Lymphatic manifestations of lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a slowly progressive, low grade, metastasizing neoplasm, associated with cellular invasion and cystic destruction of the pulmonary parenchyma. Although the source of LAM cells that infiltrate the lung is unknown, available evidence indicates that the disease spreads primarily through lymphatic channels, often involving abdominal, axial, and retroperitoneal nodes, suggestive of an origin in the pelvis. LAM cells harbor mutations in tuberous sclerosis genes and produce lymphangiogenic growth factors, which facilitate access to and movement through the lymphatic system and likely play an important role in destructive tissue remodeling in the lung. Lymphatic manifestations of LAM include thoracic duct wall invasion, lymphangioleiomyoma formation, chylous fluid collections in the peritoneal, pleural, and pericardial spaces, chyloptysis, chylocolporrheal chylometrorrhea, chyle leak from the umbilicus, chylous pulmonary congestion, and lower extremity lymphedema. LAM lesions express lymphangiogenic growth factors VEGF-C and VEGF-D; growth factor receptors, VEGFR-2 and VEGFR-3; and markers LYVE-1 and podoplanin, and are laced with chaotic lymphatic channels. Serum VEGF-D is elevated in 70% of patients with LAM and is a clinically useful diagnostic and prognostic biomarker. Molecular targeted therapy with sirolimus stabilizes lung function, is anti-lymphangiogenic, and is highly effective for the lymphatic and chylous complications of LAM. Future trials in patients with LAM who have lymphatic manifestations or elevated serum VEGF-D will likely focus on the VEGF-C/VEGF-D/VEGFR-3 axis.