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INTRODUCTION

Lymphangioleiomyomatosis (LAM) is a multisystem disorder, predominantly affecting women, that is characterized by cystic lung lesions, abdominal angiomyolipomas (AMLs), and lymphatic abnormalities. These pathologic features are caused by the proliferation of a neoplastic smooth muscle–like LAM cell that also has characteristics of immature melanocytes.1 Inherited and sporadic forms of LAM have been described. Sporadic LAM is caused by somatic mutations primarily of the tuberous sclerosis complex (TSC) 2 (TSC2) gene, presumably occurring in a “cell of origin.”2–4 Single cell sequencing of LAM lung lesions suggest that LAM cells may arise in the uterus.5 LAM can also occur in about one-third of patients with TSC, an autosomal-dominant disorder that occurs in 1 of 6000 live births, and results from germline mutations in the TSC1 or TSC2 genes leading to widespread hamartomatous tumors in several organs including the brain, heart, skin, kidney, eyes, lung, and liver.6–8

EPIDEMIOLOGY

Until the establishment of LAM registries and the subsequent introduction of treatment with inhibitors of mechanistic target of rapamycin (mTOR),9,10 LAM was considered to be a fatal disease of women of child-bearing age for which oophorectomy, antiestrogen therapy, and lung transplantation were the only available therapeutic options.11 LAM is now best characterized as a chronic disease of post- and premenopausal women with an average life expectancy spanning 29 years from diagnosis.10 Sporadic LAM is a rare disease with an estimated prevalence of 4.9 in 1,000,000 women.12 LAM can also be detected in 30% to 40% of females patients with TSC, with the frequency increasing with age. Next-generation sequencing studies commonly indicate mosaic mutations in the TSC1 or TSC2 gene in patients with TSC who have no mutation identified (NMI) on analysis of a blood sample,13,14 but mosaic TSC2 mutations are only rarely found in patients diagnosed with the sporadic form of LAM.15 Case series have identified LAM-like cystic lung disease in male patients with TSC, but clinically significant disease appears much less frequently in men than in women.16,17

CLINICAL PRESENTATION

Patients with LAM often present with a history of progressive dyspnea (Table 60-1).9,18 Pneumothorax may cause acute onset pleuritic chest pain, is often recurrent, and occurs in up to 56% of patients on initial presentation.19 The size of the lung cysts, as seen on high-resolution computed tomography (HRCT) scans (Fig. 60-1A) appears to be proportional to the incidence of pneumothorax.20 Patients may also report cough, wheezing, or hemoptysis (Table 60-1). Other modes of presentation can include symptoms related to lymphatic involvement, such as lymphangioleiomyomas, which when present occur in the posterior mediastinum, retroperitoneum, or pelvis. The lymphatic involvement may also manifest as lymphadenopathy, chylothorax, chylous ascites, chyluria, or chyloptysis (Table 60-1).9,21,22 Abdominal lymphangioleiomyomas ...

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