LAM arises from loss of function in the mTOR-suppressing hamartin-tuberin complex. Hamartin is encoded by TSC1 (chromosome 9) and tuberin by TSC2 (chromosome 16); disruption of either gene leads to unchecked mTOR signaling that drives abnormal LAM cell proliferation. mTOR inhibitors of the sirolimus class address this mechanism by blocking mTOR complex activity, replacing the suppressive function normally provided by the hamartin-tuberin complex. In TSC-associated LAM, germline pathogenic variants in TSC1 or TSC2 underlie disease susceptibility, while in sporadic LAM, somatic variants arising in individual cells during development appear to drive disease. The inheritance pattern is characterized as multifactorial in this packet, reflecting the dual etiology across sporadic and TSC-associated forms.

Evaluation of LAM involves clinical assessment alongside radiological and functional testing. High-resolution computed tomography of the chest is a central tool for identifying cystic lung changes associated with this condition. Pulmonary function testing and exercise assessments, including six-minute walk evaluation, are used to characterize the degree of respiratory impairment and monitor disease course. The clinical definition of LAM as a neoplasm with perivascular epithelioid cell differentiation informs the pathological characterization of tissue specimens when biopsy is performed. Molecular genetic testing for TSC1 and TSC2 pathogenic variants is relevant when TSC-associated LAM is under consideration. LAM is recognized as a major clinical feature in the TSC diagnostic framework, though the combination of LAM and renal angiomyolipomas without additional TSC manifestations does not independently satisfy criteria for a definite TSC diagnosis.

FDA-approved pharmacological treatments for LAM include sirolimus, available as Rapamune and as generic sirolimus, as well as FYARRO (sirolimus albumin-bound particles); all are listed as active formulations in this packet's approved treatments. Sirolimus-class agents function as mTOR inhibitors, blocking the signaling pathway that is dysregulated in LAM cells. Active clinical research has evaluated sirolimus safety and durability in LAM specifically (NCT02432560), and a Phase 3 multicenter early-disease trial (NCT03150914) examined outcomes in individuals at early stages of the condition. Management involves pulmonary medicine assessment and multidisciplinary evaluation of complications such as pleural effusions and pneumothorax. Treatment approaches address both the underlying molecular abnormality and associated pulmonary and lymphatic complications.

Natural history data specific to LAM are not certified in this packet. A dedicated natural history study (NCT00001465) has been maintained at the National Heart, Lung, and Blood Institute over many years. The progressive nature of pulmonary involvement is reflected in clinical trials that measure pulmonary function and exercise capacity as primary outcome endpoints. A pregnancy registry (NCT06160310) is evaluating outcomes in individuals with LAM or TSC during pregnancy, relevant to the predominantly female and childbearing-age demographic affected. Individual outcomes are recognized to vary, and the course of disease differs across affected individuals.

Several clinical trials are currently investigating LAM and its relationship to TSC. Active studies include evaluation of inhaled albuterol as a pulmonary intervention (NCT01799538), long-term sirolimus safety (NCT02432560), novel radiotracer imaging with [11C]-acetate PET (NCT05467397), extracellular vesicle biomarkers for pulmonary involvement (NCT07304856), and the French national LAM registry (NCT01484236). A combined TSC and LAM pregnancy registry (NCT06160310) is enrolling participants through 2029. Active clinical trials for this condition are listed on ClinicalTrials.gov.