CHAPTER 18.4 Pulmonary Langerhans \200\231 cell histiocytosis 451 provide morphological evidence for diagnosis. Samples show an increased number of LC, which can be detected under light microscope, positive for CD1 antigen or S-100 staining. If the proportion of CD1a-stained cells is greater than 5%, PLCH is very likely. However, this is not particu- larly helpful as an increased CD1a level is also found in heavy smokers and o ther ILDs. Under electron micros- copy, characteristic intracytoplasmic Birbeck granules ma y be seen. VATS biopsy is mainly used to exclude alternative diagnostic possibilities (Fig. 18.4.2). patients will deteriorate with progressive respiratory insuf- \201 ciency and cor pulmona le. 30 \200\22340% will regress to a lesser extent to be left with persisting thin walled c ysts. 50% patients will undergo partial or complete resolution of radiographic abnormalitie s. Long-term follow-up of all patients is necessary, as even after years of remission, new nodules may form, causing lung function to again deteriorate. Patients \200\231 outcome is likely to improve with the cessation of smoking, therefore this should strongly be encourag ed. Corticosteroids are thought to help accelerate resolution of the disease, particularly in symptomatic patients with systemic symptoms, but precise bene \201 ts remain unclear. C hemotherapeutic agents such as vinblastine and cyclo- phosphamide are used to treat diffuse LCH in children. However limited data is available on their efficacy in PLCH. Lung transpl ant has been successful in patients with advanced disease causing severe respiratory impair ment, or severe pulmonary arterial hypertension. Interestingly, PLCH has later recurred in the transplanted lung in several cases. Although this complication reduces the transplanted lung \200\231s function, the effect on overall survival has not been established. AUTHOR \200\231S TIPS \200 Lack of exposure to smoking and age >60 make diag- nosis unlikely. Typical cases show impai red diffusing capacity and upper-lobe predominance. Smoking cessation is vital to treatment 50% patients undergo resolution. Death from disease is rare. Fig. 18.4.2 Lung biopsy with Langerhans cells labeled with labeled for S-100 protein. (See Plate 16.) Differential diagnosis The ability to establish a diagnosis of PLCH depends on the clinical and radiological \201 ndings. The diagnosis is simple in young smokers presenting with n odular and cystic lesions. If a patient has systemic symptoms and prominent cavitary nodule s the following diseases must be considered: myco- bacterial infection, sarcoidosis, silico sis, Wegener \200\231s disease, cavitary metastatic lesions, alveolar cell carcinoma, septi c emboli, or excavated pneumocystis. LAM must be distinguished from PLCH in women with pure ly cystic lesions. \200 Further reading Caminati A, Harari S. Smoking-related interstitial pneumonias and pulmonary Langerhans cell histiocytosis. Proc Am Thorac Soc 2006; 3: 299 \200\223306. Kim CK, Park BP. Pulmonary Langerhans \200\231 cell histiocytosis pre- sented with recurren t pneumothorax. Interact CardioVasc Thorac Surg 2006; 5: 512 \200\223513. Tazi A, Soler P, Hance AJ. Adult pulmonary Langerhans \200\231 cell histiocy- tosis. Thorax 2000; 55: 405 \200\223416. Treatment and prognosis There are no reliable guidelines regarding treatment and prognosis due to the large variation in outcome seen across patients. Generally, PLCH patients \200 \231 life expectancy is shorter than that of the general population. Poor prognostic factor s include: a very young or very old age at onset of disease, ongoing systemic symptoms, rec ur- rent pnemothoraces and extrapulmonary features (exclud- ing bone involvement). It is un common for the disease to progress to advanced pulmonary fibrosis and death. Approximately 10 \200\22320% Vassallo R, Ryu JH, Colby TV, et al. Medical progress: pulmonary Langerhans \200\231-cell h istiocytosis. N Engl J Med 2003; 342(26): 1969 \200\2231978. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of Pulmonary Langerhans \200\231 -cell histiocytosis in adults. N Engl J Med 2002; 346(7): 484 \200\223490. Vassallo R, Jensen EA, Colby TV, et al. The Overlap Between Respiratory Bronchiolitis and D esquamative Interstitial Pneumonia in Pulmonary Langerhans Cell Histiocytosis. Chest 2003; 124(4): 1199 \200\2231205. S JOHNSON 452 18.5 Lymphangioleiomyomatosis Lymphangioleiomyomatosis (LAM) is a rare cystic lung dis- ease which almost exclusively aff ects women. The disease is associated with angiomyolipomas, benign tumors gen- erally occur ring in the kidneys and abnormalities of the axial lymphatics. Epidemiology LAM affects 1 \200\2232 per million of the general population (sporadic-LAM) b ut is common in tuberous sclerosis com- plex (TSC-LAM) where lung cysts are present in up t o 40% of adult women. Presentation and clinical features Most patients present between 20 and 50 years of age wit h dyspnoea or pneumothorax. Cough and wheezing are common in LAM and can lead to misdiagnos is of more common conditions. Diagnosis may follow CT scanning performed for other purposes . Less often hemorrhage from renal angiomyolipoma or symptomatic abdominal or pelvic lympha tic masses are the \201 rst symptom. LAM is exacerbated by, and may present during, pregn ancy. Missed presentations of LAM \200 \200 \200 \200 \200\230Emphysema \200\231 in younger women. \200\230Asthma \200\231 unresponsive to ther apy. Pneumothorax during pregnancy. Respiratory symptoms in TSC. Cysts develop in the lungs causing dyspnoea in most patients. Pneumothorax occurs in two th irds of patients and is frequently recurrent. Occlusion of the axial lymphat- ics results i n lymphadenopathy, cystic abdominal and pelvic masses (lymphangioleiomyomas), chylous pleur al effusions and ascites. Abdominal discomfort, bloating, or pressure symptoms occur in up to 20%. Half of patients have one or more angiomyolipomas, benign tumors of smooth muscle, fat, and blood vessels. Angio myolipomas occur mainly in the kidneys and can bleed when lar ge. A small number of patients have menin- giomas. Fig. 18.5.1 HRCT of patients with LAM. Upper panel is asymptomatic disease with minimal cys ts (arrowed) and normal parenchyma. Lower panel shows extensive disease. Investigation and diagnosis Plain radiographs may be normal in early disease or show inters titial markings with preserved lung volumes. HRCT scanning shows lung cysts with thin walls evenly distributed within normal lung parenchyma (Fig. 18.5.1). The cysts become more nume rous as the disease progresses. 80% of patients have abnormalities on abdominal imaging: 50 % with renal angiomyolipomas and a signi \201 cant number with lymphadenopathy, lymphangio leiomyomas, or chylous ascites. Abdominal CT is recommended to identify these complications , to explain abdominal symptoms and to screen for angiomyolipoma which has a characteristic appearance due to its fat content (Fig. 18.5.2). Lung function tests may be normal in earl y disease but air \202 ow obstruction with impaired gas transfer is commonly seen. Pleural complications and their treatment may lead to restrictive changes. Pathological samples sh ow abnor- mal smooth muscle type cells (LAM cells) proliferating in the lung to form nodule s which protrude into small airways and line the walls of cysts (Fig. 18.5.3). Biopsy of ex tra-thoracic lymphatics shows tissue in \201 ltrated LAM cells. Fig. 18.5.2 Angiomyolipoma in the left kidney. Characteristic mixed attenuation tumor (arro w) of low density suggesting presence of fat. Although morphology is characteristic, immunostaining for the melanoma-related protein GP10 0 with the antibody HMB45 is a helpful marker especially in early disease. LAM cells are al so smooth muscle actin and often estrogen and progesterone-receptor positive. CHAPTER 18.5 Lymphangioleiomyomatosis 453 Pregnancy is associated with an increased risk of pneumot- horax and premature birth: patie nts should be warned of this. Those with air \202 ow obstruction should be given a trial o f bronchodilators. Smoking cessation and pulmonary rehabilitation are likely to be of bene \201 t. Patients should be warned of the symptoms of pneumot- horax which is recurrent in 2/3 and early liaison with tho- racic surgeons is suggested. Chylous effusions may also req uire surgical treatment if symptomatic. Anti-estrogen therapies have been used, most common ly progesterone but also the GnRH agonists, tamoxifen and oophorectomy. Although no prospec tive studies support their use. Clinical trials of newer agents including the mTOR inhibi- tor rapamycin are currently underway and participation in clinical trials is a potential op tion for patients. Angiomyolipomas can bleed, resulting in severe haemor- rhage requiring n ephrectomy. Bleeding is associated with larger size, rapid growth and aneurysmal blood vess els. If present, angiomyolipoma should be screened regularly to detect growth. Those >4cm s hould be examined twice yearly and if symptomatic or enlarging rapidly; evaluated for possi ble embolisation or nephron sparing surgery. Angiomyolipomas may need specialist management especially in TSC-LAM patients who almost always have angiomyolipomas which are often larg e and multiple. Lung transplantation has been used for severe disease. Referral criteria ha ve not been formalized although NYHA functional class III or IV, severe impairment in lung function and exercise capacity (VO2 max <50%) with hypoxemia at rest are often used. Previo us pleural surgery is associated with increased peri-operative bleeding but has no effect o n overall survival. Although LAM may occasionally recur in the graft this does not affect t he outcome and survival data is at least as good as other indications for transplant. Fig. 18.5.3 Lung biopsy showing LAM nodules stained with A-smooth muscle actin. Diagnostic criteria for LAM have not been formally agreed, however a suggested scheme is: D e \201 nite LAM \200 characteristic HRCT. Plus one or more of: \200 \200 \200 \200 Lung or extra-pulmonary biopsy. Angiomyolipoma. Chylous collection. Tuberous sclerosis. Probable LAM (consider biopsy) \200 Characteristic HRCT plus compatible clinical history only. Differential diagnosis Emphysema may mimic LAM and vise-versa. A cystic lung appearance on CT can be seen in LCH, metastatic endome- trial sarcoma, Birt \200\223Hogg \200\223Dub sy ndrome, light chain depo- sition disease and lymphocytic interstitial pneumonia. It is impo rtant to consider TSC in LAM patients. The diag- nosis can be overlooked, particularly as 2 /3 of TSC patients have no family history of TSC and many have no learning dif \201 cultie s and only minor skin involvement. LAM in tuberous sclerosis complex LAM is common in women with TSC with 40% having cystic lu ng disease if examined by CT. Although less than 5% have symptoms some have severe disease and develop respiratory failure. These patients should be managed in the standard way inclu ding transplant evaluation where appropriate. Asymptomatic patients identi \201 ed by scre ening should probably avoid estrogen and receive advice regarding pneumothorax and pregnanc y. TSC-LAM patients are likely to have other problems including eplilepsy, angiomyolipoma, and skin lesions requir- ing specialist or multidisciplinary assessment, possibly though a TSC clinic. Clinical course Many patients develop progressive air \202 ow obstruction although rates a re variable, on average, FEV1 falls by 120 ml/year. Pneumothorax and chylous effusions may occur and can be recurrent. Respiratory failure may develop and overall survival is between 70 \200\22395% at 10 years. Some patients with sporadic LAM and many with TSC-LAM do not h ave progressive disease. At present there are no prog- nostic markers with which to predict the clinical course. Further reading Johnson SR. Lymphangioleiomyomatosis. Eur Respir J 2006; 27: 1056 \200\2231065. Juvet SC, McCormack FX, Kwiatkowski DJ, et al. Molecular patho- genesis of lymphangioleiomy omatosis: lessons learned from orphans. Am J Respir Cell Mol Biol 2007; 36: 398 \200\223408 . Management General measures: patients should avoid exogenous oes- trogen including the comb ined oral contraceptive and HRT. NHLBI LAM Registry Group. The NHLBI lymphangioleiomyomato- sis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006; 173: 105 \200\223111. J SUNTHARALINGHAM & M HETZEL 454 18.6 Primary tracheal tumors \200 De \201 nition Primary tracheal tumors arise within the trachea itself and should be disti nguished from other adjacent or distant tumors that have simply extended or metastasised to the trachea. Tracheal tumors can be either malignant (90%) or benign (10%). Empey index = FEV1 (mls)/PEFR (L/min). Flow-volume loops demonstrate flattening of both ins piratory and expiratory phases. This is because of the \201 xed nature of the upper airwa y obstruction typically associated with tracheal tumors. Radiology \200 CXR is often falsely reassuring but can reveal narrowing, distortion or deviation of the tr achea, mediastinal wid- ening or evidence of metastatic spread. CT with multiplanar reconst ruction provides an excel- lent non-invasive tool for assessing tumor stage and operability . MRI offers no clear advantages over CT at present. Epidemiology Possibly as result of heightened local immunosurveillance, primary tracheal tu mors are rare and constitute less than 0.2% of all respiratory tract malignancies. It is es timated that there are just 2.6 new cases per million population per year. Bronchoscopy \200 Pathology More than 30 different tumors have been described, orig- inating within the surfa ce epithelium, salivary glands or mesenchymal structures of the trachea. Squamous cell carc inoma (SCC) accounts for 50% of cases and is most commonly found in male smokers in their s ixth and seventh decades. The tumor grows rapidly and has metastasised in one-third of pati ents by the time of presentation. Adenoid cystic carcinoma (ACC) is the second most com- mo n tumor (20%), has no male/female predominance, is not associated with smoking and most oft en presents in the fourth and \201 fth decades. ACCs are slow growing and metastasise les s commonly than SCCs. Bronchoscopy is essential for both obtaining a tissue diagnosis and for adequately assessin g tumor stage. Flexible bronchoscopy can be safely performed in the majority of individuals . However biopsies should be avoided in patients with severe airway compromise as consequen t hemorrhage and oedema may convert critical narrowing to complete upper airway obstruction . Rigid bronchoscopy allows biopsies to be performed whilst maintaining upper airway stabil ity and ventilation and is thus the investigation of choice in patients with severe airway compromise. Acute management Patients occasionally present with acute respiratory dis- tress at their i nitial presentation. It is essential that airway Clinical presentation Upper airways obstruction \200 Patients present with dyspnoea, inspiratory stridor or expiratory wheeze and are often init ially misdiagnosed as having asthma or COPD. Tumors are typically advanced at presentation as symptoms only occur once the tracheal lumen is com- promised by 50 \200\22375%. Mucosal irritation and ulceration SCCs can present with cough or haemoptysis and as a resul t may be diagnosed earlier. Direct invasion of adjacent structures \200 Involvement of the right recurrent laryngeal nerve may lead to a right vocal cord palsy and hoarseness. Dysphagia and superior vena caval obstruction (SVCO) can also result from loca l tumor spread. Investigations Pulmonary function tests \200 PEFR is characteristically disproportionately lower than FEV1 in upper airways obstruction. This can be quanti \201 ed by an Empey index > 10, where: Fig. 18.6.2 Tracheal tumor visible at \202 exible bronchoscopy. (See Plate 17.) Fig. 18.6.1 Flow volume loop demonstrating \202 attening of both inspiratory and expirato ry limbs. CHAPTER 18.6 Primary tracheal tumors 455 control is optimized early, using the minimum number of interventions. \200 Surgery (i.e. complete resection with tracheal reconstruction) All patients must be adequat ely staged and considered for surgery at an experienced center. Although up to 70% of patie nts have resectable disease, many are denied this potentially curative treatment option thr ough a lack of awareness. Contraindications to surgery include: \200 Extensive local lymp hatic spread. \200 Mediastinal invasion of unresectable organs. \200 Distant metastases . \200 Involvement of >50% of the trachea. \200 Prior radiotherapy >60Gy to the mediast inum. Nebulised racemic adrenaline may help acutely reduce local airway in \202 ammation and oed ema. Intravenous dexamethasone can similarly provide more sustained anti-in \202 ammatory effects. Inhaled Heliox, a oxyhelium mixture in which relatively dense nitrogen is replaced by lower density helium, helps temporarily reduce the work of breathing. CT should ideally be performed, although many patients will be unable to tolerate this. Flexible bronchoscop y should be avoided in life-threatening upper airway obstruction. Rigid bronchoscopy under general anesthesia, however, can both obtain tissue for diagnosis and help alleviate upper airway obstruction through a variety of endoscopic resection techniques (see Endoscopic int erventions). Radiotherapy and endobronchial stenting are contraindi- cated until the tumor has been fully characterized and staged, as both interventions can preclude later curative surgical resection. External beam radiotherapy As both SCC and ACC are radiosensitive, external beam radiothera py can be utilized as either: \200 Adjuvant therapy following surgery, to ensure clear resection margins. Palliative therapy, in conjunction with endoscopic debri- dement, in patients with inoperable disease. Although no clear RCT evidence exists it is commonly believed that radiotherapy is inferior to surgery in achieving complete disease clearance. Endoscopic interventions The following endoscopic techniques can alleviate upper airway obs truction and thus provide long term palliative relief. All are possible via rigid bronchosc opy, whilst some can also be delivered via \202 exible bronchoscopy. \200 Endoscopic de bridement using biopsy forceps. \200 Diathermy or electrocautery/radiofrequency ablation. \200 Cryotherapy. \200 Laser photoresection. \200 Brachytherapy, particularly as sec ond line therapy. \200 Endoscopic stenting is typically reserved for extrinsic compressio n of the trachea, but also has a role in the palliative management of intraluminal obstruct ion. Prognosis Given its rarity there is relatively little published data on survival in patient s with primary tracheal tumors. It is well recognized, however, that patients with ACC have a more favorable outcome than those with SCC. A large UK based postal survey examining pat ients receiving a variety of treatment modalities suggested \201 ve-year survival rates o f 80% and 25% for ACC and SCC respectively. Fig. 18.6.3 View seen at bronchoscopy following endoscopic resection and stenting. (See Pla te 18.) AUTHOR \200\231S TIPS \200 Always consider upper airway obstruction in patients with \200\230late onset asthma \200 \231 or \200\230COPD \200\231 who fail to respond to bronchodilator therapy. Ensure all pa tients with primary tracheal tumors are fully staged and actively considered for curative s ur- gery before embarking on palliative therapy. Further reading Gelder CM, Hetzel MR. Primary tracheal tumors: a national survey. Thorax 1993; 48(7):688 \200\223692. Henning A, Gaissert MD. Primary tracheal tumors. Chest Surg Clin Fig. 18.6.4 CXR showing presence of a tracheal stent. N Am 2003; 13: 247 \200\223256. Macchiarini P. Primary tracheal tumors. Lancet Oncology 2006; Long-term management A histological diagnosis must be obtained in all patients, as benign a nd malignant tumors cannot be distinguished radiologically. Subsequent treatment options in clude: 7:83 \200\22391. C SHOVLIN 456 18.7 Pulmonary arteriovenous malformations Pulmonary arteriovenous malformations (PAVMs) are thin- walled abnormal vessels which repla ce normal capillaries between the pulmonary arterial and venous circulations (Fig. 18.7.1) providing a right-to-left (R-L) shunt. Examination \200\223 key points \200 \200 \200 \200 General: cyanosis, clubbing (for R-L shunt). HHT telangiectasia (lips; oral cavity, \201 ngers; nose). Dental hygiene (risk of brain abscess). CVS: BP (especially if nose bleeds), JVP, heart sounds and peripheral oedema (concern re pulmonary hypertension). Epidemiology Association with HHT More than 90% of macroscopic PAVMs are associated with he reditary haemorrhagic telangiectasia. HHT affects 1 in 5000 \200\2238000 and is inherited a s an autosomal dominant trait, caused by mutations in one of at least 5 different genes. HH T is usually diagnosed clinically, with 3 of 4 separate criteria (nosebleeds; telangiectasi a; visceral involvement and/or family history) required for a de \201 nite diagnosis of HH T. Most HHT patients are unaware of their diagnosis but \200 commonly experience nosebleeds (>90%) and/or have a family history of recurrent nosebleeds; display mucocutaneous telangiectasia (Fig. 18.7.2) which may not be prominent until over 4 0ys; commonly have silent visceral AVMs including PAVMs (50%), hepatic AVMs (30%), and cere bral AVMs (10%); rarely, have additional genotype-specific features (pulmonary hypertension ; juvenile polyposis). Other PAVMs Macroscopic PAVMs occasionally occur sporadically (when they are usually single ) or secondary to surgically gener- ated cavopulmonary shunts. Microscopic PAVMs merge into the spectrum of functional right \200\223to-left shunting associated most commonly with th e hepatopulmonary syndrome. Natural history Most PAVMs appear to develop at puberty, though some are present in childho od. Affected individuals are at risk of four main complications: \200 \200 Fig. 18.7.1 hypoxaemia (due to R-L shunt); paradoxical emboli (due to R-L shunt): by aged 65ys, a third of PAVM patients will have suffered a stroke or brain abscess; hemorrhage: this affects fe wer than 10%, but can be life-threatening, especially during pregnancy; Migraine. Respiratory symptoms and PAVM severity do not appear to in \202 uence the risk of later st roke/abscess or pregnancy complications. Clinical approach The aims of management are to \200 \200 reduce the risk of PAVM complications; establish whether HHT is present in the family. Establishing a diagnosis of HHT will facilitate PAVM screen- ing of relatives, and appropri ate management of HHT for all affected individuals. This should be performed without introd ucing unnecessary alarm life expectancy in HHT patients over the age of 60ys is normal. History key points \200 PAVM: dyspnoea, haemoptysis; stroke, brain abscess, TIAs, migraine. HHT: nosebleeds; GI ble eds; liver disease; epilepsy. FH: Pedigree to establish presence of these. Potential future pregnancies (for women). \200 \200 Fig. 18.7.2 CHAPTER 18.7 Pulmonary arteriovenous malformations 457 \200 \200 RS: Bruits (PAVM). Abdo: liver bruit (hepatic AVM). CNS: focal neurology indicative of earl ier CVA. HHT genes \200 Endoglin (HHT type I) most common cause of PAVMs: also associated with higher risk of cereb ral AVMs. ACVRL-1/ALK-1 (HHT type 2) most common genotype for HHT patients with pulmonary h ypertension. Smad4 (JP-HT) causes combined HHT \200\223juvenile polypo- sis syndrome: If Sm ad4 mutation detected, consult gas- troenterologists for management as juvenile polyposis ( inherited GI cancer) family. HHT3, HHT4 and further genes: mutation screening not yet avail able. Investigations \200 Radiology to con \201 rm PAVM structure (CXR, dedicated CT scan) and amenability to emboli sation. Assessment of hypoxaemia: recommend comparison of erect and supine SaO2 after 10 mi ns in each posture to detect orthodeoxia. Measurement of R-L shunt: perfusion scan or 100% O2 rebreathe shunt study (beware air bubbles in blood gas syringe leading to false positive ). Hematological investigations for polycythaemia, anemia. Consider echocardiogram if clini cal evidence of pulmo- nary hypertension. Consider cerebral MRI if neurological symptoms (? less stable cerebral AVM), or if more than one family mem- ber has had a cerebral hemorrhag e (? HHT-independ- ent familial Berry aneurysms). Consider hepatic AVM screening particular ly if evidence of pulmonary hypertension or cardiac failure. Due to late onset penetrance, no child of an HHT-affected relative should be told they do n ot have HHT without a molecular diagnosis, but if no gene mutation is found in the family, this does not mean that HHT is not present (maximum test sensitivity 80%). \200 Patient FAQs Can I \202 y? Yes consider DVT prophylaxis Are there any self-help groups? Yes: \200 UK Telangiectasia Self help group: http://www.tel- angiectasia.co.uk, email info@ telangiec tasia.co.uk HHT Foundation International: http://www.hht.org \200\223 highly informative we bsite, advice sometimes more applicable to North American healthcare, particularly with reg ard to cerebral AVM screening. Differential diagnosis \200 \200 Microscopic shunt consider HPS/liver disease. Single PAVM and no FH: consider sporadic. Management Dental hygiene Advise to optimize dental hygiene and use antibiotic proph- ylaxi s for dental and surgical procedures (reapproved post NICE). Further reading Buscarini E, Plauchu H, Garcia Tsao G, et al. Liver involvement in heredita ry hemorrhagic telangiectasia: consensus recommenda- tions. Liver Int 2006; 26: 1040 \200 \2231046. Cottin V, Plauchu H, Bayle JY, et al. Pulmonary arteriovenous mal- formations in patients w ith hereditary hemorrhagic telangiecta- sia. Am J Resp Crit Care Med 2004; 169:994 \200\223 1000. Embolisation treatment Patients with PAVMs large enough for embolisation should be offered embolisation by an experienced interventional radiologist to reduce stroke/abscess risk, an d improve oxy- genation if hypoxaemic. These considerations do not apply to individuals wit h severe pulmonary arterial hypertension. Govani PS, Shovlin CL. Hereditary haemorrhagic telangiectasia. Eur J Hum Genet 2009 (accepted subject to revisons). Kjeldsen AD, Vase P, Green A. Hereditary hemorrhagic telangiecta- sia (HHT): a population-b ased study of prevalence and mortality in Danish HHT patients. J Intern Med 1999; 245: 31 \200\22339. Pregnancy advice Inform obstetric team that while most PAVM/HHT pregna- cies proceed normal ly, pregnancy should be considered high risk. Inform patient that any haemoptysis or sudden severe dyspnoea may be a medical emergency and should precipi- tate admission. Pierucci P, Murphy J, Henderson KJ, et al. Screening for pulmonary arteriovenous malformati ons: twenty-seven-year experience. Chest 2008; 133: 653 \200\22361. Post MC, van Gent MWF, Snijder RJ, et al. Pulmonary arteriovenous malformations and migrane : a new vision. Respiration 2008; 76:228-33. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhag ic telangiectasia (Rendu-Osler-Weber syn- drome). Am J Med Genet 2000; 91: 66 \200\22367. Other HHT considerations Manage nasal and gastrointestinal bleeding, and other visceral inv olvement symptomatically by appropriate specialists. Educate patients (and medical practiti oners) that screening for cerebral or hepatic involvement is the subject of intense debate and is currently not offered in the UK except in circumstances listed earlier. When patient s ask about their children: \200 Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke and cer ebral abscess are unrelated to severity of pulmonary arteriovenous malformations in HHT. Th orax 2008; 63: 259 \200\223266. Shovlin CL, Sodhi V, McCarthy A, et al. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic tel- angiectasia (HHT, Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG 2008; 115:1108 \200\2231115. Each child of an HHT-affected parent has a 50% chance of inheriting HHT: add \200\230possi ble HHT \200\231 to medical records. Consider for all PAVM patients \200\231 children unles s clear alternative cause of PAVMs. The overwhelming majority of HHT-affected children are completely healthy. Aim to screen for PAVMs post puberty. Early PAVM development is usually symptomatic resulting in breathlessness or dizziness that prompts investigation, diagnosis and treatment. Shovlin CL, Tighe HC, Zukotynski/Chan Chow, et al. Embolization of PAVMs: no consistent eff ect on pulmonary artery pressure. ERJ 2008, in press. van Gent MWF, Post MC, Luermans JG, et al. Screenng for pulmo- nary arteriovenous malformat ions: using transthoracic contrast echocardiography: a prospective study. Eur Respire J 200 8; 33: 85 \200\22391. Zukotynski K,Chan RP, Chow CM, et al. Contact echocardiography grading predicts pulmonary a rteriovenous malformations on CT. Chest 2007; 132: 18 \200\22323. J SUNTHARALINGHAM & M HETZEL 458 18.8 Pulmonary amyloidosis De \201 nition Amyloidosis encompasses a heterogeneous collection of diseases, characteriz ed by local or systemic over-expression of amyloidogenic precursor proteins. These proteins undergo abnormal conformational changes, resulting in local or systemic deposition of an i nsoluble \201 brillar form that subsequently causes organ dysfunction. Pulmonary involvem ent occurs in up to 50% of amyloidosis cases, although it often does not contribute signi \201 cantly to over- all disease burden. Nodular pulmonary amyloidosis (local AL) presents with solitary or multiple discrete parenc hymal nodules which range from 0.4 \200\22315cm and are typically located peripher- ally or subpleurally within both lower lobes. In most cases they are asymptomatic, but must be dis tinguished from lung cancer, particularly if any of the nodules dem- onstrate dyssynchronou s growth. Diffuse alveolar-septal amyloidosis (systemic AL) occurs whenever amyloid is diff usely deposited within the intersti- tium and can vary in severity depending upon the degre e to which gas exchange is affected. The burden of lung disease, however, tends to parallel cardiac involvement and as a result overall morbidity and mortality is typically governed more by cardiac than pulmonary disease. Hilar and mediastinal adenopathy (local and systemi c AL) can occur with and without pulmonary involvement. Pleural effusions (systemic AL) usu ally result from pari- etal pleural involvement producing an exudative lym- phocytic (and o ccasionally chylous) effusion. Transudative pleural effusions can also occur in association with cardiac disease and nephrotic syndrome. Other reported manifestations include: \200 Classi \201 cation and pathophysiology The various forms of amyloidosis can be classi \201 ed by their precursor proteins: \200 AL amyloidosis results from production of monoclonal immunoglobulin light chains (typically or chains). AA amyloidosis occurs following production of acute phase reactant serum amyloid A in response to chronic in \202 ammatory conditions. ATTR amyloidosis is an auto somal dominant condition that leads to production of mutant transthyretin (TTR) protein. AB 2M amyloidosis is due to accumulation of B2 microglobulin in patients receiving dialysis. Respiratory failure secondary to diaphragmatic involvement. Haemoptysis, AV \201 stula fo rmation and precapillary pulmonary hypertension as a result of pulmonary arteriolar involve ment. Despite this wide variation in precursor proteins, the resulting insoluble protein deposit in amyloidosis is struc- turally alike in all forms of the disease, comprising B-pleated sh eets complexed with serum amyloid P (SAP) and glycosaminoglycans (GAG). This con \201 gura tion can resist proteolysis and is thus extremely stable, to the detri- ment of the organ a ffected. Whilst all forms of amyloidosis can lead to systemic dis- ease, AL amyloidosis is unique in that it can be associated with either local ( \200\230organ-limited \200\231) or systemic disease. \200 History The diagnosis of amyloidosis will rarely be made at initial presentation. However, do consider the diagnosis in patients who present with: \200 \200 \200 \200 \200 Upper airway obstructive symptoms. Haemoptysis. Incidental pulmonary nodules. Dyspnoea and parenchymal in \201 ltrates. Respiratory symptoms in the presence of an underlying parapro teinaemia. Local AL disease results from localized clonal expansion of B cells or plasma cells. The li ght chains secreted by these cells do not circulate outside of their target organ, but inst ead produce local amyloid deposits. Systemic AL disease develops following the release of m onoclonal light chains into the circulation by bone marrow-derived plasma cells. The cause of plasma cell expansion can range from a low grade plasma cell dys- crasia (i.e. primary s ystemic amyloidosis) to an overt malignancy (i.e. amyloidosis associated with myeloma). Examination Patients may exhibit: \200 \200 \200 Macroglossia (systemic AL). Inspiratory stridor (TBA). Fine inspiratory crepitations and hy poxia (diffuse alveo- lar septal amyloidosis). Clinical manifestations Although pulmonary involvement can occur with AA and ATTR disease, this is usually an incidental \201 nding and is rarely of any clinical signi \201 cance. Conversely, AL amyloidosis can present in a number of ways, some of which can overlap \200 Investigations Initial investigations \200 PFTs may demonstrate upper airways obstruction (i.e. low PEFR, abnormal \202 ow volume lo ops) in TBA, or restrictive lung disease (i.e. reduced transfer factor and vital capacity) in diffuse alveolar septal disease. CXR may reveal pulmonary nodules, diffuse parenchy- mal in \201 ltrates or pleural effusions. Laryngeal amyloidosis (local AL) presents with hoarse- ness, stridor or dyspnoea as a resul t of nodular or diffuse in \201 ltrative changes within the larynx. Tracheobronchial amylo idosis (TBA) (local AL) appears as discrete nodules that can macroscopically mimic tumor (2 8%), as submucosal in \201 ltrative plaques (44%) or as cirumferential wall thickening (28 %). All forms cause upper airway obstructive symptoms (cough, hae- moptysis, dyspnoea, and recurrent infections) and are not infrequently initially misdiagnosed as asthma. Diagnostic investigations \200 Biopsy material can be obtained as appropriate at: \200 laryngoscopy or bronchoscopy, although note that amyloid lesions can bleed readily; thoraco scopy; and thoracotomy. \200 CHAPTER 18.8 Pulmonary amyloidosis 459 Management \200 A biopsy demonstrating both congo red staining and green birefringence under polarized ligh t con \201 rms the diagnosis. Further histological analysis should be performed to identif y the precursor protein subtype as distinguishing AA and ATTR from AL disease can alter sub sequent management (Fig. 18.8.1). In many cases, particularly AA disease, ATTR disease and pulmonary nodular disease, pulmona ry involvement is an incidental \201 nding and needs no speci \201 c treatment. In local ized laryngeal or proximal tracheobronchial amy- loidosis repeated local interventions may be required for symptom control, including endoscopic resection, YAG laser therapy, stentin g and tracheostomy. In more diffuse and/or severe disease, management takes on a more suppo rtive role and includes prompt treatment of infections and emergency treatment of haemoptys is (e. g. with tranexamic acid and therapeutic bronchoscopy). In systemic AL disease chemot herapy can be given to target B cell clonal disease and thus limit the supply of precursor proteins. Both low dose melphalan and pred- nisolone and high dose melphalan with autologou s stem cell rescue have been used in this role and should be considered when detectable lev els of paraprotein are present. A centrally funded tertiary referral service for amyloido- sis is currently provided in the UK by the National Amyloidosis Center at the Royal Free Ho spital, London. Patients and clinicians may obtain further information at www.ucl.ac.uk/med icine/amyloidosis/nac/index. html Fig. 18.8.1 Histological example demonstrating the presence of apple-green birefringence. Staging investigations \200 HRCT and/or MRI may demonstrate pulmonary nod- ules, honeycombing, heterogeneous ground gla ss opaci- \201 cation or generalized lymphadenopathy. Serum electrophoresis, urinary Benc e Jones protein and bone marrow aspirate can identify an underlying parap- roteinaemia in s ystemic AL. An elevated serum ALP and hepatomegaly on ultrasound suggest liver involvement. Echocardiography 9myocardial biopsy can identify restrictive and dilated cardiomyopathy. 2 4-hour urinary protein collection is required to exclude or con \201 rm nephrotic syndrome . Radiolabelled SAP scanning can help quantify and moni- tor overall disease burden, althou gh this test is not widely available. Beware FDG-PET which can give false-positive results in pulmonary nodular amyloidosis. Prognosis Systemic AL disease has an unfavorable outcome with median survival estimated at just 13 months. Prognosis of local AL disease can vary, ranging from several months for tho se with diffuse TBA disease to unlimited for those with parenchymal nodular disease. AUTHOR \200\231S TIPS \200 Amyloidosis is one of many conditions that can mimic lung cancer always aim to obtain a tis sue diagnosis. Once amyloidosis is diagnosed it is essential that sys- temic AL be distingu ished from local AL disease, given the change this can make to management. Further reading Aylwin AC, Gishen P, Copley SJ. Imaging appearance of thoracic amyloidosis. J Thorac Imaging 2005;20(1):41 \200\22346. Berk JL, O \200\231Regan A, Skinner M. Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med 2002;23(2):155 \200\223515. Cordier JF (2005). Pulm onary amyloidosis in hematological disor- ders. Semin Respir Crit Care Med 2005;26(5):502 \200\223513 Fig. 18.8.2 MRI thorax demonstrating both TBA disease affecting the carina and nodular pare nchymal disease involving the left lower lobe. This page intentionally left blank 461 Index Note: page numbers in italics refer to Figures and Tables. A A-a gradient 28 \200\22330 AAS V (anti-neutrophil cytoplasmic antibody in pulmonary hypertension 267 AL amyloidosis 460 \200\2231 ALK-1 gene 265, 459 all-trans retinoic acid, use in AAT de \201 ciency 122 allergen avoidance 65 allergen desensitization 66 allergen immunotherapy 62 allergic bronchopulmonary aspergillosis anti-fungal therapy 198 antigen avoidance, in extrinsic allergic alveolitis 150 (ANCA)-associated systemic vasculitides) 272 \200\2235 ANCA patterns 275 \200\2236 anti-glo merular basement membrane antigen challenge tests, extrinsic allergic alveolitis 149 \200\22350 anti-glomerular basement membrane antibody disease 278 (ABPA) 196 antibody disease 278 anti-IgE therapy, asthma 74, 86 anti-in \202 ammatory therapy, cystic \201 brosis 245 an ti-leukotrienes 73 \200\2234, 80, 85 \200\2236 in cystic \201 brosis patients 237, 246 comparison 276 diffuse alveolar hemorrhage (DAH) 277 \200\2238 disease activity monitoring 277 prognosis 277 treatment 276 \200\2237 allergic occupational asthma 398 allergic rhinitis 64 in COPD 102 effectiveness in asthma control 85 anti-neutrophil cytoplasmic antibody