(cid:2) Signs \200\224vaginal examination: best method of detection \200\224speculum examination \200\224most lesions in upper 1/3 and are exophytic Staging and investigations The staging is clinical but may include results of invasive inve stiga- tions such as cystoscopy, protoscopy, and appropriate radiography in order to detect local and distant spread. MRI is the preferred investi- gation for evaluating local spread , particularly if body or transvaginal coils are used. The negative predictive values of CT and MRI for regional nodal involvement remain unsatisfactory. Treatment Radical radiotherapy with a combination of pelvic external-beam and utero-vaginal intra-cavitary brachytherapy is the treatment of choice. The literature is unclear regardi ng optimum dosimetry and \201eld design. Lower vaginal involvement should prompt consider ation of either additional groin node dissection or irradiation. Para-aortic irradiation (e xtended \201eld) is associated with high morbidity and is of uncertain value. OHO-23(417-442) 11/18/02 8:34 AM Page 433 VAGINAL AND VULVAL CANCER 433 Overall \201ve-year survival is 40%, and salvage after \201rst relapse is uncommon. Bad prognostic features are primary adenocarcinoma, large tumor bulk, tumor site (lower vagina l lesions fare worse), and posterior vaginal wall involvement. One in \201ve long-term su rvivors will suffer from serious radiotherapy-related complications. If the uterus is intact, the tumor involves the upper posterior vagina, and there is small volume disease (highly selected Stage I disease), then a radical hysterectomy, partial vagi nectomy, and bilateral pelvic lymphadenectomy may be performed. Treatment of vaginal cancer should be limited to centers with exper- tise in gynaecologic oncology. Vulval cancer Primary invasive vulval cancer occurs as commonly as cervical cancer in women over 60 years. One in four tumors occur in women under the age of 65 years. The majority ( 85%) are squamous carcinoma. Other types include basal carcinoma (10%) and malignant melano ma (4%). Etiology The known associations with oncogenic HPV DNA (types 16 and 18), p53 mutations, an d pre-existing abnormal vulval skin conditions such as a thickened epidermis (squamous hype rplasia), lichen sclerosis, and intra-epithelial atypia, suggest a complex etiology. Little prospective data exist to clarify the etiology further. Women with these skin dis- orders should be kept under regular review by experienced clinicians and advised to report persist ent symptoms or new skin changes that might herald malignant change. Symptoms and signs Many tumors are preceded by chronic vulval skin symptoms such as pruritu s and irritation, which probably re \202ect pre-existing skin dis- orders. Patients compla in of the sensation of a painful lump. Abnormal genital tract bleeding or haematuria may oc cur. A simple, thorough examination of the external genitalia will iden- tify the majority of tu mors. Persistent erythematous areas that are raised or tender should be suspected as invasi ve disease and a con \201rmatory full thickness skin biopsy should be performed. Staging and investigations Staging requires a combination of surgical and histopathological investigations. The incidence of nodal metastases rises from less than 1% for tumors with less than 1 mm depth of invasion to over 10% for tumors over 3 mm in depth. The con \201rm ation of groin lymph node status is therefore mandatory in all but early stage I disease. N on-invasive modalities such as ultrasound, CT, or MRI are of OHO-23(417-442) 11/18/02 8:34 AM Page 434 gynecological CANCER 434 insuf \201cient negative predictive value for regional (groin) node metas- tases. The rout ine dissection of groin nodes therefore remains import- ant for most stages of this disease . Treatment (cid:2) Surgical excision with clear margins and removal of groin nodes (cid:2) Care if tum or involves distal urethra, anal mucosa (preserve function) (cid:2) Extensive disease may require complex reconstruction (cid:2) Psychosexual dysfuncti on, body image problems frequent (cid:2) Chemo-irradiation for advanced disease: 5 FU and m itomycin C combined with radiotherapy \200\224encouraging results (cid:2) 5-year survival \200\22485% if node-negative (cid:2) Bad prognosis if \200\224>3 re gional nodes involved \200\224Stage III, IV disease \200\224large tumor bulk \200\224node metastases \200\224 poor performance status \200\224tumor type (melanoma) (cid:2) Treatment in specialized centers OHO-23(417-442) 11/18/02 8:34 AM Page 435 VAGINAL AND VULVAL CANCER 435 OHO-23(417-442) 11/18/02 8:34 AM Page 436 gynecological CANCER 436 Trophoblastic tumors Introduction Gestational trophoblastic disease (GTD) includes a spectrum of dis- orders ran ging from the pre-malignant complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM), to the malignant invasive mole, gestational choriocarcinoma, and the highly malignan t placental-site trophoblastic tumor (PSTT). Both CHM and PHM can develop into invasive mol es. However, it is thought that only CHM may progress to the highly malignant choriocarcino ma and the rare PSTT. Dif \201culty in diagnosis occurs most frequently with choriocarcino- mas and PSTT, which can arise after any type of pregnancy and may not present until many years later with wides pread metastases. GTD remains an important group of disorders for the clinician to recog- n ize, because they are nearly always curable if appropriately managed and, in most cases, fe rtility can be preserved. What is trophoblast? Within a few days following conception a ball of cells is formed calle d the blastocyst and the outer layer of this ball differentiates into trophoblast. This con sists of an inner layer of cytotrophoblast cells that migrate outwards and fuse to form lar ge multinucleate syn- cytiotrophoblast cells. The latter produce the pregnancy-associated h ormone, human chorionic gonadotrophin (HCG), and invade the myometrium, triggering the form ation of new maternal blood vessels which are leaky and supply nutrition to the growing fet us. Trophoblast tissue frequently invades these blood vessels, both in normal and molar pre gnancies, and circulates in the blood. Hydatidiform moles Epidemiology (cid:2) 1/1000 pregnancies in UK (cid:2) Two-fold frequency in South-East Asia (cid:2) More common after pregnancy when aged <16 years or >40 years Pathology (cid:2) Ovum lacking maternal nucleus DNA fertilized by one or two sperm \200\224duplicate its chromosomes (cid:2) Conceptus is androgenetic (cid:2) Proliferate to give abnormal trophoblastic tissue OHO-23(417-442) 11/18/02 8:34 AM Page 437 TROPHOBLASTIC tumors 437 (cid:2) Partial mole \200\224arises when two sperm fertilize an ovum that has retained nuclear DNA \200\224triploid conceptus proliferation, to give abnormal trophoblas t and variable fetal tissue \200\224abnormal trophoblast forms hydropic villi which resemble grapes Histology (cid:2) Dilated villi of hyperplastic syncytiotrophoblast and cytotro- phoblast (cid:2) Later, cisterns form (cid:2) Large AV shunts form \200\224facilitates spread Presentation and staging (cid:2) Bleeding in early pregnancy (cid:2) Anemia (cid:2) Toxemia, hyperemesis, hyperthyro idism About 15-20% of complete moles and 0.5% of partial moles will require chemotherapy. S taging of the disease involves ultrasound of the pelvis, serum HCG, and chest X-ray. In mos t instances the CXR will be normal but metastatic disease can present with: (cid:2) Cannonb all secondaries (cid:2) Pleural effusions (cid:2) Wedge infarcts (cid:2) Oligaemic areas (c id:2) Cavitating lesions (cid:2) Miliary appearance If there are chest lesions then a CT or preferably MRI brain scan is indicated prior to lumbar puncture for HCG analysis of the CS F (an HCG ratio of >1:60 (CSF: blood) indicates CNS involvement). Diagnosis (cid:2) Ultrasound \200\224large uterus for dates \200\224CHM: snow-storm appearances, no fetal parts \200\224PHM: abnormal placenta, fetal parts seen (cid:2) HCG level high (cid:2) DCIS in 2% (cid:2) Trophoblastic embolism Treatment (cid:2) Gentle suction curettage (cid:2) Spontaneous abortion OHO-23(417-442) 11/18/02 8:34 AM Page 438 gynecological CANCER 438 (cid:2) Hysterotomy, cesarean section increases the risks two-fold of chemotherapy required to eradicate persistent trophoblastic disease The information from the staging investigations is used in the scoring system to determine the risk of developing drug resistance to methotrexate. Patients who score <5 will be cured with methotrexate alone in at least 75% of cases, while only 30% are cured who score 5 \200\2238. Nevertheless, the latter patients are also offered methotrexate therapy to start with since this treatment carries no risk of long-term sequelae. Methotrexate may cause bl eeding through rapid involution of metas- tases. Patients scoring >9 receive \200\230high- risk \200\231 intravenous combination chemotherapy comprising etoposide, methotrexate, and actinomycin D (EMA), alternating weekly with cyclophosphamide and vincristine (CO). Treatme nt with either methotrexate or EMA/CO regimens con- tinues until the HCG has been normal fo r six weeks. Registration Three specialist centers in the UK register and oversee therapy of this rare t umor: Dundee, Shef \201eld, Charing Cross (London). Follow-up (cid:2) Regular HCG measurement (cid:2) Subsequent pregnancies increase risk of further mol ar pregnancy (cid:2) Rise in HCG means persistent gestational trophoblastic disease or invasive mole or choriocarcinoma has developed If the HCG plateaus or starts to rise, this indicates that the patient has persisting molar disease or has developed an invasive mole (progres- sion to choriocarcinoma and PSTT is ra re). If a repeat ultrasound shows evidence of trophoblastic proliferation within the uterus , suc- tion curettage may be performed. However, performing more than two D&Cs is not usual ly bene \201cial and will not prevent the subse- quent need for chemotherapy. Uterine perf oration is more likely if the HCG is >20 000 when a second D&C is contraindicated. Other factors which increase the risk of needing subsequent chemotherapy include age >50 ye ars and use of the oral contraceptive pill whilst HCG is still elevated. Accordingly, all p atients are advised to use a barrier method of contraception following evacuation of a mole . Choriocarcinoma Epidemiology (cid:2) Follows any type of pregnancy Incidence 1/50 000 (cid:2) (cid:2) 3% of CHM develop into choriocarcinoma (cid:2) No geographical trends OHO-23(417-442) 11/18/02 8:34 AM Page 439 TROPHOBLASTIC tumors 439 Pathology (cid:2) Highly malignant (cid:2) Soft, purple, haemorrhagic mass (cid:2) Histology \200\224 mimics early blastocyst \200\224cores of mononuclear cytotrophoblast \200\224rim of multinucleated syncytiotropho blast \200\224no chorionic villi \200\224surrounding necrosis, bleeding \200\224tumor in venous sinuses Presentation (cid:2) Presents within one year of pregnancy (cid:2) Vaginal bleeding (cid:2) Abdominal pa in (cid:2) Pelvic mass (cid:2) One third present with metastases to liver, brain, or lung Management In most instances the patient will be transferred to the specialist cen- tre. In addition to the staging investigations previously outlined, patients may undergo further t ests including: (cid:2) Measurement of other tumor markers (cid:2) Whole body CT/MRI (cid:2 ) PET scanning (cid:2) Anti-HCG antibody scanning Where it can be safely achieved, excision biopsy of a metastasis should be considered. This not only enables histological con \201r mation of the diagnosis but also permits genetic analysis to prove the gestational nature o f the tumor. If there are only maternal genes and no paternal genes present then the patien t has a non-gestational tumor (an ovar- ian choriocarcinoma or, more rarely, an epithelial tumor that has dif- ferentiated into choriocarcinoma). Frequently, however, biopsy is not p ossible and the diagnosis is made on the clinical history and other investigation \201ndi ngs. The patients are then scored and treated as described for molar disease. The indications for chemotherapy are: (cid:2) Evidence of metastases in brain, liver, or gastrointestinal tract; or radiological opacities >2 cm on chest X-ray. (cid:2) Histological evidence of choriocarcinoma. (cid:2) Heavy vaginal bleeding or evidenc e of gastrointestinal or intra- peritoneal hemorrhage. (cid:2) Pulmonary, vulval, or vaginal metastases unless HCG falling. OHO-23(417-442) 11/18/02 8:34 AM Page 440 gynecological CANCER 440 Table 23.4 Scoring system for gestational trophoblastic tumors Score* 2 Prognostic factor 0 1 6 Age (years) <39 >39 Antecedent pregnancy (AP) Mole Abortion or unknown Term Interval (end of AP to chemo in months) <4 4 \200\2237 7 \200\22312 >12 103 \200\223 \200\223104 <103 A \227 O O \227 A 104 \200\223 \200\223105 B \227 A or O AB \227 A or O >105 HCG iu/l ABO blood group (female \227 male) O or A \227 unknown 1 \200\2234 No of metastases Nil 4 \200\2238 >8 Site of metastases Not detected Spleen Lungs Kidney Vagina GI tract Brain Liver Largest tumor mass <3.0 3 \200\2235 cm >5 cm Prior chemotherapy Single drug 2 or more drugs The total score for a patient is obtained by adding the individual scores for each prognostic factor. Lower risk, 0 \200\2235; medium risk, 6 \200\2238; high risk, >9. (cid:2) Rising HCG after evacuation. (cid:2) Serum HCG = 20 000 iu/l more than 4 weeks afte r evacuation, because of the risk of uterine perforation. (cid:2) Raised HCG 6 months after evacuation even if still falling. Any of these are indica tions to treat following the diagnosis of GTD. Placental-site trophoblastic tumor (PSTT) PSTT can develop following a term delivery, non-m olar abortion, or CHM. There are currently about 100 recorded cases of PSTT in the literatu re and so estimates of its true incidence may well be inaccurate. Nevertheless, PSTT is tho ught to constitute about 1% of all tro- phoblastic tumors (choriocarcinoma, invasive mole, and PSTT). PSTTs are slow-growing, malignant tumors composed mainly of cytotrophoblast with very littl e syncytiotrophoblast, so producing little HCG. However, they often stain strongly for huma n placental lactogen (HPL) which helps to distinguish this tumor from carcino- OHO-23(417-442) 11/18/02 8:34 AM Page 441 TROPHOBLASTIC tumors 441 mas, sarcomas, exaggerated placental-site reaction, and placental nodule. The raised HPL ma y cause hyperprolactinaemia that can result in amenorrhoea and/or galactorrhoea. In most ca ses spread occurs by local in \201ltration with distant metastases occurring late via the lymphatics and blood. The behavior of PSTT is thus quite different from other forms of GTD and it is relatively c hemo-resistant. The best management is hysterectomy when the disease is localized to the ut erus. When metastatic disease is present, patients can respond and be apparently cured by m ulti-agent chemotherapy either alone or in combination with surgery. Patient follow-up and prognosis On completion of their chemotherapy, patients are advised t o avoid pregnancy for one year and remain on HCG follow-up for life to con \201rm that the ir disease is in remission. About 2% of low-risk and 4% of high-risk patients will relapse. All low-to middle-risk patients are salvaged with further chemotherapy (EMA/CO or alternat ive regimens) and the cure rate is almost 100% in this group. The high- risk group has 90% survival rate beyond 10 years. With the addition of platinum and other new agents salvage r ates for patients relapsing following EMA/CO therapy can be in excess of 70%. Neither metho - trexate nor EMA/CO therapy reduce fertility or cause abnormalities. Thus women treated fo r GTD can expect to have healthy children. Further reading 1. Advanced Ovarian Cancer Triallist Group (1998) Chemotherapy in ovarian c ancer: four systematic meta-analyzes of individual patient data from 37 randomized trials. British Journal of Cancer 78, 1479 \200\22387. 2. Rose, P.G., Bundy, B.N., Watkins, E.B. et al. (1999) Concurrent cisplatin- based chemotherapy and radiotherapy for locally advanced cervical cancer. New England Journ al of Medicine 340, 1144 \200\22353. OHO-23(417-442) 11/18/02 8:34 AM Page 442 This page intentionally left blank OHO-24(443-468) 11/18/02 8:35 AM Page 443 Chapter 24 Head and neck cancer Cancer of the larynx 444 Cancer of the oral cavity 448 Carcinoma of the nasopharynx 450 Nas al cavity and paranasal sinuses 454 Eye and orbit 458 Salivary gland tumors 462 Further rea ding 468 OHO-24(443-468) 11/18/02 8:35 AM Page 444 HEAD AND NECK CANCER 444 Cancer of the larynx Introduction The use of the operating microscope (microlaryngoscopy), rigid and \201bre l aryngoscopes, stroboscopy, CT, and MRI, and the improved histopathological diagnosis by imm unohistochemistry, electron microscopy, cytometry, and morphometry have made major contri- butions in laryngeal pathological diagnosis. Radiotherapy is, in many countries, the prime treatment for laryn- geal carcinoma. Surgery has, however, been successfully re \201ned, with various voice and airway conservation pro cedures. Rehabilitation of the laryngectomized patient has been easier with insertion of di ffering voice prostheses. Squamous cell neoplasm Tumors arising from the mucosa of the larynx make up the majority of tumors in the larynx. Juvenile laryngeal papillomas are virus- induced benign tumors that are most commonly located on the vocal cords and occasionally remain or arise in adults. Th ey may be solitary or multiple. Malignant degeneration of non-irradiated juve- nile larynge al papillomas is extremely rare. Surgical excision with the aid of the operating microscope and the carbon dioxide laser is the treatment of choice. Interferon may be used in very se lective trouble- some cases. Pre-malignant lesions Classi \201cation should be based on grade of dysplasia, as this has a bear- ing on prognosis. Most of these lesions are diagnosed on the vocal cords with hoar seness as the symptom. These lesions should be endo- scopically excised (conventional techn ique or laser) and the speci- mens should be carefully examined by an experienced pathologi st working in close collaboration with the clinician. Radiotherapy may be used for frequent ly recurring or diffuse lesions. These patients should be carefully followed up as there is not only a risk of develop- ment of invasive carcinoma but also a high risk of other prima ry malignant neoplasms, especially within the upper aero-digestive tract and lungs. Epidemiology and carcinogenesis Laryngeal cancer makes up less than 2% of all carcinomas in males, with an annual incidence of 3 \200\22310 per 100 000. It is a predominantly male di sease, with a higher incidence in urban than rural areas. OHO-24(443-468) 11/18/02 8:35 AM Page 445 CANCER OF THE LARYNX 445 Smoking and alcohol are documented risk factors and act synergisti- cally. Occupational ris k factors may include asbestos and solvents. Human papilloma virus has also been suggested as a risk factor. Symptoms Hoarseness is the most common presenting symptom for primary glottic carcinoma (th e most common laryngeal cancer in North America, England, and Scandinavia). Dysphagia, irri tation, and coughing are characteristic of supraglottic carcinomas (which make up more than 50% of the laryngeal cancers in Mediterranean coun- tries and South America). Subglottic c arcinomas are rare (<5%) and cause dyspnoea and stridor as they grow circumferentially in t he sub- glottis. They usually present late. Most laryngeal carcinomas are diag- nosed betwe en 40 \200\22380 years of age. Diagnostic examinations Indirect and direct laryngoscopy, including stroboscopy, comple- me nted by CT or MRI and histopathological studies are requirements for correct diagnosis. Ult rasound-guided \201ne-needle aspiration cytol- ogy is the most accurate technique for ass essment of neck masses. Treatment The main treatment modalities are radiotherapy and surgery with the aim to provid e optimal cure with the best functional results. Induction chemotherapy may select patients with advanced carcino- ma suitable for full-course radiotherapy to save the larynx. Patien t factors such as general condition, lifestyle, previous treatment, and personal views are all important in the treatment decision. Limited glottic carcinomas are treated with equal results by radio- therapy and surgery wit h external techniques or endoscopically using the CO2 laser, which is increasingly employed . The voice may be better spared by radiotherapy, the cure rate being 70 \200\22390%. Advanced glottic carcinomas (T3 \200\223T4) are treated by primary radio- therapy at many c enters and surgery or induction chemotherapy are reserved for salvage of failures. Near tot al laryngectomy is an opera- tion that saves the voice, but the patient is given a stoma fo r breathing In advanced carcinomas the neck nodes are included in the treat- ment planning; the survival rate is 50 \200\22360%. Partial voice conservation laryngectomy techniques ar e employed in some centers as primary treatment for early supraglottic carcinomas. Endoscop ic laser surgery is reported to give the same cure rate and less functional morbidity, at l east in experienced hands. As 30 \200\22340% of the patients have nodal metastases, neck di ssection is usually performed when surgery is the sole treatment. Primary radiotherapy give s nearly the same cure rate, but any recurrence means that a total laryngectomy is most oft en necessary. Local control rates with primary surgery and radiotherapy OHO-24(443-468) 11/18/02 8:35 AM Page 446 HEAD AND NECK CANCER 446 are 80 \200\22390%. Subglottic primary carcinomas are rare and the high risk of paratrachea l and upper mediastinal nodal metastases must be taken into account. Miscellaneous tumors Verrucous carcinoma is a distinct variant of well differentiated squam ous cell carcinoma (also named Ackerman \200\231s tumor) and is characterized by a verrucou s appearance and pushing margins histopathologically, surrounded by a marked in \202ammato ry cell response. Lymphatic spread is rare. Surgical treatment is usually advo- cated, but a good response to radiotherapy is also reported. Spindle cell carcinoma is a rare, well-described tumor making up less than 1% of laryngeal malignant tumors. The term \200\230pseudo- sarcoma \200\231 has been used for some of thes e tumors as the spindle ele- ments were once considered reactive. Immunohistochemical and e lectron microscopy suggest they are epithelial cells. Rehabilitation and follow-up after total laryngectomy The greatest handicap for the patient s after a total laryngectomy is the loss of voice. 40% of patients acquire socially useful oesophageal speech. Some people use the arti \201cial larynx. Fistula operations with inse rtion of speech valvulas are increasingly performed and well toler- ated. Heat and moisture exchangers are commonly used to lower the risk of respiratory problems and can be position ed in front of the stoma. Follow-up should be strict \200\22490% of recurrences occur within three years. The high ri sk of multiple primary malignancies (12 \200\22320%) should be considered, making routine c hest X-rays and broncho- scopies part of the follow-up program. All patients should be advi sed to stop smoking. OHO-24(443-468) 11/18/02 8:35 AM Page 447 CANCER OF THE LARYNX 447 OHO-24(443-468) 11/18/02 8:35 AM Page 448 HEAD AND NECK CANCER 448 Cancer of the oral cavity Pathology Squamous cancers of the oral cavity are associated with heavy con- sumption of bo th tobacco and alcohol. Other aetiological factors are: (cid:2) Diet (de \201cient in Vita min A, fruit, and vegetables) (cid:2) Poor dental hygiene (cid:2) Syphilis The other less common malignancies in the oral cavity include: (cid:2) Salivary tumors (ade noid cystic, mucoepidermoid, adeno- carcinoma) (cid:2) Melanomas (cid:2) Plasmacytomas (cid:2) Sarcomas Squamous cancers in the mouth present with a mucosal irregularity which progresses either into an ulcerated destru ctive lesion or a more exophytic growth. These can be highly aggressive tumors, invading an d destroying adjacent local tissues including the bone of the mandible, and disseminating t o regional lymph nodes in the neck and submandibular region. The region is divided anatomically but tumors commonly involve more than one region: (cid:2) Alveolar ridge/retromolar trigone (10%) (cid:2) Floor of mout h (15%) (cid:2) Tongue (60%) (cid:2) Hard palate (5%) (cid:2) Buccal mucosa (10%) Staging The assessment of the patient requires examination under anesthetic to assess the e xtent of disease and biopsy of the lesion. The primary and regional nodes are also usefully assessed by MRI scan. The malig- nant nature of lymphadenopathy should be con \201rmed by FNA cytol- ogy. CXR should be performed as much to exclude a coincidental lung primary as for infrequent lung metastases. Treatment (cid:2) Multidisciplinary approach is essential \200\224maxillofacial, plastics, dental OHO-24(443-468) 11/18/02 8:35 AM Page 449 CANCER OF THE ORAL CAVITY 449 \200\224radiation oncologist \200\224dietician \200\224speech therapist (cid:2) Surgery for early tumors (cid:2) Primary radiotherapy and reserve surgery for salva ge (cid:2) Neck dissection for positive nodes (cid:2) Large lesions require osteomyocutaneo us \202ap reconstruction If locally advanced \200\224combination of surgery and radiotherapy Radiation therapy is pl anned taking account not only of all clinical and radiological evidence of the tumor but al so the likely sites of occult nodal disease. Doses of 50 \200\22365 Gy are delivered to the tumor volume, depending on the extent of residual tumor. At least part of this dose can be delivered by interstitial therapy, often using iridium wire. Inevitably radical irradiatio n of the oral cavity causes mucositis and a dry mouth, that may persist depending on the am ount of sali- vary tissue spared from irradiation. Chronic ulceration of the mucosa and ost eonecrosis are risks, particularly with locally advanced tumors involving the mandible. (cid:2) As with head and neck squamous cancers at other sites, chemo- therapy (cisplatin, 5- \202u orouarcil, methotrexate, bleomycin) is active in advanced disease, but there is no proven b ene \201t for chemotherapy given as either adjuvant or neo-adjuvant therapy. OHO-24(443-468) 11/18/02 8:35 AM Page 450 HEAD AND NECK CANCER 450 Carcinoma of the nasopharynx Anatomy The nasopharynx is the part of the upper respiratory tract situated between the nas al and oropharyngeal cavities. The roof is the base of the skull and arch of the atlas with the \201rst two cervical vertebrae forming the posterior wall. The anterior border is th e posterior choanae and the \202oor is the upper surface of the palate. Epidemiology There is a wide variation of incidence of nasopharyngeal carcinoma (NPC) throu ghout the world. The highest incidence is in South China and a large part of South- East Asia (Hong Kong, Si ngapore, Malaysia, Vietnam, and North Thailand) with an average incidence of 20 \200\22330/ 100 000 per year. The incidence amongst males aged 45 \200\22355 in South China is 120/100 000. There is an intermediate incidence amongst Maghrebian Arabs (from Ageria, Tunisia, Mor occo, Libya, and Sudan) of 1.5 \200\2239/100 000 per annum. The only group in North America or Europe with a high inci- dence of NPC are Eskimos, with a prevalence similar to that of the Cantonese. Otherwise, this is a rare cancer with a typical incidence of 0.2 \200\2230. 5/100 000 (West Midlands of England). Etiology (cid:2) Epstein \200\223Barr virus (EBV) (cid:2) Genetic susceptibility \200\224major histo compatability complex pro \201le, H2, BW46, B17 antigens (cid:2) Dietary-salty \201sh \200\224contain nitrosamines (cid:2) Chinese herbal medicine contains esters \200\224tumor promoters, reactivate EBV infection (cid:2) Lack of dietary vitamin C (cid:2) EBV infection \200\224re activated 18 \200\22360 months before detectable tumor (cid:2) EBV copies inside malignant cells Pathology The WHO divided NPC into three types: (cid:2) Type 1: keratinizing squamous carci noma (cid:2) Type 2: non-keratinizing carcinoma (transitional cell carcinoma) (cid:2) Type 3: undifferentiated (lymph-epithelioma) OHO-24(443-468) 11/18/02 8:35 AM Page 451 CARCINOMA OF THE NASOPHARYNX 451 Squamous cancers are associated with a higher propensity for local persistence after treatm ent and a poorer prognosis. Undifferentiated tumors are the most common entity and, unlike most head and neck cancers, frequently spread to distant sites, initially via the lymphatic system. Presentation and methods of spread Unilateral deafness, secondary to Eustachian tube blocka ge, is the most common local symptom, followed by epistaxis. Nasal obstruc- tion is common when the tumor is advanced. NPC spreads into the parapharyngeal space laterally, anteriorly to the orbit and paranasal sinuses, inferiorly to the oropharynx, and superiorly through t he base of the skull. Any of the cranial nerves can be involved by the tumor. In practice, the Vth nerve is involved most frequently owing to tumor in or around the foramen ovale. Tu mor in the cavernous sinus can lead to diplopia secondary to compression of the IV, III, or VI nerves. The posterior cranial nerves (IX to XII) can be involved by direct parapharynge al spread or compression by retropharyngeal lymph nodes. Cervical lymph node spread is common and is a frequent presenta- tion. Bilateral or unilate ral upper deep cervical nodes just below the mastoid are frequently involved. Caudal spread of nodal disease corre- lates with distant spread and this is the basis of the Ho staging scheme. Distant spread to bone (often with sclerotic metastases), the liver, and lung is co mmon in advanced stage disease. CT scanning of the base of the skull, nasopharynx and neck, thorax, and liver is an essenti al part of pre-treatment assessment. About a fourth of patients with low cervical or suprac lavicular nodes have a positive isotope bone scan. In the Far East, the Ho staging system is used instead of the UICC scheme. It is argued tha t it is often impossible to decide whether the tumor is con \201ned to only one subsite an d the UICC T staging does not correlate well with prognosis. The nodal staging system is pa rticu- larly inappropriate as the tumor originates in the midline and bi- lateral spread is common. Nodal size or the degree of \201xation are not important prognostic variables, b ut the level of nodal spread is related to the probability of distant spread. Treatment NPC is generally both radio- and chemosensitive. Radiotherapy is the mainstay of treatment. The role of surgery is restricted to staging and the elective dissection of neck nodes that have not regressed three months after radiotherapy. Radiotherapy planning is complicated in this disease. The primary tumor should be irradiate d with a wide margin including the base of the skull. The neck is invariably irradiated owi ng to the high frequency OHO-24(443-468) 11/18/02 8:35 AM Page 452 452 HEAD AND NECK CANCER Table 24.1 Ho staging scheme (1989) T1 T2n Tumor con \201ned to nasopharynx Nasal involvement without parapharyngeal space involvement or T3 features T2o T2p T3q T3a Oropharyngeal involvement without T3 features Parapharyngeal involvement without T3 features Parapharyngeal involvement with T3 features Bone involvement below base of skull including \202oor of sphenoid sinus T3b T3c T3d N0 Involvement of base of skull Cranial nerve involvement Involvement of orbit, laryngopharynx, or infratemporal fossa No cervical lymph nodes palpable N1 Nodes wholly above the skin crease extending laterally and backwards from just below the th yroid notch N2 Nodes palpable between the skin crease and supraclavicular fossa N3 Nodes palpable in the supraclavicular fossa or skin involvement The groups can be condensed to \201ve stages: Stage I T1 N0 Stage II T2 and/or N1 Stage III T3 and/or N2 Stage IV N3 involvement irrespective of T stage Stage V Haematologous spread or nodal involvement below clavicles Table 24.2 UICC staging (1992) T1 Tumor limited to one subsite in the nasopharynx T2 Tumor involving more than one subsite T3 Tumor invades nasal cavity and/or nasopharynx T4 Tumor invades skull and/or cranial nerves N0 No regional lymph nodes N1 N2a N2b N2c N3 Single ipsilateral node <3 cm Single ipsilateral node >3 cm Multiple ipsilateral nodes >3 cm but <6 cm Bilateral or contralateral nodes all <6 cm Any node >6 cm OHO-24(443-468) 11/18/02 8:35 AM Page 453 CARCINOMA OF THE NASOPHARYNX 453 of overt and occult neck metastases. However, the radiation dose to the brain, eyes, and sp inal cord must be kept within tolerance. In order to reduce acute reactions as much normal mucosa as possible must be excluded from the irradiated volume. In general, doses of 65 \200\22370 Gy are given to the primary site in 6.5 \200\2237 weeks. Involved areas of the n eck are treated to 60 Gy with boosts of 70 Gy with electrons if necessary. Parapharyngeal m asses are also boosted. Brachytherapy may be used to increase the dose to the primary site. Local or regional recurrence developing two or more years after radiotherapy can be success fully treated by a second radical course of radiotherapy with a reported \201ve-year surv ival of 25 \200\22335% but with considerably increased morbidity. Chemotherapy (cid:2) Chemo-responsive tumor (cid:2) 20% complete response (cid:2) 70% overall response r ate in advanced disease (cid:2) 5FU, cisplatin, bleomycin (cid:2) May be advantage for chem otherapy before radiotherapy, especially in Stage IV Results The 10-year actuarial survival for 5037 patients treated in Hong Kong between 1976 and 1985 was 43%. Typical three-year survival \201gures, by stage, in Hong Kong are: (81%) I (63%) II III (54%) IV (36%) (cid:2) (cid:2) (cid:2) (cid:2) Future developments The following are under investigation: (cid:2) Development of an EBV va ccine (cid:2) Conformal radiotherapy to reduce dosage to normal tissue (cid:2) Accelerated hyperfractionated radiotherapy (cid:2) Combined radiation and chemotherapy OHO-24(443-468) 11/18/02 8:35 AM Page 454 HEAD AND NECK CANCER 454 Nasal cavity and paranasal sinuses Etiology Unlike the rest of the upper aerodigestive tract, smoking plays little if any role in malignant tumor development. However, for certain his- tology occupational factors are important. Adenocarcinoma of the ethmoids may develop from exposure to hard wood dust, wher eas soft wood dust may lead to the development of squamous cell carcinoma. The relative ris k of a wood worker developing adenocarcinoma is 70 times normal; adenocarcinoma has also be en associated with the manufacture of chrome pigment, isopropyl alcohol, textiles, clothing , leather, and shoes. Epidemiology Sinonasal malignancy is rare, constituting approximately 3% of head and neck c ancer. Global \201gures suggest an incidence of <1/100 000 people per year in most countr ies, though occupational factors pro- duce regional differences. The male to female ratio i s approximately 2:1 overall and, while the tumor may occur at any age, the majority present between 50 \200\22370 years. Pathology The sinonasal region offers a great histological diversity of tumors. Of these, s quamous cell carcinoma remains the commonest. Late pre- sentation may make it dif \201cult to de \201ne the exact site of origin. Generally, the maxillary sinus is regarded as the usual site, though lesions frequently arise in the lateral wall of the nasal cavity and eth - moids. The primary malignant tumors of the frontal and sphenoid sinuses are extremely rar e. The nasal cavity and sinuses are intimately related to the orbit and skull base (anterior a nd middle cranial fossae) \200\224areas into which the tumors may spread early and covertly . In addition, anterior spread into the soft tissues of the face, posterior involvement of the pterygoid region and nasopharynx, and inferior spread to the oral cavity may all be enc ountered, generally along the routes of least resistance. Distant lymphatic and haematogeno us spread are rare in the early stages of the disease and patients more often die of local disease before sec- ondary spread is apparent. OHO-24(443-468) 11/18/02 8:35 AM Page 455 NASAL CAVITY AND PARANASAL SINUSES 455 Table 24.3 Sinonasal malignancy Epithelial Malignancy Epidermoid/squamous Carcinoma (spindle cell, verrucous, transitional) Non-epidermoid Adenoid cycstic carcinoma Adenocarcinoma Mucoepidermoid carcinoma Acinic cell carcinoma Metastases Neuroectodermal Malignant melanoma Olfactory neuroblastoma Mesenchymal Vascular Angiosarcoma Kaposi \200\231s carcoma Haemangiopericytoma Muscular Leiomyosarcoma Rhabdomyosarcoma Cartilaginous Chondrosarcoma (mesenchymal) Osseous Osteogenic sarcoma Lymphoreticular Burkitt \200\231s lymphoma Non-Hodgkin \200\231s lymphoma Extra-medullary plasmacytoma Midline destructive lesions Miscellaneous Fibrosarcoma Liposarcoma Malignant \201brous histiocytoma Ewing \200\231s sarcoma Alveolar soft part sarcoma Presentation From the maxilla the tumor may spread into the nasal cavity pro- ducing nasal obstruction and discharge (often serosanguinous). Anterior spread along the infra-orbital c anal may produce pain and paresthesia. Orbital involvement produces displacement of the glo be with: (cid:2) Proptosis (cid:2) Diplopia (cid:2) Epiphora (cid:2) Chemosis (cid:2) Visua l loss OHO-24(443-468) 11/18/02 8:35 AM Page 456 HEAD AND NECK CANCER 456 Inferior involvement of the dental roots may lead to loosening of the teeth and/or a malign ant oro-antral \201stula or a mass in the hard palate. Posterior extension into the ptery goid and infra-temporal fossa produces pain and trismus. Spread from the ethmoid sinuses will involve the nasal cavity, con- tralateral ethmoid, and orbit with symptoms as described. Superior extension into the anterior cranial fossa is ge nerally asymptomatic. The middle cranial fossa may be involved by direct spread from the an terior cranial fossa or orbital apex, whence a cavernous sinus syn- drome may arise. Nasal cavity lesions, in addition to nasal symptoms, may spread posteriorly to obstruct the Eusta chian tube producing a unilateral serous otitis media or anteriorly to erode and displace t he nasal bones in the region of the glabella. Surgical principles The majority of tumors present late with involvement of import- ant adj acent structures. Even histologically \200\230benign \200\231 tumors may be associated wit h signi \201cant morbidity and/or mortality at this site. The principle of oncological res ection may be compromised by the proximity of vital structures. This, combined with the his to- logical diversity in this area, necessitates specialist management. Diagnosis and assessment of extent of disease relies upon expert imaging and histology. Ide ally, CT scanning (direct coronal and axial cuts with intravenous contrast enhancement) com bined with MRI should be undertaken. In addition, a chest X-ray and CT of the thorax, abdom en, and bone studies may be appropriate if occult pri- mary or systemic metastases are susp ected.