LYMPHATIC MANIFESTATIONS OF LYMPHANGIOLEIOMYOMATOSIS

Abstract

Lymphangioleiomyomatosis (LAM) is aslowly progressive, low grade, metastasizingneoplasm, associated with cellular invasionand cystic destruction of the pulmonaryparenchyma. Although the source of LAMcells that infiltrate the lung is unknown,available evidence indicates that the diseasespreads primarily through lymphatic channels,often involving abdominal, axial, andretroperitoneal nodes, suggestive of an originin the pelvis. LAM cells harbor mutations intuberous sclerosis genes and producelymphangiogenic growth factors, whichfacilitate access to and movement through thelymphatic system and likely play an importantrole in destructive tissue remodeling in thelung. Lymphatic manifestations of LAMinclude thoracic duct wall invasion, lymphangioleiomyomaformation, chylous fluidcollections in the peritoneal, pleural, andpericardial spaces, chyloptysis, chylocolporrhea/chylometrorrhea, chyle leak from theumbilicus, chylous pulmonary congestion,and lower extremity lymphedema. LAMlesions express lymphangiogenic growthfactors VEGF-C and VEGF-D; growth factorreceptors, VEGFR-2 and VEGFR-3; andmarkers LYVE-1 and podoplanin, and arelaced with chaotic lymphatic channels. SerumVEGF-D is elevated in 70% of patients withLAM and is a clinically useful diagnosticand prognostic biomarker. Molecular targetedtherapy with sirolimus stabilizes lungfunction, is anti-lymphangiogenic, and ishighly effective for the lymphatic and chylouscomplications of LAM. Future trials inpatients with LAM who have lymphaticmanifestations or elevated serum VEGF-Dwill likely focus on the VEGF-C/VEGFD/VEGFR-3 axis.