LAM is typically discovered by high-resolution CT (HRCT) scanning of patients with progressive dyspnea on exertion, pneumothorax, or chylous effusion, or less commonly by biopsy of an abdominal or retroperitoneal mass suspected to be lymphoma or ovarian cancer (Fig 2
). Routine screening of asymptomatic women with TSC identifies a subset of patients with early and often asymptomatic LAM. Biopsy-documented LAM has been reported in only four men, three with definite or probable TSC,323334 and one without TSC.35 On the average, women with LAM have symptoms for 3 to 5 years and experience an average of 2.2 pneumothoraces before the diagnosis of LAM is made.36 The diagnosis of pulmonary LAM requires an HRCT scan demonstrating thin-walled cystic change and either a positive tissue biopsy (including immunohistochemical reactivity with human melanoma black-45 [or HMB-45]) or a compatible clinical context such as clinically confirmed tuberous sclerosis, angiomyolipomata, or chylothorax. The primary differential diagnosis includes pulmonary Langerhans cell histiocytosis (LCH) and emphysema (Fig 3
). The smoking history and the morphology of the cysts, which are devoid of distinct walls in patients with emphysema, and are thicker walled, mid and upper lung zone predominant, and more irregularly shaped in patients with LCH, can be helpful in differentiating these disorders from LAM.37 Diffuse nodular changes are often present in LCH patients and can be a distinguishing feature, but can be confused with micronodular pneumocyte hyperplasia, which occurs in patients with TSC (Fig 2).38 Less common diseases that can mimic LAM and should also be considered include Sjögren syndrome,39 follicular bronchiolitis and lymphocytic interstitial pneumonitis,40 hypersensitivity pneumonitis,41 amyloidosis, light chain-deposition disease,42 bronchopulmonary dysplasia, metastatic endometrial stromal cell sarcoma,43 low-grade leiomyosarcomas and Birt-Hogg-Dubé (BHD) syndrome.44 Like TSC-LAM, BHD is a rare tumor suppressor syndrome that is associated with spontaneous pneumothorax, skin lesions, pulmonary cysts, and inherited renal cell cancer. Mutations in the folliculin gene cause BHD and familial spontaneous pneumothorax.4546 It appears that BHD is also associated with aberrant signaling through the Akt pathway, but the loss of regulation occurs upstream of mTOR.47 Lymphangiomatosis is a rare disease that is associated with abdominal and thoracic lymphatic smooth muscle infiltration, lymphadenopathy, lymphangiomas, chylous fluid collections, and variable bony involvement (Gorham disease).4849 Although lymphangiomatosis can involve the lung and is often confused with LAM, it affects men and women equally, does not produce lungs cysts, and is immunophenotypically distinct (staining with human melanoma black-45 [or HMB-45] is negative).