Pulmonary lymphangioleiomyomatosis (LAM) is rare. Its cause is not known, and it principally affects women during the childbearing years. LAM occurs sporadically (not as an inherited disease) or it can be one manifestation of tuberous sclerosis (one third of patients have LAM), which is an inheritable multiorgan hamartomatosis.
The underlying lesion that characterizes the disease is the diffuse proliferation of peri- bronchial, perivascular, and perilymphatic smooth muscle cells resulting in vascular and airway obstruction, cyst formation, and recurrent pneumothoraces (Figure 32.1a, b, c).
Extrapulmonary manifestations include lymphadenopathy, angiomyolipomas, and benign tumors, most frequently of the kidney (one third of patients).
Characteristic symptoms are progressive dyspnea, cough, and recurrent pneumotho- races; less frequent are hemoptysis and chyloptysis. In the course of the disease, chylous pleural effusion can be found, unilateral or bilateral, but not as often as previously thought occurring, in only 10% of the patients.
The cellular and proliferating LAM cells are associated with increased expression of TGF-β1 and related extracellular matrix proteins. TGF-β is a potent cytokine that pro- motes mesenchymal cell proliferation and regulates the synthesis of extracellular matrix components, particularly fibronectin. The smooth muscle cells in the disease also have an affinity to HMB45, a monoclonal antibody with specific immunoreactivity for malig- nant melanoma (Figure 32.1d).
What causes LAM remains a mystery. The female preponderance indicates that the disease may be modulated by sex steroids. Oral contraceptives often contribute to the progression of the disease. Tissue from patients with LAM often, but not always, expresses estrogen and progesterone. Cells from involved tissue grown in culture show mitogenic response to estradiol.
Diagnostic procedure includes chest radiographic analysis, lung function testing, and open lung biopsy. In the early phase of the disease, chest radiographs show hyperinflation, reticular or linear interstitial bibasilar pattern, including Kerley-B lines due to expansion of lymphathic vessels, small nodules that probably represent hyper- plastic aggregates of LAM cells (Figure 32.2a), and sometimes pleural effusion. HRCT scans are typical, cysts and nodes in the early phase (Figure 32.2b), and in the advanced phase the cysts increase in number and size (2–10 mm) (Figure 32.3a, b, c). There are other diffuse cystic diseases that can be confused with LAM (Table 32.1).
Pulmonary function tests reveal the combination of obstructive and restrictive changes, increased total lung capacity, residual volume, and reduced forced expiratory volume in the first second. DLco is reduced, with hypoxemia but rarely hypercapnia.
Recurrent pneumothoraces, chylothorax, and irreversible obstructive ventilatory changes in a never-smoking woman are of ultimate importance in differentiating LAM from other diseases with similar symptomatology. Lung biopsy shows characteristic histopathological pattern.
Pulmonary LAM responds, in selected cases, to oophorectomy, radioablation of the ovaries, or administration of progesterone, anti-estrogens, or androgens (Figure 32.4).
Recurrence of the disease in the allograft after lung transplantation has been reported.
The progression of the disease is common and the median survival is 8 to 10 years.
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Figure 32.1. A lung biopsy specimen showing a typical LAM nodule. Nodule is composed of fusiform cells resembling smooth muscle cells (a). LAM cells infiltrating the walls of vessels causing hemorrhage (b). Alveolar spaces adjacent to LAM lesion contain hemosiderin-laden macrophages (Prussian blue stain) (c). A lung biopsy specimen shows a positive reaction with the monoclonal antibody HMB 45. LAM cells differ from normal smooth cells by the presence of a glycoprotein found in melanoma that reacts with a monoclonal anti- body, HMB45 (d).
Figure 32.2. Recent onset LAM. Plain chest radiograph shows bilateral reticulonodular pattern, with majority nodules in the lung bases in a patient with recent onset of LAM (a) and multiple nodules with few thickened interlobular septa by HRCT scanning (b). The patient had few symptoms and at that moment did not require any therapy.
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Table 32.1. Causes of diffuse cystic and cavitary lung disease.
Pulmonary lymphangioleiomyomatosis Pulmonary Langerhans cell histiocytosis Honeycomb lung
Idiopathic pulmonary fibrosis
Connective tissue disease–related pulmonary fibrosis Asbestosis
Chronic hypersensitivity pneumonitis Advanced sarcoidosis
Bronchiectasis, diffuse Metastatic disease (rare)
From Ryu JH, Swensen SJ. Cystic and cavitary lung diseases: Focal and diffuse. Mayo Clin Proc 2003;78:744–752. Reprinted with permission from The Mayo Clinic College of Medicine, Rochester, MN, USA.
Figure 32.3. Advanced LA. CT scan of the lungs showing characteristic uniform cystic appearance of advanced case of LAM: (a) upper lobes; (b) middle lung fields; and (c) lower lung fields with discrete ground-glass opacifications in between the cysts. The number and the size of the cysts increase in craniocaudal direction.
174 Clinical Atlas of Interstitial Lung Disease
Bibliography
1. Glassberg M. Lymphangioleiomyomatosis. Clin Chest Med 2004;25:573–582.
2. Evans S, Colby T, Ryu T, Limper A. Transforming growth factor-beta 1 and extracellular matrix-associated fibronectin expression in pulmonary lymphangioleiomyomatosis. Chest 2004;125:1063–1070.
3. O’Brien J, Lium J, Parosa J, Deyoung B, Wick W, Trulock E. Lymphangioleiomyomatosis recurrence in the allograft after single-lung transplantation. Am J Respir Crit Care Med 1995;151:2033–2036.
4. Tanaka H, Imada A, Morikawa T, Shibusa T, Satoh M, Sekine K, Abe S. Diagnosis of pulmonary lymphan- gioleiomyomatosis by HMB45 in surgically treated pneumothorax. Eur Respir J 1995;8:1879–1882.
5. Kitaichi M, Izumi T. Lymphangioleiomyomatosis. Curr Opin Pulm Med 1995;1:417–424.
6. Ryu JH, Swensen SJ. Cystic and cavitary lung diseases: Focal and diffuse. Mayo Clin Proc 2003;78:744–752.
Figure 32.4. Clinical course of a 42-year- old Korean woman with biopsy-proved lymphangioleiomyomatosis. The patient was treated aggressively. Her disease has stabilized. Last seen in 2005, she was alive, had dyspnea, and was on supplemental oxygen.
