page  565) may evolve into multiple myeloma. This disease makes  up about 1% of all malignancies and 10% to 15% of hema-  tologic malignancies. If metastatic disease is excluded, then  multiple myeloma accounts for nearly 50% of all malignan-  cies that involve the bone. Over 22,000 cases are diagnosed  annually in the United States.   The abnormal plasma cells that compose this tumor are  typically monoclonal. The abnormal cells probably arise  from a single malignant precursor that has undergone  uncontrolled mitotic division and has spread throughout  the body. Because the neoplasm develops from a single cell,  all of the daughter cells that comprise the lesional tissue  have the same genetic makeup and produce the same pro-  teins. These proteins are the immunoglobulin components  that the plasma cell would normally produce, although in  the case of this malignant tumor the immunoglobulins are  not normal or functional. The signs and symptoms of this  disease result from the uncontrolled proliferation of the  tumor cells and the uncontrolled manufacture of their  protein products.    Multiple myeloma is typically a disease of adults, with men  being affected slightly more often than women. The median  age at diagnosis is between 60 and 70 years, and it is rarely  diagnosed before age 40. For reasons that are not under-  stood, the disease occurs twice as frequently in blacks as  whites, making this the most common hematologic malig-  nancy among black persons in the United States.   Bone pain, particularly in the lumbar spine, is the most  characteristic presenting symptom. Some patients experi-  ence pathologic fractures caused by tumor destruction of    @ Fig. 13-42 Multiple Myeloma. Multiple myeloma affecting the  mandible. The disease produced several radiolucencies with ragged,  ill-defined margins. (Courtesy of Dr. Joseph Finelli.)    bone. They may also complain of fatigue as a consequence  of myelophthisic anemia. Petechial hemorrhages of the skin  and oral mucosa may be seen if platelet production has been  affected. Fever may be present as a result of neutropenia with  increased susceptibility to infection. Metastatic calcifications  may involve the soft tissues and are thought to be caused by  hypercalcemia secondary to tumor-related osteolysis.   Radiographically, multiple well-defined, punched-out  radiolucencies or ragged radiolucent lesions may be seen in  multiple myeloma (Fig. 13-42). These may be especially  evident on a skull film. Although any bone may be affected,  the jaws have been reported to be involved in as many as  30% of cases. The radiolucent areas of the bone contain the  abnormal plasma cell proliferations that characterize mul-  tiple myeloma.   Renal failure may be a presenting sign in these patients  because the kidneys become overburdened with the excess  circulating light chain proteins of the tumor cells. These  light chain products, which are found in the urine of 30%  to 50% of patients with multiple myeloma, are called Bence  Jones proteins, after the British physician who first  described them in detail.   Approximately 10% to 15% of patients with multiple  myeloma show deposition of amyloid (see page 766) in  various soft tissues of the body, and this may be the initial  manifestation of the disease. Amyloid deposits are due to  the accumulation of the abnormal light chain proteins. Sites  that are classically affected include the oral mucosa, particu-  larly the tongue. The tongue may show diffuse enlargement  and firmness or may have more of a nodular appearance.  Sometimes the nodules are ulcerated. Another area that is  commonly affected is the periorbital skin, with the amyloid  deposits appearing as waxy, firm, plaquelike lesions (see Fig.  17-7 on page 767).    Histopathologic examination of the lesional tissue in mul-  tiple myeloma shows diffuse, monotonous sheets of    @ Fig. 13-43 Multiple Myeloma. This high-power photomicrograph  reveals sheets of malignant plasma cells with eccentric nuclei and  stippled nuclear chromatin. Immunohistochemical studies (inset) show  a uniform reaction of the lesional cells for antibodies directed against  kappa light chains, indicating a monoclonal neoplastic proliferation.    neoplastic, variably differentiated, plasmacytoid cells that  invade and replace the normal host tissue (Fig. 13-43).  Mitotic activity may be seen with some frequency. The  monoclonality of the plasma cell population can be dem-  onstrated using antibodies directed against the lambda and  kappa light chain components of the immunoglobulin  molecule. In a neoplastic proliferation of plasma cells, vir-  tually all of the lesional cells will mark with only one of  these antibodies. In contrast, a reactive plasma cell infiltrate  will show a mixture of lambda- and kappa-producing  plasma cells. Occasionally, deposition of amyloid may be  observed in association with the neoplastic cells. Like other  types of amyloid, this material appears homogeneous,  eosinophilic, and relatively acellular. It stains metachro-  matically with crystal violet and shows an afhnity for  Congo red, demonstrating apple-green birefringence on  viewing with polarized light. A biopsy specimen of bone  marrow from a patient with multiple myeloma should  show at least 10% atypical plasma cells making up the  marrow cell population.   Although the histopathologic and radiographic findings  may strongly suggest a diagnosis of multiple myeloma,  screening of the serum or urine by protein electrophoresis  should be performed. If an abnormality is detected, then  this should be confirmed by protein immunoelectrophore-  sis, which is a more sensitive test, as an additional parameter  to establish the diagnosis. The serum and urine protein  immunoelectrophoresis should show the presence of  myeloma protein (M-protein). This represents the massive  overproduction of one abnormal immunoglobulin by the  neoplastic clone of plasma cells, thus this feature is termed  monoclonal gammopathy. This monoclonal protein con-  sists of two heavy chain polypeptides of the same immuno-  globulin (Ig) class (IgA, IgG, IgM, IgD, or IgE) and one of  two light chain polypeptides of the same class (kappa or    lambda). Occasionally, the neoplastic cells produce only the  light chain component.    The goals of treatment related to multiple myeloma include  not only controlling the malignancy but also making the  patient comfortable and prolonging the patient’s survival.  Initial attempts to control multiple myeloma generally  consist of chemotherapy. Several combinations of chemo-  therapeutic agents are available, including a corticosteroid  (usually dexamethasone) in addition to one or two other  drugs, such as an alkylating agent (melphalan or cyclophos-  phamide), an immune-modulating agent (thalidomide or  lenalidomide), a proteasome inhibitor (bortezomib), and/or  an anthracycline (doxorubicin). More aggressive chemo-  therapeutic regimens, as well as stem cell or bone marrow  transplantation (either autologous or allogeneic), may be  considered in otherwise healthy patients under the age of  55 to 65 years, but these individuals comprise a minority  of multiple myeloma patients. Radiation therapy is useful  only as palliative treatment for painful bone lesions. Any  one of several bisphosphonate medications (clodronate,  pamidronate, or zoledronic acid) can be prescribed to  reduce the possibility of myeloma-related fracture with its  attendant pain, but these medications do not increase sur-  vival. A small percentage of these patients may experience  the complication of medication-related osteonecrosis of the  jaws (see page 271).   While it is unlikely that multiple myeloma can be cured,  the prognosis varies considerably among affected individu-  als. A variety of factors play a role in predicting prognosis,  with younger patients tending to do better than older ones.  Patients with other systemic diseases have a worse prognosis,  as do patients who present with more widespread lesions.  The prognosis is dependent on certain chromosomal and  molecular genetic features, with hyperdiploid lesions being  more aggressive, as well as those with certain chromosomal  translocations. Multiple myeloma that does not respond  well to initial therapy also has a worse prognosis. Hematolo-  gists often categorize the tumor as being “standard risk,”  “intermediate risk,” or “high risk,” depending on these  various features. The treatment regimen will depend on the  patient’s risk category.   Patients who fall in the standard-risk category can expect  to have a median survival rate of 6 to 7 years following  diagnosis, whereas those who are high-risk can expect a  median survival of 2 to 3 years. These figures, while not  encouraging at first glance, are much improved compared  to just one or two decades ago, when a 10% 5-year survival  was typical.    The plasmacytoma is a unifocal, monoclonal, neoplastic  proliferation of plasma cells that usually arises within bone.  Infrequently, it is seen in soft tissue, in which case, the term    extramedullary plasmacytoma is used. Some investigators  believe that this lesion represents the least aggressive part of  a spectrum of plasma cell neoplasms that extends to mul-  tiple myeloma. Therefore, the plasmacytoma is important  because it may ultimately give rise to the more serious  problem of multiple myeloma.    The plasmacytoma usually is detected in an adult male, with  an average age at diagnosis of 55 years. The male-to-female  ratio is approximately 2:1. Most of the lesions present  centrally within a single bone, and the spine is the most  commonly involved site. About one-third of the cases are  reported in that location. The initial symptoms often relate  to swelling or bone pain; occasionally, however, this lesion  is detected on routine radiographic examination. The extra-  medullary plasmacytoma appears as a relatively nondescript,  well-circumscribed, nontender soft tissue mass. A slightly  stronger male predilection is seen with this lesion, approach-  ing a 3:1 male-to-female ratio. Approximately 25% of  extramedullary plasmacytomas develop in the head and  neck region, and such lesions have been reported in the  tonsils, the nasopharynx, the paranasal sinuses, the nose,  and the parotid gland.   Radiographically, the lesion may be seen as a well-  defined, unilocular radiolucency with no evidence of scle-  rotic borders or as a ragged radiolucency similar to the  appearance of multiple myeloma (Fig. 13-44). No other  lesions should be identifiable by a skeletal survey or careful  physical examination, however.    ° Fig. 13-44 Plasmacytoma. This computed tomography (CT) scan  depicts a solitary plasmacytoma involving the left maxillary sinus and  nasal cavity.    The histopathologic features of the plasmacytoma are iden-  tical to those of multiple myeloma. Sheets of plasma cells  show varying degrees of differentiation. Immunohisto-  chemical studies demonstrate that these plasma cells are  monoclonal. As many as 25% to 50% of these patients  also show a monoclonal gammopathy on evaluation  by serum protein immunoelectrophoresis, although the  amount of abnormal protein is much less than that seen  with multiple myeloma. Solitary plasmacytoma also differs  from multiple myeloma in that no evidence of plasma cell  infiltration should be seen by a random bone marrow  biopsy, and the patient should not show signs of anemia,  hypercalcemia, or renal failure. Immunohistochemically,  extramedullary plasmacytoma appears to differ from its  intrabony counterparts in that it shows a marked decrease  or lack of immunoreactivity for antibodies directed against  cyclin D1 and CD56.    Plasmacytomas are usually treated with radiation therapy,  and typically a dose of at least 40 Gy is delivered to the  tumor site. A few lesions have been surgically excised with  good results, although this is not the preferred treatment in  most instances. Unfortunately, when patients with plasma-  cytoma of bone are observed on a long-term basis, most will  eventually develop multiple myeloma. About 50% show  evidence of disseminated disease within 2 to 3 years.  However, one third of these patients will not have symp-  toms of multiple myeloma for as long as 10 years. Extra-  medullary plasmacytoma seems to have a much better  prognosis, with less than 30% of these patients showing  progression to multiple myeloma and 70% having a 10-year  disease-free period after treatment.   Jham BC, Binmadi NO, Scheper MA, et al: Follicular hyperplasia of  the palate: case report and literature review, / Cranio-Maxillofac  Surg 37:79-82, 2009.   Kolokotronis A, Dimitrakopoulos I, Asimaki A: Follicular lymphoid  hyperplasia of the palate: report of a case and review of the litera-  ture, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 96:172-  175, 2003.   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Dimopoulos MA, Kiamouris C, Moulopoulos LA: Solitary plasma-  cytoma of bone and extramedullary plasmacytoma, Hematol Oncol  Clin North Am 13:1249-1257, 1999.   Dores GM, Landgren O, McGlynn KA, et al: Plasmacytoma of bone,  extramedullary plasmacytoma, and multiple myeloma: incidence  and survival in the United States, 1992-2004, Br J Haematol  144:86-94, 2008.   Gonzalez J, Elizondo J, Trull JM, et al: Plasma-cell tumours of the  condyle, Br J Oral Maxillofac Surg 29:274-276, 1991.   Kremer M, Ott G, Nathrath M, et al: Primary extramedullary plas-  macytoma and multiple myeloma: phenotypic differences revealed  by immunohistochemical analysis, / Pathol 205:92-101, 2005.   Lesmes D, Laster Z: Plasmacytoma in the temporomandibular joint:  a case report, Br J Oral Maxillofac Surg 46:322-324, 2008.   Majumdar S, Raghavan U, Jones NS: Solitary plasmacytoma and  extramedullary plasmacytoma of the paranasal sinuses and soft  palate, 7 Laryngol Otol 116:962—965, 2002.   Rodriguez-Caballero B, Sanchez-Santolino S, Garcid-Montesinos-  Perea B: Mandibular solitary plasmacytoma of the jaw: a case  report, Med Oral Patol Oral Cir Bucal 16:e647-e650, 2011.   Rothfield RE, Johnson JT, Slavrides A: Extramedullary plasmacytoma  of the parotid, Head Neck 12:352-354, 1990.    Osteogenesis imperfecta comprises a heterogeneous group  of heritable disorders characterized by osteopenia (low  bone density) and bone fragility. This condition represents  one of the most common heritable bone diseases, with  a worldwide prevalence of approximately 6 to 7 per 100,000  population.   More than 90% of cases exhibit an autosomal dominant  inheritance pattern with mutations in one of two type I  collagen genes: COLIAI and COLJAZ2. In addition, there  are numerous other variants (mainly autosomal recessive)  caused by recently discovered mutations in genes related to  type I collagen processing, bone mineralization, and other  functions. Sporadic cases are possible as well.   Type I collagen is a major constituent of bone, dentin,  sclerae, ligaments, and skin; osteogenesis imperfecta may  affect any of these tissue types. Type I collagen is a triple  helical molecule composed of peptide chains encoded by  COLIAI and COLIA2. Defects in the complex process of  synthesis, posttranslational modification (including hydrox-  ylation, crosslinking, and terminal propeptide cleavage),  and chaperone-guided protein folding result in abnormal  type I collagen with low tensile strength. Consequently, the  bone is brittle; upon fracture, healing will occur but may  be associated with exuberant callus formation.   Classification of the various forms of osteogenesis imper-  fecta continues to evolve as molecular genetic discoveries  are made. Table 14-1 summarizes a proposed classification  scheme based on phenotypic and genetic findings.    Severity varies widely by disease type, and mutations in even  a single gene locus may produce extensive phenotypic varia-  tion. Disease characterization as mild, moderate, or severe  generally is based on the number of bone fractures, degree  of long bone and spine deformity, degree of growth impair-  ment, and age at which abnormalities initially become  evident. For example, osteogenesis imperfecta type I—the  mildest and most common form—is characterized by a  variable number of bone fractures, minimal bone deformity,    and essentially normal growth. Typically, fractures first  occur when the patient begins to walk and decrease in fre-  quency after puberty. In contrast, osteogenesis type II is the  most severe form, characterized by extreme bone fragility  and deformity. Most patients with this disease type die in  utero or shortly after birth; death often results from respira-  tory distress due to multiple rib fractures and a small thorax.   Additional clinical findings may include blue sclerae  (Fig. 14-1), hearing loss, and joint hyperextensibility or  contractures. The radiographic hallmarks include osteope-  nia, bowing deformity of the long bones, multiple fractures,  and an increased number of Wormian bones in the skull.  Wormian bones are small sutural bones arranged in a mosaic  pattern; they also can be seen in other processes, such as  cleidocranial dysplasia.   Dental alterations that appear clinically and radiographi-  cally identical to dentinogenesis imperfecta (see page 99)  may be evident—especially in osteogenesis imperfecta types  HI and IV. Both dentitions demonstrate blue, yellow, or  brown translucence (Fig. 14-2, A); however, this finding  may be less prominent in the permanent teeth. The underly-  ing dentinal defects often lead to severe attrition, resulting  in loss of vertical dimension and potential tooth loss. Radio-  graphs typically reveal premature pulpal obliteration,  although shell teeth rarely may be seen (see Fig. 14-2, B).  The tooth roots may appear narrow or corncob-shaped.  Despite exhibiting similar tooth alterations, osteogenesis  imperfecta and dentinogenesis imperfecta are distinct dis-  eases resulting from different mutations. Therefore, the  dental defects associated with the systemic disorder osteo-  genesis imperfecta should be designated opalescent teeth,  whereas the term dentinogenesis imperfecta should be reserved  for patients with alterations isolated to the teeth.   Craniofacial findings in osteogenesis imperfecta may  include triangular facies, frontal bossing, relative macro-  cephaly, a flattened vertex and skull base, and a prominent  occiput. In addition, there is an increased prevalence of  Class III malocclusion (caused by maxillary hypoplasia,  with or without mandibular hyperplasia), crossbite, and  open bite.   ‘There are a few reported families exhibiting generalized  bone fractures combined with diffuse radiolucent, radi-  opaque, or radiolucent-radiopaque lesions of the jaws    Classical types AD Mild phenotype, minimal bone deformity, bone fractures, normal COL1A1  or near normal stature, blue sclerae, joint laxity, hearing loss, (null allele*)  rarely opalescent teeth   ll AD Perinatal lethal, multiple fractures of ribs and long bones, COL1A1  respiratory distress, limb deformities, dark blue sclerae COL1A2   Ill AD Severely deforming, very short stature, frequent fractures, COL1A1  wheelchair-dependent at an early age, triangular facies, coxa COL1A2  vara,’ “popcorn calcifications” of femoral head, blue-gray  sclerae, often opalescent teeth, most patients die during  childhood secondary to complications of kyphoscoliosis   negative interosseous membrane calcification, radiopaque metaphyseal  bands at growth plates of long bones, hypertrophic calluses,  white sclerae, no opalescent teeth, hypodontia   Mineralization Vi AR Moderate to severe skeletal changes, early-onset fractures, SERPINF1   defects deficiency, “popcorn calcifications” of femoral head, coxa vara,  white or light gray sclerae, no opalescent teeth  VIII AR Severe to perinatal lethal, white sclerae, bowing of long bones, REPRE  Wormian bones, severe growth deficiency, bulbous metaphyses  IX AR Moderate to perinatal lethal, white or gray sclerae, opalescent PPIB  teeth possible   xl AR Moderate to severe phenotype, progressive kyphoscoliosis, joint FKBP10  hypermobility, grayish white sclerae, some cases associated  with Bruck syndrome | (Severe osteogenesis imperfecta and  congenital contractures), no opalescent teeth  C-propeptide Xll AR Severe phenotype, long bone deformity, kyphoscoliosis, joint BMP1  cleavage hypermobility, high bone mass, light blue sclerae, no  defect opalescent teeth    AD, Autosomal dominant; AR, autosomal recessive; BMP7, bone morphogenetic protein 1 gene; COL71A7, collagen, type 1, alpha 1 gene; COL1A2, collagen,  type 1, alpha 2 gene; FKBP10, FK506 binding protein 10 gene; PPIB, peptidylprolyl isomerase B gene; SERPINH7, serpin peptidase inhibitor gene.   *Null allele results in a reduced amount of normal type | collagen (and, thus, a mild phenotype).   *Coxa vara: Inward hip curvature caused by reduced angle between the femoral head and shaft.    (similar to florid cemento-osseous dysplasia or gigantiform  cementoma). However, it is unclear whether such cases  represent variants of osteogenesis imperfecta. Instead, they  may belong to a distinct category known as gnatho-diaphyseal  dysplasia (see page 602).    Diagnosis requires correlation of the clinical features, radio-  graphic and/or prenatal ultrasound findings, and family  history. For diagnostic confirmation, genetic testing is more  sensitive than electrophoresis for type I collagen secreted by    cultured dermal fibroblasts. Bone biopsy may be helpful in  select cases. Serum concentrations of vitamin D, calcium,  phosphorus, and alkaline phosphatase usually are normal,  although occasionally the latter may be slightly elevated.    Management of bone fractures and deformity may be dif  ficult. The mainstays of treatment are physiotherapy, reha-  bilitation, and orthopedic surgery. In addition, intravenous  (IV) bisphosphonates typically are administered to children  with moderate to severe disease; such therapy may decrease    pain, reduce fracture rates, and improve mobility. The  benefits of bisphosphonate therapy for adult or mild child-  hood disease and the long-term safety of bisphosphonate  therapy require further study. There is limited evidence  that recombinant growth hormone—alone or in combina-  tion with bisphosphonates—may increase growth rate in  some patients. Targeted therapies (e.g., bone morphoge-  netic protein modulators, receptor activator of nuclear  factor-kappa B ligand [RANKL] inhibitors), gene therapy,  and stem cell therapy hold some promise for the future but  remain in the early stages of development.   Treatment of the dentition is similar to that for dentino-  genesis imperfecta (see page 102). Successful implant place-  ment has been reported in a few cases, although the impact  of the altered bone on osseointegration is not well studied.  In patients with significant malocclusion, orthognathic  surgery and orthodontic treatment may be performed.  Alternatively, osteodistraction may be considered to reduce  the risk of atypical fractures from conventional orthogna-  thic procedures (e.g., Le Fort I osteotomy). Presurgical    ® Fig. 14-1 Osteogenesis Imperfecta. Blue sclera in a patient with  osteogenesis imperfecta.    ® Fig. 14-2 Osteogenesis Imperfecta. A, Opalescent dentin in a patient with osteogenesis imperfecta.    planning should take into account an increased risk for  bleeding disorders, cardiac malformations, and hyperther-  mia. Intubation may be difficult because of a short neck,  kyphoscoliosis, and fragility of the mandible and cervical  vertebrae. Also, patients previously treated with bisphos-  phonates may exhibit delayed healing after osteotomy.  ‘The prognosis varies by disease type. Patients with mild  disease exhibit a normal life span, whereas those with espe-  cially severe disease die im utero or in the perinatal period.    Osteopetrosis is a group of rare hereditary skeletal disorders  characterized by markedly increased bone density. This con-  dition results from a failure of osteoclast function or dif  ferentiation. Decreased osteoclastic bone resorption results  in sclerotic bone. The disease affects approximately 1 per  100,000 to 500,000 persons.   The underlying genetic abnormality is unknown in  about 30% of patients. Mutations discovered thus far  primarily cause defects in osteoclastic proteins necessary  for acidification of resorption lacunae, regulation of ionic  charge across the osteoclast cell membrane, and subsequent  resorption of the bone matrix. In some cases, mutations in  genes encoding the cell-surface receptor RANK (receptor  activator of nuclear factor-kappa B) or RANK ligand inter-  fere with osteoclastogenesis.   Although several disease subtypes have been identified,  there are three major clinical patterns:   1. Autosomal recessive infantile (“malignant”) type  2. Autosomal recessive intermediate type  3. Autosomal dominant adult (“benign”) type   Table 14-2 summarizes a classification system based on  phenotype and corresponding genetic defects. Disease  severity varies widely, potentially even among patients with  the same disease subtype.    B, Bite-wing radiograph of the same patient showing shell teeth with thin dentin and enamel of normal    Autosomal 1 Malignant neonatal or infantile TCIRG1 Proton pump subunit  recessive 2 Intermediate RANKL Ligand that binds RANK receptor to induce  (TNFSF1 1) osteoclastic differentiation  3 Intermediate CAI Enzyme that catalyzes a proton-releasing reaction  4 Malignant infantile CLCN7 Chloride channel  5 Malignant infantile OSTM1 Chloride channel function  6 Variable, often intermediate PLEKHM1 Vesicle trafficking and acidification  i Severe RANK Cell-surface receptor involved in osteoclastic  (TNFRSF1 1A) differentiation  Autosomal 1 Adult LRP5 Bone formation by osteoblasts*  dominant. 2 Adult CLCN7 Chloride channel    CAll, Carbonic anhydrase Il gene; CLCN7, chloride channel 7 gene; LRP5, low-density lipoprotein receptor-related protein gene; OSTM1, osteopetrosis-  associated transmembrane protein 1 gene; PLEKHM7, pleckstrin homology domain gene; RANK, receptor activator of nuclear factor-kappa B gene; RANKL,  receptor activator of nuclear factor-kappa B ligand gene; TC/RG7, T-cell immune regulator 1 gene; TNFRSF17A, tumor necrosis factor receptor superfamily,  member 11A gene (also known as RANK); TNFSF17, tumor necrosis factor ligand superfamily member 11 gene (also Known as RANKL).   *Interestingly, autosomal dominant osteopetrosis type 1 is caused by dysfunction of osteoblasts rather than osteoclasts; therefore, some authorities have reclas-  sified this condition as “high bone mass disease” and no longer consider it a subtype of osteopetrosis.    This severe form usually is diagnosed at birth or in early  infancy. Typical findings include a diffusely sclerotic skele-  ton, bone marrow failure, frequent fractures, cranial nerve  compression, and growth impairment.   The initial signs often are normocytic anemia with hepa-  tosplenomegaly resulting from compensatory extramedul-  lary hematopoiesis. Granulocytopenia causes increased  susceptibility to infection. Affected children often exhibit a  broad face, hypertelorism, snub nose, and frontal bossing.  Failure of resorption and remodeling of the skull produces  narrow skull foramina and cranial nerve compression,  which may result in blindness, deafness, and facial paralysis.  The bone is dense but prone to pathologic fracture. Osteo-  myelitis of the jaws is a frequent complication of tooth  extraction (Fig. 14-3).   Radiographically, there is a widespread increase in skel-  etal density with defects in metaphyseal remodeling. The  radiographic distinction between cortical and cancellous  bone is lost (Fig. 14-4). On dental radiographs, tooth roots  often are difficult to visualize because of the density of the  surrounding bone. In addition, failure of tooth eruption is  common.    Affected patients often are asymptomatic at birth but exhibit  fractures by the end of the first decade. Mild to moderate  anemia and extramedullary hematopoiesis are common, but  bone marrow failure is rare. Short stature, mandibular prog-  nathism, unerupted teeth, and osteomyelitis also have been  reported.    @ Fig. 14-3 Osteopetrosis. This 24-year-old white man has the  infantile form of osteopetrosis. He has mandibular osteomyelitis, and  multiple draining fistulae are present on his face. (Courtesy of Dr. Dan  Sarasin.)    This most common type usually is discovered in adolescence  or adulthood and exhibits less severe manifestations. Scle-  rosis mainly affects the axial skeleton, with relative sparing  of the long bones. Marrow failure is rare, and approximately  40% of affected patients are asymptomatic. Among symp-  tomatic patients, bone pain is frequent. In some cases,  cranial nerve compression is the major finding, whereas in  other cases frequent fractures predominate.   Occasionally, the diagnosis is discovered initially on  review of dental radiographs that reveal diffusely increased  radiopacity of the medullary bone. Mandibular involve-  ment may be associated with an increased risk for fracture  and osteomyelitis following tooth extraction.    © Fig. 14-4 Osteopetrosis. Extensive mandibular involvement is apparent in this radiograph of a  31-year-old woman. She received a diagnosis of osteopetrosis as a child. There is a history of multiple  fractures and osteomyelitis of the jaws. (Courtesy of Dr. Dan Sarasin.)    @ Fig. 14-5 Osteopetrosis. Low-power photomicrograph showing  sclerotic bone that is replacing the normal cancellous bone. The inset  shows a nodular pattern of the dense bone obliterating the marrow  spaces.    Other rare conditions causing widespread osteosclerosis  should be considered in the differential diagnosis. Such  diseases include autosomal dominant osteosclerosis (endos-  teal hyperostosis, Worth type), sclerosteosis, and van  Buchem disease.    Several patterns of abnormal endosteal bone formation have  been described. These include the following:  ¢ Tortuous lamellar trabeculae replacing the cancellous  portion of the bone  ¢ Globular amorphous bone deposition in the marrow  spaces (Fig. 14-5)  ¢ Osteophytic bone formation  Osteoclasts may be increased, decreased, or normal in  number; however, they do not appear to be functional  because Howship lacunae are not visible. In osteoclast-rich    disease forms, there may be a concurrent increase in the  number of activated osteoblasts.    Adult osteopetrosis usually is associated with long-term sur-  vival. Other than management of disease complications, no  specific treatment is indicated.   In contrast, the prognosis for untreated infantile osteo-  petrosis is poor, with most patients dying during the first  decade of life. For patients with certain disease subtypes,  bone marrow transplantation potentially may cure bone  marrow failure and may improve the phenotype. ‘The ratio-  nale for this procedure is based on the hematopoietic origin  of osteoclasts. However, finding an appropriate donor can  be difficult, and the procedure is associated with consider-  able risk. The search for alternative therapies is ongoing.  Interferon gamma-1b—often combined with calcitriol and  restricted calcium intake—has been shown to reduce bone  mass, decrease the prevalence of infections, and lower the  frequency of nerve compression. Other options include cor-  ticosteroids (to stimulate bone resorption and increase cir-  culating red blood cells and platelets) and erythropoietin.   Supportive measures include transfusions and antibiotic  therapy. Osteomyelitis of the jaws requires rapid interven-  tion to minimize osseous destruction; management typically  includes drainage and surgical débridement, bacterial culture  with sensitivity testing, and prolonged IV antibiotic therapy.  Hyperbaric oxygen may be a useful adjunct in recalcitrant  cases, and surgical reconstruction may be necessary.    Best known for its dental and clavicular abnormalities, clei-  docranial dysplasia is a generalized bone disorder caused    by mutations in the RUNX2 (or CBFA1) gene on chromo-  some 6p21. This gene normally guides osteoblastic differ-  entiation, chondrocyte maturation, and appropriate bone  formation. This condition initially was thought to involve  only membranous bones (e.g., clavicles, skull, and flat  bones), but it is now known to affect endochondral ossifica-  tion as well. Studies suggest that RUNX2 additionally plays  an important role in odontogenesis via participation in  odontoblast differentiation, enamel organ formation, and  dental lamina proliferation. Disruption of these functions  might explain the distinct dental anomalies associated with  this disorder. The estimated worldwide prevalence is  1:1,000,000. There is an autosomal dominant inheritance  pattern, although as many as 40% of cases may represent  spontaneous mutations. In addition, investigators have pro-  posed that an autosomal recessive form and germline mosa-  icism are possible.    The bone defects chiefly involve the clavicles and skull,  although various other skeletal anomalies may be present    (Table 14-3). The clavicles typically are hypoplastic or dis-  continuous, either unilaterally or bilaterally; in about 10%  of cases, the clavicles are completely absent. The patient’s  neck appears long, and the shoulders are narrow with  marked drooping. The clavicular abnormalities result in  unusual hypermobility, and many patients can approximate  their shoulders anteriorly (Fig. 14-6).   Additional features include short stature, enlarged skull,  brachycephaly, and pronounced frontal and parietal bossing.  Ocular hypertelorism and a broad-based nose with a  depressed bridge often are noted. On skull radiographs, the  sutures and fontanels show delayed closure or may remain  open throughout life. Secondary centers of ossification  appear in the suture lines, and many Wormian bones may  be seen. Abnormal development of the temporal bone and  eustachian tube may lead to conductive or sensorineural  hearing loss and recurrent ear infections.   The gnathic and dental manifestations are distinctive and  may lead to the initial diagnosis. Patients often have a  narrow, high-arched palate, and there is an increased preva-  lence of cleft palate. Over-retained deciduous teeth and  delay or complete failure of permanent tooth eruption are   Numerous unerupted/variably misshapen permanent and supernumerary teeth  Retention of primary dentition; delayed eruption of permanent dentition  Mandible: Prognathism, coarse trabeculation, narrow and parallel-sided rami,    Hypoplastic iliac wings  Widening of the pubic symphysis and sacroiliac joints  Delayed ossification of the pubic bone    characteristic features. There may be abnormal spacing in  the mandibular incisor area because of widening of the  alveolar bone. On dental radiographs, the most dramatic  finding is the presence of numerous unerupted permanent  and supernumerary teeth, often exhibiting distorted crown  and root shapes (Fig. 14-7). Dentigerous cysts occasionally  may arise in association with these unerupted teeth. The    © Fig. 14-6 Cleidocranial Dysplasia. Patient can almost approxi-  mate her shoulders in front of her chest. (Courtesy of Dr. William Bruce.)    number of supernumerary teeth can be impressive, with  some patients demonstrating more than 60 such teeth. In  addition, the mandible often demonstrates coarse trabecula-  tion with areas of increased density; narrow rami with  nearly parallel anterior and posterior borders; and slender,  pointed coronoid processes with a distal curvature. In some  cases, the mandibular symphysis remains patent. There may  be a thin zygomatic arch and small or absent maxillary  sinuses. Generalized hypoplasia of the paranasal sinuses may  predispose the patient to recurrent sinus infections.   As the patient ages, a short lower face height, acute  gonial angle, anterior inclination of the mandible, and man-  dibular prognathism develop. These changes may result  from inadequate vertical growth of the maxilla and hypo-  plastic alveolar ridge development caused by delay or lack  of permanent tooth eruption.    ‘The reason for failure of permanent tooth eruption in clei-  docranial dysplasia is poorly understood. Some microscopic  studies have reported a lack of secondary cementum in  unerupted teeth, although other studies have disputed this  finding. Additional proposed hypotheses include increased  jawbone density and insufficient alveolar bone resorption—  possibly resulting from altered periodontal ligament cells  with reduced capacity to induce osteoclastogenesis.    Most patients function well. An affected individual may be  unaware of the disease until a professional calls it to his or  her attention.    ® Fig. 14-7 Cleidocranial Dysplasia. Panoramic radiograph showing multiple unerupted teeth. (Cour-  tesy of Dr. John R. Cramer.)    supernumerary teeth followed by exposure and orthodontic  extrusion of permanent teeth. The extractions may be con-  ducted in stages (according to the extent of root develop-  ment of the unerupted permanent dentition) or in a single  procedure. If completed before adulthood, then such treat-  ment may prevent short lower face height and mandibular  prognathism. Orthognathic surgery also may be considered  after growth completion. Additional treatment options  include full-mouth extractions or autotransplantation of  selected impacted teeth followed by fabrication of an appro-  priate prosthesis. In a few reported cases, dental implants  have been placed successfully; however, further studies are  needed to assess whether the altered bone might compro-  mise osseointegration.    The focal osteoporotic marrow defect is an area of hema-  topoietic marrow that is sufficient in size to produce a  radiolucency. This entity does not represent a pathologic  process, but its radiographic features may be confused with  an intraosseous neoplasm or other pathosis. The pathogen-  esis is unknown, although the following theories have been  proposed:    Approximately 75% of cases occur in adult females, and  about 70% involve the posterior mandible, most often in  edentulous areas. The defect is typically asymptomatic and  nonexpansile. Most cases are detected incidentally during  radiographic examination, which shows a radiolucency  ranging from several millimeters to several centimeters in  diameter. The borders typically appear well-circumscribed  on panoramic radiographs; however, more detailed periapi-  cal radiographs may exhibit ill-defined borders and fine  central trabeculation (Fig. 14-8).    Microscopically, the defect contains cellular hematopoietic  and/or fatty marrow (Fig. 14-9). The associated bony tra-  beculae show no evidence of abnormal osteoblastic or osteo-  clastic activity.    The radiographic findings are often suggestive of the diag-  nosis but are nonspecific. Incisional biopsy, therefore, often  is necessary to establish the diagnosis. Once the diagnosis  is made, no further treatment is needed. The prognosis is    e Fig. 14-8 Focal Osteoporotic Marrow Defect. Fairly well-  circumscribed radiolucency with fine central trabeculation in the  extraction site of a mandibular molar. (Courtesy of Dr. R. Sidney Jones.)    ° Fig. 14-9 Focal Osteoporotic Marrow Defect. Photomicrograph  showing normal hematopoietic bone marrow.    excellent, and there appears to be no significant association  with anemia or other hematologic disorders.    Idiopathic osteosclerosis represents focally increased bone  density of unknown cause. It cannot be attributed to any  inflammatory, dysplastic, neoplastic, or systemic disorder.  Idiopathic osteosclerosis also has been termed dense bone  island, bone eburnation, bone whorl, bone scar, enostosis, and  focal periapical osteopetrosis. The following discussion focuses  on jaw lesions, although similar sclerotic areas may occur  in other bones.   In addition, similar radiopaque foci may develop in  the periapical areas of teeth with nonvital or inflamed  pulps; these lesions most likely represent a response to    inflammation. Such reactive foci are termed condensing  osteitis or focal chronic sclerosing osteomyelitis (see  page 134) and should not be designated idiopathic osteoscle-  rosis. Because past studies did not distinguish between idio-  pathic and inflammatory lesions, confusion in terminology  has resulted.    ‘The estimated prevalence is 5%, with some investigators  suggesting a slightly increased frequency in blacks and  Asians. Most authors report no significant sex predilection.  According to several long-term studies, most areas of idio-  pathic osteosclerosis arise in the late first or early second  decade. The lesion may remain static or slowly increase in  size. In almost all cases, once the patient reaches full matu-  rity, the sclerotic area stabilizes. In a smaller percentage, the  lesion diminishes or undergoes complete regression. The  peak prevalence is in the third decade, with peak bone mass  in the fourth decade.   Idiopathic osteosclerosis is invariably asymptomatic and  nonexpansile. The condition typically is detected inciden-  tally during routine radiographic examination. About 90%  of cases occur in the mandible, most often in the first molar  area. The second premolar and second molar areas also are  common sites. In most patients, only one sclerotic focus is  present, although some patients have two to four foci.  For patients with multiple lesions, the possibility of  multiple osteomas within the setting of Gardner syndrome  (see page 606) should be excluded.   Radiographically, idiopathic osteosclerosis typically  appears as a well-defined radiopacity, ranging from 0.2 cm  to 2.0 cm in diameter. The radiopacity may be round, ellipti-  cal, or irregular and does not exhibit a radiolucent rim. Most    lesions are uniformly radiopaque, although large lesions  occasionally demonstrate a nonhomogeneous appearance.  Most examples are associated with a root apex, but interra-  dicular lesions and lesions unrelated to teeth also are possible  (Fig. 14-10). Rarely, the sclerotic bone may surround an  impacted tooth. Root resorption and tooth movement have  been noted infrequently.    Microscopic examination shows dense lamellar bone with  scant fibrofatty marrow. Inflammatory cells are inconspicu-  ous or absent.    Usually a diagnosis of idiopathic osteosclerosis may be made  with confidence, based on history, clinical features, and  radiographic findings. Biopsy is warranted if there are symp-  toms or significant cortical expansion. Although idiopathic  osteosclerosis demonstrates radiographic and histopatho-  logic similarities with a compact osteoma (see page 605),  lack of cortical expansion and failure of continued growth  rule against a neoplastic process. Tooth vitality and the  absence of a deep restoration or caries help to distinguish  idiopathic osteosclerosis from condensing osteitis.    If the lesion is discovered during adolescence, periodic  radiographs appear prudent until the area stabilizes. After  that point, no treatment is indicated, because there is little  or no tendency for the lesions to progress or change in    ® Fig. 14-10 Idiopathic Osteosclerosis. A, An asymptomatic area of bone sclerosis is seen between  and apical to the roots of the first and second mandibular molars. B, No appreciable change can be seen  on this radiograph taken 10 years later. (Courtesy of Dr. Michael Quinn.)    ¢ MASSIVE OSTEOLYSIS (GORHAM  DISEASE; GORHAM-STOUT SYNDROME;  VANISHING BONE DISEASE; PHANTOM  BONE DISEASE; IDIOPATHIC OSTEOLYSIS)    Massive osteolysis is a rare disease characterized by spon-  taneous and usually progressive destruction of one or more  bones. The destroyed bone is replaced by a vascular prolif-  eration and, ultimately, dense fibrous tissue without bone  regeneration.   ‘The etiopathogenesis is unknown. There is no evidence  of underlying metabolic or endocrine imbalance. Proposed  pathogenetic mechanisms include the following:   In addition, some investigators hypothesize that slow  blood flow through dilated lesional vessels causes local  hypoxia and reduced pH, thereby favoring activation of  hydrolytic enzymes that contribute to bone resorption.    The disease occurs over a broad age range (1 month to 75  years), with a predilection for children and young adults.  About 50% of patients recall prior trauma, albeit often  trivial in nature. Reported sites of involvement include  bones of the extremities, maxillofacial region, trunk, and    pelvis. Multicentric involvement and extension into soft  tissue may be evident.   Gnathic lesions most often involve the mandible. Simul-  taneous involvement of both jaws and extension to contigu-  ous extragnathic sites are possible. Signs and symptoms  include mobile teeth, pain, malocclusion, deviation of the  mandible, and clinically obvious deformity. Potential  sequelae include pathologic fracture and obstructive sleep  apnea; the latter may occur secondary to posterior man-  dibular displacement after extensive osteolysis. Temporo-  mandibular joint (TMJ) involvement may be confused with  other conditions that can cause TMJ dysfunction.   The results of laboratory studies are generally within  normal limits. Radiographically, the earliest changes consist  of intramedullary radiolucent foci of varying size with indis-  tinct margins (Fig. 14-11). These foci coalesce, enlarge, and  extend to the cortical bone. Eventually, large portions of  bone disappear (Fig. 14-12). Loss of the lamina dura and    ° Fig. 14-11 Massive Osteolysis. Periapical radiograph showing an  ill-defined radiolucency associated with vital mandibular teeth. Note  the loss of lamina dura. (Courtesy of Dr. John R. Cramer.)    e Fig. 14-12 Massive Osteolysis. Panoramic radiograph of the same patient shown in Fig. 14-11,  showing extensive bone loss and a pathologic fracture of the left mandible. This destruction occurred  over an 8-month period. (Courtesy of Dr. John R. Cramer.)    ® Fig. 14-13 Massive Osteolysis. Biopsy specimen from the same  patient shown in Figs. 14-11 and 14-12. The loose, highly vascular  connective tissue shows a diffuse chronic inflammatory cell infiltrate.    thinning of the cortical plates often precede development  of obvious radiolucency. In some cases, the bone destruc-  tion may mimic periodontitis or periapical inflammatory  disease.    Microscopically, early lesions exhibit a nonspecific vascular  proliferation intermixed with fibrous connective tissue and  chronic inflammatory cells (Fig. 14-13). Blood vessels  and/or lymphatic vessels may be present, although current  evidence suggests the latter predominate. Immunohisto-  chemistry with the D2-40 antibody may be performed to  highlight lymphatic endothelium. The vascular channels are  thin-walled and may vary in size. Despite theories regarding  their potential pathogenetic role, osteoclasts may not be  evident in the adjacent bone. In later stages, there is fibrosis  without bone regeneration.    The clinical course of massive osteolysis is variable and  unpredictable. In most cases, bone destruction progresses  over months to a few years and results in complete loss  of the affected bone or bones. Some patients, however,  experience spontaneous arrest of the process without com-  plete loss of the affected bone. Uncommonly, death results  from respiratory compromise due to severe thoracic involve-  ment or from spinal cord compression due to vertebral  destruction.   Treatment is not particularly satisfactory. Maxillofacial  lesions most commonly are treated by surgical resection  and/or radiation therapy. However, particularly in young  patients, there are concerns regarding the potential for post-  irradiation sarcoma and radiation-induced developmental  defects. Surgical reconstruction may be complicated by  bone graft resorption and inadequate bone for fixation;  therefore, it is advisable to delay reconstruction until arrest  of the osteolytic disease phase.    Alternatively, some investigators have reported disease  stabilization with administration of bisphosphonates and/  or alpha-2b interferon, although additional studies are  needed. Current clinical trials are evaluating rapamycin  therapy. Unfortunately, limited or no improvement has  been reported with various other treatments, including  estrogens, magnesium, calcium, vitamin D, fluoride, calci-  tonin, cisplatin, actinomycin D, etoposide, and imatinib.  The effectiveness of any therapeutic intervention is difficult  to evaluate, because the disease is so rare and the condition  may arrest spontaneously in some patients.    Paget disease of bone is characterized by abnormal, anar-  chic resorption and deposition of bone, resulting in skeletal  distortion and weakening. It represents the second most  common metabolic bone disorder after osteoporosis and  primarily affects older adults of Anglo-Saxon ancestry. There  is marked variation in reported prevalence by geographic  region, with the highest rates in the United Kingdom. The  disease also frequently occurs in Australia, New Zealand,  Western and Southern Europe, and North America. In the  United States, the disease affects approximately 1% to 2%  of the general population. For reasons unclear, significant  declines in disease incidence and severity have been observed  in recent decades in many high-prevalence regions.   ‘The etiology is unknown, but both genetic and environ-  mental factors have been proposed. Approximately one-  third of patients have a first-degree relative with the disease.  In about 40% of familial cases and 8% of sporadic cases,  germline mutations in the sequestosome 1 gene (SQSTM1)  (also known as p62) have been identified. Patients with  SQSTM1 mutations tend to have more severe disease than  those without such mutations. SQSTM1 activates osteo-  clasts via the nuclear factor-kappa B (NF-KB) signaling  pathway. In addition, genomic studies have identified poly-  morphisms in several other genes that appear to confer  increased susceptibility to Paget disease.   ‘The possibility that Paget disease results from a slow virus  infection has received considerable attention but remains  controversial. Inclusion bodies resembling nucleocapsids  from a paramyxovirus have been detected in osteoclasts  from affected individuals; however, attempts to demonstrate  mRNA and proteins from paramyxoviruses in patient tissue  samples have yielded variable results. In animal models,  interactions between measles virus infection and SQSTM1  mutations can produce a pagetic phenotype. Additional  circumstantial evidence is provided by epidemiologic studies  that have noted an association with rural living, thereby  suggesting possible transmission of an infectious agent via  contact with farm animals.   Cell culture studies suggest that increased bone resorp-  tion in Paget disease may result from increased vitamin D  receptor binding affinity among osteoclasts. Also, increased    osteoclastogenesis may be caused by hyperresponsiveness  of osteoclast precursors to RANKL (receptor activator of  nuclear factor kappa B ligand) and decreased inhibition of  RANK signaling. Additionally, recent findings suggest that  Paget disease may be associated with dysregulation of  autophagy (a controlled protein degradation process) in  osteoclasts. Some studies suggest that underlying defects  may reside not only in osteoclasts but also in osteoblasts.    Paget disease of bone primarily affects older patients. Disease  frequency increases with age, and the mean age at diagnosis  has been increasing in many populations. The condition is  rare in patients younger than 40 years. Most studies report  a male predilection.   At diagnosis many patients are asymptomatic, although  up to 40% of patients initially present with bone pain.  Asymptomatic disease may be discovered incidentally when  radiographic examination or serum alkaline phosphatase  measurement is performed for unrelated reasons. Bone pain  may result from either increased bone turnover or secondary  complications (e.g., osteoarthritis, spinal stenosis, patho-  logic fracture, and pseudofracture).   The disease arises in one or more bones simultaneously,  and involvement typically remains restricted to these origi-  nal sites throughout the disease course. The pelvis, femur,  lumbar vertebrae, skull, and tibia are involved most com-  monly. Affected bones become thickened, enlarged, and  weakened, with an increased risk for fracture. Involvement  of weight-bearing bones often leads to bowing deformity,  resulting in a “simian (monkeylike) stance.” Skull involve-  ment generally causes a progressive increase in head circum-  ference. Deafness and visual impairment may result from  nerve compression or other mechanisms. Cardiovascular  complications, including arterial calcifications and high-  output congestive heart failure, also are possible.   Jaw involvement is present in about 17% of patients,  with a predilection for the maxilla (approximate 2:1  maxilla-to-mandible ratio). Maxillary disease produces  enlargement of the middle third of the face and may result  in nasal obstruction, enlarged turbinates, obliterated sinuses,  and deviated septum. In extreme cases, there is a lion-like  facial deformity (leontiasis ossea). The alveolar ridges tend  to remain symmetrical but become grossly enlarged. Alveo-  lar enlargement may cause spacing between teeth, and eden-  tulous patients may complain that their dentures feel  too tight.   Radiographically, in early disease stages, the affected  bone exhibits decreased radiodensity and a coarse trabecular  pattern. Particularly in the skull, large circumscribed radio-  lucencies may be present (osteoporosis circumscripta). In  later disease stages, patchy areas of bone sclerosis form and  tend to become confluent. The patchy sclerotic areas char-  acteristically exhibit a “cotton wool” appearance (Figs.  14-14 and 14-15). In addition, the teeth may demonstrate  generalized hypercementosis.    e Fig. 14-14 Paget Disease. Lateral skull film shows marked  enlargement of the cranium with new bone formation above the outer  table of the skull and a patchy, dense, “cotton wool” appearance.  (Courtesy of Dr. Reg Munden.)    Radiographic findings of Paget disease may resemble  those of cemento-osseous dysplasia (see page 596). Patients  with presumed cemento-osseous dysplasia who develop sig-  nificant jaw expansion should be evaluated further to rule  out Paget disease.    Microscopic examination shows uncontrolled resorption  and formation of bone. In the resorptive phase, numerous  hyperactive osteoclasts surround the bone trabeculae; these  osteoclasts tend to be enlarged with an increased number  of nuclei. In addition, highly vascular fibrous connective  tissue replaces the marrow. Behind the “leading edge” of  osteoclastic activity, there is a gradual conversion from pre-  dominantly osteoclastic to osteoblastic activity. The osteo-  blasts form osteoid rims around the bone trabeculae, and  the bone lacks an organized lamellar pattern. Basophilic  reversal lines, which indicate the junction between alternat-  ing bone resorption and formation, result in a characteristic  “jigsaw puzzle” or “mosaic” appearance (Fig. 14-16). In the    sclerotic phase, there are large masses of dense bone with  prominent reversal lines.    Diagnosis typically requires correlation of the clinical and  radiographic findings with laboratory test results. In addi-  tion, bone scintigraphy may help to determine the extent  of involvement. Histopathologic examination can be con-  firmatory but often is unnecessary for diagnosis.   Laboratory testing typically shows elevated serum alka-  line phosphatase levels with normal blood calcium and  phosphorus levels. Although serum bone-specific alkaline  phosphatase is considered the most sensitive marker of bone  formation, total serum alkaline phosphatase is more widely  available and, thus, typically used in routine clinical prac-  tice. When measuring total serum alkaline phosphatase,  liver enzymes also should be assessed in order to exclude  elevated alkaline phosphatase of hepatic origin.   In patients with limited disease extent, total serum alka-  line phosphatase may be within normal range. In such cases,  it may be helpful to assess specialized markers of bone for-  mation (e.g., serum N-terminal propeptide of type 1 col-  lagen) or resorption (e.g., urinary N-terminal telopeptide of  type 1 collagen).    Paget disease is chronic and slowly progressive but seldom  fatal. Asymptomatic patients with limited disease do not  require treatment. Patients with symptomatic or extensive  disease typically receive bisphosphonate therapy (i.e., single  infusion of zoledronic acid; oral risedronate or alendronate  administered daily for several months). Studies have dem-  onstrated that such treatment can reduce bone turnover,  induce normalization of alkaline phosphatase levels, decrease  bone pain, and improve quality of life. In particular, single-  infusion therapy with zoledronic acid is highly effective in  achieving sustained disease remission. However, there is    currently insufficient evidence regarding whether bisphos-  phonates may reduce the risk for long-term complications,  such as osteoarthritis, bone deformity, and deafness. Anal-  gesics and nonsteroidal antiinflammatory drugs (NSAIDs)  may be useful for controlling pain caused by secondary  osteoarthritis. Management of Paget disease also may  include orthotics, canes or other mobility devices, and  orthopedic surgery (e.g., hip or joint replacement). Prior to  orthopedic surgery involving an active disease site, bisphos-  phonates may be administered in order to reduce the risk  for excessive blood loss.   Potential dental complications include difficulties in  extracting teeth with hypercementosis and/or ankylosis;  extensive hemorrhage from oral surgical procedures per-  formed during the vascular lytic phase; and poor wound  healing with increased susceptibility to osteomyelitis during  the avascular sclerotic phase. Edentulous patients may  require new dentures periodically to compensate for pro-  gressive alveolar enlargement. Pagetic bone and a history  of bisphosphonate therapy generally are considered unfa-  vorable factors for osseointegration of dental implants,  although successful implant placement has been reported in  a few cases.   Malignant transformation of pagetic bone into osteosar-  coma or other sarcomas is a rare disease complication, with  an estimated lifetime risk of less than 1%. A sudden increase  in bone pain or swelling should raise suspicion of possible  underlying malignancy. Osteosarcoma in adults older than  40 years is quite uncommon in individuals who do not have  Paget disease. Most Paget-related osteosarcomas develop in  the pelvis and long bones of the extremities—the skull and  jaws are affected only rarely. Osteosarcoma in Paget disease  is very aggressive and associated with a poor prognosis.  Another rare complication of Paget disease is the develop-  ment of benign and malignant giant cell tumors (see  page 586), most often involving the craniofacial skeleton.    ¢ CENTRAL GIANT CELL  GRANULOMA (GIANT CELL LESION;  GIANT CELL TUMOR)    The central giant cell granuloma is an intraosseous lesion  of unknown etiology. There is much debate regarding  whether this entity represents a reactive process or a benign  neoplasm. In the past, it was hypothesized to represent a  reparative response to trauma-induced hemorrhage—hence,  its former designation giant cell reparative granuloma.  However, there is little evidence to support a reparative  response; therefore, most oral and maxillofacial pathologists  today prefer the term giant cell granuloma or the more non-  committal term giant cell lesion. In fact, some examples  demonstrate locally aggressive behavior similar to that of a  benign neoplasm. Recent genetic studies suggest that some  giant cell lesions of the jaws are monoclonal, and reciprocal  chromosomal translocations have been identified in two  cases involving the jaws thus far. Somatic mutation of    SH3BP2 has been detected in only one case; germline muta-  tions in this gene cause cherubism (see page 587).    Central giant cell granulomas of the jaws occur over a broad  age range (2 to 80 years), although more than 60% of cases  occur before age 30. There is a female predilection, and  approximately 70% of cases arise in the mandible. Lesions  are more common in the anterior portions of the jaws, and  mandibular lesions frequently cross the midline. Although  central giant cell granulomas also have been reported in  various extragnathic sites, it is uncertain whether such cases  actually represent true giant cell tumors (see next topic).   Based on the clinical and radiographic features, central  giant cell granulomas of the jaws may be divided into two  categories:   1. Nonaggressive lesions comprise most cases. They are  relatively small, exhibit few or no symptoms, grow  slowly, and do not cause cortical perforation or root  resorption. Such lesions typically are discovered during  routine radiographic examination or as a result of pain-  less jaw expansion.   2. Aggressive lesions are characterized by pain, rapid  growth, cortical perforation, root resorption, tooth dis-  placement, and/or paresthesia. Extension into soft tissue  and ulceration of the overlying mucosal surface also are  possible (Fig. 14-17). Compared to nonaggressive lesions,  aggressive lesions tend to be larger at diagnosis, develop  in somewhat younger patients, and exhibit a greater  recurrence potential.   Radiographically, the central giant cell granuloma  appears as a unilocular or multilocular radiolucency, with  well-delineated but generally non-corticated borders. The  lesion may vary from a 5 mm incidental radiographic  finding to a destructive lesion greater than 10 cm (Fig.  14-18). Small unilocular lesions may be confused with peri-  apical granulomas or cysts (Fig. 14-19), and multilocular  lesions may appear similar to ameloblastomas.    Areas histopathologically identical to central giant cell  granuloma have been noted in aneurysmal bone cysts (see  page 591) and intermixed with central odontogenic fibro-  mas (see page 676). Because giant cell granulomas are also  histopathologically identical to brown tumors, hyperpara-  thyroidism (see page 781) should be ruled out in all  instances. Furthermore, multifocal giant cell lesions of the  jaws may occur rarely as an isolated finding or in association  with certain heritable conditions, including cherubism (see  page 587), Noonan-like/multiple giant cell lesion syn-  drome, Ramon syndrome, Jaffe-Campanacci syndrome,  and neurofibromatosis type 1 (see page 495).    Microscopically, giant cell lesions of the jaws exhibit few to  many multinucleated giant cells in a background of ovoid  to spindle-shaped mononuclear stromal cells (Fig. 14-20).  Investigators have proposed that the spindle cell component  is the proliferating cell population and recruits monocyte-  macrophage precursors, inducing them to differentiate into    ° Fig. 14-18 Central Giant Cell Granuloma. Panoramic radiograph  showing a large, expansile radiolucent lesion in the anterior mandible.  (Courtesy of Dr. Gregory R. Erena.)    @ Fig. 14-17 Central Giant Cell Granuloma. A, A blue-purple, ulcerated mass is present on the  anterior alveolar ridge of this 4-year-old white boy. B, The occlusal radiograph shows a radiolucent lesion  with cortical expansion.    ® Fig. 14-19 Central Giant Cell Granuloma. The periapical radio-  graph shows a radiolucent area involving the apex of an endodontically  treated tooth. This was considered preoperatively to represent a peri-  apical granuloma or periapical cyst.    ° Fig. 14-20 Central Giant Cell Granuloma. Numerous multinucle-  ated giant cells within a background of plump proliferating mesenchy-  mal cells. Note extensive red blood cell extravasation.    osteoclastic giant cells by activation of the RANK/RANKL  signaling pathway. The giant cells may be aggregated focally  in the lesional tissue or may be present diffusely throughout  the lesion. These cells vary considerably in size and shape  from case to case. Some are small and irregular in shape  with only a few nuclei, whereas others are large and round  with 20 or more nuclei.   The stroma may be loosely arranged and edematous or  more cellular. Older lesions may show considerable stromal  fibrosis. Erythrocyte extravasation and hemosiderin deposi-  tion are often prominent. Focal bone or osteoid formation  may be present.    Correlation of the histopathologic features with clinical  behavior remains debatable. There are conflicting reports  regarding whether more aggressive giant cell lesions of the  jaws may be associated with an increased number of giant  cells, larger giant cells, a greater fractional surface area occu-  pied by giant cells, and a higher mitotic index. A few studies  suggest that increased vascular density, increased expression  of markers of angiogenesis, and increased expression of  matrix metalloproteinases might correlate with aggressive  clinical behavior.    Central giant cell granulomas of the jaws usually are treated  by thorough curettage. Recurrent lesions may require  further curettage (at times combined with peripheral ostec-  tomy) or ev bloc resection. Alternative treatments include  intralesional corticosteroid injections, subcutaneous or  nasal calcitonin, subcutaneous interferon alpha-2a, ima-  tinib, and bisphosphonates. Although further studies are  needed, nonsurgical approaches may be desirable when sur-  gical removal of a large tumor would result in significant  deformity.   Reported overall recurrence rates range from about 11%  to 49%, with most studies noting recurrence in approxi-  mately 20% of cases. Lesions with aggressive clinicoradio-  graphic features exhibit increased recurrence potential. In  spite of the potential for recurrence, the long-term progno-  sis is good.    The relationship between giant cell tumors of the extrag-  nathic skeleton and giant cell lesions of the jaws is uncertain  and controversial. Some authors regard these two groups of  lesions as distinct entities, based on differences in clinical  findings, histopathologic features, and biologic behavior.  Extragnathic giant cell tumors most often occur in the  epiphyses of long bones. Compared to giant cell lesions of  the jaws, extragnathic tumors are more likely to cause pain  and tend to be diagnosed in patients who are 1 to 2 decades  older on average, without a significant gender predilection.  Some microscopic studies suggest that extragnathic giant  cell tumors tend to exhibit more stromal cellularity and  larger, more uniformly distributed giant cells, with a greater  number of nuclei. Nonetheless, jaw lesions occasionally may  exhibit microscopic features that are indistinguishable from  typical extragnathic giant cell tumors (Fig. 14-21). In terms  of biologic behavior, compared to jaw lesions, extragnathic  lesions tend to be more aggressive, with higher recurrence  rates after curettage. Malignant degeneration has been  reported in 15% to 30% of true giant cell tumors, with  pulmonary metastases in about 3% of extragnathic cases.  On the other hand, others have suggested that giant cell  granulomas of the jaws and giant cell tumors of the    specimen was from an aggressive lesion that had destroyed most of  the maxilla.    extragnathic skeleton represent the same disease entity or  members of a single disease spectrum. One study has found  that the two groups of lesions are similar in most respects  when substratification by clinical behavior is taken into  account. These investigators hypothesize that giant cell  lesions tend to be diagnosed earlier in the jaws compared  to other sites simply because of frequent routine dental  examinations and readily apparent changes in facial  appearance.    Cherubism is a rare developmental jaw condition that can  be inherited as an autosomal dominant trait with variable  expressivity. However, many cases appear to represent de  novo mutations. Some investigators have reported a higher  penetrance in males than in females, but others have ques-  tioned this finding.   Most cases are caused by gain-of-function mutations in  the SH3BP2 gene on chromosome 4p16. These mutations  lead to enhanced stability of the 3BP2 adaptor protein and  consequent upregulation of various signal transduction  pathways. As a result, enhanced osteoclastogenesis and  hyperactive osteoclasts produce lytic bone lesions. In addi-  tion, mouse model studies demonstrating increased produc-  tion of tumor necrosis factor-alpha (TNF-) by macrophages  suggest a role for inflammation in this disorder. However,  it is unclear why the lesions in cherubism primarily affect  the jaws. Investigators hypothesize that rapid bone remodel-  ing during childhood tooth eruption and oral commensal  bacteria may play a role.   The name cherubism was applied to this condition  because the facial appearance is similar to that of the plump-  cheeked little angels (cherubs) depicted in Renaissance  paintings. Although cherubism also has been called familial  fibrous dysplasia, this term should be avoided because  cherubism has no relationship to fibrous dysplasia of bone  (see page 592).    @ Fig. 14-22 Cherubism. This young girl shows the typical cherubic  facies resulting from bilateral expansile mandibular and maxillary  lesions. (Courtesy of Dr. Roman Carlos.)    The condition usually first becomes evident at around 2 to  5 years of age, although in mild cases the diagnosis may not  be made until 10 to 12 years. The clinical alterations typi-  cally progress until puberty, then stabilize and slowly regress.   The plump, cherub-like cheeks result from painless,  bilaterally symmetric expansion of the posterior mandible  (Fig. 14-22). In early disease, cervical lymphadenopathy  also may contribute to the apparent fullness. In severe cases,  involvement of the inferior and/or lateral orbital walls may  tilt the eyeballs upward and retract the lower eyelid, thereby  exposing the sclera below the iris to produce an “eyes  upturned to heaven” appearance. Rare reports of unilateral  cherubism are difficult to accept as true examples of this  disease unless there is a strong family history or genetic  confirmation.   In the mandible, lesions frequently develop in the angles,  ascending rami, and coronoid processes, but the condyles  usually are spared. In severe cases, most of the mandible is  affected. Involvement of the maxillary tuberosities or entire  maxilla also is possible, and there may be a V-shaped palatal  arch. Extensive jaw involvement causes marked widening  and distortion of the alveolar ridges. In addition to aesthetic  compromise, the lesions may cause tooth displacement,  tooth mobility, failure of tooth eruption, impaired mastica-  tion, speech difficulties, upper airway obstruction, and  vision or hearing loss.    ® Fig. 14-23 Cherubism. A, Panoramic radiograph of a 7-year-old white boy. Bilateral multilocular  radiolucencies can be seen in the posterior mandible. B, Same patient 6 years later. The lesions in the  mandibular rami demonstrate significant resolution, but areas of involvement are still present in the body  of the mandible. (Courtesy of Dr. John R. Cramer.)    Radiographic examination typically shows bilateral, mul-  tilocular, expansile radiolucencies (Fig. 14-23). This radio-  graphic presentation is virtually diagnostic. Less commonly,  the lesions may appear unilocular. Additional findings may  include resorption of adjacent tooth roots and thinning or  perforation of the cortical bone. Although cherubism pri-  marily is limited to the craniofacial region, rib involvement  also has been reported in a few cases.   Biochemical findings typically are normal in patients  with cherubism. If laboratory results do not suggest hyper-  parathyroidism, then most children with bilaterally sym-  metric giant cell lesions of the jaws represent examples of  cherubism. However, multiple giant cell lesions may be  seen in association with other conditions, including Ramon  syndrome, Jaffe-Campanacci syndrome, Noonan-like/  multiple giant cell lesion syndrome, and neurofibromatosis    Because the microscopic findings of cherubism are similar  to those of isolated giant cell granulomas, correlation with  the clinical and radiographic findings is essential for    diagnosis. Microscopic examination shows vascular fibrous  tissue with variable numbers of multinucleated giant cells  and scattered hemorrhage. The giant cells tend to be small  and aggregated focally (Fig. 14-24). Like the giant cells in  central giant cell granulomas, the giant cells in cherubism  express markers suggestive of osteoclastic origin. The stroma  in cherubism tends to be more loosely arranged than that  in giant cell granulomas. In some cases, cherubism reveals  eosinophilic, cuff-like deposits surrounding small blood  vessels. This eosinophilic cuffing appears to be specific for  cherubism but is present in only a small proportion of cases.  In older, resolving lesions of cherubism, the tissue becomes  more fibrous, the number of giant cells decreases, and new  bone formation is seen.    In most instances, the lesions regress spontaneously after  puberty (see Fig. 14-23). By the fourth decade, the facial  features of most patients approach normalcy. Nevertheless,  the prognosis in any given case is difficult to predict, and  persistent facial deformity or continued disease progression  is possible.    @ Fig. 14-24 Cherubism. A, Photomicrograph showing scattered  giant cells within a background of cellular, hemorrhagic mesenchymal  tissue. B, High-power view showing perivascular eosinophilic cuffing.    Because most cases regress over time, a conservative treat-  ment approach generally is preferred. Mild cases may require  only observation. However, treatment typically is indicated  for patients with aggressive lesions, severe functional impair-  ment, or marked facial deformity. Surgical intervention may  consist of curettage, recontouring, partial resection, or com-  plete resection. The surgical defects may be filled with  autogenous cancellous bone and bone marrow grafts. Out-  comes of surgery performed during the active disease phase  are variable, with some investigators reporting excellent  results and others reporting aggressive regrowth. Generally,  it is preferable to delay surgery until the disease has become  quiescent, although severe aesthetic and functional compro-  mise may demand earlier intervention. Alternative treat-  ment with calcitonin or interferon has been reported  anecdotally but requires further study. Attempts to treat  cherubism with adalimumab (a TNF-o antagonist)—alone  or in combination with bisphosphonates—have yielded dis-  appointing results thus far. Radiation therapy is contraindi-  cated because of the risk for postirradiation sarcoma.   Dental management may include extraction or orth-  odontic extrusion of impacted teeth; orthodontics for mal-  occlusion; and prostheses for missing teeth. Placement of  dental implants and autotransplantation of teeth also have  been reported in a few cases.    ¢ SIMPLE BONE CYST (TRAUMATIC BONE  CYST; HEMORRHAGIC BONE CYST;  SOLITARY BONE CYST; IDIOPATHIC BONE  CAVITY; UNICAMERAL BONE CYST)    ‘The simple bone cyst is an empty or fluid-containing bone  cavity. Because this lesion lacks an epithelial lining, it rep-  resents a pseudocyst rather than a true cyst.   ‘The etiopathogenesis is uncertain, and several theories  have been proposed. In particular, the trauma-hemorrhage  theory has many advocates, as evidenced by the widely used  designation traumatic bone cyst. According to this theory,  trauma that is insufficient to cause a bone fracture results  in an intraosseous hematoma. If the hematoma does not  undergo organization and repair, it may liquefy and result  in a pseudocystic defect. However, a history of trauma to  the affected area and the presence of blood within the cavity  have been inconsistent findings. Other proposed theories  include venous obstruction, local disturbance in bone  growth, altered calcium metabolism, ischemic marrow  necrosis, aberrant synovial development, and degeneration  of a bone tumor or cyst.    Simple bone cysts have been reported in almost every bone  of the body. Most cases involve the metaphyses of long  bones, with a predilection for the proximal humerus and  proximal femur. In addition, solitary bone cysts may arise  in the jaws, with a marked mandibular predominance.  Although any area of the mandible may be involved, the  premolar, molar, and symphyseal regions are affected most  commonly. Most solitary bone cysts are diagnosed in young  patients, with a peak in the second decade. Jaw lesions  exhibit no significant gender bias, whereas extragnathic  lesions exhibit a male predilection. Unlike extragnathic  lesions, jaw lesions tend to lack clinical signs or symptoms;  thus, the true frequency of jaw lesions is undoubtedly  greater than the literature would suggest. About 20% of  patients, however, have a painless jaw swelling. Pain and  paresthesia are noted infrequently.   Simple bone cysts of the jaws often are discovered inci-  dentally during radiographic examination for some other  reason. The lesion typically appears as a well-delineated,  unilocular radiolucency. However, ill-defined and multi-  locular lesions also are possible. The defect may range from  1 to 10 cm in diameter. Occasionally, the radiolucent defect  shows domelike projections that scallop upward between  the roots of adjacent teeth. This feature is highly suggestive  but not diagnostic of a simple bone cyst (Figs. 14-25 and  14-26). In many cases, a cone-shaped outline (pointed at  one or both ends in the anterior-posterior direction) may  be noted, particularly when the lesion is large. Oval, irregu-  lar, or rounded borders are possible as well. The adjacent  teeth are generally vital. Root resorption, loss of lamina  dura, cortical expansion, and cortical thinning are evident    incisor teeth responded normally to vitality testing, and no restorations  are present.    ® Fig. 14-26 Simple Bone Cyst. Panoramic film showing a large  simple bone cyst of the mandible in a 12-year-old girl. The scalloping  superior aspect of the cyst between the roots of the teeth is highly  suggestive of, but not diagnostic for, a simple bone cyst. (Courtesy of  Dr. Lon Doles.)    in a minority of cases. Most lesions are solitary, but multifo-  cal involvement has been reported occasionally. Extensive  lesions involving a substantial portion of the mandibular  body and ascending ramus also are possible.   Simple bone cysts at times may arise in association with  cemento-osseous dysplasia (see page 596) and other fibro-  osseous proliferations. Such cases tend to occur in older  females.    There is never an epithelial lining. Instead, the walls of the  defect are lined by a thin band of vascular fibrous connective    ® Fig. 14-27 Simple Bone Cyst. Photomicrograph of the bony wall  of a simple bone cyst. A thin, vascular connective tissue membrane is  adjacent to the bone, and no epithelial lining is identified.    ® Fig. 14-28 Simple Bone Cyst. Loose vascular connective tissue  exhibiting areas of basophilic lacelike calcification in the wall of a simple  bone cyst.    tissue (Fig. 14-27) or a thickened myxofibromatous prolif  eration with reactive bone. In addition, there may be fibrin,  scattered erythrocytes, occasional giant cells, and lacelike  dystrophic calcifications (Fig. 14-28). Some authors also  have noted amorphous, cementum-like material, which  may represent osteoid. The bony surface next to the cavity  may show resorptive areas (Howship lacunae) indicative of  past osteoclastic activity.    The radiographic features of the simple bone cyst are not  entirely specific and may be confused with a wide variety  of odontogenic and nonodontogenic radiolucent jaw  lesions. Surgical exploration is necessary to establish the  diagnosis.   Typically, little to no tissue is obtained at the time of  surgery; therefore, the diagnosis is based primarily on the  clinical, radiographic, and intraoperative findings. In about  one-third of cases, there is an empty cavity with smooth,  shiny bony walls. In about two-thirds of cases, the cavity  contains small amounts of serosanguineous fluid. The    mandibular neurovascular bundle may be seen lying free in  the cavity.    Simple bone cysts of the long bones often are treated aggres-  sively, with various combinations of curettage, cryosurgery,  decompression, intralesional steroid injections, bone substi-  tute or autologous bone marrow injection, and bone graft-  ing. Reported recurrence rates are relatively high (mean  29%, range 12% to 48%).   In contrast, simple bone cysts of the jaws typically are  managed by surgical exploration and curettage. Intraopera-  tively, the bony walls of the cavity usually appear smooth  and shiny, although it is wise to curette them and submit  the small amount of tissue obtained for microscopic exami-  nation to rule out more serious diseases. Surgical explora-  tion with or without curettage usually induces bone  regeneration; normal radiographic findings typically are  evident 12 to 17 months after surgery. Periodic radiographic  examination should be performed until complete resolution  has been confirmed. Most studies report very low recurrence  rates (approximately 1% to 2%), although some report  recurrence rates as high as 27%. There is an increased poten-  tial for recurrence when there are multiple lesions or with  lesions arising in association with cemento-osseous dyspla-  sia. In addition, one study reported an increased recurrence  potential among jaw lesions exhibiting scalloped margins,  resorption of the lamina dura, nodular bone expansion, and  multiple cavities. Some authors suggest that the use of  packing materials may decrease recurrence, but further  studies are needed. Overall, the prognosis is excellent.    The aneurysmal bone cyst is an intraosseous accumulation  of variable-sized, blood-filled spaces surrounded by cellular  fibrous connective tissue and reactive bone. Because the  lesion lacks an epithelial lining, it represents a pseudocyst  rather than a true cyst. Aneurysmal bone cysts may be clas-  sified as primary (i.e., arising de novo) or secondary (i.e.,  arising in association with another bone lesion).   The etiopathogenesis is poorly understood. Traditionally,  the aneurysmal bone cyst has been considered a reactive  lesion. Many authors have theorized that a traumatic event,  vascular malformation, or neoplasm may disrupt normal  osseous hemodynamics, resulting in an enlarging area of  hemorrhage and osteolysis. Consistent with this hypothesis  is the observation that approximately 20% to 30% of aneu-  rysmal bone cysts form in association with other lesions.   In contrast, cytogenetic evidence suggests that primary  aneurysmal bone cysts may be neoplastic in nature. The  majority of primary lesions analyzed exhibit recurrent trans-  locations and consequent transcriptional upregulation of  the ubiquitin-specific protease 6 (USP6) (also known as  Tre-2 or TRE17) oncogene on chromosome 7p13. However,  USP6 translocations have been detected in very few    craniofacial lesions thus far. The underlying mechanisms by  which USP6 upregulation leads to tumor formation remain  poorly understood, although studies suggest that nuclear  factor-kappa B (NF-«B)-mediated induction of matrix  metalloproteinases and inflammatory cytokines may play  a role.    Aneurysmal bone cysts arise primarily in the long bones or  vertebrae of patients younger than 30 years. Only about 2%  of cases involve the jaws. Gnathic lesions mainly affect  young patients (peak in the second decade) but may occur  over a broad age range. Most authors report either no sig-  nificant sex predilection or a slight female predilection. The  lesions arise more often in the mandible than the maxilla,  and the vast majority arises in the posterior segments of the  jaws. Within the mandible, involvement of the ascending  ramus and posterior body is common, whereas involvement  of the condylar and coronoid processes is infrequent.   The most common clinical manifestation is a rapidly  enlarging swelling. Pain is a variable finding; paresthesia and  crepitus have been noted rarely. Malocclusion, mobility,  migration, or resorption of involved teeth may be present.  Maxillary lesions often bulge into the adjacent sinus and  occasionally cause nasal obstruction, nasal bleeding, propto-  sis, and diplopia.   Radiographic examination shows a unilocular or multi-  locular radiolucency, often with marked cortical expansion  and thinning (Fig. 14-29). The radiographic borders may  be well defined or poorly defined. There is frequently a bal-  looning or “blow-out” distention of the affected bone.  Uncommonly, small radiopaque foci, thought to be small  trabeculae of reactive bone, are noted within the  radiolucency.   Intraoperatively, intact periosteum and a thin shell of  bone typically are evident overlying the lesion, although  cortical perforation is possible. When the periosteum and    e Fig. 14-29 Aneurysmal Bone Cyst. A large radiolucent lesion  involves most of the ascending ramus in a 5-year-old white boy. (Cour-  tesy of Dr. Samuel McKenna.)    @ Fig. 14-30 Aneurysmal Bone Cyst. Photomicrograph showing a  blood-filled space surrounded by fibroblastic connective tissue. Scat-  tered multinucleated giant cells are seen adjacent to the vascular  space.    Microscopically, the aneurysmal bone cyst is characterized  by blood-filled spaces of varying size. These blood-filled  spaces lack an endothelial or epithelial lining (Fig. 14-30).  The surrounding cellular fibroblastic tissue contains multi-  nucleated giant cells, osteoid, and woven bone. Similar to  the multinucleated giant cells in giant cell granulomas, the  multinucleated giant cells in aneurysmal bone cysts exhibit  an osteoclastic phenotype, as evidenced by immunohisto-  chemical and in situ hybridization studies. Osteoid deposits  may appear linear, nodular, or lacelike. As noted earlier,  aneurysmal bone cysts may be associated with other patho-  ses, most commonly fibro-osseous lesions or giant cell  granulomas.    Aneurysmal bone cysts of the jaws usually are treated by  curettage or enucleation, sometimes supplemented with  cryosurgery. En bloc resection is reserved for extensive or  recurrent lesions. Preoperative embolization may be consid-  ered to control bleeding but often is unnecessary, because  most gnathic lesions exhibit low-flow vascularity. Typically,  the surgical defect heals within 6 months to 1 year and  does not necessitate bone grafting. Irradiation generally is  contraindicated.   Reported recurrence rates range from 8% to 70%.  According to one comprehensive review of the literature,  approximately 13% of reported jaw lesions have recurred  within 2 years. Most reported recurrences actually represent  persistence after incomplete removal. Occasionally, recur-  rence also may be related to incomplete removal of a coex-  isting lesion, such as an ossifying fibroma or osteoblastoma.  Overall, despite recurrences, the long-term prognosis is  favorable.    Fibro-osseous lesions are a diverse group of processes that  are characterized by replacement of normal bone by fibrous  tissue containing a newly formed mineralized product. The  term fibro-osseous lesion is descriptive and does not consti-  tute a specific diagnosis. Lesions belonging to this category  may be developmental (hamartomatous), reactive, dysplas-  tic, or neoplastic.   Fibro-osseous lesions of the jaws include the following:  e Fibrous dysplasia  ¢ Cemento-osseous dysplasia   Although these conditions differ in etiology, they may  exhibit very similar histopathologic features. Therefore, cor-  relation of the histopathologic findings with the clinical and  radiographic features typically is essential for establishing a  specific diagnosis. (However, in some cases of cemento-  osseous dysplasia, a presumptive diagnosis may be made  based on the clinical and radiographic findings.) A specific  diagnosis is critical because the treatment, biologic behavior,  and prognosis of these pathoses vary greatly. Some fibro-  osseous lesions only require monitoring, whereas others  necessitate surgical recontouring or complete removal.    Fibrous dysplasia is a developmental tumorlike condition,  characterized by replacement of normal bone by a prolifera-  tion of cellular fibrous connective tissue with irregular bony  trabeculae. This sporadic condition results from postzy-  gotic, activating mutations in the GNAS gene, which  encodes the alpha subunit of a stimulatory G protein. Such  mutations have not been detected in ossifying fibroma or  cemento-osseous dysplasia.   Clinically, fibrous dysplasia may involve one bone or  multiple bones; in some cases, involvement of multiple  bones may occur in conjunction with cutaneous and endo-  crine abnormalities. The extent of disease depends on when  the GNAS mutation occurs. During early embryonic devel-  opment, mutation of a pluripotent stem cell can cause  abnormalities in multiple cell types, including osteoblasts,  melanocytes, and endocrine cells. In contrast, if the muta-  tion occurs in a skeletal progenitor cell in a later stage of  embryonic development, then only osteoblasts will be  affected. Alternatively, if the mutation occurs during post-  natal life, then osteoblasts in only a single bone will be  affected. Furthermore, the parental origin of the mutated  GNAS allele may affect the phenotype, because in certain  cell types (such as pituitary somatotrophs) genomic imprint-  ing results in expression of only the maternal allele.   Constitutive activation of G-protein signaling impairs  osteoblastic differentiation in skeletal progenitor cells,    stimulates melanin production in melanocytes, and causes  hyperplasia and hyperfunction of various endocrine  cell types. In addition, mutated osteoblasts overexpress  interleukin (IL)-6, which stimulates osteoclastic activity and  may contribute to bone lesion expansion.    About 70% to 85% of patients with fibrous dysplasia have  disease limited to a single bone (monostotic fibrous dys-  plasia). Monostotic fibrous dysplasia is diagnosed most  often during the second and third decades of life. Males and  females are affected with about equal frequency. Commonly  involved sites include the craniofacial bones, ribs, femur,  and tibia.   Among cases involving the jaws, the maxilla is affected  more often than the mandible. There is a predilection for  the posterior region. Although mandibular lesions are truly  monostotic, maxillary lesions often extend to involve adja-  cent bones (e.g., zygoma, sphenoid, ethmoid, frontal bone,  temporal bone, occiput)—in which case the term cranio-  facial fibrous dysplasia is appropriate. Painless, unilateral  swelling is the most common clinical finding (Fig. 14-31).  Growth is generally slow, and it is common for the patient  to be aware of the condition for several years before seeking  professional evaluation. Occasionally, however, the growth  may be fairly rapid. Adjacent teeth may be displaced by the  bony mass but usually remain firm.   The classic radiographic finding is a fine “ground-glass”  opacification with poorly defined margins (Figs. 14-32  through 14-34). However, some lesions may appear radio-  lucent or mixed radiolucent-radiopaque. Mandibular lesions  often exhibit buccolingual expansion and bulging of the  inferior border. There may be superior displacement of the  inferior alveolar canal. Periapical radiographs of the adjacent  dentition may demonstrate narrowing of the periodontal  ligament space and an ill-defined lamina dura that blends    with the abnormal bone. Maxillary lesions often cause supe-  rior displacement of the sinus floor and obliteration of the  antrum. In addition, extensive skull involvement may be  evident (Fig. 14-35). Bone scintigraphy may aid in deter-  mining the extent of involvement and ruling out polyostotic  disease.    A minority of patients with fibrous dysplasia exhibits  involvement of two or more bones (polyostotic fibrous  dysplasia). Most patients with polyostotic disease are diag-  nosed before 10 years of age, and there is a female predilec-  tion. The number of involved bones varies from a few to  75% of the entire skeleton.   Presenting signs and symptoms typically are related to  long bone involvement and include pain, pathologic frac-  ture, limping, leg length discrepancy, and bowing defor-  mity. Radiographic examination may reveal malformation    @ Fig. 14-31 Fibrous Dysplasia. Expansile mass of the left maxilla  in a 45-year-old woman. This lesion was known to have been present  for at least 20 years.    @ Fig. 14-32 Fibrous Dysplasia. Panoramic radiograph of the patient shown in Fig. 14-31. A diffuse  “ground-glass” radiopacity is evident. (Courtesy of Dr. Richard Brock.)    ° Fig. 14-34 Fibrous Dysplasia. Occlusal radiograph showing local-  ized expansion of the mandible and the “ground-glass” radiographic  appearance. The margins of the lesion are not well defined and blend  into the adjacent bone. (From Waldron CA, Giansanti JS: Benign fibro-  osseous lesions of the jaws: a clinical-radiologic-histologic review of  65 cases. |. Fibrous dysplasia of the jaws, Oral Surg Oral Med Oral  Pathol 35:190-201, 1973.)    ® Fig. 14-35 Fibrous Dysplasia. Computed tomography (CT) image  showing extensive involvement of the maxilla and skull.    of the proximal femur (known as coxa vara, shepherd’s crook  deformity, or hockey stick deformity). Involvement of the skull  and jaws may result in facial asymmetry (Fig. 14-36). Cra-  niofacial involvement may cause vision changes, hearing  impairment, sinonasal congestion, and airway obstruction.  Hypophosphatemia caused by renal phosphate wasting is a  fairly common finding, which appears to be related to the  release of fibroblast growth factor 23 (FGF23) by the  affected bones.   A small subset of patients may exhibit polyostotic fibrous  dysplasia in association with the following syndromes:  ¢ Jaffe-Lichtenstein syndrome, characterized by polyos-   ¢ McCune-Albright syndrome, characterized by polyos-  totic fibrous dysplasia, café au lait pigmentation, and  multiple endocrinopathies   ¢ Mazabraud syndrome, characterized by fibrous dyspla-  sia and intramuscular myxomas   The café au lait pigmentation may be congenital and  consists of well-defined, tan macules. The macules are gen-  erally unilateral and most commonly affect the skin,  although oral mucosal involvement also is possible. The  margins of the café au lait spots are typically very irregular,  resembling a map of the coastline of Maine (Fig. 14-37). In  contrast, the café au lait spots of neurofibromatosis (see page  495) tend to exhibit smooth borders (like the coast of  California).   In McCune-Albright syndrome, the most common  endocrine abnormality is sexual precocity, particularly in  females. Menstrual bleeding, breast development, and pubic  hair may be apparent within the first few months or years  of life. Other possible endocrinopathies include hyperthy-  roidism, hyperparathyroidism, hypercortisolism, and excess  growth hormone. In addition, in one study of craniofacial  fibrous dysplasia mainly occurring in McCune-Albright  syndrome, investigators have reported various dental anom-  alies, including tooth displacement, oligodontia, enamel  hypoplasia, enamel hypomineralization, taurodontism, and  retained deciduous teeth.    Microscopic examination shows irregularly shaped trabecu-  lae of immature (woven) bone in a cellular fibrous stroma  (Fig. 14-38). At the periphery, the lesional bone fuses with  normal bone, without a capsule or line of demarcation. The  abnormal bony trabeculae tend to be thin and disconnected,  with curvilinear shapes likened to Chinese characters.  Osteoblastic rimming is usually absent or minimal, and  peritrabecular clefting (artifactual retraction of the stroma  from the bony trabeculae) is common. In addition, tiny  calcified spherules rarely may be seen but are never numer-  ous. In later stages, the woven bone is replaced by lamellar  bone with roughly parallel trabeculae (Fig. 14-39). The  rather monotonous pattern of calcification in fibrous dys-  plasia differs from the more haphazard mixture of woven    ® Fig. 14-36 Polyostotic Fibrous Dysplasia. Jaffe-Lichtenstein syndrome. A, Young man exhibiting  enlargement of the right maxilla and mandible. B, Intraoral photograph showing unilateral maxillary expan-  sion. C, Panoramic radiograph showing ill-defined lesions of the right side of both jaws.    @ Fig. 14-37 Polyostotic Fibrous Dysplasia. Jaffe-Lichtenstein  syndrome. Café au lait pigmentation of the abdomen. This is the same  patient as shown in Fig. 14-36.    bone, lamellar bone, and spheroid particles characteristic of  ossifying fibroma and cemento-osseous dysplasia.   Fibrous dysplasia may appear more sclerotic in the jaw  and skull than other sites. Microscopic variations include a  pagetoid pattern (characterized by thick, interconnected  bone trabeculae) and a hypercellular pattern (characterized    by parallel bone trabeculae with numerous osteocytes and  polarized osteoblastic rimming). Secondary aneurysmal  bone cyst formation has been reported as well.   Genetic testing for GNAS mutations can be performed  on lesional tissue or, possibly, peripheral blood samples.  Such testing may be helpful when there is diagnostic uncer-  tainty, but it exhibits low sensitivity and is not performed  routinely.    Fibrous dysplasia tends to stabilize upon skeletal matura-  tion, and spontaneous regression even has been reported in  a few cases. Therefore, conservative management is pre-  ferred. Some lesions, nevertheless, exhibit continued growth  into adulthood. The risk for severe deformity and com-  plications is particularly elevated among patients with  widespread polyostotic fibrous dysplasia—especially in the  setting of McCune-Albright syndrome with uncontrolled  growth hormone excess.   Patients with minimal cosmetic and functional distur-  bances may not require surgical treatment. For young  patients with significant problems due to large or extensive  lesions, surgical contouring, shaving, or other debulking    woven bone in a fibrous stroma. B, Medium-power view showing  peripheral osteoid without osteoblastic rimming.    procedures may be performed. However, subsequent  regrowth may require additional surgery. Approximately  20% to 50% of patients show some regrowth after surgical  debulking, and the risk for regrowth is greater among  younger than older patients. Therefore, if possible, many  authorities prefer to delay surgery until the disease is quies-  cent. Some investigators have proposed that serum alkaline  phosphatase levels after incomplete surgical removal may be  predictive of disease progression, although validation studies  are needed.   Alternatively, complete surgical removal may be consid-  ered in some cases, such as monostotic lesions, very aggres-  sive lesions, or lesions refractory to repeated debulking.  Combined orthodontic treatment and orthognathic surgery  may be performed to correct malocclusion. Successful  placement of dental implants has been reported in a few  cases, but additional studies are needed. Several reports  suggest that bisphosphonates (e.g., IV pamidronate, oral  alendronate) may help to relieve bone pain in fibrous dys-  plasia. However, well-designed studies are needed to confirm  these findings, to assess the potential for inducing disease  stabilization, and to evaluate the long-term safety of such  treatment in young patients. Radiation therapy is contrain-  dicated because of the risk for postirradiation bone sarcoma.   Transformation into malignancy, usually an osteosar-  coma, is estimated to occur in less than 1% of patients    e Fig. 14-39 Mature Fibrous Dysplasia. A, This long-standing  lesion shows separate, broad trabeculae of bone within fibrous con-  nective tissue. B, Note the lamellar maturation of the bone.    with fibrous dysplasia. The risk for sarcomatous transforma-  tion is greatest among those with a history of radiation  therapy, McCune-Albright syndrome, or Mazabraud syn-  drome. Rapid lesion growth, sudden onset of pain,  neurosensory changes, or marked changes in radiographic  appearance should alert the clinician to rule out malignant  transformation.    Cemento-osseous dysplasia occurs in the tooth-bearing  areas of the jaws and is probably the most common  fibro-osseous lesion encountered in clinical practice.  Because the histopathologic features share many similarities  with fibrous dysplasia and ossifying fibroma, correct  diagnosis can be problematic but is critical for appropriate  management.   Some investigators have suggested that cemento-osseous  dysplasia originates from the periodontal ligament, because  of microscopic similarity and lesion proximity to this struc-  ture. Others believe this condition represents a defect in  extraligamentary bone remodeling that may be triggered  by local injury or, possibly, an underlying hormonal  imbalance.    Based on clinical and radiographic features, cemento-  osseous dysplasia includes the following variants: (1) focal,    Focal cemento-osseous dysplasia involves a single site.  Before the concept of focal cemento-osseous dysplasia was  clarified in the mid-1990s, most cases were misdiagnosed  as a variant of ossifying fibroma.   About 90% of cases of focal cemento-osseous dysplasia  occur in females, with an approximate mean age of 41 years  and a predilection for the third to sixth decades. The lesion  has been reported across ethnic groups—most often Ameri-  can blacks followed by East Asians and whites. In contrast  to the periapical and florid variants, the focal variant seems  to affect a greater proportion of whites, although this  finding may be due to study population bias.   Focal cemento-osseous dysplasia most commonly involves  the posterior mandible. The disease typically is asymptom-  atic and is detected incidentally by radiographic examina-  tion. Most lesions are smaller than 1.5 cm in diameter.   Radiographically, the lesion varies from completely  radiolucent to densely radiopaque with a thin peripheral  radiolucent rim. Most commonly, however, there is a  mixed radiolucent and radiopaque pattern (Fig. 14-40). The  borders tend to be well defined but slightly irregular. The  lesions typically occur around tooth apices or in extraction  sites. A focal lesion occasionally may represent an early stage  in the transition to multifocal involvement, especially in  black females.    involves the periapical region of the anterior mandible. Soli-  tary lesions may occur, but multiple foci typically are    present. There is a marked female predilection (female-to-  male ratio ranging from 10:1 to 14:1), and approximately  70% of cases affect blacks. Most patients are diagnosed  initially between 30 and 50 years of age, with the diagnosis  almost never made in individuals younger than 20 years.  The associated teeth are usually vital and seldom have  restorations.   Periapical cemento-osseous dysplasia is an asymptomatic  condition that often is discovered when radiographs are  taken for other purposes. Early lesions appear as circum-  scribed periapical radiolucencies, similar to periapical gran-  ulomas or periapical cysts (Fig. 14-41). Adjacent lesions  may fuse to form a linear radiolucency that envelops the    s Saale BIS FI : Fie, |  @ Fig. 14-41 Periapical Cemento-Osseous Dysplasia. Periapical  radiograph showing multiple radiolucent lesions at the apices of the  anterior mandibular teeth. (Courtesy of Dr. Aaron Carner.)    ® Fig. 14-40 Focal Cemento-Osseous Dysplasia. A, A radiolucent area involves the edentulous first  molar area and the apical area of the second molar. B, Radiograph of the same patient taken 9 years  later showing a mixed radiolucent and radiopaque pattern.    apices of several teeth (Fig. 14-42). Over time, the lesions  tend to “mature” and become mixed radiolucent-radiopaque  (Fig. 14-43). In the end stage, the lesions appear as circum-  scribed, dense radiopacities surrounded by narrow radiolu-  cent rims. The periodontal ligament space usually appears  intact, and fusion to the tooth is rare. Most lesions are  nonexpansile with self-limiting growth; individual lesions  seldom exceed 1.0 cm in diameter.    Florid cemento-osseous dysplasia exhibits multifocal  involvement not limited to the anterior mandible. Although  many cases affect only the posterior portions of the  jaws, synchronous involvement of the anterior mandible  may be observed as well (Fig. 14-44). Like the periapical  pattern, this form predominantly affects black females (in  some series, more than 90% of patients), with a marked    e Fig. 14-42 Periapical Cemento-Osseous Dysplasia. Later-  stage lesions exhibiting significant mineralization.    e Fig. 14-43 Periapical Cemento-Osseous Dysplasia. Later-  stage lesions exhibiting significant mineralization.    ® Fig. 14-44 Florid Cemento-Osseous Dysplasia. Multiple mixed radiolucent and radiopaque lesions  involving the anterior and posterior regions of the mandible.    predilection for middle-aged to older adults. An intermedi-  ate frequency among East Asian populations also has been  described.   The lesions show a tendency for bilateral and fairly sym-  metrical involvement of the mandible, and occasionally  there may be extensive involvement in all four quadrants.  At times the disease may be asymptomatic and discovered  only when radiographs are taken for unrelated reasons. In  other cases, patients may have dull pain, alveolar sinus  tracts, and exposure of yellowish, avascular bone to the oral  cavity (Fig. 14-45). Although rarely prominent, some jaw  expansion may be evident.   Radiographically, the lesions demonstrate a maturation  pattern similar to that noted in the other forms of    e Fig. 14-45 Florid Cemento-Osseous Dysplasia. Yellowish,  avascular cementum-like material is beginning to exfoliate through the  oral mucosa.    cemento-osseous dysplasia. Initially, the lesions are predom-  inantly radiolucent but with time become mixed, then pre-  dominantly radiopaque with only a thin radiolucent rim  (Fig. 14-46). On occasion, a lesion can become almost  totally radiopaque and blend with the adjacent normal-  appearing bone. Typically, the radiopacities remain sepa-  rated from adjacent teeth with an intervening, intact  periodontal ligament space. However, in some end-stage  lesions, the cemento-osseous material may fuse with the  tooth root surface to produce thickened root apices sur-  rounded by radiolucency (or a “hypercementosis-like”  appearance).   Both dentulous and edentulous areas may be affected,  and involvement appears to be unrelated to the presence or  absence of teeth. Sharply defined radiolucent areas, which  on surgical exploration prove to be simple bone cysts (see  page 589), may be intermixed with the other lesional ele-  ments. Investigators have suggested that these simple bone  cysts may result from interstitial fluid obstruction by the  fibro-osseous proliferation.    All three patterns of cemento-osseous dysplasia demonstrate  similar histopathologic features. There are typically frag-  ments of cellular fibrovascular connective tissue with scat-  tered hemorrhage and a variable mixture of woven bone,  lamellar bone, and cementum-like particles (Figs. 14-47  and 14-48). As the lesions mature, the ratio of fibrous con-  nective tissue to mineralized material decreases. Over time,  the bony trabeculae become thick and curvilinear, with  shapes likened to ginger roots. In the final radiopaque stage,    @ Fig. 14-46 Florid Cemento-Osseous Dysplasia. Multifocal radiopaque lesions of the posterior areas  of the jaws. (Courtesy of Dr. Solomon Israel.)    ° Fig. 14-47 Cemento-Osseous Dysplasia. Low-power photomi-  crograph showing fragments of cellular fibrous connective tissue con-  taining scattered trabeculae of bone.    ® Fig. 14-48 Cemento-Osseous Dysplasia. High-power photomi-  crograph showing spicules of bone and cementum-like hard tissue  within moderately cellular fibrous connective tissue. Note the hemor-  rhage around the bony trabeculae.    the individual trabeculae fuse to form sheetlike or globular  masses of sclerotic, disorganized cemento-osseous material    In most instances of periapical or florid cemento-osseous  dysplasia, the distinctive clinical and radiographic findings  (e.g., a black female patient with multiquadrant involve-  ment or multiple lesions involving vital lower incisor teeth)  allow a strong presumptive diagnosis. In contrast, the fea-  tures of focal cemento-osseous dysplasia tend to be less  specific, and biopsy often is needed for diagnosis.   In particular, distinguishing focal cemento-osseous dys-  plasia from ossifying fibroma can be difficult. However, the  findings at surgery may be helpful in discriminating between  these two lesions. Before the final sclerotic stage, cemento-  osseous dysplasia consists of gritty tissue that the surgeon  typically curettes into small fragments during biopsy. In  contrast, ossifying fibromas tend to separate cleanly and are  removed in one or several large masses. Microscopically,    e Fig. 14-49 Cemento-Osseous Dysplasia. Late-stage lesion  showing a sclerotic mass of cemento-osseous material.    both lesion types demonstrate a mixture of bone and  cementum-like particles, although subtle histopathologic  differences may be appreciated. The bony trabeculae in ossi-  fying fibroma tend to be more delicate and show more  prominent osteoblastic rimming compared to those in  cemento-osseous dysplasia. Also, the cementum-like parti-  cles in cemento-osseous dysplasia are irregularly shaped and  often exhibit retraction from the adjacent stroma, whereas  those in ossifying fibroma are more ovoid and often dem-  onstrate brush borders in intimate association with the  adjacent stroma. Although ossifying fibroma can exhibit  peripheral hemorrhage, cemento-osseous dysplasia typically  reveals hemorrhage throughout the lesion and sinusoidal  vascularity in close association with the bony trabeculae.    Cemento-osseous dysplasia does not appear to be neoplastic  and, therefore, generally does not require removal. During  the predominantly radiolucent phase, the lesions cause few  problems. However, in the sclerotic phase, the lesions tend  to be hypovascular and prone to necrosis and secondary  infection with minimal provocation. For the asymptomatic  patient, the best management consists of regular recall  examinations with prophylaxis and oral hygiene reinforce-  ment to control periodontal disease and prevent tooth loss.   Because the onset of symptoms usually is associated with  exposure of the sclerotic masses to the oral cavity, surgical  procedures (e.g., biopsy, elective tooth extraction) should be  avoided. In some instances, symptoms begin after lesion  exposure resulting from progressive alveolar atrophy under  a denture. Therefore, affected patients should be encouraged  to retain their teeth. Dental implant placement in an area  of cemento-osseous generally is not recommended. Man-  agement of the symptomatic patient who has developed  secondary osteomyelitis is more difficult. Antibiotics may  be indicated but often are not effective. Sequestration of the  sclerotic cementum-like masses occurs slowly and is fol-  lowed by healing. Saucerization of dead bone may speed  healing. When simple bone cysts arise within foci of    cemento-osseous dysplasia, surgical exploration is necessary  to establish the diagnosis. These simple bone cysts often do  not heal as rapidly as those noted in younger patients  without cemento-osseous dysplasia. In some cases the cysts  persist or enlarge after surgical intervention; when they fill  in, the bone retains an abnormal radiographic appearance.  Thorough curettage of the cyst and the surrounding fibro-  osseous proliferation may assist healing.   Some investigators have noted a rare subset of cases  (termed expansive osseous dysplasia) that exhibit progressive  growth but otherwise typical clinicopathologic features of  cemento-osseous dysplasia. Such lesions have been reported  most often in the anterior mandible of African black females  and typically require surgical removal.   Overall, the prognosis is good. Development of a sarcoma  within an area of cemento-osseous dysplasia has been  reported but is extremely rare.    Although the term gigantiform cementoma has been used in  the past as a synonym for florid cemento-osseous dysplasia,  most authorities now restrict use of this term to a rare  hereditary disorder known as familial gigantiform cemen-  toma. This disorder exhibits an autosomal dominant pattern  of transmission with high penetrance and variable expres-  sivity. It is characterized by a cemento-osseous proliferation  involving multiple quadrants of the jaws and often resulting  in massive expansion.   Based on microscopic similarities, some authors consider  familial gigantiform cementoma to be a variant of    cemento-osseous dysplasia. However, a tendency for pro-  gressive lesion growth suggests a truly neoplastic process;  thus, many authors prefer to regard familial gigantiform  cementoma as a distinct neoplasm or a subtype of ossifying  fibroma.   Sporadic cases with clinical and radiographic features  similar to those of familial gigantiform cementoma also  have been reported using various terms, including nonfamil-  ial gigantiform cementoma, multiple (cemento-) ossifying  fibromas, bilateral ossifying fibromas, and expansive osseous  dysplasia. Whether such cases represent spontaneous muta-  tions, multiple ossifying fibromas, or unusual progressive  forms of cemento-osseous dysplasia remains unclear. Molec-  ular genetic studies are needed to improve the understand-  ing and appropriate classification of this problematic disease  spectrum.    Unlike florid cemento-osseous dysplasia, familial giganti-  form cementoma exhibits neither a predilection for blacks  nor a significant gender predilection. Although blacks may  be affected, most reported families are white or Asian. Radio-  graphic alterations may begin to develop during the first  decade of life. By adolescence, most patients exhibit clini-  cally obvious expansion of the jaws (Fig. 14-50). The lesions  affect multiple quadrants, often with simultaneous involve-  ment of the maxilla and mandible. Lesion growth may be  rapid or slow. Ina few reported cases, especially rapid growth  has been noted during pregnancy. Although the course is  variable, many patients develop significant facial deformity,    ® Fig. 14-50 Familial Gigantiform Cementoma. Young woman with massive lesions involving all four  quadrants of the jaws. (A, From Abdelsayed RA, Eversole LR, Singh BS, et al: Gigantiform cementoma:  clinicopathologic presentation of 3 cases, Oral Surg Oral Med Oral Pathol Oral Radio! Endod 91:438-444,    as well as impaction, malposition, and malocclusion of the  involved dentition. If not treated, then the osseous enlarge-  ment eventually ceases during the fifth decade.   Radiographically, the lesions initially may appear as mul-  tiple periapical radiolucencies, resembling cemento-osseous  dysplasia. With progression, the affected sites expand to  replace much of the normal bone within the involved quad-  rant and develop a mixed radiolucent and radiopaque  pattern. With further maturation, the lesions become pre-  dominantly radiopaque but often maintain a thin radiolu-  cent rim. As noted in cemento-osseous dysplasia, the  affected bone during the final radiopaque stage is very sensi-  tive to inflammatory stimuli and becomes necrotic with  minimal provocation.   Some investigators have reported elevated serum alkaline  phosphatase that subsequently declines after surgical removal  of the osseous proliferations. Anemia also has been reported  in a number of affected females in different kindreds. In one  family, two affected females demonstrated multifocal pol-  ypoid adenomas of the uterus that were associated with  chronic hemorrhage and apparently caused anemia.   Furthermore, in a few kindreds diagnosed with familial  gigantiform cementoma, bone fragility and a tendency for  long bone fractures have been noted. However, such cases  actually may represent examples of another entity known as  gnatho-diaphyseal dysplasia (a heritable autosomal dominant  condition characterized by GDDI [or TMEMIG6E] muta-  tions, diffuse fibro-osseous lesions of the jaws with a promi-  nent psammomatoid body component, bone fragility, and  bowing/cortical sclerosis of long bones).    Histopathologically, familial gigantiform cementoma shows  the same spectrum of changes seen in florid cemento-  osseous dysplasia, and the two cannot be distinguished  microscopically.    Before the final sclerotic stage, shave-down surgical proce-  dures typically are unsuccessful because the dysplastic tissue  rapidly regrows. Once the lesions are predominantly radi-  opaque, partial removal may lead to sequestration of the  remaining affected bone. Therefore, if feasible, complete  resection and reconstruction are recommended. Because  familial gigantiform cementoma might be associated with  polypoid adenomas of the uterus, gynecologic evaluation is  prudent for female patients—especially those with anemia.    Although it can resemble focal cemento-osseous dysplasia  radiographically and histopathologically, ossifying fibroma    is a true neoplasm with significant growth potential. Ossify-  ing fibromas are relatively rare. Many examples reported in  the older literature actually represent cases of focal cemento-  osseous dysplasia.   The neoplasm is composed of fibrous tissue with a vari-  able mixture of bony trabeculae and cementum-like spher-  ules. In the past, investigators have suggested that the origin  of these tumors is odontogenic or from periodontal liga-  ment. However, such an origin is questionable, because  microscopically identical neoplasms with cementum-like  differentiation also have been reported in the orbital, frontal,  ethmoid, sphenoid, and temporal bones. Today, many  authorities regard the cementum-like material in ossifying  fibromas as a variation of bone. Indeed, some contend that  bone and cementum are essentially the same mineralized  product and only can be distinguished based on anatomic  location (i.e., presence of cementum along root surfaces).  Although various terms (including ossifying fibroma, cemento-  ossifying fibroma, and cementifying fibroma) continue to be  used for this tumor, most authorities consider it to be an  osteogenic neoplasm. In this section, all of these variations  are combined under the term ossifying fibroma.   Mutations in the tumor suppressor gene HRPT2 (which  encodes the parafibromin protein) have been identified in  patients with hyperparathyroidism-jaw tumor syndrome. This  rare syndrome is characterized by parathyroid adenoma or  carcinoma, ossifying fibromas of the jaws, renal cysts, and  Wilms tumors. In addition, investigators have found  HIRPT2 gene mutations in a few sporadic cases of ossifying  fibroma of the jaws. However, the potential pathogenetic  role of HRPT2 mutations in ossifying fibroma remains  poorly understood.    Ossifying fibromas occur over a broad age range, with a  peak in the third and fourth decades of life. There is a female  predilection, with the mandible involved far more often  than the maxilla. The mandibular premolar and molar area  is the most common site. Maxillary lesions tend to involve  the antrum.   Small lesions are often asymptomatic and may be  detected only by radiographic examination. Larger tumors  may produce painless jaw swelling (Fig. 14-51) and obvious  facial asymmetry. Some lesions may become massive and  cause considerable deformity. Pain and paresthesia are rare.  Most examples are solitary; however, multiple synchronous  lesions have been reported very rarely—either as an isolated  finding or as a component of hyperparathyroidism-jaw  tumor syndrome.   Depending on the amount of calcification, radiographic  examination typically shows a well-defined, unilocular  radiolucency or mixed radiolucency and radiopacity. Some  examples show a sclerotic border. Multilocular lesions com-  prise only a minority of cases. True ossifying fibromas that  appear largely radiopaque with only a thin radiolucent  periphery are infrequent; many reported examples with this    iS 00 Loc-194.00000 10 Pp 0  @ Fig. 14-51 Ossifying Fibroma. Clinical image (A) and computed  tomography (CT) scan (B) showing a large, expansile lesion of the  posterior maxilla. (Courtesy of Dr. Greg Cobetto.)    radiographic pattern likely represent end-stage focal  cemento-osseous dysplasia. Buccolingual bony expansion is  common; in addition, large mandibular lesions often dem-  onstrate a characteristic downward bowing of the inferior  cortex. The adjacent teeth may exhibit root divergence or  root resorption.    At surgery, the lesion tends to separate easily from the sur-  rounding bone; thus, the tumor usually is submitted as one  mass or a few large pieces (Fig. 14-52). Grossly and micro-  scopically, most lesions are well demarcated but unencap-  sulated. However, a fibrous capsule may be present in some  cases.   Microscopic examination shows cellular fibrous tissue  with mineralized product (Fig. 14-53). The mineralized  component may include a variable admixture of osteoid,    @ Fig. 14-52 Ossifying Fibroma. Gross specimen showing a well-  circumscribed tumor that shelled out in one piece and subsequently  was hemisected.    ® Fig. 14-53 Ossifying Fibroma. This low-magnification photomi-  crograph shows a well-circumscribed solid tumor mass. Trabeculae of  bone and droplets of cementum-like material can be seen forming  within a background of cellular fibrous connective tissue.    bone, and basophilic acellular (or “cementum-like”) spher-  ules. The bony trabeculae vary in size and frequently dem-  onstrate both woven and lamellar patterns. Peripheral  osteoid and osteoblastic rimming are usually present. The  cementum-like spherules often demonstrate brush borders  that blend into the adjacent connective tissue (Fig. 14-54).  Significant intralesional hemorrhage is unusual. The hetero-  geneous mineralized product characteristic of ossifying  fibroma differs from the more uniform osseous pattern of  fibrous dysplasia. Rarely, a lesion may exhibit combined  features of ossifying fibroma and central giant cell  granuloma.    The circumscribed nature of the ossifying fibroma generally  permits enucleation of the tumor with relative ease. Large  lesions that have caused considerable bone destruction may  necessitate surgical resection and bone grafting. Recurrence  after complete removal is uncommon; one systematic review  of the literature has reported a 12% recurrence rate. Overall,    e Fig. 14-54 Ossifying Fibroma. High-power photomicrograph  showing a mixture of woven bone and cementum-like material. Note  the spherules demonstrating peripheral brush borders (arrow).    the prognosis is very good, and there is no apparent poten-  tial for malignant transformation.    ¢ JUVENILE OSSIFYING FIBROMA  (JUVENILE ACTIVE OSSIFYING  FIBROMA; JUVENILE AGGRESSIVE  OSSIFYING FIBROMA)    ‘The juvenile ossifying fibroma is a controversial lesion that  has been distinguished from conventional ossifying fibroma  on the basis of patient age, site predilection, and clinical  behavior. The term includes two distinct clinicopathologic  variants: 1) trabecular and 2) psammomatoid. Among  lesions involving the craniofacial skeleton, the psammoma-  toid variant has been reported more frequently than the  trabecular variant.   The etiopathogenesis is poorly understood. In a small  number of orbital psammomatoid ossifying fibromas, inves-  tigators have demonstrated nonrandom chromosomal  breakpoints at Xq26 and 2q33 resulting in (X;2) transloca-  tion. Among studies conducted thus far, failure to detect  GNAS or HRPT2 mutations in juvenile ossifying fibromas  suggests that these lesions are distinct from fibrous dysplasia  and conventional ossifying fibromas.    Juvenile ossifying fibromas most often arise in children,  adolescents, and young adults; however, a broader age range  has been reported for the psammomatoid variant (3 months  to 72 years) than the trabecular variant (2 to 33 years).  Among various reported case series, the average age at diag-  nosis is somewhat younger for the trabecular variant (range  from 8% to 12 years) than the psammomatoid variant  (range from 16 to 33 years). Most authors report either a  slight male predilection or no significant gender predilec-  tion. The trabecular variant arises primarily in the jaws,  whereas the psammomatoid variant predominantly involves    @ Fig. 14-55 Juvenile Ossifying Fibroma. Computed tomography  (CT) scan showing a large tumor involving the left maxilla and maxillary  sinus of a 12-year-old girl. Clinically, the tumor was growing rapidly.    the paranasal sinuses and orbital region. In both variants,  gnathic involvement favors the maxilla.   Although some cases exhibit slow, progressive enlarge-  ment, others exhibit rapid, aggressive growth. Small lesions  may be discovered incidentally during routine radiographic  examination, whereas larger lesions tend to cause painless  swelling and obvious facial enlargement. Pain and paresthe-  sia are infrequent findings. Tumors arising in the paranasal  sinuses may penetrate the orbital, nasal, and cranial cavities.  Nasal obstruction, epistaxis, sinusitis, headaches, proptosis,  diplopia, and blindness may result. Rarely, intracranial  extension may cause encephalitis and meningitis.   Radiographic examination typically shows a well-  circumscribed radiolucency or mixed radiolucency and  radiopacity (Fig. 14-55). A sclerotic border may be evident  in some cases. “Ground-glass” opacification or a multilocu-  lar “honeycomb” pattern also may be observed. Aggressive  lesions often cause expansion and cortical thinning or per-  foration. Similar to conventional ossifying fibromas, juve-  nile ossifying fibromas may produce downward bowing of  the inferior cortex of the mandible. Jaw lesions also can  cause tooth displacement, root resorption, and failure of  tooth development. Sinus involvement may appear radio-  graphically as cloudy opacification mimicking sinusitis.    Both patterns are typically well demarcated but unencapsu-  lated. The fibrous stromal component exhibits variable  degrees of cellularity and collagenization. Some zones may  be so hypercellular that the cytoplasm of individual cells is  hard to discern. Other areas may appear myxomatous with    YE ANE < SN S  @ Fig. 14-56 Juvenile Ossifying Fibroma, Trabecular Variant.  Trabeculae of cellular woven bone are present in a cellular fibrous  stroma.   e Fig. 14-57 Juvenile Ossifying Fibroma, Psammomatoid  Variant. Cellular fibrous connective tissue containing spherical ossi-  cles with basophilic centers and peripheral eosinophilic rims.    a tendency for pseudocystic degeneration. Hemorrhage and  small clusters of multinucleated giant cells are common.  Mitotic figures may be present but are neither numerous  nor atypical. In the trabecular variant, microscopic zones of  hemorrhage, giant cells, and pseudocystic degeneration may  correlate with grossly evident brown, curvilinear strands on  the tumor’s cut surface.   The mineralized component differs between the two  variants. The trabecular variant shows irregular strands of  highly cellular osteoid encasing plump and irregular osteo-  cytes (Fig. 14-56). These strands often are lined by plump  osteoblasts and multinucleated osteoclasts. In contrast, the  psammomatoid variant exhibits concentric lamellated ossi-  cles that vary in size and may be round, ovoid, or crescentic  in shape. The ossicles typically appear basophilic with  peripheral eosinophilic osteoid rims and brush borders that  blend into the surrounding stroma (Fig. 14-57).   Secondary formation of a simple bone cyst or aneurys-  mal bone cyst also is possible. The latter may manifest  clinically with rapid, aggressive growth.    For small lesions, complete local excision or thorough curet-  tage appears adequate. For large or aggressive lesions, wider  resection may be required.   In contrast to the negligible recurrence rate for conven-  tional ossifying fibromas, recurrence rates of 30% to 58%  have been reported for juvenile ossifying fbromas. Many  reported recurrences actually may represent tumor persis-  tence after incomplete surgical removal. Malignant trans-  formation has not been documented. Tumor-related deaths  are extremely rare and primarily result from complications  caused by direct intracranial extension.    Osteomas are benign tumors composed of mature compact  or cancellous bone. Osteomas primarily involve the cranio-  facial skeleton and rarely, if ever, are diagnosed in other  bones. They may arise on the bone surface (periosteal,  peripheral, or exophytic osteomas) or within medullary  bone (endosteal or central osteomas). Extraskeletal oste-  omas, typically located within muscle or the dermis of the  skin (osteoma cutis), also are possible.   ‘There is some question whether osteomas represent true  neoplasms, and not all lesions designated as osteomas may  represent a single entity. Some likely represent the end stage  of an injury, inflammatory process, or hamartomatous  process, such as fibrous dysplasia. Because some osteomas  arise in areas where muscle attaches to bone, investigators  have hypothesized that muscle traction may be a contribu-  tory factor. Common palatal tori, mandibular tori, and  buccal exostoses (see page 18) are not considered to be  osteomas, although they are histopathologically identical.  Because many osteomas are small and asymptomatic, there  is little reliable information regarding their frequency and  demographic distribution.    Osteomas of the jaws most often are detected in adults, with  a predilection for the mandibular body and condyle. Lesions  involving the mandibular body frequently are found on the  lingual surface adjacent to the premolars or molars. Less  common mandibular locations include the angle (particu-  larly at the inferior border), coronoid process, and ramus.  Most examples are solitary and asymptomatic with very  slow growth. Pain, tooth displacement, and tooth impac-  tion have been reported in a minority of cases. Rarely, a  lesion may become especially large and produce marked  facial deformity. Periosteal osteomas appear as polypoid or  sessile masses on the bone surface, whereas endosteal osteo-  mas may not be evident clinically unless they are large  enough to cause expansion. Multifocal lesions may arise in  association with Gardner syndrome (see page 606).  Osteomas involving the mandibular condyle may limit  mouth opening or cause malocclusion, with deviation of    @ Fig. 14-58 Osteoma. Panoramic radiograph showing a uniformly  sclerotic mass arising from the surface of the posterior mandible.  (Courtesy of Dr. James Lemon.)    the dental midline and chin toward the unaffected side. Pain  and facial swelling also are possible. Some authorities con-  sider condylar osteomas to be true neoplasms, whereas  others designate them as /yperostoses. Distinguishing this  process from condylar hyperplasia can be difficult; however,  a condylar osteoma typically is lobulated, whereas a hyper-  plastic condyle usually retains its original shape.   Paranasal sinus osteomas are even more common than  gnathic lesions. The frontal sinus is most often involved,  followed by the ethmoid and maxillary sinuses. Such lesions  are usually asymptomatic, although pain, swelling, sinusitis,  and nasal discharge are possible. In rare cases, paranasal  sinus osteomas may expand into orbital structures and may  result in proptosis, diplopia, and decreased visual acuity.  Infrequently, intracranial extension can cause meningitis,  cerebral abscesses, and intracranial mucoceles.   Radiographically, osteomas appear as circumscribed scle-  rotic masses. Periosteal osteomas may show a uniformly  sclerotic pattern or may demonstrate a sclerotic periphery  with central trabeculation (Fig. 14-58). Smaller endosteal  osteomas are difficult, if not impossible, to differentiate  radiographically from condensing osteitis, focal chronic  sclerosing osteomyelitis, or idiopathic osteosclerosis. The  true nature of these osteomas can be confirmed only by  documentation of continued growth.    Compact osteomas are composed of normal-appearing,  dense bone with minimal marrow (Fig. 14-59). Cancellous  osteomas are composed of bony trabeculae and fibrofatty  marrow. Osteoblastic activity may be fairly prominent.    Small, asymptomatic osteomas may not require treatment  but should be observed periodically. Conservative excision  is appropriate for large or symptomatic osteomas of the    @ Fig. 14-59 Osteoma. This compact osteoma is composed of  dense bone, with only minimal marrow elements.    mandibular body. Because they are frequently symptomatic,  condylar osteomas usually are removed by local resection or  condylectomy. Symptomatic paranasal sinus osteomas may  be removed endoscopically or via an open surgical approach.  Recurrence after excision is extremely rare, and there are no  reports of malignant transformation.    Gardner syndrome is a rare disorder, characterized by  intestinal polyps as well as various abnormalities of bone,  teeth, skin, soft tissue, and other sites. This syndrome rep-  resents a variant of familial adenomatous polyposis—an  inherited condition in which patients develop hundreds to  thousands of intestinal adenomatous polyps, with nearly  100% progression to colorectal cancer if left untreated.  Both classical familial adenomatous polyposis and the  Gardner syndrome variant are highly penetrant autosomal  dominant disorders caused by mutations in the adenoma-  tous polyposis coli (APC) tumor suppressor gene on chro-  mosome 5q21. Most affected individuals have a family  history of the disease, although approximately 30% of cases  appear to represent new mutations. The severity of gastro-  intestinal disease and the prominence of extraintestinal  findings correlate with the specific position of mutations  within the APC gene. The term Gardner syndrome generally  refers to cases in which the extraintestinal manifestations  are especially prominent. The estimated frequency of  Gardner syndrome ranges from about 1:8,300 to 1: 16,000  live births.    Colorectal polyps typically develop by the second decade of  life (Fig. 14-60). The lesions often are asymptomatic but  may cause diarrhea, constipation, rectal bleeding, anemia,  and abdominal pain. The colorectal polyps are adenomatous  (i.e., precancerous with varying degrees of dysplasia) and, if  untreated, ultimately transform into adenocarcinoma. In  addition, polyps often arise in the small intestine or stomach,    although only a small percentage of polyps in these sites  undergo carcinomatous transformation.   Up to 90% of patients with Gardner syndrome demon-  strate skeletal abnormalities, the most common of which  are osteomas. The osteomas usually are noted around  puberty and often become evident before the intestinal  polyps; indeed, the presence of multiple osteomas may lead  to an early diagnosis of Gardner syndrome. Although the  osteomas may affect any part of the skeleton, they most  commonly involve the skull, paranasal sinuses, and man-  dible. Mandibular lesions often occur at the angle and may  cause marked facial deformity. Occasionally, osteomas of  the condyle may limit mouth opening. Most patients dem-  onstrate between three and six osseous lesions. The osteo-  mas appear as radiopacities that vary from a few millimeters  to several centimeters in diameter (Fig. 14-61).    © Fig. 14-60 Gardner Syndrome. A segment of resected large  bowel showing polyp formation (arrow).    Dental abnormalities occur in about 22% to 30% of  patients and include odontomas, supernumerary teeth, and  impacted teeth. The frequency of supernumerary teeth in  Gardner syndrome is not nearly as high as that noted in  cleidocranial dysplasia.   Most patients show one or several epidermoid cysts of  the skin (Fig. 14-62). Other cutaneous findings may include  lipomas, fibromas, neurofibromas, and _ leiomyomas.  Desmoid tumors (locally aggressive fibrous neoplasms of  soft tissue) arise in approximately 12% to 18% of patients.  These lesions are more frequent in females than males and  often develop in the abdominal scar that forms after colec-  tomy. In addition, numerous other extraintestinal neo-  plasms have been reported in Gardner syndrome, including  thyroid carcinoma, adrenal adenoma or adenocarcinoma,  hepatoblastoma, pancreatic adenocarcinoma, nasopharyn-  geal angiofibroma, and brain tumors.   Furthermore, pigmented lesions of the ocular fundus  (also known as congenital hypertrophy of the retinal pigment  epithelium) are evident in about 58% to 88% of patients  with familial adenomatous polyposis. This ocular abnormal-  ity correlates with specific mutated loci within the APC  gene.    Histopathologically, the osteomas are generally of the  compact type. An individual lesion cannot be differentiated  microscopically from a solitary osteoma.    The major problem for patients with Gardner syndrome is  the high risk for transformation of colorectal polyps into    e Fig. 14-61 Gardner Syndrome. Panoramic radiograph showing multiple osteomas of the jaws.  (Courtesy of Dr. Terry Day.)    @ Fig. 14-62 Gardner Syndrome. This patient has multiple, large  epidermoid cysts. (Courtesy of Dr. William Welton.)    adenocarcinoma. Without treatment, approximately 50%  of patients will develop colorectal cancer by 30 years of age,  and the frequency of malignant change approaches 100%  by the fifth decade. Therefore, prophylactic colectomy  usually is recommended. Clinical trials have shown some  regression of polyps with celecoxib or sulindac, but further  chemoprevention studies are needed.   Patients also should be monitored for development of  extracolonic malignancies or desmoid tumors. Genetic  counseling is indicated as well. Osteomas and epidermoid  cysts may be removed if they cause functional or cosmetic  problems. Dental management typically involves surgical  extraction of impacted teeth, removal of odontomas, and  prosthodontic treatment. Orthodontic tooth movement  may be difficult due to increased bone density from the  osteomas.    Osteoblastoma and osteoid osteoma are closely related  benign bone tumors that arise from osteoblasts. They exhibit  very similar histopathologic features, and some authors  regard them as variants of the same lesion. However, most  authorities currently recognize them as two distinct clinico-  pathologic entities. In particular, the osteoid osteoma exhib-  its a unique tumor nidus with a high concentration of    peripheral nerves and prostaglandins; these findings appar-  ently form the basis for characteristic nocturnal pain relieved  by nonsteroidal anti-inflammatory drugs (NSAIDs). In  addition, the osteoid osteoma exhibits more limited growth  potential than osteoblastoma. Classically, the distinction  depends on lesion size, with osteoid osteomas measuring  less than a threshold of 1.5 cm or 2 cm in diameter, whereas  osteoblastomas are larger.   Most investigators consider these lesions to be true neo-  plasms, although some have proposed that the limited  growth of osteoid osteoma suggests an inflammatory or  unusual healing process. In support of a neoplastic nature,  cytogenetic studies have identified recurrent alterations on  the long arm of chromosome 22 in some osteoid osteomas  and aggressive osteoblastomas.    Osteoblastomas are rare and represent approximately 1% of  all primary bone tumors. The most frequently affected sites  are the vertebral column, long bones, pelvis, talus, facial  bones, and small bones of the hands and feet. Among  gnathic lesions, there is a mandibular predilection, with  most examples involving the posterior regions. Approxi-  mately 85% of gnathic osteoblastomas occur before 30 years  of age, and there is a slight female predominance.   Most osteoblastomas are between 2 and 4 cm, but they  may be as large as 10 cm. Dull pain, tenderness, and swell-  ing are common presenting features. Unlike the pain associ-  ated with osteoid osteoma, the pain associated with  osteoblastoma usually is not relieved by NSAIDs. Painful  jaw lesions may be misinterpreted as odontogenic infec-  tions. Gnathic tumors also may cause tooth mobility, root  resorption, or tooth displacement.   Radiographically, the osteoblastoma typically appears as  a well- or ill-defined, round to oval radiolucency with  patchy areas of mineralization (Fig. 14-63). Some examples  demonstrate considerable mineralization. Surrounding  reactive sclerosis is less prominent in osteoblastoma than  osteoid osteoma. Most osteoblastomas arise within medul-  lary bone, although a periosteal or intracortical origin also  is possible.   A small subset of osteoblastomas (aggressive osteoblas-  tomas) is characterized by atypical histopathologic features  and locally aggressive behavior. These tumors usually occur  in patients older than 30 years. A variety of bones, including  the mandible, may be involved. Pain is common and may  be severe. Aggressive osteoblastomas exhibit radiographic  findings similar to those of conventional osteoblastoma  but tend to be larger (typically greater than 4 cm in  diameter).    Osteoid osteoma comprises about 3% of all primary bone  tumors. The lesion occurs most often in the femur and tibia  but is very rare in the jaws. Among reported gnathic tumors,  there is a slight mandibular predominance, with most    ® Fig. 14-63 Osteoblastoma. Computed tomography (CT) image  showing an expansile, mixed radiolucent and radiopaque lesion of the  maxilla. (Courtesy of Dr. Michael Zetz.)    ® Fig. 14-64 Osteoid Osteoma. A circumscribed, mixed radiolucent  and radiopaque lesion near the apex of mesial root of mandibular first  molar. The patient had dull, nocturnal pain that was relieved by aspirin.  (Courtesy of Dr. Ellen Eisenberg.)    patients diagnosed during the second and third decades of  life (mean age 25 years). Although extragnathic lesions  demonstrate a male predilection, jaw lesions exhibit no  significant gender predilection. The most prominent clinical  symptom is pain that is most severe at night and alleviated  by NSAIDs. However, nocturnal pain relieved by NSAIDs  has been documented more often among extragnathic  lesions than jaw lesions.   Radiographically, the osteoid osteoma typically appears  as a well-circumscribed, round to ovoid radiolucency (or  “nidus”) with a variable degree of surrounding reactive scle-  rosis. The radiolucent nidus may contain a small, central  radiopacity, resulting in a target-like appearance (Fig.  14-64). The nidus typically measures less than 1.5 cm in  diameter and most commonly arises within cortical bone,  although a medullary or periosteal origin also is possible. A  periosteal reaction occasionally may be seen.    e Fig. 14-65 Osteoblastoma. High-power photomicrograph  showing irregular bony trabeculae with prominent osteoblastic rimming  and osteoclasts.    Microscopically, both osteoid osteoma and osteoblastoma  centrally exhibit irregular trabeculae of osteoid or woven  bone, which are surrounded by numerous osteoblasts and  scattered osteoclasts. The osteoblasts have ample cytoplasm  and hyperchromatic nuclei (Fig. 14-65). The loose fibrous  stroma includes dilated vessels and occasional hemorrhage.  The vascularity tends to be more prominent in osteoblas-  toma than osteoid osteoma. At the periphery, there is typi-  cally a more prominent zone of dense, sclerotic bone in  osteoid osteoma than osteoblastoma.   Aggressive osteoblastomas are characterized by large (epi-  thelioid) osteoblasts with increased mitotic activity and  sheets or lacelike areas of osteoid production. Differentia-  tion between aggressive osteoblastoma and low-grade osteo-  sarcoma may be very difficult, although infiltrative growth,  marked cytologic atypia, and atypical mitotic figures favor  the latter.    Most osteoid osteomas and osteoblastomas of the jaws are  treated by local excision or curettage. Some osteoid osteo-  mas may regress spontaneously; however, most clinicians  prefer surgical removal over long-term observation and pain  management with NSAIDs. For extragnathic lesions, mini-  mally invasive techniques (e.g., computed tomography  [CT]-guided excision and radiofrequency ablation) have  gained popularity recently.   Recurrence after complete removal is uncommon; many  reported recurrences may be attributed to incomplete exci-  sion. Osteoid osteoma exhibits no potential for malignant  transformation, and osteoblastoma only rarely transforms  into osteosarcoma. Whether aggressive osteoblastoma  exhibits a greater recurrence potential than conventional  osteoblastoma is controversial, although metastasis or death  from aggressive osteoblastoma has not been reported.    © Fig. 14-66 Cementoblastoma. A, A densely mineralized mass is seen at the apex of the distal root  of the first molar. The root is partially resorbed. B, The surgical specimen shows that the mass is attached    Cementoblastoma is a benign neoplasm of cementoblasts  and represents less than 1% of all odontogenic tumors.  Many authorities believe this lesion represents the only  true neoplasm of cementum. Alternatively, because cement-  oblastoma bears a close histopathologic resemblance to  osteoblastoma (see previous section), others consider  cementoblastoma to be a variant of osteoblastoma. The  primary distinguishing factor is whether or not the lesion  is fused to a tooth root. Because of its similarity to osteo-  blastoma, cementoblastoma is discussed here rather than in    Approximately 80% of cases arise in the mandible, primar-  ily in the molar and premolar region. In particular, almost  50% of cases involve the mandibular first permanent molar.  Impacted, unerupted, or deciduous teeth rarely may be  affected as well. There is no definite sex predilection. The  neoplasm predominantly affects young patients, with about  50% arising by 20 years of age and 75% by 30 years. Pain  and swelling are present in approximately two-thirds of  reported cases. The associated tooth usually responds nor-  mally to vitality tests. Most investigators consider this lesion  rather innocuous; however, signs of locally aggressive behav-  ior may be observed, including bony expansion, cortical  erosion, displacement of adjacent teeth, envelopment of  multiple teeth, maxillary sinus involvement, and infiltration  into the pulp chamber and root canals.   Radiographically, the tumor appears as a radiopaque  mass that is fused to one or more tooth roots and is  surrounded by a thin radiolucent rim (Fig. 14-66). The  outline of the root or roots of the involved tooth usually  is obscured by root resorption and fusion of the tumor  with the tooth.    © Fig. 14-67 Cementoblastoma. Low-power photomicrograph  showing the tumor attached to the roots of the tooth.    The histopathologic features of cementoblastoma closely  resemble those of osteoblastoma. However, the primary dis-  tinguishing feature of cementoblastoma is fusion with the  involved tooth (Fig. 14-67). Microscopic examination  shows sheets and thick trabeculae of mineralized material  with irregularly placed lacunae and prominent basophilic  reversal lines. The background stroma is comprised of cel-  lular fibrovascular tissue. Multinucleated giant cells often  are present, and prominent blast-like cells frequently line  the mineralized trabeculae (Fig. 14-68). Radiating columns  of uncalcified matrix typically are seen at the periphery,  corresponding to the radiolucent rim seen radiographically.    In few instances, the lesion may infiltrate the pulp chamber  and root canals of the involved tooth.    Treatment usually consists of surgical extraction of the tooth  and the attached calcified mass. A potential alternative is  excision of the mass with root amputation followed by  endodontic treatment of the remaining tooth. Some inves-  tigators suggest that supplementing extraction or excision  with osseous curettage may decrease the risk for recurrence.  Historically, most authorities have considered the recur-  rence potential to be very low; however, one large series with  an extensive literature review has reported an overall recur-  rence rate of 22%. Completeness of removal is most closely  related to recurrence.    Chondromas are benign tumors of mature hyaline carti-  lage. They comprise about 16% of benign bone tumors and  most often arise in the small bones of the hands and feet.  However, a diagnosis of chondroma in the craniofacial  bones should be viewed with great skepticism because many  purported cases have recurred and exhibited malignant  behavior. There are only a few individual reports and small  series of gnathic chondromas, with most examples thought  to arise from cartilage or cartilaginous rests in the condyle,  anterior maxilla, mandibular symphysis, and coronoid  process. Recent studies have shown that chondromas fre-  quently harbor somatic mutations in the isocitrate dehydro-  genase 1 (IDH1) gene.    Approximately 50% of chondromas are diagnosed in the  second, third, and fourth decades of life, and there is a  female predilection. Most gnathic examples occur in the  condyle or anterior maxilla of adult patients. Usually, the    lesions are painless and grow slowly. However, condylar  tumors may cause pain, limited mouth opening, and devia-  tion of the mandible from the midline. Lesions arising  adjacent to teeth may cause tooth mobility and root resorp-  tion. Radiographically, the chondroma typically appears as  a well-defined radiolucency with central opacification. Most  cases arise within medullary bone (enchondromas), but some  may arise just beneath the periosteum (periosteal chondro-  mas). Most chondromas are solitary, although multiple  lesions may develop in Ollier disease (sporadic chondro-  matosis with a unilateral tendency) or Maffucci syndrome  (sporadic chondromatosis with soft tissue angiomas).    Histopathologically, a chondroma appears as a_ well-  circumscribed, lobular mass of mature hyaline cartilage. The  cartilage typically demonstrates well-formed lacunae con-  taining small chondrocytes with pale cytoplasm and small,  round nuclei. Microscopic distinction between a chon-  droma and a low-grade chondrosarcoma of the jaws may be  difficult (see page 618).    It is wise to consider any jaw lesion diagnosed as a chon-  droma to represent a potential chondrosarcoma. Treatment  typically consists of complete surgical removal.    ‘The chondromyxoid fibroma is a rare, benign cartilaginous  neoplasm that represents less than 1% of all primary bone  tumors. Cytogenetic studies are limited but have detected  frequent abnormalities in chromosome 6, where a number  of candidate cartilage-related and tumor suppressor genes  are located.    Chondromyxoid fibromas most commonly involve the  metaphyseal region of long bones, especially the tibia. Only  about 2% of cases arise in the craniofacial bones.   Among reported jaw lesions, the average age at diagnosis  is 28 years (range 9 to 67 years), with a peak in the second  and third decades. There is no significant sex predilection.  Approximately three-quarters occur in the mandible. Initial  signs and symptoms often include swelling (65%) and pain  (22%). However, some cases are asymptomatic and detected  incidentally by radiographic examination.   Radiographically, chondromyxoid fibromas of the jaws  typically appear as well-circumscribed radiolucencies with  sclerotic or scalloped margins. The maximum diameter  may range from 1.0 to 6.5 cm (average 3.3 cm). Cortical  destruction is common, but the periosteum usually remains  intact. Central radiopacities are evident in about 10%  of cases.    © Fig. 14-69 Chondromyxoid Fibroma. Myxoid connective tissue  with scattered giant cells and foci of cartilaginous differentiation.    Microscopic examination shows lobules of spindle-shaped  or stellate cells with abundant myxoid or chondroid inter-  cellular substance. The lobules characteristically exhibit  increased cellularity at the periphery. Between the lobules  there is cellular fibrous tissue with spindle-shaped or round  cells and varying numbers of multinucleated giant cells  (Fig. 14-69). Focal calcifications and residual bone spicules  also may be present. Occasionally, large pleomorphic  cells may cause confusion with chondrosarcoma; however,  chondrosarcoma typically shows hypercellularity through-  out the tumor lobules and lacks a benign radiographic  appearance.    There is controversy regarding the most appropriate treat-  ment for chondromyxoid fibroma. Many authors advocate  conservative surgical removal, whereas others prefer wide  resection. In general, relatively small lesions of the jaws are  treated by local enucleation or curettage, but larger lesions  often necessitate resection. In addition, some investigators  have reported that filling the surgical defect with bone graft  material following curettage results in a lower recurrence  rate than curettage alone. Radiation therapy is contraindi-  cated because of the risk for inducing malignant transfor-  mation or osteoradionecrosis.   Although the chondromyxoid fibroma is a benign tumor,  approximately 25% of cases in the long bones recur after  curettage alone. Among reported jaw tumors, the overall  recurrence rate is about 10%.    Synovial chondromatosis is a rare, benign arthropathy  characterized by development of cartilaginous nodules  within the synovial membrane. The etiopathogenesis is  poorly understood. Traditionally, synovial chondromatosis    has been regarded as a reactive, metaplastic process. However,  recent cytogenetic studies and transgenic mouse model  studies suggest that it might represent a true, benign neo-  plasm. Examples may be subclassified as primary synovial  chondromatosis (i.e., cases with no identifiable etiologic  factors) or, more commonly, secondary synovial chondroma-  tosis (i.e., cases associated with trauma, joint overuse, inflam-  matory joint disease, or noninflammatory arthropathy).  The condition typically proceeds through three stages. In  the first stage, cartilaginous or osteocartilaginous nodules  develop in the synovial lining. Subsequently, these nodules  begin to detach, with some lying free in the joint space and  others remaining in the synovial membrane. In the final  stage, the nodules are found only in the joint space. The  detached particles are called loose bodies (or “joint mice”).    The disease most commonly affects large joints, such as the  knee, elbow, hip, and shoulder. Temporomandibular joint  (TMJ) involvement is uncommon, although in recent years  there has been an increase in reported cases, possibly because  of improved imaging techniques and increased disease  awareness.   Synovial chondromatosis of the TMJ occurs over a broad  age range (12 to 82 years), with a peak in the fourth and fifth  decades of life. In contrast to the findings in other joints,  there is a predilection for females. The clinical presentation  is nonspecific and, thus, delay in diagnosis is common.  Typical findings include periarticular swelling, pain, crepi-  tus, and limitation of joint motion. Headache, sensory dis-  turbances, and facial nerve paralysis are infrequent. In rare  instances, the disease may produce no symptoms.   The process usually is confined to a single joint. However,  bilateral involvement and extraarticular extension (e.g.,  TMJ lesions with erosion of the condylar head, skull base,  or intracranial structures) have been reported in a few cases.  Within the TMJ, the disease primarily involves the superior  compartment, although involvement of the inferior com-  partment also is possible.   Radiographically, the loose bodies in the joint may  appear as round to irregular, radiopaque structures of vari-  able size (Fig. 14-70). Other findings may include irregular-  ity of the joint surface, widening of the joint space, and  sclerosis or hyperostosis of the glenoid fossa or condyle.  Similar features, however, may be seen in other degenerative  joint diseases. Likewise, failure to detect loose bodies on  imaging studies does not preclude a diagnosis of synovial  chondromatosis. CT and magnetic resonance imaging  (MRI) are more sensitive than plain radiography for dem-  onstrating many of the characteristic features of synovial  chondromatosis.    Nodules of hyaline cartilage are present within the synovium  and lie loose in the joint space. There may be anywhere from   @ Fig. 14-70 Synovial Chondromatosis. Computed tomography  (CT) scan showing opacites of variable size within the temporoman-  dibular joint (TMJ) region. (Courtesy of Dr. K. Krishnan Unni.)    @ Fig. 14-71 Synovial Chondromatosis. Photomicrograph from  one of many nodules removed at the time of synovectomy. The carti-  lage shows some degree of atypia, and in a different clinical setting  this histopathology could be interpreted to represent a low-grade  chondrosarcoma.    1 to more than 200 loose bodies. The cartilaginous nodules  often become calcified or ossified. Particularly in primary  lesions, the chondrocytes may appear atypical with enlarged,  hyperchromatic nuclei and binucleation (Fig. 14-71).  However, correlation with the clinical and radiographic  findings may aid in distinguishing synovial chondromatosis  from chondrosarcoma.    Synovial chondromatosis of the TMJ typically is treated by  partial or complete synovectomy and removal of all loose  bodies, at times combined with meniscectomy. Condylec-  tomy is reserved for unusual cases with severe condylar  destruction. Surgery is performed most commonly via open  arthrotomy, although arthroscopy or arthrocentesis may be  used for biopsy and, in select cases, for treatment. A wider    approach is typically necessary for rare cases with extensive  extraarticular involvement.   ‘The prognosis is good, with an overall low frequency of  recurrence after surgical excision. However, some investiga-  tors have noted more aggressive behavior and a higher recur-  rence rate among primary lesions compared to secondary  lesions. Thus periodic follow-up examinations would appear  to be prudent. Malignant transformation of synovial chon-  dromatosis of the TMJ is extremely rare.    The desmoplastic fibroma of bone is a benign, locally  aggressive, myofibroblastic neoplasm that comprises less  than 1% of primary bone tumors. Clinicopathologic, ultra-  structural, and immunohistochemical findings suggest that  this tumor represents the osseous counterpart of soft tissue  fibromatosis (desmoid tumor) (see page 481). Thus far,  however, limited genetic studies of desmoplastic fibromas  of bone have not identified mutations in the CTTNBI  gene, which encodes beta-catenin and often is mutated in  soft tissue fibromatosis. In a few cases, desmoplastic fibroma-  like lesions of the jaws have been reported in association  with tuberous sclerosis.    Most desmoplastic fibromas of bone arise in patients  younger than 30 years old. The most common locations are  the mandible, femur, tibia, radius, humerus, and pelvis.   Among jaw lesions reported in the English literature, the  age range is 10 months to 60 years, with a mean of approxi-  mately 14 years. There is no significant sex predilection.  More than 80% of cases affect the mandible—most often  the posterior body, the angle, and the ramus. Most patients  exhibit a painless swelling with slow to rapid growth,  although pain has been reported in some examples. Limited  opening, malocclusion, tooth mobility, tooth displacement,  proptosis, concurrent infection, and dysesthesia also are  possible.   Radiographically, the lesion appears as a multilocular or  unilocular radiolucency with well- or ill-defined margins  (Fig. 14-72). The bone is expanded, and the cortex is  thinned; cortical reaction mimicking the appearance of an  osteosarcoma is rare. Erosion through the cortex and exten-  sion into soft tissue may be evident. In such cases, it may  be difficult to determine whether the lesion is a desmoplas-  tic fibroma of bone with soft tissue extension or a soft tissue  fibromatosis with extension into bone.    The tumor is composed of small, elongated fibroblasts and  abundant collagen fibers (Fig. 14-73). The degree of cellu-  larity may vary within a given lesion, and the cellular areas  may show plump fibroblasts. However, the fibroblasts are  not atypical, and mitoses are absent or sparse. Bone spicules    ® Fig. 14-72 Desmoplastic Fibroma. |ll-defined, destructive radio-  lucency of the left mandible.    oer LD AMR tows:  ® Fig. 14-73 Desmoplastic Fibroma. The tumor consists of a cel-  lular proliferation of fibroblasts arranged in interlacing fascicles.    may be present at the interface between the tumor and  adjacent bone but are never an integral part of the lesion.  This reactive bone at the periphery may be mistaken for  osteoid production, which may lead to a misdiagnosis of a  benign fibro-osseous lesion or osteosarcoma. Therefore,  diagnostic biopsies should be sampled generously from the  center rather than the periphery of the lesion.    Although the desmoplastic fibroma is a benign tumor, it  often behaves in a locally aggressive fashion, with extensive  bone destruction and soft tissue extension; thus, radical  surgery may be required to control the disease. Most cases  are treated by resection, although curettage may be adequate  for localized lesions without cortical perforation or soft  tissue extension. The recurrence rate is approximately 30%  for lesions treated by curettage or enucleation, compared  with about 5% for those treated by resection. Given the    potential for recurrence, patients should be monitored post-  operatively for at least 3 years. The long-term prognosis is  good, but there may be considerable morbidity. Malignant  transformation is rare.   It may be very difficult to distinguish desmoplastic  fibroma of bone from well-differentiated fibrosarcoma.  Some authorities suggest that all desmoplastic fibromas of  bone be considered potentially malignant.    Osteosarcoma is a malignancy of mesenchymal cells that  have the ability to produce osteoid or immature bone.  Excluding hematopoietic neoplasms, osteosarcoma is the  most common malignancy to originate within bone. In the  United States, the age-adjusted annual incidence is approxi-  mately 3 cases per million population.   The etiology of osteosarcoma is largely unknown. A  strong association with the adolescent growth spurt and the  metaphyses of long bones suggests that rapid bone growth  and hormonal factors may play a role. Additional risk  factors include radiation exposure, alkylating agents, Paget  disease of bone, Li-Fraumeni syndrome, hereditary retino-  blastoma, and Rothmund-Thompson syndrome. Studies  have demonstrated a complex genetic profile among osteo-  sarcomas, with alterations frequently detected in p53, RBI,  and chromosome 21q.   Osteosarcomas may be classified as central (arising within  the medullary cavity), surface (arising in the juxtacortical  region), or, vary rarely, extraskeletal (arising within soft  tissue) (Table 14-4). The vast majority of cases are central.  Surface osteosarcomas are discussed in the next section  (see page 617). In addition, some authors regard gnathic  osteosarcomas as a separate entity, because these lesions  exhibit somewhat distinctive clinical features and biologic  behavior.    Extragnathic osteosarcoma demonstrates a bimodal age dis-  tribution, with a major peak during adolescence and a lesser  peak among adults older than 60 years. The initial peak  occurs during the period of greatest bone growth; accord-  ingly, most of these osteosarcomas arise in the distal femoral  and proximal tibial metaphyses. In older patients, osteosar-  coma often is attributed to Paget disease of bone or previous  irradiation, and the axial skeleton and flat bones are involved  most frequently.   About 6% of all osteosarcomas arise in the jaws. Jaw  lesions occur over a broad age range, with a peak in the  third through fifth decades of life. The mean age is approxi-  mately 33 to 39 years, which is about 1 to 2 decades older  than the mean age for osteosarcomas of the long bones.  Both gnathic and extragnathic osteosarcomas exhibit a  slight male predilection.    ° Fig. 14-74 Osteosarcoma. A, This patient shows a firm, painful swelling of the left maxilla of recent  onset. B, The periapical radiograph shows a dense sclerotic change in the bone pattern. (Courtesy of Dr.    Most studies report either a fairly even distribution  between the mandible and maxilla or a slight mandibular  predilection. Mandibular tumors arise most frequently in  the body, followed by the angle, symphysis, and ramus.  Maxillary lesions develop more often in the inferior portion  (alveolar ridge, sinus floor, and/or palate) than the superior  aspect (zygoma and orbital rim).   Swelling and pain are the most common clinical findings  (Figs. 14-74 and 14-75). Tooth mobility, paresthesia, and  nasal obstruction (in the case of maxillary tumors) also may  be noted. Some patients report symptoms for relatively long  periods before diagnosis, which suggests that some osteo-  sarcomas of the jaws grow rather slowly.   Radiographic examination may show a radiopaque,  mixed radiolucent-radiopaque, or entirely radiolucent  lesion with ill-defined borders (Figs. 14-74, B, 14-75, B,  and 14-76). Cortical destruction, cortical expansion, and a  periosteal reaction also may be evident. The latter may  appear as a “classic” sunburst pattern (present in about 25%  of jaw osteosarcomas) or a triangular elevation of the    periosteum (Codman triangle). Occasionally, the adjacent  teeth exhibit “spiking” root resorption (with tapered nar-  rowing of the root). Symmetrical widening of the periodon-  tal ligament space (Fig. 14-77) may be an important clue  for diagnosis of early osteosarcoma, although this feature  also may be seen in other malignancies. At times an exten-  sive osteosarcoma may show only subtle variation in the  trabecular pattern. Plain radiography often is used for initial  evaluation. However, MRI is superior for assessment of  primary tumor extent, and CT is important for detection  of pulmonary metastasis.    Although osteosarcomas exhibit considerable histopatho-  logic variation, the essential microscopic criterion is direct  production of osteoid by malignant mesenchymal cells (Fig.  14-78). In addition to osteoid, the tumor cells may produce  chondroid and fibrous connective tissue. The tumor cells  may vary from relatively uniform, round or spindle-shaped    ® Fig. 14-75 Osteosarcoma. A, This massive tumor had been present for many months before the  patient sought treatment. B, Intraoral photograph of the tumor mass. C, The panoramic radiograph shows  a “sunburst” pattern of trabeculation.    @ Fig. 14-76 Osteosarcoma. Computed tomography (CT) scan  showing a mottled radiopacity of the mandible with cortical destruction  and a focal “sunburst” periosteal reaction. (Courtesy of Dr. Steve  Anderson.)    ® Fig. 14-77 Osteosarcoma. This 26-year-old woman had a 6-cm  painful tumor of the anterior mandible. The periapical radiograph  shows widening of the periodontal ligament spaces and a mottled  radiopacity superimposed on the teeth. (Courtesy of Dr. Charles  Ferguson.)    cells to highly pleomorphic cells with bizarre nuclear  and cytoplasmic shapes. The amount of matrix produced  by the tumor may vary considerably. In some instances,  osteoid production may be very minimal and difficult to  demonstrate.   Depending on the relative amounts of osteoid, cartilage,  or collagen produced by the tumor, many pathologists sub-  classify conventional osteosarcomas into the following  types:   These histopathologic types, however, do not have any  great bearing on the prognosis. Less common variants are  listed in Table 14-4.   Chondroblastic osteosarcomas constitute a substantial  proportion of all osteosarcomas of the jaws. Some exam-  ples may be composed almost entirely of malignant carti-  lage growing in lobules with only small foci of direct  osteoid production by tumor cells (Fig. 14-79). Such  lesions, however, should be classified as osteosarcomas  rather than chondrosarcomas. Interestingly, one recent    study has shown that chondroblastic osteosarcomas lack  IDHI1 mutations, whereas such mutations are frequent  among chondrosarcomas.   Low-grade osteosarcomas show minimal cellular atypia  and abundant bone formation. On microscopic examina-  tion, these lesions may be difficult to differentiate from  benign bone lesions, such as fibrous dysplasia or ossifying  fibroma. Correlation with imaging studies is essential for  accurate diagnosis. Immunohistochemical expression of  MDM2 and CDK4 also may help to distinguish low-grade  osteosarcoma from benign fibro-osseous lesions and other  benign bone tumors.    ‘The treatment of choice for osteosarcoma of the jaws is wide  surgical resection. The additional use of chemotherapy and/  or radiotherapy for gnathic osteosarcomas is controversial  but may be considered in some cases (e.g., tumors of ques-  tionable resectability, surgical margins positive for tumor,  and recurrent tumors). For high-grade osteosarcomas of the  long bones, management usually consists of neoadjuvant  (preoperative) chemotherapy followed by radical surgery  and adjuvant (postoperative) chemotherapy. Among patients  with localized disease at diagnosis, such treatment has  resulted in 5-year survival rates of approximately 60% to  80%, compared to only about 20% with surgery alone.  However, for patients with gnathic osteosarcomas, such  protocols have yielded variable outcomes, and further  studies are needed.   The most important prognostic factor is the ability to  achieve initial complete surgical removal. Compared to  mandibular lesions, maxillary lesions often are more diffi-  cult to resect and exhibit a worse prognosis. Additional  adverse factors include prior radiation exposure and under-  lying Paget disease of bone. Interestingly, some investigators  have reported a better prognosis for osteosarcoma of the  jaws than osteosarcoma of the long bones. This observation  may be related to a tendency for gnathic osteosarcomas to  exhibit a low rate of metastasis despite often high-grade  histopathologic features. However, other studies have shown  no significant survival advantage among patients with  gnathic osteosarcoma.   For patients with osteosarcoma of the jaws, death results  more often from uncontrolled local disease than from  distant metastases. Most deaths from uncontrolled local  disease occur within 2 years of initial treatment. Metastases  most often affect the lungs. In recent years, most large series  of jaw tumors have reported 5-year overall survival rates of  approximately 60% to 70%, and some centers have reported  greater than 80% survival.    Although most osteosarcomas arise within the medullary  cavity of bone, some cases originate in the periosteal or    ® Fig. 14-80 Peripheral (Juxtacortical) Osteosarcoma. |llustra-  tion comparing different types of peripheral osteosarcoma. Parosteal  osteosarcoma presents as a lobulated nodule without a peripheral  periosteal reaction. Periosteal osteosarcoma presents as a sessile  mass associated with significant periosteal new bone formation.    cortical region with little or no medullary involvement.  Such surface lesions typically involve the long bones,  although gnathic cases rarely have been reported. Surface  osteosarcoma includes the following subtypes:   Parosteal osteosarcoma appears as a lobulated, exo-  phytic nodule attached to the cortex by a short, broad stalk  (Fig. 14-80). There is no elevation of the periosteum and  no peripheral periosteal reaction. Radiographs may demon-  strate a radiolucent line (“string sign”) that corresponds to  the periosteum between the sclerotic tumor and the under-  lying cortex. Histopathologic examination shows a spindle  cell fibroblast-like proliferation with well-developed, elon-  gated bony trabeculae, often arranged in a parallel streaming  or “pulled steel wool” pattern. A cartilaginous component  also may be evident in some cases. Parosteal osteosarcomas  are low-grade tumors, with a low risk for recurrence and  metastasis following radical excision. However, long-  standing or inadequately excised tumors may become higher  grade osteosarcomas.   Periosteal osteosarcoma appears as a sessile lesion that  arises between the cortex and the inner (or cambium) layer  of the periosteum (see Fig. 14-80). Thus, a periosteal reac-  tion often is evident radiographically. The tumor frequently  perforates the periosteum and extends into the surround-  ing soft tissue. Histopathologically, the tumor demon-  strates primitive sarcomatous cells with chondroblastic  differentiation. Close inspection reveals focal osteoid or  immature bone formation. Radical surgical excision is the    therapy of choice. Periosteal osteosarcoma is an intermediate-  grade tumor, with a prognosis better than conventional  intramedullary osteosarcoma but worse than _parosteal  osteosarcoma.   High-grade surface osteosarcoma is extremely rare.  This variant is similar to conventional intramedullary osteo-  sarcoma in terms of microscopic features and biologic  behavior.    Sarcoma arising in bone previously subjected to radiation  therapy is an uncommon but well-recognized phenomenon.  The jaws and craniofacial bones are among the more  common sites for such tumors. Bone sarcomas have been  reported to develop 3 to 55 years after radiation exposure,  with a mean latency period of about 4 to 17 years. Studies  estimate that 0.03% to 0.2% of irradiated patients develop  postirradiation bone or soft tissue sarcomas. The risk appears  to increase with increasing radiation dose. Reported mean  and median radiation doses for postirradiation bone sarco-  mas vary from 43 to 64 Gy. Some investigators have sug-  gested that the risk is negligible with a dose less than 10  Gy; however, a recent prospective study of atomic bomb  survivors in Japan suggests an increased risk for bone  sarcoma with a radiation dose as low as 0.85 Gy. Osteosar-  coma is the most common postirradiation bone sarcoma  type, accounting for 49% to 85% of cases. Other reported  types include undifferentiated pleomorphic sarcoma (malig-  nant fibrous histiocytoma), fibrosarcoma, and chondrosar-  coma. The lesions tend to be poorly differentiated, and the  prognosis is generally poor.    Chondrosarcoma is a malignant neoplasm in which the  tumor cells form cartilage but not bone. Chondrosarcoma  is about half as common as osteosarcoma and twice as  common as Ewing sarcoma. Chondrosarcomas comprise  about 11% of all primary malignant bone tumors but  involve the jaws only rarely. Approximately 1% to 12%  of all chondrosarcomas arise in the head and neck, and  such lesions comprise only 0.1% of all head and neck  malignancies.   Chondrosarcoma may develop de novo (primary chondro-  sarcoma) or from a preexisting benign cartilaginous tumor  (secondary chondrosarcoma). The histogenesis is controver-  sial; investigators have hypothesized that the tumor may  originate from chondrocytes, embryonal chondroid, or plu-  ripotential mesenchymal stem cells. Interestingly, there is an  increased risk for chondrosarcoma among patients with  Ollier disease and Maffucci syndrome (see page 611). These  forms of chondromatosis are associated with somatic muta-  tions in isocitrate dehydrogenase 1 (DH) gene and isoci-  trate dehydrogenase 2 (IDH2) gene; likewise, chondromas  and chondrosarcomas of bone frequently exhibit LDH  mutations.    Although chondrosarcoma develops over a broad age range,  most affected patients are older. In the United States, the  mean age at diagnosis is approximately 51 years, and there  is a slight male predilection. The most frequently involved  sites are the ilium, femur, humerus, and ribs.   Gnathic chondrosarcomas exhibit a predilection for the  anterior maxilla. In contrast, mandibular tumors tend to  favor the posterior region. Other possible sites of involve-  ment in the head and neck include the paranasal sinuses,  nasal septum, skull base, and cervical vertebrae. Most head  and neck chondrosarcomas develop within bone, but  approximately one-third of cases originate in either laryn-  gotracheal cartilage or soft tissue. According to one large  case series, chondrosarcomas of gnathic and facial bones  occur over a broad age range with peak prevalence in the  seventh decade and a mean age at diagnosis of approxi-  mately 42 years. Some studies have noted a greater propor-  tion of young patients with craniofacial chondrosarcomas  compared to chondrosarcomas in other sites; however, other  studies have not confirmed this finding.   A painless swelling is the most common presenting sign.  In contrast to osteosarcoma, pain is an unusual complaint.  Jaw lesions may cause separation or loosening of teeth.  Maxillary tumors may cause nasal obstruction, congestion,  epistaxis, photophobia, or visual loss.   Radiographically, chondrosarcoma usually appears as an  ill-defined radiolucency with radiopaque foci (Fig. 14-81).  These radiopaque foci correspond to calcification or ossifi-  cation of the cartilage matrix. Some cases show extensive  calcification and primarily appear radiopaque. Infrequently,  there is lobular growth with minimal or no calcification;  such lesions may appear as multilocular radiolucencies that  mimic a benign process. Penetration of the cortex can result  in a sunburst pattern similar to that seen in some osteosar-  comas. Jaw tumors may cause root resorption or symmetri-  cal widening of the periodontal ligament space of adjacent  teeth.    Chondrosarcomas tend to be highly infiltrative. Although  plain radiography typically is used for initial evaluation,  MRI is the best method for assessing tumor extent. In addi-  tion, CT may help to demonstrate calcifications.    Chondrosarcomas are composed of cartilage showing  varying degrees of maturation and cellularity. In most cases,  lacunar formation within the chondroid matrix is evident,  although this feature may be scarce in poorly differentiated  tumors. The tumor often shows a lobular growth pattern.  The central areas of the lobules demonstrate the greatest  degree of maturation, whereas the peripheral areas tend to  exhibit immature cartilage and mesenchymal tissue consist-  ing of round or spindle-shaped cells. Calcification or ossi-  fication may occur within the chondroid matrix. Neoplastic  cartilage may be replaced by bone in a manner similar to  normal endochondral ossification. Distinction between  metaplastic bone formation and malignant osteoid produc-  tion is important for differentiating chondrosarcoma from  chondroblastic osteosarcoma.   Chondrosarcomas may be assigned a_ histopathologic  grade of I through HI. Low-grade tumors closely resemble  normal cartilage and may be very difficult to distinguish  from chondromas. With increasing tumor grade, there is a  decreased amount of cartilaginous matrix but increased cel-  lularity, nuclear size, nuclear pleomorphism, binucleated or  multinucleated chondrocytes, cellular spindling, mitotic  activity, and necrosis. Most chondrosarcomas of the jaws are  grade I or II (Fig. 14-82).   ¢ Clear cell chondrosarcoma is a low-grade variant exhib-  iting cells with abundant clear cytoplasm. This variant  may be difficult to differentiate from metastatic clear cell  carcinoma.    ¢ Dedifferentiated chondrosarcoma is a_ high-grade  variant that shows an admixture of well-differentiated  chondrosarcoma and a high-grade sarcoma. This variant  is exceedingly rare in the jaws.   ¢ Myxoid chondrosarcoma classically is described as a  soft tissue tumor, although intraosseous lesions are pos-  sible. This variant is characterized by a proliferation of  cells with clear, vacuolated, or eosinophilic cytoplasm  within a background of mucoid material.    Surgical resection is the mainstay of treatment for chondro-  sarcoma. Curettage followed by cryosurgery may be an  alternative for grade I chondrosarcomas confined within  bone, although this technique mainly is used for long bone  tumors. Radiation and chemotherapy are less effective for  chondrosarcoma than osteosarcoma and are used primarily  for high-grade chondrosarcomas. Radiation also may be  considered for residual, recurrent, or unresectable disease.   Major prognostic factors for chondrosarcoma include  clinical stage, histopathologic grade, and adequacy of resec-  tion. In the United States, the relative 5-year survival rate  is approximately 75%. The 30-year disease-specific survival  rates for patients with localized disease, regional metastasis,  and distant metastasis are 43%, 22%, and less than 10%,  respectively. Because recurrence often is a late sequela,  patients must be followed for their lifetime.   Head and neck chondrosarcomas typically are locally  aggressive with low metastatic potential. Metastasis mainly  is seen among rare high-grade tumors. Nevertheless, death  may occur by direct extension into vital structures. In par-  ticular, maxillary tumors often are large at diagnosis, occur  adjacent to the central nervous system, and are difficult to  resect; therefore, they are difficult to cure. In the National  Cancer Database series of 400 head and neck chondrosar-  comas, the overall 5- and 10-year disease-specific survival  rates were 87.2% and 70.6%, respectively. In the Mayo  Clinic series of 56 chondrosarcomas of the jaws and facial  bones, the 5-, 10-, and 15-year survival rates were 67.6%,    Mesenchymal chondrosarcoma is an aggressive variant of  chondrosarcoma with a distinctive biphasic histopathologic  pattern. It is considered high-grade based on clinical behav-  ior rather than histopathologic features. This variant repre-  sents only about 1% to 9% of all chondrosarcomas.    In contrast to other chondrosarcoma types, the mesenchy-  mal variant is unusual in that it most frequently affects  individuals in the second and third decades of life and most    © Fig. 14-83 Mesenchymal Chondrosarcoma. Periapical radio-  graph showing an ill-defined radiolucency with associated root resorp-  tion. (Courtesy of Dr. Michael Robinson.)    photomicrograph showing sheets of small basophilic cells with focal  areas of cartilaginous differentiation (right).    often arises in the jaws (22% to 27% of cases). Other com-  monly affected sites are the ribs, shoulder, pelvic girdle, and  vertebrae. In addition, about one-third of cases arise in soft  tissue rather than bone.   Swelling and pain, often of fairly short duration, are the  most common symptoms. Radiographically, the tumor  typically appears as an ill-defined radiolucency with or  without stippled calcification (Fig. 14-83). However, some  examples may appear predominantly radiopaque, particu-  larly within the maxilla.    Microscopic examination shows two distinct elements: well-  differentiated cartilaginous nodules and sheets of small,  undifferentiated, spindled or round cells (Fig. 14-84). The  degree of cellularity and atypia within the cartilaginous  component may vary from that of a benign chondroma to  a low-grade chondrosarcoma. ‘The undifferentiated compo-  nent may exhibit a branching vascular pattern that mimics  hemangiopericytoma. In addition, the undifferentiated    component may appear similar to rhabdomyosarcoma,  Ewing sarcoma, lymphoma, or metastatic small cell  carcinoma.    Surgical excision with wide margins is the mainstay of  therapy. Some studies have suggested that supplemental  radiation therapy and/or chemotherapy may be beneficial,  although further investigation is needed. Close long-term  follow-up is recommended, because local recurrence and  metastasis are common and may be discovered more than  20 years after initial therapy. Metastasis most frequently  develops in the lungs. Reported overall 5- and 10-year sur-  vival rates range from 35% to 65% and 20% to 40%,  respectively. Some authors have suggested that jaw lesions  exhibit a favorable prognosis with a 5-year survival rate of  82%, although a recent review of maxillary lesions reported  a 5-year survival rate of only 59%.    Ewing sarcoma is a malignant neoplasm composed of  small, undifferentiated round cells. In the United States, the  annual incidence is approximately 1 per million population.  Although rare, Ewing sarcoma is the second most common  primary malignant bone tumor in pediatric patients after  osteosarcoma. The term Ewing sarcoma (or the Ewing  sarcoma family of tumors) includes classical Ewing sarcoma  of bone, extraosseous Ewing sarcoma, primitive neuroecto-  dermal tumor (Ewing sarcoma with neuronal differentia-  tion), and Askin tumor (small round cell tumor of the chest  wall). Based on shared histologic, immunohistochemical,  and genetic characteristics, authorities currently consider  these entities to represent the same tumor type.   The histogenesis of Ewing sarcoma is unknown. Investi-  gators previously have hypothesized that the tumor origi-  nates from the neural crest. However, current evidence  favors an origin from mesenchymal stem cells with potential  for limited neural differentiation. At the molecular level,  Ewing sarcoma is defined by balanced chromosomal trans-  locations that result in fusion of the RNA-binding protein  EWS (or the closely related FUS protein) with ETS family  transcription factors (e.g., FLI1, ERG, ETV1, ETV4, and  FEY). In particular, more than 85% of cases demonstrate  the translocation t(11;22) (q24;q12), which encodes the  EWS-FLI1 fusion protein.    Most patients with Ewing sarcoma are adolescents, and the  median age at diagnosis is 15 years. However, advances in  molecular diagnosis have led to a recent increase in the  number of cases diagnosed in young adults. There is a slight  male predominance, and the majority of patients are white.  Osseous lesions most frequently involve the long bones,  pelvis, and ribs. Only 1% to 2% of cases arise in the gnathic    @ Fig. 14-85 Ewing Sarcoma. A rapidly growing, ulcerated tumor  of the right posterior mandible. (Courtesy of Dr. George Blozis.)    or craniofacial bones. Primary extraosseous lesions are also  possible but very rare.   The most common clinical findings are pain and swell-  ing. Fever, leukocytosis, and an elevated erythrocyte sedi-  mentation rate also may be present in advanced disease.  The tumor often penetrates the cortex, resulting in a soft  tissue mass overlying the affected area of the bone (Fig.  14-85). Jaw involvement is more common in the mandible  than the maxilla and may result in paresthesia and tooth  mobility. The nonspecific clinicoradiographic presentation  may lead to a misdiagnosis of odontogenic infection or  osteomyelitis.   Radiographically, most osseous lesions appear as ill-  defined radiolucencies, although a mixed radiolucent and  radiopaque pattern also is possible. Cortical destruction or  expansion may or may not be present. The characteristic  “onionskin” periosteal reaction, commonly observed in  Ewing sarcoma of long bones, seldom is seen in jaw lesions.  Although plain radiography often is used for initial evalua-  tion, CT and MRI are superior for assessing lesion extent.    Ewing sarcoma typically is composed of broad sheets of  small, monotonous, round cells with well-delineated nuclear  outlines and ill-defined cellular borders (Fig. 14-86). In  some cases, variable-sized nests of tumor cells are separated  by fibrovascular septa, creating a lobular pattern. Extensive  necrosis and hemorrhage are common.   Diagnosis may be difficult. Ewing sarcoma must be dif-  ferentiated from other pediatric small round cell tumors,  such as metastatic neuroblastoma, malignant lymphoma,  small cell osteosarcoma, and alveolar rhabdomyosarcoma.  Metastatic small cell carcinoma also may be considered in  the differential diagnosis of a suspected Ewing sarcoma in  an older patient.   Ewing sarcomas typically exhibit cytoplasmic periodic  acid-Schiff (PAS)-positive glycogen granules and membra-  nous immunoreactivity for CD99 (MIC2), although these  findings are nonspecific. Immunohistochemical expression    © Fig. 14-86 Ewing Sarcoma. Broad sheets of small round cells  with well-defined nuclear outlines and ill-defined cytoplasmic borders.    of Flil also has been described, although with variable sen-  sitivity and specificity. Identification of characteristic chro-  mosomal translocations by reverse transcription polymerase  chain reaction (RT-PCR) or fluorescence in situ hybridiza-  tion (FISH) may aid in confirming the diagnosis.    Treatment usually consists of multidrug chemotherapy with  surgery and/or radiotherapy. Systemic chemotherapy typi-  cally is indicated, because seemingly localized disease often  is associated with occult micrometastases. Investigational  treatments include insulin-like growth factor-1 receptor  (IGF1R) blocking agents and myeloablative stem cell  transplantation.   With the development of modern multimodal therapy,  the prognosis for patients with Ewing sarcoma has improved  dramatically in recent decades. Current 5-year survival rates  for patients with apparently localized versus metastatic  disease at presentation are approximately 70% and 25%,  respectively. The presence of metastasis is the most impor-  tant prognostic factor, and metastasis is evident at initial  diagnosis in about 25% of patients. The most common sites  of metastasis are the lungs and bones; for reasons unknown,  patients with extrapulmonary metastasis tend to fare worse  than those with metastasis confined to the lungs. There is  limited data regarding gnathic Ewing sarcoma, although  lesions arising in the jaws appear to exhibit a more favorable  prognosis compared to those arising in the long bones  and pelvis.    Metastatic carcinoma is the most common form of cancer  involving bone. The most common primary sites for carci-  nomas that metastasize to bone are the breast, lung, thyroid,  prostate, and kidney. The bones that most frequently exhibit  metastasis include the vertebrae, ribs, pelvis, and skull.  Jaw metastasis is rare but may occur more often than  generally appreciated. In an autopsy study of mandibles    ° Fig. 14-87 Thyroid Carcinoma Metastatic to the Jaws. Radio-  graph showing an ill-defined, destructive radiolucency with irregular  borders at the angle of the mandible. (Courtesy of Dr. Terry Day.)    from patients with various extraoral primary carcinomas,  microscopic examination revealed metastasis in 16% of  cases, with most of these metastases found to be clinically,  radiographically, and grossly undetectable. Metastatic spread  of a carcinoma to the jaws usually occurs by the hematog-  enous route. Sarcomas arising in soft tissues or other bones  metastasize to the jaws only very rarely.    Jaw metastases have been reported over a broad age range  but most often affect older adults; the mean age is approxi-  mately 43 to 52 years, with no significant gender bias. There  is a marked predilection for the mandible, especially the  molar region.   Clinical signs and symptoms of jaw metastasis may  include pain, swelling, tooth mobility, trismus, and pares-  thesia. In particular, mandibular metastasis with involve-  ment of the mental nerve may produce paresthesia in the  lower lip and chin (numb-chin syndrome). The rarity of  jaw metastases and the nonspecific clinical presentation may  lead to a mistaken impression of an inflammatory process.  Sometimes an osseous metastasis is discovered in a nonheal-  ing extraction site from which a tooth was removed because  of local pain or significant mobility. In other instances, the  patient may be completely asymptomatic, and the lesion is  discovered incidentally by radiographic examination.   Occasionally, diagnosis of a jaw metastasis is the first  indication that the patient has a primary malignancy at  some other anatomic site. Location of the occult primary  tumor may be difficult and may require extensive  evaluation.   Most radiographically evident jaw metastases appear as  ill-defined or “moth-eaten” radiolucencies (Fig. 14-87).  However, some examples—particularly metastatic prostate  and breast carcinomas—may appear radiopaque or mixed  radiocent-radiopaque. Osteolytic (bone-resorbing) and/or  osteoblastic (bone-forming) activity may result from various  growth factors and other substances produced by tumor    ° Fig. 14-88 Carcinoma Metastatic to the Jaws. Periapical radio-  graph showing widening of the periodontal ligament spaces.    cells. Some lesions may mimic periapical inflammatory  disease or periodontal disease. Cortical erosion, pathologic  fracture, and widening of the periodontal ligament space  may be noted as well (Fig. 14-88). Compared to plain  radiography, bone scintigraphy is more sensitive for detect-  ing osseous metastases.    The microscopic appearance of metastatic carcinoma in  bone varies. In some instances, the metastasis exhibits well-  differentiated features that suggest an origin from a specific  site, such as the kidney, colon, or thyroid. More often,  however, metastatic carcinomas are poorly differentiated,  and the tumor origin is not readily apparent (Fig. 14-89).  Poorly differentiated metastatic carcinoma may be difficult  to differentiate from lymphoma, melanoma, or anaplastic  sarcoma. In such cases, immunohistochemistry may aid in  diagnosis. Definitive diagnosis requires correlation of labo-  ratory studies with a thorough medical history, complete  physical examination, and imaging studies.    Although a solitary metastatic focus may be treated by exci-  sion or radiation therapy, jaw metastasis almost always is  associated with widely disseminated disease. Management  depends on the specific underlying tumor type and often is    @ Fig. 14-89 Carcinoma Metastatic to the Jaws. 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Whaley JT; Indelicato DJ, Morris CG, et al: Ewing sarcoma of the  head and neck, Am J Clin Oncol 33:321-326, 2010.   Akinbami BO: Metastatic carcinoma of the jaws: a review of litera-  ture, Mig J Med 18:139-142, 2009.   D’Silva NJ, Summerlin DJ, Cordell KG, et al: Metastatic tumors in  the jaws: a retrospective study of 114 cases, J Am Dent Assoc  137:1667-1672, 2006.   Hashimoto N, Kurihara K, Yamasaki H, et al: Pathologic character-  istics of metastatic carcinoma in the human mandible, J Oral    Hirshberg A, Shnaiderman-Shapiro A, Kaplan I, et al: Metastatic  tumors to the oral cavity—pathogenesis and analysis of 673 cases,    Oral Oncol 44:743-752, 2008.  Kumar GS, Manjunatha BS: Metastatic tumors to the jaws and oral  cavity, J Oral Maxillofac Pathol 17:71-75, 2013.    Odontogenic cysts and tumors constitute an important  aspect of oral and maxillofacial pathology. Odontogenic  cysts are encountered relatively commonly in dental prac-  tice. Odontogenic tumors, by contrast, are uncommon  lesions. Even in the specialized oral and maxillofacial pathol-  ogy laboratory, less than 1% of all specimens received are  odontogenic tumors.    With rare exceptions, epithelium-lined cysts in bone are  seen only in the jaws. Other than a few cysts that may result  from the inclusion of epithelium along embryonic lines of  fusion, most jaw cysts are lined by epithelium that is derived  from odontogenic epithelium. These are referred to as  odontogenic cysts. (Nonodontogenic jaw cysts are dis-  cussed in Chapter 1.)   Odontogenic cysts are subclassified as developmental or  inflammatory in origin. The inciting factors that initiate the  formation of developmental cysts are unknown, but these  lesions do not appear to be the result of an inflammatory  reaction. Inflammatory cysts are the result of inflamma-  tion. Box 15-1 presents categories of odontogenic cysts  modified from the 2005 World Health Organization  (WHO) classification. (The periapical cyst is discussed in  Chapter 3.)    ‘The dentigerous cyst is defined as a cyst that originates by  the separation of the follicle from around the crown of an  unerupted tooth. This is the most common type of devel-  opmental odontogenic cyst, making up about 20% of all  epithelium-lined cysts of the jaws. The dentigerous cyst  encloses the crown of an unerupted tooth and is attached  to the tooth at the cementoenamel junction (Fig. 15-1). The  pathogenesis of this cyst is uncertain, but apparently it  develops by accumulation of fluid between the reduced  enamel epithelium and the tooth crown.   Although most dentigerous cysts are considered to be  developmental in origin, there are some examples that  appear to have an inflammatory pathogenesis. For example,    it has been suggested that, on occasion, a dentigerous cyst  may develop around the crown of an unerupted permanent  tooth as a result of periapical inflammation from an overly-  ing primary tooth. Another scenario involves a partially  erupted mandibular third molar that develops an inflamed  cystlike lesion along the distal or buccal aspect. Although  many such lesions probably are due to inflammation associ-  ated with recurrent pericoronitis, these lesions are usually  diagnosed as examples of dentigerous cyst, especially because  it is impossible to determine histopathologically whether  the inflammatory component is primary or secondary in  nature. The term paradental cyst sometimes has been  applied to these lesions, but the use of this term in the  literature is confusing because it also has been used to  describe examples of what is known as the buccal bifurcation  cyst (see page 650).    Although dentigerous cysts may occur in association with  any unerupted tooth, most often they involve mandibular  third molars, accounting for approximately 65% of all cases.  Other relatively frequent sites include maxillary canines,  maxillary third molars, and mandibular second premolars.  Dentigerous cysts rarely involve unerupted deciduous teeth.  Occasionally, they are associated with supernumerary teeth  or odontomas. Multiple dentigerous cysts have been  reported, although this is an infrequent finding.   Although dentigerous cysts may be encountered in  patients across a wide age range, they are discovered most  frequently in patients between 10 and 30 years of age. There  is a slight male predilection, and the prevalence is higher  for whites than for blacks. Small dentigerous cysts are  usually completely asymptomatic and are discovered only  on a routine radiographic examination or when films are  taken to determine the reason for the failure of a tooth to  erupt. Dentigerous cysts can grow to a considerable size,  and large cysts may be associated with a painless expansion  of the bone in the involved area. Extensive lesions may  result in facial asymmetry. Large dentigerous cysts are  uncommon, and most lesions that are considered to be large  dentigerous cysts on radiographic examination prove to be  odontogenic keratocysts (OKCs) or ameloblastomas. Den-  tigerous cysts may become infected and be associated with   Odontogenic keratocyst (OKC)*  Orthokeratinized odontogenic cyst  Gingival (alveolar) cyst of the newborn  Gingival cyst of the adult    e Periapical (radicular) cyst  e Residual periapical (radicular) cyst  e Buccal bifurcation cyst    *Although the OKC is included with the odontogenic tumors in the 2005 World  Health Organization (WHO) classification (“keratocystic odontogenic tumor’),  the authors still favor including it in the odontogenic cyst category.   TAlthough the calcifying odontogenic cyst is included with odontogenic tumors  in the 2005 WHO classification (“calcifying cystic odontogenic tumor’), it is  discussed with the odontogenic cysts in this chapter.    ° Fig. 15-1 Dentigerous Cyst. Gross specimen of a dentigerous  cyst involving a maxillary canine tooth. The cyst has been cut open to  show the cyst-to-crown relationship.    pain and swelling. Such infections may arise in a dentiger-  ous cyst that is associated with a partially erupted tooth or  by extension from a periapical or periodontal lesion that  affects an adjacent tooth.   Radiographically, the dentigerous cyst typically shows a  unilocular radiolucent area that is associated with the crown  of an unerupted tooth. The radiolucency usually has a well-  defined and often corticated border, but an infected cyst  may show ill-defined borders. A large dentigerous cyst may  give the impression of a multilocular process because of the  persistence of bone trabeculae within the radiolucency. The  cyst-to-crown relationship shows several radiographic varia-  tions. In the central variety, which is the most common,  the cyst surrounds the crown of the tooth and the crown  projects into the cyst (Fig. 15-2). The lateral variety is  usually associated with mesioangular impacted mandibular    e Fig. 15-2 Dentigerous Cyst. Central type showing the crown  projecting into the cystic cavity. (Courtesy of Dr. Stephen E. Irwin.)    @ Fig. 15-3 Dentigerous Cyst. Lateral variety showing a large cyst  along the mesial root of the unerupted molar. This cyst exhibited  mucous cell prosoplasia. (Courtesy of Dr. John R. Cramer.)    third molars that are partially erupted. The cyst grows later-  ally along the root surface and partially surrounds the crown  (Fig. 15-3). In the circumferential variant, the cyst sur-  rounds the crown and extends for some distance along the  root so that a significant portion of the root appears to lie  within the cyst (Fig. 15-4). Rarely, a third molar may be  displaced to the lower border of the mandible or higher up  into the ascending ramus. Maxillary anterior teeth may be  displaced into the floor of the nose, and other maxillary  teeth may be moved through the maxillary sinus to the floor  of the orbit. Dentigerous cysts may displace the involved  tooth for a considerable distance. Root resorption of adja-  cent erupted teeth can occur.   Radiographic distinction between a small dentigerous  cyst and an enlarged follicle about the crown of an  unerupted tooth is difficult and may be largely an aca-  demic exercise (Fig. 15-5). For the lesion to be considered  a dentigerous cyst, some investigators believe that the  radiolucent space surrounding the tooth crown should  be at least 3 to 4 mm in diameter. Radiographic find-  ings are not diagnostic for a dentigerous cyst, however,  because OKCs, unilocular ameloblastomas, and many  other odontogenic and nonodontogenic tumors may have    ® Fig. 15-4 Dentigerous Cyst. Circumferential variety showing cyst  extension along the mesial and distal roots of the unerupted tooth.  (Courtesy of Dr. Richard Marks.)    ® Fig. 15-5 Dentigerous Cyst or Enlarged Follicle. Radiolucent  lesion involving the crown of an unerupted mandibular premolar. Dis-  tinction between a dentigerous cyst and an enlarged follicle for a lesion  of this size by radiographic and even histopathologic means is difficult,  if not impossible. (Courtesy of Dr. Wally Austelle.)    radiographic features that are essentially identical to those  of a dentigerous cyst.    The histopathologic features of dentigerous cysts vary,  depending on whether the cyst is inflamed or not inflamed.  In the noninflamed dentigerous cyst, the fibrous connec-  tive tissue wall is loosely arranged and contains considerable  glycosaminoglycan ground substance. Small islands or cords  of inactive-appearing odontogenic epithelial rests may be  present in the fibrous wall. Occasionally these rests may be  numerous, and at times pathologists who are not familiar  with oral lesions have misinterpreted this finding as amelo-  blastoma. The epithelial lining consists of two to four layers  of flattened nonkeratinizing cells, and the epithelium and  connective tissue interface is flat (Fig. 15-6).   In the fairly common inflamed dentigerous cyst, the  fibrous wall is more collagenized, with a variable infiltration  of chronic inflammatory cells. The epithelial lining may  show varying amounts of hyperplasia with the development    dentigerous cyst  shows a thicker epithelial lining with hyperplastic rete ridges. The  fibrous cyst capsule shows a diffuse chronic inflammatory infiltrate.    of rete ridges and more definite squamous features (Fig.  15-7). A keratinized surface is sometimes seen, but these  changes must be differentiated from those observed in the  OKC. Focal areas of mucous cells may be found in the  epithelial lining of dentigerous cysts (Fig. 15-8). Rarely,  ciliated columnar cells are present. Small nests of sebaceous  cells rarely may be noted within the fibrous cyst wall. These  mucous, ciliated, and sebaceous elements are believed to  represent the multipotentiality of the odontogenic epithelial  lining in a dentigerous cyst.   Gross examination of the wall of a dentigerous cyst may  reveal one or several areas of nodular thickening on the  luminal surface. These areas must be examined microscopi-  cally to rule out the presence of early neoplastic change.   Because a thin layer of reduced enamel epithelium nor-  mally lines the dental follicle surrounding the crown of an  unerupted tooth, it can be difficult to distinguish a small  dentigerous cyst from simply a normal or enlarged dental  follicle based on microscopic features alone. Again, this  distinction often represents largely an academic exercise; the  most important consideration is ensuring that the lesion  does not represent a more significant pathologic process  (e.g., OKC or ameloblastoma).    The usual treatment for a dentigerous cyst is careful enucle-  ation of the cyst together with removal of the unerupted  tooth. If eruption of the involved tooth is considered fea-  sible, then the tooth may be left in place after partial removal  of the cyst wall. Patients may need orthodontic treatment  to assist eruption. Large dentigerous cysts also may be  treated by marsupialization. This permits decompression of  the cyst, with a resulting reduction in the size of the bone  defect. The cyst can then be excised at a later date, with a  less extensive surgical procedure.   ‘The prognosis for most dentigerous cysts is excellent, and  recurrence seldom is noted after complete removal of the  cyst. However, several potential complications must be con-  sidered. Much has been written about the possibility that  the lining of a dentigerous cyst might undergo neoplastic  transformation to an ameloblastoma. Although undoubt-  edly this can occur, the frequency of such neoplastic trans-  formation is low. Rarely, a squamous cell carcinoma may  arise in the lining of a dentigerous cyst (see page 651). It is  likely that some intraosseous mucoepidermoid carcino-  mas (see page 457) develop from mucous cells in the lining  of a dentigerous cyst.    The eruption cyst is the soft tissue analogue of the dentiger-  ous cyst. The cyst develops as a result of separation of the  dental follicle from around the crown of an erupting tooth  that is within the soft tissues overlying the alveolar bone.    The eruption cyst appears as a soft, often translucent swell-  ing in the gingival mucosa overlying the crown of an erupt-  ing deciduous or permanent tooth. Most examples are seen  in children younger than age 10. Although the cyst may  occur with any erupting tooth, the lesion is most commonly    e Fig. 15-9 Eruption Cyst. This soft gingival swelling contains  considerable blood and can also be designated as an eruption  hematoma.    @ Fig. 15-10 Eruption Cyst. A cystic epithelial cavity can be seen  below the mucosal surface.    associated with the deciduous mandibular central incisors,  the first permanent molars, and the deciduous maxillary  incisors. Surface trauma may result in a considerable amount  of blood in the cystic fluid, which imparts a blue to purple-  brown color. Such lesions sometimes are referred to as erup-  tion hematomas (Fig. 15-9).    Intact eruption cysts seldom are submitted to the oral and  maxillofacial pathology laboratory, and most examples  consist of the excised roof of the cyst, which has been  removed to facilitate tooth eruption. These show surface  oral epithelium on the superior aspect. The underlying  lamina propria shows a variable inflammatory cell infiltrate.  The deep portion of the specimen, which represents the roof  of the cyst, shows a thin layer of nonkeratinizing squamous  epithelium (Fig. 15-10).    Treatment may not be required because the cyst usually  ruptures spontaneously, permitting the tooth to erupt. If    this does not occur, then simple excision of the roof of the  cyst generally permits speedy eruption of the tooth.    The concept and meaning of the term primordial cyst  often have been controversial and confusing. In the older  classification of cysts used in the United States, the primor-  dial cyst was considered to originate from cystic degenera-  tion of the enamel organ epithelium before the development  of dental hard tissue. Therefore, the primordial cyst would  occur in place of a tooth.   In the mid-1950s, oral and maxillofacial pathologists in  Europe introduced the term odontogenic keratocyst  (OKC) to denote a cyst with specific histopathologic fea-  tures and clinical behavior, which was believed to arise from  the dental lamina (i.e., the dental primordium). Subse-  quently, this concept was widely accepted, and the terms  odontogenic keratocyst and primordial cyst were used synony-  mously. The 1972 WHO classification used the designation  primordial cyst as the preferred term for this lesion. The  1992 WHO classification, however, listed odontogenic kera-  tocyst as the preferred designation.   Almost all examples of so-called primordial cysts (i.e., a  cyst that develops in the place of a tooth) microscopically  will be OKCs (Fig. 15-11). Whether there could be such a  radiographic presentation that is not microscopically an  OKC is still unsettled. If such a lesion exists, then it must  be exceedingly rare.    The odontogenic keratocyst (OKC) is a distinctive form  of developmental odontogenic cyst that deserves special  consideration because of its specific histopathologic    ® Fig. 15-11 Primordial Cyst. This patient gave no history of extrac-  tion of the third molar. A cyst is located in the third molar area. The  cyst was excised, and histopathologic examination revealed an odon-  togenic keratocyst (OKC).    features and clinical behavior. There is general agreement  that the OKC arises from cell rests of the dental lamina.  This cyst shows a different growth mechanism and bio-  logic behavior from the more common dentigerous cyst  and radicular cyst. Most authors believe that dentigerous  and radicular cysts continue to enlarge as a result of  increased osmotic pressure within the lumen of the cyst.  This mechanism does not appear to hold true for OKCs,  and their growth may be related to genetic factors inher-  ent in the epithelium itself or enzymatic activity in the  fibrous wall.   Several investigators have suggested that the OKC be  regarded as a benign cystic neoplasm rather than a cyst, and  in the latest WHO monograph on head and neck tumors,  this lesion has been given the name keratocystic odonto-  genic tumor (KCOT). The arguments to support this  change in nomenclature largely rely on studies that have  shown certain molecular genetic alterations that are also  present in some neoplasms. When compared to other odon-  togenic cysts, the OKC shows significantly greater expres-  sion of proliferating cell nuclear antigen (PCNA) and  Ki-67, especially in the suprabasilar layer. Almost 30% of  sporadic OKCs and over 85% of OKCs associated with the  nevoid basal cell carcinoma syndrome show mutations of  PTCH1, an important molecule in the Hedgehog signalling  pathway. Also, genetic analyses have demonstrated loss of  heterozygosity for various other tumor suppressor genes  (p16, p53, MCC, TSLCI, LATS2, and FHIT) in many  OKCs.   Whether such molecular findings warrant reclassification  of the OKC as a neoplasm (KCOT) remains a hotly debated  topic in oral pathology circles. The authors currently favor  retaining “odontogenic keratocyst” as the primary term for  this lesion, although both terms will be found in the litera-  ture and should be considered synonymous. Regardless of  which term is preferred, these lesions are significant for  three reasons:   Although there are wide variations in the reported fre-  quency of OKCs compared with that of other types of  odontogenic cysts, most studies indicate that OKCs make  up 3% to 11% of all odontogenic cysts.    OKCs may be found in patients who range in age from  infancy to old age, but about 60% of all cases are diagnosed  in people between 10 and 40 years of age. There is a slight  male predilection. The mandible is involved in 60% to 80%  of cases, with a marked tendency to involve the posterior  body and ramus (Fig. 15-12).   Small OKCs are usually asymptomatic and discovered  only during the course of a radiographic examination.    ® Fig. 15-12 Odontogenic Keratocyst (OKC). Relative distribution  of OKGs in the jaws.    @ Fig. 15-13 Odontogenic Keratocyst (OKC). Large, multilocular  cyst involving most of the ascending ramus. (Courtesy of Dr. S.C.  Roddy.)    Larger OKCs may be associated with pain, swelling, or  drainage. Some extremely large cysts, however, may cause  no symptoms.   OKCs tend to grow in an anteroposterior direction  within the medullary cavity of the bone without causing  obvious bone expansion. This feature may be useful in dif-  ferential clinical and radiographic diagnosis because dentig-  erous and radicular cysts of comparable size are usually  associated with bony expansion. Multiple OKCs may be  present, and such patients should be evaluated for other  manifestations of the nevoid basal cell carcinoma (Gorlin)  syndrome (see page 640).   OKCs demonstrate a well-defined radiolucent area with  smooth and often corticated margins. Large lesions, par-  ticularly in the posterior body and ramus of the mandible,  may appear multilocular (Fig. 15-13). An unerupted tooth  is involved in the lesion in 25% to 40% of cases; in such  instances, the radiographic features suggest the diagnosis of  dentigerous cyst (Figs. 15-14 and 15-15). In these cases, the  cyst has presumably arisen from dental lamina rests near an  unerupted tooth and has grown to envelop the unerupted  tooth. Resorption of the roots of erupted teeth adjacent to    ® Fig. 15-14 Odontogenic Keratocyst (OKC). This cyst involves  the crown of an unerupted premolar. Radiographically, this lesion  cannot be differentiated from a dentigerous cyst.    @ Fig. 15-15 Odontogenic Keratocyst (OKC). Computed tomog-  raphy (CT) scan showing a large cyst involving the crown of an  unerupted maxillary third molar. The cyst largely fills the maxillary sinus.  (Courtesy of Dr. E.B. Bass.)    OKCs is less common than that noted with dentigerous and  radicular cysts.   The diagnosis of OKC is based on the histopathologic  features. The radiographic findings, although often highly  suggestive, are not diagnostic. The radiographic findings in  an OKC may simulate those of a dentigerous cyst, a radicu-  lar cyst, a residual cyst, a lateral periodontal cyst (Fig.  15-16), or the so-called globulomaxillary cyst (which is no  longer considered to be a true entity). OKCs of the anterior  midline maxillary region can mimic nasopalatine duct cysts.  For unknown reasons, this particular subset of keratocyst  usually occurs in older individuals with a mean age of nearly  70 years. Rare examples of peripheral OKCs within the  gingival soft tissues have been reported.    ® Fig. 15-16 Odontogenic Keratocyst (OKC). This cyst cannot be  radiographically differentiated from a lateral periodontal cyst. (Courtesy  of Dr. Keith Lemmerman.)    Histopathologic Features  The OKC typically shows a thin, friable wall, which is    often difficult to enucleate from the bone in one piece.  The cystic lumen may contain a clear liquid that is similar  to a transudate of serum, or it may be filled with a cheesy  material that, on microscopic examination, consists of  keratinaceous debris. Microscopically, the thin fibrous wall  is usually devoid of significant inflammation. The epithelial  lining is composed of a uniform layer of stratified squa-  mous epithelium, usually six to eight cells in thickness.  The epithelium and connective tissue interface is usually  flat, and rete ridge formation is inconspicuous. Detachment  of portions of the cyst-lining epithelium from the fibrous  wall is commonly observed. The luminal surface shows  flattened parakeratotic epithelial cells, which exhibit a wavy  or corrugated appearance (Fig. 15-17). On occasion, iso-  lated foci of orthokeratin production may be found in  addition to the parakeratin. The basal epithelial layer is  composed of a palisaded layer of cuboidal or columnar  epithelial cells, which are often hyperchromatic. Small  satellite cysts, cords, or islands of odontogenic epithelium  may be seen within the fibrous wall. These structures have  been present in 7% to 26% of cases in various reported  series. In rare instances, cartilage has been observed in the  wall of an OKC.   In the presence of inflammatory changes, the typical  features of the OKC may be altered. The parakeratinized  luminal surface may disappear, and the epithelium may  proliferate to form rete ridges with the loss of the charac-  teristic palisaded basal layer (Fig. 15-18). When these  changes involve most of the cyst lining, the diagnosis of    @ Fig. 15-17 Odontogenic Keratocyst (OKC). The epithelial lining  is 6 to 8 cells thick, with a hyperchromatic and palisaded basal cell  layer. Note the corrugated parakeratotic surface.    microscopic features have been lost in the central area of this portion  of the cystic lining because of the heavy chronic inflammatory cell  infiltrate.    OKC cannot be confirmed unless other sections show the  typical features described earlier.   In the past, some investigators recognized a purely ortho-  keratotic variant of the OKC. However, these cysts do not  demonstrate a hyperchromatic and palisaded basal cell layer,  which is so characteristic of true OKCs. In addition, the  clinical behavior of these orthokeratinized cysts differs  markedly from that of the typical parakeratinized cysts  described in this section. The authors believe that it is more  logical to discuss these orthokeratinizing cysts separately  (see following section).    Although the presence of an OKC may be suspected on  clinical or radiographic grounds, histopathologic confirma-  tion is required for the diagnosis. Consequently, most  OKCs are treated similarly to other odontogenic cysts—i.e.,  by enucleation and curettage. Complete removal of the cyst  in one piece is often difficult because of the thin, friable  nature of the cyst wall. In contrast to other odontogenic    cysts, OKCs often tend to recur after treatment. Whether  this is due to fragments of the original cyst that were not  removed at the time of the operation or a “new” cyst that  has developed from dental lamina rests in the general area  of the original cyst cannot be determined with certainty.   The reported frequency of recurrence in various studies  ranges from 5% to 62%. This wide variation may be related  to the total number of cases studied, the length of follow-up  periods, and the inclusion or exclusion of orthokeratinized  cysts in the study group. Several reports that include large  numbers of cases indicate a recurrence rate of approximately  30%. Recurrence is encountered more often in mandibular  OKCs, particularly those in the posterior body and ramus.  Multiple recurrences are not unusual. Although many  OKCs recur within 5 years of the original surgery, a signifi-  cant number of recurrences may not be manifested until 10  or more years after the original surgical procedure. Long-  term clinical and radiographic follow-up, therefore, is  necessary.   Many surgeons recommend peripheral ostectomy of the  bony cavity with a bone bur to reduce the frequency of  recurrence. Others advocate chemical cauterization of the  bony cavity with Carnoy’s solution after cyst removal  (although use of Carnoy’s solution may not be permitted  by some hospitals). Intraluminal injection of Carnoy’s solu-  tion also has been used to free the cyst from the bony  wall, thereby allowing easier removal with a lower recur-  rence rate. After cystotomy and incisional biopsy, some  surgeons have treated large OKCs by insertion of a poly-  ethylene drainage tube to allow decompression and sub-  sequent reduction in size of the cystic cavity (Fig. 15-19).  Such decompression treatment results in thickening of the  cyst lining, allowing easier removal with an apparently  lower recurrence rate.   Other than the tendency for recurrences, the overall  prognosis for most OKCs is good. Occasionally, a locally  aggressive OKC cannot be controlled without local resec-  tion and bone grafting. In extremely rare instances, kerato-  cysts have been seen to extend up into the skull base region.  A few examples of carcinoma arising in an OKC have been  reported, but the propensity for an OKC to undergo malig-  nant alteration is no greater and is possibly less than that  for other types of odontogenic cysts. Patients with OKCs  should be evaluated for manifestations of the nevoid basal  cell carcinoma syndrome (see page 640), particularly if the  patient is in the first or second decade of life or if multiple  keratocysts are identified.    ‘The designation orthokeratinized odontogenic cyst does  not denote a specific clinical type of odontogenic cyst but  refers only to an odontogenic cyst that microscopically has  an orthokeratinized epithelial lining. Although such lesions  were originally called the orthokeratinized variant of    e Fig. 15-19 Decompression of an Odontogenic Keratocyst  (OKC). A, Large unilocular radiolucency associated with the right  mandibular third molar. B, Six months after insertion of a polyethylene  drainage tube to allow decompression, the cyst has shrunk and the  third molar has migrated downward and forward. (Courtesy of Dr. Tom  Szakal.)    odontogenic keratocyst, it is generally accepted that they are  clinicopathologically different from the more common  parakeratinized odontogenic keratocyst (OKC) and should  be placed into a different category. Orthokeratinized odon-  togenic cysts represent 7% to 17% of all keratinizing jaw    Orthokeratinized odontogenic cysts occur predominantly  in young adults and show over a 2:1 male-to-female ratio.  The lesion occurs more frequently in the mandible than the  maxilla (3:1 ratio), with a tendency to involve the posterior  areas of the jaws. They have no clinical or radiographic  features that differentiate them from other inflammatory or  developmental odontogenic cysts. The lesion usually appears  as a unilocular radiolucency, but occasional examples have  been multilocular. About two-thirds of orthokeratinized  odontogenic cysts are encountered in a lesion that appears  clinically and radiographically to represent a dentigerous  cyst; they most often involve an unerupted mandibular  third molar tooth (Figs. 15-20 and 15-21). The size can vary  from less than 1 cm to large lesions greater than 7 cm in  diameter.    ® Fig. 15-20 Orthokeratinized Odontogenic Cyst. Small unilocu-  lar radiolucency associated with the impacted mandibular left third  molar. (Courtesy of Dr. Tom McDonald.)    © Fig. 15-21 Orthokeratinized Odontogenic Cyst. A large cyst  involving a horizontally impacted lower third molar. (Courtesy of  Dr. Carroll Gallagher.)    The cyst lining is composed of stratified squamous epithe-  lium, which shows an orthokeratotic surface of varying  thickness. Keratohyaline granules may be prominent in the  superficial epithelial layer subjacent to the orthokeratin. The  epithelial lining may be relatively thin, and a prominent  palisaded basal layer, characteristic of the OKC, is not  present (Fig. 15-22).    Enucleation with curettage is the usual treatment for ortho-  keratinized odontogenic cysts. Recurrence has rarely been  noted, and the reported frequency is around 2%, which is  in marked contrast with the 30% or higher recurrence rate  associated with OKCs. It has been suggested that cysts with  an orthokeratinized surface may be at slightly greater risk  for malignant transformation, but evidence for this is scant.  Orthokeratinized odontogenic cysts typically are not associ-  ated with nevoid basal cell carcinoma syndrome.    Fig. 15-22 Orthokeratinized Odontogenic Cyst. Microscopic  features showing a thin epithelial lining. The basal epithelial layer does  not demonstrate palisading. Keratohyaline granules are present, and  a thick layer of orthokeratin is seen on the luminal surface.    Nevoid basal cell carcinoma syndrome (Gorlin syn-  drome) is an autosomal dominant inherited condition that  exhibits high penetrance and variable expressivity. The syn-  drome is caused by mutations in patched (PTCH), a tumor  suppressor gene that has been mapped to chromosome  9q22.3-q31. Approximately 35% to 50% of affected  patients represent new mutations. One of the most common  clinical features is development of OKCs, which can lead  to early diagnosis. The prevalence of Gorlin syndrome is  estimated to be anywhere from 1 in 19,000 to 1 in 256,000,  depending on the population studied.    There is great variability in the expressivity of nevoid basal  cell carcinoma syndrome, and no single component is  present in all patients. The most common and significant  features are summarized in Box 15-2. The patient often has  a characteristic facies, with frontal and temporoparietal  bossing, which results in an increased cranial circumference  (more than 60 cm in adults). The eyes may appear widely  separated, and many patients have true mild ocular hyper-  telorism. Mild mandibular prognathism is also commonly  present (Fig. 15-23).   Basal cell carcinomas of the skin are a major component  of the syndrome. These tumors usually begin to appear at  puberty or in the second and third decades of life, although  they can develop in young children. The lesions may vary  from flesh-colored papules to ulcerating plaques. They often  appear on skin that is not exposed to sunlight, but they are  most commonly located in the midface area (Fig. 15-24).  The number of skin tumors may vary from only a few to  many hundreds. Blacks with the syndrome tend to develop  basal cell carcinomas less frequently than whites (40%  versus 90%), and they have fewer of these lesions, probably  because of protective skin pigmentation.   Rib anomalies (splayed, fused, partially missing, and/or bifid)  Mild ocular hypertelorism   Kyphoscoliosis or other vertebral anomalies  Pectus excavatum or carinatum  Strabismus (exotropia)    Palmar and plantar pits are present in about 65% to 85%  of patients (Fig. 15-25). These punctate lesions represent a  localized impairment of the maturation of basal epithelial  cells, resulting in a focally depressed area as the result of a  markedly thinned keratin layer. Basal cell carcinomas rarely  may develop at the base of the pits.   Ovarian cysts and fibromas have been reported in 25%  to 50% of women with this syndrome. A number of other  tumors also have been reported to occur with lesser fre-  quency. These include medulloblastoma within the first 2  years of life, meningioma, cardiac fibroma, and fetal  rhabdomyoma.   Skeletal anomalies are present in 60% to 75% of patients  with this syndrome. The most common anomaly is a bifid  rib or splayed ribs (Fig. 15-26). This anomaly may involve  several ribs and may be bilateral. Kyphoscoliosis has been  observed in about 30% to 40% of patients, and a number  of other anomalies, such as spina bifida occulta and short-  ened metacarpals, seem to occur with unusual frequency. A  distinctive lamellar calcification of the falx cerebri, noted on  an anteroposterior skull radiograph or computed tomogra-  phy (CT) image, is a common finding and is present in  most affected patients (Fig. 15-27).   Jaw cysts are one of the most constant features of the  syndrome and are present in 90% of the patients. The cysts    e Fig. 15-23 Nevoid Basal Cell Carcinoma Syndrome. This  11-year-old girl shows hypertelorism and mandibular swelling. (Cour-  tesy of Dr. Richard DeChamplain.)    are OKCs, although there are some differences between the  cysts in patients with nevoid basal cell carcinoma syndrome  and in those with isolated OKCs. The cysts are frequently  multiple; some patients have had as many as ten separate  cysts. The patient's age when the first OKC is removed is  significantly younger in those affected by this syndrome  than in those with isolated OKCs. For most patients with  this syndrome, their first OKC is removed before age 19.  About one-third of patients with nevoid basal cell carci-  noma syndrome have only a solitary cyst at the time of the    initial presentation, but in most cases additional cysts will  develop over periods ranging from 1 to 20 years.   Radiographically, the cysts in patients with nevoid basal  cell carcinoma syndrome do not differ significantly from  isolated OKCs. The cysts in patients with this syndrome are  often associated with the crowns of unerupted teeth; on  radiographs they may mimic dentigerous cysts (Fig. 15-28).   Diagnostic criteria for the nevoid basal cell carcinoma  syndrome are provided in Box 15-3.    The cysts in the nevoid basal cell carcinoma syndrome  histopathologically are invariably OKCs. The keratocysts  in patients with this syndrome tend to have more sat-  ellite cysts, solid islands of epithelial proliferation, and    @ Fig. 15-27 Nevoid Basal Cell Carcinoma Syndrome. Antero-  posterior skull film showing calcification of the falx cerebri. (Courtesy  of Dr. Ramesh Narang.)    odontogenic epithelial rests within the fibrous capsule  than do isolated keratocysts (Fig. 15-29). Foci of calci-  fication also appear to be more common. ‘These features,  however, are not diagnostic for nevoid basal cell carcinoma  syndrome because they may be seen in isolated kerato-  cysts. OKCs associated with this syndrome have been  shown to demonstrate overexpression of p53 and cyclin  D1 (bcl-1) oncoproteins when compared with nonsyn-  drome keratocysts.   The basal cell tumors of the skin cannot be distinguished  from ordinary basal cell carcinomas. They exhibit a wide  spectrum of histopathologic findings, from superficial  basal cell lesions to aggressive, noduloulcerative basal cell  carcinomas.    Most of the anomalies in nevoid basal cell carcinoma syn-  drome are minor and usually not life threatening. The  prognosis generally depends on the behavior of the skin  tumors. In a few cases, aggressive basal cell carcinomas  have caused the death of the patient as a result of tumor  invasion of the brain or other vital structures (Figs. 15-30  and 15-31). Because the development of the basal cell  carcinomas seems to be triggered by ultraviolet (UV) light  exposure, patients should take appropriate precautions to  avoid sunlight. For the same reason, radiation therapy  should be avoided if at all possible. The jaw cysts are  treated in the same manner as isolated OKCs, but in many  patients additional cysts will continue to develop. Varying  degrees of jaw deformity may result from the operations  for multiple cysts. Infection of the cysts in patients with    * BOX 15-3 Diagnostic Criteria for the Nevoid Basal Cell Carcinoma Syndrome    1. Five or more basal cell carcinomas or one before the age of  30 years   Congenital malformation: Cleft lio or palate, frontal bossing,  coarse facial features, and/or hypertelorism   Rib or vertebral abnormalities: bifid, splayed, or extra ribs;  bifid vertebrae    *In a recent consensus conference, it was suggested that medulloblastoma should be considered a major criterion.    @ Fig. 15-28 Nevoid Basal Cell Carcinoma Syndrome. Large cysts are present in the right and left  mandibular molar regions, together with a smaller cyst involving the right maxillary canine in the same  patient shown in Fig. 15-23. (Courtesy of Dr. Richard DeChamplain.)    @ Fig. 15-29 Nevoid Basal Cell Carcinoma Syndrome. Odonto-  genic keratocyst (OKC) showing numerous odontogenic epithelial rests  in the cyst wall.    e Fig. 15-30 Nevoid Basal Cell Carcinoma Syndrome. This  52-year-old man had more than 100 basal cell carcinomas removed  from his face over a 30-year period. Several basal cell carcinomas are  present in this photograph. The lesion at the inner canthus of the left  eye was deeply invasive and was eventually fatal as a result of brain  invasion.    e Fig. 15-31 Nevoid Basal Cell Carcinoma Syndrome. Facial  deformity secondary to multiple surgical procedures to remove basal  cell carcinomas.    this syndrome is also relatively common. Some investigators  have suggested that affected children should have magnetic  resonance imaging (MRI) studies every 6 months until 7  years of age to monitor for the development of medullo-  blastoma. Genetic counseling is appropriate for affected  individuals.    Gingival cysts of the newborn are small, superficial,  keratin-filled cysts that are found on the alveolar mucosa of  infants. These cysts arise from remnants of the dental  lamina. They are common lesions, having been reported in  up to half of all newborns. However, because they disappear  spontaneously by rupture into the oral cavity, the lesions  seldom are noticed or sampled for biopsy. Similar inclusion  cysts (e.g., Epstein’s pearls and Bohn’s nodules) are also  found in the midline of the palate or laterally on the hard  and soft palate (see page 24).    Gingival cysts of the newborn appear as small, usually mul-  tiple whitish papules on the mucosa overlying the alveolar  processes of neonates (Fig. 15-32). The individual cysts are    @ Fig. 15-32 Gingival Cyst of the Newborn. Multiple whitish  papules on the alveolar ridge of a newborn infant.    usually no more than 2 to 3 mm in diameter. The maxillary  alveolus is more commonly involved than the mandibular.    Examination of an intact gingival cyst of the newborn  shows a thin, flattened epithelial lining with a parakeratotic  luminal surface. The lumen contains keratinaceous debris.    No treatment is indicated for gingival cysts of the newborn  because the lesions spontaneously involute as a result of the  rupture of the cysts and resultant contact with the oral  mucosal surface. The lesions are rarely seen after 3 months  of age.    ‘The gingival cyst of the adult is an uncommon lesion. It  is considered to represent the soft tissue counterpart of the  lateral periodontal cyst (see next topic), being derived  from rests of the dental lamina (rests of Serres). The diag-  nosis of gingival cyst of the adult should be restricted to  lesions with the same histopathologic features as those of  the lateral periodontal cyst. On rare occasions, a cyst may  develop in the gingiva at the site of a gingival graft; however,  such lesions probably represent epithelial inclusion cysts that  are a result of the surgical procedure.    Like the lateral periodontal cyst, the gingival cyst of the  adult shows a striking predilection to occur in the mandibu-  lar canine and premolar area (60% to 75% of cases). Gin-  gival cysts of the adult are most commonly found in patients  in the fifth and sixth decades of life. They are almost invari-  ably located on the facial gingiva or alveolar mucosa. Maxil-  lary gingival cysts are usually found in the incisor, canine,  and premolar areas.    ® Fig. 15-33 Gingival Cyst of the Adult. Tense, fluid-filled swelling  on the facial gingiva.    @ Fig. 15-34 Gingival Cyst of the Adult. Low-power photomicro-  graph showing a thin-walled cyst in the gingival soft tissue.    Clinically, the cysts appear as painless, domelike swell-  ings, usually less than 0.5 cm in diameter, although rarely  they may be somewhat larger (Fig. 15-33). They are often  bluish or blue-gray. In some instances, the cyst may cause  a superficial “cupping out” of the alveolar bone, which is  usually not detected on a radiograph but is apparent when  the cyst is excised. If more bone is missing, one could argue  that the lesion may be a lateral periodontal cyst that has  eroded the cortical bone rather than a gingival cyst that  originated in the mucosa.    The histopathologic features of the gingival cyst of the adult  are similar to those of the lateral periodontal cyst, consisting  of a thin, flattened epithelial lining with or without focal  plaques that contain clear cells (Figs. 15-34 and 15-35).  Small nests of these glycogen-rich clear cells, which repre-  sent rests of the dental lamina, also may be seen in the  surrounding connective tissue. Sometimes the cystic lining  is so thin that it is easily mistaken for the endothelial lining    @ Fig. 15-35 Gingival Cyst of the Adult. High-power photomicro-  graph showing a plaquelike thickening of the epithelial lining.    ‘The gingival cyst of the adult responds well to simple surgi-  cal excision. The prognosis is excellent.    The lateral periodontal cyst is an uncommon type of  developmental odontogenic cyst that typically occurs along  the lateral root surface of a tooth. It is believed to arise from  rests of the dental lamina, and it represents the intrabony  counterpart of the gingival cyst of the adult. The lateral  periodontal cyst accounts for less than 2% of all epithelium-  lined jaw cysts.   In the past, the term Jateral periodontal cyst was used. to  describe any cyst that developed along the lateral root  surface, including lateral radicular cysts (see page 120) and  OKCs (see page 636). However, the lateral periodontal cyst  has distinctive clinical and microscopic features that distin-  guish it from other lesions that sometimes develop in the  same location.    The lateral periodontal cyst is most often an asymptomatic  lesion that is detected only during a radiographic examina-  tion. It most frequently occurs in patients in the fifth  through the seventh decades of life; rarely does it occur in  someone younger than age 30. Around 75% to 80% of  cases occur in the mandibular premolar-canine-lateral  incisor area. Maxillary examples also usually involve this  same tooth region (Fig. 15-36).   Radiographically, the cyst usually appears as a well-  circumscribed radiolucent area located laterally to the root  or roots of vital teeth. Most such cysts are less than 1.0 cm  in greatest diameter (Figs. 15-37 and 15-38). In rare  instances, multifocal lateral periodontal cysts have been  described. In addition, some examples can develop in eden-  tulous sites.    e Fig. 15-36 Lateral Periodontal Cyst. Relative distribution of  lateral periodontal cysts in the jaws.    ° Fig. 15-37 Lateral Periodontal Cyst. Raciolucent lesion between  the roots of a vital mandibular canine and first premolar.    Occasionally, the lesion may have a polycystic appear-  ance; such examples have been termed botryoid odonto-  genic cysts. Grossly and microscopically, they show a  grapelike cluster of small individual cysts (Fig. 15-39).  ‘These lesions are generally considered to represent a variant  of the lateral periodontal cyst, possibly the result of cystic  degeneration and subsequent fusion of adjacent foci of  dental lamina rests. The botryoid variant often shows a  multilocular radiographic appearance, but it also may  appear unilocular.   The radiographic features of the lateral periodontal cyst  are not diagnostic; an OKC that develops between the roots  of adjacent teeth may show identical radiographic findings.  An inflammatory radicular cyst that occurs laterally to a  root in relation to an accessory foramen or a cyst that arises  from periodontal inflammation also may simulate a lateral    periodontal cyst radiographically (see page 120). In one  study of 46 cases of cystic lesions in the lateral periodontal  region, only 13 met the histopathologic criteria for the  lateral periodontal cyst; eight were OKCs, 20 were inflam-  matory cysts, and five were of undetermined origin.    The lateral periodontal cyst has a thin, generally nonin-  flamed, fibrous wall, with an epithelial lining that is only  one to three cells thick in most areas. This epithelium  usually consists of flattened squamous cells, but sometimes  the cells are cuboidal in shape. Foci of glycogen-rich clear  cells may be interspersed among the lining epithelial cells.  Some cysts show focal nodular thickenings of the lining    4 Ls yy g 4 ~ Res  @ Fig. 15-40 Lateral Periodontal Cyst. A, This photomicrograph  shows a thin epithelial lining with focal nodular thickenings. B, These  thickenings often show a swirling appearance of the cells.    epithelium, which are composed chiefly of clear cells (Fig.  15-40). Clear cell epithelial rests sometimes are seen within  the fibrous wall. Rarely, lateral periodontal cysts exhibit  focal areas that histopathologically are suggestive of the  glandular odontogenic cyst (see page 649).    Conservative enucleation of the lateral periodontal cyst is  the treatment of choice. Usually, this can be accomplished  without damage to the adjacent teeth. Recurrence is unusual,  although it has been reported with the botryoid variant,  presumably because of its polycystic nature. An exceedingly  rare case of squamous cell carcinoma, which apparently  originated in a lateral periodontal cyst, also has been  reported.    ¢ CALCIFYING ODONTOGENIC CYST  (CALCIFYING CYSTIC ODONTOGENIC  TUMOR; GORLIN CYST; DENTINOGENIC  GHOST CELL TUMOR; GHOST CELL  ODONTOGENIC CARCINOMA)    First described in 1962 by Gorlin and associates, the calci-  fying odontogenic cyst is part of a spectrum of lesions    @ Fig. 15-41 Calcifying Odontogenic Cyst. Relative distribution of  calcifying odontogenic cysts in the jaws.    characterized by odontogenic epithelium containing “ghost  cells,” which then may undergo calcification. Although  most examples grow in a cystic fashion, some lesions  occur as solid tumorlike growths (dentinogenic ghost cell  tumor). Therefore, in the current WHO classification  system, these lesions have been categorized as odontogenic  tumors under three categories (based on the cystic, solid, or  malignant nature of the lesion):  1. Calcifying cystic odontogenic tumor  2. Dentinogenic ghost cell tumor  3. Ghost cell odontogenic carcinoma   The overwhelming majority of intraosseous ghost cell  odontogenic lesions grow as cystic lesions, and less than 5%  of cases can be classified as solid dentinogenic ghost cell  tumors. Therefore, the authors still prefer to use the simpler  designation “calcifying odontogenic cyst” for the cystic  examples. Approximately one-third of peripheral lesions  will be solid in nature, although these peripheral examples  are not as aggressive as their intraosseous counterparts.   ‘The calcifying odontogenic cyst may be associated with  other recognized odontogenic tumors, most commonly  odontomas. However, adenomatoid odontogenic tumors  and ameloblastomas have also been associated with calcify-  ing odontogenic cysts.    Intraosseous calcifying odontogenic cysts occur with about  equal frequency in the maxilla and mandible. About 65%  of cases are found in the incisor and canine areas (Fig.  15-41). The mean age is 30 years, and most cases are diag-  nosed in the second to fourth decades of life. Calcifying  odontogenic cysts that are associated with odontomas tend  to occur in younger patients, with a mean age of 17 years.   The central calcifying odontogenic cyst is usually a uni-  locular, well-defined radiolucency, although the lesion occa-  sionally may appear multilocular. Radiopaque structures  within the lesion, either irregular calcifications or toothlike  densities, are present in about one-third to one-half of cases  (Fig. 15-42). In approximately one-third of cases, the radio-  lucent lesion is associated with an unerupted tooth, most    often a canine. Most calcifying odontogenic cysts are  between 2.0 and 4.0 cm in greatest diameter, but lesions as  large as 12.0 cm have been noted. Root resorption or diver-  gence of adjacent teeth is seen with some frequency (Fig.  15-43).   Extraosseous examples comprise from 5% to 17% of all  cases, appearing as localized sessile or pedunculated gingival  masses with no distinctive clinical features (Fig. 15-44).  They can resemble common gingival fibromas, gingival  cysts, or peripheral giant cell granulomas. Peripheral exam-  ples tend to occur later in life, with peak prevalence during  the sixth to eighth decades.    The calcifying odontogenic cyst most commonly occurs as  a well-defined cystic lesion with a fibrous capsule and a  lining of odontogenic epithelium of four to ten cells in  thickness. The basal cells of the epithelial lining may be  cuboidal or columnar and are similar to ameloblasts. The    e Fig. 15-42 Calcifying Odontogenic Cyst. Well-circumscribed  mixed radiolucent/radiopaque lesion in the right body of the mandible.  (Courtesy of Dr. John Wright.)    overlying layer of loosely arranged epithelium may resemble  the stellate reticulum of an ameloblastoma.   The most characteristic histopathologic feature of the  calcifying odontogenic cyst is the presence of variable  numbers of “ghost cells” within the epithelial component.  These eosinophilic ghost cells are altered epithelial cells that  are characterized by the loss of nuclei with preservation of  the basic cell outline (Fig. 15-45).   The nature of the ghost cell change is controversial. Some  believe that this change represents coagulative necrosis or  accumulation of enamel protein; others contend it is a form  of normal or aberrant keratinization of odontogenic epithe-  lium. Masses of ghost cells may fuse to form large sheets of  amorphous, acellular material. Calcification within the  ghost cells is common. ‘This first appears as fine basophilic  granules that may increase in size and number to form  extensive masses of calcified material. Areas of an eosino-  philic matrix material that are considered by some authors  to represent dysplastic dentin (dentinoid) also may be  present adjacent to the epithelial component. This is  believed to be the result of an inductive effect by the    @ Fig. 15-44 Peripheral Calcifying Odontogenic Cyst. Nodular  mass of the mandibular facial gingiva.    ® Fig. 15-43 Calcifying Odontogenic Cyst. A, Expansion of the posterior maxillary alveolus caused  by a large calcifying odontogenic cyst. B, Panoramic radiograph of the same patient showing a large  radiolucency in the posterior maxilla. A small calcified structure is seen in the lower portion of the cyst.    ® Fig. 15-45 Calcifying Odontogenic Cyst. The cyst lining shows  ameloblastoma-like epithelial cells, with a columnar basal layer. Large  eosinophilic ghost cells are present within the epithelial lining.    ® Fig. 15-46 Calcifying Odontogenic Cyst. Eosinophilic dentinoid  material is present adjacent to a sheet of ghost cells.   Several variants of the cystic type of calcifying odonto-  genic cyst are seen. In some cases, the epithelial lining  proliferates into the lumen so that the lumen is largely filled  with masses of ghost cells and dystrophic calcifications.  Multiple daughter cysts may be present within the fibrous  wall, and a foreign body reaction to herniated ghost cells  may be conspicuous.   In another variant, unifocal or multifocal epithelial pro-  liferation of the cyst lining into the lumen may resemble  ameloblastoma. These proliferations are intermixed with  varying numbers of ghost cells. These epithelial prolifera-  tions superficially resemble, but do not meet, the strict  histopathologic criteria for ameloblastoma.   About 20% of calcifying odontogenic cysts are associated  with odontomas. This variant is usually a unicystic lesion  that shows the features of a calcifying odontogenic cyst  together with those of a small complex or compound  odontoma.   Solid dentinogenic ghost cell tumors may occur intraos-  seously or extraosseously. The extraosseous forms appear to    be more common. These show varying-sized islands of  odontogenic epithelium in a fibrous stroma. The epithelial  islands show peripheral palisaded columnar cells and central  stellate reticulum, which resemble ameloblastoma. Nests of  ghost cells, however, are present within the epithelium,  and juxtaepithelial dentinoid is commonly present. These  features differentiate this lesion from the peripheral  ameloblastoma.   ‘The rare intraosseous variant is a solid tumor that con-  sists of ameloblastoma-like strands and islands of odonto-  genic epithelium in a mature fibrous connective tissue  stroma. Variable numbers of ghost cells and juxtaepithelial  dentinoid are present.   A small number of aggressive or malignant epithelial  odontogenic ghost cell tumors (ghost cell odontogenic  carcinoma) have been reported. These lesions have cellular  pleomorphism and mitotic activity with invasion of the  surrounding tissues.    The prognosis for a patient with a calcifying odontogenic  cyst is good; only a few recurrences after simple enucleation  have been reported. Peripheral examples appear to have  the same prognosis as a peripheral ameloblastoma, with  a minimal chance of recurrence after simple surgical  excision.   When a calcifying odontogenic cyst is associated with  some other recognized odontogenic tumor, such as an ame-  loblastoma, the treatment and prognosis are likely to be the  same as for the associated tumor. Although few cases have  been reported, ghost cell odontogenic carcinomas appear to  have an unpredictable behavior. Recurrences are common,  and a few patients have died from either uncontrolled local  disease or metastases. An overall 5-year survival rate of 73%  has been calculated for reported cases.    The glandular odontogenic cyst is a rare type of develop-  mental odontogenic cyst that can show aggressive behavior.  Although it is generally accepted as being of odontogenic  origin, it also shows glandular or salivary features that pre-  sumably are an indication of the pluripotentiality of odon-  togenic epithelium.    The glandular odontogenic cyst occurs most commonly in  middle-aged adults, with a mean age of 46 to 51 years at  the time of diagnosis; rarely does it occur before the age of  20. Approximately 75% of reported cases have occurred in  the mandible. The cyst has a strong predilection for the  anterior region of the jaws, and many mandibular lesions  will cross the midline.    ‘The size of the cyst can vary from small lesions less than  lcm in diameter to large destructive lesions that may  involve most of the jaw. Small cysts may be asymptomatic;  however, large cysts often produce clinical expansion, which  sometimes can be associated with pain or paresthesia (Fig.  15-47).   Radiographically, the lesion presents as either a unilocu-  lar or multilocular radiolucency. The margins of the radio-  lucency are usually well defined with a corticated rim.    The glandular odontogenic cyst is lined by squamous epi-  thelium of varying thickness. The interface between the  epithelium and the fibrous connective tissue wall is gener-  ally flat. The fibrous cyst wall is usually devoid of any  inflammatory cell infiltrate. The superficial epithelial cells  that line the cyst cavity tend to be cuboidal to columnar,  resulting in an uneven hobnail and sometimes papillary  surface (Fig. 15-48). The surface layer often includes mucin-  producing goblet cells, occasionally with the presence of  cilia. Glandular, ductlike spaces within the epithelial lining  are another characteristic finding. These spaces are lined by  cuboidal cells and often contain mucicarmine-positive fluid.  In focal areas, the epithelial lining cells may form spherical  nodules, similar to those seen in lateral periodontal cysts.  There is some histopathologic overlap between the fea-  tures of the glandular odontogenic cyst and those of some  intraosseous, low-grade, predominantly cystic mucoepider-  moid carcinomas (see page 457). In selected microscopic  fields, the microscopic features may be identical. Examina-  tion of multiple sections, however, usually permits the dif-  ferentiation of these lesions. Also, glandular odontogenic  cysts will not show MAML2 gene rearrangements, which  often are found in central mucoepidermoid carcinomas.    Most cases of glandular odontogenic cyst have been treated  by enucleation or curettage. However, this cyst shows a    propensity for recurrence, which is observed in approxi-  mately 30% of all cases. Recurrence appears to be more  common among the lesions that present in a multilocular  fashion. Because of its potentially aggressive nature and  tendency for recurrence, some authors have advocated en  bloc resection, particularly for multilocular lesions. Marsu-  pialization and decompression may be attempted for larger  lesions to promote shrinkage prior to surgery.    The buccal bifurcation cyst is an uncommon inflamma-  tory odontogenic cyst that characteristically develops on the  buccal aspect of the mandibular first permanent molar,  although some cases have involved the second molar. The  pathogenesis of this cyst is uncertain. Some of these lesions  have been associated with teeth that demonstrate buccal  enamel extensions into the bifurcation area (see page 86).  Such extensions may predispose these teeth to buccal pocket  formation, which could then enlarge to form a cyst in    ~ ahs ~ ‘ ey os . -  is meee > < 2 (FS Oe, a. gh 57> % od  @ Fig. 15-48 Glandular Odontogenic Cyst. The cyst is lined by  stratified squamous epithelium that exhibits surface columnar cells with  cilia. Numerous microcysts containing mucinous material are present.    @ Fig. 15-47 Glandular Odontogenic Cyst. A, Expansile lesion of the anterior mandible. B, The  panoramic radiograph shows a large multilocular radiolucency. (Courtesy of Dr. Cheng-Chung Lin.)    response to pericoronitis. It has been speculated that when  the tooth erupts, an inflammatory response may occur in  the surrounding follicular tissues that stimulates cyst  formation.   ‘The term paradental cyst sometimes has been used syn-  onymously for the buccal bifurcation cyst. Such lesions  typically occur distal or buccal of partially erupted man-  dibular third molars with a history of pericoronitis. The  pathogenesis of the so-called paradental cyst also is uncer-  tain. However, the distinction of paradental cysts from sec-  ondarily inflamed dentigerous cysts is difficult, if not  impossible, in many instances (see page 632).    The buccal bifurcation cyst typically occurs in children from  5 to 13 years of age. The patient has slight-to-moderate  tenderness on the buccal aspect of the mandibular first or  second molar, which may be in the process of erupting. The  patient often notes associated clinical swelling and a foul-  tasting discharge. Periodontal probing usually reveals pocket  formation on the buccal aspect of the involved tooth.  Around one-third of patients have been reported to have  bilateral involvement of the first molars.   Radiographs typically show a well-circumscribed uni-  locular radiolucency involving the buccal bifurcation and  root area of the involved tooth (Fig. 15-49). The average  size of the lucent defect is 1.2 cm, but the lesion may be as  large as 2.5 cm in diameter. An occlusal radiograph is most  helpful in demonstrating the buccal location of the lesion.  The root apices of the molar are characteristically tipped  toward the lingual mandibular cortex (Fig. 15-50). Many    @ Fig. 15-49 Buccal Bifurcation Cyst. Well-circumscribed unilocu-  lar radiolucency superimposed on the roots of the mandibular first  permanent molar. (Courtesy of Dr. Michael Pharoah.)    cases are associated with proliferative periostitis (see page  134) of the overlying buccal cortex, which is characterized  by a single or multiple layers of reactive bone formation.    The microscopic features are nonspecific and show a cyst  that is lined by nonkeratinizing stratified squamous epithe-  lium with areas of hyperplasia. A prominent chronic inflam-  matory cell infiltrate is present in the surrounding connective  tissue wall.    The buccal bifurcation cyst is usually treated by enucleation;  extraction of the associated tooth is unnecessary. Within 1  year of surgery, there is usually complete healing with nor-  malization of periodontal probing depths and radiographic  evidence of bone fill. Several reports have described cases  that resolved without surgery—either with no treatment at  all or by daily irrigation of the buccal pocket with saline  and hydrogen peroxide.    Carcinoma arising within bone is a rare lesion that is essen-  tially limited to the jaws. Because the putative source of the  epithelium giving rise to the carcinoma is odontogenic,  these intraosseous jaw carcinomas are collectively known as  odontogenic carcinomas. Odontogenic carcinomas may  arise in an ameloblastoma, rarely from other odontogenic  tumors, de novo (without evidence of a preexisting lesion),  or from the epithelial lining of odontogenic cysts. Some  intraosseous mucoepidermoid carcinomas (see page 457)  also may arise from mucous cells lining a dentigerous cyst.    @ Fig. 15-50 Buccal Bifurcation Cyst. Axial computed tomography  (CT) image showing a circumscribed radiolucency buccal to the roots  of the mandibular first molar. (Courtesy of Dr. Robert Clark.)    Most intraosseous carcinomas apparently arise in odon-  togenic cysts. Although infrequently documented in the  literature, carcinomatous transformation of the lining of an  odontogenic cyst may be more common than is generally  appreciated. Several studies have shown that 1% to 2% of  all oral cavity carcinomas seen in some oral and maxillofa-  cial pathology services may originate from odontogenic  cysts. The pathogenesis of carcinomas arising in odonto-  genic cysts is unknown. Occasionally, areas within the  lining of odontogenic cysts histopathologically demonstrate  varying degrees of epithelial dysplasia, and such changes  likely give rise to the carcinoma.    Although carcinomas arising in cysts may be seen in patients  across a wide age range, they are encountered most often in  older patients. The mean reported age is 60 years. This  lesion is over twice as common in men as in women. Pain  and swelling are the most common complaints. However,  many patients have no symptoms, and the diagnosis of  carcinoma is made only after microscopic examination of a  presumed odontogenic cyst.   Radiographic findings may mimic those of any odonto-  genic cyst, although the margins of the radiolucent defect  are usually irregular and ragged. CT scans of the lesion may  demonstrate a destructive pattern that is not appreciated on  viewing plain radiographs. A lesion considered to be a resid-  ual periapical cyst is apparently the most common type  associated with carcinomatous transformation, although  routine periapical cysts can also exhibit malignant change.  These account for 60% of reported cases. In about 16% of  cases, the carcinoma appeared to have arisen in a dentiger-  ous cyst (Fig. 15-51). In one patient, the carcinoma was  thought to originate from a lateral periodontal cyst.   A number of examples of carcinoma arising in an OKC  also have been documented (Fig. 15-52). However, some  reported examples do not appear to have arisen in true    @ Fig. 15-51 Carcinoma Arising in a Dentigerous Cyst. Raciolu-  cent lesion surrounding the crown of an impacted third molar in a  56-year-old woman. This was clinically considered to be a dentigerous  cyst. (Courtesy of Dr. Richard Ziegler.)    Most carcinomas arising in cysts histopathologically have  been well-differentiated or moderately well-differentiated  squamous cell carcinomas. Sometimes it is possible to  identify a transition from a normal-appearing cyst lining  to invasive squamous cell carcinoma (Figs. 15-53 and    The treatment of patients with carcinomas arising in cysts  has varied from local block excision to radical resection,  with or without radiation or adjunctive chemotherapy. The  prognosis is difficult to evaluate because most reports consist  of isolated cases. Metastases to regional lymph nodes have  been demonstrated in a few cases. One review showed an  overall 2-year survival rate of 62%, but the 5-year survival  rate dropped to 38%.   Before a given lesion can be accepted as an example of  primary intraosseous carcinoma, the possibility that the  tumor represents metastatic spread from an intraoral or  extraoral site must be ruled out by appropriate studies.    @ Fig. 15-52 Carcinoma Arising in a Cyst. There is a massive  carcinoma of the mandible, with extension into the parotid gland, the  face, and the base of the brain. Nineteen years previously, a large  odontogenic keratocyst (OKC) with areas of epithelial dysplasia had  been removed from the ascending ramus. The patient had suffered  multiple recurrences, with eventual change into invasive carcinoma.    @ Fig. 15-53 Carcinoma Arising in a Cyst. High-power view of a  dentigerous cyst from a 53-year-old man. The lining demonstrates  full-thickness epithelial dysplasia.    ° Fig. 15-54 Carcinoma Arising in a Cyst. Same case as Fig.  15-53 showing islands of invasive epithelial cells in the cyst wall.    Odontogenic tumors comprise a complex group of lesions  of diverse histopathologic types and clinical behavior. Some  of these lesions are true neoplasms and may rarely exhibit  malignant behavior. Others may represent tumorlike mal-  formations (hamartomas).   Odontogenic tumors, like normal odontogenesis, dem-  onstrate varying inductive interactions between odonto-  genic epithelium and odontogenic ectomesenchyme. ‘This  ectomesenchyme was formerly referred to as mesenchyme  because it was thought to be derived from the mesodermal  layer of the embryo. It is now accepted that this tissue dif  ferentiates from the ectodermal layer in the cephalic portion  of the embryo. Tumors of odontogenic epithelium are  composed only of odontogenic epithelium without any par-  ticipation of odontogenic ectomesenchyme.   Other odontogenic neoplasms, sometimes referred to as  mixed odontogenic tumors, are composed of odontogenic  epithelium and ectomesenchymal elements. Dental hard  tissue may or may not be formed in these lesions.    |. Tumors of odontogenic epithelium  A. Ameloblastoma  1. Malignant ameloblastoma  2. Ameloblastic carcinoma  B. Clear cell odontogenic carcinoma  C. Adenomatoid odontogenic tumor  D. Calcifying epithelial odontogenic tumor  E. Squamous odontogenic tumor  ll. Mixed odontogenic tumors  . Ameloblastic fibroma  . Ameloblastic fibro-odontoma  . Ameloblastic fibrosarcoma  . Odontoameloblastoma  . Compound odontoma  . Complex odontoma  lll. Tumors of odontogenic ectomesenchyme  A. Odontogenic fibroma  B. Granular cell odontogenic tumor  C. Odontogenic myxoma  D. Cementoblastoma    A third group, tumors of odontogenic ectomesen-  chyme, is composed principally of ectomesenchymal ele-  ments. Although odontogenic epithelium may be included  within these lesions, it does not appear to play any essential  role in their pathogenesis.   Box 15-4 presents categories of odontogenic tumors  modified from the 2005 WHO classification.   Because many of these lesions are quite rare, it is some-  times difficult to assess certain epidemiologic features accu-  rately, as well as recommendations regarding treatment. It  should be kept in mind that reports in the literature may  be biased due to geopolitical/economic variations in sub-  mission of biopsies or the tendency of journal editors to  publish reports of lesions that are unusual or aggressive.    Epithelial odontogenic tumors are composed of odonto-  genic epithelium without participation of odontogenic  ectomesenchyme. Several distinctly different tumors are  included in the group; ameloblastoma is the most impor-  tant and common of them.    ‘The ameloblastoma is the most common clinically signifi-  cant odontogenic tumor. Its relative frequency equals the  combined frequency of all other odontogenic tumors,  excluding odontomas. Ameloblastomas are tumors of odon-  togenic epithelial origin. Theoretically, they may arise from  rests of dental lamina, from a developing enamel organ,  from the epithelial lining of an odontogenic cyst, or from  the basal cells of the oral mucosa. Ameloblastomas are    slow-growing, locally invasive tumors that run a benign  course in most cases. They typically have been described as  having three different clinicoradiographic presentations,  which deserve separate consideration because of potentially  differing therapeutic considerations and prognosis:   of all cases)  2. Unicystic (about 13% to 21% of all cases)  3. Peripheral (extraosseous) (about 1% to 4% of all cases)    Conventional solid or multicystic intraosseous amelo-  blastoma is encountered in patients across a wide age range.  It is rare in children younger than age 10 and relatively  uncommon in the 10- to 19-year-old group. The tumor  shows an approximately equal prevalence in the third to  seventh decades of life. There is no significant sex predilec-  tion. Some studies indicate a greater frequency in blacks;  others show no racial predilection. About 80% to 85% of  conventional ameloblastomas occur in the mandible, most  often in the molar-ascending ramus area. About 15% to  20% of ameloblastomas occur in the maxilla, usually in the  posterior regions (Fig. 15-55). The tumor is often asymp-  tomatic, and smaller lesions are detected only during a  radiographic examination. A painless swelling or expansion  of the jaw is the usual clinical presentation (Figs. 15-56 and  15-57). If untreated, then the lesion may grow slowly to  massive or grotesque proportions (Fig. 15-58). Pain and  paresthesia are uncommon, even with large tumors.   The most typical radiographic feature is that of a multi-  locular radiolucent lesion, although one large international  study suggested that a unilocular presentation was just as  likely. Multilocular lesions are described as having a “soap  bubble” appearance (when the radiolucent loculations are  large) or as being “honeycombed” (when the loculations are  small) (Figs. 15-59 to 15-61). Buccal and lingual cortical    @ Fig. 15-55 Ameloblastoma. Relative distribution of ameloblasto-  mas in the jaws.    expansion is frequently present. Resorption of the roots of  teeth adjacent to the tumor is common. In many cases an  unerupted tooth, most often a mandibular third molar, is  associated with the radiolucent defect. Solid ameloblasto-  mas may radiographically appear as unilocular radiolucent  defects, which may resemble almost any type of cystic lesion  (Fig. 15-62). The margins of these radiolucent lesions,  however, often show irregular scalloping. Although the  radiographic features, particularly of the typical multilocu-  lar defect, may be highly suggestive of ameloblastoma, a    @ Fig. 15-56 Ameloblastoma. Large expansile mass of the anterior  mandible. (Courtesy of Dr. Michael Tabor.)    variety of odontogenic and nonodontogenic lesions may  show similar radiographic features (see Appendix).   One form of ameloblastoma that does not have these  characteristic features is the desmoplastic ameloblastoma, a  variant that Eversole and colleagues documented initially in  the literature in 1984. The desmoplastic ameloblastoma has  a marked predilection to occur in the anterior regions of    ® Fig. 15-58 Ameloblastoma. Massive tumor of the anterior man-  dible. (Courtesy of Dr. Ronald Baughman.)    the jaws, with equal distribution between the mandible and  the maxilla. Radiographically, this type may not suggest the  diagnosis of ameloblastoma; the majority of these tumors  resemble a fibro-osseous lesion because of their mixed radio-  lucent and radiopaque appearance (Fig. 15-63). This mixed  radiographic appearance is due to osseous metaplasia within  the dense fibrous septa that characterize the lesion, not  because the tumor itself is producing a mineralized product.    Conventional solid or multicystic intraosseous ameloblasto-  mas show a remarkable tendency to undergo cystic change;  grossly, most tumors have varying combinations of cystic  and solid features. The cysts may be seen only at the micro-  scopic level or may be present as multiple large cysts that  include most of the tumor. Several microscopic subtypes of    @ Fig. 15-59 Ameloblastoma. Large multilocular lesion involving the  mandibular angle and ascending ramus. The large loculations show  the “soap bubble” appearance. An unerupted third molar has been  displaced high into the ramus.    @ Fig. 15-61 Ameloblastoma. Destructive radiolucent lesion with  root resorption of the associated posterior teeth. (Courtesy of Dr. Louis  Beto.)    @ Fig. 15-62 Ameloblastoma. This small unilocular radiolucency  lesion could easily be mistaken for a lateral periodontal cyst. (Courtesy  of Dr. Tony Traynham.)    conventional ameloblastoma are recognized, but these  microscopic patterns generally have little bearing on the  behavior of the tumor. Large tumors often show a combina-  tion of microscopic patterns.   The follicular and plexiform patterns are the most  common. Less common histopathologic patterns include  the acanthomatous, granular cell, desmoplastic, and    The follicular histopathologic pattern is the most common  and recognizable. Islands of epithelium resemble enamel  organ epithelium in a mature fibrous connective tissue  stroma. The epithelial nests consist of a core of loosely    ® Fig. 15-63 Desmoplastic Ameloblastoma. Large mixed radiolu-  cent and radiopaque lesion of the anterior and right body of the  mandible. (Courtesy of Dr. Roman Carlos.)    of odontogenic epithelium demonstrating peripheral columnar differen-  tiation with reverse polarization. The central zones resemble stellate  reticulum and exhibit foci of cystic degeneration.    arranged angular cells resembling the stellate reticulum of  an enamel organ. A single layer of tall columnar ameloblast-  like cells surrounds this central core. The nuclei of these  cells are located at the opposite pole to the basement mem-  brane (reversed polarity). In other areas, the peripheral  cells may be more cuboidal and resemble basal cells. Cyst  formation is common and may vary from microcysts, which  form within the epithelial islands, to large macroscopic  cysts, which may be several centimeters in diameter (Figs.  15-64 and 15-65). Ifan incisional biopsy is taken from such  an area, an inappropriate diagnosis of “unicystic ameloblas-  toma’ may be rendered by the pathologist.    The plexiform type of ameloblastoma consists of long, anas-  tomosing cords or larger sheets of odontogenic epithelium.  The cords or sheets of epithelium are bounded by columnar  or cuboidal ameloblast-like cells surrounding more loosely    @ Fig. 15-65 Ameloblastoma (Follicular Pattern). This high-power  photomicrograph highlights the peripheral columnar cells exhibiting  reverse polarization.    arranged epithelial cells. The supporting stroma tends to be  loosely arranged and vascular. Cyst formation is relatively  uncommon in this variety. When it occurs, it is more often  associated with stromal degeneration rather than cystic    When extensive squamous metaplasia, often associated with  keratin formation, occurs in the central portions of the  epithelial islands of a follicular ameloblastoma, the term  acanthomatous ameloblastoma is sometimes applied. This  change does not indicate a more aggressive course for the  lesion; histopathologically, however, such a lesion may be  confused with squamous cell carcinoma or squamous odon-  togenic tumor (Fig. 15-67).    Ameloblastomas may sometimes show transformation of  groups of lesional epithelial cells to granular cells. These  cells have abundant cytoplasm filled with eosinophilic gran-  ules that resemble lysosomes ultrastructurally and histo-  chemically. Although originally considered to represent an    © Fig. 15-67 Ameloblastoma (Acanthomatous Pattern). Islands  of ameloblastoma demonstrating central squamous differentiation.    e Fig. 15-68 Ameloblastoma (Granular Cell Variant). Tumor  island exhibiting central cells with prominent granular cytoplasm.    aging or degenerative change in long-standing lesions, this  variant has been seen in young patients. When this granular  cell change is extensive in an ameloblastoma, the designa-  tion of granular cell ameloblastoma is appropriate (Fig.  15-68).    This type of ameloblastoma contains small islands and cords  of odontogenic epithelium in a densely collagenized stroma.  Immunohistochemical studies have shown increased pro-  duction of the cytokine known as transforming growth  factor-B (TGF-B) in association with this lesion, suggesting  that this may be responsible for the desmoplasia. Peripheral  columnar ameloblast-like cells are inconspicuous about the    The basal cell variant of ameloblastoma is the least common  type. These lesions are composed of nests of uniform basa-  loid cells, and they histopathologically are very similar to    basal cell carcinoma of the skin. No stellate reticulum is  present in the central portions of the nests. The peripheral  cells about the nests tend to be cuboidal rather than colum-  nar (Fig. 15-70).    Patients with conventional solid or multicystic intraosseous  ameloblastomas have been treated by a variety of means.  These range from simple enucleation and curettage to en  bloc resection (Fig. 15-71). The optimal method of treat-  ment has been the subject of controversy for many years.  The conventional ameloblastoma tends to infiltrate between  intact cancellous bone trabeculae at the periphery of the  lesion before bone resorption becomes radiographically  evident. Therefore, the actual margin of the tumor often  extends beyond its apparent radiographic or clinical margin.  Attempts to remove the tumor by curettage often leave  small islands of tumor within the bone, which later manifest  as recurrences. Recurrence rates of 50% to 90% have been  reported in various studies after curettage. Recurrence often    takes many years to become clinically manifest, and 5-year  disease-free periods do not indicate a cure.   Marginal resection is the most widely used treatment,  but recurrence rates of up to 15% have been reported after  marginal or block resection. Some surgeons advocate a more  conservative approach to treatment by planning surgery  after careful evaluation of CT scans of the tumor. Removal  of the tumor, followed by peripheral ostectomy, often  reduces the need for extensive reconstructive surgery. Some  tumors may not be amenable to this approach because of  their size or growth pattern.   Other surgeons advocate that the margin of the resection  should be at least 1.0 to 2.0 cm past the radiographic limits  of the tumor. Ameloblastomas of the posterior maxilla are  particularly dangerous because of the difficulty of obtaining  an adequate surgical margin around the tumor. Orbital  invasion by maxillary ameloblastomas occasionally has been  described. Although some studies suggest that the amelo-  blastoma may be radiosensitive, radiation therapy has  seldom been used as a treatment modality because of the  intraosseous location of the tumor and the potential for    @ Fig. 15-71 Ameloblastoma. A, Gross photograph of a mandibular resection specimen. B, The  radiograph of the specimen shows a large radiolucent defect associated with an inferiorly displaced third  molar. (Courtesy of Dr. Mary Richardson.)   The conventional ameloblastoma is a persistent, infiltra-  tive neoplasm that very seldom may kill the patient by  progressive spread to involve vital structures. Most of these  tumors, however, are not life-threatening lesions. Rarely, an  ameloblastoma exhibits frank malignant behavior. These are  discussed separately.    The unicystic ameloblastoma has for several decades been  given separate consideration based on its clinical, radio-  graphic, and pathologic features. Although its response to  treatment in reports from the 1970s and 1980s suggested  that this lesion might behave in a less aggressive fashion,  recent reports have disputed this concept. Unicystic amelo-  blastomas account for 10% to 46% of all intraosseous  ameloblastomas in various studies. Whether the unicystic  ameloblastoma originates de novo as a neoplasm or whether  it is the result of neoplastic transformation of nonneoplastic  cyst epithelium has been long debated. Both mechanisms  probably occur, but proof of which is involved in an indi-  vidual patient is virtually impossible to obtain.    Unicystic ameloblastomas are seen most often in younger  patients, with about 50% of all such tumors diagnosed  during the second decade of life. The average age in one  large series was 23 years. More than 90% of unicystic ame-  loblastomas are found in the mandible, usually in the pos-  terior regions. The lesion is often asymptomatic, although  large lesions may cause a painless swelling of the jaws.   In many patients, this lesion typically appears as a cir-  cumscribed radiolucency that surrounds the crown of an  unerupted mandibular third molar (Figs. 15-72 and 15-73),  clinically resembling a dentigerous cyst. Other tumors  simply appear as sharply defined radiolucent areas and are  usually considered to be a primordial, radicular, or residual  cyst, depending on the relationship of the lesion to teeth in  the area. In some instances, the radiolucent area may have  scalloped margins but is still a unicystic ameloblastoma.  Whether a unicystic ameloblastoma can have a truly mul-  tilocular radiographic presentation is arguable.   The surgical findings may also suggest that the lesion in  question is a cyst, and the diagnosis of ameloblastoma is  made only after microscopic study of the specimen.    Three histopathologic variants of unicystic ameloblastoma  have been described. In the first type (luminal unicystic  ameloblastoma), the tumor is confined to the luminal  surface of the cyst. The lesion consists of a fibrous cyst wall  with a lining composed totally or partially of ameloblastic  epithelium. The lining demonstrates a basal layer of    ® Fig. 15-72 Unicystic Ameloblastoma. A large radiolucency asso-  ciated with the crown of the developing mandibular third molar. (Cour-  tesy of Dr. Antonia Kolokythas.)    @ Fig. 15-73 Unicystic Ameloblastoma (Intraluminal Plexiform  Type). Coronal computed tomography (CT) image that shows a large  cystic lesion with an intraluminal mass arising from the cyst wall  (arrow).    columnar or cuboidal cells with hyperchromatic nuclei that  show reverse polarity and basilar cytoplasmic vacuolization  (Fig. 15-74). The upper epithelial cells are loosely cohesive  and resemble stellate reticulum. This finding does not seem  to be related to inflammatory edema.   In the second microscopic variant, one or more nodules  of ameloblastoma project from the cystic lining into the  lumen of the cyst. This type is called an intraluminal uni-  cystic ameloblastoma. These nodules may be relatively  small or largely fill the cystic lumen. In some cases, the  nodule of tumor that projects into the lumen demonstrates  an edematous, plexiform pattern that resembles the plexi-  form pattern seen in conventional ameloblastomas (Fig.  15-75). These lesions are sometimes referred to as plexi-  form unicystic ameloblastomas. The intraluminal cellular  proliferation does not always meet the strict histopathologic    is lined by ameloblastic epithelium showing a hyperchromatic, polar-  ized basal layer. The overlying epithelial cells are loosely cohesive and  resemble stellate reticulum.    Pen, ie ea ES ' = Kee  @ Fig. 15-75 Unicystic Ameloblastoma (Intraluminal Plexiform  Type). Photomicrograph of an intraluminal mass arising from the cyst  wall. The inset shows the intraluminal mass at higher magnification.    criteria for ameloblastoma, and this may be secondary to  inflammation that nearly always accompanies this pattern.  Typical ameloblastoma, however, may be found in other,  less inflamed parts of the specimen.   In the third variant, known as mural unicystic amelo-  blastoma, the fibrous wall of the cyst is infiltrated by typical  follicular or plexiform ameloblastoma. The extent and  depth of the ameloblastic infiltration may vary considerably.  With any presumed unicystic ameloblastoma, multiple sec-  tions through many levels of the specimen are necessary to  rule out the possibility of mural invasion of tumor cells    The clinical and radiographic findings in most cases of  unicystic ameloblastoma suggest that the lesion is an odon-  togenic cyst. These tumors are usually treated as cysts by  enucleation. The diagnosis of ameloblastoma is made only  after microscopic examination of the presumed cyst. If the  ameloblastic elements are confined to the lumen of the cyst    ee ‘i < > N oe  @ Fig. 15-76 Unicystic Ameloblastoma (Mural Type). The epithe-  lial lining of the cystic component can be seen on the left edge of the  photomicrograph. Islands of follicular ameloblastoma are infiltrating  into the fibrous connective tissue wall on the right.    with or without intraluminal tumor extension, then the cyst  enucleation has probably been adequate treatment. The  patient, however, should be kept under long-term follow-up.  If the specimen shows extension of the tumor into the  fibrous cyst wall for any appreciable distance, then subse-  quent management of the patient is more controversial.  Some surgeons believe that local resection of the area is  indicated as a prophylactic measure; others prefer to keep  the patient under close radiographic observation and delay  further treatment until there is evidence of recurrence.   Recurrence rates of 10% to 20% were described after  enucleation and curettage of unicystic ameloblastomas in  many of the earlier series of cases. This range is considerably  less than the 50% to 90% recurrence rates noted after curet-  tage of conventional solid and multicystic intraosseous  ameloblastomas. A systematic review of the literature before  2005 determined that 30% of these lesions recurred after  enucleation, and a recent single-center study showed an  identical recurrence rate of 60% after enucleation for both  solid and unicystic ameloblastoma. These findings suggest  that this lesion may not be as innocuous as previously  thought. Alternatively, it is possible that some of those  tumors that are designated as “unicystic” may, in fact, have  a more characteristic invasive component that has not been  detected histopathologically because it is essentially impos-  sible to examine these lesions in every 360-degree plane of  section.    The peripheral ameloblastoma is uncommon and accounts  for about 1% to 4% of all ameloblastomas. This tumor  probably arises from rests of dental lamina beneath the oral  mucosa or from the basal epithelial cells of the surface epi-  thelium. Histopathologically, these lesions have the same  features as the intraosseous form of the tumor.    @ Fig. 15-77 Peripheral Ameloblastoma. Sessile gingival mass.  (Courtesy of Dr. Dean K. White.)    ‘The peripheral ameloblastoma is usually a painless, nonul-  cerated sessile or pedunculated gingival or alveolar mucosal  lesion. The clinical features are non-specific, and most  lesions are clinically considered to represent a fibroma or  pyogenic granuloma. Most examples are smaller than  1.5 cm, but larger lesions have been reported (Fig. 15-77).  The tumor has been found in patients across a wide age  range, but most are seen in middle-aged persons, with an  average reported age of 52 years.   Peripheral ameloblastomas are most commonly found on  the posterior gingival and alveolar mucosa, and they are  somewhat more common in mandibular than in maxillary  areas. In some cases, the superficial alveolar bone becomes  slightly eroded, but significant bone involvement does not  occur. A few examples of a microscopically identical lesion  have been reported in the buccal mucosa at some distance  from the alveolar or gingival soft tissues.    Peripheral ameloblastomas have islands of ameloblastic epi-  thelium that occupy the lamina propria underneath the  surface epithelium (Fig. 15-78). The proliferating epithe-  lium may show any of the features described for the intraos-  seous ameloblastoma; plexiform or follicular patterns are  the most common. Connection of the tumor with the basal  layer of the surface epithelium is seen in about 50% of cases.  ‘This may represent origin of the tumor from the basal layer  of the epithelium in some cases, but in other instances the  tumor could develop in the gingival connective tissue and  merge with the surface epithelium.   Basal cell carcinomas of the gingival mucosa have been  reported, but most of these would be designated best as  peripheral ameloblastomas. A peripheral odontogenic  fibroma may be confused microscopically with a peripheral  ameloblastoma, particularly if a prominent epithelial com-  ponent is present in the former. The presence of dysplastic  dentin or cementum-like elements in the peripheral    odontogenic fibroma and the lack of peripheral columnar  epithelial cells showing reverse polarity of their nuclei  should serve to distinguish the two lesions.    Unlike the intraosseous ameloblastoma, the peripheral ame-  loblastoma shows an innocuous clinical behavior. Patients  respond well to local surgical excision. Although local recur-  rence has been noted in 15% to 20% of cases, further local  excision almost always results in a cure. Several examples of  malignant change in a peripheral ameloblastoma have been  reported, but this is rare.    Rarely, an ameloblastoma exhibits frank malignant behavior  with development of metastases. The frequency of malignant  behavior in ameloblastomas is difficult to determine but  probably occurs in far less than 1% of all ameloblastomas.   ‘The terminology for these lesions is somewhat confusing,  but should not be considered controversial. The term malig-  nant ameloblastoma is used for a tumor that shows the  histopathologic features of ameloblastoma, both in the  primary tumor and in the metastatic deposits. This is a very  rare neoplasm, with fewer than 30 well-documented cases  described in the literature. The term ameloblastic carcinoma  should be reserved for an ameloblastoma that has cytologic  features of malignancy in the primary tumor, in a recur-  rence, or in any metastatic deposit. This is also a rare condi-  tion, although approximately 200 cases have been reported.  These lesions may follow a markedly aggressive local course,  but metastases do not necessarily occur.    Malignant ameloblastomas have been observed in patients  who range in age from 6 to 61 years (mean age, 30 years),    @ Fig. 15-79 Ameloblastic Carcinoma. A, Rapidly growing tumor showing prominent labial expansion  of the mandible in the incisor and premolar area. B, The panoramic radiograph shows irregular destruction  of the mandible. (From Neville BW, Damm DD, White DK: Color atlas of clinical oral pathology, ed 2,    and no sex predilection is seen. For patients with docu-  mented metastases, the interval between the initial treat-  ment of the ameloblastoma and first evidence of metastasis  varies from 3 to 45 years. In nearly one-third of cases,  metastases do not become apparent until 10 years after  treatment of the primary tumor. Ameloblastic carcinomas,  in contrast, tend to develop later in life, with the mean  age at diagnosis typically being in the sixth decade of life.  Men are affected twice as frequently as women.   Metastases from ameloblastomas are found most often  in the lungs. These have sometimes been regarded as aspira-  tion or implant metastases. However, the peripheral loca-  tion of some of these lung metastases suggests that they  must have occurred by blood or lymphatic routes rather  than aspiration.   Cervical lymph nodes are the second most common site  for metastasis of an ameloblastoma. Spread to vertebrae,  other bones, and viscera has also occasionally been  confirmed.   The radiographic findings of malignant ameloblastomas  may be essentially the same as those in typical nonmetasta-  sizing ameloblastomas. Ameloblastic carcinomas are often  more aggressive lesions, with ill-defined margins and corti-  cal destruction (Fig. 15-79).    With malignant ameloblastomas, the primary jaw tumor  and the metastatic deposits show no microscopic features  that differ from those of ameloblastomas with a com-  pletely benign local course. With ameloblastic carcinomas,  the metastatic deposit or primary tumor shows the  microscopic pattern of ameloblastoma in addition to  cytologic features of malignancy. These include an increased  nuclear-to-cytoplasmic ratio, nuclear hyperchromatism,  and the presence of mitoses (Fig. 15-80). Necrosis in  tumor islands and areas of dystrophic calcification may  also be present.    The prognosis of patients with malignant ameloblastomas  appears to be poor, but the paucity of documented cases  with long-term follow-up does not permit accurate assump-  tions to be made. About 50% of the patients with docu-  mented metastases and long-term follow-up have died of  their disease. Lesions designated as ameloblastic carcinoma  have demonstrated a uniformly aggressive clinical course,  with perforation of the cortical plates of the jaw and exten-  sion of the tumor into adjacent soft tissues.    Clear cell odontogenic carcinoma is a rare jaw tumor that  was first described in 1985. To date, approximately 80  examples have been documented. The tumor appears to be  of odontogenic origin, but its histogenesis is uncertain.  Histochemical and ultrastructural studies have suggested  that the clear cells, which are the prominent feature of this  neoplasm, may have similarities to glycogen-rich presecre-  tory ameloblasts. Recent molecular studies, however, have  identified rearrangements of the EWSRI gene in clear cell  odontogenic carcinoma. This genetic alteration can be  found in a variety of tumors, but it is often seen in hyalin-  izing clear cell carcinoma, a rare salivary gland malignancy.  Consequently some authors have postulated that perhaps  some clear cell odontogenic carcinomas may represent an  intraosseous variant of hyalinizing clear cell carcinoma.    The clear cell odontogenic carcinoma exhibits a variable  clinical pattern. A wide age range (from 14 to 89 years of  age) has been described, but most cases are diagnosed in    — Sa % bie et i “f  e Fig. 15-80 Ameloblastic Carcinoma. Ameloblastic epithelium  demonstrating hyperchromatism, pleomorphism, and numerous  mitotic figures.    ® Fig. 15-81 Clear Cell Odontogenic Carcinoma. A radiolucent  defect at the apex of the mandibular first molar. (Courtesy of Dr. John  Werther.)    patients older than age 50. Nearly 80% of the lesions  develop in the mandible. Some patients complain of pain  or lower lip paresthesia, and bony swelling may be present.  Other patients are relatively symptom free. Approximately  60% of patients will have evidence of soft tissue involve-  ment by the tumor at the time of diagnosis because the  lesion perforates bone.   Radiographically, the lesions appear as unilocular or  multilocular radiolucencies. The margins of the radiolu-  cency are often somewhat ill-defined or irregular (Fig.  15-81).    Three histopathologic patterns have been described for clear  cell odontogenic carcinoma. The biphasic pattern consists  of varying-sized nests of epithelial cells, with a clear or  faintly eosinophilic cytoplasm admixed with more eosino-  philic polygonal epithelial cells (Fig. 15-82). The second  pattern is more monophasic, characterized by only clear  cells that are arranged in nests and cords. Thin strands of    Sa wb \ : Sw Me  ® Fig. 15-82 Clear Cell Odontogenic Carcinoma. Hyperchromatic  epithelial nests including clusters of cells with abundant clear  cytoplasm.    hyalinized connective tissue often separate the clear cell  nests. The third pattern has a resemblance to ameloblastoma  in that the peripheral cells of the clear cell islands may  infrequently demonstrate palisading (Fig. 15-83). Often the  lesional cells do not exhibit a significant degree of nuclear  or cytologic pleomorphism. Furthermore, mitoses are gen-  erally sparse and necrosis is not a prominent feature. The  clear cells contain small amounts of glycogen, but mucin  stains are negative. In some cases, islands more typical of  ameloblastoma are interspersed among the other tumor  elements.   Hyalinizing clear cell carcinoma resembles clear cell  odontogenic carcinoma, and although the salivary gland  tumor develops in the soft tissues, for those lesions that have  significant bone destruction, it may be difficult to identify  the site of origin. Clear cell odontogenic carcinoma also  may be difficult to distinguish from intraosseous mucoepi-  dermoid carcinoma with a prominent clear cell component,  although the negative mucin stains are consistent with the  former. Amyloid stains would confirm the diagnosis of clear  cell variant of the calcifying epithelial odontogenic tumor,  because amyloid would not be present in clear cell    odontogenic tumor. A metastatic clear cell neoplasm, such  as a renal cell carcinoma, clear cell breast carcinoma, or clear  cell melanoma, may also need to be ruled out before the  diagnosis of clear cell odontogenic carcinoma can be    Clear cell odontogenic carcinomas largely demonstrate an  aggressive clinical course, with invasion of contiguous struc-  tures and a significant tendency to recur, particularly if the  initial treatment is enucleation or curettage. Most patients  require fairly radical surgery. Metastatic involvement of  regional lymph nodes has been documented in 20% to 25%  of these patients, and pulmonary metastases have been  described as well.    The adenomatoid odontogenic tumor represents 2% to  7% of all odontogenic tumors, and more than 750 examples  have been reported in the literature. Although this lesion  was formerly considered to be a variant of the ameloblas-  toma and was designated as “adenoameloblastoma,” its  clinical features and biologic behavior indicate that it is a  separate entity. Postulated histogenetic sources of the tumor  cells have included enamel organ epithelium, reduced  enamel epithelium, and rests of Malassez; however, some  investigators recently have suggested that the lesion arises  from remnants of dental lamina associated with the guber-  nacular cord.    Adenomatoid odontogenic tumors are largely limited to  younger patients, and two-thirds of all cases are diagnosed  when patients are 10 to 19 years of age. This tumor is defi-  nitely uncommon in a patient older than age 30. It has a  striking tendency to occur in the anterior portions of the  jaws and is found twice as often in the maxilla as in the  mandible (Fig. 15-84). Females are affected about twice as  often as males.   Most adenomatoid odontogenic tumors are relatively  small. They seldom exceed 3 cm in greatest diameter,  although a few large lesions have been reported. Peripheral  (extraosseous) forms of the tumor are also encountered. but  are rare. These usually appear as small, sessile masses on the  facial gingiva of the maxilla. Clinically, these lesions cannot  be differentiated from the common gingival fibrous lesions.   Adenomatoid odontogenic tumors are frequently asymp-  tomatic and are discovered during the course of a routine  radiographic examination or when films are made to deter-  mine why a tooth has not erupted. Larger lesions cause a  painless expansion of the bone.   In about 75% of cases, the tumor appears as a circum-  scribed, unilocular radiolucency that involves the crown of  an unerupted tooth, most often a canine. This follicular    @ Fig. 15-84 Adenomatoid Odontogenic Tumor. Relative distribu-  tion of adenomatoid odontogenic tumor in the jaws.    e Fig. 15-85 Adenomatoid Odontogenic Tumor. Radiolucent  lesion involving an unerupted mandibular first premolar. In contrast to  the usual dentigerous cyst, the radiolucency extends almost to the  apex of the tooth. (Courtesy of Dr. Tony Traynham.)    type of adenomatoid odontogenic tumor may be impossible  to differentiate radiographically from the more common  dentigerous cyst. The radiolucency associated with the fol-  licular type of adenomatoid odontogenic tumor sometimes  extends apically along the root past the cementoenamel  junction. This feature may help to distinguish an adeno-  matoid odontogenic tumor from a dentigerous cyst  (Fig. 15-85).   Less often the adenomatoid odontogenic tumor is a well-  delineated unilocular radiolucency that is not related to an  unerupted tooth, but rather is located between the roots of  erupted teeth (extrafollicular type) (Fig. 15-86).   The lesion may appear completely radiolucent; often,  however, it contains fine (snowflake) calcifications (Fig.  15-87). This feature may be helpful in differentiating the  adenomatoid odontogenic tumor from a dentigerous cyst.    The adenomatoid odontogenic tumor is a well-defined  lesion that is usually surrounded by a thick, fibrous capsule.    ® Fig. 15-86 Adenomatoid Odontogenic Tumor. A small radiolu-  cency is present between the roots of the lateral incisor and canine.  (Courtesy of Dr. Ramesh Narang.)    e Fig. 15-87 Adenomatoid Odontogenic Tumor. Well-defined  pericoronal radiolucency enveloping the maxillary right lateral incisor in  a 14-year-old male. Note the subtle snowflake-like calcifications within  the lesion. (Courtesy of Dr. Jason Barker.)    When the lesion is bisected, the central portion of the  tumor may be essentially solid or may show varying degrees  of cystic change (Fig. 15-88).   Microscopically, the tumor is composed of spindle-  shaped epithelial cells that form sheets, strands, or whorled  masses of cells in a scant fibrous stroma. ‘The epithelial cells  may form rosettelike structures about a central space, which  may be empty or contain small amounts of eosinophilic  material. This material may stain for amyloid.   The tubular or ductlike structures, which are the charac-  teristic feature of the adenomatoid odontogenic tumor, may  be prominent, scanty, or even absent in a given lesion. These  consist of a central space surrounded by a layer of columnar  or cuboidal epithelial cells. The nuclei of these cells tend to  be polarized away from the central space. The mechanism  of formation of these tubular structures is not entirely clear  but is likely the result of the secretory activity of the tumor  cells, which appear to be preameloblasts. In any event, these  structures are not true ducts, and no glandular elements are  present in the tumor (Fig. 15-89).   Small foci of calcification may also be scattered through-  out the tumor. These have been interpreted as abortive  enamel formation. Some adenomatoid odontogenic tumors  contain larger areas of matrix material or calcification. This  material has been interpreted as dentinoid or cementum.  Some lesions also have another pattern, particularly at the  periphery of the tumor adjacent to the capsule. This consists  of narrow, often anastomosing cords of epithelium in an  eosinophilic, loosely arranged matrix.   The histopathologic features of this lesion are distinctive  and should not be confused with any other odontogenic    e Fig. 15-88 Adenomatoid Odontogenic Tumor. A_ well-  circumscribed cystlike mass can be seen enveloping the crown of a  maxillary cuspid. Note the intraluminal vegetations, which represent  nodular tumor growth.    @ Fig. 15-89 Adenomatoid Odontogenic Tumor. A, Low-power  view demonstrating a thick capsule surrounding the tumor. B, Higher  magnification showing the ductlike epithelial structures. The nuclei of  the columnar cells are polarized away from the central spaces.    tumor. Interestingly, some adenomatoid odontogenic  tumors have been described with focal areas that resemble  calcifying epithelial odontogenic tumor, odontoma, or cal-  cifying odontogenic cyst. These lesions appear to behave as  a routine adenomatoid odontogenic tumor, however. The  chief problem relates to mistaking this tumor for an amelo-  blastoma by a pathologist who is not familiar with this  lesion. This error can lead to unnecessary radical surgery.    ‘The adenomatoid odontogenic tumor is completely benign;  because of its capsule, it enucleates easily from the bone.  Aggressive behavior has not been documented, and recur-  rence after enucleation seldom, if ever, occurs.    ‘The calcifying epithelial odontogenic tumor, also widely  known as the Pindborg tumor, is an uncommon lesion that  accounts for less than 1% of all odontogenic tumors.  Approximately 200 cases have been reported to date.    @ Fig. 15-90 Calcifying Epithelial Odontogenic Tumor. Relative  distribution of calcifying epithelial odontogenic tumor in the jaws.    @ Fig. 15-91 Calcifying Epithelial Odontogenic Tumor. Honey-  combed multilocular radiolucency containing fine calcifications.    Although the tumor is clearly of odontogenic origin, its  histogenesis is uncertain. The tumor cells bear a close mor-  phologic resemblance to the cells of the stratum interme-  dium of the enamel organ; however, some investigators have  recently suggested that the tumor arises from dental lamina  remnants based on its anatomic distribution in the jaws.  Mutations of the PTCH/ gene have been identified in one  small series of this neoplasm. This gene is characteristically  associated with nevoid basal cell carcinoma syndrome (see  page 640), but the calcifying epithelial odontogenic tumor  is not a component of that condition.    Although the calcifying epithelial odontogenic tumor has  been found in patients across a wide age range and in many  parts of the jaw, it is most often encountered in patients  between 30 and 50 years of age. There is no sex predilection.  About two-thirds of all reported cases have been found in  the mandible, most often in the posterior areas (Fig. 15-90).  A painless, slow-growing swelling is the most common pre-  senting sign.   Radiographically, the tumor exhibits either a unilocular  or a multilocular radiolucent defect (Fig. 15-91), with the    unilocular pattern encountered more commonly in the  maxilla. The margins of the lytic defect are often scalloped  and usually relatively well defined. However, approximately  20% of cases have an ill-defined periphery, and an addi-  tional 20% exhibit a corticated border. The tumor is  frequently associated with an impacted tooth, most often  a mandibular molar. The lesion may be entirely radiolu-  cent, but calcified structures of varying size and density  are commonly seen. Although some authors have suggested  that these are often most prominent around the crown  of the impacted tooth (Fig. 15-92), a review of the lit-  erature identified this feature in only 12% of published  cases with adequate radiographic documentation. Similarly,  the description of a “driven-snow” pattern of the calcifica-  tions appears to be much less common than previously  believed.   A few cases of peripheral (extraosseous) calcifying epithe-  lial odontogenic tumor have been reported. These appear as  nonspecific, sessile gingival masses, most often on the ante-  rior gingiva. Some of these have been associated with  cupped-out erosion of the underlying bone.    The calcifying epithelial odontogenic tumor has discrete  islands, strands, or sheets of polyhedral epithelial cells in a  fibrous stroma (Fig. 15-93). The cellular outlines of the  epithelial cells are distinct, and intercellular bridges may be  noted. The nuclei show considerable variation, and giant  nuclei may be seen. Some tumors show considerable nuclear  pleomorphism, but this feature is not considered to indicate  malignancy. Large areas of amorphous, eosinophilic, hyalin-  ized (amyloid-like) extracellular material are also often  present. The tumor islands frequently enclose masses of this  hyaline material, resulting in a cribriform appearance. Cal-  cifications, which are a distinctive feature of the tumor,  develop within the amyloid-like material and form concen-  tric rings (Liesegang ring calcifications) (Fig. 15-94). These  tend to fuse and form large, complex masses.    ® Fig. 15-92 Calcifying Epithelial Odontogenic Tumor. Prominent  calcification around the crown of an impacted second molar that is  involved in the tumor. (Courtesy of Dr. Harold Peacock.)    Several microscopic variations may be encountered.  Some tumors consist of large sheets of epithelial cells with  minimal production of amyloid-like material and calcifica-  tions. Others show large diffuse masses of amyloid-like  material that contain only small nests or islands of epithe-  lium. A clear cell variant has been described, in which  clear cells constitute a significant portion of the epithelial    ® Fig. 15-94 Calcifying Epithelial Odontogenic Tumor. Multiple  concentric Liesegang ring calcifications.    e Fig. 15-95 Calcifying Epithelial Odontogenic Tumor. With  Congo red staining, the pools of amyloid exhibit an apple-green bire-  fringence when viewed with polarized light.    component, and this tumor also has been reported to have  a cystic growth pattern.   The amyloid-like material in the Pindborg tumor has  been extensively investigated by histochemical, immunohis-  tochemical, and biochemical methods, as well as by electron  microscopy. The material generally stains as amyloid (i.e.,  positive staining results with Congo red). After Congo red  staining, the amyloid will exhibit apple-green birefringence  when viewed with polarized light (Fig. 15-95). Investigators  have identified this material as a unique protein that is  produced by this tumor, as well as by the normal odonto-  genic apparatus and other odontogenic neoplasms. Both the  protein structure and the DNA sequence of the responsible  gene have been described, and this material has been  designated as odontogenic ameloblast-associated protein    Although it was originally believed that the calcifying epi-  thelial odontogenic tumor had about the same biologic  behavior as the ameloblastoma, accumulating experience  indicates that it tends to be less aggressive. Conservative  local resection to include a narrow rim of surrounding bone  appears to be the treatment of choice, although lesions in  the posterior maxilla should probably be treated more  aggressively. A recurrence rate of about 15% has been  reported; tumors treated by curettage have the highest fre-  quency of recurrence. The overall prognosis appears good,  although rare examples of malignant or borderline malig-  nant calcifying epithelial odontogenic tumor have been  reported, with documented metastasis to regional lymph  nodes and lung.    Squamous odontogenic tumor is a rare benign odonto-  genic neoplasm that was first described in 1975 and is now  recognized as a distinct entity. Approximately 50 examples  have been reported to date. Most of these have been located    © Fig. 15-96 Squamous Odontogenic Tumor. Lucent defect  extending along the roots of the lateral incisor and first premolar teeth.  (Courtesy of Dr. Ed McGaha.)    within bone, although a few peripheral examples have been  described. Before 1975, this lesion was probably believed to  represent an atypical acanthomatous ameloblastoma or even  a squamous cell carcinoma. The squamous odontogenic  tumor may arise from neoplastic transformation of dental  lamina rests or perhaps the epithelial rests of Malassez. In  some cases, the tumor appears to originate within the peri-  odontal ligament that is associated with the lateral root  surface of an erupted tooth.    Squamous odontogenic tumors have been found in patients  whose ages ranged from 8 to 74 years (average age, 38).  They are randomly distributed throughout the alveolar pro-  cesses of the maxilla and mandible, with no site of predilec-  tion. A few patients have had multiple squamous odontogenic  tumors that involved several quadrants of the mouth; one  family with three affected siblings who each had multiple  lesions has been reported. There is no apparent sex predilec-  tion. A painless or mildly painful gingival swelling, often  associated with mobility of the associated teeth, is the most  common complaint. About 25% of reported patients have  had no symptoms, and their lesions were detected during a  radiographic examination.   The radiographic findings are not specific or diagnostic  and consist of a triangular radiolucent defect lateral to the  root or roots of the teeth (Fig. 15-96). In some instances,  this suggests vertical periodontal bone loss. The radiolucent  area may be somewhat ill defined or may show a well-  defined, corticated margin. Most examples are relatively  small lesions that seldom exceed 1.5 cm in greatest  diameter.    The microscopic findings of squamous odontogenic tumor  are distinctive and consist of varying-shaped islands of  bland-appearing squamous epithelium in a mature fibrous  connective tissue stroma. The peripheral cells of the    epithelial islands do not show the characteristic polarization  seen in ameloblastomas (Fig. 15-97). Vacuolization and  individual cell keratinization within the epithelial islands  are common features. Small microcysts are sometimes  observed within the epithelial islands. Laminated calcified  bodies and globular eosinophilic structures, which do not  stain for amyloid, are present within the epithelium in some  cases. The former probably represents dystrophic calcifica-  tions; the nature of the latter is unknown.   Islands of epithelium that closely resemble those of the  squamous odontogenic tumor have been observed within  the fibrous walls of dentigerous and radicular cysts. These  have been designated as squamous odontogenic tumorlike pro-  liferations in odontogenic cysts. These islands do not appear  to have any significance relative to the behavior of the cyst,  and evaluation of the clinical, radiographic, and histopatho-  logic features should permit differentiation from a squa-  mous odontogenic tumor.   In published reports, some squamous odontogenic  tumors have been misdiagnosed initially as ameloblastomas,  resulting in unnecessary radical surgery.    Conservative local excision or curettage appears to be effec-  tive for patients with squamous odontogenic tumors, and    tomicrograph showing islands of bland-appearing squamous epithe-  lium in a fibrous stroma. B, Higher-power photomicrograph showing  bland appearance of the epithelium with microcyst formation.    most reported cases have not recurred after local excision.  A few instances of recurrence have been reported, but these  have responded well to further local excision. Maxillary  squamous odontogenic tumors may be somewhat more  aggressive than mandibular lesions, with a greater tendency  to invade adjacent structures. This may be because of the  porous, spongy nature of the maxillary bone. The multicen-  tric lesions have typically exhibited a less aggressive, almost  hamartomatous behavior when compared with solitary  lesions. A well-documented example of apparent malignant  transformation of squamous odontogenic tumor has been  reported.    The group of mixed odontogenic tumors, composed of  proliferating odontogenic epithelium in a cellular ectomes-  enchyme resembling the dental papilla, poses problems in  classification. Some of these lesions show varying degrees of  inductive effect by the epithelium on the mesenchyme,  leading to the formation of varying amounts of enamel and  dentin. Some of these lesions (the common odontomas)  are clearly nonneoplastic developmental anomalies; others  appear to be true neoplasms. The nature of others is  uncertain.   In some instances, the histopathologic findings alone  cannot distinguish between the neoplastic lesions and the  developmental anomalies. Clinical and radiographic fea-  tures often are of considerable assistance in making this  distinction.    The ameloblastic fibroma is considered to be a true mixed  tumor in which the epithelial and mesenchymal tissues are  both neoplastic. It is an uncommon tumor, but the data  regarding its frequency are difficult to evaluate because (par-  ticularly in earlier reports) some lesions that were diagnosed  as ameloblastic fibroma may actually have represented the  early developing stage of an odontoma.    Ameloblastic fibromas tend to occur in younger patients;  most lesions are diagnosed in the first two decades of life.  This lesion, however, is occasionally encountered in middle-  aged patients. The tumor is slightly more common in males  than in females. Small ameloblastic fibromas are asymptom-  atic; larger tumors are associated with swelling of the jaws.  The posterior mandible is the most common site; about  70% of all cases are located in this area (Fig. 15-98). Con-  vincing examples of this tumor arising within the gingival  soft tissue have been described, but this appears to represent  a rare phenomenon.   Radiographically, either a unilocular or multilocular  radiolucent lesion is seen, with the smaller lesions tending  to be unilocular. The radiographic margins tend to be well  defined, and they may be corticated. An unerupted tooth    @ Fig. 15-98 Ameloblastic Fibroma. Relative distribution of amelo-  blastic fibroma in the jaws.    @ Fig. 15-99 Ameloblastic Fibroma. Multilocular radiolucent defect  associated with an unerupted second molar. (Courtesy of Dr. Mark  Chishom.)    is associated with the lesion in about 75% of cases (Fig.  15-99). The ameloblastic fibroma may grow to a large size,  and cases that involve a considerable portion of the body  and ascending ramus of the mandible have been reported.    The ameloblastic fibroma appears as a solid, soft tissue mass  with a smooth outer surface. A definite capsule may or may  not be present. Microscopically, the tumor is composed of  a cell-rich mesenchymal tissue resembling the primitive  dental papilla admixed with proliferating odontogenic epi-  thelium. The latter may have one of two patterns, both of  which are usually present in any given case. The most  common epithelial pattern consists of long, narrow cords of  odontogenic epithelium, often in an anastomosing arrange-  ment. These cords are usually only two cells in thickness  and are composed of cuboidal or columnar cells (Fig.  15-100). In the other pattern, the epithelial cells form small,  discrete islands that resemble the follicular stage of the  developing enamel organ. These show peripheral columnar    © Fig. 15-100 Ameloblastic Fibroma. A, Long, narrow cords of  odontogenic epithelium supported by richly cellular, primitive connec-  tive tissue. B, Basophilic epithelial islands with peripheral nuclear  palisading.    cells, which surround a mass of loosely arranged epithelial  cells that resemble stellate reticulum. In contrast to the fol-  licular type of ameloblastoma, these follicular islands in  the ameloblastic fibroma seldom demonstrate microcyst  formation.   The mesenchymal portion of the ameloblastic fibroma  consists of plump stellate and ovoid cells in a loose matrix,  which closely resembles the developing dental papilla. Col-  lagen formation is generally inconspicuous. Juxtaepithelial  hyalinization of the mesenchymal portion of the tumor is  sometimes seen, and occasionally diffuse areas of hyalinized  acellular lesional tissue are evident.   A few examples of ameloblastic fibroma occurring in  conjunction with calcifying odontogenic cyst also have been  reported.    The proper management of ameloblastic fibroma has been  an ongoing topic of debate. Although initially it was believed  that the ameloblastic fibroma was an innocuous lesion that  seldom recurred after simple local excision or curettage,  subsequent reports seemed to indicate a substantial risk of  recurrence after conservative therapy. The highest recur-  rence rate (43.5%) was recorded in a series of cases from    the Armed Forces Institute of Pathology, and it could be  argued that this was a biased sample of larger lesions that  were inherently more difficult to manage. In other series of  cases, from 0% to 18% of ameloblastic fibromas were  reported to recur after conservative removal and an ade-  quate follow-up period. Based on these data, recent recom-  mendations have emphasized conservative initial therapy  for ameloblastic fibroma. More aggressive surgical excision  should probably be reserved for recurrent lesions. Approxi-  mately 35% of the cases of the rare ameloblastic fibrosar-  coma develop in the setting of a recurrent ameloblastic  fibroma.    The ameloblastic fibro-odontoma is defined as a tumor  with the general features of an ameloblastic fibroma but  that also contains enamel and dentin. Some investigators  believe that the ameloblastic fibro-odontoma is only a  stage in the development of an odontoma and do not  consider it to be a separate entity. Certainly the histo-  pathologic features of a developing odontoma may overlap  somewhat with ameloblastic fibro-odontoma. There are  well-documented examples, however, of this tumor exhibit-  ing progressive growth and causing considerable deformity  and bone destruction. Such lesions appear to be true  neoplasms. However, distinguishing between a developing  odontoma and an ameloblastic fibro-odontoma may be  difficult based on histopathologic grounds alone.    The ameloblastic fibro-odontoma is usually seen in children  with an average age of 10 years. It is rarely encountered in  adults. Like the ameloblastic fibroma, ameloblastic fibro-  odontomas occur more frequently in the posterior regions    of the jaws, and the majority involves the mandible  (Fig. 15-101). Males are affected somewhat more often than  females, with a 3:2 ratio noted in the literature. The lesion  is commonly asymptomatic and is discovered when radio-  graphs are taken to determine the reason for failure of a  tooth to erupt. Large examples may be associated with a  painless swelling of the affected bone.   Radiographically, the tumor shows a well-circumscribed  unilocular or, infrequently, multilocular radiolucent defect  that contains a variable amount of calcified material with  the radiodensity of tooth structure. The calcified material  within the lesion may appear as multiple, small radiopacities  or as a solid conglomerate mass (Fig. 15-102). In most  instances, an unerupted tooth is present at the margin of  the lesion, or the crown of the unerupted tooth may be  included within the defect. Approximately 5% of amelo-  blastic fibro-odontomas contain only a minimal amount  of calcifying enamel and dentin matrix and appear    @ Fig. 15-101 Ameloblastic Fibro-Odontoma. Relative distribution  of ameloblastic fibro-odontoma in the jaws.    e Fig. 15-102 Ameloblastic Fibro-Odontoma. Radiolucent defect in the ramus containing small  calcifications having the radiodensity of tooth structure.    ® Fig. 15-103 Ameloblastic Fibro-Odontoma. Unilocular radiolu-  cent defect displacing the developing mandibular third molar posteri-  orly. Flecks of mineralized material are present in the radiolucent  defect. (Courtesy of Dr. Dominic Adornato.)    radiographically as radiolucent lesions (Fig. 15-103). These  cannot be differentiated from the wide variety of unilocular  radiolucencies that may involve the jaws. At the other  extreme, some ameloblastic fibro-odontomas appear as  largely calcified masses with only a narrow rim of radiolu-  cency about the periphery of the lesion.    The soft tissue component of the ameloblastic fibro-  odontoma is microscopically identical to the ameloblastic  fibroma and has narrow cords and small islands of odon-  togenic epithelium in a loose primitive-appearing connec-  tive tissue that resembles the dental papilla. The calcifying  element consists of foci of enamel and dentin matrix forma-  tion in close relationship to the epithelial structures (Fig.  15-104). The more calcified lesions show mature dental  structures in the form of rudimentary small teeth or con-  glomerate masses of enamel and dentin. Some researchers  have designated a similar tumor in which the calcifying  component consists only of dentin matrix and dentinoid  material as ameloblastic fibro-dentinoma. It is question-  able whether this lesion represents a separate entity, and it  is probably best considered as only a variant of the amelo-  blastic fibro-odontoma.    A patient with an ameloblastic fibro-odontoma is generally  treated by conservative curettage, and the lesion usually  separates easily from its bony bed. The tumor is well cir-  cumscribed and does not invade the surrounding bone.   ‘The prognosis is excellent, and the recurrence rate after  conservative removal is estimated to be about 7%. Develop-  ment of an ameloblastic fibrosarcoma after curettage of an  ameloblastic fibro-odontoma has been reported, but this is  exceedingly rare.    @ Fig. 15-104 Ameloblastic Fibro-Odontoma. A, The soft tissue  component of the tumor is indistinguishable from an ameloblastic  fibroma. B, Formation of disorganized tooth structure can be seen.    ‘The rare ameloblastic fibrosarcoma is considered to be the  malignant counterpart of the ameloblastic fibroma, and  approximately 70 cases have been documented in the litera-  ture. Interestingly, in most cases, only the mesenchymal  portion of the lesion shows features of malignancy; the  epithelial component remains rather bland. These tumors  may apparently arise de novo; however, in at least one-third  of known cases, the malignant lesion represents a recurrence  of a tumor previously diagnosed as an ameloblastic fibroma  or an ameloblastic fibro-odontoma.    Ameloblastic fibrosarcomas occur about 1.5 times as often  in males as in females. The lesion tends to occur in younger  patients (mean reported age, 27.5 years). Although either the  maxilla or the mandible may be involved, about 80% of cases  have occurred in the mandible. Pain and swelling associated  with rapid clinical growth are the common complaints.    @ Fig. 15-105 Ameloblastic Fibrosarcoma. A, A 21-year-old woman complained of facial asymmetry  and recent increase in size of a mandibular mass that had been present for some years. B, Radiograph  of the same patient. Note the lytic destruction of the posterior mandible. (Courtesy of Dr. Sam McKenna.)    Radiographically, the ameloblastic fibrosarcoma shows  an ill-defined destructive radiolucent lesion that suggests a  malignant process (Fig. 15-105).    Ameloblastic fibrosarcomas contain an epithelial compo-  nent similar to that seen in the ameloblastic fibroma,  although it is frequently less prominent. The epithelial com-  ponent appears histopathologically benign and does not  demonstrate any cytologic atypia. The mesenchymal portion  of the tumor, however, is highly cellular and shows hyper-  chromatic and often bizarre pleomorphic cells (Fig. 15-106).  Mitoses are usually prominent. In some cases with multiple  recurrences, the epithelial component becomes progres-  sively less conspicuous so that the tumor eventually shows  only a poorly differentiated fibrosarcoma.   In a few instances, dysplastic dentin or small amounts  of enamel may be formed. Some have called such lesions  ameloblastic dentinosarcomas or ameloblastic fibro-  odontosarcomas. This additional subclassification, however,  appears unnecessary. Another rare event that actually may  be overrepresented in the literature is concurrent malignant  transformation of both the epithelial and mesenchymal ele-  ments of an ameloblastic fibroma, resulting in an amelo-  blastic carcinosarcoma.    Once the diagnosis of ameloblastic fibrosarcoma has been  confirmed, radical surgical excision appears to be the treat-  ment of choice. Curettage or local excision is usually fol-  lowed by rapid local recurrence. The tumor is locally  aggressive and infiltrates adjacent bone and soft tissues.  The long-term prognosis is difficult to ascertain because  of the few reported cases with adequate follow-up, with the  best estimates suggesting that 20% of these patients will  succumb to their tumor. Most deaths have resulted from  uncontrolled local disease, and metastatic tumor has been  documented in only four of 54 evaluable cases.    chymal tissue shows hyperchromatism and atypical cells. A small  island of ameloblastic epithelium is present.    The odontoameloblastoma is an extremely rare odonto-  genic tumor that contains an ameloblastomatous compo-  nent and odontoma-like elements. Fewer than 20 cases have  been reported with sufficient documentation to support this  diagnosis. This tumor was formerly called ameloblastic odon-  toma and was confused with the more common (though  still relatively rare) lesion currently designated as amelo-  blastic fibro-odontoma. Because the clinical behavior of  these two tumors is quite different, they should be distin-  guished from one another. This neoplasm is also frequently  confused with an odontoma that is in its early stages of  development.    Because of the rarity of odontoameloblastomas, little reli-  able information is available. The lesion appears to occur  more often in younger patients, and either jaw can be  affected. Pain, delayed eruption of teeth, and expansion of  the affected bone may be noted.    Radiographically, the tumor shows a radiolucent, destruc-  tive process that contains calcified structures. These have the  radiodensity of tooth structure and may resemble miniature  teeth or occur as larger masses of calcified material similar  to a complex odontoma.    The histopathologic features of the odontoameloblastoma  are complex. The proliferating epithelial portion of the  tumor has features of an ameloblastoma, most often of the  plexiform or follicular pattern. The ameloblastic component  is intermingled with immature or more mature dental tissue  in the form of developing rudimentary teeth, which is  similar to the appearance of a compound odontoma, or  conglomerate masses of enamel, dentin, and cementum, as  seen in a complex odontoma.    Multiple recurrences of odontoameloblastomas have been  reported after local curettage, and it appears that this tumor  has the same biologic potential as the ameloblastoma. It is  probably wise to treat a patient with this lesion in the same  manner as one with an ameloblastoma. However, there are  no valid data on the long-term prognosis.    Odontomas are the most common types of odontogenic  tumors. Their prevalence exceeds that of all other odonto-  genic tumors combined. Odontomas are considered to be  developmental anomalies (hamartomas), rather than true  neoplasms. When fully developed, odontomas consist  chiefly of enamel and dentin, with variable amounts of pulp  and cementum. In their earlier developmental stages,  varying amounts of proliferating odontogenic epithelium  and mesenchyme are present.   Odontomas are further subdivided into compound and  complex types. The compound odontoma is composed of  multiple, small toothlike structures. The complex odon-  toma consists of a conglomerate mass of enamel and dentin,  which bears no anatomic resemblance to a tooth. In most  series, compound odontomas are more frequently diag-  nosed than complex, and it is possible that some compound  odontomas are not submitted for microscopic examination  because the clinician is comfortable with the clinical and  radiographic diagnosis. Occasionally, an odontoma may  show both compound and complex features.    Most odontomas are detected during the first two decades  of life, and the mean age at the time of diagnosis is 14 years.  The majority of these lesions are completely asymptomatic,  being discovered on a routine radiographic examination or  when films are taken to determine the reason for failure of    a tooth to erupt. Odontomas are typically relatively small  and seldom exceed the size of a tooth in the area where they  are located. However, large odontomas up to 6 cm or more  in diameter are occasionally seen. These large odontomas  can cause expansion of the jaw.   Odontomas occur somewhat more frequently in the  maxilla than in the mandible. Although compound and  complex odontomas may be found in any site, the com-  pound type is more often seen in the anterior maxilla;  complex odontomas occur more often in the molar regions  of either jaw. Occasionally, an odontoma will develop com-  pletely within the gingival soft tissues.   Radiographically, the compound odontoma appears as  a collection of toothlike structures of varying size and shape  surrounded by a narrow radiolucent zone (Figs. 15-107 and  15-108). The complex odontoma appears as a calcified    @ Fig. 15-107 Compound Odontoma. A small cluster of toothlike  structures is preventing the eruption of the maxillary canine. (Courtesy  of Dr. Robert J. Powers.)    ® Fig. 15-108 Compound Odontoma. Multiple toothlets preventing  the eruption of the mandibular cuspid. (Courtesy of Dr. Brent Bernard.)    ® Fig. 15-109 Complex Odontoma. A large radiopaque mass is overlying the crown of the mandibular  right second molar, which has been displaced to the inferior border of the mandible.    mass with the radiodensity of tooth structure, which is also  surrounded by a narrow radiolucent rim. An unerupted  tooth is frequently associated with the odontoma, and the  odontoma prevents eruption of the tooth (Fig. 15-109).  Some small odontomas are present between the roots of  erupted teeth and are not associated with disturbance in  eruption. The radiographic findings are usually diagnostic,  and the compound odontoma is seldom confused with any  other lesion. A developing odontoma may show little evi-  dence of calcification and appear as a circumscribed radio-  lucent lesion. A complex odontoma, however, may be  radiographically confused with an osteoma or some other  highly calcified bone lesion.    The compound odontoma consists of multiple structures  resembling small, single-rooted teeth, contained in a loose  fibrous matrix (Fig. 15-110). The mature enamel caps of  the toothlike structures are lost during decalcification for  preparation of the microscopic section, but varying amounts  of enamel matrix are often present. Pulp tissue may be seen    @ Fig. 15-111 Complex Odontoma. This decalcified section shows  a disorganized mass of dentin intermixed with small pools of enamel  matrix.    in the coronal and root portions of the toothlike structures.  In patients with developing odontomas, structures that  resemble tooth germs are present.   Complex odontomas consist largely of mature tubular  dentin. This dentin encloses clefts or hollow circular struc-  tures that contained the mature enamel that was removed  during decalcification. The spaces may contain small  amounts of enamel matrix or immature enamel (Fig.  15-111). Small islands of eosinophilic-staining epithelial  ghost cells are present in about 20% of complex odontomas.  These may represent remnants of odontogenic epithelium  that have undergone keratinization and cell death from the  local anoxia. A thin layer of cementum is often present  about the periphery of the mass. Occasionally, a dentigerous  cyst may arise from the epithelial lining of the fibrous  capsule of a complex odontoma.    Odontomas are treated by simple local excision, and the  prognosis is excellent.    The central odontogenic fibroma is an uncommon and  somewhat controversial lesion. Approximately 100 exam-  ples have been reported. Formerly, some oral and maxillo-  facial pathologists designated solid fibrous masses that were  almost always associated with the crown of an unerupted  tooth as odontogenic fibromas. Most oral and maxillofacial  pathologists today consider such lesions to represent only  hyperplastic dental follicles, and these should not be con-  sidered to be neoplasms.    Odontogenic fibromas have been reported in patients whose  ages ranged from 4 to 80 years (mean age, 40 years). Of  those cases reported in the literature, a 1.8:1.0 female-to-  male ratio has been noted, indicating a strong female pre-  dilection. The maxilla and mandible are affected nearly  equally, with most maxillary lesions located anterior to the  first molar tooth (Fig. 15-112). In the mandible, however,  about half of the tumors are located posterior to the first  molar. One-third of odontogenic fibromas are associated  with an unerupted tooth. Smaller odontogenic fibromas are  usually completely asymptomatic; larger lesions may be  associated with localized bony expansion or loosening of  teeth. Interestingly, the palatal mucosa that overlies the  tumor occasionally may exhibit a defect or groove.  Radiographically, smaller odontogenic fibromas tend to  be well-defined, unilocular, radiolucent lesions often associ-  ated with the periradicular area of erupted teeth (Fig.  15-113). Larger lesions tend to be multilocular radiolucen-  cies. Many lesions have a corticated border. Root resorption  of associated teeth is common, and lesions located between    the teeth often cause root divergence. Approximately 12%  of central odontogenic fibromas will exhibit radiopaque  flecks within the lesion.    Lesions reported as central odontogenic fibroma have shown  considerable histopathologic diversity; this has led some  authors to describe two separate types, although this concept  has been questioned. The World Health Organization  (WHO) recognizes an epithelium-poor variant of central    @ Fig. 15-113 Odontogenic Fibroma. A, Clinical image showing a  groove or defect in the palatal mucosa, a feature that has been  described with maxillary lesions. B, Radiograph of this patient, depict-  ing a multilocular radiolucency of the anterior maxilla. (Courtesy of  Dr. Greg Adams.)    odontogenic fibroma (so-called simple odontogenic  fibroma) and an epithelium-rich variant (so-called WHO  odontogenic fibroma). The simple type of odontogenic  fibroma is composed of stellate fibroblasts, often arranged  in a whorled pattern with fine collagen fibrils and consider-  able ground substance (Fig. 15-114). Small foci of odonto-  genic epithelial rests should be present according to the  WHO definition. Spindle cell collagenous lesions that do  not have epithelial rests may represent other entities, such  as desmoplastic fibroma, myofibroma, or neurofibroma.  Occasional foci of dystrophic calcification may be seen.  The epithelium-rich odontogenic fibroma has a more  complex pattern, which often consists of a fairly cellular  fibrous connective tissue with collagen fibers arranged in  interlacing bundles. Odontogenic epithelium in the form  of long strands or isolated nests is present throughout the  lesion and may be a prominent component (Fig. 15-115).  The fibrous component may vary from myxoid to densely  hyalinized. Calcifications composed of cementum-like    @ Fig. 15-114 Odontogenic Fibroma (Simple Type). Scattered  fibroblasts within a collagenous background. No epithelial rests were  found on multiple sections from this tumor.    @ Fig. 15-115 Odontogenic Fibroma (World Health Organiza-  tion [WHO] Type). A cellular fibroblastic lesion containing narrow  cords of odontogenic epithelium.    material or dentinoid are present in some cases. Focal  deposits of odontogenic ameloblast-associated protein  (ODAM), which represent a form of amyloid, have been  described in a few central odontogenic fibromas, and the  possibility that some of these lesions may represent calcify-  ing epithelial odontogenic tumors cannot be excluded.  Approximately 20 examples of central odontogenic fibroma  associated with a giant cell granuloma—like component  have been reported since 1992 (Fig. 15-116). It seems  unlikely that this process represents a “collision” tumor  with synchronous occurrence of an odontogenic fibroma  and a giant cell granuloma. Several of these lesions have  recurred, and the recurrences typically exhibit both com-  ponents. Whether the odontogenic fibroma somehow  induced a giant cell response in these patients, a giant cell  granuloma triggered formation of an odontogenic fibroma,  or whether this is a distinct biphasic lesion remains to be    ated Giant Cell Granuloma. A, Unilocular radiolucency between the  left mandibular bicuspids. B, Microscopic examination reveals two  distinct patterns. On the left, one can see cords of odontogenic epi-  thelium within a fibrous background, consistent with odontogenic  fibroma (WHO type). Typical features of central giant cell granuloma  are present on the right side of the field.    Odontogenic fibromas are usually treated by enucleation  and vigorous curettage. Although the tumor does not have  a definite capsule, it appears to have a limited growth poten-  tial, particularly in the anterior regions of the jaws. A few  recurrences have been documented, but the prognosis is  very good.    The relatively uncommon peripheral odontogenic fibroma  is considered to represent the soft tissue counterpart of the  central (intraosseous) odontogenic fibroma. In the past,  some authors have designated clinically and histopathologi-  cally similar lesions as odontogenic epithelial hamartoma  or as peripheral fibroameloblastic dentinoma. It is likely  that all of these terms refer to the same lesion, and periph-  eral odontogenic fibroma seems to be the most appropriate  designation. A few series of this lesion have been reported  in the past three decades, bringing the total number of cases  in the literature to over 375.    The peripheral odontogenic fibroma appears as a firm, slow-  growing, and usually sessile gingival mass covered by  normal-appearing mucosa (Fig. 15-117). Rarely, multifocal  or diffuse lesions have been described. Clinically, the  peripheral odontogenic fibroma cannot be distinguished  from the much more common fibrous gingival lesions (see  Chapter 12). The lesion is most often encountered on the  facial gingiva of the mandible. Most lesions are between  0.5 and 1.5 cm in diameter, and they infrequently cause  displacement of the teeth. Peripheral odontogenic fibromas  have been recorded in patients across a wide age range,  with most identified from the second to the fourth decades    @ Fig. 15-117 Peripheral Odontogenic Fibroma. This sessile gin-  gival mass cannot be clinically distinguished from the common periph-  eral ossifying fibroma. (Courtesy of Dr. Jerry Stovall.)    Radiographic studies demonstrate a soft tissue mass,  which in some cases has shown areas of calcification. The  lesion typically does not involve the underlying bone,  although occasionally a “cupped out” appearance has been  noted.    The peripheral odontogenic fibroma shows similar histo-  pathologic features to the central odontogenic fibroma  (WHO type). The tumor consists of interwoven fascicles of  cellular fibrous connective tissue, which may be interspersed  with areas of less cellular, myxoid connective tissue. A gran-  ular cell change has been rarely identified in the connective  tissue component, and giant cell granuloma—like areas have  been described in a few lesions. Islands or strands of odon-  togenic epithelium are scattered throughout the connective  tissue. These may be prominent or scarce. The epithelial  cells may show vacuolization. Dysplastic dentin, amorphous  ovoid cementum-like calcifications, and trabeculae of  osteoid may also be present.    The peripheral odontogenic fibroma is treated by local sur-  gical excision, and the prognosis is good. Recurrence of this  lesion has been documented, however, so the patient and  clinician should be aware of this possibility.    The rare granular cell odontogenic tumor was initially  reported as “granular cell ameloblastic fibroma.” Subse-  quently, it was designated as granular cell odontogenic  fibroma, but the noncommittal term granular cell odon-  togenic tumor is probably more appropriate, given the  controversial nature of the lesion. Approximately 30 cases  of this unusual tumor have been reported.    Patients with granular cell odontogenic tumors have all  been adults at the time of diagnosis, with more than half  being older than 40 years of age. More than 70% of the  cases have developed in women. The tumor occurs pri-  marily in the mandible and most often in the premolar  and molar region. Some lesions are completely asymp-  tomatic; others present as a painless, localized expansion  of the affected area. A few cases of granular cell odonto-  genic tumor have been described in the gingival soft tissues  as well.   Radiographically, the lesion appears as a well-demarcated  radiolucency, which may be unilocular or multilocular and  occasionally shows small calcifications (Fig. 15-118).    @ Fig. 15-118 Granular Cell Odontogenic Tumor. Radiolucent  lesion involving the apical area of endodontically treated maxillary  teeth. (Courtesy of Dr. Steve Ferry.)    @ Fig. 15-119 Granular Cell Odontogenic Tumor. Sheet of larg  granular mesenchymal cells with small nests of odontogenic  epithelium.    The granular cell odontogenic tumor is composed of large  eosinophilic granular cells, which closely resemble the gran-  ular cells seen in the soft tissue granular cell tumor (see page  502) or the granular cells seen in the granular cell variant  of the ameloblastoma (see page 657). Narrow cords or small  islands of odontogenic epithelium are scattered among the  granular cells (Fig. 15-119). Small cementum-like or dys-  trophic calcifications associated with the granular cells have  been seen in some lesions.   The nature of the granular cells is controversial. Ultra-  structural studies reveal the features of mesenchymal cells,  and bodies consistent with lysosomal structures have been  identified within the lesional cell cytoplasm. Immunohisto-  chemically, the granular cells in the granular cell odonto-  genic tumor do not react with antibodies directed against  S-100 protein, in contrast to the positive S-100 reactivity  of the granular cell tumor.    ® Fig. 15-120 Odontogenic Myxoma. Relative distribution of odon-  togenic myxoma in the jaws.    ‘The granular cell odontogenic fibroma appears to be com-  pletely benign in the overwhelming majority of instances  and responds well to curettage. Only one recurrence has  been documented, and a solitary example of a malignant  central granular cell odontogenic fibroma has been reported.    Myxomas of the jaws are believed to arise from odontogenic  ectomesenchyme. They bear a close microscopic resem-  blance to the mesenchymal portion of a developing tooth.  Formerly, some investigators made a distinction between  odontogenic myxomas (derived from odontogenic mesen-  chyme) and osteogenic myxomas (presumably derived  from primitive bone tissue). However, most authorities in  orthopedic pathologic practice do not accept that myxomas  occur in the extragnathic skeleton, and all myxomas of the  jaws are currently considered to be of odontogenic origin.    Myxomas are predominantly found in young adults but  may occur across a wide age group. The average age for  patients with myxomas is 25 to 30 years. There is no sex  predilection. The tumor may be found in almost any area  of the jaws, and the mandible is involved more commonly  than the maxilla (Fig. 15-120). Smaller lesions may be  asymptomatic and are discovered only during a radiographic  examination. Larger lesions are often associated with a pain-  less expansion of the involved bone. In some instances,  clinical growth of the tumor may be rapid; this is probably  related to the accumulation of myxoid ground substance in  the tumor.   Radiographically, the myxoma appears as a unilocular or  multilocular radiolucency that may displace or cause resorp-  tion of teeth in the area of the tumor (Fig. 15-121). The  margins of the radiolucency are often irregular or scalloped.  The radiolucent defect may contain thin, wispy trabeculae    : ae Bae  e Fig. 15-121 Odontogenic Myxoma. Unilocular radiolucency  between the right mandibular lateral incisor and cuspid.    of residual bone, which are often arranged at right angles  to one another (Fig. 15-122). Large myxomas of the man-  dible may show a “soap bubble” radiolucent pattern, which  is indistinguishable from that seen in ameloblastomas (Fig.    At the time of surgery or gross examination of the specimen,  the gelatinous, loose structure of the myxoma is obvious  (Fig. 15-124). Microscopically, the tumor is composed of  haphazardly arranged stellate, spindle-shaped, and round  cells in an abundant, loose myxoid stroma that contains  only a few collagen fibrils (Fig. 15-125). Histochemical    ® Fig. 15-123 Odontogenic Myxoma. Multilocular expansile radio-  lucency of the posterior mandible. (Courtesy of Dr. Steve Anderson.)    @ Fig. 15-124 Odontogenic Myxoma. Gross specimen of case  shown in Fig. 15-121, demonstrating a white gelatinous mass.    @ Fig. 15-125 Odontogenic Myxoma. A loose, myxomatous tumor  can be seen filling the marrow spaces between the bony trabeculae.  The inset shows stellate-shaped cells and fine collagen fibrils.    study shows that the ground substance is composed of  glycosaminoglycans, chiefly hyaluronic acid and chondroi-  tin sulfate. Immunohistochemically, the myxoma cells show  diffuse immunoreactivity with antibodies directed against  vimentin, with focal reactivity for muscle-specific actin.    Small islands of inactive-appearing odontogenic epithelial  rests may be scattered throughout the myxoid ground sub-  stance. These epithelial rests are not required for the diag-  nosis and are not obvious in most cases. In some patients,  the tumor may have a greater tendency to form collagen  fibers; such lesions are sometimes designated as fibromyxo-  mas or myxofibromas. There is no evidence that the more  collagenized variants deserve separate consideration,  although some investigators have suggested that these may  represent part of a spectrum that includes the central odon-  togenic fibroma at the other endpoint. Myxomas may rarely  exhibit cementum-like calcifications.   A myxoma may be microscopically confused with other  myxoid jaw neoplasms, such as the rare chondromyxoid  fibroma (see page 611) or the myxoid neurofibroma (see  page 494). Chondromyxoid fibroma should have areas of  cartilaginous differentiation, whereas myxoid neurofibro-  mas tend to have areas in which lesional cells are arranged in  vague fascicles, as well as scattered cells that are positive for  antibodies directed against S-100 protein. Myxoid change  in an enlarged dental follicle or the dental papilla of a devel-  oping tooth may be microscopically similar to a myxoma.  Evaluation of the clinical and radiographic features, however,  prevents overdiagnosis of these lesions as myxomas.    Small myxomas are generally treated by curettage, but  careful periodic reevaluation is necessary for at least 5 years.  For larger lesions, more extensive resection may be required  because myxomas are not encapsulated and tend to infiltrate  the surrounding bone. Complete removal of a large tumor  by curettage is often difficult to accomplish, and lesions of  the posterior maxilla, in particular, should be treated more  aggressively in most instances. Recurrence rates from various  studies average approximately 25%. In spite of local recur-  rences, the overall prognosis is good, and metastases do not  occur.   In rare cases the myxoma microscopically shows marked  cellularity and cellular atypism. Some have designated these  lesions as myxosarcomas or malignant odontogenic myxoma.  They appear to have a more aggressive local course than do  the usual myxomas. Death because of involvement of vital  structures by the tumor has been described, but distant  metastases have not been reported.    Many oral and maxillofacial pathologists consider the  cementoblastoma to represent an odontogenic tumor.  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Zhao M, Lu Y, Takata T, et al: Immunohistochemical and histo-  chemical characterisation of the mucosubstances of odontogenic  myxoma: histogenesis and differential diagnosis, Pathol Res Pract    Ectodermal dysplasia represents a group of inherited con-  ditions in which two or more ectodermally derived ana-  tomic structures fail to develop. Thus depending on the type  of ectodermal dysplasia, hypoplasia or aplasia of tissues  (e.g., skin, hair, nails, teeth, and sweat glands) may be seen.  ‘The various types of this disorder may be inherited in any  one of several genetic patterns, including autosomal domi-  nant, autosomal recessive, and X-linked patterns. Even  though by some accounts almost 200 different subtypes of  ectodermal dysplasia can be defined, these disorders are  considered to be relatively rare, with an estimated frequency  of seven cases occurring in every 10,000 births. For fewer  than 20% of these conditions, the specific genetic muta-  tions and their chromosomal locations have been identified.  Systematically classifying these conditions can be challeng-  ing because of their wide-ranging clinical features; however,  some investigators have suggested that a classification  scheme based on the molecular genetic alteration associated  with each type might be appropriate. Thus groups of ecto-  dermal dysplasia syndromes could be categorized as being  caused by mutations in genes encoding cell-cell signals,  genes encoding adhesion molecules, or genes regulating  transcription.    Perhaps the best known of the ectodermal dysplasia syn-  dromes is hypohidrotic ectodermal dysplasia. In most  instances, this disorder seems to show an X-linked inheri-  tance pattern, with the gene mapping to Xq12-q13.1; there-  fore, a male predominance is usually seen. However, a few  families have been identified that show autosomal recessive  or autosomal dominant patterns of inheritance.   Affected individuals typically display heat intolerance  because of a reduced number of eccrine sweat glands. Some-  times the diagnosis is made during infancy because the baby  appears to have a fever of undetermined origin; however,  the infant simply cannot regulate body temperature appro-  priately because of the decreased number of sweat glands.  Uncommonly, death results from the markedly elevated  body temperature, although this generally happens only  when the condition is not identified. Sometimes, as a    diagnostic aid, a special impression can be made of the  patient’s fingertips and then examined microscopically to  count the density of the sweat glands. Such findings should  be interpreted in conjunction with appropriate age-matched  controls.   Other signs of this disorder include fine, sparse hair,  including a reduced density of eyebrow and eyelash hair  (Fig. 16-1). The periocular skin may show a fine wrinkling  with hyperpigmentation (Fig. 16-2), and midface hypopla-  sia is frequently observed, often resulting in protuberant  lips. Because the salivary glands are ectodermally derived,  these glands may be hypoplastic or absent, and patients may  exhibit varying degrees of xerostomia. The nails may also  appear dystrophic and brittle.   The teeth are usually markedly reduced in number (oli-  godontia or hypodontia), and their crown shapes are char-  acteristically abnormal (Fig. 16-3). The incisor crowns  usually appear tapered, conical, or pointed, and the molar  crowns are reduced in diameter. Complete lack of tooth  development (anodontia) has also been reported, but this  appears to be uncommon.   Female patients may show partial expression of the  abnormal gene; that is, their teeth may be reduced in  number or may have mild structural changes. This incom-  plete presentation can be explained by the Lyon hypothe-  sis, with half of the female patient's X chromosomes  expressing the normal gene, and the other half expressing  the defective gene.    Histopathologic examination of the skin from a patient  with hypohidrotic ectodermal dysplasia shows a decreased  number of sweat glands and hair follicles. The adnexal struc-  tures that are present are hypoplastic and malformed.    Management of hypohidrotic ectodermal dysplasia warrants  genetic counseling for the parents and the patient. The  dental problems are best managed by prosthetic replace-  ment of the dentition with complete dentures, overden-  tures, or fixed appliances, depending on the number and  location of the remaining teeth. With careful site selection,    hyperpigmentation, and mild midfacial hypoplasia are characteristic  features evident in this affected patient.    © Fig. 16-2 Ectodermal Dysplasia. Closer view of the same patient  depicted in Fig. 16-1. Fine periocular wrinkling, as well as sparse  eyelash and eyebrow hair, can be observed.    endosseous dental implants may be considered for facilitat-  ing prosthetic management of patients older than 6 years  of age.    White sponge nevus is a relatively rare genodermatosis (a  genetically determined skin disorder) that is inherited as an    ® Fig. 16-3 Ectodermal Dysplasia. Oligodontia and conical crown  forms are typical oral manifestations. (Courtesy of Dr. Charles Hook  and Dr. Bob Gellin.)    ° Fig. 16-4 White Sponge Nevus. Diffuse, thickened white plaques  of the buccal mucosa.    autosomal dominant trait displaying a high degree of pen-  etrance and variable expressivity. This condition is due to a  defect in the normal keratinization of the oral mucosa. In  the 30-member family of keratin filaments, the pair of kera-  tins known as keratin 4 and keratin 13 is specifically  expressed in the spinous cell layer of mucosal epithelium.  Mutations in either of these keratin genes have been shown  to be responsible for the clinical manifestations of white  sponge nevus.    The lesions of white sponge nevus usually appear at birth  or in early childhood, but sometimes the condition devel-  ops during adolescence. Symmetrical, thickened, white,  corrugated or velvety, diffuse plaques affect the buccal  mucosa bilaterally in most instances (Fig. 16-4). Other  common intraoral sites of involvement include the ventral  tongue, labial mucosa, soft palate, alveolar mucosa, and  floor of the mouth, although the extent of involvement  can vary from patient to patient. Extraoral mucosal sites,  such as the nasal, esophageal, laryngeal, and anogenital    ® Fig. 16-5 White Sponge Nevus. This low-power photomicrograph  shows prominent hyperparakeratosis, marked thickening (acanthosis),  and vacuolation of the spinous cell layer.    @ Fig. 16-6 White Sponge Nevus. This high-power photomicro-  graph shows vacuolation of the cytoplasm of the cells of the spinous  layer, with no evidence of epithelial atypia. Perinuclear condensation  of keratin tonofilaments can also be observed in some cells.    mucosa, appear to be less commonly affected. Patients are  usually asymptomatic.    ‘The microscopic features of white sponge nevus are charac-  teristic but not necessarily pathognomonic. Prominent  hyperparakeratosis and marked acanthosis with clearing of  the cytoplasm of the cells in the spinous layer are common  features (Figs. 16-5 and 16-6); however, similar microscopic  findings may be associated with leukoedema and hereditary  benign intraepithelial dyskeratosis (HBID). In some  instances, an eosinophilic condensation is noted in the peri-  nuclear region of the cells in the superficial layers of the  epithelium, a feature that is unique to white sponge nevus.  Ultrastructurally, this condensed material can be identified  as tangled masses of keratin tonofilaments.   Exfoliative cytologic studies may provide more definitive  diagnostic information. A cytologic preparation stained  with the Papanicolaou method often shows the eosinophilic    ® Fig. 16-7 White Sponge Nevus. This high-power photomicro-  graph of a Papanicolaou-stained cytologic preparation shows the  pathognomonic perinuclear condensation of keratin tonofilaments.    perinuclear condensation of the epithelial cell cytoplasm  to a greater extent than does the histopathologic section    Hereditary benign intraepithelial dyskeratosis (HBID)  is a rare autosomal dominant genodermatosis primarily  affecting descendants of a triracial isolate (Native American,  black, and white) of people who originally lived in North  Carolina. Examples of HBID have sporadically been  reported from other areas of the United States because of  migration of affected individuals, and descriptions of  affected patients with no apparent connection to North  Carolina have also appeared in the literature.    The lesions of HBID usually develop during childhood, in  most instances affecting the oral and conjunctival mucosa.  ‘The oral lesions are similar to those of white sponge nevus,  with both conditions showing thick, corrugated white  plaques involving the buccal and labial mucosa (Fig. 16-8).  Milder cases may exhibit the opalescent appearance of leu-  koedema. Other oral mucosal sites, such as the floor of the  mouth and lateral tongue, may also be affected. These  oral lesions may exhibit a superimposed candidal infection  as well.   The most interesting feature of HBID is the ocular  lesions, which begin to develop very early in life. These    (HBID). Oral lesions appear as corrugated white plaques of the buccal  mucosa. (Courtesy of Dr. John McDonald.)    e Fig. 16-9 Hereditary Benign Intraepithelial Dyskeratosis  (HBID). Ocular lesions appear as gelatinous plaques (arrow) of the  bulbar conjunctivae. (Courtesy of Dr. Carl Witkop.)    appear as thick, opaque, gelatinous plaques affecting the  bulbar conjunctiva adjacent to the cornea (Fig. 16-9) and  sometimes involving the cornea itself. When the lesions are  active, patients may experience tearing, photophobia, and  itching of the eyes. In many patients, the plaques are most  prominent in the spring and tend to regress during the  summer or autumn. Sometimes blindness may result from  the induction of vascularity of the cornea secondary to the  shedding process.    The histopathologic features of HBID include prominent  parakeratin production in addition to marked acanthosis. A  peculiar dyskeratotic process, similar to that of Darier  disease, is scattered throughout the upper spinous layer of  the surface oral epithelium (Fig. 16-10). With this dyskera-  totic process, an epithelial cell appears to be surrounded or  engulfed by an adjacent epithelial cell, resulting in the  so-called cell-within-a-cell phenomenon.   COGS a, i TOONS  e Fig. 16-10 Hereditary Benign Intraepithelial Dyskeratosis  (HBID). A, Medium-power photomicrograph exhibiting hyperparakera-  tosis, acanthosis, and dyskeratosis. B, Higher magnification showing  dyskeratotic cells.    Because HBID is a benign condition, no treatment is gener-  ally required or indicated for the oral lesions. If superim-  posed. candidiasis develops, then an antifungal medication  can be used. Patients with symptomatic ocular lesions  should be referred to an ophthalmologist. Typically, the  plaques that obscure vision must be surgically excised. This  procedure, however, is recognized as a temporary measure  because the lesions often recur.    Pachyonychia congenita is a group of rare genodermatoses  that are usually inherited as an autosomal dominant trait.  Mutations of genes that encode for keratin 6a, 6b, 16, or  17 are responsible for this condition, with different pheno-  typic expressions depending on the particular mutation.  The nails, especially the toenails, are dramatically affected  in most patients. Oral lesions are seen most frequently in  patients who have mutation of the keratin 6a (KRTGA)  gene, but can be found in a reduced percentage of the other    @ Fig. 16-11 Pachyonychia Congenita. The nails often have a  tubular configuration due to keratin accumulation beneath the nailbed.    keratin mutations. Throughout the world, approximately  5000 to 10,000 people are thought to have this condition.  Historically, pachyonychia congenita has been divided into  the Jadassohn-Lewandowsky type (pachyonychia congenita,  type 1) and the Jackson-Lawler type (pachyonychia con-  genita, type 2). It may be more appropriate, however, to  categorize this group of disorders based on the specific  keratin mutation that affects a particular patient.    Virtually all patients with pachyonychia congenita exhibit  characteristic nail changes, either at birth or in the early  neonatal period. The free margins of the nails are lifted up  because of an accumulation of keratinaceous material in the  nail beds. This results in a pinched, tubular configuration  (Fig. 16-11). Ultimately, nail loss may occur.   Other skin changes that may occur include marked  hyperkeratosis of the palmar and plantar surfaces, produc-  ing thick, callous-like lesions (Fig. 16-12). Hyperhidrosis of  the palms and soles is also commonly present. The rest of  the skin shows punctate papules, representing an abnormal  accumulation of keratin in the hair follicles. One disabling  feature of the syndrome is severe pain with walking, which  is believed to be due to the formation of blisters beneath  the thick calluses on the soles of the feet. Fissuring of the  thickened plantar calluses can also occur and cause pain  upon walking.   The oral lesions seen in pachyonychia congenita consist  of thickened white plaques that involve the lateral margins  and dorsal surface of the tongue. Other oral mucosal regions  that are frequently exposed to mild trauma, such as the  palate, buccal mucosa, and alveolar mucosa, may also be  affected (Fig. 16-13). Neonatal teeth are seen in a majority  of patients with mutations of the keratin 17 gene, but only  one-third of these individuals have oral white lesions.  Hoarseness and dyspnea have been described in some  patients as a result of laryngeal mucosal involvement.    @ Fig. 16-12 Pachyonychia Congenita. The soles of the feet of  affected patients typically show marked callus-like thickenings.    Microscopic examination of lesional oral mucosa shows  marked hyperparakeratosis and acanthosis with perinuclear  clearing of the epithelial cells.    Because the oral lesions of pachyonychia congenita show no  apparent tendency for malignant transformation, no treat-  ment is required. The nails are often lost or may need to be  surgically removed because of the deformity. In addition,  the keratin accumulation on the palms and soles can be  quite uncomfortable and distressing to many of the affected  individuals. Most patients have to pay continuous attention    ® Fig. 16-13 Pachyonychia Congenita. Although tongue lesions  are more common in patients with pachyonychia congenita, other oral  mucosal sites exposed to minor trauma, such as the alveolar mucosa,  may develop thickened white patches. (Courtesy of Dr. John Lenox.)    to removal of the excess keratin, and issues related to quality  of life often arise. Oral retinoids may be of some benefit for  select patients, but the dosage has to be carefully monitored  in order to minimize medication side effects. Patients should  receive genetic counseling, as an aid in family planning.  Chorionic villus sampling can be used to identify the various  keratin mutations associated with these disorders, thereby  allowing prenatal diagnosis.    Dyskeratosis congenita is a rare genodermatosis that is  usually inherited as an X-linked recessive trait, resulting in  a striking male predilection. Autosomal dominant and auto-  somal recessive forms, although less common, have been  reported. Mutations in the DKCI gene initially were deter-  mined to cause the X-linked form of dyskeratosis congenita.  The mutated gene appears to disrupt the normal mainte-  nance of telomerase, an enzyme that is critical in determin-  ing normal cellular longevity. Subsequently, mutations of  six other genes responsible for telomere maintenance have  been identified for the other inheritance patterns of dyskera-  tosis congenita. The clinician should be aware of the condi-  tion because the oral lesions may undergo malignant  transformation, and patients are susceptible to aplastic  anemia.    Dyskeratosis congenita usually becomes evident during the  first 10 years of life. A reticular pattern of skin hyperpig-  mentation develops, affecting the face, neck, and upper  chest. In addition, abnormal, dysplastic changes of the nails  are evident at this time (Fig. 16-14).    ® Fig. 16-15 Dyskeratosis Congenita. Atrophy and hyperkeratosis  of the dorsal tongue mucosa are visible.    Intraorally, the tongue and buccal mucosa develop  bullae; these are followed by erosions and, eventually, leu-  koplakic lesions (Fig. 16-15). The leukoplakic lesions are  considered to be premalignant, and approximately one-  third of them become malignant in a 10- to 30-year period.  The actual rate of transformation may be higher, but this  may not be appreciated because of the shortened life span  of these patients. Rapidly progressive periodontal disease  has been reported sporadically.   Thrombocytopenia is usually the first hematologic  problem that develops, typically during the second decade  of life, followed by anemia. Ultimately, aplastic anemia  develops in approximately 80% of these patients (see page  541). Mild to moderate intellectual disability may also be  present. Generally, the autosomal recessive and X-linked  recessive forms show a more severe pattern of disease  expression.    Biopsy specimens of the early oral mucosal lesions show  hyperorthokeratosis with epithelial atrophy. As the lesions  progress, epithelial dysplasia develops until frank squamous  cell carcinoma evolves.    The discomfort of the oral lesions is managed symptomati-  cally, and careful periodic oral mucosal examinations are  performed to check for evidence of malignant transforma-  tion. Routine medical evaluation is warranted to monitor  the patient for the development of aplastic anemia. Certain  anabolic steroids have been shown to increase telomerase  activity, and treatment with these drugs may result in  temporary improvement in the hematologic status. Bone  marrow failure ultimately ensues, however. Selected patients  may be considered for allogeneic hematopoietic stem cell  transplantation once the aplastic anemia is identified.   As a result of these potentially life-threatening complica-  tions, the prognosis is guarded. The average life span for the  more severely affected patients is 32 years of age. The parents  and the patient should receive genetic counseling.    Xeroderma pigmentosum is a rare genodermatosis in  which numerous cutaneous malignancies develop at a very  early age. The prevalence of the condition in the United  States is estimated to be 1 in 250,000 to 500,000. The  condition is inherited as an autosomal recessive trait and is  caused by one of several defects in the excision repair and/  or postreplication repair mechanism of DNA. As a result of  the inability of the epithelial cells to repair ultraviolet (UV)  light-induced damage, mutations in the epithelial cells  occur, leading to the development of nonmelanoma skin  cancer at a rate 10,000 times what would normally be  expected in people younger than 20 years of age.    During the first few years of life, patients affected by xero-  derma pigmentosum show a markedly increased tendency  to sunburn. Skin changes, such as atrophy, freckled pigmen-  tation, and patchy depigmentation, soon follow (Fig.  16-16). In early childhood, actinic keratoses begin devel-  oping, a process that normally does not take place before  40 years of age. These lesions quickly progress to squamous  cell carcinoma, with basal cell carcinoma also appearing;  consequently, in most patients a nonmelanoma skin cancer  develops during the first decade of life. Melanoma develops  in about 5% of patients with xeroderma pigmentosum, but  it evolves at a slightly later time. As a consequence of sun  exposure, the head and neck region is the site most fre-  quently affected by these cutaneous malignancies. Neuro-  logic degenerative changes occur in 20% to 30% of affected  patients and include subnormal intelligence, ataxia, senso-  rineural deafness, and impaired eyesight. The precise cause  for the neurologic problems is currently unclear.   Oral manifestations, which often occur before 20 years  of age, include development of squamous cell carcinoma  of the lower lip and the tip of the tongue. This latter site is  most unusual for oral cancer, and its involvement is again    ° Fig. 16-16 Xeroderma Pigmentosum. The atrophic changes and  pigmentation disturbances shown are characteristic of xeroderma  pigmentosum.    undoubtedly related to the increased sun exposure, however  minimal, which this area receives in contrast to the rest of  the oral mucosa.   The diagnosis of xeroderma pigmentosum is usually  made when the patient is evaluated for the cutaneous  lesions, because it is highly unusual for a very young person  to have skin cancer. Because xeroderma pigmentosum is an  autosomal recessive trait, a family history of the disorder is  not likely to be present, but the possibility of a consanguine-  ous relationship of the affected child’s parents should be  investigated.    The histopathologic features of xeroderma pigmentosum are  relatively nonspecific, in that the cutaneous premalignant  lesions and malignancies that occur are microscopically  indistinguishable from those observed in unaffected patients.    Treatment of xeroderma pigmentosum is challenging  because in most instances significant sun damage has already  occurred by the time of diagnosis. Patients are advised to  avoid sunlight and unfiltered fluorescent light and to wear  appropriate protective clothing and sunscreens if they  cannot avoid sun exposure. Before receiving dental treat-  ment, a calibrated UV light meter should be used to    evaluate the amount of UV light being emitted from various  sources in the dental office, such as the examination light,  the radiograph view box, computer screens in the area,  fiber-optic lights, or lights that are used for curing compos-  ite restorations. Some authors have suggested that any  reading greater than 0 nm/cm? would be unacceptable. A  dermatologist should evaluate the patient every 3 months  to monitor the development of cutaneous lesions.   Topical chemotherapeutic agents (e.g., 5-fluorouracil)  may be used to treat actinic keratoses. Nonmelanoma skin  cancers should be excised conservatively, preferably with  microscopically controlled excision (Mohs surgery) to  preserve as much normal tissue as possible. Patients should  also receive genetic counseling, because a high number  of consanguineous marriages have been reported in some  series.   The prognosis is still poor. Most patients die 30 years  earlier than the normal population, either directly from  cutaneous malignancy or from complications associated  with the treatment of the cancer. The outlook is much better  if patients adhere to a strict program of life-long UV light  avoidance, but this can be difficult to achieve.    Hereditary mucoepithelial dysplasia is a rare disorder that  may occur sporadically or may be inherited as an autosomal  dominant trait. Approximately 30 cases have been reported,  although affected patients may not be recognized due to the  rarity of condition. For reasons that are not entirely under-  stood, the mucosal epithelial cells do not develop in a  normal fashion, and for this reason the designation of dys-  plasia has been given. However, in this situation, no  increased risk of malignant transformation is seen. When a  cervical exfoliative cytologic preparation (Pap smear) is  done, the epithelial cells that are harvested may be inter-  preted as appearing cytologically unusual or atypical; in the  past, some female patients have been advised to undergo  hysterectomy because of this misinterpretation. Conse-  quently, accurate identification of this disorder is extremely  important for these patients.    Hereditary mucoepithelial dysplasia is characterized by both  cutaneous and mucosal abnormalities. Patients typically  have sparse, coarse hair with nonscarring alopecia. Eyelashes  and eyebrows are generally affected (Fig. 16-17). Severe  photophobia develops at an early age, and most of these  patients will have evidence of cataracts beginning in child-  hood or early adult life. Corneal vascularization, keratitis  secondary to corneal erosions, cataracts, and nystagmus are  also commonly described. As would be expected, vision is  usually markedly impaired for these patients. Other skin  manifestations include a prominent perineal rash that    ® Fig. 16-17 Hereditary Mucoepithelial Dysplasia. Sparse hair is  noted on the eyebrows and eyelashes.    appears during infancy, as well as a widespread rough, dry  texture because of follicular keratosis.   Pulmonary complications related to mucoepithelial dys-  plasia can range in severity, presumably because of the  degree of gene expression. In one family, cavitary bullae  were reported to form within the lung parenchyma, and  these led to recurrent bouts of pneumonia, often resulting  in life-threatening complications.   The oral manifestations of hereditary mucoepithelial dys-  plasia are usually quite striking, appearing as demarcated  fiery-red erythema of the hard palate (Fig. 16-18), with  generally less involvement of the attached gingivae and  tongue mucosa. These mucosal alterations are typically  asymptomatic, despite their remarkable clinical appearance.  The nasal, conjunctival, vaginal, cervical, urethral, and  bladder mucosa may have the same unusual erythematous  features.    Biopsies of the mucosal lesions of hereditary mucoepithelial  dysplasia show epithelium with minimal keratinization and  a disorganized maturation pattern. The squamous epithelial  cells may have a relatively high nuclear/cytoplasmic ratio,    ® Fig. 16-19 Hereditary Mucoepithelial Dysplasia. Disorganized  epithelium exhibiting scattered intracytoplasmic vacuoles.    but significant nuclear or cellular pleomorphism is not  observed. Cytoplasmic vacuoles have been described and  may appear as grayish inclusions (Fig. 16-19). These vacu-  oles also may be observed in exfoliative cytology samples.  Ultrastructurally, the lesional cells have been described as  having reduced numbers of desmosomes and internalized  gap junctions.    Given the genetic nature of this disease, supportive care and  genetic counseling are typically offered. Affected patients  should be monitored for development of pulmonary disease.    Incontinentia pigmenti is a relatively rare inherited disor-  der, with approximately 800 cases reported worldwide. It  typically evolves in several stages, primarily affecting the  skin, eyes, and central nervous system (CNS), as well as oral  structures. There is a marked female predilection, with a  37:1 female-to-male ratio reported. The condition is inher-  ited as an X-linked dominant trait, with the single unpaired  gene on the X chromosome being lethal for most males.  The mutated gene responsible for producing the phenotypic  features of incontinentia pigmenti maps to the Xq28 locus,  where the genetic information related to nuclear factor-KB  essential modulator (NEMO) is found. Of the few males who  survive, a small percentage have Klinefelter syndrome (XXY  karyotype), whereas the rest usually show mosaicism for the  NEMO gene, suggesting a postzygotic mutation.    @ Fig. 16-20 Incontinentia Pigmenti. Swirling pattern of pigmenta-  tion on the abdomen of an infant.    The clinical manifestations of incontinentia pigmenti  usually begin in the first few weeks of infancy. There are  four classic stages associated with the cutaneous lesions:   1. Vesicular stage: Vesiculobullous lesions appear on the  skin of the trunk and limbs. Spontaneous resolution  occurs within 4 months.   2. Verrucous stage: Verrucous cutaneous plaques develop,  affecting the limbs. These clear by 6 months of age,  evolving into the third stage.   3. Hyperpigmentation stage: Macular, brown skin lesions  appear, characterized by a strange swirling pattern (Fig.  16-20), although these tend to fade around the time of  puberty.   4, Atrophy and depigmentation stage: Atrophy and depig-  mentation of the skin ultimately occur. Considerable  overlap among these stages can occur at times, however.  CNS abnormalities occur in approximately 30% of   The oral manifestations of incontinentia pigmenti, noted  in 70% to 95% of the cases, include oligodontia (hypodon-  tia), delayed eruption, and hypoplasia of the teeth (Fig.  16-21). The teeth are small and cone shaped; both the  primary and permanent dentitions are affected.    The microscopic findings in incontinentia pigmenti  vary, depending on when a biopsy of the skin lesions is  performed.   In the initial vesicular stage, intraepithelial clefts filled  with eosinophils are observed. During the verrucous stage,  hyperkeratosis, acanthosis, and papillomatosis are noted.  The hyperpigmentation stage shows numerous melanin-  containing macrophages (melanin incontinence) in the    subepithelial connective tissue, the feature from which the  disorder derives its name.    Treatment of incontinentia pigmenti is directed toward the  various abnormalities. Dental management includes appro-  priate prosthodontic and restorative care, although this is  sometimes difficult if CNS problems are severe. Prenatal  genetic testing can be performed, but currently this is not  widely available.    Darier disease is an uncommon genodermatosis with  rather striking skin involvement and relatively subtle oral  mucosal lesions. The condition is inherited as an autosomal  dominant trait, having a high degree of penetrance and  variable expressivity. A lack of cohesion among the surface  epithelial cells characterizes this disease, and mutation of a  gene (identified as A7P2A2) that encodes an intracellular  calcium pump (SERCA2—sarco/endoplasmic reticulum  Ca”*-ATPase isoform 2) has been identified as the cause for  abnormal desmosomal organization in the affected epithe-  lial cells. Estimates of the prevalence of Darier disease in  Northern European populations range from 1 in 36,000 to  1 in 100,000.    Patients with Darier disease have numerous erythematous,  often pruritic, papules on the skin of the trunk and the scalp  that develop during the first or second decade of life (Fig.  16-22). An accumulation of keratin, producing a rough  texture, may be seen in association with the lesions, and a  foul odor may be present as a result of bacterial degradation  of the keratin. The process generally becomes worse during  the summer months, either because of sensitivity of some    ® Fig. 16-22 Darier Disease. Erythematous cutaneous papules on  the chest.    @ Fig. 16-23 Darier Disease. The oral mucosa may show multiple  white papules. (Courtesy of Dr. George Blozis.)    patients to UV light or because increased heat results in  sweating, which induces more epithelial clefting. The palms  and soles often exhibit pits and keratoses. The nails show  longitudinal lines, ridges, or painful splits.   The oral lesions are typically asymptomatic and are dis-  covered on routine examination. The frequency of occur-  rence of oral lesions ranges from 15% to 50%. They consist  of multiple, normal-colored or white, flat-topped papules  that, if numerous enough to be confluent, result in a cobble-  stone mucosal appearance (Fig. 16-23). These lesions affect  the hard palate and alveolar mucosa primarily, although the  buccal mucosa or tongue may be occasionally involved. If  the palatal lesions are prominent, then the condition may  resemble inflammatory papillary hyperplasia or nicotine  stomatitis. Some patients with this condition also experi-  ence recurrent obstructive parotid swelling secondary to  duct abnormalities.    Microscopic examination of the cutaneous or mucosal  lesions shows a dyskeratotic process characterized by a    ° Fig. 16-24 Darier Disease. Low-power photomicrograph showing  a thick keratin plug, intraepithelial clefting, and elongated rete ridges.    central keratin plug that overlies epithelium exhibiting a  suprabasilar cleft (Fig. 16-24). This intraepithelial clefting  phenomenon, also known as acantholysis, is not unique to  Darier disease and may be seen in conditions, such as pem-  phigus vulgaris (see page 712). In addition, the epithelial  rete ridges associated with the lesions appear narrow, elon-  gated, and “test tube’-shaped. Closer inspection of the  epithelium reveals varying numbers of two types of dyskera-  totic cells, called corps ronds (round bodies) or grains  (because they resemble cereal grains).    Treatment of Darier disease depends on the severity of  involvement. Photosensitive patients should use a sun-  screen, and all patients should minimize unnecessary expo-  sure to hot environments. For relatively mild cases,  keratolytic agents or emollients may be the only treatment  required. For more severely affected patients, systemic reti-  noids are often beneficial, but the side effects of such medi-  cations are often quite bothersome to the patient and can  be significant; therefore, the physician should carefully  monitor their use. Although the condition is not premalig-  nant or otherwise life threatening, genetic counseling is  appropriate.    ¢ WARTY DYSKERATOMA (ISOLATED  DARIER DISEASE; ISOLATED  DYSKERATOSIS FOLLICULARIS; FOCAL  ACANTHOLYTIC DYSKERATOSIS;  FOLLICULAR DYSKERATOMA)    The warty dyskeratoma is a distinctly uncommon solitary  lesion that can occur on skin or oral mucosa. It is histo-  pathologically identical to Darier disease. For this reason  the lesion has been termed isolated Darier disease. The  lesion is not otherwise related to Darier disease, however,  and its cause remains unknown.    ® Fig. 16-25 Warty Dyskeratoma. Umbilicated papule on the hard  palate. (Courtesy of Dr. Greg Adams.)    filled with a thick parakeratin plug. There is hyperplasia of the basilar  cells with a suprabasilar cleft.    The cutaneous warty dyskeratoma typically appears as a  solitary, asymptomatic, umbilicated papule on the skin of  the head or neck of an older adult. The intraoral lesion also  develops in patients older than age 40, and a slight male  predilection has been identified. The intraoral warty dys-  keratoma appears as a pink or white, umbilicated papule  located on the keratinized mucosa, especially the hard palate  and the alveolar ridge (Fig. 16-25). A warty or roughened  surface is noted in some lesions. Most warty dyskeratomas  are smaller than 0.5 cm in diameter.    Histopathologically, the warty dyskeratoma appears very  similar to keratosis follicularis. Both conditions display  dyskeratosis, basilar hyperplasia, and a suprabasilar cleft  (Fig. 16-26). The warty dyskeratoma is a solitary lesion,  however, and the formation of corps ronds and grains is not  a prominent feature.    Treatment of the warty dyskeratoma consists of conservative  excision. The prognosis is excellent; these lesions have not  been reported to recur, and they have no apparent malig-  nant potential. Careful histopathologic evaluation of the  tissue should be performed, because some epithelial dyspla-  sias may show a marked lack of cellular cohesiveness, result-  ing in a similar acantholytic appearance microscopically.    Peutz-Jeghers syndrome is a relatively rare but well-  recognized condition, having a prevalence of approximately  1 in 50,000 to 200,000 births. It is characterized by freckle-  like lesions of the hands, perioral skin, and oral mucosa, in  conjunction with intestinal polyposis and predisposition for  affected patients to develop cancer. The syndrome is gener-  ally inherited as an autosomal dominant trait, although as  many as 35% of cases represent new mutations. Mutation  of the tumor suppressor gene, STK11 (also known as LKB1)  is responsible for most cases of Peutz-Jeghers syndrome.  This gene, which encodes for a serine/threonine kinase, is  located on chromosome 19p13.3.    ‘The skin lesions of Peutz-Jeghers syndrome usually develop  early in childhood and involve the periorificial areas (e.g.,  mouth, nose, anus, and genital region). The skin of the  extremities is affected in about 50% of patients (Fig. 16-27).  The lesions resemble freckles, but they do not wax and wane  with sun exposure, as do true freckles.   ‘The intestinal polyps, generally considered to be hamar-  tomatous growths, are scattered throughout the mucus-  producing areas of the gastrointestinal tract. The jejunum  and ileum are most commonly affected. Patients often have  problems with intestinal obstruction because of intussus-  ception (“telescoping” of a proximal segment of the bowel    into a distal portion), a problem that usually becomes  evident during the third decade of life. Most of these epi-  sodes are self-correcting, but surgical intervention is some-  times necessary to prevent ischemic necrosis of the bowel,  with subsequent peritonitis. Gastrointestinal adenocarci-  noma develops in a significant percentage of affected  patients, although the polyps themselves do not appear to  be premalignant. In one large series of cases, 9% of the  patients had developed gastrointestinal malignancy by 40  years of age and 33% by 60 years of age. This compares to  0.1% and 1.0%, respectively, in the general population.  Other tumors affecting the pancreas, male and female  genital tract, breast, and ovary may also develop. In women,  the risk of developing breast cancer approaches 50% by 60  years of age. The increased frequency of malignancy in these  patients overall is estimated to be approximately 10 to 18  times greater than normal.   The oral lesions essentially represent an extension of the  perioral freckling. These 1- to 4-mm brown to blue-gray  macules primarily affect the vermilion zone, the labial and  buccal mucosa, and the tongue; they are seen in more than  90% of these patients (Fig. 16-28). The number of lesions  and the extent of involvement can vary markedly from  patient to patient. Some degree of fading of the pigmented  lesions may be noted during adolescence.    ‘The gastrointestinal polyps of Peutz-Jeghers syndrome his-  topathologically represent benign overgrowths of intestinal  glandular epithelium supported by a core of smooth muscle.  Epithelial atypia is not usually a prominent feature, unlike  the polyps of Gardner syndrome (see page 606).  Microscopic evaluation of the pigmented cutaneous  lesions shows slight acanthosis of the epithelium with elon-  gation of the rete ridges. No apparent increase in melano-  cyte number is detected by electron microscopy, but the  dendritic processes of the melanocytes are elongated. Fur-  thermore, the melanin pigment appears to be retained in    ° Fig. 16-27 Peutz-Jeghers Syndrome. Cutaneous lesions appear  as brown, macular, freckle-like areas, often concentrated around the  mouth or on the hands. (Courtesy of Dr. Anmed Uthman.)    e Fig. 16-28 Peutz-Jeghers Syndrome. Oral manifestations  include multiple, dark, freckle-like lesions of the lips. (Courtesy of Dr.  Ahmed Uthman.)    Patients with Peutz-Jeghers syndrome should be monitored  for development of intussusception or tumor formation.  Genetic counseling is also appropriate.    Hereditary hemorrhagic telangiectasia (HHT) is an  uncommon mucocutaneous disorder that is inherited as an  autosomal dominant trait, and epidemiologic studies  suggest a prevalence that ranges from 1 in 5,000 to 18,000  people, depending on the geographic region. Mutation of  either one of two different genes at two separate loci is  responsible for the condition. HHT1 is caused by a muta-  tion of the endoglin (ENG) gene on chromosome 9, whereas  mutation of activin receptor-like kinase-1 (ALK1; ACVRL1),  a gene located on chromosome 12, produces HHT2. The  proteins produced by these genes may play a role in blood  vessel wall integrity. With both types of HHT, numerous  vascular hamartomas develop, affecting the skin and mucosa;  however, other vascular problems, such as arteriovenous  fistulas, may also be seen. Patients affected with HHT1 tend  to have more pulmonary and cerebral involvement, whereas  those with HHT2 generally have a later onset of their tel-  angiectasias and a greater degree of hepatic involvement. A  much less common mutation, involving the MADH4 gene,  has also been identified, and these patients exhibit an  overlap syndrome characterized by HHT and juvenile pol-  yposis. The polyps involve both the upper and lower gas-  trointestinal tract, and these patients have an increased risk  for developing colorectal carcinoma at an early age. The  clinician should be familiar with HHT because the oral  lesions are often the most dramatic and most easily identi-  fied component of this syndrome.    Patients with HHT are often diagnosed initially because of  frequent episodes of epistaxis. On further examination, the  nasal and oropharyngeal mucosae exhibit numerous scat-  tered red papules, 1 to 2 mm in size, which blanch when  diascopy is used. This blanching indicates that the red color  is due to blood contained within blood vessels (in this case,  small collections of dilated capillaries [telangiectasias] that  are close to the surface of the mucosa). These telangiectatic  vessels are most frequently found on the vermilion zone of  the lips, tongue, and buccal mucosa, although any oral  mucosal site may be affected (Figs. 16-29 and 16-30). With  aging, the telangiectasias tend to become more numerous  and slightly larger.    eS aes A 4 ue  ® Fig. 16-29 Hereditary Hemorrhagic Telangiectasia (HHT). The  tongue of this patient shows multiple red papules, which represent  superficial collections of dilated capillary spaces.    ® Fig. 16-30 Hereditary Hemorrhagic Telangiectasia (HHT). Red  macules similar to the tongue lesions are observed on the buccal  mucosa.    In many patients, telangiectasias are seen on the hands  and feet. The lesions are often distributed throughout the  gastrointestinal mucosa, the genitourinary mucosa, and the  conjunctival mucosa. The gastrointestinal telangiectasias  have a tendency to rupture, which may cause significant  blood loss. Chronic iron-deficiency anemia is often a  problem for such individuals. Significantly, arteriovenous  fistulas may develop in the lungs (15% to 45% of HHT  patients), liver (30%), or brain (10% to 20%). The pulmo-  nary arteriovenous malformations seem to predispose these  patients to the development of brain abscesses due to right-  to-left shunting of bacteria that might be introduced into  the bloodstream. In at least one instance, periodontal vas-  cular malformations were felt to be the cause of septic  pulmonary emboli that resolved only after several teeth with  periodontal abscesses were extracted.   A diagnosis of HHT can be made if a patient has three  of the following four criteria:    pe WPA As RSS :  ® Fig. 16-31 Hereditary Hemorrhagic Telangiectasia (HHT). This  low-power photomicrograph shows multiple dilated vascular spaces    In some instances, CREST syndrome (Calcinosis cutis,  Raynaud phenomenon, Esophageal dysfunction, Sclerodac-  tyly, and Telangiectasia) (see page 747) must be considered  in the differential diagnosis. In these cases, serologic studies  for anticentromere autoantibodies often help to distinguish  between the two conditions because these antibodies typi-  cally would be present only in CREST syndrome.    If one of the telangiectasias is submitted for biopsy, the  microscopic features essentially show a superficially located  collection of thin-walled vascular spaces that contain eryth-  rocytes (Fig. 16-31).    For mild cases of HHT, no treatment may be required.  Moderate cases may be managed by selective cryosurgery or  electrocautery of the most bothersome of the telangiectatic  vessels. Laser ablation of the telangiectatic lesions has also  been used, although this approach appears to be most suc-  cessful for patients with mild to moderate disease. More  severely affected patients, particularly those troubled by  repeated episodes of epistaxis, may require a surgical proce-  dure of the nasal septum (septal dermoplasty). The involved  nasal mucosa is removed and replaced by a skin graft;  however, some long-term follow-up studies suggest that the  grafts eventually become revascularized, resulting in recur-  rence of the problem. Nasal closure is another surgical tech-  nique that has been performed for patients with severe  epistaxis in whom other methods have failed.   Combined progesterone and estrogen therapy may  benefit some patients, but because of the potentially serious  side effects, this should be limited to the most severely  affected individuals. Bevacizumab, an antibody directed  against vascular endothelial growth factor, has shown  some promise in controlling epistaxis, but this is a costly  medication. Iron replacement therapy is indicated for the    iron-deficient patient, and occasionally blood transfusions  may be necessary to compensate for blood loss.   From a dental standpoint, some authors recommend the  use of prophylactic antibiotics before dental procedures that  might cause bacteremia in patients with HHT and evidence  of a pulmonary arteriovenous malformation. For patients  with a history of HHT, such antibiotics are advocated until  a pulmonary arteriovenous malformation is ruled out  because of the 1% prevalence of brain abscesses in affected  individuals. Researchers believe that antibiotic coverage,  similar to that for endocarditis prophylaxis, may prevent  this serious complication. Patients with a history of HHT  should be screened for arteriovenous malformations, which  can be eliminated by embolization or other vasodestructive  techniques using interventional radiologic methods. The  decision to treat such a lesion often depends on the ana-  tomic site and the severity of the malformation.   The prognosis is generally good, although a 1% to 2%  mortality rate is reported from complications related to  blood loss. For patients with brain abscesses, the mortality  rate can range up to 10%, even with early diagnosis and  appropriate therapy.    ‘The Ehlers-Danlos syndromes, a group of inherited con-  nective tissue disorders, are relatively heterogeneous. At least  ten types have been described over the years, but recent  clinical and molecular evidence suggests that seven catego-  ries of this disease may be more appropriate. The patient  exhibits problems that are usually attributed to the produc-  tion of abnormal collagen, the protein that is the main  structural component of the connective tissue. Because the  production of collagen necessitates many biochemical steps  that are controlled by several genes, the potential exists for  any one of these genes to mutate, producing selective defects  in collagen synthesis. The various forms of abnormal col-  lagen result in many overlapping clinical features for each  of the types of the Ehlers-Danlos syndrome (Table 16-1).  This discussion concentrates on the most common and  significant forms of this group of conditions.   Typical clinical findings include hypermobility of the  joints, easy bruisability, and marked elasticity of the skin.  Some affected individuals have worked in circus sideshows  as the “rubber” man and the “contortionist” as a result of    The pattern of inheritance and the clinical manifestations  vary with the type of Ehlers-Danlos syndrome being exam-  ined. About 80% of patients have the classical type in  either the mild or severe form. Classical Ehlers-Danlos  syndrome is inherited as an autosomal dominant trait, and  defects of type I collagen have been reported in some fami-  lies, whereas problems with type V collagen have been    Classical (Severe) Hyperextensible skin, easy bruising, AD Collagen type V mutations  hypermobile joints, papyraceous  scarring of skin    Kyphoscoliosis Ocular globe fragility, hyperextensible AR Lysyl hydroxylase point mutations  skin, hypermobile joints, scoliosis   Other (includes X-linked, X-linked and periodontal similar to XLR, AD, AR Not known; possible collagen type | and  periodontal, and mild classic type; fibronectin has lll defect; possible defect in fibronectin  fibronectin types) platelet defect    identified in others, suggesting genetic heterogeneity.  Hyperelasticity of the skin (Fig. 16-32) and cutaneous fra-  gility can be observed. An unusual healing response that  often occurs with relatively minor injury to the skin is  termed papyraceous scarring because it resembles crum-  pled cigarette paper (Fig. 16-33).   Patients with the hypermobility type of Ehlers-Danlos  syndrome exhibit remarkable joint hypermobility but no  evidence of unusual scarring.   The vascular type of Ehlers-Danlos used to be known  as the ecchymotic type because of the extensive bruising  that occurs with everyday trauma. Defects in type III col-  lagen have been identified in this disorder. This form is  inherited in an autosomal dominant pattern, and a young  patient may be mistaken for a victim of child abuse. The  life expectancy of these patients is often greatly reduced  because of the tendency for aortic aneurysm formation and  rupture.   One rare form of Ehlers-Danlos syndrome (type VIII)  has dental manifestations as a hallmark feature, with patients  showing marked periodontal disease activity at a relatively  early age. Although these patients may have overlapping  features with either the classical or vascular forms of the  disease, studies of five affected families in Sweden have sug-  gested that this form of Ehlers-Danlos syndrome is linked @ Fig. 16-32 Ehlers-Danlos Syndrome. The hyperelasticity of the  to a specific mutation of a gene that has been mapped to skin is evident in this patient affected by the mild form of classical  chromosome 12p13. Ehlers-Danlos syndrome.   The oral manifestations of Ehlers-Danlos syndrome  include the ability of 50% of these patients to touch the tip  of their nose with their tongue (Gorlin sign), a feat that    i eek a ;  @ Fig. 16-33 Ehlers-Danlos Syndrome. Scarring that resembles  crumpled cigarette paper (papyraceous scarring) is associated with  minimal trauma in patients with Ehlers-Danlos syndromes. These  lesions involve the skin of the knee.    can be achieved by less than 10% of the general population.  Some authors have noted easy bruising and bleeding during  minor manipulations of the oral mucosa; others state that  oral mucosal friability is present. A tendency for recurrent  subluxation of the temporomandibular joint (TMJ) and  the development of other TMJ disorders has also been  reported.   Most patients with Ehlers-Danlos syndrome have normal  teeth. A variety of dental abnormalities have been described,  however, including malformed, stunted tooth roots, large  pulp stones, and hypoplastic enamel. Although most of  these findings have not been consistently correlated with  any particular type of the syndrome, pulp stones seem to  occur more commonly in patients affected by classical  Ehlers-Danlos syndrome.    The prognosis for the patient with Ehlers-Danlos syndrome  depends on the type. Some forms, such as the vascular type,  can be very serious, with sudden death occurring from  rupture of the aorta secondary to the weakened, abnormal  collagen that constitutes the vessel wall. The mild classical  type is generally compatible with a normal life span,  although affected women may have problems with placental  tearing and hemorrhage during gestation.   Accurate diagnosis is important because it affects the  prognosis heavily. Similarly, because the various types of this  syndrome show a variety of inheritance patterns, an accurate  diagnosis is required so that appropriate genetic counseling  can be provided.    © Fig. 16-34 Tuberous Sclerosis. Patients typically have multiple  papular facial lesions that microscopically are angiofibromas.    Tuberous sclerosis is an uncommon syndrome that is clas-  sically characterized by intellectual disability, seizure disor-  ders, and angiofibromas of the skin. The condition is often  inherited as an autosomal dominant trait, but two-thirds of  the cases are sporadic and appear to represent new muta-  tions. These mutations involve either one of two genes:  TSCI (found on chromosome 9) or, more commonly,  TSC2 (found on chromosome 16). Both of these gene prod-  ucts are believed to contribute to the same intracellular  biochemical pathway that seems to have a tumor suppressor  function. The multiple hamartomatous growths that are  seen in this disorder are thought to arise from disruption of  the normal tumor suppressor function of these genes.  Tuberous sclerosis has a wide range of clinical severity,  although patients who have the 7SC2 mutation have a more  severe expression of the disease than patients who have the  TSC] mutation. Milder forms of tuberous sclerosis may be  difficult to diagnose.   The prevalence is at least 1 in 10,000 in the general  population, although in some long-term care facilities  tuberous sclerosis accounts for as high as 1% of the intel-  lectually disabled patients. Nevertheless, average intelligence  is present in over half of tuberous sclerosis patients.    Several clinical features characterize tuberous sclerosis. The  first of these, facial angiofibromas, used to be called  adenoma sebaceum. Because these lesions are neither  adenomas nor sebaceous, the use of that term should be  discontinued. Facial angiofibromas appear as multiple,  smooth-surfaced papules and occur primarily in the naso-  labial fold area (Fig. 16-34). Similar lesions, called ungual  or periungual fibromas, are seen around or under the margins  of the nails (Fig. 16-35).   Two other characteristic skin lesions are connective tissue  hamartomas called shagreen patches and ovoid areas of    ° Fig. 16-35 Tuberous Sclerosis. Examination of the fingers often  shows periungual fibromas.    ® Fig. 16-36 Tuberous Sclerosis. Patchy calcifications (arrows)  associated with intracranial hamartoma formation are seen on this  lateral skull radiograph. (Courtesy of Dr. Reg Munden.)    hypopigmentation called ash-leaf spots. Even though  approximately 5% of the general population may have an  ash-leaf spot, studies have reported that 90% to 98% of  children with tuberous sclerosis display these lesions. The  shagreen patches, so named because of their resemblance to  sharkskin-derived shagreen cloth, affect the skin of the  trunk. The ash-leaf spots may appear on any cutaneous  surface and may be best visualized using UV (Wood's lamp)  illumination.   CNS manifestations include seizure disorders in 70% to  80% of affected patients and intellectual disability in  approximately 30%. In addition, hamartomatous prolifera-  tions in the CNS develop into the potato-like growths  (“tubers”) seen at autopsy, from which the term tuberous  sclerosis is derived (Fig. 16-36). The tuberous hamartomas  can best be visualized using T2-weighted magnetic reso-  nance imaging (MRI) and are present in 80% to 95% of  these patients. Also, approximately 10% of tuberous sclero-  sis patients will develop a type of benign brain tumor known  as subependymal giant cell astrocytoma.   A relatively rare tumor of the heart muscle, called cardiac  rhabdomyoma, is also typically associated with this syn-    @ Fig. 16-37 Tuberous Sclerosis. Patients often exhibit gingival  hyperplasia, which may be secondary to phenytoin medications used  to control seizures in some cases. Fibrous papules of the gingiva  (arrows) may also be present.    drome. This lesion, which probably represents a hamartoma  rather than a true neoplasm, occurs in approximately 30%  to 50% of affected patients and is typically identified in  early childhood. Problems with myocardial function may  develop as a result of this process, but many of these tumors  undergo spontaneous regression.   Another hamartomatous type of growth related to this  disorder is the angiomyolipoma. This is a benign neoplasm  composed of vascular smooth muscle and adipose tissue and  occurs primarily in the kidney, typically bilaterally. Even  though the angiomyolipoma is benign, the tumors are  often associated with large dilated blood vessels, and signifi-  cant clinical problems can arise if these vessels rupture  spontaneously.   Oral manifestations of tuberous sclerosis include devel-  opmental enamel pitting on the facial aspect of the anterior  permanent dentition in 50% to 100% of patients. These pits  are more readily appreciated after applying a dental plaque—  disclosing solution to the teeth. Multiple fibrous papules  affect 11% to 56% of patients. The fibrous papules are seen  predominantly on the anterior gingival mucosa (Fig. 16-37),  although the lips, buccal mucosa, palate, and tongue may be  involved. Diffuse fibrous gingival enlargement is reported in  affected patients—even those who are not taking phenytoin;  however, most cases of gingival hyperplasia in these indi-  viduals are probably related to medication taken to control  seizures. Some patients with tuberous sclerosis may also  exhibit radiolucencies of the jaws that represent dense  fibrous connective tissue proliferations (Fig. 16-38).   The diagnosis of tuberous sclerosis can be based on  finding at least two of the following major features:  ¢ Facial angiofibromas  ¢ Ungual or periungual fibromas  ¢ Hypomelanotic macules (three or more)    © Fig. 16-38 Tuberous Sclerosis. Periapical radiograph exhibiting  a well-defined radiolucency apical to the maxillary left lateral incisor.  Biopsy revealed an intraosseous fibrous proliferation.    ¢ Renal angiomyolipoma  ¢ Multiple retinal nodular hamartomas  ‘The presence of one major and two minor features may  also confirm the diagnosis. The minor features include the  following:  ¢ Multiple, randomly distributed enamel pits  ¢ Gingival fibromas  ¢ Bone “cysts” (actually fibrous proliferations)  ¢ Multiple renal cysts  e Hamartomatous rectal polyps    Microscopic examination of the fibrous papules of the oral  mucosa or the enlarged gingivae shows a nonspecific fibrous  hyperplasia. Similarly, the radiolucent jaw lesions consist of  dense fibrous connective tissue that resembles desmoplastic  fibroma or the simple type of central odontogenic fibroma.  The angiofibroma of the skin is a benign aggregation of  delicate fibrous connective tissue characterized by plump,  uniformly spaced fibroblasts with numerous interspersed  thin-walled vascular channels.    For patients with tuberous sclerosis, most of the treatment  is directed toward the management of the seizure disorder  with anticonvulsant agents. Periodic MRI of the head may  be done to screen for intracranial lesions, whereas ultrasound  evaluation is performed for evaluation of kidney involve-  ment. Intellectually disabled patients may have problems  with oral hygiene procedures, and poor oral hygiene    contributes to phenytoin-induced gingival hyperplasia.  Recent studies examining medications (such as, everolimus)  that block the metabolic pathway that causes tuberous scle-  rosis have shown significant shrinkage of several tumor types  associated with this disorder, including renal angiomyoli-  poma, facial angiofibroma, and subependymal giant cell  astrocytoma. Patients affected by tuberous sclerosis have a  slightly reduced life span compared with the general popula-  tion, with death usually related to CNS or kidney disease.  Genetic counseling is also appropriate for affected patients,  and genetic testing is available for both TSC and TSC2  mutations if prenatal or preimplantation family planning is    Multiple hamartoma syndrome is a rare condition that  has important implications for the affected patient, because  malignancies, in addition to the benign hamartomatous  growths, develop in a high percentage of these individuals.  Usually, the syndrome is inherited as an autosomal domi-  nant trait showing a high degree of penetrance and a range  of expressivity. The gene responsible for this disorder has  been mapped to chromosome 10, and a mutation of the  phosphatase and tensin homolog deleted on chromosome 10  (PTEN) gene has been implicated in its pathogenesis. The  estimated prevalence of this condition is approximately 1 in  200,000, and more than 300 affected patients have been  described in the literature. In recent years, overlapping  clinical features of multiple hamartoma syndrome with  Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba  syndrome, and Proteus-like syndrome have been noted,  and all of these disorders have demonstrated mutations of  the PTEN gene.    Cutaneous manifestations are present in almost all patients  with multiple hamartoma syndrome, usually developing  during the second decade of life. The majority of the skin  lesions appear as multiple, small (less than 1 mm) papules,  primarily on the facial skin, especially around the mouth,  nose, and ears (Fig. 16-39). Microscopically, most of these  papules represent hair follicle hamartomas called trichilem-  momas. Other commonly noted skin lesions are acral kera-  tosis, a warty-appearing growth that develops on the dorsal  surface of the hand, and palmoplantar keratosis, a promi-  nent callus-like lesion on the palms or soles. Cutaneous  hemangiomas, neuromas, xanthomas, and lipomas have  also been described.   Other problems can appear in these patients as well.  Thyroid disease usually appears as either a goiter or a thyroid  adenoma, but papillary or follicular adenocarcinoma may  develop. In one large series, thyroid malignancy was    e Fig. 16-39 Multiple Hamartoma Syndrome. These _ tiny  cutaneous facial papules represent hair follicle hamartomas  trichilemmomas).    identified in 14% of patients with this condition. In women,  fibrocystic disease of the breast is frequently observed. Unfor-  tunately, breast cancer occurs with a relatively high frequency  (25% to 50%) in these patients. The mean age at diagnosis  of breast malignancy is 40 years, which is much younger than  usual. In the gastrointestinal tract, multiple benign hamar-  tomatous polyps may be present. In addition, several types  of benign and malignant tumors of the female genitourinary  tract occur more often than in the normal population.   The oral lesions vary in severity from patient to patient  and usually consist of multiple papules affecting the gingi-  vae, dorsal tongue, and buccal mucosa (Figs. 16-40 and  16-41). These lesions have been reported in more than 80%  of affected patients and generally produce no symptoms.  Other possible oral findings include a high-arched palate,  periodontitis, and extensive dental caries, although it is  unclear whether the latter two conditions are significantly  related to the syndrome.    The histopathologic features of the oral lesions are rather  nonspecific, essentially representing fibroepithelial hyper-    @ Fig. 16-41 Multiple Hamartoma Syndrome. Multiple papules on  the left buccal mucosa.    plasia. Other lesions associated with this syndrome have  their own characteristic histopathologic findings, depend-  ing on the hamartomatous or neoplastic tissue origin.    The diagnosis can be based on the finding of two of the  following three pathognomonic signs:  1. Multiple facial trichilemmomas  2. Multiple oral papules  3. Acral keratoses   A variety of other major and minor diagnostic criteria,  as well as a positive family history, are also helpful in con-  firming the diagnosis. Genetic testing for mutations of the  PTEN gene are clinically available, but 20% of patients who  otherwise have characteristic multiple hamartoma syn-  drome will not demonstrate a genetic abnormality; there-  fore, a negative test does not necessarily preclude the  diagnosis of multiple hamartoma syndrome.    Treatment of multiple hamartoma syndrome is controver-  sial. Although most of the tumors that develop are benign,  the prevalence of malignancy is higher than in the general  population; therefore, annual physical examinations should  be performed that focus specifically on anatomic sites of  increased tumor prevalence, particularly breast, uterus, and  thyroid. Some investigators recommend bilateral prophy-  lactic mastectomies as early as the third decade of life for  female patients because of the associated increased risk of  breast cancer.    ‘The term epidermolysis bullosa describes a heterogeneous  group of inherited blistering mucocutaneous disorders.  Each has a specific defect in the attachment mechanisms of  the epithelial cells, either to each other or to the underlying  connective tissue. Recent advances in the understanding of    the clinical features, epidemiology, immunofluorescence  mapping, and molecular genetic abnormalities of these con-  ditions have led to the identification of approximately 34  different forms. Depending on the defective mechanism of  cellular cohesion, there are four broad categories:   Each category consists of several forms of the disorder.  A variety of inheritance patterns may be seen, depending  on the particular form. The degree of severity can range  from relatively mild, annoying forms, such as the simplex  types, through a spectrum that includes severe, fatal disease.  For example, many cases of junctional epidermolysis  bullosa result in death at birth because of the significant  sloughing of the skin during passage through the birth  canal. Specific mutations in the genes encoding keratin 5  and keratin 14 have been identified as being responsible for  most of the simplex types, whereas mutations in the genetic  codes of laminin-332, type XVII collagen, or #6[4 integrin  have been documented for the junctional types. Most of  the dystrophic types are caused by mutations in the genes  responsible for type VII collagen production, with over 300  distinctly different mutations identified to date. Kindler  syndrome is the most recently characterized pattern of this  group of disorders, and mutations of the gene that encodes  for a hemidesmosomal attachment protein, kindlin-1, are  responsible for this rare condition.   A few representative examples of the types of epider-  molysis bullosa are summarized in Table 16-2. Because oral  lesions are most commonly observed in the dystrophic  forms, this discussion centers on these forms. Dental    abnormalities, such as anodontia, enamel hypoplasia, pitting  of the enamel, neonatal teeth, severe periodontitis, and  severe dental caries, have been variably associated with  several of the different types of epidermolysis bullosa,  although studies have suggested that the prevalence of  dental abnormalities is significantly increased only with the  junctional type. A disorder termed epidermolysis bullosa  acquisita is mentioned because of the similarity of its name;  however, this is an unrelated condition, having an autoim-  mune (rather than a genetic) origin (see page 721).    The dystrophic forms of epidermolysis bullosa that are  inherited in an autosomal dominant fashion are not usually  life threatening, although they may certainly be disfiguring  and pose many problems. The initial lesions are vesicles or  bullae, which are seen early in life and develop on areas  exposed to low-grade, chronic trauma, such as the knuckles  or knees (Fig. 16-42). The bullae rupture, resulting in ero-  sions or ulcerations that ultimately heal with scarring. In  the process, appendages such as fingernails may be lost.   The oral manifestations are typically mild, with some  gingival erythema and tenderness. Gingival recession and  reduction in the depth of the buccal vestibule may be  observed (Fig. 16-43).    Generalized recessive dystrophic epidermolysis bullosa rep-  resents one of the more debilitating forms of the disease.  Vesicles and bullae form with even minor trauma. Second-  ary infections are often a problem because of the large  surface areas that may be involved. If the patient manages    Blistering of the hands and feet; mucosal  involvement uncommon; blisters heal without  scarring; prognosis usually good    Severe blistering at birth; granulation tissue around  the mouth; oral erosions common; pitted enamel    Severe mucosal involvement; mittenlike scarring;  deformities of hands and feet; patients usually do  not survive past early adulthood    @ Fig. 16-42 Epidermolysis Bullosa. A young girl, affected by the  dominant dystrophic form of epidermolysis bullosa, shows the char-  acteristic hemorrhagic bullae, scarring, and erosion associated with  minimal trauma to the hands.    ° Fig. 16-43 Epidermolysis Bullosa. A teenaged boy, affected by  dominant dystrophic epidermolysis bullosa, shows a reduced depth of  the labial vestibule caused by repeated mucosal tearing and healing  with scarring.    to survive into the second decade, then hand function is  often greatly diminished because of the repeated episodes  of cutaneous breakdown and healing with scarring, result-  ing in fusion of the fingers into a mittenlike deformity (Fig.  16-44).   The oral problems are no less severe. Bulla and vesicle  formation is induced by virtually any food having some  degree of texture. Even with a soft diet, the repeated cycles  of scarring often result in microstomia (Fig. 16-45) and  ankyloglossia. Similar mucosal injury and scarring may  cause severe stricture of the esophagus. Because a soft diet  is usually highly cariogenic, carious destruction of the denti-  tion at an early age is common.    The histopathologic features of epidermolysis bullosa vary  with the type being examined. The simplex form shows  intraepithelial clefting by light microscopy. Junctional,  dystrophic, and Kindler forms show subepithelial clefting    ® Fig. 16-44 Epidermolysis Bullosa. A 19-year-old man, affected  by recessive dystrophic epidermolysis bullosa, shows the typical mit-  tenlike deformity of the hand caused by scarring of the tissue after  damage associated with normal activity.    ® Fig. 16-45 Epidermolysis Bullosa. Same patient as depicted in  Fig. 16-44. Microstomia has been caused by repeated trauma and  healing with scarring. Note the severe dental caries activity associated  with a soft cariogenic diet.    (Fig. 16-46). Electron microscopic examination reveals  clefting at the level of the lamina lucida of the basement  membrane in the junctional forms and below the lamina  densa of the basement membrane in the dystrophic forms.  In contrast, the Kindler form shows clefting just below the  basal cell layer, at its interface with the lamina lucida.  Immunohistochemical evaluation of perilesional tissue is  now typically used to identify specific defects to classify and  subtype the condition further. Molecular genetic analysis  may also be helpful for confirming the diagnosis in some  instances.    Treatment of epidermolysis bullosa varies with the type. For  milder cases, no treatment other than local wound care may  be needed. Sterile drainage of larger blisters and the use of  topical antibiotics are often indicated in these situations.  For the more severe cases, intensive management with oral  antibiotics may be necessary if cellulitis develops; despite    epithelium from the connective tissue is seen in this photomicrograph  of a tissue section obtained from a patient affected by a junctional form  of epidermolysis bullosa.    intensive medical care, some patients die as a result of infec-  tious complications.   The “mitten” deformity of the hands, seen in recessive  dystrophic epidermolysis bullosa, can be corrected with  plastic surgery, but the problem usually recurs after a period  of time, and surgical intervention is required every 2 years  on average. With esophageal involvement, dysphagia may  be a significant problem, resulting in malnutrition and  weight loss. Placement of a gastrostomy tube may be neces-  sary at times. Patients with the recessive dystrophic forms  are also predisposed to development of cutaneous squa-  mous cell carcinoma. This malignancy often develops in  areas of chronic ulceration during the second through third  decades of life and represents a significant cause of death  for these patients. Infrequently, the lingual mucosa of  affected patients has been reported to undergo malignant  transformation as well.   Management of the oral manifestations also depends on  the type of the disease. For patients who are susceptible to  mucosal bulla formation, dental manipulation should be  kept to a minimum. To achieve this, topical 1% neutral  sodium fluoride solution should be administered daily to  prevent dental caries. A soft diet that is as noncariogenic as  possible, as well as atraumatic oral hygiene procedures,  should be encouraged. Maintaining adequate nutrition for  affected patients is critical to ensure optimal wound healing.  Endosseous dental implants, followed by fixed dental pros-  theses, have been successfully placed in some patients with  recessive dystrophic epidermolysis bullosa.   If dental restorative care is required, the lips should be  lubricated to minimize trauma. Injections for local anesthe-  sia can usually be accomplished by depositing the anesthetic  slowly and deeply within the tissues. For extensive dental  care, endotracheal anesthesia may be performed without  significant problems in most cases.   Unfortunately, because of the genetic nature of these  diseases, no cure exists. Genetic counseling of affected fami-    lies is indicated. Both prenatal diagnosis and preimplanta-  tion diagnosis are available as adjuncts to family planning.    Several conditions discussed in this chapter are the result of  inappropriate production of antibodies by the patient  (autoantibodies). These autoantibodies are directed against  various constituents of the molecular apparatus that hold  epithelial cells together or that bind the surface epithelium  to the underlying connective tissue. The ensuing damage  produced by the interaction of these autoantibodies with  the host tissue is seen clinically as a disease process, often  termed an immunobullous disease. Because each disease is  characterized by production of specific types of autoanti-  bodies, identification of the antibodies and the tissues  against which they are targeted is important diagnostically.  The two techniques that are widely used to investigate the  immunobullous diseases are 1) direct immunofluorescence  and 2) indirect immunofluorescence studies. Following is a  brief overview of how they work.   Direct immunofluorescence is used to detect autoanti-  bodies that are bound to the patient’s tissue. Before testing  can take place, several procedures must occur. Inoculating  human immunoglobulins into a goat creates antibodies  directed against these human immunoglobulins. The anti-  bodies raised in response to the human immunoglobulins  are harvested from the animal and tagged with fluorescein,  a dye that glows when viewed with UV light. As illustrated  on the left side of Fig. 16-47, a frozen section of the patient's  tissue is placed on a slide, and this is incubated with  fluorescein-conjugated goat antihuman antibodies. These  antibodies bind to the tissue at any site where human  immunoglobulin is present. The excess antibody suspension  is washed off, and the section is then viewed with a micro-  scope having a UV light source.   With indirect immunofluorescence studies, the patient  is being evaluated for presence of antibodies that are circu-  lating in the blood. As shown on the right side of Fig.  16-47, a frozen section of tissue that is similar to human  oral mucosa (e.g., Old World monkey esophagus) is placed  on a slide and incubated with the patient’s serum. If there  are autoantibodies directed against epithelial attachment  structures in the patient’s serum, then they will attach to  the homologous structures on the monkey esophagus. The  excess serum is washed off, and fluorescein-conjugated goat  antihuman antibody is incubated with the section. The  excess is washed off, and the section is examined with UV  light to detect the presence of autoantibodies that might  have been in the serum.   Examples of the molecular sites of attack of the autoan-  tibodies are seen diagrammatically in Fig. 16-48. Each site  is distinctive for a particular disease; however, the complexi-  ties of the epithelial attachment mechanisms are still being  elucidated, and more precise mapping may be possible in  the future. A summary of the clinical, microscopic, and    @ Fig. 16-47 Immunofluorescence Techniques. Comparison of  the techniques for direct and indirect immunofluorescence. The left  side depicts the direct immunofluorescent findings in cicatricial pem-  phigoid, a disease that has autoantibodies directed toward the base-  ment zone. The right side shows the indirect immunofluorescent  findings for pemphigus vulgaris, a disease that has autoantibodies  directed toward the intercellular areas between the spinous cells of the  epithelium. /g, Immunoglobulin; UV, ultraviolet.    immunopathologic features of the more important immune-  mediated mucocutaneous diseases is found in Table 16-3.    The condition known as pemphigus represents four related  diseases of an autoimmune origin:   Only the first two of these affect the oral mucosa, and  the discussion is limited to pemphigus vulgaris. Pemphi-  gus vegetans is rare; most authorities now feel it represents  simply a variant of pemphigus vulgaris.   Pemphigus vulgaris is the most common of these disor-  ders (vulgaris is Latin for common). Even so, it is not seen  very often. The estimated incidence is one to five cases per  million people diagnosed each year in the general popula-  tion. Nevertheless, pemphigus vulgaris is an important con-  dition because, if untreated, it often results in the patient’s  death. Furthermore, the oral lesions are often the first sign  of the disease, and they are the most difficult to resolve with  therapy. This has prompted the description of the oral  lesions as “the first to show, and the last to go.”   The blistering that typifies this disease is due to an abnor-  mal production, for unknown reasons, of autoantibodies  that are directed against the epidermal cell surface glycopro-  teins, desmoglein 3 and desmoglein 1. These desmogleins  are components of desmosomes (structures that bond epi-  thelial cells to each other), and the autoantibodies attach to  these desmosomal components, effectively inhibiting the  molecular interaction that is responsible for adherence. As    ° Fig. 16-48 Epithelial Attachment Apparatus. Schematic diagram demonstrating targeted structures  in several immune-mediated diseases. BMZ, Basement membrane zone.    a result of this immunologic attack on the desmosomes, a  split develops within the epithelium, causing a blister to  form. Desmoglein 3 is preferentially expressed in the para-  basal region of the epidermis and oral epithelium, whereas  desmoglein 1 is found primarily in the superficial portion  of the epidermis, with minimal expression in oral epithe-  lium. Patients who have developed autoantibodies directed  against desmoglein 3, with or without desmoglein 1, will  histopathologically show intraepithelial clefting just above  the basal layer, and clinically oral mucosal blisters of  pemphigus vulgaris will form. Patients who develop auto-  antibodies directed against only desmoglein 1 will histo-  pathologically show superficial intraepithelial clefting of the  epidermis, but oral mucosa will not be affected. Clinically,  the fine scaly red lesions of pemphigus foliaceus or pemphi-  gus erythematosus will be evident.   Occasionally, a pemphigus-like oral and cutaneous erup-  tion may occur in patients taking certain medications  (e.g., penicillamine, angiotensin-converting enzyme [ACE]  inhibitors, nonsteroidal antiinflammatory drugs [NSAIDs])  or in patients with malignancy, especially lymphoreticular  malignancies (so-called paraneoplastic pemphigus) (see  page 716). Similarly, a variety of other conditions may  produce chronic vesiculoulcerative or erosive lesions of the  oral mucosa, and these often need to be considered in the  differential diagnosis (see Table 16-3). In addition, a rare  genetic condition termed chronic benign familial pem-  phigus or Hailey-Hailey disease may have erosive cutane-  ous lesions, but oral involvement in that process appears to  be uncommon.    The initial manifestations of pemphigus vulgaris often  involve the oral mucosa, typically in adults. The average age  at diagnosis is 50 years, although rare cases may be seen in  childhood. No sex predilection is observed, and the condi-  tion seems to be more common in persons of Mediterra-  nean, South Asian, or Jewish heritage.   Patients usually complain of oral soreness, and examina-  tion shows superficial, ragged erosions and ulcerations dis-  tributed haphazardly on the oral mucosa (Figs. 16-49 to  16-52). Such lesions may affect virtually any oral mucosal  location, although the palate, labial mucosa, buccal mucosa,  ventral tongue, and gingivae are often involved. Patients  rarely report vesicle or bulla formation intraorally, and such  lesions can seldom be identified by the examining clinician,  probably because of early rupture of the thin, friable roof  of the blisters. More than 50% of the patients have oral  mucosal lesions before the onset of cutaneous lesions, some-  times by as much as | year or more. Eventually, however,  nearly all patients have intraoral involvement. The skin  lesions appear as flaccid vesicles and bullae (Fig. 16-53) that  rupture quickly, usually within hours to a few days, leaving  an erythematous, denuded surface. Infrequently ocular  involvement may be seen, usually appearing as bilateral  conjunctivitis. Unlike cicatricial pemphigoid, the ocular    »* 2 :S  ® Fig. 16-49 Pemphigus Vulgaris. Multiple erosions of the left  buccal mucosa and soft palate.    rs el _ ,  @ Fig. 16-50 Pemphigus Vulgaris. Large, irregularly shaped ulcer-  ations involving the floor of the mouth and ventral tongue.    @ Fig. 16-51 Pemphigus Vulgaris. Multiple erosions affecting the  marginal gingiva.    lesions of pemphigus typically do not cause scarring and  symblepharon formation (see page 719).   Without proper treatment, the oral and cutaneous  lesions tend to persist and progressively involve more surface  area. A characteristic feature of pemphigus vulgaris is that  a bulla can be induced on normal-appearing skin if   ® Fig. 16-52 Pemphigus Vulgaris. The patient, with a known diag-  nosis of pemphigus vulgaris, had been treated with immunosuppres-  sive therapy. The oral erosions shown here were the only persistent  manifestation of her disease.    ® Fig. 16-53 Pemphigus Vulgaris. This flaccid cutaneous bulla is  characteristic of skin involvement.    Biopsy specimens of perilesional tissue show characteristic  intraepithelial separation, which occurs just above the basal  cell layer of the epithelium (Fig. 16-54). Sometimes the  entire superficial layers of the epithelium are stripped away,  leaving only the basal cells, which have been described as  resembling a “row of tombstones.” The cells of the spinous  layer of the surface epithelium typically appear to fall apart,  a feature that has been termed acantholysis, and the loose  cells tend to assume a rounded shape (Fig. 16-55). This  feature of pemphigus vulgaris can be used in making a  diagnosis based on the identification of these rounded cells  (Tzanck cells) in an exfoliative cytologic preparation. A  mild-to-moderate chronic inflammatory cell infiltrate is  usually seen in the underlying connective tissue.   The diagnosis of pemphigus vulgaris should be con-  firmed by direct immunofluorescence examination of fresh  perilesional tissue or tissue submitted in Michel’s solution.    @ Fig. 16-54 Pemphigus Vulgaris. Low-power photomicrograph of  perilesional mucosa affected by pemphigus vulgaris. An intraepithelial  cleft is located just above the basal cell layer.    @ Fig. 16-55 Pemphigus Vulgaris. High-power photomicrograph  showing rounded, acantholytic epithelial cells sitting within the intraepi-  thelial cleft.    With this procedure, antibodies (usually IgG or IgM) and  complement components (usually C3) can be demonstrated  in the intercellular spaces between the epithelial cells (Fig.  16-56) in almost all patients with this disease. Indirect  immunofluorescence is also typically positive in 80% to  90% of cases, demonstrating the presence of circulating  autoantibodies in the patient’s serum. Enzyme-linked  immunosorbent assays (ELISAs) have been developed to  detect circulating autoantibodies as well.   It is critical that perilesional tissue be obtained for both  light microscopy and direct immunofluorescence to maxi-  mize the probability of a diagnostic sample. If ulcerated  mucosa is submitted for testing, then the results are often  inconclusive because of either a lack of an intact interface  between the epithelium and connective tissue or a great deal  of nonspecific inflammation.    A diagnosis of pemphigus vulgaris should be made as early  in its course as possible because control is generally easier  to achieve. Pemphigus is a systemic disease; therefore,    ® Fig. 16-56 Pemphigus Vulgaris. Photomicrograph depicting the  direct immunofluorescence pattern of pemphigus vulgaris. Immunore-  actants are deposited in the intercellular areas between the surface  epithelial cells, resulting in a “chicken wire” pattern.    treatment consists primarily of systemic corticosteroids  (usually prednisone), often in combination with other  immunosuppressive drugs (so-called steroid-sparing agents),  such as mycophenolate mofetil or azathioprine. Although  some clinicians have advocated the use of topical cortico-  steroids in the management of oral lesions, the observed  improvement is undoubtedly because of the absorption of  the topical agents, resulting in a greater systemic dose. The  potential side effects associated with the long-term use of  systemic corticosteroids are significant and include the  following:   Ideally, a physician with expertise in immunosuppressive  therapy should manage the patient. The most common  approach is to use relatively high doses of systemic cortico-  steroids initially to clear the lesions, and then attempt to  maintain the patient on as low a dose of corticosteroids as  is necessary to control the condition. Often the clinician  can monitor the success of therapy by measuring the titers  of circulating autoantibodies using indirect immunofluores-  cence, because disease activity frequently correlates with the  abnormal antibody levels. The use of rituximab, a mono-  clonal antibody that targets B-lymphocytes, represents  another promising approach to managing this disease, as it  targets the cells responsible for producing the autoantibod-  ies that cause pemphigus.   Pemphigus may undergo complete resolution, although  remissions and exacerbations are common. One study sug-  gested that up to 75% of patients will have disease resolu-  tion after 10 years of treatment, although most centers  report a remission rate of approximately 30%.    Before the development of corticosteroid therapy, as  many as 60% to 90% of these patients died, primarily as a  result of infections and electrolyte imbalances. Even today,  the mortality rate associated with pemphigus vulgaris is in  the range of 5% to 10%, usually because of the complica-  tions of long-term systemic corticosteroid use.    Paraneoplastic pemphigus is a rare vesiculobullous disor-  der that affects patients who have a neoplasm, usually lym-  phoma or chronic lymphocytic leukemia. Approximately  250 cases have been documented. Although the precise  pathogenetic mechanisms are unknown, some evidence sug-  gests abnormal levels of the cytokine, interleukin-6 (IL-6),  could be produced by host lymphocytes in response to the  patient’s tumor. IL-6 may then be responsible for stimulat-  ing the abnormal production of antibodies directed against  antigens associated with the desmosomal complex and the  basement membrane zone of the epithelium. In addition to  a variety of different antibodies that attack these epithelial  adherence structures, some investigators have described  cutaneous and mucosal damage that appears to be mediated  by cytotoxic T lymphocytes in some cases of paraneoplastic  pemphigus. As a result of this multifaceted immunologic  attack, the disease manifests in an array of clinical features,  histopathologic findings, and immunopathologic findings  that may be perplexing if the clinician is unfamiliar with  this condition.    Patients typically have a history of a malignant lymph-  oreticular neoplasm, or less commonly, a benign lymph-  oproliferative disorder such as angiofollicular lymph node  hyperplasia (Castleman disease). In approximately one-  third of reported cases, paraneoplastic pemphigus devel-  oped before a neoplasm was identified, thus signaling the  presence of a tumor. The neoplastic disease may or may not  be under control at the time of onset of the paraneoplastic  condition. Signs and symptoms of paraneoplastic pemphi-  gus usually begin suddenly and may appear polymorphous.  In some instances, multiple vesiculobullous lesions affect  the skin (Fig. 16-57) and oral mucosa. Palmar or plantar  bullae may be evident, a feature that is uncommon in pem-  phigus vulgaris. For other patients, skin lesions can appear  more papular and pruritic, similar to cutaneous lichen  planus. The lips often show hemorrhagic crusting similar to  that of erythema multiforme (Fig. 16-58). Oral mucosal  involvement is an early, consistent feature of paraneoplastic  pemphigus, and patients develop multiple areas of erythema  and diffuse, irregular ulceration (Fig. 16-59), affecting vir-  tually any oral mucosal surface. If the lesions remain    @ Fig. 16-57 Paraneoplastic Pemphigus. The bulla and crusted  ulcerations on this patient’s arm are representative of the polymor-  phous cutaneous lesions.    baat  ° Fig. 16-58 Paraneoplastic Pemphigus. Crusted, hemorrhagic lip  lesions may be mistaken for erythema multiforme or herpes simplex  infection.    untreated, then they persist and worsen. Some patients may  develop only oropharyngeal lesions, without cutaneous  involvement.   Other mucosal surfaces are also commonly affected, with  70% of patients having involvement of the conjunctival  mucosa. In this area, a cicatrizing (scarring) conjunctivitis    develops, similar to that seen with cicatricial pemphigoid  (Fig. 16-60). The anogenital, nasopharyngeal, esophageal,  and respiratory tract mucosa may also be involved. Involve-  ment of the bronchiolar mucosa is particularly significant  because the lining epithelium sloughs and occludes the  bronchiolar lumina and the alveoli of the lung, resulting in  a condition known as bronchiolitis obliterans.    ‘The features of paraneoplastic pemphigus on light micro-  scopic examination may be as diverse as the clinical features.  In most cases, a lichenoid mucositis is seen, usually with  subepithelial clefting (like pemphigoid) or intraepithelial  clefting (like pemphigus) (Fig. 16-61).   Direct immunofluorescence studies may show a weakly  positive deposition of immunoreactants (IgG and comple-  ment) in the intercellular zones of the epithelium and/or a  linear deposition of immunoreactants at the basement  membrane zone. Although antibodies directed against  desmoglein 1 and 3, as well as the bullous pemphigoid  antigens are often produced, antibodies directed against the  plakin family of desmosomal components are more com-  monly identified and are more specific for paraneoplastic    pemphigus. ELISA or immunoblotting techniques are used  to confirm the presence of antibodies directed against peri-  plakin or envoplakin specifically. If these tests are not avail-  able, then indirect immunofluorescence can be conducted  using a transitional type of epithelium (e.g., rat urinary  bladder mucosa) as the substrate due to its rich expression  of plakins. This technique shows a fairly specific pattern of  antibody localization to the intercellular areas of the epithe-  lium. Examples of paraneoplastic pemphigus that show only  a lichenoid reaction with no demonstrable autoantibody  production have infrequently been described.    Paraneoplastic pemphigus is often a very serious condition  with a high morbidity and mortality rate, with some series  having a mortality rate of 90%. For the infrequent cases  associated with a benign lymphoproliferative condition,  surgical removal of the tumor may result in regression of  the paraneoplastic pemphigus. For those cases associated  with malignancy, treatment usually consists of systemic  prednisone combined with cyclosporine. Cyclophospha-  mide, another immunosuppressive agent, may be added to  this regimen, although other immunosuppressive and  immune-modulating drugs are also being evaluated. As with  pemphigus vulgaris, the skin lesions usually respond more  quickly to treatment than the oral lesions. Unfortunately,  although the immunosuppressive therapy often manages to  control the autoimmune disease, this immunosuppression  often seems to trigger a reactivation of the malignant neo-  plasm. Thus a high mortality rate is seen, with patients  succumbing to complications of the vesiculobullous lesions,  complications of immune suppressive therapy, respiratory  failure due to bronchiolitis obliterans, or progression of  malignant disease. Occasionally, long-term survivors are  reported, but these seem to be in the minority. As more of  these patients are identified, therapeutic strategies can be  better evaluated and modified for optimal care in the future.    Evidence has accumulated to suggest that mucous mem-  brane pemphigoid represents a group of chronic, blister-  ing, mucocutaneous autoimmune diseases in which  tissue-bound autoantibodies are directed against one or  more components of the basement membrane. As such, this  condition has a heterogeneous origin, with autoantibodies  being produced against any one of a variety of basement  membrane components, all of which produce similar clini-  cal manifestations. The precise prevalence is unknown, but  most authors believe that it is at least twice as common as  pemphigus vulgaris.   ‘The term pemphigoid is used because clinically it often  appears similar (the meaning of the -o/d sufhx) to pemphi-    gus. The prognosis and microscopic features of pemphi-  goid, however, are very different.   Although a variety of terms have been used over the  decades to designate this condition, a group of experts from  both medicine and dentistry met in 1999 and came to an  agreement that mucous membrane pemphigoid would be  the most appropriate name for the disease. Cicatricial pem-  phigoid, another commonly used name for this process, is  derived from the word cicatrix, meaning scar. When the  conjunctival mucosa is affected, the scarring that results is  the most significant aspect of this disorder because it invari-  ably results in blindness unless the condition is recognized  and treated. Interestingly, the oral lesions seldom exhibit  this tendency for scar formation.    Mucous membrane pemphigoid usually affects older adults,  with an average age of 50 to 60 years at the onset of disease.  Females are affected more frequently than males by a 2:1  ratio. Oral lesions are seen in most patients, but other sites,  such as conjunctival, nasal, esophageal, laryngeal, and  vaginal mucosa, as well as the skin (Fig. 16-62), may be  involved.   ‘The oral lesions of pemphigoid begin as either vesicles or  bullae that may occasionally be identified clinically (Fig.  16-63). In contrast, patients with pemphigus rarely display  such blisters. The most likely explanation for this difference  is that the pemphigoid blister forms in a subepithelial loca-  tion, producing a thicker, stronger roof than the intraepi-  thelial, acantholytic pemphigus blister. Eventually, the oral  blisters rupture, leaving large, superficial, ulcerated, and  denuded areas of mucosa (Fig. 16-64). The ulcerated lesions  are usually painful and persist for weeks to months if  untreated.   Often this process is seen diffusely throughout the  mouth, but it may be limited to certain areas, especially  the gingiva (Fig. 16-65). Gingival involvement produces a  clinical reaction pattern termed desquamative gingivitis    © Fig. 16-62 Mucous Membrane Pemphigoid. Although cutane-  ous lesions are not common, tense bullae such as these may develop  on the skin of 20% of affected patients. (Courtesy of Dr. Charles  Camisa.)    ° Fig. 16-63 Mucous Membrane Pemphigoid. One or more intra-  oral vesicles, as seen on the soft palate, may be detected in patients  with cicatricial pemphigoid. Usually, ulcerations of the oral mucosa are  also present.    @ Fig. 16-65 Mucous Membrane Pemphigoid. Often the gingival  tissues are the only affected site, resulting in a clinical pattern known  as desquamative gingivitis. Such a pattern may also be seen with  lichen planus and pemphigus vulgaris.    ® Fig. 16-66 Mucous Membrane Pemphigoid. Although the earli-  est ocular changes are difficult to identify, patients with ocular involve-  ment may show adhesions (symblepharons) between the bulbar and  palpebral conjunctivae before severe ocular damage occurs.    © Fig. 16-67 Mucous Membrane Pemphigoid. The disease has  caused the upper eyelid of this patient to turn inward (entropion),  resulting in the eyelashes rubbing against the eye itself (trichiasis). Also  note the obliteration of the lower fornix of the eye.    (see page 148). This pattern may also be seen in other condi-  tions, such as erosive lichen planus or, much less fre-  quently, pemphigus vulgaris.   The most significant complication of mucous membrane  pemphigoid, however, is ocular involvement. Although  exact figures are not available, up to 25% of patients with  oral lesions may eventually develop ocular disease. One eye  may be affected before the other. The earliest change is  subconjunctival fibrosis, which usually can be detected by  an ophthalmologist using slit-lamp microscopic examina-  tion. As the disease progresses, the conjunctiva becomes  inflamed and eroded. Attempts at healing lead to scarring  between the bulbar (lining the globe of the eye) and  palpebral (lining the inner surface of the eyelid) conjuncti-  vae. Adhesions called symblepharons result (Fig. 16-66).  Without treatment the inflammatory changes become more  severe, although conjunctival vesicle formation is rarely seen  (Fig. 16-67). Scarring can ultimately cause the eyelids to    e Fig. 16-68 Mucous Membrane Pemphigoid. A patient with  ocular involvement shows severe conjunctival inflammation. An oph-  thalmologist removed the lower eyelashes because of trichiasis associ-  ated with entropion.    ® Fig. 16-69 Mucous Membrane Pemphigoid. In this patient, the  ocular involvement has resulted in nearly complete scarring between  the conjunctival mucosa and the eyelids themselves, producing  blindness.    turn inward (entropion). This causes the eyelashes to rub  against the cornea and globe (trichiasis) (Fig. 16-68). The  scarring closes off the openings of the lacrimal glands as  well, and with the loss of tears, the eye becomes extremely  dry. The cornea then produces keratin as a protective mech-  anism; however, keratin is an opaque material, and blind-  ness ensues. End-stage ocular involvement may also be  characterized by adhesions between the upper and lower  eyelids themselves (Fig. 16-69).   Other mucosal sites may also be involved and cause  considerable difficulty for the patient. In females, the vaginal  mucosal lesions may cause considerable pain during attempts  at intercourse (dyspareunia).   Laryngeal lesions, which are fairly uncommon, may be  especially significant because of the possibility of airway  obstruction by the bullae that are formed. Patients who  experience a sudden change in vocalization or who have  difficulty breathing should undergo examination with    ® Fig. 16-71 Mucous Membrane Pemphigoid. Direct immunofluo-  rescence studies show a deposition of immunoreactants at the base-  ment membrane zone of the epithelium. (Courtesy of Dr. Ronald  Grimwood.)    Biopsy of perilesional mucosa shows a split between the  surface epithelium and the underlying connective tissue in  the region of the basement membrane (Fig. 16-70). A mild  chronic inflammatory cell infiltrate is present in the super-  ficial submucosa.   Direct immunofluorescence studies of perilesional  mucosa show a continuous linear band of immunoreactants  at the basement membrane zone in nearly 90% of affected  patients (Fig. 16-71). The immune deposits consist primar-  ily of IgG and C3, although IgA and IgM may also be  identified. One study has suggested that, when IgG and IgA  deposits are found in the same patient, the disease may be  more severe. All of these immunoreactants may play a role  in the pathogenesis of the subepithelial vesicle formation by  weakening the attachment of the basement membrane  through a variety of mechanisms, including complement  activation with recruitment of inflammatory cells, particu-  larly neutrophils.    Indirect immunofluorescence is positive in only 5% to  25% of these patients, indicating a relatively consistent lack  of readily detectable circulating autoantibodies. One type  of mucous membrane pemphigoid produces low levels of  circulating autoantibodies to epiligrin (laminin-5), a com-  ponent of the basement membrane. Antiepiligrin mucous  membrane pemphigoid seems to have more widespread  involvement, affecting oral, nasal, ocular, and laryngeal  mucosa, compared with other forms of mucous membrane  pemphigoid. In contrast, another group of investigators has  shown that pemphigoid patients with only oral mucosal  involvement have circulating autoantibodies to 06 integrin,  a component of the hemidesmosome.   For an accurate diagnosis, perilesional tissue—rather  than the ulcerated lesion itself—should be obtained. Often  the epithelium in the area of the lesion is so loosely attached  that it strips off as the clinician attempts to perform the  biopsy. Such tissue is not usually adequate for diagnostic  purposes because the interface between the epithelium and  connective tissue is no longer intact (although some inves-  tigators have shown positive immunofluorescence with this  tissue).   Other relatively rare conditions can mimic pemphigoid  histopathologically. These include linear IgA bullous der-  matosis, angina bullosa hemorrhagica, and epidermoly-  sis bullosa acquisita.    Linear IgA bullous dermatosis, as the name indicates, is  characterized by the linear deposition of only IgA along the  basement membrane zone. Even though some cases of  mucous membrane pemphigoid may have IgA antibodies,  linear IgA bullous dermatosis predominantly affects the skin  and, therefore, can usually be distinguished from mucous  membrane pemphigoid on a clinical basis.    Angina bullosa hemorrhagica is a rare, poorly characterized  oral mucosal disorder that exhibits variably painful,  blood-filled vesicles or bullae, usually affecting the soft  palate of middle-aged or older adults (Fig. 16-72). The  blisters typically rupture spontaneously and heal without  scarring. A subepithelial cleft is noted microscopically.  No hematologic or immunopathologic abnormalities have  been detected, and although the cause is unknown,  many patients have a history of trauma or corticosteroid  inhaler use.    Epidermolysis bullosa acquisita is an immunologically  mediated condition characterized by autoantibodies directed  against type VII collagen, the principal component of the  anchoring fibrils. The anchoring fibrils play an important  role in bonding the epithelium to the underlying connective  tissue. As a result, their immunologic destruction leads to  the formation of bullous lesions of the skin and mucosa  with minimal trauma. The disease was named epidermolysis    @ Fig. 16-72 Angina Bullosa Hemorrhagica. Hemorrhagic blisters  on the soft palate in a patient who regularly used a corticosteroid  inhaler. (Courtesy of Dr. Peter Lyu.)    bullosa acquisita (“acquisita” means “acquired”) because of  its clinical resemblance to the inherited condition, dystro-  phic epidermolysis bullosa. Unlike the inherited disorder,  epidermolysis bullosa acquisita typically affects middle-aged  or older adults.   Oral lesions are present in nearly 50% of the cases,  although such lesions are uncommon in the absence of  cutaneous lesions. To distinguish epidermolysis bullosa  acquisita from other immunobullous diseases with subepi-  thelial clefting, a special technique is performed. A sample  of the patient’s perilesional skin is incubated in a concen-  trated salt solution; this causes the epithelium to separate  from the connective tissue, forming an artificially induced  bulla. Immunohistochemical evaluation shows deposition  of IgG autoantibodies on the floor (connective tissue side)  of the bulla where type VII collagen resides. This finding is  in contrast to that of most forms of mucous membrane  pemphigoid, in which the autoantibodies are usually local-  ized to the roof of the induced blister.    Once the diagnosis of mucous membrane pemphigoid has  been established by light microscopy and direct immuno-  fluorescence, the patient should be referred to an ophthal-  mologist who is familiar with the ocular lesions of this  condition for a baseline examination of the conjunctivae.  This should be done whether or not the patient is experienc-  ing ocular complaints. In addition, if the patient is  experiencing symptoms at other anatomic sites, then the  appropriate specialist should be consulted.   Because this condition is characterized by heterogeneous  pathogenetic mechanisms, it is not surprising that treat-  ments advocated over the years have been varied. In fact,  there is no single good therapy for every patient; treatment  must be individualized, depending on lesional distribution,  disease activity, and therapeutic response. Perhaps as the    various forms of pemphigoid are better defined immuno-  pathologically, more specific, directed therapy can be  devised.    If only oral lesions are present, sometimes the disease can  be controlled with application of one of the more potent  topical corticosteroids to the lesions several times each day.  Once control is achieved, the applications can be discontin-  ued, although the lesions are certain to flare up again.  Sometimes alternate-day application prevents such exacer-  bations of disease activity.   Patients with only gingival lesions often benefit from  good oral hygiene measures, which can help to decrease the  severity of the lesions and reduce the amount of topical  corticosteroids required. As an additional aid in treating  gingival lesions, a flexible mouth guard may be fabricated  to use as a carrier for the corticosteroid medication.    If topical corticosteroids are unsuccessful, systemic treat-  ments are available. Dapsone, which is a sulfa drug deriva-  tive, can be used to treat patients with mild-to-moderate  involvement by mucous membrane pemphigoid. Systemic  treatment with dapsone typically has fewer serious side  effects when compared to systemic corticosteroid therapy,  for example.   Some centers report good results with dapsone, but  others observe that a minority of patients respond ade-  quately. Contraindications to its use include glucose-  6-phosphate dehydrogenase deficiency or allergy to sulfa  drugs.   Another alternative systemic therapy that may be used  for patients with less severe disease is tetracycline or mino-  cycline and niacinamide (nicotinamide). Systemic daily  divided doses of 0.5 to 2.0 g of each drug have been reported  (in open-label trials) to be effective in controlling mucous  membrane pemphigoid. Double-blind, placebo-controlled  studies on larger groups of patients should be done to  confirm this form of therapy, however.   For more severely affected patients with mucous  membrane pemphigoid, corticosteroids plus other  immunosuppressive/immune modulating agents, (such as,  rituximab, mycophenolate mofetil, or cyclophosphamide)  may be used. This type of aggressive treatment is often  indicated in the presence of advancing ocular disease, but  it must be realized that many of these patients are older and  may have preexisting medical conditions that may preclude  aggressive immune suppression. Some studies have sug-  gested that treatment with intravenous (IV) human immu-  noglobulin (which is very expensive) may be more effective  in managing ocular lesions of pemphigoid than systemic  corticosteroid therapy. Attempts at surgical correction of  any symblepharons that might have formed must be done  when the disease is under control or quiescent; otherwise,  the manipulation often induces an acute flare of the ocular  lesions.    Bullous pemphigoid is the most common of the autoim-  mune blistering conditions, occurring at an estimated  rate of ten cases per million population per year. The  disease is characterized by the production of autoantibodies  directed against components of the basement membrane.  In many respects, bullous pemphigoid resembles mucous  membrane pemphigoid, but most investigators note  that there are enough differences to consider these diseases  as distinct but related entities. One significant difference  is that the clinical course in patients with bullous pemphi-  goid is usually characterized by periods of remission fol-  lowed by relapse, whereas the course in patients with  mucous membrane pemphigoid is usually protracted and  progressive.    Bullous pemphigoid typically develops in older people;  most patients are between 75 and 80 years of age. No  sex or racial predilection is generally reported, although  one group of investigators noted that men are overrepre-  sented in this disease by a 2:1 margin when one corrects  for the skewing of the aging population toward the female  gender. Pruritus is often an early symptom. ‘This is followed  by the development of multiple, tense bullae on either  normal or erythematous skin (Fig. 16-73). These lesions  eventually rupture after several days, causing a superficial  crust to form. Eventually, healing takes place without  scarring.   Oral mucosal involvement is uncommon, with approxi-  mately 10% to 20% of patients being affected. The oral  lesions, like the skin lesions, begin as bullae, but they tend  to rupture sooner, probably as a result of the constant low-  grade trauma to which the oral mucosa is subjected. Large,  shallow ulcerations with smooth, distinct margins are  present after the bullae rupture (Fig. 16-74).    e Fig. 16-73 Bullous Pemphigoid. Cutaneous vesiculobullous  lesions of the heel. The bullae eventually rupture, leaving hemorrhagic  crusted areas.    ® Fig. 16-74 Bullous Pemphigoid. These oral lesions appear as  large, shallow ulcerations involving the soft palate.    Microscopic examination of tissue obtained from the  perilesional margin of a bulla shows separation of the epi-  thelium from the connective tissue at the basement mem-  brane zone, resulting in a subepithelial separation. Modest  numbers of both acute and chronic inflammatory cells are  typically seen in the lesional area, and the presence of eosin-  ophils within the bulla itself is characteristic.   Direct immunofluorescence studies show a continuous  linear band of immunoreactants, usually IgG and C3, local-  ized to the basement membrane zone in 90% to 100% of  affected patients. These antibodies bind to proteins associ-  ated with hemidesmosomes, structures that bind the basal  cell layer of the epithelium to the basement membrane and  the underlying connective tissue. These proteins have been  designated as bullous pemphigoid antigens (BP180 and  BP230), and immunoelectron microscopy has demon-  strated the localization of BP180 to the upper portion of  the lamina lucida of the basement membrane.   In addition to the tissue-bound autoantibodies, 50% to  90% of the patients also have circulating autoantibodies in  the serum, producing an indirect immunofluorescent  pattern that is identical to that of the direct immunofluo-  rescence. Unlike pemphigus vulgaris, the antibody titers  seen in bullous pemphigoid do not appear to correlate with  disease activity. The antibodies alone do not appear to be  capable of inducing bullae in this disease. Instead, binding  of the antibodies to the basement membrane initiates the  complement cascade, which in turn results in degranulation  of mast cells, with recruitment of neutrophils and eosino-  phils to the area. The damage to the basement membrane  is thought to be mediated by elastases and matrix metallo-  proteinases released by these inflammatory cells.    Treatment of patients with mild or localized bullous pem-  phigoid consists of application of one of the stronger topical  corticosteroid preparations. Management of the patient  with moderate-to-severe, widespread bullous pemphigoid    consists of systemic immunosuppressive therapy. Moderate  daily doses of systemic prednisone usually control the con-  dition, after which alternate-day therapy may be given to  reduce the risk of corticosteroid complications. If the lesions  do not respond to prednisone alone, then another immu-  nosuppressive agent (such as, azathioprine, methotrexate, or  mycophenolate mofetil) may be added to the regimen.  Dapsone, a sulfa derivative, may be used as an alternative  therapeutic agent, and tetracycline and niacinamide therapy  is reported to be effective for some patients. The more  severe, resistant cases require prednisone combined with  cyclophosphamide; however, this regimen has the potential  for significant side effects.   The prognosis is generally good with respect to control  of the skin lesions, with many patients experiencing remis-  sion. Recent reports based on a relatively large series of  bullous pemphigoid patients have suggested that problems  frequently develop due to the immunosuppressive therapy  used in this older adult population. Mortality rates that are  three times that of an age- and sex-matched control popula-  tion may be seen, with approximately 20% of patients  expiring 1 year after diagnosis.    Erythema multiforme is a blistering, ulcerative mucocuta-  neous condition of uncertain etiopathogenesis. This is prob-  ably an immunologically mediated process, although the  cause is poorly understood. In about 50% of the cases, the  clinician can identify an apparent precipitating cause,  usually a preceding infection, such as herpes simplex  ot Mycoplasma pneumoniae, or less commonly, exposure  to any one of a variety of drugs and medications, particu-  larly antibiotics or analgesics. These agents may trigger  the immunologic derangement that produces the disease.  Sophisticated techniques in molecular biology have demon-  strated the presence of herpes simplex DNA in patients with  recurrent erythema multiforme, thus supporting the concept  of an immunologic precipitating event. Interestingly, direct  and indirect immunofluorescence studies are nonspecific  and are not really very useful diagnostically except to rule  out other vesiculobullous diseases.   For many years it was thought that erythema multiforme  exhibited a spectrum of severity, ranging from erythema  multiforme minor through erythema multiforme major  (traditionally thought to be synonymous with Stevens-  Johnson syndrome) and toxic epidermal necrolysis (Lyell  disease). Most authorities currently feel that erythema mul-  tiforme minor and major may represent a distinctly differ-  ent process from the latter two conditions. Therefore,  Stevens-Johnson syndrome and toxic epidermal necrolysis  will be discussed separately in the next section.    Erythema multiforme typically has an acute onset and  usually affects young adults in their 20s or 30s, with a slight    @ Fig. 16-75 Erythema Multiforme. The concentric erythematous  pattern of the cutaneous lesions on the fingers resembles a target or  bull’s-eye.    female predilection in current series of cases. Prodromal  symptoms are often present and include fever, malaise,  headache, cough, and sore throat, occurring approximately  1 week before onset. The condition may show varying  degrees of severity in affected patients. Milder cases, known  as erythema multiforme minor, usually begin with the  development of slightly elevated, round, dusky-red patches  on the skin of the extremities. These lesions may have a  variety of appearances, however (multiforme means many  forms). Some of these skin lesions develop features that are  highly characteristic for the disease. These lesions appear as  concentric circular erythematous rings resembling a target  or bull’s-eye (target lesions) (Fig. 16-75). In more severe  cases, these may evolve into bullae with necrotic centers.   The oral cavity is the most frequently involved mucosal  site, although the conjunctival, genitourinary, and respira-  tory mucosa also may be affected. Involvement of extraoral  mucosal areas is usually associated with the more severe  form of this condition, erythema multiforme major.   The frequency of oral involvement is difficult to deter-  mine and is reported to range from 25% to 70%. Discrep-  ancies in the prevalence may be due to referral patterns or  degree of scrutiny of the oral mucosa. The oral lesions begin  as erythematous patches that undergo epithelial necrosis  and evolve into large, shallow erosions and ulcerations with  irregular borders (Fig. 16-76). Hemorrhagic crusting of the  vermilion zone of the lips is common (Fig. 16-77). These  oral lesions, like the skin lesions, emerge quickly and are  uncomfortable. Sometimes patients are dehydrated because  they are unable to ingest liquids as a result of mouth pain.  The ulcerations often have a diffuse distribution. The lips,  labial mucosa, buccal mucosa, tongue, floor of the mouth,  and soft palate are the most common sites of involvement.  Usually, the gingivae and hard palate are relatively spared.    A diagnosis of erythema multiforme major can be made if  two or more mucosal sites are affected in conjunction with  widespread skin lesions. In most cases the oral mucosa is    © Fig. 16-76 Erythema Multiforme. Focal hemorrhagic crusting of  the lips is seen in conjunction with diffuse shallow ulcerations and  erosions involving this patient’s mandibular labial mucosa.    ® Fig. 16-77 Erythema Multiforme. Same patient as Figure 16-76.  Diffuse shallow ulcerations of varying sizes are noted on the right  buccal mucosa. The patient had finished a course of sulfamethoxazole  and trimethoprim for a urinary tract infection a few days before the  onset of the lesions.    involved in addition to either the ocular (Fig. 16-78) or  genital mucosae. With severe ocular involvement, scarring  (symblepharon formation) may occur, similar to that in  cicatricial pemphigoid (see page 719).    Histopathologic examination of the perilesional mucosa in  erythema multiforme reveals a pattern that is characteristic  but not pathognomonic. Subepithelial or intraepithelial  vesiculation may be seen in association with necrotic basal  keratinocytes (Fig. 16-79). A mixed inflammatory infiltrate  is present, consisting of lymphocytes, neutrophils, and often  eosinophils. Sometimes these cells are arranged in a perivas-  cular orientation (Fig. 16-80). Because the immunopatho-  logic features are also nonspecific, the diagnosis is often  based on the clinical presentation and the exclusion of other  vesiculobullous disorders.    @ Fig. 16-78 Erythema Multiforme Major. While involvement of  other mucosal surfaces is more frequently seen with Stevens-Johnson  syndrome, this patient’s condition was preceded by oral herpetic infec-  tion. This finding, combined with his cutaneous manifestations, resulted  in a diagnosis of erythema multiforme major, in this case causing the  severe conjunctivitis depicted in this photograph.    ® Fig. 16-79 Erythema Multiforme. This medium-power photomi-  crograph shows inflammation and intraepithelial vesicle formation in  the basilar portion of the epithelium. Numerous necrotic and apoptotic  eosinophilic keratinocytes are present in the blister area.    @ Fig. 16-80 Erythema Multiforme. This medium-power photomi-  crograph shows the perivascular inflammatory infiltrate, typically seen  in erythema multiforme.    Management of erythema multiforme, in many respects,  remains controversial. In the past, the use of systemic or  topical corticosteroids was often advocated, especially in the  early stages of the disease. Although there is little good  clinical evidence from controlled trials that such treatment  is beneficial, this treatment is typically used at most centers.  If a causative drug is identified or suspected, then it should  be discontinued immediately.   If the patient is dehydrated as a result of an inability to  eat because of oral pain, then IV rehydration may be neces-  sary along with topical anesthetic agents to decrease  discomfort.   Even though the disease is self-limiting, usually lasting 2  to 6 weeks, about 20% of patients experience recurrent  episodes, usually in the spring and autumn. If recurrent  episodes of erythema multiforme are a problem, then an  initiating factor, such as recurrent herpesvirus infection or  drug exposure, should be sought. If disease is triggered by  herpes simplex, then continuous oral acyclovir or valacyclo-  vir therapy can prevent recurrences. Very infrequently  patients may have continuous lesions of erythema multi-  forme. In most cases erythema multiforme is not life-  threatening except in its most severe form.    In the past, many dermatologists considered Stevens-  Johnson syndrome and toxic epidermal necrolysis to repre-  sent the most severe end of the erythema multiforme  spectrum. As careful documentation of the clinical features  of these uncommon diseases was compiled, it became  evident that there were subtle, but distinct, differences  between these two conditions. Although the inciting event  in erythema multiforme is usually a herpesvirus infection,  Stevens-Johnson syndrome and toxic epidermal necrolysis  are almost always triggered by drug exposure, with more  than 200 different medications having been implicated.  Recent studies have shown that the damage to the epithe-  lium is due to increased apoptosis of the epithelial cells, and  several mechanisms have been postulated to account for this  phenomenon.    The difference between Stevens-Johnson syndrome and  toxic epidermal necrolysis is the degree of skin involvement,  with Stevens-Johnson syndrome having less than 10% of  the body surface affected by lesions, and toxic epidermal  necrolysis having more than 30% involvement. These severe  blistering diseases are rare. Stevens-Johnson syndrome  occurs at an average rate of one to seven cases per million  population per year, whereas toxic epidermal necrolysis  occurs at a rate of about one case per million per year. In    © Fig. 16-81 Stevens-Johnson Syndrome. Genital ulcerations,  demonstrated in this patient by the involvement of the glans penis,  may be a component of Stevens-Johnson syndrome, which tends to  be more severe than erythema multiforme major.    ® Fig. 16-82 Toxic Epidermal Necrolysis. This serious mucocuta-  neous disorder is characterized by diffuse bullous skin lesions. (Cour-  tesy of Dr. Peter Larsen.)    contrast to Stevens-Johnson syndrome, which is usually  seen in younger patients, toxic epidermal necrolysis tends  to occur in people over 60 years of age. A female predilec-  tion is observed.   These patients usually have flu-like prodromal signs and  symptoms, including fever, malaise, sore throat, headache,  and loss of appetite. Within a few days, skin lesions begin  to develop, but unlike erythema multiforme, the cutaneous  lesions of Stevens-Johnson syndrome and toxic epidermal  necrolysis initially appear on the trunk, presenting as ery-  thematous macules (completely flat). Within 1 to 14 days,  however, sloughing of the skin and flaccid bullae develop.  Virtually all of these patients will have mucosal sites of  involvement (Fig. 16-81), particularly the oral mucosa.  Diffuse sloughing ofa significant proportion of the skin and  mucosal surfaces makes it appear as if the patient had been  badly scalded (Figs. 16-82 and 16-83). If the patient sur-  vives, then the cutaneous process resolves in 3 to 5 weeks;  however, oral lesions may take longer to heal, and signifi-  cant residual ocular damage is evident in half of the patients.    ® Fig. 16-83 Toxic Epidermal Necrolysis. The desquamation of the  skin of the foot is characteristic of the diffuse sloughing cutaneous  lesions. (Courtesy of Dr. Peter Larsen.)    Biopsy of a developing bulla of Stevens-Johnson syndrome  or toxic epidermal necrolysis typically shows a subepithelial  blister that is characterized by degenerating, necrotic basal  keratinocytes. The underlying connective tissue usually  supports a rather sparse population of chronic inflamma-  tory cells.    One of the most important aspects in managing patients  with Stevens-Johnson syndrome and toxic epidermal  necrolysis is identifying and immediately discontinuing any  drug that might be initiating the condition. Because the  lesions of toxic epidermal necrolysis are analogous to those  suffered by burn patients, management of these patients in  the burn unit of the hospital is recommended. Corticoste-  roids should be avoided in the management of toxic epider-  mal necrolysis because some investigators have found that  such drugs may be detrimental. IV administration of pooled  human immunoglobulins has been shown in several open-  label trials to produce remarkable resolution of toxic epi-  dermal necrolysis, presumably because of blockade of Fas  ligand, which is believed to play a role in inducing epithelial  cell apoptosis. The mortality rate in patients with toxic  epidermal necrolysis historically has been approximately  25% to 30%; the rate in those with Stevens-Johnson syn-  drome is 1% to 5%.    ¢ ERYTHEMA MIGRANS (GEOGRAPHIC  TONGUE; BENIGN MIGRATORY  GLOSSITIS; WANDERING RASH OF THE  TONGUE; ERYTHEMA AREATA MIGRANS;  STOMATITIS AREATA MIGRANS)    Erythema migrans is a common benign condition that  primarily affects the tongue. It is often detected on routine    examination of the oral mucosa. The lesion occurs in 1%  to 3% of the population. Some epidemiologic studies have  shown that females are affected more frequently than males  by a 2:1 ratio, whereas other series do not identify a gender  predilection. Patients occasionally may consult a health care  professional if they happen to notice the unusual appear-  ance of their tongue or if the lingual mucosa becomes sensi-  tive to hot or spicy foods as a result of the process.   Even though erythema migrans has been documented  for many years, the etiopathogenesis is still unknown. Some  investigators have suggested that erythema migrans occurs  with increased frequency in atopic individuals; however,  one large epidemiologic study in the United States found  no statistically significant association between erythema  migrans and a variety of conditions that had previously been  postulated either to cause or influence this process. Ery-  thema migrans was not seen as frequently in cigarette  smokers, while there seemed to be no significant differences  in frequency related to age, sex, oral contraceptive use, pres-  ence of allergies, diabetes mellitus, or psychological or der-  matologic conditions. A similar study in Turkey essentially  agreed with these findings, with the exception of an associa-  tion with a history of allergy or atopy.    The characteristic lesions of erythema migrans are seen on  the anterior two-thirds of the dorsal tongue mucosa. They  appear as multiple, well-demarcated zones of erythema  (Figs. 16-84 and 16-85), concentrated at the tip and lateral  borders of the tongue. This erythema is due to atrophy of  the filiform papillae, and these atrophic areas are typically  surrounded at least partially by a slightly elevated, yellow-  white, serpentine or scalloped border (Fig. 16-86). The  patient who is aware of the process is often able to describe    e Fig. 16-84 Erythema Migrans. The erythematous,  well-  demarcated areas of papillary atrophy are characteristic of erythema  migrans affecting the tongue (benign migratory glossitis). Note the  asymmetrical distribution and the tendency to involve the lateral  aspects of the tongue.    the lesions as appearing quickly in one area, healing within  a few days or weeks, and then developing in a very different  area. Frequently, the lesion begins as a small white patch,  which then develops a central erythematous atrophic zone  and enlarges centrifugally. Approximately one-third of  patients with fissured tongue (see page 11) are affected  with erythema migrans as well. Some patients may have  only a solitary lesion, but this is uncommon. ‘The lesions  are usually asymptomatic, although a burning sensation or  sensitivity to hot or spicy foods may be noted when the  lesions are active. Only rarely is the burning sensation more  constant and severe.   Very infrequently, erythema migrans may occur on oral  mucosal sites other than the tongue. In these instances, the  tongue is almost always affected; however, other lesions  develop on the buccal mucosa, on the labial mucosa, and  (less frequently) on the soft palate or floor of the mouth  (Figs. 16-87 and 16-88). These lesions typically produce no  symptoms and can be identified by a yellow-white serpen-  tine or scalloped border that surrounds an erythematous  zone. These features should prevent confusion with such  conditions as candidiasis or erythroplakia.    © Fig. 16-85 Erythema Migrans. Lingual mucosa of a different  patient than the one in Fig. 16-84. The lateral distribution of the lesions  is shown.    ® Fig. 16-86 Erythema Migrans. Striking involvement of the dorsal  and lateral surfaces of the tongue.    . P eee 4  @ Fig. 16-88 Erythema Migrans. These palatal lesions show well-  demarcated erythematous areas surrounded by a white border, similar  to the process involving the tongue.    If a biopsy specimen of the peripheral region of erythema  migrans is examined, a characteristic histopathologic pattern  is observed. Hyperparakeratosis, spongiosis, acanthosis, and  elongation of the epithelial rete ridges are seen (Fig. 16-89).  In addition, collections of neutrophils (Munro abscesses)  are observed within the epithelium (Fig. 16-90); lympho-  cytes and neutrophils involve the lamina propria. The  intense neutrophilic infiltrate may be responsible for the  destruction of the superficial portion of the epithelium, thus  producing an atrophic, reddened mucosa as the lesion pro-  gresses. Because these histopathologic features are reminis-  cent of psoriasis, this is called a psoriasiform mucositis.  Despite the apparent lack of association between dermato-  logic conditions and erythema migrans in some reports, at  least one case-control study of psoriatic patients showed  that erythema migrans occurred at a rate of about 10%;  only 2.5% of an age-matched and sex-matched population  were affected. A Brazilian study determined that both  patients with psoriasis and those with benign migratory  glossitis were more likely to have the same human leukocyte  antigen (HLA) group, namely HLA-Cw6. Whether these  findings mean that erythema migrans represents oral    Migrans. This low-power photomicrograph  shows the elongation of the rete ridges with parakeratosis and neu-  trophilic infiltration. Such features are also common in psoriasis, which  explains why this is known as a psoriasiform mucositis.    graph shows collections of neutrophils in the superficial spinous layer  of the epithelium.    psoriasis or that patients with psoriasis are just more sus-  ceptible to erythema migrans is open to debate.    Generally no treatment is indicated for patients with ery-  thema migrans. Reassuring the patient that the condition is  completely benign is often all that is necessary. Infrequently,  patients may complain of tenderness or a burning sensation  that is so severe that it disrupts their lifestyle. In such cases,  topical corticosteroids, such as fluocinonide or betametha-  sone gel, may provide relief when applied as a thin film  several times a day to the lesional areas.    Reactive arthritis represents a group of uncommon diseases  that most likely have an immunologically mediated cause.    Current evidence suggests that these disorders may be trig-  gered by any one of several infectious agents in a genetically  susceptible person. In some instances, the arthritis will be  accompanied by mucocutaneous findings, including oral  lesions. A classic triad of signs has been described:  1. Nongonococcal urethritis  2. Arthritis  3. Conjunctivitis   However, most patients do not exhibit all three of  these signs. Although reactive arthritis with a mucocu-  taneous component is also known as Reiter syndrome,  some authors have advocated removing the Reiter eponym  because of Hans Reiter’s Nazi criminal activities during  World War H, and he was not the first to describe this  syndrome.   It is interesting that reactive arthritis has been reported  with some frequency in patients infected with the human  immunodeficiency virus (HIV).    Reactive arthritis is particularly prevalent in young adult  men. In some series, a male-to-female ratio of up to 9:1  has been reported. The majority (60% to 80%) of these  patients are positive for HLA-B27, a haplotype present in  only 10% of the population. The syndrome usually develops  1 to 4 weeks after an episode of dysentery or venereal  disease; in fact, two French physicians published a descrip-  tion of this entity affecting four postdysenteric soldiers 1  week before Reiter's paper appeared.   Urethritis is often the first sign and is seen in both  affected males and females. Females may also have inflam-  mation of the uterine cervix. Conjunctivitis usually appears  concurrently with the urethritis, and after several days,  arthritis ensues. The arthritis usually affects the joints of  the lower extremities, although TMJ involvement has  been identified in one-third of these patients, typically as  erosion of the condylar head. Skin lesions often take the  form of a characteristic lesion of the glans penis (balanitis  circinata). These lesions develop in about 20% to 30%  of patients with reactive arthritis, and they appear as  well-circumscribed erythematous erosions with a scalloped,  whitish linear boundary.   The oral lesions, which occur in slightly less than 20%  of patients with this disorder, are described in various ways.  Some reports mention painless erythematous papules dis-  tributed on the buccal mucosa and palate; other reports  describe shallow, painless ulcers that affect the tongue,  buccal mucosa, palate, and gingiva. Some authors have even  implied that geographic tongue may be a component of  reactive arthritis, probably because geographic tongue bears  a superficial resemblance to the lesions of balanitis  circinata.   The American Rheumatism Association has defined reac-  tive arthritis based on the clinical findings of a peripheral  arthritis that lasts longer than 1 month in conjunction with  urethritis, cervicitis, or both.    The histopathologic findings of the cutaneous lesions in  patients with reactive arthritis are frequently similar to those  found in patients with psoriasis, particularly with respect  to the presence of microabscesses within the superficial  layers of the surface epithelium. Other features in common  with psoriasis include hyperparakeratosis with elongated,  thin rete ridges.    Some patients with reactive arthritis experience spontane-  ous resolution of their disease after 3 to 12 months, but  many others have chronic symptoms that may wax and  wane. Treatment may not be necessary for the milder cases.  NSAIDs are initially used for managing arthritis, and  sulfasalazine may be helpful in resolving cases that do  not respond. Immunosuppressive or immune modulating  agents, including corticosteroids, azathioprine, etanercept,  and methotrexate, are reserved for the most resistant cases  if they are not associated with HIV infection.   Physical therapy probably helps to reduce joint fibrosis  associated with arthritis. About 15% to 20% of patients  with this disorder have severe disability, usually from  arthritis.    Lichen planus is a relatively common, chronic dermato-  logic disease that often affects the oral mucosa. The strange  name of the condition was provided by the British physician  Erasmus Wilson, who first described it in 1869. Lichens are  primitive plants composed of symbiotic algae and fungi.  The term planus is Latin for flat. Wilson probably thought  that the skin lesions looked similar enough to the lichens  growing on rocks to merit this designation. Even though  the term /ichen planus suggests a flat, fungal condition,  current evidence indicates that this is an immunologically  mediated mucocutaneous disorder.   A variety of medications may induce lesions that can  appear clinically very similar to the idiopathic form of the  condition; however, the term lichenoid mucositis (or  lichenoid dermatitis, depending on the site involved) is  probably a better name for the drug-related alterations (see  page 317). Similarly, foreign material that becomes inadver-  tently embedded in the gingiva may elicit a host response  that is termed lichenoid foreign body gingivitis (see page  146). Reports of hepatitis C infection associated with oral  lichen planus occasionally have appeared in the literature,  usually from the Mediterranean countries, but this does not  appear to be a significant association in the United States  or Great Britain. More recent, carefully controlled epide-  miologic studies do not appear to support an association of  oral lichen planus with hepatitis C. However, genetic influ-  ences presumably may have an effect on the expression of  lichen planus in select populations.    The relationship of stress or anxiety to the development  of lichen planus is controversial, and most cited cases appear  to be anecdotal or lack appropriate controls. Those studies  that have applied psychologic questionnaires often find  increased levels of anxiety in these patients; however, many  patients who have been told that they have lichen planus  are aware that anxiety has been linked to the disorder.  Whether this awareness may influence the manner in which  they answer the psychologic questionnaires could be  debated. In one study that used psychologic questionnaires  to attempt to resolve this question, patients with oral lichen  planus had no greater degree of stress in their lives than did  age-matched and sex-matched control patients. It might be  that stress has no bearing on the pathogenesis of lichen  planus; however, an alternative explanation might be that  those patients who have lichen planus simply respond in  this fashion to levels of stress that do not induce lesions in  other people.    Most patients with lichen planus are middle-aged adults. It  is rare for children to be affected. Women predominate in  most series of cases, usually by a 3:2 ratio over men.  Approximately 1% of the population may have cutaneous  lichen planus. The prevalence of oral lichen planus is  between 0.1% and 2.2%.   The skin lesions of lichen planus have been classically  described as purple, pruritic, polygonal papules (Fig. 16-91).  These usually affect the flexor surfaces of the extremities.  Excoriations may not be visible, despite the fact that the  lesions itch, because it hurts the patient when he or she  scratches them.   Careful examination of the surface of the skin papules  reveals a fine, lacelike network of white lines (Wickham  striae) (Fig. 16-92). Other sites of extraoral involvement  include the glans penis, the vulvar mucosa, and the nails.  Essentially there are two forms of oral lesions: reticular and  erosive.    ® Fig. 16-91 Lichen Planus. The cutaneous lesions on the wrist  appear as purple, polygonal papules.    Reticular lichen planus is much more common than the  erosive form, but the erosive form predominates in several  studies. This is probably because of referral bias (because the  erosive form is symptomatic and, therefore, the patient is  more likely to be referred to an academic center for evalu-  ation). The reticular form usually causes no symptoms and  involves the posterior buccal mucosa bilaterally (Fig. 16-93).  Post-inflammatory melanosis occasionally accompanies the  reticular striae, particularly in persons of color (Fig. 16-94).  Other oral mucosal surfaces may also be involved concur-  rently, such as the lateral and dorsal tongue, the gingivae,  the palate, and vermilion border (Fig. 16-95).   Reticular lichen planus is thus named because of its  characteristic pattern of interlacing white lines (also referred  to as Wickham striae); however, the white lesions may appear  as papules in some instances. These lesions are typically not  static but wax and wane over weeks or months (Fig. 16-96).  The reticular pattern may not be as evident in some sites,    ® Fig. 16-92 Lichen Planus. Closer view of a skin lesion of lichen  planus. Careful examination shows a network of fine white lines  (Wickham striae) on the surface of the papules.    @ Fig. 16-93 Lichen Planus. The interlacing white lines and papules  are typical of reticular lichen planus involving the buccal mucosa, the  most common site of oral involvement.    @ Fig. 16-94 Lichen Planus. In persons of color who develop lichen  planus, it is not unusual to see patchy areas of reactive (benign) mela-  nosis develop in the lesions, presumably due to stimulation of the  melanocytes in this area by the inflammatory cells that cause this  condition.    Fis8 at  @ Fig. 16-95 Lichen Planus. Reticular lesions of the lower lip  vermilion.    such as the dorsal tongue, where the lesions appear more as  keratotic plaques with atrophy of the papillae (Fig. 16-97).  In addition, superficial mucoceles may develop within, or  adjacent to, mucosal areas that are involved by lichen  planus.    Erosive lichen planus, although not as common as the retic-  ular form, is more significant for the patient because the  lesions are usually symptomatic. Clinically, there are atro-  phic, erythematous areas with central ulceration of varying  degrees. The periphery of the atrophic regions is usually  bordered by fine, white radiating striae (Figs. 16-98 and  16-99). Sometimes the atrophy and ulceration are confined  to the gingival mucosa, producing the reaction pattern  called desquamative gingivitis (see page 148) (Fig. 16-100).  In such cases, biopsy specimens should be obtained for light  microscopic and immunofluorescent studies of perilesional  tissue, because mucous membrane pemphigoid (see page  718) and pemphigus vulgaris (see page 712) may appear in  a similar fashion.   If the erosive component is severe, epithelial separation  from the underlying connective tissue may occur. This  results in the relatively rare presentation of bullous lichen  planus.    The histopathologic features of lichen planus are character-  istic but may not be specific, because other conditions,  such as lichenoid drug reaction, lichenoid amalgam reac-  tion, oral graft-versus-host disease (GVHD), lupus ery-  thematosus (LE), chronic ulcerative stomatitis, and oral  mucosal cinnamon reaction may also show a similar his-  topathologic pattern. Varying degrees of orthokeratosis and  parakeratosis may be present on the surface of the epithe-  lium, depending on whether the biopsy specimen is taken  from an erosive or reticular lesion.    ® Fig. 16-96 Lichen Planus. A, A middle-aged woman with mild reticular lichen planus of the left buccal  mucosa. B, Same patient 2 weeks later, showing exacerbation of the lesions. Such waxing and waning  is characteristic of lichen planus.    @ Fig. 16-97 Lichen Planus. With involvement of the dorsal tongue  by reticular lichen planus, the characteristic interlacing striae seen in  the buccal mucosal lesions are usually not present. Instead, smooth  white plaques are typically observed replacing the normal papillary  surface of the tongue.    =  ® Fig. 16-98 Lichen Planus. Ulceration of the buccal mucosa shows  peripheral radiating keratotic striae, characteristic of oral erosive lichen  planus.    The thickness of the spinous layer can also vary. The rete  tidges may be absent or hyperplastic, but they classically  have a pointed or “saw-toothed” shape (Fig. 16-101).   Destruction of the basal cell layer of the epithelium  (hydropic degeneration) is also evident. This is accompa-  nied by an intense, bandlike infiltrate of predominantly T  lymphocytes immediately subjacent to the epithelium (Fig.  16-102). Degenerating keratinocytes may be seen in the  area of the epithelium and connective tissue interface and  have been termed colloid, cytoid, hyaline, or Civatte  bodies. No significant degree of epithelial atypia is expected  in oral lichen planus, although lesions having a superim-  posed candidal infection may appear worrisome. These  should be reevaluated histopathologically after the candidal  infection is treated. On occasion, the chronic inflammatory  host response to the atypical cells of epithelial dysplasia  can appear virtually indistinguishable histopathologically  from lichen planus, particularly in milder cases of epithelial  dysplasia. Such ambiguity may contribute to the contro-  versy related to the malignant transformation potential of  lichen planus.   The immunopathologic features of lichen planus are  nonspecific. Most lesions show the deposition of a shaggy  band of fibrinogen at the basement membrane zone.    The diagnosis of reticular lichen planus can often be made  based on the clinical findings alone. The interlacing white  striae appearing bilaterally on the posterior buccal mucosa  are virtually pathognomonic. Difficulties in diagnosis may  arise if candidiasis is superimposed on the lesions because  the organism may alter the characteristic reticular pattern  of the lichen planus (Fig. 16-103).   Erosive lichen planus is sometimes more challenging to  diagnose (based on clinical features alone) than the reticular  form. If the typical radiating white striae and erythematous,    ® Fig. 16-99 Lichen Planus. A, The dorsal surface of the tongue shows extensive ulceration caused  by erosive lichen planus. Note the fine white streaks at the periphery of the ulcerations. B, Same patient  after systemic corticosteroid therapy. Much of the mucosa has reepithelialized, with only focal ulcerations    ® Fig. 16-100 Lichen Planus. Erosive lichen planus often appears  as a desquamative gingivitis, producing gingival erythema and  tenderness.    atrophic mucosa are present at the periphery of well-  demarcated ulcerations on the posterior buccal mucosa  bilaterally, then the diagnosis can sometimes be rendered  without the support of histopathologic findings. However,  a biopsy, often with direct immunofluorescence studies,  may be necessary to rule out other ulcerative or erosive  diseases, such as lupus erythematosus or chronic ulcerative  stomatitis.   Specimens of isolated erosive lichenoid lesions, particu-  larly those of the soft palate, the lateral and ventral tongue,  or the floor of the mouth, should be obtained for biopsy to  rule out premalignant changes or malignancy. Another con-  dition that may mimic an isolated lesion of lichen planus,  both clinically and histopathologically, is a lichenoid reac-  tion to dental amalgam (see page 324).    Reticular lichen planus typically produces no symptoms,  and no treatment is needed. Occasionally, affected patients    tosis, saw-toothed rete ridges, and a bandlike infiltrate of lymphocytes immediately subjacent to the  epithelium. B, Higher-power view showing migration of lymphocytes into the lower epithelium with inter-   basal cell layer and no inflammation. B, High-power photomicrograph of lichen planus showing degenera-  tion of the basal epithelial layer and an intense lymphocytic infiltrate in the superficial lamina propria.    ® Fig. 16-103 Lichen Planus. A, These relatively nondescript white lesions affected the buccal mucosa  of a patient who had complained of a burning sensation. Histopathologic evaluation of the lesion showed  a lichenoid mucositis with superimposed candidiasis. B, Same patient 2 weeks after antifungal therapy.  Once the mucosal reaction to the candidal organism was eliminated, the characteristic white striae of    may have superimposed candidiasis, in which case they may  complain of a burning sensation of the oral mucosa. Anti-  fungal therapy is necessary in such a case. Some investiga-  tors recommend annual reevaluation of the reticular lesions  of oral lichen planus.   Erosive lichen planus is often bothersome because of  the open sores in the mouth. Because it is an immunologi-  cally mediated condition, corticosteroids are recommended.  The lesions respond to systemic corticosteroids, but such  drastic therapy is usually not necessary. One of the stronger  topical corticosteroids (e.g., fluocinonide, betamethasone,  or clobetasol gel) applied as a thin film several times per day  to the most symptomatic areas is usually sufficient to induce  healing within 1 or 2 weeks. The patient should be warned  that the condition will undoubtedly flare up again, in which  case the corticosteroids should be reapplied. In addition, the  possibility of iatrogenic candidiasis associated with cortico-  steroid use should be monitored (Fig. 16-104). Some inves-  tigators have recommended compounding corticosteroid  ointments with an adhesive methylcellulose base, but patient  compliance may be reduced because this material is difficult  to apply. Although the use of agents (such as, topical reti-  noids, tacrolimus, mycophenolate mofetil, or cyclosporine)  has occasionally been advocated for recalcitrant cases of  erosive lichen planus, reports of their efficacy have usually  been limited to small series of cases or have been contradic-  tory. Furthermore, their side effects can be significant, and  in the case of tacrolimus or cyclosporine, the cost of the  drug may be prohibitive. Some investigators suggest that  patients with oral erosive lichen planus be evaluated every  3 to 6 months, particularly if the lesions are not typical.   The question of the malignant potential of lichen planus,  particularly the erosive form, is yet to be resolved. Most  cases of reported malignant transformation are rather poorly  documented. Some of these reported cases may not have  been true lichen planus, but rather they may have actually  been dysplastic leukoplakias with a secondary lichenoid    inflammatory infiltrate that mimicked lichen planus  (“lichenoid dysplasia’). In addition, the argument can be  made that because both lichen planus and squamous cell  carcinoma are not rare, some people may have both prob-  lems simultaneously, and the two processes may be unrelated  to one another. Conversely, some investigators say that the  atrophic epithelium of lichen planus may be more suscep-  tible to the action of carcinogens, resulting in an increased  risk of malignant transformation. Two studies have exam-  ined the molecular characteristics of classic reticular lichen  planus, comparing the loss of heterozygosity at purported  tumor suppressor gene loci in these lesions with that of  varying grades of oral epithelial dysplasia, squamous cell  carcinoma, normal oral mucosa, and oral reactive lesions.  The molecular profile of oral lichen planus more closely  resembled that of normal or reactive oral mucosa, a finding  that provides less support for the concept of lichen planus  being precancerous. Another study evaluated the malignant  transformation rate of typical oral lichen planus compared  with oral “lichenoid” lesions. The lichenoid lesions had some  features of lichen planus, but were not completely represen-  tative, either clinically or histopathologically, of that disease.  These investigators found that there was no transformation  of characteristic lichen planus, although several of the  “lichenoid” lesions developed into squamous cell carcinoma.  Additional prospective clinical studies with strict clinical  and histopathologic criteria for the definition of oral lichen  planus will need to be performed to resolve this question.  If the potential for malignant transformation exists, then it  appears to be small. Most of the reported cases have been  confined to patients with either the erosive or so-called  plaque-type form of lichen planus.    Chronic ulcerative stomatitis is another immune-mediated  disorder that affects the oral mucosa. This condition was    @ Fig. 16-104 Lichen Planus. A, This patient was diagnosed with  erosive lichen planus affecting the buccal mucosa and was treated  with topical corticosteroids. B, Same patient 2 weeks later. The  creamy-white plaques of pseudomembranous candidiasis have devel-  oped as a result of the corticosteroid therapy. C, Same patient after  antifungal therapy. At this point, he was asymptomatic.    initially described in 1989, and slightly more than 40 cases  have been reported. Although the precise pathogenetic  mechanisms are unknown, these patients develop autoanti-  bodies against a 70-kD nuclear protein, ANp63a, an  isoform of p63, and in vitro studies suggest that these anti-  bodies play a role in development of this disease by inter-  rupting the normal maintenance of the epithelium/  connective tissue interface.   The prevalence of this disease may be more common  than is realized. Because of its clinical similarity to erosive    @ Fig. 16-105 Chronic Ulcerative Stomatitis. A, Gingival lesions  having a “desquamative gingivitis” presentation, requiring biopsy with  direct immunofluorescence studies for diagnosis. B, Buccal mucosal  involvement. The lesions appear somewhat lichenoid, although classic  Wickham striae are not evident.    lichen planus, it is possible that only a clinical diagnosis is  made when an affected patient is encountered, and a biopsy  is not performed. Even if a biopsy is done, the tissue is often  submitted for routine light microscopy alone, and the direct  immunofluorescence studies that are required for its diag-  nosis are not ordered. Distinction from lichen planus should  be made because chronic ulcerative stomatitis typically does  not respond as well to corticosteroid therapy, and just as is  the case with lupus erythematosus (LE), chronic ulcerative  stomatitis often can be effectively treated using antimalarial  drugs.    Chronic ulcerative stomatitis usually affects adult women,  and the mean age at diagnosis is late in the sixth decade of  life. The condition may appear as desquamative gingivitis,  although ulcerations or erosions of the tongue or buccal  mucosa are also quite common (Fig. 16-105). The ulcers  are generally surrounded by patchy zones of erythema and  streaky keratosis that somewhat resemble lichen planus,  although classic striae formation is not evident. The ulcers    atrophy with a heavy chronic inflammatory cell infiltrate in the superficial lamina propria. B, High-power  photomicrograph showing interface degeneration of the basilar epithelium in association with the inflam-  mation. Unlike lichen planus, this infiltrate includes numerous plasma cells, as well as lymphocytes.    heal without scarring and often migrate around the oral  mucosa. As is typical with most immune-mediated condi-  tions, the severity of the oral lesions tends to wax and wane.  Fewer than 20% of affected patients will develop concurrent  lichenoid skin lesions.    Although the histopathologic features of chronic ulcerative  stomatitis are similar to those of lichen planus, the epithe-  lium is generally more atrophic and the inflammatory infil-  trate usually contains significant numbers of plasma cells in  addition to lymphocytes (Fig. 16-106). Artifactual epithe-  lial separation from the underlying connective tissue is not  unusual,    The diagnosis of chronic ulcerative stomatitis is essentially  based on its characteristic immunopathologic pattern.  Although it may not be economically feasible to do immu-  nologic testing on every case of lichen planus, this proce-  dure should be considered for erosive lichenoid lesions that  do not have a characteristic appearance or distribution, as  well as for erosive lesions that do not respond to topical  corticosteroid therapy. With direct immunofluorescence  studies, autoantibodies (usually IgG) that are directed  against the nuclei of stratified squamous epithelial cells in  the basal and parabasal regions of the epithelium are detected  (Fig. 16-107). Indirect immunofluorescence studies are also  positive for these stratified epithelium-specific antinuclear  antibodies (ANAs), and some investigators believe that con-  firmation of the diagnosis is necessary using serum for indi-  rect immunofluorescence evaluation. An ELISA test has  been developed, and if it becomes commercially available,  this should make screening for this condition much more  cost-effective. Other immune-mediated conditions (e.g.,  systemic sclerosis and LE) may show ANA deposition with    ® Fig. 16-107 Chronic Ulcerative Stomatitis. Direct immunofluo-  rescence studies show presence of IgG in the basal and parabasal  epithelial nuclei.    direct immunofluorescence; however, nuclei throughout  the entire thickness of the epithelium are positive with  those diseases.    Unlike the lesions of erosive lichen planus, the lesions asso-  ciated with chronic ulcerative stomatitis may not respond  as well to topical or systemic corticosteroid therapy. If the  lesions are not adequately controlled with corticosteroids,  then management with hydroxychloroquine, an antima-  larial drug, should be considered. Hydroxychloroquine  therapy, however, requires both periodic ophthalmologic  evaluation to monitor for drug-related retinopathy and  periodic hematologic evaluation.    Graft-versus-host disease (GVHD) occurs mainly in recipi-  ents of allogeneic bone marrow transplantation, a procedure    performed on approximately 8000 patients in the United  States each year. Such transplants are performed at major  medical centers to treat life-threatening diseases of the  blood or bone marrow, such as leukemia, lymphoma, mul-  tiple myeloma, aplastic anemia, thalassemia, sickle cell  anemia, or disseminated metastatic disease. Cytotoxic drugs,  radiation, or both may be used to destroy the malignant  cells, but in the process the normal hematopoietic cells of  the patient are destroyed. To provide the patient with an  immune system, an HLA-matched donor must be found.  The donor supplies hematopoietic stem cells obtained from  bone marrow, peripheral blood, or umbilical cord blood.  These stem cells are transfused into the patient, whose  own hematopoietic and immune cells have been destroyed.  The transfused hematopoietic cells make their way to the  recipient’s bone marrow and begin to reestablish normal  function.   Unfortunately, the HLA match is not always exact, and  despite the use of immunomodulating and immunosup-  pressive drugs (such as, cyclosporine, methotrexate, and  prednisone), the engrafted cells often recognize that they are  not in their native environment. When this happens, these  cells start attacking what they perceive as a foreign body.  The result of this attack is GVHD, and it can be quite  devastating to the patient.   In recent years, oncologists have taken advantage of this  type of immunologic attack when treating leukemia patients,  and often a beneficial “graft-versus-leukemia” effect is seen  when the donor cells interpret the leukemic cells as being  foreign. For older patients, who tend to have more signifi-  cant side effects with traditional bone marrow transplanta-  tion, the concept of a “mini-allograft” has been developed.  Not all of the patient’s white blood cells (WBCs) are  destroyed in this procedure, which is also known as nonmy-  eloablative allogenic hematopoietic cell transplantation, to  allow the donor cells to mount a more aggressive assault on  the patient’s leukemic cells.   Autologous stem cell transplantation has also become an  increasingly popular method of treatment for some of these  life-threatening diseases. Because these cells are derived  from the patient, there is no risk of GVHD in this setting.    The systemic signs of GVHD are varied, depending on the  organ system involved and whether the problem is acute or  chronic. The severity of GVHD depends on several factors,  with milder disease seen in patients who have a better his-  tocompatibility match, are younger, have received cord  blood, and are female.   Acute GVHD is typically observed within the first few  weeks after bone marrow transplantation. Although acute  GVHD has arbitrarily been defined as occurring within 100  days after the procedure, most investigators make this diag-  nosis based on the clinical features rather than a specific  time point. The disease affects about 50% of bone marrow  transplant patients. The skin lesions that develop may range    from a mild rash to a diffuse severe sloughing that resembles  toxic epidermal necrolysis (see page 725). These signs may  be accompanied by diarrhea, nausea, vomiting, abdominal  pain, and liver dysfunction.   Chronic GVHD may represent a continuation of a pre-  viously diagnosed case of acute GVHD, or it may develop  later than 100 days after bone marrow transplantation,  sometimes not appearing for several years after the proce-  dure. Chronic GVHD can be expected to develop in 30%  to 70% of bone marrow transplant recipients, and it often  mimics any one of a variety of autoimmune conditions,  such as systemic lupus erythematosus (SLE), Sjogren syn-  drome, or primary biliary cirrhosis. Skin involvement,  which is the most common manifestation, may resemble  lichen planus or even systemic sclerosis.   The oral mucosal manifestations of GVHD can also vary,  depending on the duration and severity of the attack and  the targeted oral tissues. Of patients with acute GVHD,  33% to 75% will have oral involvement; of patients with  chronic GVHD, 80% or more will have oral lesions. Some-  times the oral lesions of GVHD are the only sign of the  disorder. In most patients with oral GVHD, there is a fine,  reticular network of white striae that resembles oral lichen  planus, although a more diffuse pattern of pinpoint white  papules has also been described (Figs. 16-108 to 16-110).  The tongue, the labial mucosa, and the buccal mucosa are  the oral mucosal sites most frequently involved. Patients  often complain of a burning sensation of the oral mucosa,  and care must be taken not to overlook possible candidiasis.  Atrophy of the oral mucosa may be present, and this can  contribute to the mucosal discomfort. Ulcerations that are  related to the chemotherapeutic conditioning and neutro-  penic state of the patient often develop during the first 2  weeks after bone marrow transplantation. Ulcers that persist  longer than 2 weeks may represent acute GVHD, and these  should be differentiated from intraoral herpesvirus infection  or bacterial infection. Bone marrow transplant patients have  a small but increased risk for the development of both oral    © Fig. 16-108 Graft-Versus-Host Disease (GVHD). Confluent,  interlacing white linear lesions of the vermilion zone superficially resem-  ble oral lichen planus.    ° Fig. 16-109 Graft-Versus-Host Disease (GVHD). Lichenoid  lesions of the left buccal mucosa.    ® Fig. 16-110 Graft-Versus-Host Disease (GVHD). Involvement of  the tongue showing erosions and ulcerations that resemble erosive  lichen planus.    and cutaneous epithelial dysplasia and squamous cell carci-  noma. Demarcated white or red plaques of the oral mucosa  that do not have the characteristic lichenoid features should  be biopsied to rule out preneoplastic or neoplastic changes  (Fig. 16-111).   Xerostomia is also a common complaint. If the patient  is not taking drugs that dry the mouth, it is likely that the  immunologic response is destroying the salivary gland  tissue. Other evidence of salivary gland involvement includes  the development of small superficial mucoceles, particularly  on the soft palate.    The histopathologic features of GVHD resemble those of  oral lichen planus to a certain degree. Both lesions display  hyperorthokeratosis, short and pointed rete ridges, and  degeneration of the basal cell layer. The inflammatory  response in GVHD is usually not as intense as in lichen  planus. With advanced cases, an abnormal deposition of  collagen is present, similar to the pattern in systemic scle-  rosis. Minor salivary gland tissue usually shows periductal    e Fig. 16-111 Squamous Cell Carcinoma Arising in Graft-  Versus-Host Disease (GVHD). Erythematous, ulcerated mass arising  on the lateral border of the tongue. Note the surrounding mucosal  erosions, which represent GVHD.    inflammation in the early stages, with gradual acinar  destruction and extensive periductal fibrosis appearing later.    The diagnosis of GVHD may be difficult because of the  varied clinical manifestations. Such a diagnosis is of great  clinical significance to the patient because complications of  the condition and its treatment may be lethal. Although the  diagnosis of GVHD is based on the clinical and histopatho-  logic findings, each patient may have a different constella-  tion of signs and symptoms. Oral lesions appear to have  value as a highly predictive index of the presence of    The primary strategy for dealing with GVHD is to reduce  or prevent its occurrence. Careful tissue histocompatibility  matching is performed, and the patient is given prophylac-  tic therapy with immunomodulatory and immunosuppres-  sive agents, such as prednisone in combination with either  cyclosporine or tacrolimus. If GVHD develops, then the  doses of these drugs may be increased or similar pharmaco-  logic agents, such as mycophenolate mofetil, or azathio-  prine, may be added. The drug thalidomide has shown some  promise for cases of chronic GVHD that have been resistant  to standard therapy.   Topical corticosteroids may facilitate the healing of focal  oral ulcerations associated with GVHD, and some reports  have suggested that topical tacrolimus may be useful in  managing ulcers that are resistant to corticosteroids. Topical  anesthetic agents are administered to provide patient  comfort while the lesions are present, although narcotic  analgesics may be required in some cases. The use of pso-  ralen and ultraviolet A (PUVA) therapy also has been shown  to improve the cutaneous and oral lesions of patients with    the lichenoid form of GVHD. If significant xerostomia  is present in a dentulous patient, then topical fluorides  should be used daily to prevent xerostomia-related caries.  If significant amounts of salivary acinar tissue remain,  then treatment with pilocarpine hydrochloride or cevime-  line hydrochloride may improve the salivary flow. Current  recommendations are to evaluate the oral status of patients  before bone marrow transplantation and eliminate any  potential sources of infection. Interestingly, one study  showed no differences in posttransplant infections or sur-  vival between a group of patients who received dental treat-  ment before their transplant and a group who did not.   In general, some degree of GVHD is expected in most  allogeneic bone marrow transplant recipients. The prognosis  depends on the extent to which the condition progresses  and whether or not it can be controlled. The significance of  this complication is reflected in the survival of more than  70% of patients with relatively mild GVHD at 6 years  posttransplant, compared with approximately 15% of  patients with severe GVHD.    Psoriasis is a common chronic skin disease affecting  approximately 2% of people in the United States. Accord-  ing to some estimates, roughly 6 million people in this  country have psoriasis, and up to 250,000 new cases are  diagnosed each year.   Psoriasis is characterized by an increased proliferative  activity of the cutaneous keratinocytes. Recent advances in  cell kinetics, immunology, and molecular biology have  increased the understanding of the etiopathogenesis of the  keratinocyte proliferation in this disorder. Although the  triggering agent has yet to be identified, activated T lym-  phocytes appear to orchestrate a complex scenario that  includes abnormal production of cytokines, adhesion mol-  ecules, chemotactic polypeptides, and growth factors.  Genetic factors also seem to play a role, because as many as  one-third of these patients have affected relatives. Currently  nine different genetic loci have been identified that may be  related to the development of psoriasis. If one twin in a set  of identical twins has psoriasis, there is a 35% to 72%  chance that the other twin will have it. This suggests that  genetic factors are not entirely responsible for the condition,  and that one or more unidentified environmental agents  must influence its pathogenesis.    Psoriasis often has its onset during the second or third  decade of life and tends to persist for years, with periods of  exacerbation and quiescence. Patients frequently report that  the lesions improve during the summer and worsen during  the winter, an observation that may be related to lesional  exposure to UV light. The lesions are typically symmetri-  cally distributed in certain favored locations, such as the  scalp, elbows, and knees. The classic description is a    ® Fig. 16-112 Psoriasis. Characteristic cutaneous lesion, character-  ized by an erythematous plaque surmounted by silvery keratotic  scales.    ® Fig. 16-113 Psoriasis. This is an example of relatively rare involve-  ment of the oral mucosa by psoriasis. The erythematous linear patches  tended to flare with the patient’s cutaneous lesions. (Courtesy of Dr.  George Blozis.)    well-demarcated, erythematous plaque with a silvery scale  on its surface (Fig. 16-112). The lesions are often asymp-  tomatic, but it is not unusual for a patient to complain of  itching—in fact, the term psoriasis is derived from the Greek  word for itching. An unfortunate complication affecting  approximately 11% of these patients is psoriatic arthritis,  which may involve the TMJ.   Oral lesions may occur in patients with psoriasis, but  they are distinctly uncommon. Because descriptions of  these lesions have ranged from white plaques to red plaques  to ulcerations, it is difficult to determine the true nature of  intraoral psoriasis (Fig. 16-113). To render a diagnosis of  intraoral psoriasis, some investigators say that the activity  of the oral lesions should parallel that of the cutaneous  lesions. Some authors refer to erythema migrans (see page  726) as intraoral psoriasis, and the prevalence of erythema  migrans in psoriatic patients appears to be slightly greater  than that seen in the rest of the population. It is difficult,  however, to prove a direct correlation of that common  mucosal alteration with psoriasis.    elongation of the rete ridges, hyperkeratosis, and inflammation of the  papillary dermis.    Microscopically, psoriasis has a characteristic pattern. The  surface epithelium shows marked parakeratin production,  and the epithelial rete ridges are elongated (Fig. 16-114).  The connective tissue papillae, which contain dilated capil-  laries, approach close to the epithelial surface, and a peri-  vascular chronic inflammatory cell infiltrate is present. In  addition, collections of neutrophils (Munro abscesses), are  seen within the parakeratin layer.   With respect to oral lesions, good correlation with skin  disease activity should be seen in addition to the character-  istic histopathologic features, because other intraoral lesions,  such as erythema migrans and oral mucosal cinnamon reac-  tion (see page 322), exhibit a psoriasiform microscopic  appearance.    The treatment of psoriasis depends on the severity of the  disease activity. For mild lesions, no treatment may be  necessary.   For moderate involvement, topical corticosteroids are  commonly prescribed in the United States. Coal tar deriva-  tives and keratolytic agents also may be used. Other topical  drugs that have proven effective include vitamin D, ana-  logues (calcipotriene, calcipotriol, and calcitriol), and taz-  arotene, a retinoid (vitamin A) compound. Newer topical  biologic agents include the calcineurin inhibitors, tacroli-  mus and pimecrolimus, although these are usually reserved  for recalcitrant lesions. Exposure to UV radiation may also  be helpful for mild to moderate disease.   For severe cases, psoralen and ultraviolet A (PUVA)  therapy or ultraviolet B (UVB) therapy may be needed.  Methotrexate or cyclosporine may also be used as systemic  treatments for severe disease; however, these drugs have  significant side effects. Newer systemic biologic agents that  target specific disease-related components include inflix-  imab, adalimumab, and etanercept (directed against tumor    necrosis factor-alpha [TNF-@]); alefacept (directed against  T-cell receptors); or ustekinumab (directed against IL-12  and IL-23).   Although the mortality rate is not increased in patients  with psoriasis, the condition often persists for years despite  therapy. A recent 30-year prospective study has shown a  definite increase in the risk for cutaneous squamous cell  carcinoma in psoriasis patients who have received over 350  life-time PUVA treatments, but those who received fewer  than 150 had a very modest increase. Interestingly, the risk  for development of basal cell carcinoma did not seem to be  significantly elevated.    Lupus erythematosus (LE) is a classic example of an  immunologically mediated condition, and is the most  common of the so-called collagen vascular or connective  tissue diseases in the United States, with more than 1.5  million people affected. It may exhibit any one of several  clinicopathologic forms.   Systemic lupus erythematosus (SLE) is a serious mul-  tisystem disease with a variety of cutaneous and oral mani-  festations. There is an increase in the activity of the humoral  limb (B lymphocytes) of the immune system in conjunction  with abnormal function of the T lymphocytes. Although  genetic factors probably play a role in the pathogenesis of  SLE, the precise cause is unknown. Undoubtedly, interplay  between genetic and environmental factors occurs, for if  SLE develops in one monozygotic (identical) twin, then the  other twin has a 24% chance of having SLE as well. In  contrast, if one dizygotic (fraternal) twin has SLE, then the  other twin has only a 2% chance of being affected.   Chronic cutaneous lupus erythematosus (CCLE) may  represent a different, but related, process. It primarily affects  the skin and oral mucosa, and the prognosis is good.    third form of the disease, which has clinical features inter-  mediate between those of SLE and CCLE.    SLE can be a very difficult disease to diagnose in its early  stages because it often appears in a nonspecific, vague  fashion, frequently with periods of remission or disease  inactivity. Women are affected nearly 8 to 10 times more  frequently than men. The average age at diagnosis is 31  years. Common findings include fever, weight loss, arthritis,  fatigue, and general malaise. In 40% to 50% of affected  patients, a characteristic rash, having the pattern of a but-  terfly, develops over the malar area and nose (Fig. 16-115),  typically sparing the nasolabial folds. Sunlight often makes  the lesions worse.   The kidneys are affected in approximately 40% to 50%  of SLE patients. This complication may ultimately lead to  kidney failure; thus it is typically the most significant aspect  of the disease.    2 4  @ Fig. 16-115 Systemic Lupus Erythematosus (SLE). The ery-  thematous patches seen in the malar regions are a characteristic sign.    ® Fig. 16-116 Systemic Lupus Erythematosus (SLE). This ulcer-  ation of the buccal mucosa exhibits fine radiating white striae at its  periphery, clinically appearing similar to erosive lichen planus.    Cardiac involvement is also common, with pericarditis  being the most frequent complication. At autopsy nearly  50% of SLE patients display warty vegetations affecting the  heart valves (Libman-Sacks endocarditis). Its significance  is debatable, although some patients may develop superim-  posed subacute bacterial endocarditis on these otherwise  sterile outgrowths of fibrinoid material and connective  tissue cells.   Oral lesions of SLE develop in 5% to 25% of these  patients, although some studies indicate prevalence as high  as 40%. The lesions usually affect the palate, buccal mucosa,  and gingivae. Sometimes they appear as lichenoid areas, but  they may also look nonspecific or even somewhat granulo-  matous (Fig. 16-116). Involvement of the vermilion zone  of the lower lip (lupus cheilitis) is sometimes seen. Varying  degrees of ulceration, pain, erythema, and hyperkeratosis  may be present. Other oral complaints such as xerostomia,  stomatodynia, candidiasis, periodontal disease, and dysgeu-  sia have been described, but the direct association of these  problems with SLE remains to be proven.   Confirming the diagnosis of SLE can often be difficult,  particularly in the early stages. Criteria for making the    e Fig. 16-117 Chronic Cutaneous Lupus Erythematosus  (CCLE). The skin lesions are characterized by scaling, atrophy, and  pigmentary disturbances, which are most evident on sun-exposed  skin.    diagnosis of SLE have been established by the American  Rheumatism Association, and these include both clinical    Patients with CCLE usually have few or no systemic signs  or symptoms, with lesions being limited to skin or mucosal  surfaces. The skin lesions of CCLE most commonly present  as discoid lupus erythematosus. They begin as scaly, ery-  thematous patches that are frequently distributed on sun-  exposed skin, especially in the head and neck area (Fig.  16-117). Patients may indicate that the lesions are exacer-  bated by sun exposure. With time, the lesions may heal  spontaneously in one area, only to appear in another area.  The healing process usually results in cutaneous atrophy  with scarring and hypopigmentation or hyperpigmentation  of the resolving lesion. Conjunctival involvement by CCLE  has rarely been reported to cause cicatrizing conjunctivitis,  clinically similar to mucous membrane pemphigoid.   In most cases the oral manifestations of CCLE essentially  appear clinically identical to the lesions of erosive lichen  planus. Unlike the oral lesions of lichen planus, however,  the oral lesions of CCLE seldom occur in the absence of  skin lesions. An ulcerated or atrophic, erythematous central  zone, surrounded by white, fine, radiating striae, character-  izes the oral lesion of CCLE (Figs. 16-118 and 16-119).  Sometimes the erythematous, atrophic central region of a  lesion may show a fine stippling of white dots. As with  erosive lichen planus, the ulcerative and atrophic oral lesions  of CCLE may be painful, especially when exposed to acidic  or salty foods.    Patients with SCLE have clinical manifestations intermedi-  ate between those of SLE and CCLE. ‘The skin lesions are  the most prominent feature of this variation. They are char-  acterized by photosensitivity and are, therefore, generally  present in sun-exposed areas. These lesions do not show the  induration and scarring seen with the skin lesions of CCLE.    Weight Loss  MUSCULOSKELETAL 95%  SYMPTOMS  Arthralgia/myalgia 95%  Nonerosive polyarthritis 60%  CUTANEOUS SIGNS 80%  Photosensitivity 70%  Malar rash 50%  Oral ulcers 40%  Discoid rash 20%  HEMATOLOGIC SIGNS 85%  Anemia (chronic disease) 70%  Leukopenia (<4000/uL) 65%  Lymphopenia (<1500/uL) 50%  Thrombocytopenia 15%  (<100,000/uL)  Hemolytic anemia 10%  NEUROLOGIC SIGNS 60%  AND SYMPTOMS  Cognitive disorder 50%  Headache 25%  Seizures 20%  CARDIOPULMONARY 60%  SIGNS  Pleurisy, pericarditis, effusions 30%-50%  Myocarditis, endocarditis 10%  RENAL SIGNS 30%-50%    Adapted from Hahn BH: Systemic lupus erythematosus. In Longo DL,  Fauci AS, Kasper DL, et al, editors: Harrison’s principles of internal  medicine, ed 18, New York, 2012, McGraw-Hill, pp 2724-2735. Repro-  duced with permission of The McGraw-Hill Companies.    Oral lesions similar to those of CCLE have been described  in this variant of lupus as well. Usually, the renal or neuro-  logic abnormalities associated with SLE are not present,  although most patients will have arthritis or musculoskeletal  problems. SCLE may be triggered by any one of a variety  of medications (see page 317).    e Fig. 16-118 Chronic Cutaneous Lupus Erythematosus  (CCLE). Radiating keratotic striae surround erythematous zones of the  buccal mucosa. These features are similar to those of erosive lichen  planus.    e Fig. 16-119 Chronic Cutaneous Lupus Erythematosus  (CCLE). Oral involvement may also include relatively nondescript ery-  thematous patches, such as this one in the palate.    The histopathologic features of the skin and oral lesions of  the various forms of LE show some features in common but  are different enough to warrant separate discussions.   The skin lesions of CCLE are characterized by hyperkera-  tosis, often displaying keratin packed into the openings of  hair follicles (“follicular plugging”). In all forms of LE,  degeneration of the basal cell layer is frequently observed,  and the underlying connective tissue supports patchy to  dense aggregates of chronic inflammatory cells (Figs. 16-120  and 16-121). In the deeper connective tissue, the inflam-  matory infiltrate often surrounds the small blood vessels.   The oral lesions demonstrate hyperkeratosis, alternating  atrophy and thickening of the spinous cell layer, degenera-  tion of the basal cell layer, and subepithelial lymphocytic  infiltration. These features may also be seen in oral  lichen planus; however, the two conditions can usually be  distinguished by the presence in LE of patchy deposits of a  periodic acid-Schiff (PAS)-positive material in the basement  membrane zone, subepithelial edema (sometimes to the  point of vesicle formation), and a more diffuse, deep    @ Fig. 16-120 Lupus Erythematosus (LE). Low-power photomi-  crograph showing hyperparakeratosis with interface mucositis and  perivascular inflammation.    @ Fig. 16-121 Lupus Erythematosus (LE). High-power photomi-  crograph of the interface mucositis.    inflammatory infiltrate, often in a perivascular orientation.  Some authorities, however, feel that differentiating lichen  planus from LE is best done by direct immunofluorescence  studies or histopathologic examination of the cutaneous  lesions.    In addition to the clinical and microscopic features, a  number of additional immunologic studies may be helpful  in making the diagnosis of LE.   Direct immunofluorescence testing of lesional tissue  shows deposition of one or more immunoreactants (usually  IgM, IgG, or C3) in a shaggy or granular band at the base-  ment membrane zone. In addition, direct immunofluores-  cence testing of clinically normal skin of SLE patients often    shows a similar deposition of IgG, IgM, or complement  components. This finding is known as a positive lupus  band test. Although a positive lupus band test is consistent  with the diagnosis of LE, it is now known that other condi-  tions, such as rheumatoid arthritis, Sjogren syndrome, and  systemic sclerosis, may also have similar positive findings.  Furthermore, some patients with LE may not have a posi-  tive lupus band test; therefore, this study must always be  interpreted in the context of other clinical signs.   Evaluation of serum obtained from a patient with SLE  shows various immunologic abnormalities. Approximately  95% of these patients have antibodies directed against  multiple nuclear antigens (ie., antinuclear antibodies  [ANAs]). Although this is a nonspecific finding that may  be seen in other autoimmune diseases, as well as in other-  wise healthy older individuals, it is nevertheless useful as a  screening study. Furthermore, if results are negative on  multiple occasions, then the diagnosis of SLE should prob-  ably be doubted. Antibodies directed against double-  stranded DNA are noted in 70% of patients with SLE, and  these are more specific for the disease. Another 30% of  patients show antibodies directed against Sm, a protein  that is complexed with small nuclear RNA. This finding is  very specific for SLE.   A summary of selected immunologic findings in LE is  shown in Table 16-5.    Patients with SLE should avoid excessive exposure to sun-  light because UV light may precipitate disease activity. Mild  active disease may be effectively managed using NSAIDs  combined with antimalarial drugs, such as hydroxychloro-  quine. For more severe, acute episodes that involve arthritis,  pericarditis, thrombocytopenia, or nephritis, systemic cor-  ticosteroids are generally indicated; these may be combined  with other immunosuppressive and immunomodulating  agents. If oral lesions are present, they typically respond to  the systemic therapy.   As with SLE patients, patients with CCLE should avoid  excessive sunlight exposure. Because most of the manifesta-  tions of CCLE are cutaneous, topical corticosteroids are  often reasonably effective. Topical calcineurin inhibitors  (tacrolimus or pimecrolimus) may also be used, although  these medications are relatively expensive. For cases that are  resistant to topical therapy, systemic antimalarial drugs,  immunosuppressive drugs, immunomodulating drugs, or  low-dose thalidomide may produce a response. Topical cor-  ticosteroids are also helpful in treating the oral lesions of  COLE,   The prognosis for the patient with SLE is variable. For  patients undergoing treatment today, the 5-year survival  rate is approximately 95%; however, by 20 years, the sur-  vival rate falls to 75%. Ultimately, the prognosis depends  on which organs are affected and how frequently the disease  is reactivated. The most common cause of death is renal  failure; however, chronic immunosuppression also predis-  poses these patients to increased mortality because of    Direct immunofluorescence, lesional skin CCLE: 90% May help distinguish among the various types of LE  SLE: 95%  Direct immunofluorescence, normal skin CCLE: 0% Lupus band test    Very sensitive for SLE, but not very specific; not  useful for CCLE diagnosis    CCLE, Chronic cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; LE, lupus erythematosus.    infection and development of malignancy. For reasons that  are poorly understood, the prognosis is worse for men than  for women. In addition, blacks tend to fare more poorly  than whites.   The prognosis for patients with CCLE is considerably  better than that for patients with SLE, although transforma-  tion to SLE may be seen in approximately 5% of CCLE  patients. Usually, CCLE remains confined to the skin, but  it may persist and be quite a nuisance. For about 50% of  CCLE patients, the problem eventually resolves after several  years.    Systemic sclerosis is a relatively rare condition that prob-  ably has an immunologically mediated pathogenesis involv-  ing abnormal interactions among vascular tissue, connective  tissue, and immune cells in genetically predisposed indi-  viduals. For reasons that are not understood, dense collagen  is deposited in the tissues of the body in extraordinary  amounts. Although its most dramatic effects are seen in  association with the skin, the disease is often quite serious,  with most organs of the body affected.    Systemic sclerosis affects approximately 10 to 20 persons  per million population each year. Women have the condi-  tion three to five times more frequently than do men. Most  patients are adults. The onset of the disease is generally  insidious, with the cutaneous changes often responsible for  bringing the problem to the patient’s attention.   Often one of the first signs of the disease is Raynaud  phenomenon, a vasoconstrictive event triggered by emo-  tional distress or exposure to cold. Raynaud phenomenon    @ Fig. 16-122 Systemic Sclerosis. The tense, shiny appearance of  the skin is evident. Note that the fingers are fixed in a clawlike position,  with some showing shortening as a result of acro-osteolysis.    (see CREST syndrome, on page 747) is not specific for  systemic sclerosis, however, because it may be present in  other immunologically mediated diseases and in otherwise  healthy people. Resorption of the terminal phalanges (acro-  osteolysis) and flexion contractures produce shortened,  clawlike fingers (Fig. 16-122). The vascular events and the  abnormal collagen deposition contribute to the production  of ulcerations on the fingertips (Fig. 16-123).   The skin develops a diffuse, hard texture (sclero = hard;  derma = skin), and its surface is usually smooth. Involve-  ment of the facial skin by subcutaneous collagen deposition  results in the characteristic smooth, taut, masklike facies  (Fig. 16-124). Similarly, the nasal alae become atrophied,  resulting in a pinched appearance to the nose, called a mouse  facies. When the skin changes are confined to the hands,  face, feet, and lower portions of the limbs, the designation  of limited cutaneous systemic sclerosis is applied. If these  changes progress rapidly to involve the skin of the trunk  and the proximal limbs, or if the changes begin in  these areas, then the process is termed diffuse cutaneous    © Fig. 16-124 Systemic Sclerosis. The involvement of the facial  skin with abnormal collagen deposition produces a masklike facies.  Note the loss of the alae of the nose.    systemic sclerosis. These two presentations seem to have dif-  ferent prognoses.   Involvement of other organs may be subtle at first, but  the results are more serious. Fibrosis of the lungs, heart,  kidneys, and gastrointestinal tract are seen primarily in  patients with diffuse cutaneous systemic sclerosis, and the  abnormal collagen deposition leads to organ failure, typi-  cally within the first 3 years after the diagnosis is made.  Pulmonary fibrosis is particularly significant, leading to pul-  monary hypertension and heart failure, a primary cause of  death for these patients. Patients with limited cutaneous  systemic sclerosis tend to develop pulmonary hypertension  later than those with a diffuse presentation.    16-124. Because of the associated microstomia, this is the patient’s  maximal opening.    The oral manifestations occur in varying degrees. Micro-  stomia often develops as a result of collagen deposition in  the perioral tissues. This causes a limitation of opening the  mouth in nearly 70% of these patients (Fig. 16-125). Char-  acteristic furrows radiating from the mouth produce a  “purse string” appearance. Loss of attached gingival mucosa  and multiple areas of gingival recession may occur in some  patients. Dysphagia often develops as a result of deposition  of collagen in the lingual and esophageal submucosa, pro-  ducing a firm, hypomobile (boardlike) tongue and an  inelastic esophagus, thus hindering swallowing. Xerostomia  is frequently identified in these patients, and the possibility  of concurrent secondary Sjogren syndrome may require  consideration.   On dental radiographs, diffuse widening of the periodon-  tal ligament space is often present throughout the dentition.  ‘The extent of the widening may vary, with some examples  being subtle and others quite dramatic (Fig. 16-126).  Varying degrees of resorption of the posterior ramus of the  mandible, the coronoid process, the chin, and the condyle  may be detected on panoramic radiographs, affecting  approximately 10% to 20% of patients (Fig. 16-127). In    ® Fig. 16-128 Localized Scleroderma (Morphea). The cutaneous  alteration on the patient’s forehead represents a limited form of sclero-  derma called en coup de sabre, because the lesion resembles a scar  that might result from a cut with a sword.    theory, these areas are resorbed because of the increased pres-  sure associated with the abnormal collagen production.  Individual tooth resorption has also been reported to occur  at a higher frequency in these patients.   A milder condition that resembles cutaneous systemic  sclerosis has been called localized scleroderma or morphea,  and it usually affects only a solitary patch of skin. Because  these lesions often look like scars, the name en coup de sabre  (“strike of the sword”) is used to describe them (Fig. 16-128).  This problem is primarily cosmetic and, unlike systemic  sclerosis, it is rarely life threatening. For this reason, many  authorities now feel that this disorder may be unrelated to  systemic sclerosis.    Microscopic examination of tissue involved by systemic  sclerosis shows diffuse deposition of dense collagen within  and around the normal structures (Fig. 16-129). This  abnormal collagen replaces and destroys the normal tissue,  causing the loss of normal tissue function.    During the early phases, it may be difficult to make a diag-  nosis of systemic sclerosis. Generally, the clinical signs  of stiffened skin texture along with the development of  Raynaud phenomenon are suggestive of the diagnosis. A  skin biopsy may be supportive of the diagnosis if abundant  collagen deposition is observed microscopically.  Laboratory studies may be helpful to the diagnostic  process if anticentromere antibodies or anti-Scl 70 (topoi-  somerase I) is detected. Anti-topoisomerase I antibodies are  seen more often with diffuse cutaneous systemic sclerosis  and development of pulmonary fibrosis; anticentromere  antibodies are usually associated with limited cutaneous  systemic sclerosis (including CREST syndrome—see next  topic), as well as development of pulmonary hypertension.    The management of systemic sclerosis is difficult. Unfortu-  nately, many of the recommended treatments have not been  examined in controlled trials, and the natural waxing and  waning course of the disease makes it difficult to assess the  effectiveness of a given treatment in an open-label trial.  Systemic medications, such as penicillamine, are prescribed  in an attempt to inhibit collagen production. One double-  blind study, however, showed no difference in measured  patient outcomes with high-dose versus low-dose penicil-  lamine, suggesting that perhaps this medication has limited  efficacy. Surprisingly, corticosteroids are of little benefit, and  some studies have suggested that their use may increase  the risk of renal disease. Extracorporeal photochemotherapy  has shown some beneficial effect on the skin lesions;  however, no improvement of the pulmonary function tests  is observed.   Other management strategies are directed at controlling  symptoms. Such techniques as esophageal dilation are used,  for example, to temporarily correct the esophageal dysfunc-  tion and dysphagia. Calcium channel blocking agents help  to increase peripheral blood flow and lessen the symptoms  of Raynaud phenomenon, but many patients can reduce  episodes by keeping warm (especially their hands and feet)  or by stopping cigarette smoking. Angiotensin-converting  enzyme (ACE) inhibitors often effectively control hyperten-  sion if kidney involvement is prominent.   From a dental standpoint, problems may develop for  patients who wear prostheses because of the microstomia  and inelasticity of the mouth. Collapsible dental appliances  with special hinges have been made to facilitate the inser-  tion and removal of dentures. Microstomia and inelastic  soft tissue also hamper the maintenance of good oral  hygiene, and affected patients have a decreased ability to  manipulate a toothbrush as a result of sclerotic changes in  the fingers and hands. Surgical correction of open bite asso-  ciated with condylar resorption has been described. Infre-  quently, the resorption of the mandible may become so  great as to cause a pathologic fracture.    The prognosis is poor, although the outlook is better for  patients with limited cutaneous involvement than for those  with diffuse involvement. If the heart is affected, then the  prognosis is particularly poor, but most patients die because  of pulmonary involvement. Overall survival figures are dif-  ficult to calculate due to a variety of factors, including the  rarity of the disease, the inherent variability of its natural  course, and the variation in treatments provided at medical  centers around the world. With current treatment regimens,  it is estimated that 10-year survival rates for patients with  limited cutaneous systemic sclerosis approach 75% to 80%,  whereas survival drops to 55% to 60% for patients with  diffuse cutaneous systemic sclerosis.    CREST syndrome is an uncommon condition that some  authorities now believe represents a variant of limited cuta-  neous systemic sclerosis. The term CREST is an acronym  for Calcinosis cutis, Raynaud phenomenon, Esophageal  dysfunction, Sclerodactyly, and Telangiectasia.    As with all types of systemic sclerosis, most patients with  CREST syndrome are women in the sixth or seventh decade  of life. The characteristic signs may not appear synchro-  nously but instead may develop sequentially over a period  of months to years.   Calcinosis cutis occurs in the form of movable, non-  tender, subcutaneous nodules, 0.5 to 2.0 cm in size, which  are usually multiple (Fig. 16-130). Larger, more numerous  or superficial calcifications may occasionally become both-  ersome and require removal.   Raynaud phenomenon may be observed when a per-  son’s hands or feet are exposed to cold temperatures. The  initial clinical sign is a dramatic blanching of the digits,  which appear dead-white in color as a result of severe vaso-  spasm. A few minutes later, the affected extremity takes on  a bluish color because of venous stasis. After warming,  increased blood flow results in a dusky-red hue with the  return of hyperemic blood flow. This may be accompanied  by varying degrees of throbbing pain.   Esophageal dysfunction, caused by abnormal collagen  deposition in the esophageal submucosa, may not be notice-  able in the early phases of CREST syndrome. Often the  subtle initial signs of this problem must be demonstrated  by barium swallow radiologic studies.   The sclerodactyly of CREST syndrome is rather remark-  able. The fingers become stiff, and the skin takes on a  smooth, shiny appearance. Often the fingers undergo per-  manent flexure, resulting in a characteristic “claw” defor-  mity (Fig. 16-131). As with other forms of cutaneous  systemic sclerosis, this change is due to abnormal deposition  of collagen within the dermis in these areas.    © Fig. 16-130 CREST Syndrome. The subcutaneous nodules on  this patient’s arm represent deposition of calcium salts (calcinosis  cutis). (Courtesy of Dr. Roman Carlos.)    The telangiectasias in this syndrome are similar to those  seen in hereditary hemorrhagic telangiectasia (HHT) (see  page 702). As with that condition, significant bleeding from  the superficial dilated capillaries may occur. The facial skin  and the vermilion zone of the lips are commonly affected  (Fig. 16-132).    The histopathologic findings in CREST syndrome are  similar, although milder, to those seen in systemic sclerosis.  Superficial dilated capillaries are observed if a telangiectatic  vessel is included in the biopsy specimen.    Sometimes, HHT may be considered in the differential  diagnosis if the history is unclear and the other signs of  CREST syndrome are not yet evident. In these cases, labo-  ratory studies directed at identifying anticentromere anti-  bodies may be useful, because this test is relatively specific  for CREST syndrome and other types of limited cutaneous    @ Fig. 16-132 CREST Syndrome. The patient shows numerous red  facial macules representing telangiectatic blood vessels.    The treatment of patients with CREST syndrome is essen-  tially the same as that of those with systemic sclerosis.  Because CREST syndrome usually is not as severe, the treat-  ment does not have to be as aggressive. Although the prog-  nosis for this condition is much better than that for systemic  sclerosis, patients should be monitored for an increased risk  of developing pulmonary hypertension or primary biliary  cirrhosis, generally more than 10 years after the initial  diagnosis.    Acanthosis nigricans is an acquired dermatologic problem  characterized by the development of a velvety, brownish  alteration of the skin. In some instances, this unusual condi-  tion develops in conjunction with a malignancy, usually  gastrointestinal cancer, and is termed malignant acanthosis  nigricans. The cutaneous lesion itself is benign, yet it is  significant because it represents a cutaneous marker for  internal malignancy. The cause of malignant acanthosis  nigricans is unknown, although a cytokine-like peptide  capable of affecting the epidermal cells may be produced by  the malignancy.   Most cases, estimated to affect as many as 5% of adults,  are not associated with a malignancy and are termed benign  acanthosis nigricans. A clinically similar form, pseudoac-  anthosis nigricans, may occur in some obese people. Some    ° Fig. 16-133 Acanthosis Nigricans. The lesions are characterized  by numerous fine, almost velvety, confluent papules. The lesions most  often affect the flexural areas, such as the axilla depicted in this pho-  tograph. (From Hall JM, Moreland A, Cox GJ, et al: Oral acanthosis  nigricans: report of a case and comparison of oral and cutaneous  pathology, Am J Dermatopathol 10:68-73, 1988.)    benign forms of acanthosis nigricans may be inherited or  may occur in association with various endocrinopathies,  such as diabetes mellitus, Addison disease, hypothyroidism,  and acromegaly. Furthermore, benign acanthosis nigricans  may occur with certain syndromes (e.g., Crouzon syn-  drome) or drug ingestion (e.g., oral contraceptives or cor-  ticosteroids). These forms of the condition are typically  associated with resistance of the tissues to the effects of  insulin, similar to the insulin resistance seen in non—insulin-  dependent diabetes mellitus (NIDDM). Even though the  affected individuals may not have overt diabetes mellitus,  they often show increased levels of insulin or an abnormal  response to exogenously administered insulin.    The malignant form of acanthosis nigricans develops in  association with an internal malignancy, particularly adeno-  carcinoma of the gastrointestinal tract. Approximately 20%  of the cases of malignant acanthosis nigricans are identified  before the malignancy is found, but most appear at about  the same time as discovery of the gastrointestinal tumor or  thereafter.   Both forms of acanthosis nigricans affect the flexural  areas of the skin predominantly, appearing as finely papil-  lary, hyperkeratotic, brownish patches that are usually  asymptomatic (Fig. 16-133). The texture of the lesions has  been variably described as either velvety or leathery.   Oral lesions of acanthosis nigricans have also been  reported and may occur in 25% to 50% of affected patients,    ® Fig. 16-134 Acanthosis Nigricans. The vermilion zone of the lips  is affected. (Courtesy of Dr. George Blozis.)    especially those with the malignant form. These lesions  appear as diffuse, finely papillary areas of mucosal alteration  that most often involve the tongue or lips, particularly the  upper lip (Figs. 16-134 and 16-135). The buccal mucosa  may also be affected. The brownish pigmentation associated  with the cutaneous lesions is usually not seen in oral acan-  thosis nigricans.    The histopathologic features of the various forms of acan-  thosis nigricans are essentially identical. The epidermis  exhibits hyperorthokeratosis and papillomatosis. Usually,  some degree of increased melanin deposition is noted, but  the extent of acanthosis (thickening of the spinous layer) is  really rather mild. 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The mucopolysaccharidoses are a heterogeneous group of  metabolic disorders that are usually inherited in an autoso-  mal recessive fashion. These disorders are all characterized  by the lack of any one of several normal enzymes needed to  process the important intercellular substances known as  glycosaminoglycans. These substances used to be known as  mucopolysaccharides, thus the term mucopolysaccharidosis.  Examples of glycosaminoglycans include the following:  ¢ Heparan sulfate  ¢ Dermatan sulfate  ¢ Keratan sulfate  ¢ Chondroitin sulfate   The type of mucopolysaccharidosis that is seen clinically  depends on which of these substrates lacks its particular  enzyme. The mucopolysaccharidoses as a group occur with  a frequency of approximately 1 in 15,000 to 29,000 live  births, although some types are much less common.    The clinical features of the mucopolysaccharidoses vary,  depending on the particular syndrome that is examined  (Table 17-1). Furthermore, affected patients with a par-  ticular type of this disorder often exhibit a wide range of  severity of involvement. Most types of mucopolysaccharido-  sis are associated with some degree of intellectual disability.  Often the facial features of affected patients are somewhat  coarse, with heavy brow ridges (Fig. 17-1), and there are  other skeletal changes, such as stiff joints. Cloudy degen-  eration of the corneas, a problem that frequently leads to  blindness, is seen in several forms of mucopolysaccharidosis.   The oral manifestations vary according to the par-  ticular type of mucopolysaccharidosis. Most types show  some degree of macroglossia. Gingival hyperplasia may be  present, particularly in the anterior regions, as a result of  the drying and irritating effects of mouth breathing. The  dental changes include thin enamel with pointed cusps on  the posterior teeth, although this seems to be a feature    unique to mucopolysaccharidosis type IVA. Other dental  manifestations include numerous impacted teeth with  prominent follicular spaces (Fig. 17-2), possibly caused  by the accumulation of glycosaminoglycans in the follicu-  lar connective tissue. Some investigators have reported  the occurrence of multiple impacted teeth that are congre-  gated in a single large follicle, forming a rosette pattern  radiographically.   Although the clinical findings may suggest that a patient  is affected by one of the mucopolysaccharidoses, the diag-  nosis is confirmed by finding elevated levels of glycosami-  noglycans in the urine, as well as deficiencies of the specific  enzymes in the patient’s leukocytes and fibroblasts.    No satisfactory systemic treatment of the mucopolysac-  charidoses exists at this time. Several forms of mucopolysac-  charidosis are associated with a markedly reduced life span  and with intellectual disability. Attempts to improve the  survival and quality of life of these patients using hemato-  poietic stem cell transplantation have met with some success.  Unfortunately, not all aspects of the disease are corrected,  and the complications associated with transplantation must  be addressed. Such complications are associated with a 15%  to 20% mortality rate. Enzyme replacement therapy  currently is available for mucopolysaccharidosis types I, II,  and VI. Initiation of the respective recombinant human  enzymes—laronidase, idursulfase, and galsulfase—early in  the patient’s life appears to improve significantly many of  the aspects of the disease, although complete resolution  does not occur. Because of the rarity of these conditions and  the expense of developing the treatments, the annual cost  for such therapy can range from $176,000 for laronidase to  $657,000 for idursulfase, which currently has the dubious  distinction of being the most expensive prescription medi-  cation. Genetic counseling is indicated for the parents and  siblings of a patient affected by one of the mucopolysac-  charidosis syndromes. Prenatal diagnosis is available for  family planning as well.   Hunter X-linked R Iduronate-2-sulfatase HS and DS Appears at 1 to 2 years of age; clear  corneas, reduced intelligence, growth  impairment, stiff joints   I-A Sanfilippo-A AR Heparan N-sulphatase HS Appears at 4 to 6 years of age; clear  corneas, reduced intelligence, mild  skeletal changes; death in adolescence   V-A Morquio-A AR Galactose-6-sulfatase KS and CS___ Appears at 1 to 2 years of age; cloudy  corneas, normal intelligence, lax joints;  may survive to middle age    AR, Autosomal recessive; CS, chondroitin sulfate; DS, dermatan sulfate; HS, heparan sulfate; KS, keratan sulfate; R, recessive    e Fig. 17-1 Mucopolysaccharidosis. This patient affected by  Hunter syndrome exhibits the characteristic facial features of this  disorder.    @ Fig. 17-2 Mucopolysaccharidosis. Radiographic examination of  the dentition of a child affected by Hunter syndrome typically shows  radiolucencies (arrows) associated with the crowns of unerupted teeth.    Management of the dental problems of these patients is  essentially no different from that of other patients. However,  several factors may have to be taken into account:  ¢ Degree of intellectual disability (if any)   e Presence or absence of a seizure disorder  ¢ Degree of joint stiffening  e Extent of other related medical problems   Depending on which of these factors is present and the  extent of involvement, dental care may warrant sedation,  hospitalization, or general anesthesia of the patient for  optimal results. General anesthesia and sedation may be chal-  lenging, however, because of excess amounts of pharyngeal    tissues that often produce a smaller than normal airway. In  severely affected patients, general anesthesia probably should  be considered only in life-threatening situations.    The lipid reticuloendothelioses are a relatively rare group  of inherited disorders. These include the following  conditions:   These conditions are seen with increased frequency in  patients with Ashkenazi Jewish heritage. Affected patients  lack certain enzymes necessary for processing specific lipids;  this results in an accumulation of the lipids within a variety  of cells. Because of this accumulation, it appeared that  cells were attempting to store these substances; therefore,  the term storage disease was commonly used for these  disorders.   In Gaucher disease (the most common of the reticulo-  endothelioses), a lack of glucocerebrosidase results in the  accumulation of glucosylceramide, particularly within the  lysosomes of cells of the macrophage and monocyte lineage.  Three types of Gaucher disease are now recognized: type 1  (nonneuronopathic) is seen primarily in the Ashkenazi  Jewish population, and types 2 and 3 (neuronopathic) have  a panethnic distribution.   Niemann-Pick disease is characterized by a deficiency  of acid sphingomyelinase, resulting in the accumulation of  sphingomyelin, also within the lysosomes of macrophages.   Tay-Sachs disease is caused by a lack of B-hexosaminidase  A, which results in the accumulation of a ganglioside, prin-  cipally within the lysosomes of neurons.   All these disorders are inherited as autosomal recessive  traits. The genetic mutation known to cause Gaucher disease  has been evaluated for the Ashkenazi Jewish population,  and approximately 1 in 12 to 17 persons carry the defective  gene. Most of the individuals identified as having the gene,  however, were heterozygous and, therefore, asymptomatic.    The clinical features of Gaucher disease are generally the  result of the effects of the abnormal storage of glucosylce-  ramide. Macrophages laden with this glucocerebroside are  typically rendered relatively nonfunctional, and they tend  to accumulate within the liver, spleen, and bone marrow of  the affected patient. Bone marrow accumulation displaces  the normal hematopoietic cells and produces anemia and  thrombocytopenia. In addition, these patients are suscep-  tible to bone infarctions. The resulting bone pain is often  the presenting complaint. Characteristic Erlenmeyer flask  deformities of the long bones, particularly of the femur, are  often identified. Accumulations of the macrophages in the  spleen and liver result in visceral enlargement. Many affected  patients show a significant degree of growth impairment.    Neurologic deterioration occurs in patients with the less  common types 2 and 3 Gaucher disease. Jaw lesions typi-  cally appear as ill-defined radiolucencies that usually affect  the mandible, producing thinning of the cortical bone  without causing devitalization of the teeth or significant  resorption of the lamina dura. The walls of the mandibular  canal may also be obliterated by the disease process.  Decreased salivary flow has been documented for patients  with Gaucher disease compared with an age- and sex-  matched population, although this decrease may not be  clinically important.    Niemann-Pick disease occurs as three different types, each  associated with a different clinical expression and prognosis.  Types A and B are caused by a deficiency of acid sphingo-  myelinase, whereas type C is primarily the result of muta-  tions of either NMPC-1 or NPC-2, genes involved with  cholesterol processing. Types A and C have neuronopathic  features, characterized by psychomotor impairment, demen-  tia, spasticity, and hepatosplenomegaly, with death occur-  ring during the first or second decade of life. Type B patients  normally survive into adulthood and exhibit visceral signs,  primarily hepatosplenomegaly, and sometimes pulmonary  involvement.    Tay-Sachs disease may have a wide clinical range because  the condition is genetically heterogeneous. Some forms are  mild, with patients surviving into adulthood. In the severe  infantile form, however, rapidly progressive neuronal degen-  eration develops shortly after birth. Signs and symptoms  include blindness, developmental impairment, and intrac-  table seizures. Death usually occurs by 3 to 5 years of age.    Histopathologic examination of an osseous lesion of  Gaucher disease shows sheets of lipid-engorged macro-  phages (Gaucher cells) exhibiting abundant bluish cyto-  plasm, which has a fine texture resembling wrinkled silk.  In Niemann-Pick disease, the characteristic cell seen on  examination of a bone marrow aspirate is the “sea blue”  histiocyte.    For patients with a mild expression of Gaucher disease, no  treatment may be necessary. For more severe forms of  Gaucher disease, enzyme replacement therapy with one of  the macrophage-targeted glucocerebrosidases, including  imiglucerase, velaglucerase alfa, and taliglucerase alfa, is  used. All of these medications require intravenous (IV) infu-  sion and are quite expensive, often costing more than  $150,000 per year for treatment. After 9 to 12 months of  therapy, patients exhibit improvement in the status of their  anemia, a decrease in plasma glucocerebroside levels, and a    decrease in hepatosplenomegaly. Resolution of the radio-  graphic bone changes takes place over a longer period. Chil-  dren treated with this regimen may show significant gain in  height. Unfortunately enzyme replacement therapy has  shown minimal effect on the neuronopathic Gaucher disease  types 2 and 3, primarily because the medication cannot cross  the blood-brain barrier. Bone marrow transplantation has  also been attempted; however, the problems inherent in  graft-versus-host disease (GVHD) are still present with that  form of therapy, and thus it is not recommended. A case-  control study showed that adults with Gaucher disease have  an increased risk for hematologic malignancies, particularly  lymphoma and multiple myeloma. Genetic counseling  should be provided to all affected patients.    The neuronopathic forms of Niemann-Pick disease and the  infantile form of Tay-Sachs disease are associated with a  poor prognosis. Genetic counseling should be provided for  affected families. Molecular markers of these disorders have  been developed to identify carriers. Such identification  allows earlier intervention in terms of counseling, and tar-  geted population screening for the gene that causes Tay-  Sachs disease has resulted in a marked decrease in affected  patients during the past three decades.    A rare condition, lipoid proteinosis is inherited as an auto-  somal recessive trait. It is characterized by the deposition of  a waxy material in the dermis and submucosal connective  tissue of affected patients. The earliest thorough description  of lipoid proteinosis was by Urbach and Wiethe in 1929,  and more than 300 patients, most being of European back-  ground, have been reported to date. Mutations of the ECM1  gene, which encodes a glycoprotein known as extracellular  matrix protein 1, have been identified as the cause for this  condition.    The laryngeal mucosa and vocal cords are usually the sites  that are initially affected by lipoid proteinosis. Therefore,  the first sign of the disease may be one of the following:  e An inability of the infant to make a crying sound  e A hoarse cry in infancy  ¢ The development of a hoarse voice during early  childhood  The vocal cords become thickened as the accumulation  of an amorphous material begins to affect the laryngeal  mucosa. This infiltrative mucosal process may also involve  the pharynx, esophagus, tonsils, vulva, and rectum. Skin  lesions also develop early in life, appearing as thickened,  yellowish, waxy papules; plaques; or nodules that often    = ee A  ® Fig. 17-3 Lipoid Proteinosis. Thickened papules are present  along the margin of the eyelid. (Courtesy of Dr. Maria Copete.)    @ Fig. 17-4 Lipoid Proteinosis. The upper labial mucosa exhibits  yellow-white, nodular thickening. (Courtesy of Dr. Maria Copete.)    affect the face, particularly the lips and the margins of the  eyelids (Fig. 17-3). Some lesions may begin as dark-crusted  vesicles that heal as atrophic hyperpigmented patches.   Eventually, most patients exhibit a thickened, furrowed  appearance of the skin. Other areas of the skin that may be  involved include the neck, palms, axillae, elbows, scrotum,  knees, and digits. In those areas subjected to chronic trauma,  a hyperkeratotic, verrucous surface often develops. In addi-  tion to the cutaneous manifestations, symmetrical intracra-  nial calcifications of the medial temporal lobes have been  identified in approximately 70% of affected patients. These  lesions are usually asymptomatic, although a few patients  with such calcifications have been reported to have a seizure  disorder.   The oral mucosal abnormalities typically become evident  in the second decade of life. The tongue, labial mucosa, and  buccal mucosa become nodular, diffusely enlarged, and  thickened because of infiltration with waxy, yellow-white  plaques and nodules (Fig. 17-4). The dorsal tongue papillae  are eventually destroyed, and the tongue develops a smooth  surface. The accumulation of the amorphous material  within the tongue may result in its being bound to the floor  of the mouth. Therefore, the patient may not be able to    ® Fig. 17-5 Lipoid Proteinosis. A, This medium-power photomicrograph shows perivascular deposition    of a lamellar, acellular material. B, The periodic acid-Schiff (PAS) method is used to stain and highlight  the perivascular deposits. (Courtesy of Dr. Maria Copete.)    protrude the tongue. Gingival enlargement appears to be  an infrequent finding.    A biopsy specimen of an early lesion of lipoid proteinosis  typically reveals the deposition of a lamellar material around  the blood vessels, nerves, hair follicles, and sweat glands.  This material stains positively with the periodic acid-Schiff  (PAS) method and is not digested by diastase. The location  of this material, its staining properties, and the presence of  increased laminin, type IV collagen, and type V collagen  suggest a basement membrane origin.   A biopsy specimen of a lesion in its later stages usually  shows not only the lamellar material but also deposition of  an amorphous substance within the dermal connective  tissue (Fig. 17-5).    Generally, no specific treatment is available for lipoid pro-  teinosis other than genetic counseling. In rare instances, the  infiltration of the laryngeal mucosa may produce difficult  breathing for some infants, in which case debulking of the  mucosal lesions may be necessary. Most patients with lipoid  proteinosis have a normal life span. Certainly, however, the  vocal hoarseness and the appearance of the skin may influ-  ence the quality of life for affected patients. As is the  case with several other hyperkeratotic genodermatoses, the  rough, scaly skin lesions may respond to systemic retinoid  therapy, but the deposits of abnormal material in the dermis  and submucosa do not.    Jaundice is a condition characterized by excess bilirubin in  the bloodstream. The bilirubin accumulates in the tissues,    which results in a yellowish discoloration of the skin and  mucosa. To understand jaundice, it is important to know  something about the metabolism of bilirubin. Most biliru-  bin is derived from the breakdown of hemoglobin, the  oxygen-carrying pigment of erythrocytes. The average life  span of an erythrocyte in the circulation is 120 days. After  this time, it undergoes physiologic breakdown. The hemo-  globin is degraded and processed by the cells of the reticu-  loendothelial system, and bilirubin is liberated into the  bloodstream in an unconjugated state. In the liver, bilirubin  is taken up by the hepatocytes and conjugated with gluc-  uronic acid, which produces conjugated bilirubin, a soluble  product that can be excreted in the bile.   There are numerous causes for increased serum levels of  bilirubin; some are physiologic, and many are pathologic.  Therefore, the presence of jaundice is not a specific sign and  generally necessitates physical examination and laboratory  studies to determine the precise cause. The basic distur-  bances associated with increased bilirubin levels include an  increased production of bilirubin. This occurs when the red  blood cells (RBCs) are being broken down at such a rapid  rate that the liver cannot keep pace with processing. This  breakdown is seen in such conditions as autoimmune  hemolytic anemia or sickle cell anemia.   In addition, the liver may not be functioning correctly,  resulting in decreased uptake of the bilirubin from the  circulation or decreased conjugation of bilirubin in the liver  cells. Jaundice is frequently present at birth as a result of  the low level of activity of the enzyme system that conju-  gates bilirubin. Defects in this enzyme system may also be  seen with certain inherited problems, one of the more  common of which is Gilbert syndrome. This innocuous  condition is often detected on routine examination, and it  is estimated to affect up to 5% of people in the United  States. Because most of these examples of jaundice occur  with impaired processing of bilirubin, laboratory studies  usually show unconjugated bilirubin in the serum.    ® Fig. 17-6 Jaundice. The yellow color of the sclera represents a  common finding.    The presence of conjugated bilirubinemia in jaundice  can usually be explained by the reduced excretion of biliru-  bin into the bile ducts. This can be the result of swelling of  the hepatocytes (resulting in an occlusion of the bile cana-  liculi) or hepatocyte necrosis, with disruption of the bile  canaliculi and liberation of conjugated bilirubin. Thus liver  function may be disturbed because of any one of a variety  of infections (e.g., viruses) or toxins (e.g., alcohol). Occlu-  sion of the bile duct from gallstones, stricture, or cancer can  also force conjugated bilirubin into the bloodstream.    The patient affected by jaundice exhibits a diffuse, uniform,  yellowish discoloration of the skin and mucosa. The color  varies in intensity, depending on the serum level of bilirubin  and the anatomic site. Because elastin fibers have an affinity  for bilirubin, tissues that have a high content of elastin,  including the sclera, lingual frenum, and soft palate, are  prominently affected. The sclera of the eye is often the first  site at which the yellow color is noted (Fig. 17-6). The  yellow discoloration caused by hypercarotenemia (result-  ing from excess ingestion of carotene, a vitamin-A precursor  found in yellow vegetables and fruits) may be confused with  jaundice, but the sclera is not involved in that condition.   Other signs and symptoms associated with jaundice vary  with the underlying cause of the hyperbilirubinemia. For  example, patients with viral hepatitis usually have a fever,  abdominal pain, anorexia, and fatigue. The patient with  jaundice typically requires a complete medical evaluation to  determine the precise cause of the condition so that proper  therapy can be instituted.    The treatment and prognosis of the patient with jaundice  vary with the cause. The jaundice that is commonly noted  at birth often resolves spontaneously; however, if the infant  is placed under special lights, then the clearing will occur  more quickly because conjugation of the bilirubin molecule    is triggered by exposure to blue light. If the episode of  jaundice is due to significant liver damage, as may be seen  with viral hepatitis B or hepatotoxic chemical injury, then  the prognosis will vary, depending on the extent of liver  damage. The prognosis for patients with jaundice secondary  to liver damage associated with metastatic malignancy  is poor.    Amyloidosis represents a heterogeneous group of condi-  tions characterized by the deposition of an extracellular  proteinaceous substance called amyloid. Virchow coined  the term amyloid in the middle of the nineteenth century  because he believed it to be a starch-like material (amyl =  starch; oid = resembling). We now understand that amyloid  can be formed in a variety of settings, each with its own  specific type of amyloid protein. Many of these amyloid  proteins have been identified precisely with respect to their  biochemical composition, and ideally an attempt should be  made to categorize the type of amyloid specifically when  this diagnosis is made. The various amyloid proteins are  designated with an A, to indicate amyloid, followed by an  abbreviation for the specific amyloid protein. For example,  AL would identify amyloid composed of immunoglobulin  light (L) chain molecules. Although amyloid may have  several sources, all types of amyloid have the common  feature of a B-pleated sheet molecular configuration, which  can be seen with x-ray diffraction crystallographic analysis.  Because of this similarity of molecular structure, the differ-  ent types of amyloid have similar staining patterns with  special stains.   Amyloidosis can produce a variety of effects, depending  on the organ of involvement and the extent to which the  amyloid is deposited. With limited cutaneous forms of amy-  loidosis, virtually no effect on survival is seen. With some  forms of systemic amyloidosis, however, death may occur  within a few years of the diagnosis as a result of cardiac or  renal failure. Furthermore, the presence of amyloid may be  associated with other problems, such as multiple myeloma  or chronic infections.    Several classifications of amyloidosis have been proposed in  the past decade, each evolving as the knowledge of this  unusual condition increases. None of the classifications is  completely satisfactory, although in recent years, the bio-  chemical makeup of these proteins has figured more promi-  nently in most classifications. This discussion attempts to  be as concise and direct as possible. Essentially, amyloidosis  may be divided into organ-limited and systemic forms  from a clinical standpoint.    Organ-Limited Amyloidosis  Although organ-limited amyloidosis may occur in a variety  of organs, it has infrequently been reported in the oral soft    lesion in the periocular region, a finding that is characteristic of this  condition.    tissues. An example of a limited form of amyloidosis is the  amyloid nodule, which appears as a solitary, otherwise  asymptomatic, submucosal deposit. Most of the organ-  limited forms of amyloidosis consist of aggregates of immu-  noglobulin light chains, which in some cases are produced  by a focal collection of monoclonal plasma cells. By defini-  tion, such amyloid deposits are not associated with any  systemic alteration.    The primary and myeloma-associated forms of amyloidosis  usually affect older adults (average age, 65 years), and a  slight male predilection is present. These types of amyloi-  dosis are caused by deposition of light chain molecules (thus  the designation AZ), with most cases being idiopathic,  although approximately 15% to 20% are associated with  multiple myeloma. The initial signs and symptoms may be  nonspecific, often resulting in a delayed diagnosis. Fatigue,  weight loss, paresthesia, hoarseness, edema, and orthostatic  hypotension are among the first indications of this disease  process. Eventually, carpal tunnel syndrome, mucocutane-  ous lesions, hepatomegaly, and macroglossia develop as a  result of the deposition of the amyloid protein. The skin  lesions appear as smooth-surfaced, firm, waxy papules and  plaques. These most commonly affect the eyelid region (Fig.  17-7), the retroauricular region, the neck, and the lips. The  lesions are often associated with petechiae and ecchymoses.  Macroglossia has been reported in 10% to 40% of these  patients and may appear as diffuse or nodular enlargement  of the tongue (Fig. 17-8). Sometimes oral amyloid nodules  show ulceration and submucosal hemorrhage overlying the    ® Fig. 17-8 Amyloidosis. The patient exhibits an enlarged and cre-  nated tongue. (Courtesy of Dr. Gregory Erena.)    lesions. Infrequently, patients may complain of dry eyes or  dry mouth, which is secondary to amyloid infiltration and  destruction of the lacrimal and salivary glands. When sig-  nificant blood vessel infiltration has occurred, claudication  of the jaw musculature may be noticed.    Secondary amyloidosis is so named because it characteristi-  cally develops as a result of a chronic inflammatory process,  such as long-standing osteomyelitis, tuberculosis, or sar-  coidosis. Cleavage fragments of a circulating acute-phase  reactant protein appear to comprise this type of amyloido-  sis, which is thus designated AA. The heart is usually not  affected as in other forms of amyloidosis. Liver, kidney,  spleen, and adrenal involvement are typical, however. With  the advent of modern antibiotic therapy, this form of amy-  loidosis has become much less common in the United  States.    Patients who have undergone long-term renal dialysis also  are susceptible to amyloidosis, although in this case the  amyloid protein has been identified as B,-microglobulin,  and this type of amyloidosis is designated as ABM. B,-  Microglobulin is a normally occurring protein that usually  is not removed by the dialysis procedure, and it accumulates  in the plasma. Eventually, it forms deposits, particularly in  the bones and joints. Often, carpal tunnel syndrome occurs,  as well as cervical spine pain and dysfunction. Tongue  involvement has been reported. This type of amyloidosis  may become less of a problem in the future because of  increased use of dialyzers with larger pores that permit  removal of the large B.-microglobulin molecule.    Heredofamilial amyloidosis is an uncommon but significant  form of the disease. Several kindred have been identified in  Swedish, Portuguese, and Japanese populations, and most  types are inherited as autosomal dominant traits. An    @ Fig. 17-9 Amyloidosis. This medium-power photomicrograph  shows the eosinophilic, acellular deposits that are characteristic of  amyloid deposition.    autosomal recessive form, known as familial Mediterranean  fever, has also been described. Several of these conditions  appear as polyneuropathies, although other manifestations,  such as cardiomyopathy, cardiac arrhythmias, congestive  heart failure, and renal failure, eventually develop as the  amyloid deposition continues.    Biopsy of rectal mucosa has classically been used to confirm  a diagnosis of primary or myeloma-associated amyloidosis,  with up to 80% of such biopsy specimens being positive.  Aspiration biopsy of abdominal subcutaneous fat is a  simpler procedure, however, and the sensitivity of this tech-  nique has been reported to range from 55% to 75%. Alter-  native tissue sources, however, are the gingiva and labial  salivary glands. Histopathologic examination of gingival  tissue that has been affected by amyloidosis shows extracel-  lular deposition in the submucosal connective tissue of an  amorphous, eosinophilic material, which may be arranged  in a perivascular orientation or may be diffusely present  throughout the tissue (Fig. 17-9). Relatively low sensitivity  has been reported for gingival biopsies, whereas labial sali-  vary gland tissue shows deposition of amyloid in a periduc-  tal or perivascular location in more than 80% of the cases.   If the amorphous eosinophilic material represents  amyloid, it will be stained by the dye, Congo red, which  has an affinity for the abnormal protein. In tissue sections  stained with Congo red, the amyloid appears red. When the  tissue that takes up the Congo red stain is viewed with  polarized light, it exhibits an apple-green birefringence (Fig.  17-10). This Congo red staining method is considered to  be the “gold standard” for identifying the presence of  amyloid. Other techniques have been used, but these are  less sensitive or specific. Microscopic sections stained with  crystal violet reveal a characteristic metachromasia; this nor-  mally purple dye appears more reddish when it reacts with  amyloid. Staining with thioflavine T, a fluorescent dye, also  gives positive results if amyloid is present. Ultrastructurally,    ® Fig. 17-10 Amyloidosis. High-power photomicrograph of a Congo  red-stained section, demonstrating characteristic apple-green birefrin-  gence when viewed with polarized light. (Courtesy of Dr. John Kalmar.)    amyloid is seen as a collection of 7.5- to 10-nm diameter,  nonbranching, linear fibrils.    Once the histopathologic diagnosis of amyloidosis has been  made, the patient must be evaluated medically to determine  the type of amyloidosis that is present. This often entails a  workup that includes serum immunoelectrophoresis to  determine whether a monoclonal gammopathy exists so  that multiple myeloma can be ruled out. Immunohisto-  chemical studies are proving to be very useful in distinguish-  ing the specific type of amyloid protein. Family history and  physical examination findings are also important.    In most instances, no effective therapy is available for amy-  loidosis. Surgical debulking of amyloid deposition in the  tongue has met with limited success. Selected forms of amy-  loidosis may respond to treatment, or at least their progres-  sion may be slowed, depending on the underlying cause. In  cases of secondary amyloidosis associated with an infectious  agent, treatment of the infection and reduction of the  inflammation often result in clinical improvement. Renal  transplantation may arrest the progression of the bone  lesions in hemodialysis-associated amyloidosis, but this pro-  cedure apparently does not reverse the process. Liver trans-  plantation can improve the prognosis of several forms of  inherited amyloidosis, particularly the transthyretin variant.  Familial Mediterranean fever may respond to systemic col-  chicine therapy. Genetic counseling is also appropriate for  patients affected by the inherited forms of amyloidosis.  Treatment of primary amyloidosis (AL) with colchicine,  prednisone, and melphalan appears to improve the progno-  sis of patients who do not have cardiac or renal involvement,  although the outlook is guarded to poor in most instances.  Most patients die of cardiac failure, arrhythmia, or renal  disease within months to a few years after the diagnosis.    @ Fig. 17-11 Xanthelasma. These soft yellowish plaques on the  medial aspect of the skin of the upper eyelid are characteristic of  xanthelasma.    Xanthelasma is the most common of the cutaneous xan-  thomas, occurring in approximately 1% of the adult popu-  lation. The condition is mentioned because these lesions  appear somewhat similar to cutaneous amyloid deposits. In  addition, the presence of xanthelasma has been related to  an increased risk of atherosclerosis as well as elevated serum    Xanthelasma is typically identified in middle-aged or older  adults, presenting as one or more soft, yellowish plaques  associated with the periocular skin (Fig. 17-11). The lesions  tend to develop on the medial aspect of the upper eyelid.  Their soft consistency and yellow color clinically should  help distinguish xanthelasma from amyloid deposits.    Biopsy of xanthelasma shows a collection of lipid-laden his-  tiocytes in the superficial to mid-dermal connective tissue.    Treatment of xanthelasma itself is not necessary and is gen-  erally considered a cosmetic procedure. If the patient has  not been evaluated recently with respect to their cholesterol  levels, referral to a primary care physician for serum lipid  assessment would be prudent. The lesions can be surgically  removed, although recurrence is not unusual, even if serum  lipids are controlled.    In the United States today, significant vitamin deficiencies  are not common. Patients with malabsorption syndromes   Vitamin A (retinol) is essential for the maintenance of  vision, and it also plays a role in growth and tissue differ-  entiation. Vitamin A can be obtained directly from dietary  sources, such as organ meats (particularly liver), or the body  can synthesize it from B-carotene, which is abundant in red  and yellow vegetables.   Vitamin B, (thiamin) acts as a coenzyme for several  metabolic reactions and is thought to maintain the proper  functioning of neurons. Thiamin is found in many animal  and vegetable food sources.   Vitamin B, (riboflavin) is necessary for cellular oxidation-  reduction reactions. Foods that contain significant amounts  of riboflavin include milk, green vegetables, lean meat, fish,  legumes, and eggs.   Vitamin B; (niacin) acts as a coenzyme for oxidation-  reduction reactions. Rich sources include food from animal  sources, especially lean meat and liver, milk, eggs, whole  grains, peanuts, yeast, and cereal bran or germ.   Vitamin Bg (pyridoxine) serves as a cofactor associated  with enzymes that participate in amino acid synthesis. It is  found in many animal and vegetable food sources.   Vitamin C (ascorbic acid) is necessary for the proper  synthesis of collagen. This vitamin is present in a wide  variety of vegetables and fruits, although it is particularly  abundant in citrus fruits.   Vitamin D, which is now considered to be a hormone,  can be synthesized in adequate amounts within the epider-  mis if the skin is exposed to a moderate degree of sunlight.  Most milk and processed cereal is fortified with vitamin D  in the United States today, however. Appropriate levels of  vitamin D and its active metabolites are necessary for  calcium absorption from the gut.   Vitamin E (a-tocopherol) is a fat-soluble vitamin that is  widely stored throughout the body. It probably functions as  an antioxidant. Vegetable oils, meats, nuts, cereal grains, and  fresh greens and vegetables are good sources of vitamin E.   Vitamin K is a fat-soluble vitamin found in a wide  variety of green vegetables, as well as milk, butter, and liver;  intestinal bacteria also produce it. This vitamin is necessary  for the proper synthesis of various proteins, including the  clotting factors H, VII, IX, and X.    A severe deficiency of vitamin A during infancy may result  in blindness. The early changes associated with a lack of this  vitamin later in life include an inability of the eye to adapt  to reduced light conditions (i., night blindness). With  more severe, prolonged deficiency, dryness of the skin and  conjunctiva develop, and the ocular changes may progress  to ulceration of the cornea, leading to blindness.    Thiamin  A deficiency of thiamin results in a condition called beri-  beri, a problem that is relatively uncommon in the Western    world except in alcoholics or other individuals who do not  receive a balanced diet. Thiamin deficiency has also been  documented in patients who have had gastric bypass surgery  for weight control, presumably because an adequate amount  of the vitamin is not obtained in the diet. The condition  became prevalent in Southeast Asia when the practice of  removing the outer husks of the rice grain by machine was  introduced. Because these outer husks contained nearly all  of the thiamin, people who subsisted on the “polished” rice  became deficient in this vitamin. The disorder is manifested  by cardiovascular problems (e.g., peripheral vasodilation,  heart failure, and edema) and neurologic problems (includ-  ing peripheral neuropathy and Wernicke encephalopathy).  Patients with Wernicke encephalopathy experience vomit-  ing, nystagmus, and progressive mental deterioration, which  may lead to coma and death.    A diet that is chronically deficient in riboflavin causes a  number of oral alterations, including glossitis, angular chei-  litis, sore throat, and swelling and erythema of the oral  mucosa. A normocytic, normochromic anemia may be  present, and seborrheic dermatitis may affect the skin.  Niacin   A deficiency of niacin causes a condition known as pellagra,  a term derived from the Italian words pelle agra, meaning  rough skin. This condition may occur in populations that  use maize as a principal component of their diets, because  corn is a poor source of niacin. Pellagra was once common  in the southeastern United States and may still be seen in  some parts of the world. The classic systemic signs and  symptoms include the triad of dermatitis, dementia, and  diarrhea. The dermatitis is distributed symmetrically; sun-  exposed areas, such as the face, neck, and forearms, are  affected most severely (Fig. 17-12). The oral manifestations  have been described as stomatitis and glossitis, with the  tongue appearing red, smooth, and raw. Without correction  of the niacin deficiency, the disease may evolve and persist  over a period of years, eventually leading to death.   A deficiency of pyridoxine is unusual because of its wide-  spread occurrence in a variety of foods. A number of drugs,  such as the antituberculosis drug isoniazid, act as pyridoxine  antagonists; therefore, patients who receive these medica-  tions may have a deficiency state. Because the vitamin plays  a role in neuronal function, patients may show weakness,  dizziness, or seizure disorders. Cheilitis and glossitis,  reported in people with pellagra, are also reported in patients  with pyridoxine deficiency.    A deficiency of vitamin C is known as scurvy, and its occur-  rence in the United States is usually limited to people whose  diets lack fresh fruits and vegetables. Commonly affected  groups include inner-city infants (whose diets often consist    @ Fig. 17-12 Pellagra. The skin on the foot is rough and hyperpig-  mented, except for a central band that was protected from sunlight  by a sandal strap. (Courtesy of Dr. Sylvie Brener.)    @ Fig. 17-13 Scurvy. Hemorrhagic gingival enlargement (scorbutic  gingivitis) because of capillary fragility. (Courtesy of Dr. James Hargan.)    entirely of milk) and older edentulous men, particularly  those who live alone.   The clinical signs of scurvy are typically related to inad-  equate collagen synthesis. For example, weakened vascular  walls may result in widespread petechial hemorrhage and  ecchymosis. Similarly, wound healing is delayed, and  recently healed wounds may break down. In childhood,  painful subperiosteal hemorrhages may occur.   ‘The oral manifestations are well documented and include  generalized gingival swelling with spontaneous hemorrhage,  ulceration, tooth mobility, and increased severity of peri-  odontal infection and periodontal bone loss. The gingival  lesions have been termed scorbutic gingivitis (Fig. 17-13).  If untreated, scurvy may ultimately lead to death, often as  a result of intracranial hemorrhage.    ® Fig. 17-14 Vitamin D Deficiency. Hypocalcification of the teeth  is seen in this child who had vitamin D deficiency related to a diet of  breast milk exclusively and lack of adequate sunlight exposure. (Cour-  tesy of Dr. Pamela McDonald.)    A deficiency of vitamin D during infancy results in a condi-  tion called rickets; adults who are deficient in this vitamin  develop osteomalacia. With the vitamin-D supplementa-  tion of milk and cereal, rickets is a relatively uncommon  disease today in the United States. In past centuries, however,  rickets was often seen, particularly in the temperate zones  of the world, which often do not receive adequate sunlight  to ensure physiologic levels of vitamin D. Even today in the  United States, children who are dark-skinned and do not  receive adequate sun exposure, as well as solely breast-fed  infants, remain at risk for developing rickets. Nutritional  rickets remains a problem in many developing countries,  although the condition is thought to be associated more  with calcium deficiency than vitamin-D deficiency.   Clinical manifestations of rickets include irritability,  growth impairment, and prominence of the costochondral  junctions (rachitic rosary). As the child ages and begins to  put weight on the long bones of the legs, significant bowing  results because of the poor mineralization of the skeleton.  Vitamin-D deficiency occurring during the period of tooth  development will result hypomineralization of the teeth  (Fig. 17-14).   A similar pattern of poorly mineralized bone is seen in  osteomalacia in adults. Bone normally undergoes continu-  ous remodeling and turnover, and the osteoid that is pro-  duced during this process does not have sufficient calcium  to mineralize completely. Thus a weak, fragile bone struc-  ture results. Patients affected by osteomalacia frequently  complain of diffuse skeletal pain, and their bones are sus-  ceptible to fracture with relatively minor injury.    A deficiency of vitamin E is rare and occurs primarily in  children who suffer from chronic cholestatic liver disease.  These patients have severe malabsorption of all fat-soluble  vitamins, but particularly vitamin E. Multiple neurologic    signs develop as a result of abnormalities in the central  nervous system (CNS) and peripheral nervous system.    A deficiency of vitamin K may be seen in patients with  malabsorption syndromes or in those whose intestinal  microflora has been eliminated by long-term, broad-  spectrum antibiotic use. Oral anticoagulants in the dicuma-  rol family also inhibit the normal enzymatic activity of  vitamin K. A deficiency or inhibition of synthesis of vitamin  K leads to a coagulopathy because of the inadequate syn-  thesis of prothrombin and other clotting factors. Intraorally,  this coagulopathy is most often manifested by gingival  bleeding. If the coagulopathy is not corrected, death may  result from uncontrolled systemic hemorrhage.    Replacement therapy is indicated for vitamin deficiencies.  However, such deficiencies are uncommon, except for the  situations described earlier. In fact, vitamin excess is perhaps  more likely to be encountered in the United States today  because so many people self-medicate with unnecessary and  potentially harmful vitamin supplements. For example,  excess vitamin A may cause abdominal pain, vomiting,  headache, joint pain, and exostoses, whereas excess vitamin  C may induce the formation of additional kidney stones in  individuals with a history of nephrolithiasis. Similarly, an  increased prevalence of kidney stones can be seen with  excess oral intake of vitamin D.    Iron-deficiency anemia is the most common cause of  anemia in the United States and throughout the world. This  form of anemia develops when the amount of iron available  to the body cannot keep pace with the need for iron in the  production of red blood cells (RBCs). This type of anemia  develops under four conditions:   It is estimated up to 11% of women of childbearing age  in the United States are iron deficient as a result of the  chronic blood loss associated with excessive menstrual flow  (menorrhagia). Similarly, 2% of adult men are iron defi-  cient because of chronic blood loss, usually associated with  gastrointestinal disease, such as peptic ulcer disease, diver-  ticulosis, hiatal hernia, or malignancy.   An increased demand for erythrocyte production occurs  during childhood growth spurts and during pregnancy. A  decreased intake of iron may be seen during infancy when  the diet consists of relatively iron-poor foods, such as cereals  and milk. Likewise, the diets of older people may be defi-  cient if their dental condition prohibits them from eating  the proper foods or if they cannot afford iron-rich foods,    such as meats and vegetables. In the developing world,  intestinal parasites (especially hookworms) are a common  cause of iron deficiency in children and pregnant women.   Decreased absorption is a much less common problem;  however, it can be seen in patients who have had a complete  gastrectomy or who have celiac sprue, a condition that  results in severe chronic diarrhea because of sensitivity to  the plant protein, gluten.    Patients with iron-deficiency anemia that is severe enough to  cause symptoms may complain of fatigue, easy tiring, palpi-  tations, lightheadedness, and lack of energy. Oral manifesta-  tions include angular cheilitis and atrophic glossitis or  generalized oral mucosal atrophy. The glossitis has been  described as a diffuse or patchy atrophy of the dorsal tongue  papillae, often accompanied by tenderness or a burning  sensation. Such findings are also evident in oral candidiasis,  and some investigators have suggested that iron deficiency  predisposes the patient to candidal infection, which results  in the changes seen at the corners of the mouth and on the  tongue. Such lesions are rarely seen in the United States,  perhaps because the anemia is usually detected relatively early  before the oral mucosal changes have hada chance to develop.    The diagnosis should be established by means of a complete  blood count with RBC indices because many other condi-  tions, such as hypothyroidism, other anemias, or chronic  depression, may elicit similar systemic clinical complaints.  The laboratory evaluation characteristically shows hypo-  chromic microcytic RBCs, which may be reduced in  numbers. Additional supporting evidence for iron defi-  ciency includes the findings of low serum iron levels and  ferritin concentration together with elevated total iron-  binding capacity.    Therapy for most cases of iron-deficiency anemia consists  of dietary iron supplementation by means of oral ferrous  sulfate. For patients with malabsorption problems or severe  anemia, parenteral iron may be given periodically. The  response to therapy is usually prompt, with red cell param-  eters returning to normal within 1 to 2 months. The under-  lying cause of the anemia should be identified so that it may    Plummer-Vinson syndrome is a rare condition character-  ized by iron-deficiency anemia, seen in conjunction with    a! ee  © Fig. 17-16 Plummer-Vinson Syndrome. The diffuse papillary  atrophy of the dorsal tongue is characteristic of the oral changes.  (From Neville BW, Damm DD, White DK: Color atlas of clinical oral  pathology, ed 2, Philadelphia, 1999, Lippincott Williams & Wilkins.)    glossitis and dysphagia. Its prevalence in developed coun-  tries has been declining, probably as a result of the improved  nutritional status of the populations. The condition is sig-  nificant in that it has been associated with a high frequency  of both oral and esophageal squamous cell carcinoma; there-  fore, it is considered a premalignant process.    Most reported patients with Plummer-Vinson syndrome  have been women of Scandinavian or Northern European  background, between 30 and 50 years of age. Patients typi-  cally complain of a burning sensation associated with the  tongue and oral mucosa. Sometimes this discomfort is so  severe that dentures cannot be worn. Angular cheilitis is  often present and may be severe (Fig. 17-15). Marked  atrophy of the lingual papillae, which produces a smooth,  red appearance of the dorsal tongue, is seen clinically  (Fig. 17-16).   Patients also frequently complain of difficulty in swal-  lowing (dysphagia) or pain on swallowing. An evaluation    with endoscopy or esophageal barium contrast radiographic  studies usually shows the presence of abnormal bands of  tissue in the esophagus, called esophageal webs. Another  sign is an alteration of the growth pattern of the nails, which  results in a spoon-shaped configuration (koilonychia). The  nails may also be brittle.   Symptoms of anemia may prompt patients with Plummer-  Vinson syndrome to seek medical care. Fatigue, shortness of  breath, and weakness are characteristic symptoms.    Hematologic studies show a hypochromic microcytic  anemia that is consistent with an iron-deficiency anemia.    A biopsy specimen of involved mucosa from a patient  with Plummer-Vinson syndrome typically shows epithelial  atrophy with varying degrees of submucosal chronic inflam-  mation. In advanced cases, evidence of epithelial atypia or  dysplasia may be seen.    Treatment of Plummer-Vinson syndrome is primarily  directed at correcting the iron-deficiency anemia by means  of dietary iron supplementation. This therapy usually  resolves the anemia, relieves the glossodynia, and may  reduce the severity of the esophageal symptoms. Occasion-  ally, esophageal dilation is necessary to help improve the  symptoms of dysphagia. Patients with Plummer-Vinson  syndrome should be evaluated periodically for oral, hypo-  pharyngeal, and esophageal cancer because a 5% to 50%  prevalence of upper aerodigestive tract malignancy has been  reported in affected persons.    Pernicious anemia is an uncommon condition that occurs  with greatest frequency among older patients of Northern  European heritage, although recent studies have identified  the disease in black and Hispanic populations as well. Asian  populations seem to be affected much less frequently. The  disease is a megaloblastic anemia caused by poor absorption  of cobalamin (vitamin Bj, extrinsic factor). Intrinsic factor,  which is produced by the parietal cells of the stomach  lining, is needed for vitamin-B,, absorption. Normally,  when cobalamin is ingested, it binds to intrinsic factor in  the duodenum. Because the lining cells of the intestine  preferentially take up the cobalamin-intrinsic factor  complex, significant amounts of the vitamin cannot be  absorbed unless both components are present.   In the case of pernicious anemia, most patients lack  intrinsic factor because of an autoimmune destruction of  the parietal cells of the stomach; this results in decreased  absorption of cobalamin. Antibodies directed against    intrinsic factor are also found in the serum of these patients.  Vitamin By deficiency may occur for other reasons,  and although the resulting signs and symptoms may be  identical to those of pernicious anemia, these should be  considered as distinctly different deficiency disorders. For  example, a decreased ability to absorb cobalamin may also  occur after gastrointestinal bypass operations. In addition,  because cobalamin is primarily derived from animal sources,  some strict vegetarians (vegans) may develop vitamin By)  deficiency.   Because cobalamin is necessary for normal nucleic acid  synthesis, anything that disrupts the absorption of the  vitamin causes problems, especially for cells that are multi-  plying rapidly and, therefore, synthesizing large amounts  of nucleic acids. The cells that are the most mitotically  active are affected to the greatest degree, especially the  hematopoietic cells and the gastrointestinal lining epithe-    With respect to systemic complaints, patients with perni-  cious anemia often report fatigue, weakness, shortness of  breath, headache, and feeling faint. Such symptoms are  associated with most anemias and probably reflect the  reduced oxygen-carrying capacity of the blood. Vitamin B,,  also functions to maintain myelin throughout the nervous  system; therefore, with reduced levels of the vitamin, many  patients report paresthesia, tingling, or numbness of the  extremities. Difficulty in walking and diminished vibratory  and positional sense may be present. Psychiatric symptoms  of memory loss, irritability, depression, and dementia have  also been described.   Oral symptoms often consist of a burning sensation of  the tongue, lips, buccal mucosa, or other mucosal sites.  Clinical examination may show focal patchy areas of oral  mucosal erythema and atrophy (Fig. 17-17), or the process  may be more diffuse, depending on the severity and dura-  tion of the condition. The tongue may be affected in as  many as 50% to 60% of patients with pernicious anemia,  but it may not show as much involvement as other areas of  the oral mucosa in some instances. The atrophy and ery-  thema may be easier to appreciate on the dorsal tongue than  at other sites, however.    Histopathologic examination of an erythematous portion  of the oral mucosa shows marked epithelial atrophy with  loss of rete ridges, an increased nuclear-to-cytoplasmic  ratio of the surface epithelial cells, and prominent nucleoli  (Fig. 17-18). This pattern can be misinterpreted as epithelial  dysplasia at times, although the nuclei in pernicious  anemia typically are pale staining and show peripheral chro-  matin clumping. A patchy diffuse chronic inflammatory  cell infiltrate is usually noted in the underlying connective  tissue.    ® Fig. 17-18 Pernicious Anemia. This medium-power photomicro-  graph shows epithelial atrophy and atypia with chronic inflammation  of the underlying connective tissue. These features are characteristic  of a megaloblastic anemia, such as pernicious anemia.    Hematologic evaluation of vitamin B,. deficiency shows a  macrocytic anemia and reduced serum cobalamin levels.  The Schilling test for pernicious anemia has been used to  determine the pathogenesis of the cobalamin deficiency by  comparing absorption and excretion rates of radiolabeled  cobalamin. However, this study is rather complicated to  perform, and is now considered to be obsolete. The presence  of serum antibodies directed against intrinsic factor is quite  specific for pernicious anemia.    Once the diagnosis of pernicious anemia is established,  treatment traditionally has consisted of monthly intramus-  cular injections of cyanocobalamin. The condition responds  rapidly once therapy is initiated, with reports of clearing of  oral lesions within 5 days. High-dose oral cobalamin therapy  has also been shown to be an equally effective treatment,  however, with advantages being its cost-effectiveness and    ® Fig. 17-17 Pernicious Anemia. A, The dorsal tongue shows erythema and atrophy. B, After therapy    the elimination of painful injections. One recent systematic  literature review has identified what appears to be an  increased risk of gastric carcinoma, with pernicious anemia  patients being seven times more likely to develop this tumor  compared to the general population. Both vitamin B,, defi-  ciency and folate deficiency will cause megaloblastic anemia,  and it is important to distinguish between the two prob-  lems. Treatment of vitamin B,. deficiency with folate will  resolve the anemia and the oral mucosal atrophy, but  reduced myelin production will continue, resulting in    Pituitary dwarfism is a relatively rare condition that results  from either the diminished production of growth hormone  by the anterior pituitary gland, abnormalities of the growth  hormone molecule, or a reduced capacity of the tissues to  respond to growth hormone. Affected patients are typically  much shorter than normal, although their body proportions  are generally appropriate.   Several conditions may cause short stature, and a careful  evaluation of the patient must be performed to rule out  other possible causes, such as the following:   1. Intrinsic defects in the patient’s tissues (e.g., certain skel-  etal dysplasias, chromosomal abnormalities, and idio-  pathic short stature)   2. Alterations in the environment of the growing tissues  (e.g., malnutrition, hypothyroidism, and diabetes  mellitus)   Ifa lack of growth hormone is detected, the cause should  be determined. Sometimes the fault lies with the pituitary  gland itself (e.g., aplasia or hypoplasia). In other instances,  the problem may be related to destruction of the pituitary  or hypothalamus by tumors, therapeutic radiation, or  infection.   If the hypothalamus is affected, a deficiency in growth  hormone-releasing hormone, which is produced by the  hypothalamus, results in a deficiency of growth hormone.  Often deficiencies in other hormones, such as thyroid    hormone and cortisol, are also detected in patients with  primary pituitary or hypothalamic disorders.   Some patients exhibit normal or even elevated levels of  growth hormone, yet still show little evidence of growth.  These individuals usually have inherited an autosomal  recessive trait, resulting in abnormal and reduced growth  hormone receptors on the patients’ cells. Thus normal  growth cannot proceed.    Perhaps the most striking feature of pituitary dwarfism is  the remarkably short stature of the affected patient. Some-  times this is not noticed until the early years of childhood,  but a review of the patient’s growth history should show a  consistent pattern of failure to achieve the minimal height  on the standard growth chart. Often the patient’s height  may be as much as three standard deviations below normal  for a given age. Unlike the body proportions in many of the  dysmorphic syndromes and skeletal dysplasias, the body  proportions of patients affected by a lack of growth hormone  are usually normal. One possible exception is the size of the  skull, which is usually within normal limits. Because the  facial skeleton does not keep pace with the skull, however,  the face of an affected patient may appear smaller than it  should be. Mental status is generally within normal limits.   The maxilla and mandible of affected patients are smaller  than normal, and the teeth show a delayed pattern of erup-  tion. The delay ranges from 1 to 3 years for teeth that  normally erupt during the first decade of life and from 3 to  10 years for teeth that normally erupt in the second decade  of life. Often the shedding of deciduous teeth is delayed by  several years, and the development of the roots of the per-  manent teeth also appears to be delayed. A lack of develop-  ment of the third molars seems to be a common finding.  The size of the teeth is usually reduced in proportion to  the other anatomic structures. One recent study suggested  that growth hormone-deficient patients may exhibit more  severe periodontal disease compared to a matched control  population.    Radioimmunoassay for human growth hormone shows  levels that are markedly below normal.    Replacement therapy with human growth hormone is the  treatment of choice for patients with pituitary dwarfism if  the disorder is detected before closure of the epiphyseal  growth plates. In the past, growth hormone was extracted  from cadaveric pituitary glands; today, genetically engi-  neered human growth hormone is produced with recombi-  nant DNA technology. For patients with a growth hormone  deficiency caused by a hypothalamic defect, treatment with  growth hormone-releasing hormone is appropriate. If    patients are identified and treated at an early age, they can  be expected to achieve a relatively normal height. The cra-  niofacial bone structure also assumes a less childlike pattern.  Evaluation of a series of patients who had been treated for  long periods with growth hormone determined that up to  half developed acromegalic features, including larger feet  and a larger mandible. For patients who lack growth  hormone receptors, no treatment is available.    Gigantism is a rare condition caused by an increased pro-  duction of growth hormone, usually related to a functional  pituitary adenoma. The increased production of growth  hormone takes place before closure of the epiphyseal plates,  and the affected person grows at a much more rapid pace,  becoming abnormally tall. Although the average height of  the population of the United States has been gradually  increasing during the past several decades, individuals who  exceed the mean height by more than three standard devia-  tions may be considered candidates for endocrinologic  evaluation. Familial examples of gigantism have also been    Patients with gigantism usually show markedly accelerated  growth during childhood, irrespective of normal growth  spurts. Radiographic evaluation of the skull often shows an  enlarged sella as a result of the presence of a pituitary  adenoma. The adenoma may result in hormonal deficien-  cies, such as hypothyroidism and hypoadrenocorticism, if  the remaining normal pituitary gland tissue is compressed  and destroyed. McCune-Albright syndrome (polyostotic  fibrous dysplasia and café au lait pigmentation with associ-  ated endocrinologic disturbances) (see page 593) may  account for as many as 20% of the cases of gigantism.   If the condition remains uncorrected for a prolonged  period, extreme height (more than 7 feet tall) will be  achieved, and enlargement of the facial soft tissues, the  mandible, and the hands and feet will become apparent.  These changes often resemble those seen in acromegaly  (discussed later). Another oral finding is true generalized  macrodontia.    Appropriate management of gigantism involves the surgical  removal of the functioning pituitary adenoma, usually by a  transsphenoidal approach. Radiation therapy may also be  used, as well as one of the somatostatin analogues and a  growth hormone receptor antagonist (discussed in the next  topic, acromegaly).   The life span of patients with gigantism is usually mark-  edly reduced. Complications associated with hypertension,  peripheral neuropathy, osteoporosis, and pulmonary disease  contribute to increased morbidity and mortality.    Acromegaly is an uncommon condition characterized by  the excess production of growth hormone after closure of  the epiphyseal plates in the affected patient. Usually, this  increase in growth hormone is due to a functional pituitary  adenoma. ‘The incidence is estimated to be approximately  three to five new cases diagnosed per million population per  year. The prevalence is now believed to be between 40 and  130 affected patients per million.    Because most patients with acromegaly have a pituitary  adenoma, symptoms related directly to the space-occupying  mass of the tumor may be present. These symptoms include  headaches, visual disturbances, and other signs of a brain  tumor. Sometimes pressure atrophy of the residual normal  pituitary by the adenoma results in diminished production  of other pituitary hormones and causes other indirect endo-  crine problems. The direct effects of increased levels of  growth hormone include a variety of problems, such as  hypertension, heart disease, hyperhidrosis, arthritis, and  peripheral neuropathy.   Renewed growth in the small bones of the hands and  feet (Fig. 17-19) and in the membranous bones of the skull  and jaws is typically observed. Patients may complain of  gloves, rings, or hats becoming “too small.” The soft tissue  is also often affected, producing a coarse facial appearance  (Fig. 17-20). Hypertrophy of the soft palatal tissues may  cause or accentuate sleep apnea. Because these signs and  symptoms are slow to develop and are vague at the onset,  an average time of 6 to 10 years elapses from the onset of  symptoms to the diagnosis of disease. The average age at  diagnosis is 42 years, and no sex predilection is seen.   From a dental perspective, these patients have mandibu-  lar prognathism as a result of the increased growth of the  mandible (Fig. 17-21), which may cause apertognathia  (anterior open bite). Growth of the jaws also may cause    © Fig. 17-19 Acromegaly. Enlargement of the bones of the hands.  (Courtesy of Dr. William Bruce.)    spacing of the teeth, resulting in diastema formation. Soft  tissue growth often produces uniform macroglossia in  affected patients.    If acromegaly is suspected, measurement of serum growth  hormone levels is done after giving the patient a measured    © Fig. 17-21 Acromegaly. This lateral skull film shows the dramatic  degree of mandibular enlargement that may occur.    quantity of glucose orally. Normally, this glucose challenge  will reduce the production of growth hormone, but if the  patient has acromegaly, growth hormone will not be sup-  pressed. Usually magnetic resonance imaging (MRI) will  identify the pituitary adenoma that is responsible for inap-  propriate growth hormone secretion.    The treatment of a patient with acromegaly is typically  directed at the removal of the pituitary tumor mass and the  return of the growth hormone levels to normal. The most  effective treatment with the least associated morbidity is  surgical excision by a transsphenoidal approach. The prog-  nosis for such a procedure is good, although a mortality rate  of approximately 1% is still expected. The condition is  usually controlled with this procedure, but patients with  larger tumors and markedly elevated growth hormone levels  are less likely to be controlled.   Radiation therapy may be used in some instances, but  the return of the growth hormone levels to normal is not  as rapid or as predictable as with surgery. Because some  patients also experience hypopituitarism caused by radia-  tion effects on the rest of the gland, some centers may offer  radiation therapy as treatment only when surgery fails or is  too risky. Pharmacotherapy with one of the somatostatin  analogues (e.g., octreotide, lanreotide, and vapreotide) helps  to control acromegaly if surgical treatment is unsuccessful  or ifsurgery is contraindicated. A growth hormone receptor—  blocking agent, pegvisomant, has also been developed and  may be used in conjunction with one of the somatostatin  analogues or by itself if the patient cannot tolerate the  somatostatin analogue. Pegvisomant is injected daily and  acts in the peripheral tissues to inhibit the action of growth  hormone. These drugs are also used as an adjunct to radia-  tion therapy during the prolonged period that is sometimes  necessary for that treatment to take effect.   The prognosis for untreated patients is guarded, with  an increased mortality rate compared with that of the  general population. Hypertension, diabetes mellitus, coro-  nary artery disease, congestive heart failure, respiratory  disease, and colon cancer are seen with increased frequency  in acromegalic patients, and each of these contributes to the  increased mortality rate. Although treatment of the patient  with acromegaly helps to control many of the other com-  plicating problems and improves the prognosis, the life span  of these patients still is shortened, particularly for those with  persistent elevated growth hormone levels, cardiomyopathy,  or hypertension.    Hypothyroidism is a condition that is characterized by  decreased levels of thyroid hormone. When this decrease  occurs during infancy, the resulting clinical problem is    known as cretinism. If an adult has markedly decreased  thyroid hormone levels for a prolonged period, then  deposition of a glycosaminoglycan ground substance is  seen in the subcutaneous tissues, producing a nonpitting  edema. Some call this severe form of hypothyroidism myx-  edema; others use the terms myxedema and hypothyroidism  interchangeably.   Hypothyroidism may be classified as either primary or  secondary. In primary hypothyroidism, the thyroid gland  itself is in some way abnormal; in secondary hypothyroid-  ism, the pituitary gland does not produce an adequate  amount of thyroid-stimulating hormone (TSH), which is  necessary for the appropriate release of thyroid hormone.  Secondary hypothyroidism, for example, often develops  after radiation therapy for brain tumors, resulting in  unavoidable radiation damage to the pituitary gland. Most  cases, however, represent the primary form of the disease.   Screening for this disorder is routinely carried out at  birth, and the prevalence of congenital hypothyroidism in  North America is approximately 1 in 4000 births. Usually,  this is due to hypoplasia or agenesis of the thyroid gland.  In other areas of the world, hypothyroidism in infancy is  usually due to a lack of dietary iodine. In adults, hypothy-  roidism is often caused by autoimmune destruction of the  thyroid gland (known as Hashimoto thyroiditis) or iatro-  genic factors, such as radioactive iodine therapy or surgery  for the treatment of hyperthyroidism. Because thyroid  hormone is necessary for normal cellular metabolism, many  of the clinical signs and symptoms of hypothyroidism can  be related to the decreased metabolic rate in these patients.    The most common features of hypothyroidism include such  signs and symptoms as lethargy, dry and coarse skin, swell-  ing of the face (Fig. 17-22) and extremities, huskiness of  the voice, constipation, weakness, and fatigue. The heart  rate is usually slowed (bradycardia). Reduced body tem-  perature (hypothermia) may be present, and the skin often  feels cool and dry to the touch. In the infant, these signs  may not be readily apparent, and the failure to grow nor-  mally may be the first indication of the disease.   With respect to the oral findings, the lips may appear  thickened because of the accumulation of glycosaminogly-  cans. Diffuse enlargement of the tongue occurs for the same  reason (Fig. 17-23). If the condition develops during child-  hood, the teeth may fail to erupt, although tooth formation  may not be impaired (Figs. 17-24 and 17-25).    The diagnosis is made by assaying the free thyroxine (T,)  levels. If these levels are low, then TSH levels are measured  to determine whether primary or secondary hypothyroid-  ism is present. With primary thyroid disease, TSH levels are  elevated. With secondary disease caused by pituitary dys-  function, TSH levels are normal or borderline.    tion of tissue edema secondary to severe hypothyroidism. B, Same patient after 1 year of thyroid hormone  replacement therapy. Note the eruption of the maxillary permanent teeth.    @ Fig. 17-23 Hypothyroidism. The enlarged tongue (macroglossia)  is secondary to edema associated with adult hypothyroidism (myx-  edema). (Courtesy of Dr. George Blozis.)    Thyroid replacement therapy, usually with levothyroxine, is  indicated for confirmed cases of hypothyroidism. The  prognosis is generally good for adult patients. If the condi-  tion is recognized within a reasonable time, the prognosis  is also good for children. If the condition is not identified  in a timely manner, however, permanent damage to  the CNS may occur, resulting in intellectual disability. For  affected children, thyroid hormone replacement therapy  often results in a dramatic resolution of the condition (see  Fig. 17-22).    @ Fig. 17-24 Hypothyroidism. Photograph of the same patient  depicted in Fig. 17-22 before hormone replacement therapy. Note the  retained deciduous teeth, for which the patient was initially referred.    Hyperthyroidism is a condition caused by excess produc-  tion of thyroid hormone. This excess production results in  a state of markedly increased metabolism in the affected  patient. Most cases (60% to 90%) are due to Graves  disease, a condition that was initially described in the early  nineteenth century. It is thought to be triggered by autoan-  tibodies that are directed against receptors for thyroid-  stimulating hormone (TSH) on the surface of the thyroid  cells. When the autoantibodies bind to these receptors, they  seem to stimulate the thyroid cells to release inappropriate  thyroid hormone.    @ Fig. 17-25 Hypothyroidism. Panoramic radiograph of the same  patient in Figs. 17-22 and 17-24. Note the unerupted, yet fully devel-  oped permanent dentition.    Other causes of hyperthyroidism include hyperplastic  thyroid tissue and thyroid tumors, both benign and malig-  nant, which secrete inappropriate thyroid hormone. Simi-  larly, a pituitary adenoma may produce TSH, which can  then stimulate the thyroid to secrete excess thyroid hormone.    Graves disease is five to ten times more common in women  than in men and is seen with some frequency. It affects  almost 2% of the adult female population. Graves disease  is most commonly diagnosed in patients during the third  and fourth decades of life.   Most patients with Graves disease exhibit diffuse thyroid  enlargement. Many of the signs and symptoms of hyper-  thyroidism can be attributed to an increased metabolic rate  caused by the excess thyroid hormone. Patients usually  complain about nervousness, heart palpitations, heat intol-  erance, emotional lability, and muscle weakness. The fol-  lowing are often noted during the clinical evaluation:  ¢ Weight loss despite increased appetite  ¢ Tachycardia  e Excessive perspiration  e Widened pulse pressure (increased systolic and decreased   Ocular involvement, which develops in 20% to 40% of  affected patients, is perhaps the most striking feature of this  disease. In the early stages of hyperthyroidism, patients have  a characteristic stare with eyelid retraction and lid lag. With  some forms of Graves disease, protrusion of the eyes (exoph-  thalmos or proptosis) develops (Fig. 17-26). This bulging  of the eyes is due to an accumulation of glycosaminoglycans  in the retro-orbital connective tissues.    The diagnosis of hyperthyroidism is made by assaying free  Ty (thyroxine) and TSH levels in the serum. In affected  patients, the Ty levels should be elevated and the TSH  concentration is typically depressed.    @ Fig. 17-26 Hyperthyroidism. The prominent eyes are character-  istic of the exophthalmos associated with Graves disease.    Diffuse enlargement and hypercellularity of the thyroid  gland are seen in patients with Graves disease, typically with  hyperplastic thyroid epithelium and little apparent colloid  production. Lymphocytic infiltration of the glandular  parenchyma is also often noted.    In the United States, radioactive iodine ('*'I) is the most  commonly used form of therapy for adult patients with  Graves disease. The thyroid gland normally takes up iodine  from the bloodstream because this element is a critical com-  ponent of thyroid hormone. When radioactive iodine is  given to a patient with Graves disease, the thyroid gland  quickly removes it from the bloodstream and sequesters the  radioactive material within the glandular tissue. The radio-  activity then destroys the hyperactive thyroid tissue, bring-  ing the thyroid hormone levels back to normal. Most of the  radiation is received during the first few weeks because the  half-life of '°'I is short.   Other techniques include drug therapy with agents that  block the normal use of iodine by the thyroid gland, and  this form of therapy is initially favored in most European  centers. The two drugs that have been widely prescribed in  the United States are propylthiouracil (PTU) and methima-  zole. PTU has been associated with liver toxicity in some  patients, and the US Food and Drug Administration has  recommended that its use should be limited to specific  circumstances, such as methimazole allergy or during the  first trimester of pregnancy. Sometimes methimazole may  be administered chronically in the hope that a remission  may be induced. In addition, the thyroid gland, or a sig-  nificant portion of it, may be removed surgically, thereby  reducing thyroid hormone production. Methimazole is  often given prior to either surgical removal of the thyroid  or treatment with radioactive iodine in order to bring  thyroid hormone levels into the normal range.    Drug therapy alone is often unsuccessful in controlling  hyperthyroidism, and approximately half of patients treated  in this way will relapse. Unfortunately, with radioactive  iodine and surgery, the risk of hypothyroidism is relatively  great, and thyroid hormone replacement therapy is often  needed.   In a patient with uncontrolled hyperthyroidism, a defi-  nite risk exists with respect to an inappropriate release of  large amounts of thyroid hormone at one time, resulting  in a condition called a thyroid storm. A thyroid storm  may be precipitated by infection, psychologic trauma, or  stress. Clinically, patients may have delirium, convulsions,  an elevated temperature (up to 106° F), and tachycardia  (sometimes more than 140 beats/minute). Such individu-  als should be hospitalized immediately because the mortal-  ity rate associated with thyroid storm is approximately  20%. ‘The clinician should be aware of the potential for  this problem, and patients with hyperthyroidism should  ideally have the condition under control before dental  treatment.    Calcium levels in extracellular tissues are normally regulated  by parathyroid hormone (PTH) (parathormone) in con-  junction with vitamin D. If calcium levels drop below a  certain point, then the release of PTH is stimulated. The  hormone then acts directly on the kidney and the osteo-  blasts of the bone to restore the calcium to normal levels.  In the kidney, calcium reabsorption is promoted, phosphate  excretion is enhanced, and the production of vitamin D is  stimulated, which increases the absorption of calcium from  the gut. Osteoblasts are stimulated to produce a variety of  cytokines that subsequently increase osteoclastic differentia-  tion and metabolically activate the osteoclasts to resorb  bone, thus liberating calcium.   If a reduced amount of PTH is produced, the relatively  rare condition known as hypoparathyroidism results.  Usually, hypoparathyroidism is due to inadvertent surgical  removal of the parathyroid glands when the thyroid  gland is excised for other reasons, but sometimes it is  the result of autoimmune destruction of the parathyroid  tissue. Rare syndromes, such as DiGeorge syndrome  and the autoimmune polyendocrinopathy-candidiasis-  ectodermal dystrophy syndrome (endocrine-candidiasis  syndrome, autoimmune polyglandular syndrome, type  1), may be associated with hypoparathyroidism.    With the loss of parathyroid function, the serum levels of  calcium drop, resulting in hypocalcemia. Often the patient  with chronic hypoparathyroidism adapts to the presence of  hypocalcemia and is asymptomatic unless situations that  further reduce the calcium levels are encountered. Such situ-  ations include metabolic alkalosis, as seen during hyperven-  tilation, when a state of tetany may become evident.    @ Fig. 17-27 Hypoparathyroidism. Enamel hypoplasia has affected  the dentition of this patient, who had hypoparathyroidism while the  teeth were forming.    Chvostek sign is an oral finding of significance, charac-  terized by a twitching of the upper lip when the facial nerve  is tapped just below the zygomatic process. A positive  response suggests a latent degree of tetany. If the hypopara-  thyroidism develops early in life during odontogenesis, then  a pitting enamel hypoplasia and failure of tooth eruption  may occur (Fig. 17-27). The presence of persistent oral  candidiasis in a young patient may signal the onset of auto-  immune _polyendocrinopathy-candidiasis-ectodermal dys-  trophy syndrome (see page 196). Hypoparathyroidism may  be only one of several endocrine deficiencies associated with  this condition.    PTH can be measured by means of a radioimmunoassay. If  serum PTH levels are decreased in conjunction with a  decreased serum calcium concentration, elevated serum  phosphate level, and normal renal function, then a diagno-  sis of hypoparathyroidism can be made.    Patients with hypoparathyroidism are usually treated with  oral doses of an active form of vitamin D, calcitriol  (1,25-dihydroxycholecalciferol, vitamin D3). Additional  supplements of dietary calcium are also typically necessary  to maintain the proper serum calcium levels. With this  regimen, patients can often live a fairly normal life. Teripa-  ratide, a recombinant form of the active component of  human parathormone, has been developed but is not  approved in the United States for management of hypopara-  thyroidism. Clinical trials have shown that, when given  twice daily as subcutaneous injections, this drug may have  promise as an alternative management strategy for hypo-  parathyroidism, although it is relatively expensive.    The rare condition known as pseudohypoparathyroidism  represents at least two broad disorders in which normal  parathyroid hormone (PTH) is present in adequate amounts  but the biochemical pathways responsible for activating the  target cells are not functioning properly. The clinical result  is a patient who appears to have hypoparathyroidism.   In the case of pseudohypoparathyroidism type I, three  subcategories have been defined. For type Ia, a molecular  defect of a specific intracellular binding protein known as  G,@ seems to prevent the formation of cyclic adenosine  monophosphate (cAMP), a critical component in the acti-  vation of cell metabolism. Because other hormones also  require binding with G,a@ to carry out their functions,  patients have multiple problems with other endocrine  organs and functions. This condition is usually inherited as  an autosomal dominant trait.   With respect to pseudohypoparathyroidism type Ib, the  problem is thought to be caused by defective receptors for  the PTH on the surface of the target cells (the proximal  renal tubules). For this reason, no other endocrine tissues  or functions are affected. An autosomal dominant mode of  inheritance has been suggested for a few families affected by  type Ib pseudohypoparathyroidism, but most cases are  apparently sporadic. The mechanism of action for pseudo-  hypoparathyroidism type Ic is less clear, but it may involve  a defect in adenylate cyclase or a subtle G,@ alteration.   Pseudohypoparathyroidism type II is characterized by  the induction of cAMP by PTH in the target cells; however,  a functional response by the cells is not invoked. All of the  reported cases of this form of the disease appear to be  sporadic.    Pseudohypoparathyroidism most commonly appears as type  Ia disease. Patients affected by pseudohypoparathyroidism,  either type Ia or Ic, have a characteristic array of features  that includes mild intellectual disability, obesity, round face,  short neck, and markedly short stature. Midfacial hypopla-  sia is also commonly observed. The metacarpals and meta-  tarsals are usually shortened, and the fingers appear short  and thick. Subcutaneous calcifications (osteoma cutis) may  be identified in some patients. Other endocrine abnormali-  ties that are typically encountered include hypogonadism  and hypothyroidism.   Patients with type Ib and II disease clinically appear  normal, aside from their symptoms of hypocalcemia.   Dental manifestations of pseudohypoparathyroidism  include generalized enamel hypoplasia, widened pulp cham-  bers with intrapulpal calcifications, oligodontia, delayed  eruption, and blunting of the apices of the teeth. The pulpal  calcifications are often described as “dagger” shaped.    The diagnosis of pseudohypoparathyroidism is made  based on elevated serum levels of PTH seen concurrently  with hypocalcemia, hyperphosphatemia, and otherwise  normal renal function. More sophisticated studies are neces-  sary to delineate the various subtypes.    Pseudohypoparathyroidism is managed by the administra-  tion of vitamin D and calcium. The serum calcium levels  and urinary calcium excretion are carefully monitored.  Because of individual patient differences, the medication  may need to be carefully adjusted; however, the prognosis  is considered to be good.    Excess production of parathyroid hormone (PTH) results  in the condition known as hyperparathyroidism. PTH  normally is produced by the parathyroid glands in response  to a decrease in serum calcium levels.   Primary hyperparathyroidism is the uncontrolled pro-  duction of PTH, usually asa result ofa parathyroid adenoma  (80% to 90% of cases) or parathyroid hyperplasia (10% to  15% of cases). Rarely (approximately 1% of cases), a para-  thyroid carcinoma may be the cause of primary hyperpara-  thyroidism. Infrequently this endocrine disturbance is  caused by any one of several inherited syndromes, including  multiple endocrine neoplasia type 1 or type 2a, or  hyperparathyroidism—jaw tumor syndrome. In the latter  condition, affected patients develop multiple jaw lesions  that histopathologically are consistent with central ossifying  fibroma (see page 602). There also appears to be an increased  risk for these patients to develop parathyroid carcinoma.   Secondary hyperparathyroidism develops when PTH  is continuously produced in response to chronic low levels  of serum calcium, a situation usually associated with chronic  renal disease. The kidney processes vitamin D, which is  necessary for calcium absorption from the gut. Therefore,  in a patient with chronic renal disease, active vitamin D is  not produced and less calcium is absorbed from the gut,  resulting in lowered serum calcium levels.    Most patients with primary hyperparathyroidism are older  than 60 years of age. Women have this condition two  to four times more often than men do. In developed coun-  tries, the condition typically is identified on routine sero-  logic testing, and the majority of patients are relatively  asymptomatic.   Patients with the classic triad of signs and symptoms of  hyperparathyroidism are described as having “stones, bones,  and abdominal groans.” Affected individuals are more likely  to present with these signs and symptoms in economically  less developed countries where serologic evaluation is not  done on a routine basis.    “Stones” refers to the fact that these patients, particu-  larly those with primary hyperparathyroidism, have a  marked tendency to develop renal calculi (kidney stones,  nephrolithiasis) because of the elevated serum calcium  levels. Metastatic calcifications are also seen, frequently  involving other soft tissues, such as blood vessel walls, sub-  cutaneous soft tissues, the sclera, the dura, and the regions  around the joints.   “Bones” refers to a variety of osseous changes that may  occur in conjunction with hyperparathyroidism. One of the  first clinical signs of this disease is seen radiographically as  subperiosteal resorption of the phalanges of the index and  middle fingers. Generalized loss of the lamina dura sur-  rounding the roots of the teeth is also seen as an early  manifestation of the condition (Fig. 17-28). Alterations in  trabecular pattern characteristically develop next. A decrease  in trabecular density and blurring of the normal trabecular  pattern occur; often a “ground glass” appearance results.   With persistent disease, other osseous lesions develop,  such as the so-called brown tumor of hyperparathyroidism.  This lesion derives its name from the color of the tissue  specimen, which is usually a dark red-brown because of the  abundant hemorrhage and hemosiderin deposition within  the tumor. These lesions appear radiographically as well-  demarcated unilocular or multilocular radiolucencies (Fig.  17-29). They commonly affect the mandible, clavicles, ribs,  and pelvis. They may be solitary but are often multiple, and  long-standing lesions may produce significant cortical  expansion. Typically, the other osseous changes are observ-  able if brown tumors are present. The most severe skeletal  manifestation of chronic hyperparathyroidism has been  called osteitis fibrosa cystica, a condition that develops  from the central degeneration and fibrosis of long-standing  brown tumors. In patients with secondary hyperparathy-  roidism caused by end-stage renal disease (renal osteodys-  trophy; chronic kidney disease—mineral and bone  disorder), striking enlargement of the jaws has been known    ® Fig. 17-29 Hyperparathyroidism. This occlusal radiograph of the  edentulous maxillary anterior region shows a multilocular radiolucency  characteristic of a brown tumor of primary hyperparathyroidism. (Cour-  tesy of Dr. Brian Blocher.)    to occur (Fig. 17-30) and produce a “ground-glass” radio-  graphic pattern (see Fig. 17-28).   “Abdominal groans” refers to the tendency for the  development of duodenal ulcers. In addition, changes in  mental status are often seen, ranging from lethargy and  weakness to confusion or dementia.    ‘The brown tumor of hyperparathyroidism is histopathologi-  cally identical to the central giant cell granuloma of the  jaws, a benign tumorlike lesion that usually affects teenagers  and young adults (see page 584). Both lesions are character-  ized by a proliferation of exceedingly vascular granulation  tissue, which serves as a background for numerous multi-  nucleated osteoclast-type giant cells (Fig. 17-31). Some  lesions may also show a proliferative response characterized  by a parallel arrangement of spicules of woven bone set in  a cellular fibroblastic background with variable numbers of  multinucleated giant cells (Fig. 17-32). This pattern is often    ® Fig. 17-31 Hyperparathyroidism. This high-power photomicro-  graph of a brown tumor of hyperparathyroidism shows scattered mul-  tinucleated giant cells within a vascular and proliferative fibroblastic  background.    OF \ & yy UGE ne  @ Fig. 17-32 Hyperparathyroidism. This medium-power photomi-  crograph shows trabeculae of cellular woven bone and clusters of  multinucleated giant cells within a background of cellular fibrous con-  nective tissue. These features are characteristic of tissue changes seen  in renal osteodystrophy.    associated with secondary hyperparathyroidism related to  chronic renal disease (renal osteodystrophy).    In primary hyperparathyroidism, the hyperplastic para-  thyroid tissue or the functional tumor must be removed  surgically to reduce PTH levels to normal. Localization of  the parathyroid adenoma is often facilitated by a sestamibi  scan, which is a nuclear medicine technique using a tech-  netium 99-labeled small protein that is preferentially taken  up by the tumor. Such tumors are frequently removed by a  minimally invasive surgical technique, and intraoperative  assessment of the adequacy of excision can be determined  by noting a drop in parathormone levels within 10 minutes  of removing the adenoma.   Secondary hyperparathyroidism may evolve to produce  signs and symptoms related to renal calculi or renal    osteodystrophy. Restriction of dietary phosphate, use of  phosphate-binding agents, and pharmacologic treatment  with an active vitamin D metabolite (e.g., calcitriol) and a  calcimimetic agent, such as cinacalcet, may avert problems.  Cinacalcet sensitizes the calcium receptors of the parathy-  roid cells to extracellular calcium, causing the cells to reduce  their output of parathormone. Exposure to aluminum salts,  which inhibit bone mineralization, should be eliminated  also. Patients who do not respond to medical therapy may  require parathyroidectomy. Renal transplantation may  restore the normal physiologic processing of vitamin D, as  well as phosphorus and calcium reabsorption and excretion;  however, this does not occur in every case.    Hypercortisolism is a clinical condition that results from a  sustained increase in glucocorticoid levels. In most cases this  increase is due to corticosteroid therapy that is prescribed for  other medical purposes. The increase is less commonly  caused by an endogenous source, such as production of  adrenocorticotropic hormone (ACTH) by an adrenal tumor  or pituitary adenoma. If a pituitary adenoma is responsible,  then the term Cushing disease is applied. This condition is  rather rare and usually affects young adult women.    ‘The signs of Cushing syndrome usually develop slowly. The  most consistent clinical observation is weight gain, particu-  larly in the central areas of the body. The accumulation of  fat in the dorsocervical spine region results in a “buffalo  hump” appearance; fatty tissue deposition in the facial  area results in the characteristic rounded facial appearance  known as moon facies (Fig. 17-33). Other common findings  include the following:    If the patient has been receiving large amounts of cortico-  steroids (greater than the equivalent of 20 mg of predni-  sone) on a daily basis for several months, then the diagnosis  is rather obvious, given the classic signs and symptoms  described earlier. The diagnosis may be more difficult to  establish in patients with a functioning adrenal cortical  tumor or an ACTH-secreting pituitary adenoma. Evalua-  tion of these patients should include the measurement of    e Fig. 17-33 Cushing Syndrome. The rounded facial features  (“moon facies”) of this patient are due to the abnormal deposition of  fat, which is induced by excess corticosteroid hormone. (Courtesy of  Dr. George Blozis.)    free cortisol in the urine and an assay of the effect of dexa-  methasone (a potent artificial corticosteroid) on the serum  ACTH and cortisol levels. In an unaffected patient, the  levels of free cortisol should be within normal limits, and  the administration of an exogenous corticosteroid, such as  dexamethasone, should suppress the normal level of ACTH,  with a concomitant decrease in the cortisol levels. Because  functioning tumors do not respond to normal feedback  mechanisms, the anticipated decreases in ACTH and corti-  sol would not be seen in a patient with such a tumor.    The clinician should be aware of the signs and symptoms  of hypercortisolism to refer affected patients for appropriate  endocrinologic evaluation and diagnosis. Once the diagno-  sis is established and the cause is determined to be an  adrenal or pituitary tumor, surgical removal of the lesion is  the treatment of choice. Radiation therapy also may be  effective, particularly in younger patients. For patients with  unresectable tumors, drugs that inhibit cortisol synthesis  (such as, ketoconazole, metyrapone, or aminoglutethimide)  may be used to help control the excess production of  cortisol.   Most cases of hypercortisolism, however, are caused by  systemic corticosteroid therapy that is given for a variety of  immunologic reasons, including treatment of autoimmune    diseases and allogeneic transplant recipients. Certain strate-  gies, such as the use of corticosteroid-sparing agents or  alternate-day therapy, may minimize the corticosteroid dose  needed. The goal should be for patients to use the lowest  dose possible to manage immunologic disease.   In normal situations, cortisol is critical to the function  of the body, particularly in dealing with stress. As the  hormone is metabolized and serum levels drop, feedback to  the pituitary gland signals it to produce ACTH, which  stimulates the adrenal gland to produce additional cortisol.  Unfortunately, therapeutic corticosteroids suppress the pro-  duction of ACTH by the pituitary gland to the extent that  the pituitary gland may not be able to produce ACTH in  response to stress, and an acute episode of hypoadrenocorti-  cism (addisonian crisis) may be precipitated. Therefore, the  clinician must be aware of the potential side effects of  chronic high-dose corticosteroid use and must be able to  adapt the treatment of the patient accordingly. For stressful  dental and surgical procedures especially, it is often neces-  sary to increase the corticosteroid dose because of the greater  need of the body for cortisol. Consultation with the physi-  cian who is managing the corticosteroid therapy is advised  to determine to what extent the dose should be adjusted.    Insufficient production of adrenal corticosteroid hormones  caused by the destruction of the adrenal cortex results in  the condition known as Addison disease, or primary  hypoadrenocorticism. The incidence of new cases diag-  nosed in the Western hemisphere is approximately 4 per  million population per year, while the prevalence is about   e Infections (e.g., tuberculosis and deep fungal diseases,  particularly in patients with acquired immunodeficiency  syndrome [AIDS])   e Rarely, metastatic tumors, sarcoidosis, hemochromatosis,  or amyloidosis  If the pituitary gland is not functioning properly, sec-   decreased production of ACTH, the hormone responsible  for maintaining normal levels of serum cortisol.    The clinical features of hypoadrenocorticism do not actually  begin to appear until at least 90% of the glandular tissue has  been destroyed. With gradual destruction of the adrenal  cortex, an insidious onset of fatigue, irritability, depression,  weakness, and hypotension is noted over a period of months.  A generalized hyperpigmentation of the skin occurs,  classically described as bronzing. The hyperpigmentation is    ® Fig. 17-34 Addison Disease. Diffuse pigmentation of the maxillary  facial gingiva in a patient with Addison disease. (Courtesy of Dr. John  Kalmar.)    generally more prominent on sun-exposed skin and over  pressure points, such as the elbows and knees; it is caused by  increased levels of beta-lipotropin or ACTH, each of which  can stimulate melanocytes. The patient usually complains of  gastrointestinal upset with anorexia, nausea, vomiting, diar-  thea, weight loss, and a peculiar craving for salt, due  to hyponatremia caused by lack of the mineralocorticoid,  aldosterone. When hypoadrenocorticism is accompanied by  hypoparathyroidism and mucocutaneous candidiasis, the  possibility of autoimmune polyendocrinopathy-candidiasis-  ectodermal dystrophy syndrome should be considered (see  page 196).   The oral manifestations include diffuse or patchy, brown,  macular pigmentation of the oral mucosa caused by excess  melanin production (Fig. 17-34). Often the oral mucosal  changes are the first manifestation of the disease, with the  skin hyperpigmentation occurring afterward. Sometimes  the oral hypermelanosis may be difficult to distinguish from  physiologic racial pigmentation, but a history of a recent  onset of oral pigmentation should suggest the possibility of  Addison disease.    The diagnosis of hypoadrenocorticism is confirmed by a  rapid ACTH stimulation test and measurement of serum  cortisol levels and plasma ACTH levels. If serum cortisol  levels are below 18 ug/dL, then the patient has adrenal  insufficiency. In primary hypoadrenocorticism, the plasma  ACTH levels are high (>100 ng/L). In secondary hypoad-  renocorticism, the levels are normal (9 to 52 ng/L) or low,  as would be expected because the condition results from  decreased ACTH production by the pituitary gland.    Addison disease is managed with replacement therapy,  including both a glucocorticoid (such as, hydrocortisone)  and mineralocorticoid (such as, fludrocortisone). The physi-    ologic dose of glucocorticoid is considered to be approxi-  mately 30 to 45 mg of hydrocortisone or its equivalent per  day, usually given in divided doses. Because the body’s need  for corticosteroid hormones increases during stressful events,  the patient must take this into account and increase the dose  accordingly. This adjustment is generally not required for  dental procedures performed using local anesthesia and  lasting less than 1 hour, but an increased dose may be neces-  sary for certain dental and oral surgical procedures that are  more lengthy or are done under general anesthesia.   Before the availability of corticosteroids, the prognosis  for patients with hypoadrenocorticism was poor, with most  patients surviving less than 2 years. Even today, if the condi-  tion is not recognized promptly, death may result in a rela-  tively short period of time. With proper diagnosis and  management, most patients with hypoadrenocorticism  can expect to have a normal life span, although a recent  population-based study suggested an increased mortality  rate related to malignancy and cardiovascular disease.    Diabetes mellitus is a common disorder of carbohydrate  metabolism that is thought to have several causes, although  the basic problem is one of either decreased production of  insulin or tissue resistance to the effects of insulin. The net  result of this abnormal state is an increase in the blood  glucose level (hyperglycemia).   1. Type I—characterized by complete, or nearly complete,  lack of insulin production   2. Type I—characterized by inadequate insulin production  or resistance of target tissues to the effects of insulin   Type I diabetes mellitus was formerly known as insulin-  dependent diabetes mellitus or juvenile-onset diabetes, but  these terms are not considered to be accurate. Type II dia-  betics often require insulin injections in order to manage  their disease, and from 5% to 10% of type 1 diabetics  develop their disease after 30 years of age. Patients with type  1 diabetes mellitus usually exhibit severe hyperglycemia and  ketoacidosis without treatment, and they require exogenous  insulin injections to survive.   Type II diabetes mellitus is sometimes more difficult  to diagnose. It usually occurs in older, obese adults, but it  may be seen in obese adolescents as well. For this reason,  the term “adult-onset diabetes” was abandoned. Although  hyperglycemia is present, ketoacidosis rarely develops. Fur-  thermore, patients can produce some endogenous insulin.  Certain patients may require insulin to help control their  disease; the insulin injections, however, are usually not nec-  essary for the patient’s survival.   With respect to epidemiology, in the United States dia-  betes mellitus affects approximately 8% of the population,  or 26 million people, although approximately 6 million of  these cases remain undiagnosed. More than 1.5 million new  cases are identified each year in the United States. Of these    affected patients, most have type II diabetes; only 5% to  10% have type I.   Diabetes is an important disease when we consider the  many complications associated with it and the economic  effect it has on society. One of the main complications of  diabetes is peripheral vascular disease, a problem that  results in kidney failure, as well as ischemia and gangrenous  involvement of the limbs. By some estimates, 25% of all  new cases of kidney failure occur in diabetic patients. Thus  diabetes is the leading cause of kidney failure in the United  States. Each year more than 50,000 amputations are per-  formed for the gangrenous complications of diabetes. This  disease is the leading cause of lower limb amputations in  the United States. Retinal involvement often results in  blindness; thus the leading cause of new cases of blindness  in working-age adults in the United States is diabetes, with  more than 12,000 people affected annually. Complications  because of diabetes are estimated to contribute to the deaths  of more than 200,000 Americans each year.   The cause of diabetes mellitus is essentially unknown,  although most cases of type I diabetes appear to be caused  by autoimmune destruction of the pancreatic islet cells, and  this immunologic attack may be precipitated by a viral  infection in a genetically susceptible individual. Type II  diabetes does not appear to have an autoimmune cause,  however, because no destruction of the islet cells is seen  microscopically. Instead, genetic abnormalities have been  detected in patients with certain types of type II diabetes,  which may explain why the condition occurs so often in  families. If one parent is affected by type II diabetes, then  the chances of a child having the disorder is about 40%.  Similarly, if one identical twin has type II diabetes, then the  chances are 90% that the disease will also develop in the  other twin.    Although a complete review of the pathophysiology of dia-  betes mellitus is beyond the scope of this text, the clinical  signs and symptoms of a patient with this disease are easier  to understand with some basic knowledge of the process.  The hormone insulin, produced by the beta cells of the  pancreatic islets of Langerhans, is necessary for the uptake  of glucose by the cells of the body. When insulin binds to  its specific cell surface receptor, a resulting cascade of intra-  cellular molecular events causes the recruitment of intracel-  lular glucose-binding proteins, which facilitate the uptake  of glucose by each cell.    Because patients with type I diabetes have a deficiency  in the amount of insulin, the body’s cells cannot absorb  glucose and it remains in the blood. Normal blood glucose  levels are between 70 and 120 mg/dL; in diabetic patients,  these levels are often between 200 and 400 mg/dL. Above  300 mg/dL, the kidneys can no longer reabsorb the glucose;  therefore, it spills over into the urine. Because glucose is the    main source of energy for the body, and because none of  this energy can be used because glucose cannot be absorbed,  the patient feels tired and lethargic. The body begins to use  other energy sources, such as fat and protein, resulting in  the production of ketones as a by-product of those energy  consumption pathways. The patient often loses weight,  despite increased food intake (polyphagia). With the  hyperglycemia, the osmolarity of the blood and urine  increases. The increased osmolarity results in frequent uri-  nation (polyuria) and thirst, which leads to increased water  intake (polydipsia). Clinically, most patients with type I  diabetes are younger (average age at diagnosis being 14  years), and they have a thin body habitus.    By contrast, patients with type II diabetes are usually older  than 40 years of age at diagnosis, and 80% to 90% of them  are obese. In this situation, it is thought that a decrease in  the number of insulin receptors or abnormal post-binding  molecular events related to glucose uptake results in glucose  not being absorbed by the body’s cells. Thus patients are  said to show “insulin resistance” because serum insulin  levels are usually within normal limits or even elevated. If  the hyperglycemia is taken into account, however, the  amount of circulating insulin is typically not as much as  would be present in a normal person with a similar level  of blood glucose. Therefore, many of these patients are  described as having a relative lack of insulin.   ‘The symptoms associated with type II diabetes are much  more subtle in comparison to those seen with type I. The  first sign of type II diabetes is often detected with routine  hematologic examination rather than any specific patient  complaint. Ketoacidosis is rarely seen in patients with type  II diabetes. Nevertheless, many of the other complications  of diabetes are still associated with this form of the disease.    Many complications of diabetes mellitus are directly related  to the microangiopathy caused by the disease. The micro-  angiopathy results in occlusion of the small blood vessels,  producing peripheral vascular disease. The resultant decrease  in tissue perfusion results in ischemia. The ischemia pre-  disposes the patient to infection, particularly severe infec-  tions such as gangrene. Another contributing factor is the  impairment of neutrophil function, particularly neutrophil  chemotaxis.   Amputation of the lower extremity often is necessary  because of the lack of tissue perfusion and the patient's  inability to cope with infection. Similar vascular occlusion  may affect the coronary arteries (which places the patient at  risk for myocardial infarction) or the carotid arteries and  their branches (predisposing the patient to cerebrovascular  accident, or stroke). When microvascular occlusion affects  the retinal vessels, blindness typically results. Kidney failure  is the outcome of renal blood vessel involvement. If the  ketoacidosis is not corrected in type I diabetes, the patient  may lapse into a diabetic coma.    e Fig. 17-35 Diabetes Mellitus. A, This diffuse, erythematous  enlargement of the gingival tissues developed in a diabetic patient who  discontinued taking her insulin. B, The gingival tissues have greatly  improved after reinstitution of regular insulin injections. Several incisors  were extracted because of severe periodontal bone loss.    The oral manifestations of diabetes mellitus are generally  limited to patients with type I diabetes. Problems include  periodontal disease, which occurs more frequently and pro-  gresses more rapidly than in normal patients. Healing after  surgery may be delayed, and the likelihood of infection is  probably increased. Diffuse, nontender, bilateral enlarge-  ment of the parotid glands, called diabetic sialadenosis (see  page 437), may be seen in patients with either form of  diabetes. In uncontrolled or poorly controlled diabetic  patients, a striking enlargement and erythema of the  attached gingiva has been described (Fig. 17-35). In addi-  tion, these patients appear to be more susceptible to oral  candidiasis in its various clinical forms (see page 191).  Erythematous candidiasis, which appears as central papil-  lary atrophy of the dorsal tongue papillae, is reported in up  to 30% of these patients. Mucormycosis (see page 208)  may occur in patients with poorly controlled type I diabe-  tes. Some investigators have identified an increased preva-  lence of benign migratory glossitis (see page 726) in  patients with type I diabetes; however, others have not been  able to confirm this finding. Xerostomia, a subjective  feeling of dryness of the oral mucosa, has been reported as  a complaint in one-third of diabetic patients. Unfortunately,  studies that attempt to confirm an actual decrease in salivary  flow rate in diabetic patients have produced conflicting    results. Some studies show a decrease in salivary flow; some,  no difference from normal; and some, an increased salivary  flow rate.    For patients with type II diabetes, dietary modification  coupled with exercise may be the only treatment necessary,  with the goal being weight loss. The dietary and lifestyle  changes may need to be coupled with one or more  oral hypoglycemic agents. These drugs are designed to  affect different pathophysiologic aspects of the disease. For  example, secretagogues increase the insulin supply. These  include the second-generation sulfonylurea medications,  such as glipizide or glyburide. Metformin is a biguanide that  increases glucose utilization and decreases insulin resistance  and hepatic glucose production. Thiazolidinediones, such  as rosiglitazone and pioglitazone, also reduce insulin resis-  tance. Acarbose and miglitol are o-glucosidase inhibitors  that reduce the absorption of glucose from the gastrointes-  tinal tract by inhibiting enzymatic degradation of more  complex sugars. If these modalities do not control the blood  glucose levels, then treatment with insulin is necessary.   For patients with type I diabetes, injections of insulin are  required to control blood glucose levels. Different types of  insulin are marketed, each type having different degrees of  duration and times of peak activity. Insulin was previously  extracted primarily from beef and pork pancreata. In some  patients, however, antibodies developed to this foreign  protein and rendered the insulin useless. To overcome this  problem, pharmaceutical companies have developed brands  of insulin that have the molecular structure of human  insulin. Laboratories produce this human insulin with  genetically engineered bacteria using recombinant DNA  technology.   ‘The patient’s schedule of insulin injections must be care-  fully structured and monitored to provide optimal control  of blood glucose levels. This schedule is carefully formulated  by the patient’s physician and takes into account such  factors as the patient’s activity level and the severity of the  insulin deficiency. It is imperative that adequate dietary  carbohydrates be ingested after the administration of the  insulin; otherwise, a condition known as insulin shock may  occur. If carbohydrates are not consumed after an insulin  injection, then the blood glucose levels may fall to danger-  ously low levels. The brain is virtually dependent on blood  glucose as its energy source. If the blood glucose level drops  below 40 mg/dL, the patient may go into shock. This con-  dition can be treated by administration of sublingual dex-  trose paste, IV infusion of a dextrose solution, or injection  of glucagon.   In summary, diabetes mellitus is a common, complex  medical problem with many complications. The prognosis  is guarded. Studies suggest that strict control of blood  glucose levels results in a slowing of the development of the  late complications of type I diabetes (e.g., blindness, kidney  damage, and neuropathy) and reduces the frequency of    these complications. Health care practitioners should be  aware of the problems these patients may have and should  be prepared to deal with them. Consultation with the  patient’s physician may be necessary, particularly for patients  with type I diabetes that show poor blood glucose control,  have active infections, or require extensive oral surgical  procedures.    Hypophosphatasia is a rare metabolic bone disease that is  characterized by a deficiency of tissue-nonspecific alkaline  phosphatase. Approximately 150 distinct mutations of the  gene responsible for alkaline phosphatase production have  been described. One of the first presenting signs of hypo-  phosphatasia may be the premature loss of the primary  teeth, presumably caused by a lack of cementum on the root  surfaces. In the homozygous autosomal recessive form, there  are rather severe manifestations, and many of these patients  are identified in infancy. The milder forms of the disease are  inherited in an autosomal dominant or recessive fashion,  appearing in childhood or even adulthood, with variable  degrees of expression. Generally, the younger the age of  onset, the more severe the expression of the disease. The  common factors in all types include the following:  ¢ Reduced levels of the bone, liver, and kidney isozyme of   Most authorities believe that the decreased alkaline phos-  phatase levels probably are responsible for the clinically  observed abnormalities. Alkaline phosphatase is thought to  play a role in the production of bone, but its precise mecha-  nism of action is unknown.    Six types of hypophosphatasia are now recognized, depend-  ing on the severity and the age of onset of the symptoms:  . Perinatal lethal    The perinatal lethal form has the most severe manifesta-  tions. It is usually diagnosed at birth, and the infant rarely  survives for more than a few hours. Death is due to respira-  tory failure. Marked hypocalcification of the skeletal struc-  tures is observed.    The perinatal benign form of hypophosphatasia appears  similar to the lethal form, but these infants have a clinical    ® Fig. 17-36 Hypophosphatasia. Premature loss of the mandibular  anterior teeth. (Courtesy of Dr. Jackie Banahan.)    course similar to infantile hypophosphatasia. Some investi-  gators have noted that skeletal calcification may be detected  in some of these fetuses during the third trimester of preg-  nancy, in contrast to the lethal form.    Babies affected by infantile hypophosphatasia may appear  normal up to 6 months of age; after this time, they  begin to show a failure to grow. Vomiting and hypotonia  may develop as well. Skeletal malformations that suggest  rickets are typically observed; these malformations include  shortened, bowed limbs. Deformities of the ribs predispose  these patients to pneumonia, and skull deformities cause  increased intracranial pressure. Nephrocalcinosis and neph-  rolithiasis also produce problems for these infants. Radio-  graphs show a markedly reduced degree of ossification with  a preponderance of hypomineralized osteoid. If these infants  survive, premature shedding of the deciduous teeth is  often seen.    The childhood form is usually detected at a later age and  has a wide range of clinical expression. One of the more  consistent features is the premature loss of the primary teeth  without evidence of a significant inflammatory response  (Figs. 17-36 and 17-37). The deciduous incisor teeth are  usually affected first and may be the only teeth involved. In  some patients, this may be the only expression of the disease.  The teeth may show enlarged pulp chambers in some  instances, and a significant degree of alveolar bone loss may  be seen. More severely affected patients may have open  fontanelles with premature fusion of cranial sutures. This  early fusion occasionally leads to increased intracranial pres-  sure and subsequent brain damage. Affected patients typi-  cally have a short stature, bowed legs, and a waddling gait.  The development of motor skills is often delayed.  Radiographically, the skull of more severely affected indi-  viduals may show uniformly spaced, poorly defined, small  radiolucencies, a pattern that has been described as resem-  bling “beaten copper.” This appearance may be the result of    @ Fig. 17-37 Hypophosphatasia. This panoramic radiograph shows  the loss of the mandibular anterior teeth. (Courtesy of Dr. Jackie  Banahan.)    areas of thinning of the inner cortical plate produced by the  cerebral gyri.    The adult form is typically mild. Patients often have a  history of premature loss of their primary or permanent  dentition, and many of these patients are edentulous. Stress  fractures that involve the metatarsal bones of the feet may  be a presenting sign of the condition, or an increased  number of fractures associated with relatively minor trauma  may alert the clinician to this disorder.    This form of hypophosphatasia is perhaps the most contro-  versial. Affected patients present with premature loss of the  incisor teeth as the only clinical sign of disease, although  serologic studies will be consistent with hypophosphatasia.  Some investigators have suggested that this may simply  represent a mild expression of the disorder.    The diagnosis of hypophosphatasia is based on the clinical  manifestations and the finding of decreased levels of serum  alkaline phosphatase and increased amounts of phospho-  ethanolamine in both the urine and the blood. Interestingly,  as some patients grow older, serum alkaline phosphatase  levels may approach normal.    The histopathologic evaluation of bone sampled from a  patient affected with the infantile form of hypophosphata-  sia shows abundant production of poorly mineralized  osteoid. In the childhood or adult form, the bone may  appear relatively normal or it may show an increased amount  of woven bone, which is a less mature form of osseous tissue.   The histopathologic examination of either a primary or  permanent tooth that has been exfoliated from an affected    ® Fig. 17-38 Hypophosphatasia. This medium-power photomicro-  graph of an exfoliated tooth shows no cementum associated with the  root surface.    patient often shows an absence or a marked reduction of  cementum that covers the root’s surface (Fig. 17-38). This  reduced amount of cementum is thought to predispose to  tooth loss because of the inability of periodontal ligament  fibers to attach to the tooth and to maintain it in its normal  position.    The treatment of hypophosphatasia is essentially symptom-  atic because the lack of alkaline phosphatase cannot be  corrected. Attempts to treat this condition by infusing alka-  line phosphatase have been unsuccessful, presumably  because the enzyme functions within the cell rather than in  the extracellular environment. Basically, fractures are treated  with orthopedic surgery, followed by rehabilitation. Pros-  thetic appliances are indicated to replace missing teeth, but  satisfactory results are not always possible because the alveo-  lar bone is hypoplastic. In patients who are skeletally mature,  dental implants have also been used successfully in manag-  ing the edentulous spaces. Because mutational analysis of  DNA can identify carriers of the defective gene, patients  and their parents should be provided with genetic counsel-  ing. As stated earlier, the prognosis varies with the onset of  symptoms; the perinatal and infantile types are associated  with a rather poor outcome. The childhood and adult forms  are usually compatible with a normal life span.    After the use of vitamin D to treat rickets became wide-  spread, it was recognized that some individuals with clinical  features characteristic of rickets did not seem to respond to  therapeutic doses of the vitamin. For this reason, this condi-  tion in these patients was called vitamin D-resistant  rickets. Most cases of this rare condition appear to be    inherited as an X-linked dominant trait; therefore, males are  usually affected more severely than females, who presum-  ably have attenuated features because of lyonization. In the  United States, this condition occurs at a frequency of 1 in  20,000 births. In addition to the rachitic changes, these  patients are also hypophosphatemic and show a decreased  capacity for reabsorption of phosphate from the renal  tubules. The disorder is caused by mutations in a zinc metal-  loproteinase gene known as phosphate-regulating gene with  endopeptidase activity on the X chromosome (PHEX). Although  the precise mechanisms of action of this gene are unclear,  it appears to play a role in vitamin D metabolism.   In contrast, patients affected by the rare autosomal reces-  sive condition known as vitamin D-—dependent rickets  exhibit hypocalcification of the teeth, unlike those with  vitamin D-resistant rickets. Otherwise, the two disorders  have similar clinical features. Vitamin D—dependent rickets  is caused by a lack of 10-hydroxylase, the enzyme respon-  sible for converting the relatively inactive vitamin D precur-  sor, 25-hydroxycholecalciferol (calcifediol) to the active  metabolite 1,25-dihydroxycholecalciferol (calcitriol) in the  kidney. Therefore, these patients respond to replacement  therapy with active vitamin D (calcitriol).    Patients with vitamin D-resistant rickets have a short  stature. The upper body segment appears more normal, but  the lower body segment is shortened. The lower limbs are  generally shortened and bowed.   Laboratory investigation reveals hypophosphatemia with  diminished renal reabsorption of phosphate and decreased  intestinal absorption of calcium. This typically results  in rachitic changes that are unresponsive to vitamin D  (calciferol). With aging, ankylosis of the spine frequently  develops.   From a dental standpoint, the teeth have large pulp  chambers, with pulp horns extending almost to the denti-  noenamel junction (Figs. 17-39 and 17-40). In some cases    ® Fig. 17-39 Vitamin D-Resistant Rickets. This radiograph of an  extracted tooth shows a prominent pulp chamber with pulp horns  extending out toward the dentinoenamel junction.    the cuspal enamel may be worn down by attrition to the  level of the pulp horn, causing pulpal exposure and pulp  death. The exposure may be so small that the resulting  periapical abscesses and gingival sinus tracts seem to affect  what appear to be otherwise normal teeth (Fig. 17-41).  Studies have also shown that microclefts may develop in the  enamel, giving the oral microflora access to the dentinal  tubules and subsequently to the pulp. One study examined  a series of affected children and found that 25% of these  patients had multiple abscesses involving the primary denti-  tion. Affected adults also have an increased frequency of  endodontic problems, with an average of approximately  seven endodontically treated teeth per person in people over  40 years of age, compared to two endodontically treated  teeth per person in a matched control group.    Microscopic examination of an erupted tooth from a patient  with vitamin D-resistant rickets usually shows markedly    @ Fig. 17-41 Vitamin D-Resistant Rickets. This patient exhibits  multiple nonvital teeth with associated parulides. This arose in the  absence of caries or trauma.    enlarged pulp horns. The dentin appears abnormal and is  characterized by the deposition of globular dentin, which  often exhibits clefting. The clefts may extend from the pulp  chamber to the dentinoenamel junction. Microclefts are  also seen within the enamel. The pulp frequently is nonvital,  presumably because of the bacterial contamination associ-  ated with both the enamel and the dentinal clefts.    For a normal stature to develop, patients with vitamin D—  resistant rickets usually need early treatment with calcitriol  and multiple daily doses of phosphate. Endodontic therapy  is necessary for the pulpally involved teeth. Initiating  therapy in early childhood with a synthetic vitamin D  compound (10-hydroxycholecalciferol) appears to reduce  dental problems in affected patients when compared with  untreated historic controls. Interestingly, the radiographic  dental abnormalities do not seem to be improved. Some  investigators have suggested that application of the newer  dental sealants may reduce the frequency of pulpal necro-  sis, but long-term follow-up studies will be necessary to  confirm this. Although serum and urine calcium levels  must be monitored carefully to prevent nephrocalcinosis  with its potential for kidney damage, patients generally  have a normal life span.    Crohn disease is an inflammatory and probably an immu-  nologically mediated condition of unknown cause that pri-  marily affects the distal portion of the small bowel and the  proximal colon. It is now well established that the manifes-  tations of Crohn disease may be seen anywhere in the gas-  trointestinal tract, from the mouth to the anus. In addition,  other extraintestinal sites of disease involvement (such as,  the skin, eyes, and joints) have also been identified. The oral  lesions are significant because they may precede the gastro-  intestinal lesions in as many as 30% of the cases that have  both oral and gastrointestinal involvement. It is interesting  that the prevalence of Crohn disease appears to be increas-  ing, but the reasons for this increase have not been deter-  mined. Familial clustering of cases has suggested that genetic  factors play a role in the pathogenesis of this disease.    Most patients with Crohn disease are teenagers when the  disease first becomes evident, although another diagnostic  peak of disease activity occurs in patients more than 60  years of age. Gastrointestinal signs and symptoms usually  include abdominal cramping and pain, nausea, and diar-  thea, occasionally accompanied by fever. Weight loss and  malnutrition may develop, which can lead to anemia,  decreased growth, and short stature.    mucosae was caused by repeated ulceration and healing of the  mucosa at this site.    A wide range of oral lesions has been clinically reported  in Crohn disease; however, many of the abnormalities  described are relatively nonspecific and may be associated  with other conditions that cause orofacial granulomatosis  (see page 312). The more prominent findings include diffuse  or nodular swelling of the oral and perioral tissues, a cobble-  stone appearance of the mucosa, and deep, granulomatous-  appearing ulcers. The ulcers are often linear and develop in  the buccal vestibule (Fig. 17-42). Patchy erythematous  macules and plaques involving the attached and unattached  gingivae have been termed mucogingivitis and may represent  one of the more common lesions related to Crohn disease.  Soft tissue swellings that resemble denture-related fibrous  hyperplasia may be seen, as well as smaller mucosal tags.  Another manifestation that has been reported is aphthous-  like oral ulcerations, although the significance of this finding  is uncertain because aphthous ulcerations are found rather  frequently in the general population, including the same age  group that is affected by Crohn disease. One large study  showed no difference in the prevalence of aphthous ulcers  in patients with Crohn disease compared with a control  population. Less than 1% of patients with Crohn disease  may develop diffuse stomatitis, with some cases apparently  caused by Staphylococcus aureus, and others being nonspe-  cific. In at least one instance, recurrent severe buccal space  infections resulted in cutaneous salivary fistula formation.  Infrequently, pyostomatitis vegetans (see next topic) has  been associated with Crohn disease.    Microscopic examination of lesional tissue obtained from  the intestine or from the oral mucosa should show non-  necrotizing granulomatous inflammation within the sub-  mucosal connective tissue (Fig. 17-43). The severity of the  granulomatous inflammation may vary tremendously from  patient to patient and from various sites in the same patient.  Therefore, a negative biopsy result at any one site and time    @ Fig. 17-43 Crohn Disease. This medium-power photomicrograph  of an oral lesion shows a nonnecrotizing granuloma in the submucosal  connective tissue.    may not necessarily rule out a diagnosis of Crohn disease.  As with the clinical lesions, the histopathologic pattern is  relatively nonspecific, resembling orofacial granulomatosis.  Special stains should be performed to rule out the possibil-  ity of deep fungal infection, syphilis, or mycobacterial  infection.    Most patients with mild Crohn disease are initially treated  medically with mesalamine (5-aminosalicylic acid) or sul-  fasalazine, a drug that is enzymatically broken down by  bacteriainthecolontoformsulfapyridineand 5-aminosalicylic  acid. Some patients respond well to this medication, typically  when it is combined with an antibiotic such as metronida-  zole. With moderate to severe involvement, systemic pred-  nisone may be used and is often effective, particularly when  combined with an immunosuppressive drug, such as azathio-  prine, methotrexate, or 6-mercaptopurine. For more severe  or refractory cases of Crohn disease, one of the tumor necro-  sis factor- inhibitors (such as, infliximab, adalimumab, or  certolizumab pegol) may be used. Sometimes the disease  cannot be maintained in remission by medical therapy, and  complications develop that require surgical intervention.  Complications may include bowel obstruction or fistula or  abscess formation. If a significant segment of the terminal  ileum has been removed surgically or is involved with the  disease, then periodic injections of vitamin B,, may be neces-  sary to prevent megaloblastic anemia secondary to the lack  of ability to absorb the vitamin. Similar supplementation of  magnesium, iron, the fat-soluble vitamins, and folate may  also be required because of malabsorption. Cigarette smoking  is known to exacerbate Crohn disease, and patients should  be advised to stop this habit.   Oral lesions have been reported to clear with treatment  of the gastrointestinal process in many cases. Occasionally  persistent oral ulcerations will develop, and these may  have to be treated with topical or intralesional corticoste-  roids. Systemic thalidomide and infliximab have been    © Fig. 17-44 Pyostomatitis Vegetans. The characteristic lesions  are seen on the buccal mucosa, appearing as yellow-white pustules.    Pyostomatitis vegetans is a relatively rare condition that  has a controversial history. It has been associated in the past  with diseases such as pemphigus or pyodermatitis vegetans.  Most investigators today, however, believe that pyostomati-  tis vegetans is an unusual oral expression of inflammatory  bowel disease, particularly ulcerative colitis or Crohn  disease. The pathogenesis of the condition, like that of  inflammatory bowel disease, is poorly understood. A few  patients with pyostomatitis vegetans have also been noted  to have one of several concurrent liver abnormalities.    Patients with pyostomatitis vegetans exhibit characteristic  yellowish, slightly elevated, linear, serpentine pustules set on  an erythematous oral mucosa. The lesions primarily affect  the buccal and labial mucosa, soft palate, and ventral tongue  (Figs. 17-44 and 17-45). These lesions have been called  “snail track” ulcerations, although in most instances the  lesions are probably not truly ulcerated. Oral discomfort is  variable but can be surprisingly minimal in some patients.  This variation in symptoms may be related to the number  of pustules that have ruptured to form ulcerations. The oral  lesions may appear concurrently with the bowel symptoms,  or they may precede the intestinal involvement.    A biopsy specimen of an oral lesion of pyostomatitis vege-  tans usually shows marked edema, causing an acantholytic  appearance of the involved epithelium. This may be the  result of the accumulation of numerous eosinophils within  the spinous layer, often forming intraepithelial abscesses  (Fig. 17-46). Subepithelial eosinophilic abscesses have been    ° Fig. 17-45 Pyostomatitis Vegetans. A, Characteristic “snail  track” lesions involve the soft palate. B, Same patient after 5 days of  prednisone therapy. (From Neville BW, Laden SA, Smith SE, et al:  Pyostomatitis vegetans, Am J Dermatopathol 7:69-77, 1985.)    reported in some instances. The underlying connective  tissue usually supports a dense mixed infiltrate of inflam-  matory cells that consists of eosinophils, neutrophils, and  lymphocytes. Perivascular inflammation may also be present.    Usually, the intestinal signs and symptoms of inflammatory  bowel disease are of most concern for patients with pyosto-  matitis vegetans. Medical management of the bowel disease  with sulfasalazine or systemic corticosteroids also produces  clearing of the oral lesions (see Fig. 17-45). Often the oral  lesions clear within days after systemic corticosteroid therapy  has begun, and they may recur if the medication is with-  drawn. If the bowel symptoms are relatively mild, then the  oral lesions have been reported to respond to topical therapy  with some of the more potent corticosteroid preparations.    Patients who have either acute or chronic renal failure  typically show markedly elevated levels of urea and other  nitrogenous wastes in the bloodstream. Uremic stomatitis  represents a relatively uncommon complication of renal  failure. In two series that included 562 patients with renal  failure, only eight examples of this oral mucosal condition  were documented. Nevertheless, for the patients in whom  uremic stomatitis develops, this can be a painful disorder.  The cause of the oral lesions is unclear, but some investiga-  tors suggest that urease, an enzyme produced by the oral  microflora, may degrade urea secreted in the saliva. This  degradation results in the liberation of free ammonia, which  presumably damages the oral mucosa.    Most cases of uremic stomatitis have been reported in  patients with acute renal failure. The onset may be abrupt,  with white plaques distributed predominantly on the buccal  mucosa, tongue, and floor of the mouth (Fig. 17-47).  Patients may complain of unpleasant taste, oral pain, or a  burning sensation with the lesions, and the clinician may  detect an odor of ammonia or urine on the patient’s breath.  The clinical appearance occasionally has been known to  mimic oral hairy leukoplakia.    In some instances, uremic stomatitis may clear within a few  days after renal dialysis, although such resolution may take  place over 2 to 3 weeks. In other instances, treatment with  a mildly acidic mouth rinse, such as diluted hydrogen per-  oxide, seems to clear the oral lesions. For control of pain  while the lesions heal, patients may be given palliative  therapy with ice chips or a topical anesthetic, such as viscous  lidocaine or dyclonine hydrochloride. 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Nico MMS, Hussein TP, Aoki V, et al: Pyostomatitis vegetans and its  relation to inflammatory bowel disease, pyoderma gangrenosum,  pyodermatitis vegetans, and pemphigus, / Oral Pathol Med  41:584-588, 2012.   Thornhill MH, Zakrzewska JM, Gilkes JJH: Pyostomatitis vegetans:  report of three cases and review of the literature, J Oral Pathol Med  21:128-133, 1992.   Halazonetis J, Harley A: Uremic stomatitis: report of a case, Oral Surg  Oral Med Oral Pathol 23:573-577, 1967.   Hovinga J, Roodvoets AP, Gailliard J: Some findings in patients with  uraemic stomatitis, / Maxillofac Surg 3:124-127, 1975.   Leao JC, Gueiros LAM, Segundo AVL, et al: Uremic stomatitis in  chronic renal failure, Clinics 60:259-262, 2005.   McCreary CE, Flint SR, McCartan BE, et al: Uremic stomatitis mim-  icking oral hairy leukoplakia. Report of a case, Oral Surg Oral Med  Oral Pathol Oral Radiol Endod 83:350-353, 1997.   Proctor R, Kumar N, Stein A, et al: Oral and dental aspects of chronic  renal failure, ] Dent Res 84:199-208, 2005.   Ross WF, Salisbury PL: Uremic stomatitis associated with undiag-  nosed renal failure, Gen Dent 42:410-412, 1994.    Bell palsy is an acute weakness or paralysis of the facial  nerve without an identifiable cause. Although the etiology  is uncertain, evidence suggests that the condition may be  related to either a herpes virus infection (herpes simplex or  varicella-zoster) or a cell-mediated autoimmune reaction  resulting in demyelination of the nerve. A variety of factors  may increase the risk for developing Bell palsy, including:  e Pregnancy (especially third trimester)  ¢ Preeclampsia  e Diabetes  ¢ Hypertension  © Obesity  ¢ Upper respiratory infections   Depending on the population studied, the annual inci-  dence of Bell palsy ranges from 11.5 to 53.3 per 100,000  persons. The lifetime risk for developing this condition is 1  in 60. Although Bell palsy is the most common cause of  facial paresis or paralysis, it is a diagnosis of exclusion that  should be reserved for idiopathic cases of sudden onset.  Other specific conditions may cause facial nerve paralysis,  including neoplasms, sarcoidosis, orofacial granulomatosis  (Melkersson-Rosenthal syndrome), Lyme disease, congeni-  tal malformations, inappropriate administration of local  anesthesia, trauma, and postsurgical damage.    Bell palsy can occur at any age, but it develops most fre-  quently in young and middle-aged adults. The condition is  characterized by an abrupt loss of muscular control on one  side of the face, imparting a rigid masklike appearance and  resulting in the inability to smile, to close the eye, to wink,    or to raise the eyebrow (Fig. 18-1). The paralysis may take  several hours to become complete, but patients frequently  awaken in the morning with a full-fledged case. The corner  of the mouth often droops, causing saliva to drool onto the  skin. Speech becomes slurred and taste may be abnormal.  Because the eyelid cannot close, conjunctival dryness or  ulceration may occur. A few patients will experience pro-  dromal pain on the affected side before the onset of  paralysis.   Infrequently, bilateral involvement is seen. However,  rapid onset of bilateral facial weakness should alert the clini-  cian to the possibility of other diseases, such as Guillain-  Barré syndrome or a form of sarcoidosis known as  uveoparotid fever (see Heerfordt syndrome, page 310). If  multiple cranial nerve deficits accompany facial nerve paral-  ysis, then central nervous system (CNS) infectious diseases  and basilar skull tumors must be considered in the differ-  ential diagnosis. If the patient has symptoms of vertigo or  tinnitus, then a diagnosis of Ramsay Hunt syndrome must  be suspected (see page 228).    Bell palsy is a self-limiting condition, and most patients will  recover over a 3 to 4 month period. Without treatment,  complete facial nerve function will be restored in nearly  three-quarters of patients with complete paralysis and in  over 90% of patients with partial paralysis. However, as  many as 20% to 30% of patients will not recover com-  pletely. The most consistently effective treatment is systemic  corticosteroid therapy, which has been shown to improve  recovery rates by 12.8% to 15%. A 10-day tapering course  of prednisone is often prescribed, beginning at a dosage of  60 mg per day. Antiviral therapy (acyclovir, famciclovir, or  valacyclovir) may be associated with a modest improvement  in recovery, when given in combination with corticoste-  roids. However, antiviral therapy alone is not recommended.    @ Fig. 18-1 Bell Palsy. Paralysis of the facial muscles on the patient’s left side. A, Patient is trying to    raise the eyebrows. B, Patient is attempting to close the eyes and smile. (Courtesy of Dr. Bruce B. Brehm.)    Surgical decompression of the facial nerve has been  attempted in select cases, but evidence for the effectiveness  of this approach is lacking. Eye protection is critical for  patients with impaired eye closure. Topical ocular antibiot-  ics and artificial tears may be required to prevent corneal  ulceration, and the eyelid may have to be taped shut.    Named for Polish neurologist Lucja Frey, Frey syndrome is  characterized by facial flushing and sweating along the dis-  tribution of the auriculotemporal nerve. These signs occur  in response to gustatory stimuli, and the syndrome results  from injury to the nerve.   The auriculotemporal nerve, in addition to supplying  sensory fibers to the preauricular and temporal regions,  carries parasympathetic fibers to the parotid gland and sym-  pathetic vasomotor and sudomotor (sweat stimulating)  fibers to the preauricular skin. After parotid abscess, trauma,  mandibular surgery, or parotidectomy, the parasympathetic  nerve fibers may be severed. In their attempt to reestablish  innervation, these fibers occasionally become misdirected  and regenerate along the sympathetic nerve pathways,  establishing communication with the sympathetic nerve  fibers of sweat glands and blood vessels of the facial skin.    The most widely accepted mechanism of Frey syndrome is  aberrant neuronal regeneration. Subsequent to these aber-  rant neural connections, when salivation is stimulated, local  sweat glands are activated inadvertently and the patient’s  cheek becomes flushed and moist.   More than 40% of patients with parotidectomies will  develop clinically evident Frey syndrome as a complication  of surgery, although a much higher frequency (70% to  100%) can be documented if objective testing is performed  (Minor starch-iodine test). The condition is rare in infancy  but has been seen after forceps delivery. Neonatal cases typi-  cally do not occur until the child begins to eat solid foods,  at which time it may be interpreted as an allergy. Interest-  ingly, more than one-third of diabetics with neuropathy will  experience bilateral gustatory sweating of the face and neck,  especially those who also have severe kidney damage.   Related phenomena may accompany an operation or  injury to the submandibular gland (chorda tympani syn-  drome) or the facial nerve proximal to the geniculate gan-  glion (gustatory lacrimation syndrome, “crocodile  tears”). The chin and submental skin demonstrate sweating  and flushing in the former. Chewing food in the latter  syndrome produces abundant tear formation.    The presenting signs and symptoms of Frey syndrome  include sweating, flushing, warmth, and occasionally pain    @ Fig. 18-2 Frey Syndrome. This patient received an injury to her  auriculotemporal nerve during orthognathic surgery 3 years earlier.  Notice the region of sweating detected during mastication by a color  change of the starch in the Minor starch-iodine test.    in the preauricular and temporal regions during chewing.  Within 2 months to 2 years (average, 9 months) after the  nerve injury, the sweating and flushing reactions commence  and become steadily more severe for several months, remain-  ing constant thereafter. When flushing occurs, the local skin  temperature may be raised as much as 2° C. This may occur  without sweating, especially in females. Pain, when present,  is usually mild, and hypesthesia (hypoesthesia) or hyperes-  thesia are common features.   To detect sweating, a Minor starch-iodine test may be  used. A 1% iodine solution is painted on the affected area  of the skin. This solution is allowed to dry, and the area is  then coated with a layer of starch. When the patient is given  something to eat, the moisture of the sweat that is produced  will mix with the iodine on the skin. This allows the iodine  to react with the starch and produce a blue color (Fig. 18-2).  Iodine-sublimated paper, which changes color when wet,  also can be used, and thermography or surface thermome-  ters will document the temperature changes of the skin.    Most cases are mild enough that treatment is not required.  Moreover, approximately 5% of adult patients and almost  all affected infants experience spontaneous resolution of the  syndrome.   If treatment is desired, intracutaneous injections of botu-  linum toxin A can provide long-term relief, although injec-  tions may need to be repeated. Topically applied  anticholinergic medications, such as scopolamine and gly-  copyrrolate, also have been used for short-term control.  Surgical management, such as insertion of various tissue  barriers or tympanic neurectomy, rarely is indicated or  required. The initial risk for developing Frey syndrome is  greatly diminished by positioning a musculofascial flap or  allograft between the gland and the overlying skin of the  cheek at the time of parotidectomy.    Pain is a universal experience, and our understanding of  pain and pain management has increased significantly over  the past 30 years. For the most part, pain is a protective  mechanism that alerts the organism to the possibility of  harm. As pain is the primary motivation for the majority  of health care encounters in our culture, it is prudent to  consider pain in a broader context prior to discussing spe-  cific pain entities common to the head and neck region.  Customarily pain is divided in acute and chronic forms,  with acute pain management having the most predictable  clinical outcomes. Estimates suggest that between 17% to  26% of the general population experience orofacial pain,  and for 7% to 12% that pain presentation will become  chronic. The majority of acute pain presentations in dental  practice are associated with the teeth and their supporting  structures, and dentists usually diagnose and treat these  conditions with relative ease. Inflammatory conditions of  the pulp and periodontium are managed so successfully that  patients commonly seek dental services for any and all pains  occurring in the head and neck region.   The diagnosis and management of non-odontogenic  head and neck pain presents a challenge to even the most  skilled diagnosticians. The complexity of the neural and  vascular networks of the orofacial region contributes to the  diagnostic difficulties. Ultimately pain fibers from this  region travel to the spinal nucleus caudalis of the trigeminal  nerve in a process known as trigeminal convergence. This  convergence often makes it virtually impossible for patients  to distinguish the site of their pain from the source of their  pain in a reliable fashion. For this reason, it is important  that health care providers have a working knowledge of the  myriad of diagnostic possibilities for those patients present-  ing with chronic orofacial pain. Although it is well beyond  the scope of this chapter to discuss each of these entities,  differential considerations related to chronic orofacial pain  are summarized in Box 18-1. In general, if the pain is  thought to be of non-dental origin, then a comprehensive  pain evaluation, complete with diagnostic anesthesia and  appropriate laboratory testing, is warranted.    ‘The head and neck region is a common site for neuralgias  (pain extending along the course of a nerve). Because facial  neuralgias produce pain that often mimics pain of dental  origin, the dental profession is frequently called on to rule  out odontogenic or inflammatory causes. Trigeminal neu-  ralgia, the most serious and the most common of the facial  neuralgias, is characterized by an extremely severe electric  shocklike or lancinating (i.e., sharp, jabbing) pain limited  to one or more branches of the trigeminal nerve. In the  majority of cases the pain is located in the maxillary (V2)    Joint pain  Arthralgia  Arthritis  Joint disorders  Disc-condyle complex disorder  Hypomobility disorders  Adhesions  Ankylosis  lypermobility disorders  Subluxation  Luxation  Joint diseases  Degenerative joint disease  Condylysis  Osteochondritis dissecans  Osteonecrosis  Synovial chondromatosis  Congenital/developmental disorders of the condyle  Aplasia  Hypoplasia  Hyperplasia    Muscle pain limited to the orofacial region  Myalgia  Myositis  Masticatory muscle pain attributed to systemic/central  disorders  Fibromyalgia  Centrally mediated myalgia    Migraine headache  Tension-type headache (TTH)  Trigeminal autonomic cephalalgias (TACS)  Cluster headache  Paroxysmal hemicrania  Short-lasting unilateral neuralgia headache attacks with  conjunctival injection and tearing (SUNCT)    Other primary headaches  Primary exertional headache  Primary thunderclap headache  Hypnic headache  Hemicrania continua    Trigeminal neuralgia  Pretrigeminal neuralgia  Glossopharyngeal neuralgia  Nervus intermedius neuralgia  Superior laryngeal neuralgia  Occipital neuralgia  Painful ophthalmoplegia   Connective tissue diseases  Systemic lupus erythematosus  Rheumatoid arthritis (RA)  Sjégren syndrome  Systemic sclerosis    Modified from de Leeuw R, Klasser GD, editors: Orofacial pain—qguidelines for assessment, diagnosis and management, ed 5, Chicago, 2013,    or the mandibular (V3) distribution of the nerve. The sig-  nificance of this disorder is underscored by the fact that it  has one of the highest suicide rates of any disease and is  regarded as one of the most painful afflictions known.   Classical trigeminal neuralgia has no definite etiology,  although it is often thought to be related to compression of  the trigeminal nerve by aging blood vessels, which renders  the nerve susceptible to localized demyelination. Secondary  or symptomatic trigeminal neuralgia may develop in patients  with multiple sclerosis, or occur secondary to compression  of the nerve by tumors or arteriovenous malformations.   In the United States, the reported incidence of trigeminal  neuralgia is 4 to 5 cases per 100,000 population annually.  However, recent studies from Europe have reported much    higher incidence rates of 26.8 to 28.9 per 100,000. From  2% to 4% of cases occur in patients with multiple sclerosis;  conversely, approximately 2% to 4% of patients with mul-  tiple sclerosis will develop trigeminal neuralgia.    Trigeminal neuralgia characteristically affects individuals  older than 50 years of age, although it can develop at any  age, including young children. Women are affected more  often than men by a ratio of 1.5:1. One or more branches  of the trigeminal nerve may be involved, but the ophthalmic  division is affected alone in only 4% of cases. Bilateral  involvement is unusual and may suggest the possibility of    underlying multiple sclerosis. Trigeminal neuralgia associ-  ated with multiple sclerosis also tends to develop at a  younger age.   In the early stages, the pain of trigeminal neuralgia may  be rather mild and is often described by the patient as a  twinge, dull ache, or burning sensation. This clinical pre-  sentation may be attributed erroneously to disorders of the  teeth, jaws, and paranasal sinuses, leading to inappropriate  treatment. With time, the attacks occur at more frequent  intervals and the pain becomes increasingly intense, some-  times being described as feeling like “an electric shock,” “a  bolt of lightning,” or “being stabbed by an ice pick.” Patients  often clutch at the face and experience spasmodic contrac-  tions of the facial muscles during attacks, a feature that long  ago led to the use of the term tic douloureux (i.e., painful  jerking) for this disease.   For most patients, the pain will be provoked by stimula-  tion of a specific trigger zone along the distribution of the  trigeminal nerve, often in the nasolabial fold or intraoral  region. Sudden onset of pain will occur following mild  stimulation of this trigger area, such as:   Each painful episode typically lasts for no longer than  2 minutes, followed by a refractory period in which stimula-  tion of the trigger zone will not elicit another attack.  This refractory period can be useful, clinically, in distin-  guishing trigeminal neuralgia from  stimulus-provoked  odontogenic pain.   Specific and strict criteria must be met for an accurate  diagnosis (Box 18-2). If the pain pattern does not meet  these criteria, then a different diagnosis should be consid-  ered. When these criteria are partially fulfilled, alternative  terms such as atypical trigeminal neuralgia, persistent idio-  pathic facial pain, and atypical facial neuralgia are applied.  Another distinguishing feature of trigeminal neuralgia is  that objective signs of sensory loss cannot be demonstrated  on physical examination. The presence of objective facial  sensory loss, facial weakness, or ataxia should raise the dis-  tinct possibility of a CNS tumor.    There have been rare reports of spontaneous permanent  remissions of trigeminal neuralgia. However, more often  than not, this disease is characterized by a protracted clinical  course with increasing frequency and severity of exacerba-  tions. The initial treatment for trigeminal neuralgia is phar-  macological, with carbamazepine (an anticonvulsant) being  the first drug of choice. Approximately 80% of patients will  respond favorably to this medication, and an unequivocal  response to carbamazepine can be used as a diagnostic test  for this disease. Other anticonvulsant medications (phe-  nytoin, oxcarbazepine, gabapentin, lamotrigine, and topira-   e The duration of a single pain “spasm” is less than 2 minutes,  although the overall attack may consist of numerous  repeating spasms of short duration.   e The pain must be limited to the Known distribution of one or   e The pain is dramatically diminished, at least initially, with the  use of carbamazepine.   e Spontaneous remissions occur, often lasting more than 6  months, especially during the early phase of the disease.    e Repositioning of blood vessels impinging on trigeminal nerve  (microvascular decompression)   e Injection of caustic material near nerves leaving or entering  the gasserian ganglion (glycerol rhizotomy)   e Removal of skull base bony irregularities impinging on  trigeminal nerve (decompression)   e Selective destruction of the sensory fibers of the nerve by  crushing or by the application of heat (percutaneous  radiofrequency rhizotomy)    mate) also have been used, either alone or in combination  with baclofen—a skeletal muscle relaxant. These drugs,  unfortunately, often have significant side effects and may  not be tolerated for long by the patient. Also, the effective-  ness of anticonvulsants in controlling pain often decreases  over time. Interestingly, opioid medications are typically  ineffective in managing the pain of trigeminal neuralgia.   If medical management fails, a variety of surgical treat-  ments may be considered (Box 18-3). Suboccipital micro-  vascular decompression of the trigeminal nerve root is an  invasive, but nondestructive, technique that attempts to  alleviate the presumed cause of most cases of classical tri-  geminal neuralgia—i.e., compression of the nerve by adja-  cent blood vessels. This is a major neurosurgical procedure  that is associated with a mortality rate of 0.2% to 1.2%.  However, 65% to 73% of patients will be pain free 10 years  or longer after surgery. Potential long-term complications  include facial numbness and ipsilateral hearing loss.   Less invasive surgical techniques are aimed at destroying  affected portions of the trigeminal nerve. These procedures  include radiofrequency rhizotomy of the affected branch of  the trigeminal nerve, percutaneous retrogasserian glycerol  thizotomy, balloon microcompression of the gasserian    ganglion, and stereotactic radiosurgery (Gamma Knife).  Short-term pain relief from these methods ranges from 60%  to 79% at 2 years. However, repeated surgical procedures  often become necessary, and techniques that deliberately  damage neural tissues leave the patient with a sensory  deficit. After surgery, up to 8% of patients develop distorted  sensations of the facial skin (facial dysesthesia) or a com-  bination of anesthesia and spontaneous pain (anesthesia  dolorosa). Anesthesia dolorosa is a dreaded form of central  pain that can occur after any neurosurgical procedure that  causes a variable amount of sensory loss, but this complica-  tion occurs more commonly with procedures that totally  denervate a region.    Neuralgia of the ninth cranial nerve, glossopharyngeal  neuralgia, is similar to trigeminal neuralgia (see previous  topic) except in the anatomic location of the pain. In glos-  sopharyngeal neuralgia, the pain is centered on the tonsil  and the ear. The pain often radiates from the throat to the  ear because of the involvement of the tympanic branch of  the glossopharyngeal nerve. Some unfortunate individuals  have a combination of glossopharyngeal neuralgia and tri-  geminal neuralgia.   Glossopharyngeal neuralgia is rare, representing only  0.2% to 1.3% of facial pain syndromes. The pain also may  affect sensory areas supplied by the pharyngeal and auricular  branches of the vagus nerve. As with trigeminal neuralgia,  two subtypes of glossopharyngeal neuralgia are recognized:  classical and symptomatic (secondary). Classical glossopha-  ryngeal is unassociated with any underlying disorder and  often is attributed to arterial compression of the nerve as it  courses through the subarachnoid space to the jugular  foramen. Symptomatic glossopharyngeal neuralgia occurs  secondary to compression of the nerve by a specific lesion,  such as intracranial or cranial base tumors, oropharyngeal  tumors, pagetic bone, or calcified stylohyoid ligament  (Eagle syndrome; see page 21). Unlike trigeminal neuralgia,  it is uncommon for glossopharyngeal neuralgia to be associ-  ated with multiple sclerosis.    Glossopharyngeal neuralgia usually occurs in middle-aged  and older adults. There is no sex predilection, and only  rarely is there bilateral involvement. The paroxysmal pain  may be felt in the ear (tympanic plexus neuralgia), infra-  auricular area, tonsil, base of the tongue, posterior mandi-  ble, or lateral wall of the pharynx; however, the patient often  has difficulty localizing the pain in the oropharynx.   The episodic pain in this unilateral neuralgia is sharp,  lancinating (jabbing), and extremely intense. Attacks have  an abrupt onset and a short duration (seconds to minutes).    The pain typically radiates upward from the oropharynx to  the ipsilateral ear. Talking, chewing, swallowing, yawning,  or touching a blunt instrument to the tonsil on the affected  side may precipitate the pain, but a definite trigger zone is  not easily identified. Because the pain is related to jaw  movement, it may be confused with the pain of temporo-  mandibular joint dysfunction.   Patients frequently point to the neck immediately below  the angle of the mandible as the site of greatest pain, but  trigger points are not found on the external skin, except  within the ear canal. Excessive vagal effects will occur in  approximately 10% of patients, resulting in syncope, hypo-  tension, seizures, bradycardia, or cardiac arrest (vagoglos-  sopharyngeal neuralgia).    As in trigeminal neuralgia, glossopharyngeal neuralgia  is subject to unpredictable remissions and recurrences. It  is not unusual during the early stages for remissions to  last 6 months or more. Painful episodes are of varying sever-  ity but generally become more severe and more frequent  with time.   Many patients will experience pain relief when a topical  anesthetic agent is applied to the tonsil and pharynx on the  side of the pain. Because this relief lasts only 60 to 90  minutes, it is used more as a diagnostic tool and emergency  measure than a long-term treatment. Repeated applications  to a trigger point for 2 or 3 days may extend the pain-free  episode enough to allow the patient to obtain much needed  rest and nutrition.   For most patients with classical glossopharyngeal neural-  gia, the first line of therapy is pharmacological. Anticonvul-  sants medications (such as, carbamazepine, oxcarbazepine,  baclofen, phenytoin, and lamotrigine) may relieve the neu-  ralgic pain for a long period, but no therapy is considered  to be uniformly effective. For individuals with vagoglosso-  pharyngeal neuralgia, atropine can be used to prevent the  related cardiac phenomena. If a patient with glossopharyn-  geal neuralgia fails drug therapy, then surgical options  should be considered. The preferred neurosurgical treat-  ments are microvascular decompression or surgical section-  ing of the glossopharyngeal nerve and the upper two rootlets  of the vagus nerve. Other possible procedures include radio-  frequency nerve ablation, balloon compression, and stereo-  tactic radiosurgery (Gamma Knife ablation). If the pain is  secondary to another condition (e.g., tumor or Eagle syn-  drome), then management of the underlying lesion must be    Giant cell arteritis is an immune-mediated vasculitis that  affects medium-sized and larger arteries, leading to vascular    occlusion and ischemia. Because the superficial temporal  artery is the most commonly affected site, the condition also  is known as temporal arteritis. Although giant cell arteritis  most often affects head and neck vessels, it is considered to  be a systemic condition that can affect multiple vessels,  including the aorta and its proximal branches. Although the  exact cause is uncertain, there appears to be a strong genetic  predisposition, with a higher frequency of disease in patients  who express certain human leukocyte antigen (HLA) types,  such as HLA-DR4. Because geographic and seasonal varia-  tions have been observed, an infectious etiology or trigger  also has been suggested.   Giant cell arteritis occurs primarily in older individuals;  the condition demonstrates an annual incidence rate of 15  to 25 per 100,000 population past the age of 50 years, with  an increased incidence associated with advancing age. The  disease shows a predilection for individuals of Scandinavian  and northern European descent.    Women are affected by giant cell arteritis more than twice  as often as men, and patients are rarely younger than 50  years of age at the time of diagnosis (average age, 70 years).  The disease most frequently involves the temporal artery,  presenting with symptoms of severe headache and scalp  tenderness. A highly characteristic feature is jaw claudica-  tion, which is described as cramping pain of the masseter  and temporalis muscles that increases with usage (chewing  or talking) but is relieved by rest. The superficial temporal  artery is exquisitely sensitive to palpation and eventually  appears erythematous, swollen, tortuous, or sometimes  ulcerated. Rare examples of unilateral or bilateral tongue  necrosis secondary to lingual artery involvement also have  been described.   The most significant complication in the head and  neck region is vision loss, which usually is due to vascu-  litis of the posterior ciliary artery and ischemic optic  neuropathy. Ocular involvement has been reported in  anywhere from 14% to 70% of patients, often resulting  in partial or total loss of vision in one or both eyes.  Permanent loss of vision occurs in 15% of patients. Visual  disturbances often are an early manifestation of giant cell  arteritis, sometimes occurring before the onset of other  symptoms.   Systemic signs and symptoms include fever, malaise,  fatigue, anorexia, and weight loss. Many patients develop  polymyalgia rheumatica, which is characterized by aching  pain and morning stiffness in the neck, shoulders, and  pelvic girdle. Giant cell arteritis will affect the aorta and  other large vessels in at least 50% of cases, although such  involvement often is asymptomatic. On occasion, however,  undetected aortic inflammation may be associated with  aortic aneurysm and rupture. Rare manifestations include  cerebrovascular accidents and cardiac infarction. Vasculitis  of the extremities can lead to limb claudication and isch-  emic changes.    The diagnosis of giant cell arteritis usually is confirmed by  biopsy of the temporal artery. Microscopic changes tend to  be segmental and can be missed if the specimen is too small.  At least 1 cm of the affected vessel must, therefore, be  examined for proper evaluation.   The disease is characterized by chronic inflammation of  the tunica intima and tunica media of the involved artery,  with narrowing of the lumen from edema and proliferation  of the tunica intima. Necrosis of the smooth muscle and  elastic lamina is frequent. A variable number of multinucle-  ated giant cells are mixed with macrophages and lympho-  cytes. Thrombosis or complete occlusion of the lumen is  not unusual.   Clinical laboratory features often include an elevated  erythrocyte sedimentation rate, increased C-reactive protein  levels, and an elevated platelet count.    Because of the risk for sudden and permanent loss of vision,  prompt treatment of giant cell arteritis is critical. The disease  typically responds well to high-dose systemic corticosteroid  therapy, and symptoms often subside within a few days.  However, many cases are chronic and require treatment for  years. Methotrexate or azathioprine sometimes will be  added for their steroid-sparing effects.    ¢ BURNING MOUTH DISORDER  (STOMATOPYROSIS; STOMATODYNIA;  GLOSSOPYROSIS; GLOSSODYNIA;  BURNING TONGUE SYNDROME; BURNING  MOUTH SYNDROME)    Burning mouth disorder (BMD) is a confounding pain  condition that is generally considered neuropathic in nature  with both peripheral and central components. Because dys-  geusia (altered taste) and xerostomia frequently accompany  the onset of burning sensation, this condition was previously  referred to as burning mouth syndrome. Whether the presence  of these additional clinical findings actually constitute a  syndrome is a matter of much debate and, therefore, it is  probably more appropriate to designate this condition as a  disorder rather than a syndrome. Interestingly, more than  two-thirds of patients with BMD report dysgeusia and these  patients characteristically describe this alteration as a “metal-  lic taste.” Although there is considerable debate in the pain  community regarding the pathophysiology of BMD, current  research suggests that primary BMD is related to problems  with both taste and sensory nerves. BMD may result from  hyperactivity of the sensory component of the trigeminal  system and loss of central inhibition secondary to damage to  the chorda tympani or from a disturbance in the balance  between the gustatory and sensory systems.   Atypical facial pain or neuralgia  Angioedema (angioneurotic edema)  Oral candidiasis  Temporomandibular dysfunction  Oral submucous fibrosis  Fusospirochetal infection    Vitamin B deficiency  e Vitamin B, or B, deficiency  e Pernicious anemia (B;2)  e Pellagra (niacin deficiency)  e Folic acid deficiency  Diabetes mellitus  Chronic gastritis or regurgitation  Chronic gastric hypoacidity  Hypothyroidism  Mercurialism  Estrogen deficiency  Anxiety, stress, and depression  Parkinson disease  Acquired immunodeficiency syndrome (AIDS)    BMD is consistently described by the patient as a burning  sensation of the oral mucosa. When this pain occurs in the  absence of both clinical and laboratory findings, the condi-  tion is classified as primary or idiopathic BMD. Secondary  BMD is reserved for those clinical presentations which are  associated with underling local or systemic factors. Although  the tongue is most commonly affected (glossopyrosis),  other mucosal surfaces also may be symptomatic (stomato-  pyrosis). The anterior hard palate and the mucosal aspect  of the lower lip are frequently involved.   Various local and systemic factors have been postulated  to cause this condition (Box 18-4), but none have been  proven. The disorder has been reported to be strongly asso-  ciated with depression and anxiety states, but the relation-  ship of the clinical presentation to the development of  psychologic distress is unknown.   Burning tongue syndrome affects 0.7% to 15% of adults  to some degree (12.2% of postmenopausal women). Asians  and Native Americans have a considerably higher risk than  whites or blacks, and there is increasing prevalence with  advancing age, especially after 55 years of age. This disorder  is one of the most common non-dental orofacial pains  encountered in the clinical practice.    Women are four to seven times more likely to present with  burning tongue syndrome than men. The syndrome is rare  before the age of 30 years (40 years for men), and the onset  in women usually occurs within 3 to 12 years after  menopause.   Typically, this disorder has an abrupt onset, although it  may be quite gradual. The dorsum of the tongue develops  a burning sensation, usually strongest in the anterior two-  thirds. Occasionally, patients will describe an irritated or  raw feeling that can be exacerbated by spicy or acidic foods.  Mucosal changes are seldom visible, although some patients  will show diminished numbers and size of filiform papillae,  and individuals who habitually rub the tongue against the  teeth often have erythematous and edematous papillae on  the tip of the tongue. If the dorsum is significantly ery-  thematous and smooth, an underlying systemic or local  infectious process, such as anemia or erythematous candi-  diasis, should be suspected.   Further questioning often confirms that other oral sites  are affected similarly, especially the anterior hard palate and  the lips. There is seldom a significant decrease in stimulated  salivary output in tests, despite the frequent patient com-  plaint of xerostomia. Salivary levels of various proteins,  immunoglobulins, and phosphates may be elevated, and  there may be a decreased salivary pH or buffering capacity.   One frequently described pattern is that of mild discom-  fort on awakening, with increasing intensity throughout the  day. Other affected patients describe a waxing and waning  pattern that occurs over several days or weeks. Usually the  condition does not interfere with sleep. A persistently  altered (salty, bitter) or diminished taste may accompany  the burning sensation. Contact with hot food or liquid  often intensifies the symptoms. A minority describe a con-  stant degree of discomfort. Most individuals with burning  tongue disorder report that their symptoms flare in the  presence of increased personal stressors as is typical with  many chronic pain conditions.   As with other chronic discomforts, affected patients fre-  quently demonstrate psychologic dysfunction, usually  depression, anxiety, or irritability. The dysfunction often  disappears, however, with resolution of the burning or  painful tongue condition, and there is no correlation  between duration and intensity of the burning sensation  and the amount of psychologic dysfunction.    If an underlying systemic or local cause can be identified  and corrected, the burning symptoms should predictably  disappear. Almost two-thirds of patients with idiopathic  disease show at least some improvement of their symptoms  with pharmacologic therapies including: anxiolytics, anti-  oxidants, antidepressants and/or anticonvulsants alone or in  combination. Evidence from randomized controlled trials  suggests that a clinical trial of clonazepam should be    deployed as a first line therapy in patients with BMD. The  use of topical or systemically administered clonazepam in  conjunction with the antioxidant alpha lipoic acid (600 mg)  has shown promise in the management of BMD. However,  some studies have failed to confirm the effectiveness of  alpha lipoic acid alone over placebo. Cognitive behavioral  therapy alone or in combination with the evidence-based  pharmacologic management described above may be par-  ticularly useful in those patients with significant underlying  psychological factors.   The long-term prognosis for BMD is variable. It is  reported that one-third to one-half of patients experience a  spontaneous or gradual remission months or years after the  onset of symptoms. However, other patients may be refrac-  tory to therapeutic interventions and continue to experi-  ence symptoms throughout the rest of their lives. Even  though the condition is chronic and may not always respond  to therapy, patients should be reassured that BMD is benign    Dysgeusia is defined as a persistent abnormal taste and this  condition was mentioned briefly in the previous section on  burning mouth disorder. However, dysgeusia occurs inde-  pendently of this association and merits additional discus-  sion here. Interestingly, the majority of purported taste  disorders are in fact disorders of smell, and deficiencies in  one or both of these senses has a potentially significant  impact on the patient’s quality of life. Dysgeusia is consider-  ably less common than simple deficiencies in smell    (hyposmia, anosmia) and taste (hypogeusia, ageusia) per-  ception, which are found in approximately 2 million Ameri-  can adults. Dysgeusia is less tolerated than hypogeusia or  hyposmia, explaining why it accounts for more than one-  third of patients in chemosensory centers. In general, both  taste and smell discriminatory capability decreases with  advancing age.   Most cases of dysgeusia are produced by or associated  with an underlying systemic disorder or by radiation therapy  to the head and neck region (Box 18-5). Trauma, tumors,  or inflammation of the peripheral nerves of the gustatory  system usually produce transient hypogeusia rather than  dysgeusia. In contrast, relatively common upper respiratory  tract infections produce a temporary and mild dysgeusia in  almost one-third of cases, although they seldom produce  hypogeusia. CNS neoplasms predominantly produce dys-  geusia, not hypogeusia or ageusia, and taste hallucinations  are fairly common during migraine headaches, Bell palsy,  or herpes zoster of the geniculate ganglion. Ischemia and  infarction of the brainstem can lead to ageusia of only half  of the tongue (hemiageusia) on the same side as the brain-  stem lesion.   The perception of a particular taste depends on its con-  centration in a liquid environment; hence, persons with  severe dry mouth may suffer from both hypogeusia and  dysgeusia. In addition, more than 200 drugs are known to  produce taste disturbances (Table 18-1). Even without  medication-induced alterations, 40% of persons with clini-  cal depression complain of dysgeusia. Dysgeusia is also a  relatively common complaint (second only to drug-induced  alopecia) in patients undergoing chemotherapy with stan-  dard chemotherapeutic regimens. This is particularly dis-  concerting as it may lead to food aversion and subsequent    * BOX 18-5 Local and Systemic Factors Associated with Altered Taste Sensations (Dysgeusia) or Diminished   Oral trichomoniasis  Desquamative gingivitis  Oral galvanism  Periodontitis or gingivitis  Chlorhexidine rinse   Nutritional overdose (zinc, vitamin A, or pyridoxine)  Food sensitivity or allergy   Temporal lobe central nervous system (CNS) tumor  Nerve trauma, gustatory nerves  Herpes zoster, geniculate ganglion  Upper respiratory tract infection  Chronic gastritis or regurgitation  Bell palsy    Examples of Pharmaceutical Agents That May Be Associated with Altered Taste    Amphotericin B, ampicillin, griseofulvin, idoxuridine, lincomycin,  metronidazole, streptomycin, tetracycline, and tyrothricin   Opiate Codeine and morphine  Sympathomimetic Amphetamines and phenmetrazine  Vasodilator Oxyfedrine and bamifylline    weight loss, which contributes to treatment delays in this  patient cohort. The clinician should be especially diligent  in assessing local, intraoral causes of dysgeusia, such as  periodontal or dental abscess, oral candidiasis, and routine  gingivitis or periodontitis.    In contrast to hypogeusia, dysgeusia is discerned promptly  and distressingly by affected individuals. The clinician must  be certain that the patient’s alteration is, in fact, a taste  disorder rather than an olfactory one, because 75% of  “flavor” information (e.g., taste, aroma, texture, tempera-  ture, and irritating properties) is derived from smell. Abnor-  mal taste function should be verified through formal taste  testing by using standard tastants that are representative of  each of the four primary taste qualities (i.e., sweet, sour,  salty, and bitter) in a nonodorous solution. Additional elec-  trical and chemical analysis of taste bud function is fre-  quently required. Because this is outside the scope of most  general practices, patients are typically referred to a taste and  smell center.   Affected patients may describe their altered taste as one  of the primary ones, but many describe the new taste as  metallic, foul, or rancid. The latter two are more likely to  be associated with aberrant odor perception (parosmia)  than with dysgeusia. The altered taste may require a stimu-  lus, such as certain foods or liquids, in which case the taste  is said to be distorted. If no stimulus is required, then the  dysgeusia is classified as a phantom taste.    If an underlying disease or process is identified and treated  successfully, the taste function should return to normal. For  idiopathic cases there is no effective pharmacologic therapy.  Dysgeusia in particular tends to affect lifestyles and inter-  personal relationships significantly, perhaps leading to  depression, anxiety, or nutritional deficiencies from altered  eating habits. Fortunately, two-thirds of dysgeusia patients  experience spontaneous resolution (average duration, 10  months). Idiopathic hypogeusia is less of a problem for the  patient, but slowly tends to become worse over time. For-  tunately, spontaneous resolution is still a possibility for idio-  pathic hypogeusia.    Osteoarthritis is a common degenerative and destructive  alteration of the joints that until recently was considered  to be the inevitable result of simple wear and tear on  aging anatomic structures. Osteoarthritis is thought by  some to be unavoidable; almost everyone older than 50  years of age is affected to some extent, and it is almost  universal after age 65. However, the condition is now  known to have a strong inflammatory component as well—  especially in small joints, such as the temporomandibular  joint (TMJ).    Patients with osteoarthritis of the TMJ tend to be  younger than those with disease affecting the large weight-  bearing joints. In addition, osteoarthritis of the TMJ may  not be clinically apparent, although it has been noted  microscopically in 40% of older adults and radiographically  in 14%. The disease accounts for approximately 10% of  patients evaluated for TMJ pain.   Presumably, with advancing age, there is slower and less  complete replacement of chondroblasts and chondrocytes  in joint cartilage. The cartilage matrix (fibrocartilage in the  case of the TMJ) turns over less rapidly, forcing available  fibers to work longer and become susceptible to fatigue. The  matrix also holds less water, becoming desiccated and  brittle, in part because underlying marrow blood flow  diminishes, providing poor nutrition. With continued joint  use, the surface fibers break down and portions of the  hyaline or fibrocartilage are destroyed, often breaking away  to expose underlying bone. The exposed bone then under-  goes a dual process of degenerative destruction and  proliferation.    Osteoarthritis usually involves multiple joints, typically the  large weight-bearing joints. The disease is characterized by  a gradually intensifying deep ache and pain, usually worse  in the evening than in the morning. Some degree of morning  joint stiffness and stiffness after inactivity is present in 80%  of cases. The affected joint may become swollen and warm  to the touch, rarely with erythema of the overlying skin.  Degenerative changes occur in areas of greatest impact, and  the joint may become so deformed that it limits motion.  Crepitation (i.e., crackling noise during motion) is a late  sign of the disease and is, therefore, associated with more  pronounced damage.   These changes are seen also when the TMJ is affected,  except that patients seldom experience stiffness of the TMJ.  In addition, the muscles of mastication frequently exhibit  tenderness because of the constant strain of “muscle guard-  ing” (i.e., attempting to keep the painful joint immobile).   Radiographically, joints affected by osteoarthritis demon-  strate mild changes early in the course of the disease. However,  as the disease progresses, the radiographic presentation  becomes more characteristic of arthritic joints in general with  some combination of the following: erosion of the cortical  outline, narrowing or obliteration of the joint space, surface  irregularities and protuberances (exostoses, osteophytes),  flattening of the articular surface, osteosclerosis and osteoly-  sis of bone beneath the cartilage, radiolucent subchondral  cysts, and ossification within the synovial membrane (ossi-  cles). More sensitive diagnostic techniques, such as com-  puted tomography (CT) scanning arthrography, magnetic  resonance imaging (MRI), and arthroscopy, reveal the same  features but in much more detail; hence, they are able to  identify earlier changes. With arthroscopy, 90% of the joints  will show evidence of synovitis, usually before cartilage  surface changes are radiographically demonstrable.    The articulating surface of a joint affected by osteoarthritis  has a diminished number of chondrocytes, is roughened,  and contains variable numbers of vertical clefts; in older  cases the clefts extend to the underlying bone. The surface  is proliferative in some areas and degenerative in others. The  bone beneath the cartilage shows a loss of osteocytes,  minimal osteoblastic or osteoclastic activity, fatty degenera-  tion or necrosis of the marrow, marrow fibrosis, infiltration  by chronic inflammatory cells, and perhaps the formation  of a large degenerative space beneath the articular cartilage  (subchondral cyst). Inflammation and thickening of the  synovial membrane is seen, sometimes with the formation  of metaplastic bone (ossicles) or hyaline cartilage granules  (chondral bodies), which may number in the hundreds  within a single joint. The synovial joint fluid typically con-  tains inflammatory and degradation molecules, the levels of  which have prognostic significance.   The TMJ is unique because of its fibrocartilage covering  and its meniscus. The disk may be centrally destroyed, and  there is little vertical clefting of the articular surface. All  other features of TMJ osteoarthritis, however, are similar to  those noted in other joints.    The treatment of osteoarthritis is usually palliative and con-  sists of analgesics and nonsteroidal antiinflammatory drugs  (NSAIDs) for the symptoms. Occlusal adjustment and  occlusal splints may reduce TMJ symptoms by relieving the  pressure on the joint surfaces, and orofacial physiotherapy  and hot or cold packs may be helpful to relax involved  muscles. Arthroscopic lavage provides short-term pain relief  in many cases, and low-dose doxycycline (collagenase inhib-  itor, anti-matrix metalloproteinase) has been shown to  reduce symptoms. Glucosamine and chondroitin sulfate,  common therapies for large joint arthritis, have shown some  success in TMJ osteoarthritis patients.   Aggressive therapy might not be indicated for this disease  except in its most severe form. A 30-year follow-up inves-  tigation found radiographic evidence of continued joint  destruction, but the clinical signs and symptoms were no  more severe than they had been initially. In general, surgical  management of TMJ osteoarthritis is not recommended  unless all conservative, nonsurgical means have failed and  the patient’s symptoms warrant an escalation of therapy.  Arthrocentesis has shown some promising results in those  patients refractory to conservative treatment protocols.  Arthroplasty and joint replacement often are required for  severely involved heavy weight-bearing joints and are used  occasionally in the TMJ.    Rheumatoid arthritis (RA) is a chronic, autoimmune  disorder characterized by nonsuppurative inflammatory    destruction of synovium and subsequent destruction of  the affected joints. Like most autoimmune diseases, the  clinical course of RA is protean and protracted and the  etiology is unknown. Investigators hypothesize that it  may result from a cross-reaction of antibodies generated  against hemolytic streptococci or other microorganisms or  from an antibody attack against bacterial cell walls or  viral capsule fragments deposited within the synovium.  Some examples show a familial pattern, and more than  twenty genes have been studied to determine their contri-  bution to the development of RA. The human leukocyte  antigen (HLA) locus DRB1 has long been identified as  the most significant genetic association for the develop-  ment of RA. In 2003, gene peptidylarginine deiminase  type 4 (PAD/4) was identified as a second risk factor for  RA, and since that time, several additional genes have  been implicated. Environmental factors also have been  shown to contribute to the development of RA in suscep-  tible individuals.   This disease affects 2.0% to 2.5% of people in the United  States to at least some degree, and approximately 200,000  new cases are diagnosed yearly. The temporomandibular  joint (TMJ) eventually becomes involved in 50% to 75%  of patients, although the involvement is usually so mild as  to be clinically insignificant. RA demonstrates both intra-  articular and extra-articular features. Systemic manifesta-  tions are relatively common in RA and include: vasculitis,  interstitial lung diseases, cardiovascular diseases, anemia,  osteoporosis, and ocular involvement (scleritis, keratocon-  junctivitis, and uveitis).   In contrast to osteoarthritis (see previous topic), RA  begins as an attack against the periarticular structures,  such as the synovial membrane (synovitis). A reactive  macrophage-laden fibroblastic proliferation (pannus) from  the synovium creeps onto the joint surface. This releases  collagenases and other proteases, which destroy the cartilage  and underlying bone. Attempted remodeling by the  damaged bone results in a characteristic deformation of the  joint.    RA affects women three times more frequently than men,  although the condition in men usually is diagnosed at a  somewhat younger age (25 to 35 years) than in women (35  to 45 years). The onset and course of the disease are  extremely variable. For many patients, only one or two  joints become involved and significant pain or limitation of  motion never develops. In others, the disease rapidly pro-  gresses to debilitating polyarthralgia.   Typically, the signs and symptoms become more severe  over time and include swelling, stiffness, pain, joint defor-  mity, and disability, with possible fibrous or bony fusion of  opposing articular surfaces (ankylosis). Periods of remis-  sion often are interspersed with periods of exacerbation.  Symmetric polyarticular involvement of the small joints of  the hands and feet almost always is present, but it is not    unusual for knees and elbows to be affected. The hands  often display a classic ulnar deviation with swan neck defor-  mities of the fingers. The hip joint, the joint most often  affected by osteoarthritis, is the joint least affected by RA.  Twenty percent of patients have firm, partially movable,  nontender rheumatoid nodules beneath the skin near the  affected joint. These are considered pathognomonic for the  disease.   Joints involved with RA have a characteristic “anvil”  shape, with an irregular flattening of the central articular  surface and a splaying of the lateral bone. Unlike the situ-  ation in osteoarthritis, narrowing of the joint space is seldom  seen, except when ankylosis has occurred.   The TMJ is clinically affected to some degree in more  than 40% of persons with RA. When present, TMJ involve-  ment is usually bilateral and occurs late in the clinical course  of the disease. The signs and symptoms are seldom as severe  as in other joints and include stiffness, crepitation, pain or  ache, tenderness, or limitation of mouth opening. Swelling  is less obvious than with other joints.   Frequently, the pain of TMJ RA is not related to motion  but rather to pressure on the joint. Clenching the teeth on  one side produces pain of the contralateral joint. Similarly,  subluxation or ankylosis is less frequent in the TMJs than  in other joints, but gross destruction of the condylar heads  may be so severe that a progressive class II malocclusion and  anterior open bite develop. Permanent TMJ subluxation has  been reported.   Radiographically, involved TMJs demonstrate a flattened  condylar head with irregular surface features, an irregular  temporal fossa surface, perhaps with remodeling of the fossa  itself, and anterior displacement of the condyle. Several  diagnostic techniques are available besides routine TMJ  radiographs. CT scans, scanning arthrography, and arthros-  copy are excellent tools for assessing TMJ damage. Ther-  mography is used commonly in Europe to detect early  disease. Ultrasonography is valuable for larger joints but has  been used little in TMJ disease. Nuclear medicine scans that  use scintigraphy have, in recent years, been largely replaced  by MRI scans.    Anti-citrullinated protein antibodies (ACPAs) have been  identified as specific serological markers of RA. The pres-  ence of these antibodies leads to the formation of immune  complexes and subsequent inflammation of the type seen  in RA. Additionally 80% of patients with RA exhibit sig-  nificant elevations of rheumatoid factor (RF), an autoanti-  body thought to be directed toward an altered host IgG  antibody that is no longer recognized by the body as “self.”  In addition, antinuclear antibodies (ANAs) can be detected  in about 50% of the patients with RA, although it is not  diagnostically specific because it also may be associated with  other autoimmune diseases. During active phases of the  disease, almost all patients have an elevated erythrocyte  sedimentation rate (90%) and this test, although not highly    specific for RA, can be used to monitor the clinical course  of the disease. In addition, some affected patients have mild  anemia (25%).    Needle biopsy is the most popular technique for obtaining  diagnostic synovial material, but aspiration and analysis of  synovial fluid from the affected joint frequently are under-  taken to rule out other forms of arthritis. These techniques  are seldom used for TMJ involvement.   Microscopically, early cases of RA demonstrate hyperpla-  sia of the synovial lining cells with deeper portions of the  membrane showing hyperemia, edema, and infiltration by  lymphocytes, macrophages, and occasional neutrophils.  Older lesions show continued, often pronounced synovial  proliferation and edema, with cholesterol crystals and fewer  inflammatory cells. Typically, the membrane protrudes into  the joint space as villi or fingerlike projections. These projec-  tions occasionally undergo necrosis, producing rice  bodies—small whitish villi fragments composed of cellular  debris admixed with fibrin and collagen. When the TMJ is  severely involved, the meniscus is typically perforated or  replaced completely by fibrous scar.   The rheumatoid nodule is represented by a moderately  well-demarcated area of amorphous, eosinophilic necrosis  surrounded by a thick layer of mononuclear cells. The  mononuclear cells closest to the amorphous center are typi-  cally large and palisaded.    No cure exists for RA, and current treatments strive only to  suppress the process as much as possible. The treatment for  RA is lifelong and consists primarily of patient education,  physical therapy, exercise, and medications. The various  therapies that are used are largely empirical and aimed at  nonspecific suppression of the inflammatory or immuno-  logic process in an effort to attenuate not only the symp-  toms but also the progressive damage to articular structures.  Drug therapy in early and mild cases consists of NSAIDs,  perhaps aided by occasional corticosteroid injections into  the joint. The latter injections are used sparingly, however,  because frequent use is associated with additional degenera-  tive changes and fibrous ankylosis.   Second-line medications often are required, and the wide  variability in responses to these drugs typically results in an  extended course of constantly changing doses and agents  in an effort to achieve optimal relief. Systemic glucocorticoid  therapy has been shown to be effective in providing  symptomatic relief for patients with RA. A number of  agents appear to have the capacity to modify the course  of RA, and these medications are referred to as disease-  modifying antirheumatic drugs. Agents such as gold injec-  tions, D-penicillamine, sulfasalazine, the antimalarials, and  methotrexate are included in this group. Patients report  clinical improvement with the use of these medications; they    also demonstrate an improvement in serologic evidence of  disease activity with reductions in C-reactive protein, eryth-  rocyte sedimentation rate, and RE Emerging evidence indi-  cates that the early and aggressive use of disease-modifying  antirheumatic drugs may actually retard the development  of bone erosions and potentially facilitate healing of existing  lesions. However, toxicity is a problem with all of these  agents, and at present, no one drug has demonstrated a  consistent advantage over the others. Methotrexate, a folic  acid antagonist, is the most frequently used first-line agent  in the disease-modifying group. The literature suggests that  patients who fail or who have shown a suboptimal response  to disease-modulating therapy might benefit from tumor  necrosis factor-alpha (TNF-a) neutralizing agents (e.g.,  etanercept and infliximab), used alone or in combination  with standard disease-modulation algorithms.   Immunosuppressive drugs (such as, azathioprine, cyclo-  sporine, and cyclophosphamide) appear to be no more  effective in the management of RA than the previously  mentioned disease-modulating antirheumatic drugs, and  the side effect profile ofimmunosuppressive therapy includes  increased risk for serious infections and potential predispo-  sition to the development of malignant neoplasms. There-  fore, immunosuppressive therapy should be reserved for  those patients who have failed all other efforts at disease  modulation.   Severely damaged joints may require surgical replace-  ment, with the goals of therapy being attenuation of pain  and reduction of disability. Total joint replacement of the  hips, knees, and shoulders are reported to have the highest  satisfaction rates associated with surgical management of  these patients.    Temporomandibular disorders (TMDs) are broadly  defined by the American Association for Dental Research  as “a group of musculoskeletal and neuromuscular condi-  tions that involve the temporomandibular joints (TMJs),  the masticatory muscles, and all associated tissues.” Pain in  the preauricular area is the most frequent clinical presenta-  tion for this group of disorders and the TMDs are the  leading contributor to non-dental orofacial pain. Painful  TMDs are generally myogenous (muscle) or arthrogenous  (joint) in nature. Estimates suggest that 5% to 12% of the  general population experience one or more episodes of pre-  auricular pain, but only about one-third of these individuals  develop symptoms that are significant enough to warrant  medical attention. Multicenter studies have shown that  TMD is not an isolated facial pain and that TMDs have  underlying neurophysiologic mechanisms common to  many chronic pain conditions.   Although the etiology of TMD is not known, it is gener-  ally agreed that a variety of conditions may reduce the  organic physiologic adaptive capacity of the masticatory  system and result in TMDs. The classification of TMDs  (Box 18-6) remains a challenge due to our limited    Disc displacement (internal derangement)  Hypomobility of the disc (adhesions or scars)  Dislocation and subluxation    understanding of their etiology and the lack of universally  accepted diagnostic criteria for the myriad of conditions  presenting as TMDs. Many national and international sub-  committees on chronic pain management are in continuous  collaboration to define and refine diagnostic criteria in an  effort to inform future scientific endeavor and improve  patient outcomes. Our understanding of the TMDs has  evolved as our understanding of the complex biopsychoso-  cial nature of chronic pain has developed over the past five  decades. These discoveries have led to the development of  new diagnostic and treatment algorithms, not just for the  orofacial pain patient cohort but also for the millions of  chronic pain sufferers in general. Multicenter research efforts  like the long-running clinical study, Orofacial Pain: Prospec-  tive Evaluation and Risk Assessment (OPPERA), attest to  the idea that TMD is a complex multifactorial disease with  genetic, physiological, and psychological implications.    TMDsare seen primarily in young and middle-aged women,  but they may affect any age and both sexes. Pain is primary  motivation for seeking treatment, but limitations in jaw  movement during functional excursions, and restricted joint  movement with or without associated joint noises, are fre-  quent complaints. The pain usually is localized to the pre-  auricular area but may radiate to the temporal, frontal, or  occipital areas. The pain may present as a headache (cepha-  lalgia), a ringing in the ears (tinnitus), an earache (otalgia),  a toothache (odontalgia), or any combination of these  symptoms. The pain usually is associated with the surround-  ing musculature and soft tissue more than the TMJ itself.  Muscle splinting can lead to involuntary CNS-induced  muscular contractions (myospasm), or the muscle fibers  themselves may become inflamed (myositis).    Myofascial trigger point pain is common in TMD, but  it is seldom noted in other TMJ disorders. It is characterized  by circumscribed regions, often referred to as taut bands  within the muscle (“trigger points”), that elicit local or  referred pain on palpation and may be a source of constant  deep pain. In many instances, patients are aware only of the  referred pain and not the trigger points themselves. The  exact nature of the trigger points is not known, but they  seem similar to small areas of myospasm and can, through  their chronic nature, induce CNS excitatory effects. This  hyperexcitability of the CNS produces the clinical findings  of hyperalgesia (an exaggerated response to a painful stimu-  lus) and allodynia (a painful response to a non-painful  stimulus), which are characteristic of chronic pain  conditions.   Non-arthritic inflammatory disorders of the TMJ are  characterized by continuous deep pain or ache. The pain is  evoked by palpation of the affected joint or by mandibular  movement, especially chewing and clenching. Both TMJs  may be involved, at the same time or at differing times.   Derangements of the condyle and meniscus complex are  more often associated with dysfunction (arthropathy) than  with joint pain (arthralgia). Articular disc displacements  can occur in an anterior, posterior, and mediolateral direc-  tion and are characterized by a variety of joint noises and  limitations in jaw opening. Laxity and elongation of the  joint ligaments are thought to be major contributing factors  to disc-condyle displacement disorders. Studies suggest that  poor joint lubrication and osteoarthritis are implicated in  the development of disc derangements. Disc-condyle disor-  ders include both disc displacement with reduction and disc  displacement without reduction. MRI of the TMJ complex  reveals that up to 35% of asymptomatic individuals appear  to have disc displacements.   Many systemic conditions are thought to contribute  to the development of TMDs and must be included  in the differential diagnosis of chronic orofacial pain.  Inflammatory conditions of the musculoskeletal system and  autoimmune-mediated connective tissue disorders (such as,  lupus erythematosus, rheumatoid arthritis, and progressive  systemic sclerosis) are frequently co-morbid with the TMDs.   There are many conventional and advanced imaging  modalities for radiographic evaluation of the TMJ complex.  The selection of imaging technique depends largely upon  what type of information is needed from this adjunctive  examination and how this information will affect patient  management. Panoramic radiographs routinely are used as  screening films for patients presenting with preauricular  pain, and the interpretation of these films will influence the  decision for the use of advanced imaging modalities. For  TMD associated with internal joint damage or derange-  ment, CT and MRI provide excellent diagnostic images of  the TMJ. Transcranial and cephalometric radiographic  images are still in use, but they have largely been replaced  by tomography. Advances in CT, including cone beam com-  puted tomography (CBCT), offer reduced radiation expo-  sure and increased patient acceptance.   Other nonsteroidal antiinflammatory drugs (NSAIDs)  Centrally acting muscle relaxants (methocarbamol and  chlorzoxazone)   e Benzodiazepine derivatives (diazepam and chlordiazepoxide)  e Glucocorticoids (cortisone and prednisone)    The natural clinical course of the TMDs is poorly under-  stood and we cannot reliably determine which conditions  will progress to more significant long term consequences.  As many TMDs are transient and self-limiting, reversible  and conservative therapies are encouraged. Conservative  treatments include simple rest or immobilization of the  joint, application of cold (usually reserved for acute injuries)  or heat, occlusal splints and adjustment, and physical  therapy. Various medications also have been used for TMD  with some success (Box 18-7), although few TMD treat-  ments have been examined in a blinded, controlled fashion.  Long-term follow-up of large numbers of patients treated  conservatively indicates that 85% to 90% experience sig-  nificant or complete reduction of symptoms and that sus-  tainable symptom reduction was achieved between 6 and  12 months after the initiation of therapy. Early conservative  treatment not only provides greater patient satisfaction but  also reduces the probability of developing a chronic condi-  tion. Because the clinical progression of the TMDs is not  assured and owing to the demonstrated efficacy of revers-  ible, conservative therapies, escalation of therapy should  generally be avoided in all but the most extreme cases.   Surgical intervention may be required for severely  affected joints, especially those with internal meniscal  derangements, condylar dislocation or fracture, ankylosis,  and degenerative or developmental deformities. Usually,  TMD is treated conservatively for several years without  improvement before surgery is attempted. Although surgery  has frequently been used to treat a variety of painful condi-  tions involving the TMJ, a review of the literature provides  little objective evidence regarding the efficacy of most of  these procedures. Therefore, the indications for surgery are  limited. Of all patients sent to a specialist for TMD surgery,  less than 1% actually undergoes surgery.   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Yatani H, Minakuchi H, Matsuka Y, et al: The long-term effect of  occlusal therapy on self-administered treatment outcomes of    Forensic dentistry, which is also referred to as forensic odon-  tology, is the area of dentistry concerned with the correct  management, examination, evaluation, and presentation of  dental evidence in criminal or civil legal proceedings in the  interest of justice. Thus the forensic dentist must be knowl-  edgeable in both dentistry and law.   Classically, forensic dentistry can be considered a subspe-  cialty of oral and maxillofacial pathology. This is analogous  to the relationship in medicine between forensic pathology  and pathology. The requirements of forensic dental field  work, however, often demand an interdisciplinary knowl-  edge of dental science. This has resulted in other dental  specialists and general dentists joining oral and maxillofacial  pathologists in providing legal authorities with dental  expertise.   Regardless of background, forensic dentists assist legal  authorities by preparing dental evidence in the following  situations:   e Management and maintenance of dental records that  comply with legal requirements to document all unique  dental information—these data are the foundation on  which dental identification of the patient is accomplished  and potential malpractice litigation is reduced.   ¢ Identification of human remains, through the compari-  son of antemortem and postmortem dental information,  in cases that involve the death of an individual or mul-  tiple deaths in multiple fatality incident (MFI) situa-  tions. Collection and analysis of patterned marks (bite  marks) in inanimate material or injured tissue that can  be analyzed and potentially compared with a specific  human or animal dentition.   ¢ Recognition of the signs and symptoms of human abuse  (including intimate partner violence [IPV], elder abuse,  and child abuse) and the rights and responsibilities of the  dental health care practitioner when reporting such  abuse.   ¢ Presentation of dental evidence as an expert witness in  identification, bite mark, human abuse, malpractice,  fraud, and personal injury cases.    The dental record is a legal document, owned by the dentist  or an incorporated dental practice, which contains all sub-  jective and objective information about the patient. In the  United States, the Privacy Rule governing the use of pro-  tected health information (PHI) is regulated under the  federal Health Insurance Portability and Accountability Act  (HIPAA) of 1996. Under this legislation the patient has the  right to view original documents and obtain copies.   Despite the establishment of the Privacy Rule, the ability  and necessity of forensic dentists, law enforcement person-  nel, medical examiners (MEs), and coroners to obtain  released antemortem dental and medical records for forensic  purposes without requiring consent of next-of-kin or a  guardian was recognized and provided for in the HIPAA  legislation—45 Code of Federal Regulations §164.512(g)  (1).   Initially, demographic information is secured when the  medical and dental history of the patient is obtained. Results  of the physical examination of the dentition and supporting  oral and paraoral structures are recorded.   In addition, the results of clinical laboratory tests, study  casts, photographs, and radiographs become components of  the record. With this database, the dentist can develop  a thorough assessment of all of the patient’s medical  and dental problems. Subsequent documentation of this  “problem list” facilitates the development of a plan of treat-  ment and prognosis for the patient.   The treatment plan addresses the management of both  systemic and oral problems. It can then be periodically  revised and updated as problems resolve or as new ones  develop. Supplemental material, such as dental laboratory  authorizations, referral letters from other practitioners,  statements of informed consent, written prescriptions, and  insurance and financial statements, also is included and  stored in the record.   The progress notes (i.e., daily log of actual treatment  rendered) should contain information about restorative and    @ Fig. 19-1 The x-ray fluorescence (XRF) spectrum from a particle recovered from a cremation retort.  The spectrum makes this a match for the restorative resin Four Seasons or Tetric Ceram (lvoclar Vivadent,  Amherst, NY). (Courtesy of Dr. Mary A. Bush and Peter J. Bush.)    therapeutic procedures provided. This information should  include documentation of the specific brand of dental mate-  rial used in restorative procedures. This concept has forensic  import because each dental restorative product contains  inorganic materials, trace elements, and fillers that are  unique to that product and can be detected by x-ray fluo-  rescence (XRF) technology even after incineration. The  XRE trace element and major element analysis of dental  remains may be useful as an adjunct to traditional evalua-  tion of dental information in some forensic settings, includ-  ing cremation and dismemberment cases (Fig. 19-1).   Unusual physiologic and psychological reactions and the  patient’s comments concerning therapy are entered in the  record. Summaries of telephone conversations with patients,  consultants, insurance company representatives, or legal  authorities should be noted. All entries should be signed  or initialed by recording personnel. Changes in the record  should not be erased but corrected by a single line  drawn through the incorrect material. This method permits  the original entry to remain readable and removes any  questions concerning fraudulent intent to alter recorded  information.   By 2015 medical and dental records in the United States  must be maintained in an electronic format and numerous  commercial and individually designed computer software  programs have been marketed to assist physicians, dentists,  health care facilities, hospitals, and insurance companies in  collecting and preserving the medical and dental informa-  tion of patients. The obvious advantage of electronic medical,  health, or dental record (EMR, EHR, and EDR) systems is  facilitation of networking and exchange of records among  the different formats (“interoperability”) for routine profes-  sional consultation or use in forensic identification cases  requiring medical and dental records for comparison.   However, the increased use of EHRs and EDRs has also  created legal, financial, and ethical issues concerning patient    privacy. Additionally, there may be a potential for insurance  fraud associated with the computer enhancement of dental  lesions or restorations on electronically generated dental  radiographs.   The potential charge of insurance fraud associated with  the enhancement of dental lesions or restorations on  computer-generated or scanned digital radiography (DR)  can be avoided if a clinician stores and maintains unaltered  images. This is accomplished using programs with unchange-  able, secure tagged block file extensions in their native file  formats. When duplicates or copies are required, working  images should be generated.   Computer-assisted management technology (e.g., WinID3  dental comparison software bridged with the Dexis DR  program) has been an asset in expediting the comparison of  antemortem and postmortem dental record information  in recent MFI events, including the World Trade Center  terrorist attack, the Indian Ocean tsunami disaster, and  the Hurricane Katrina recovery effort. Additionally, soft-  ware such as Adobe Photoshop and Mideo Systems CASE-  WORKSeis facilitates the superimposition of digitally  scanned radiographs and photographs for comparison.   Whether preserved in written form or by using a  computer database, the principles of record management  describe a mechanism that ensures that dental information,  which may be required to resolve a forensic problem, is  properly maintained and retrievable. Additionally, records  preserved in this manner are reliable evidentiary material  if subpoenaed in peer review or malpractice litigation  proceedings.   Time limits concerning how long records must be  retained vary among the states. As a rule, states mandate  that records be kept for 7 to 10 years. Federal legislation  related to the problem of missing persons in the United  States requires that records of pediatric dental patients be  retained until the patient reaches the age of majority    (adulthood). Depending on the jurisdiction this can vary  from 18 to 21 years of age.   The maintenance period for EHR and EDR patient data  exceeds the duration of paper records and may vary from  20 to 100 years. Provisions for security and integrity of  stored archival information in EHRs and EDRs must  support ethical and legal principles regarding privacy because  the technology used to input information will be unavailable  to those who may need to examine this data in the future.    Legal situations often revolve around the establishment of  a person’s proper identity. Any death not certified by an  individual’s own physician must be referred to the medical  examiner (ME) or coroner for review. However, cases requir-  ing an autopsy to determine the time, cause, and manner  of death represent a small percentage of cases. When  required, these tasks are the responsibility of a coroner or  ME. ‘These officials are charged with the role of establishing  identification; determining the cause, mechanism, and  mode or manner of death; and issuing a death certificate.  Besides identification of the decedent, these key issues of  death investigation for the coroner or ME are defined  according to the following:  ¢ Cause of death. The disease, injury, or chemical or  physical agent responsible for initiating the lethal  sequence of events (e.g., myocardial infarction, cancer,  bullet, knife, poison, ligature, lightning, and infectious  agents)  ¢ Mechanism of death. The pathologic process that results  in death (e.g., congestive heart failure, cardiac arrhyth-  mias, asphyxia, sepsis, exsanguination, renal failure, and  hepatic failure)  ¢ Mode or manner of death. According to the NASH  classification, the mode or manner of death is considered  to be Natural, Accidental, Suicide, or Homicide. Natural  deaths are caused exclusively by disease. Accidental  deaths result from an environmental or human tragedy   (e.g., lightning strike or vehicular incident).  ¢ Undetermined death. Although the cause and mecha-   nism of death may be resolved, the manner or mode may   not be established because of decomposition, dismem-  berment, or postmortem destruction of the remains by  insects or feral animals.   The coroner is an elected official and, depending on  the laws of each state, does not necessarily have to be a  physician or have advanced training in death investigation.  An ME is an appointed official who is a pathologist specifi-  cally trained in forensic medicine. Many jurisdictions use  forensic pathologists, and this trend has contributed to the  professionalizing of a position increasingly involved with  the interpretation of advanced scientific techniques requir-  ing knowledge of toxicology, ballistics, pharmacology, and  criminalistics, as well as pathology.   A death certificate, identifying the decedent, is required  before probation of a will, release of life insurance claims,   fraudulent misidentification may also require the expertise  of forensic dentists and other forensic scientists trained in  identification techniques. ‘These professionals act as consul-   Besides analysis of the dentition, the most common  methods of identification include personal recognition, fin-  gerprinting (friction ridge analysis), physical anthropologic  examination of bones, and serologic and genetic (DNA)  comparison techniques.   Additionally, the use of facial superimposition tech-  niques (when the teeth are visible) and facial reconstruction  techniques may also permit scientifically supported com-  parisons for identification. Each method has its advantages  and disadvantages. However, all rely on the principle that  identification is the positive correlation obtained by com-  paring known information about a suspect or victim with  unique facts retrieved by physical examination of the suspect  or victim.   Regardless of the method used to identify a decedent,  the results of the antemortem and postmortem data com-  parison lead to one of the following four situations:   1. Positive identification. There is sufficient uniqueness  among the comparable items in the antemortem and  postmortem databases, and no major differences are  observed.   2. Presumptive (possible) identification. There are com-  monalities among the comparable items in the ante-  mortem and postmortem databases; however, enough  information may be missing from either source to prevent  the establishment of a positive identification.   3. Insufficient identification evidence. There is insuffi-  cient supportive evidence available to compare and arrive  at a conclusion based on scientific principles.   4, Exclusion of identification evidence. Either explain-  able or unexplainable discrepancies exist among com-  parable items in the antemortem and postmortem  databases. This results in inconsistencies that prevent  the establishment of any identification. Exclusion may  be just as important as a determination of positive  identification.    Personal recognition is the least reliable method used to  identify an individual. It is often based on the visual iden-  tification of a decedent by a family member, friend, or  acquaintance. This process assesses artifactual material, such  as clothing, jewelry, keys, wallet contents, luggage, other  personal effects, scars, and tattoos to determine identifica-  tion. Evidence in this type of identification can be acciden-  tally or purposely exchanged between bodies. This can occur  in MFI situations or when there is criminal intent to create  a misidentification in cases of identity theft or alias associ-  ated with criminal activity.    ® Fig. 19-2 Unrecognizable partially decomposed human remains  with a maxillary removable partial denture in place. Notice that the skin  tissue of the neck that has been protected by the windbreaker jacket  has not reached the stage of decomposition of the tissues of the  exposed face. (Courtesy of Dr. Raymond D. Rawson.)    @ Fig. 19-3 A burn victim requiring identification by dental, DNA, or  fingerprint methodology rather than personal recognition. (Courtesy of  Dr. Raymond D. Rawson.)    Even when a body is viewed shortly after death, dis-  traught relatives can inadvertently misidentify the decedent.  After the occurrence of postmortem changes associated with  soft tissue decomposition, insect and burn artifact, or dis-  memberment, this method of identification may be pre-    Anthropometry was the first “scientific” system police used  to identify criminals. The French law enforcement officer,  Alphonse Bertillon, developed this system in the latter part  of the nineteenth century. The method was unreliable  and flawed because it relied on biometric physical measure-  ments of the head and body, individual markings including  scars and tattoos, and other personal characteristics. Bertil-  lon’s anthropometry identification process was eventually  replaced by analysis of the epidermal friction ridges of  the fingers, palms, and feet commonly referred to as  fingerprinting.    By the beginning of the twentieth century, forensic  science had recognized that the ridge-like patterns on the  fingertips and palms are unique for each person. These fric-  tion ridges are genetically determined, and not even homo-  zygous twins have the same patterns of loops, arches, and  whorls. A principal variation in the fingerprints of twins  is that they appear as mirror images of each other. The  morphometric variation in combinations of the loops,  arches, and whorls permits a scientific comparison of fin-  gerprint records with the friction ridges of an unidentified  decedent.   Because the fingerprint pattern is inherited, it is a static  characteristic and remains unchanged throughout life. This  is an important advantage when one compares fingerprint  identification with dental identification. The teeth and sup-  porting structures have fluid characteristics. Dental patterns  change as teeth erupt, exfoliate, decay, become restored,  and, perhaps, are eventually extracted and replaced with  implants or other prosthetic devices.   Unlike dental records, which are principally retained in  private dental offices in the Americas and Western Europe,  fingerprint information is maintained by governmental  agencies. Several states retain records of non-criminals who  work in sensitive occupations. In this regard, Nevada has a  fingerprint database for employees in the gaming industry.  The Criminal Justice Information Services (CJIS) Division  of the Federal Bureau of Investigation (FBI) contains the  largest biometric database in the world with approximately  130 million fingerprint records included in criminal, civil,  and known and suspected terrorist formats.   Currently, these records are retained within the Inte-  grated Automated Fingerprint Identification System  (IAFIS). LAFIS permits input, matching, and retrieval of  even a single fingerprint image for identification. Next Gen-  eration Identification (NGI) technology is being developed  for the FBI to expand the morphometric information con-  tained in IAFIS to include palm print, iris, and facial iden-  tification data.   The establishment of the CJIS Division’s IAFIS files  permits automated computer data entry and search capa-  bilities for matching and retrieval of fingerprint images. This  information is available for electronic exchange among law  enforcement agencies for identification purposes. Included  in the IAFIS database are criminal and civil ten-print fin-  gerprint records, latent fingerprint services, and subject and  criminal history search capabilities. Information from this  fingerprint repository is shared with international legal  agencies, such as Interpol and the Royal Canadian Mounted  Police.   Fingerprint nomenclature is standardized in IAFIS, and  all fingerprint experts use the same terminology worldwide.  This advantage is not observed in dental identification, in  which numerous charting and tooth-numbering systems are  used. Because soft tissues decompose shortly after death, the  friction ridge patterns within the epidermis may not be  retrievable for fingerprint comparison. This is the principal  disadvantage of fingerprint identification.    Forensic anthropologists and forensic dentists often work  together to resolve problems associated with identification.  Both disciplines are concerned with analysis of calcified  structures of the body—bones and teeth. Historically, this  anatomic material has assisted forensic anthropologists and  dentists in determining the race, age, and sex of a person  (Table 19-1). These characteristics have become less distinct  in some populations as individuals from different cultures  and races have intermarried and blended these genetically  determined features in their offspring.   In addition to the study of osseous material and despite  variations in crown and root development within the denti-  tion, the teeth can be studied clinically, radiographically,  histologically, and biochemically to determine the age of a  living individual or decedent.   Forensically, this information is essential in casework  involving the need to establish legal age of majority    Skeletal Anthropologic Variations  Associated with Racial and Sexual  Characteristics of the Skull    Width Narrow Narrow Broad  Height High Low Intermediate  Profile Straight Prognathic Intermediate  Orbit Triangular/ Square Circular  teardrop  Nasal Tapered Wide Rounded  opening  Palate Narrow Wide Intermediate  Size Large Small  Glabellar Pronounced Not developed  (supraorbital)  ridges  Mastoid process Large Small  Occipital area Pronounced Minimal  muscle lines muscle lines  Mandible Larger, broader Smaller  ramus  Forehead Steeper, slopes Rounded,  posteriorly more vertical    (adulthood), medicolegal age at death, clarification of the  age of undocumented immigrants, age estimation of  unidentified remains, and separation of comingled remains  in a multiple fatality incident among others.   From fetal development to adolescence tooth maturation  intervals are the principal method of dental age assessment.  Lewis and Senn emphasize that dental age estimation of  children becomes more accurate when teeth having less  variance are used in these analyses and data derived from  multiple teeth is considered. Additionally, studies have been  performed to assess differences in crown and root formation  and eruption sequences among children of both genders  and various racial and ethnic populations.   As one approaches adulthood, age estimation acquired  by analysis of the dentition can be supplemented with  radiographic data obtained from the calcification centers of  the hand and wrist, ribs, clavicles, and other bones to deter-  mine the precise age of a person younger than 20 years of  age.   Biochemical laboratory procedures or assessment of  dental post-formation changes are used to determine the  age of adult individuals. Historically, dental post-formation  changes of adult teeth included the study of their ground  sections for variations in patterns of:  ¢ Attrition  ¢ Periodontal attachment  e Secondary dentin  ¢ Cementum apposition  ¢ Root resorption  e ‘Transparency of root dentin   This approach, developed by Gustafson in 1947, has  been modified to determine which of these factors are most  significant—secondary dentin and transparency of root  dentin. Additionally, these contemporary methods of dental  post-formation analysis have been supplemented by those  relying on the following techniques:   e Evaluation of the rate of racemization of levels of meta-  bolically stable aspartic acid enantiomers in enamel and  dentin to determine an exact age.   ¢ Occlusal tooth wear which can provide reliable estimates  of age to within 3 to 5 years. Often, anthropologic  analysis is helpful in arriving at a presumptive identifica-  tion based on these criteria.   There are variations in the calcification and eruption  patterns among various ethnic and cultural groups, and  studies have been undertaken to delineate these differences  further. After the third molars, long bones, and bones of  the wrist and hand are completely developed, evaluation of  biochemical components of the calcified structures and col-  lagen is the most accurate method for determining chrono-  logic age.   Methods that rely on an analysis of the rate of racemiza-  tion of the stereoisomers of aspartic acid in enamel and  dentin can be used to determine an accurate chronologic  age. This is related to the fact that the change from the  L-form of this amino acid to its mirror image D-form  occurs over time. Thus the ratio of the L- to D-forms of    © Fig. 19-4 Reconstruction of the facial soft tissue uses predeter-  mined, standard anthropologic thickness measurements for specific  points around the face. These measurements are based on variables  that are related to racial and sexual characteristics. (Courtesy of Dr.  Cleve Smith.)    aspartic acid in the dentition is directly related to the age  of the individual. Often, anthropologic and dental age  analysis is helpful in arriving at a presumptive identification  based on the criteria noted previously.   Positive identification may be achievable when the skull  and facial bones are used as a foundation to reconstruct the  facial soft tissues (Figs. 19-4 to 19-6). Three-dimensional  (3D) computer images, computed tomography (CT)  images, and radiographs have even been used in the replica-  tion of the face of Europe’s oldest mummified human, a  male dubbed Otzi, whose 5300-year-old remains were  removed from glacial ice in the Otztal Alps on the Austrian-  Italian border.   With knowledge of the anatomic relationships between  the skull and face, antemortem facial photographs or radio-  graphs can be superimposed for comparison with the skull  of an unknown. Video superimposition with two television  cameras and an electronic mixing device has been used suc-  cessfully to overlay a photograph of a human face on an  image of a skull for identification. The development of  computer software programs capable of superimposition  has further facilitated the process.   The anterior dentition of the skull can be overlaid and  compared with a smiling antemortem photograph. The  shapes and positions of the individual teeth and their rela-  tionships to each other have been considered distinctive  enough features on which to base identification, as have  certain significant cranial and facial landmarks, including  the orbits, nasal openings, malar eminence, and chin. Pros-  thetic joint replacements, intraosseous and dental implants,    ® Fig. 19-5 The soft tissue thickness points can be connected with  sculpting clay or digitized on a computer screen. The ultimate result  of these techniques is a re-creation of the contour of the soft tissue  features that permits a visual identification. (Courtesy of Dr. Cleve  Smith.)    ® Fig. 19-6 The width of the mouth is related to the interpupillary  distance. The length and shape of the nose are determined by the  relationship between the inferior and superior nasal spines. If Known,  then the addition of a specific hairstyle, eyeglasses, and eye color can  further individualize a facial reconstruction. (Courtesy of Dr. Cleve  Smith.)    and radiographic signs of prior bone fracture are other  anthropologic findings that can be used to facilitate  identification.   Additionally, prosthetic devices, implanted defibrillators  and pacemakers, and osseous implants are designated with  individual identification code numbers provided by their  manufacturers. These codes can be visualized in the various  devices and are useful in identifying individuals in crema-  tion and dismemberment scenarios when the teeth and  fingerprints are not available for evaluation.    Every individual is unique by virtue of his or her chromo-  somal DNA—a polymer structured as a double helix and  composed of four different nucleotides. The polymorphic  sequencing of these nucleotides along the two strands of the  DNA molecule accounts for the genetic diversity of all living  things. This “ultimate identification material” was first used  forensically to obtain a conviction in a criminal case in 1986,  and DNA comparison has since become an accepted foren-  sic method to resolve problems of identification.   Before 1986, comparison of antigenic markers found on  red blood cells (RBCs) and in body fluids of secretors of  these markers among the human population was tradition-  ally used as a means of exculpatory (exclusionary) evidence.  Because the ABH antigenic surface markers of RBCs are  not discriminatory, this type of evidence was primarily used  to exclude a suspect or victim when negative comparative  results were achieved. Positive comparisons were justified  only to place the suspect or victim in a population of indi-  viduals having similar serologic antigens.   Although DNA has become the principal biologic sub-  stance used to effect a positive identification, antigenic  surface markers A, B, and H of the ABO blood group  system, as well as various components of the rhesus (Rh)  and Lewis systems, continue to be accepted for medicolegal  comparison. The ability to secrete the ABH antigens in  saliva and other body fluids is genetically determined, and  more than 80% of individuals are secretors. With appropri-  ate laboratory tests, even dried samples of fluid and blood  can be analyzed for these markers.   DNA found in human cells is composed of chromo-  somal and mitochondrial DNA (mtDNA). Two copies of  chromosomal DNA are incorporated into the nuclei of a  person’s cells by DNA provided from both parents. However,  hundreds of copies of mtDNA are contained in the cyto-  plasm of these cells. This DNA is only maternally trans-  ferred and can be isolated from cells without nuclei, such  as RBCs. Unlike nuclear DNA, mtDNA is single stranded  and circular. Because there is no mixing of sequence types  from generation to generation in maternally transferred  mtDNA, it can be compared with that of distant maternal  relatives to effect identification when other reference sources  are unavailable.   Restriction fragment length polymorphism (RFLP) and  polymerase chain reaction (PCR) analyses are the principal    laboratory techniques used to compare and evaluate frag-  ments of DNA material from a suspect or victim's biologic  forensic specimens (e.g., semen, vaginal fluid, teeth, soft  tissues, and saliva). Both are extremely accurate, precise, and  reproducible; these methods are used when the conditions  of the sample DNA presented dictate the need for their  respective advantages.   RFLP methods result in splitting source DNA into thou-  sands of fragments using “biologic scissors” known as restric-  tion enzymes. Fragment size varies among individuals related  to the variable number of tandem repeats (VNTR) of base  pairs. These short segments of DNA contain a number of  repeat units that differ among individuals. After gel separa-  tion of the fragments and transfer to a nylon mesh, specific  DNA fragments are identified using oligonucleotides labeled  with radioisotopes. Analysis of a series of different VNTR  loci permits generation of an individual DNA profile.   A match of four or more VNTR loci is consistent with  a positive match between DNA evidence gathered from  suspect, victim, or crime scene evidence. The RFLP method  requires large amounts of high molecular weight DNA, a  major disadvantage. Small DNA samples (< 100 ng) or  degraded evidence in which the DNA has become dena-  tured because of extreme heat or pH variation requires an  analytic method other than RFLP.   The evaluation of minute quantities of DNA or DNA that  has undergone degradation can be accomplished with the  highly sensitive PCR test. Using this laboratory technique,  smaller VNTR loci of a specific DNA sequence can be ampli-  fied into enough copies for sufficient analysis. Because of its  high degree of sensitivity, PCR analysis has been used to  evaluate small amounts of DNA from a suspect’s clothing left  at the scene of a crime, as well as from bone fragments from  the Vietnam War. DNA amplification of microsatellite loci  (referred to as STRs) and minisatellite loci (or LTRs) using  PCR, is referred to as AmpFLP analysis.   The hard and soft tissues of the oral cavity and saliva are  often good sources for DNA material. However, if the teeth  or other hard structures of the mouth are to be used for the  collection of DNA evidence, then the identification value  of these structures should be considered (beyond their  ability to yield a harvest DNA). A tooth or jaw fragment  capriciously destroyed can result in the loss of valuable  radiographic and anatomic sources for eventual dental iden-  tification. Besides the obvious source of DNA from human  tissues, the forensic dentist often considers the evaluation  of chewed gum, cigarette remains, licked envelopes, stamps,  or similar inanimate objects as potential sources for DNA  evidence using PCR analysis described previously.   Regardless of the surface from which DNA evidence may  be harvested, the two-swab protocol developed by Dr.  David Sweet and others at the Bureau of Legal Dentistry,  University of British Columbia is the recovery method of  choice:  ¢ A sterile cotton swab is moistened with distilled water   and rolled over the surface of the skin or object using   e A second dry cotton swab is rolled over the same surface  of the skin or object using moderate pressure and circular  motion to absorb all moisture left by the first swab.   ¢ Both swabs are placed in properly labeled storage con-  tainers and submitted to the laboratory for frozen storage  at —20° C (-4° F).   Control samples may be collected from whole blood,  autopsy tissue samples or oral buccal swabs from a living  individual.   Passage of the DNA Identification Act of 1994 and the  establishment of the FBI’s National DNA Index System  (NDIS) in 1998 have facilitated the exchange and compari-  son of DNA profiles among federal, state, and local crime  laboratories in the United States. This is accomplished elec-  tronically through the FBI Laboratory's Combined DNA  Index System (CODIS). Through the CODIS computer  program's forensic and offender indexes, biologic evidence  from crime scenes can be linked to DNA profiles of individu-  als convicted of sex offenses and other felonies. As of March  2007, the total number of DNA profiles contained in the  CODIS databases was more than 4.5 million. More than  47,000 successful comparisons (“hits”) were made among  cases in which the CODIS system was activated. This repre-  sents a 98% success rate linking DNA from a crime scene  with similar material from the convicted offender profiles.   The US Department of Defense has initiated a policy of  obtaining DNA samples on all military personnel. This  DNA “fingerprint” has significantly reduced the possibility  of another unknown soldier among future military casual-  ties. Despite the positive effects of DNA evidence in resolv-  ing questions of identity, the technique is not without  controversy. Challenges have been made by population  geneticists, concerned about random matching and varia-  tions among racial subgroups.    In an identification case, the principal advantage of dental  evidence is that, like other hard tissue, it is often preserved  indefinitely after death. Although the status of a person’s  teeth changes throughout life, the combination of decayed,  missing, and filled teeth is measurable, reproducible, and  comparable at any fixed point in time. Therefore, like the  comparison of unique patterns in a fingerprint, a scientific,  objective analysis of antemortem and postmortem dental  variables is achievable.   The presence and position of individual teeth and the  respective anatomic, restorative, and pathologic compo-  nents provide the database for the antemortem and post-  mortem comparison (Fig. 19-7). The pattern of the palatal  rugae, ridges on the lip surface, and radiographic outline of  the maxillary and frontal sinuses are also considered unique  (Fig. 19-8). In addition, the legal community accepts the  fact that dentists can recognize procedures that they have  performed.    @ Fig. 19-7 The combination of decayed, missing, and filled teeth,  along with unique anatomic and pathologic findings, provides the  database for comparison in a dental identification. Note the microdont  in the maxillary left quadrant.    @ Fig. 19-8 The outline shape of the frontal sinus is a unique mor-  phometric factor that may be used in human identification when com-  paring cone-beam computed tomography (CBCT) and anterior-posterior  radiographs of a known individual with those of an unknown person  or decedent. (Courtesy of Dr. Robert Danforth.)    Problems associated with dental identification informa-  tion are often related to acquiring and interpreting ante-  mortem records. Most antemortem dental records are  retrieved from private-sector dental providers. However,  dental records may be recovered from insurance carriers,  dental schools, hospitals, clinics, state and federal prisons,  military files, and the FBI National Crime Information  Center (NCIC) data bases.   To initiate a request for antemortem records, a putative  (suspected) identification is required. Reports of missing  and unidentified persons, obtained from law enforcement  agencies, are the principal source for this material. Thou-  sands of victims who cannot be identified by fingerprint  methods remain unidentified because a putative identifica-  tion has not been established.   The FBI-NCIC computer registry of missing and  unidentified persons was established to help rectify this  problem. This computer system maintains demographic,  dental, and medical information on missing persons. It  attempts to match these data with similar facts obtained  from unidentified bodies. The latter information is submit-  ted by various investigative and legal agencies. Potentially,    the otherwise unidentifiable victims of random violence,  serial homicides, terrorist acts, and child abduction can now  be identified without the need to determine a putative  identification. A disadvantage of the NCIC computer iden-  tification system is that it does not have the capability  to identify possible decedents based solely on dental  information.   The National Dental Image Repository (NDIR) has been  established to address this issue. Law enforcement agencies  can voluntarily post supplemental dental images related to  NCIC Missing, Unidentified, and Wanted Person records  on the NDIR secure website. Thus access, retrieval, and  review of dental information by qualified forensic odontolo-  gists who are members of the NDIR Review Panel can  facilitate dental comparisons. The NDIR website is located  at Law Enforcement Online (LEO) at http://cgate.leo.gov.  This repository permits law enforcement, criminal justice,  and public safety authorities to maintain a national and  international method of electronic communication, educa-  tion, and sharing of dental information.   The Armed Forces, Department of Veterans Affairs, and  many states require that identifying markings be placed on  removable dental prostheses (Fig. 19-9). The American  Dental Association also supports this policy. It is an attempt  to provide a basis for identification among the substantial  population of completely or partially edentulous individuals  in the United States.   Identifying markings in dental prostheses are important  because even if dental records of an edentulous person can  be obtained, they may not reflect the current status of the  ridges and alveolar bone. Commonly used information for  identifying marking in removable dental prostheses includes  the person’s name, driver’s license number, and/or other  identification number.   Even when a suspected identification is achieved, it may  still be difficult to secure antemortem dental records. The    @ Fig. 19-9 Denture identification is accomplished by inserting a  typed name or code number (i.¢., Social Security number or hospital  patient number) in an area of the denture that will not interfere with the  aesthetics of the prosthesis. This procedure is performed in the labora-  tory during the final acrylic pack. Information also can be engraved in  the framework of an all-metal appliance.    family or acquaintances of the victim may not know where  dental treatment was sought. Reviewing the victim’s can-  celed bank checks or medical deductions on tax records may  be helpful in locating antemortem dental records in such  cases.   Although records obtained from institutional or govern-  mental dental facilities routinely indicate all restored teeth,  this is not true of charts forwarded from private dentists. In  these instances, previously restored teeth often are not  charted unless the current dentist intends to re-treat them.  Therefore, in these records, the antemortem radiographs  and progress notes become the principal sources for dental  information.   Unfortunately, the nomenclature associated with dental  charting systems is not standardized (Table 19-2). In 1984,    Alternate Universal Numbering System  AD) 3D) (6D) 7D) Ib) 2b) OD) WD 12) WD)  PAC|B) 2Xs\D) 27D) 2Xe\B) 2e|D) 21D) Zis|B) “Z21B) ZAID) A0})    55 54 53 52 51 61 62 63 64 65  85 84 83 82 81 71 72 73 74 75    the American Dental Association adopted the Universal  Tooth Numbering System. All insurance companies, the  Armed Forces, dental schools, and most dentists in the  United States now use this system. It should be used in all  forensic dental cases.   In the Universal Numbering System, a consecutive  number from 1 to 32 is assigned to the adult dentition. It  begins with the maxillary right third molar and ends with  the mandibular right third molar. The deciduous dentition  is identified by letters from A to T, beginning with the  maxillary right deciduous second molar and ending with  the mandibular right deciduous second molar. Thus the  quadrants are identified in a clockwise direction, beginning  with the maxillary right.   Other tooth numbering methods include the Zsigmondy/  Palmer System and the Federation Dentaire Internationale  (FDI) Two-Digit System. Each uses a different coding tech-  nique to identify dental quadrants and specific teeth.   The Zsigmondy/Palmer System stresses the anatomic  likeness of the eight tooth types in each symbolically identi-  fied dental quadrant. Homologous permanent teeth are  assigned the same number from 1 to 8. Deciduous teeth are  assigned letters A through E.   The FDI Two-Digit System is endorsed by the World  Health Organization (WHO) and is used in most devel-  oped countries, except the United States. The first digit  represents the quadrant. Quadrants 1 to 4 are assigned for  permanent teeth; 5 to 8 represent quadrants for the primary  dentition. As in the Universal Numbering System, the  quadrants are identified in a clockwise direction, beginning  with the maxillary right. The second digit designates the  permanent tooth type from 1 to 8, or deciduous tooth type  from | to 5.   Thus in the Universal Numbering System, tooth 12 is  the maxillary left first bicuspid. In the FDI Two-Digit  System, tooth 12 (one-two) is the maxillary right lateral  incisor. In the Zsigmondy/Palmer System, all lateral incisors  are designated with a No. 2 code. The position of a specific  No. 2 tooth is diagrammatically indicated by a symbolic  quadrant.   Unless the forensic dentist knows which system has been  used to encode the teeth in the antemortem record, all teeth  should be referred to by their actual names. This method  will prevent errors because all dentists use the same ana-  tomic nomenclature when referring to individual teeth.   Dental identification problems may be further com-  pounded because dental radiographs can be mounted and  viewed from right to left or vice versa. Intraoral radio-  graphic duplicating film does not contain a raised dot to  assist the dentist in orienting the film for mounting. The  lack of this orienting device can lead to transposition of  dental evidence and potential misidentification based on an  incorrect comparison. Besides the lack of a raised dot, pan-  oramic radiographic duplicating film can be detected  because of its single-sided emulsion and series of notches  on one edge to indicate that the image is not an original  (Fig. 19-10, A).    ® Fig. 19-10 A, Panoramic duplicating film has a series of notches  (arrow) on one edge to indicate that the image is not an original.  B, When phosphor digital plates are inadvertently exposed from the  wrong side, the error may not be detected because the “a” position  marker always appears in the same location after processing regard-  less of which side of the sensor has been exposed. This problem can  be prevented by placing a metal indicator on the side of the device  that should not be exposed. (Courtesy of Dr. Richard A. Weems.)    Additionally, when using intraoral digital sensors the  operator must be careful not to inadvertently expose the  device from the wrong side. This orientation error can  remain undetected because the “a” placed on the sensor  (which serves the same function as the raised dot on radio-  graphic film) always appears in the same position after  processing regardless of which side of the sensor has been  exposed (see Fig. 19-10, B).   With the advent of aesthetic materials for posterior res-  torations and the reduction in the prevalence of caries, it  may be difficult for the forensic dentist to determine  whether restorations are present by simple visual assessment  of the teeth. In addition, the postmortem dental evaluation  is often performed in an autopsy room, temporary morgue,  or funeral home. In these locations, proper lighting and  access to dental instruments, which can facilitate analysis of  the oral structures, are not readily available for detailed  examination.   Often, there are additional demands for immediacy in  providing a coroner, ME, or other legal agent with the  results of a dental identification. These demands further  compound the forensic dentist’s technical and stress-related  problems while performing the tasks related to this disci-  pline. Because of the previous caveats, the forensic dentist  should prepare an equipment kit (Box 19-1). The kit should  be portable, containing instruments and supplies specifi-  cally required for the performance of dental procedures in  an autopsy room environment. 
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