Lymphangioleiomyomatosis

Lymphangioleiomyomatosis results from uncontrolled proliferation of LAM cells, which are smooth muscle-like cells of unknown origin (possibly derived from perivascular epithelioid cells, PEComas). TSC-associated LAM results from somatic TSC1 or TSC2 mutations in LAM cells leading to constitutive mTOR activation. Sporadic LAM has somatic TSC2 mutations in LAM cells without germline TSC mutations. The TSC complex normally acts as a negative regulator of mTOR signaling; loss of TSC function leads to unchecked mTOR activity driving LAM cell proliferation. LAM cells produce multiple cytokines and growth factors including VEGF, FGF, and HGF that promote angiogenesis, lymphangiogenesis, and further cell proliferation. LAM is characterized by progressive cystic lung destruction with characteristic features on HRCT of thin-walled cysts of varying sizes distributed throughout both lungs. Progressive air trapping and cyst formation lead to loss of functional lung parenchyma and progressive airflow obstruction. Spontaneous pneumothorax occurs in 40% of LAM patients due to cyst rupture. Lymphatic obstruction by LAM cell infiltration leads to chylous effusions, chylothorax, and ascites. Renal involvement (angiomyolipomas) occurs in up to 80% of LAM patients and can lead to life-threatening hemorrhage. Disease progression varies widely, from slow progression with minimal symptoms to rapidly progressive respiratory failure requiring transplantation. Estrogen dependency is suggested by disease exacerbation during pregnancy and with hormone replacement therapy.