Rare Diseases C 1 Lymphangioleiomyomatosis: Clinical Features, Management and Basic Mechanisms

254 Thorax 1999;54:254–264 Rare diseases c 1 Thorax: first published as 10.1136/thx.54.3.254 on 1 March 1999. Downloaded from Series editors: A E Tattersfield, R M du Bois Lymphangioleiomyomatosis: clinical features, management and basic mechanisms Simon Johnson Lymphangioleiomyomatosis, a rare disease of Much of our knowledge of this unusual dis- unknown aetiology, aVects women only. It order is anecdotal, coming from case reports mainly involves the lungs where, as its name and reviews of patients attending tertiary refer- suggests, lymphatics (lymph), blood vessels ral centres, which may not represent the full (angio), and airways are surrounded by smooth spectrum of the disease. This will change over muscle (leiomyo) proliferation. It is character- the next few years as patient registries are being ised by progressive dyspnoea, haemoptysis, compiled for research purposes in the United pneumothorax, and chylous pleural eVusions Kingdom, United States, and France. This Division of and runs a variable course culminating usually approach, coupled with recent advances in the Respiratory Medicine, in respiratory failure.12 Lymph nodes in the cell biology of lymphangioleiomyomatosis, will University of abdomen and pelvis may be involved and up to it is hoped improve management and the Nottingham, City outcome for patients. This article will cover the Hospital, Hucknall half the patients have renal angiomyolipomas. Road, Nottingham The disease usually arises spontaneously al- clinical features and natural history of isolated NG5 1PB, UK though it also occurs in some patients with lymphangioleiomyomatosis, discuss issues in S Johnson tuberous sclerosis.3 diagnosis and management, and finally review what is known of the aetiology and cell biology of the disease. Clinical features, diagnosis, and management http://thorax.bmj.com/ INCIDENCE AND DEMOGRAPHIC FEATURES The reported prevalence of lymphangioleiomyomatosis is around one per million in the United Kingdom,4 France,5 and the United States, although the true prevalence is likely to be greater. The disease is well described in Asia6 although data on prevalence are not available. Lymphangioleiomyomatosis is exclusively on September 26, 2021 by guest. Protected copyright. confined to women, the mean age of onset being 34 years.1 2 6–8 Presentation after the menopause is very unusual, occurring in only eight of 186 patients in the larger series,1246–8 six of whom were taking oestrogen containing hormone replacement therapy. This fits with evidence suggesting that oestrogen administration9 and pregnancy10–12 may acceler- ate disease progression whereas oophorectomy and progesterone24may reduce it (see below). PATHOLOGICAL FEATURES The lung in lymphangioleiomyomatosis con- tains numerous cysts, ranging in diameter from millimetres to centimetres,1 and these are responsible for the pneumothoraces and the striking appearance of blebs over the lung sur- face (fig 1). Infiltration of lung and pleural lymphatics causes obliteration and dilatation of the lymphatic channels leading to lymph stasis, chyloptysis, and septal lines on the chest radiograph. The thoracic duct is often thickened and formed of multiple narrow channels leading to Figure 1 (A) Thoracotomy showing abnormal lung surrounded by a chylous collection. chylous pleural eVusions and ascites. (B) Close up of the lung showing the characteristic appearance of multiple blebs. Pulmonary vascular occlusion can cause Lymphangioleiomyomatosis 255 endoplasmic reticulum, microfilament bundles with dense bodies, numerous electron dense Thorax: first published as 10.1136/thx.54.3.254 on 1 March 1999. Downloaded from membrane bound granules13 18—and they char- acteristically stain with the monoclonal antibody HMB 45.19 20 There appear to be three forms of LAM cell according to their micro- scopic appearance, large spindle shaped cells, smaller cells with little cytoplasm, and epithe- lioid cells.14 Interestingly, the three cell types also have diVering immunophenotypes which suggests that they have diVerent functions.13 14 Receptors for oestrogen and/or progesterone are found on cells from roughly half the patients.21–24 The significance of these findings is uncertain and is discussed below. Angiomyolipomas are rare mesenchymal tumours containing smooth muscle, fat and blood vessels, which also contain HMB 45 positive smooth muscle cells. CLINICAL FEATURES Patients with lymphangioleiomyomatosis present most commonly with dyspnoea (59%), pneumothorax (49%), and cough (39%) according to the larger series.125625 Chest pain (22%), chylous pleural eVusions (13%), haemoptysis (18%), and wheeze are less common. Chyloptysis, presenting as white, sticky spu- tum, may occur7 and, following pleurodesis, patients may complain of occasional gurgling in their chest (possibly due to ruptured cysts). Extrapulmonary features include lymph node masses, cystic soft tissue masses,26 27 and chylous ascites in up to a third of patients.125 Uterine fibroids (leiomyomas)8 and renal angiomyolipomas28 29 are also seen; angiomyolipomas are often asymptomatic although http://thorax.bmj.com/ bleeding may occur (see below). Figure 2 Photomicrographs showing nodular proliferation of abnormal smooth muscle and The natural history of lymphangioleiomyo- cysts in (A) a lung biopsy specimen stained with haematoxylin and eosin and (B) brown HMB 45 positive LAM cells lining a cystic space. matosis is of progressive airflow obstruction leading to respiratory failure and cor pulmonary haemorrhage, haemoptysis, and pulmonale.1 The rate of progression is highly haemosiderosis.1 variable between patients, ranging from a rapid Microscopically the lungs are characterised decline over a few years1 to a more indolent 230 by cystic air spaces and a nodular proliferation disease over two or three decades. In a on September 26, 2021 by guest. Protected copyright. of abnormal smooth muscle cells (LAM cells). review of 47 patients with lymphangioleiomyo- In early lesions LAM cells accumulate in the matosis in the UK the mean fall in forced alveolar walls, collagen and elastic fibres are expiratory volume in one second (FEV1)was partially degraded, and oedema, haemorrhage 118 ml/year although there was marked vari- and haemosiderin laden macrophages are seen ability between patients.4 Two thirds of women around the alveoli.13 14 With more advanced will develop a pneumothorax and these were disease the nodules are larger and associated recurrent in more than two thirds of our with compact collagen bundles whereas patients. Chylous pleural eVusions occur in a oedema, haemorrhage, and macrophages are fifth of patients.5 less prominent. Estimates of life expectancy in lymphangio- The thin walled cysts are lined by flattened leiomyomatosis are still relatively uncertain as epithelial and ciliated bronchiolar epithelial previous figures were based on series from ter- cells14 and are thought to be formed by the tiary referral centres and the advent of CT amalgamation of damaged alveoli, probably as scanning may enable the diagnosis to be made a result of uncontrolled proteolytic activity.13 14 earlier. The most recent series reports a 10 year The nodules surround and may jut into the survival of 79%5 but some caution is needed cysts, alveoli, and bronchioles causing thicken- since case ascertainment will inevitably favour ing of the small airway walls, often in an those with a better prognosis. irregular fashion (fig 2). LAM cells appear to Lung function tests in patients with be of smooth muscle origin since they stain for lymphangioleiomyomatosis show a variety of vimentin, desmin, and á-smooth muscle abnormalities with airflow obstruction and actin,15–17 and myofilaments are seen on elec- impaired gas transfer the predominant fea- tron microscopy. The cells also display features tures. Restrictive lung defects are sometimes that are not typical of muscle cells—namely, seen but usually in combination with airflow multiple indented round nuclei, a prominent obstruction and often as the result of pleural 256 Johnson eVusions, pleurectomy, or thoracotomy.163132 Lung function is occasionally normal at Thorax: first published as 10.1136/thx.54.3.254 on 1 March 1999. Downloaded from presentation632but disease progression is associated with increased airflow obstruction and impaired gas transfer.25 DIAGNOSIS Because lymphangioleiomyomatosis often presents with dyspnoea and airflow obstruction, the diagnosis is often missed initially. The mean interval between onset of symptoms and diagnosis was over four years in our series (range 0–25 years) and the picture is similar elsewhere.2 The diagnosis should be suspected in women when dyspnoea or asthma is associated with a pneumothorax, haemoptysis or abnormal chest radiograph, when emphysema has been diagnosed without a history of smok- ing or á1-antitrypsin deficiency, or when inter- stitial lung disease occurs with airflow obstruction. Open lung biopsy has been the gold standard for the diagnosis of lymphangioleiomyomatosis. The sensitivity and specificity of histologi- cal analysis has improved considerably with the use of the monoclonal antibody HMB 45 which, in the lung, will only stain LAM cells19 20 thus excluding conditions which may mimic lymphangioleiomyomatosis such as metastatic 33 endometrial sarcoma. Open lung biopsy can Figure 3 (A) Chest radiograph showing a reticular determine the hormone receptor status of pattern which appears most prominent at the bases. (B) LAM cells and whether smooth muscle prolif- High resolution CT scan showing

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