Lymphatic Involvement in Lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease affecting primarily premenopausal women. The disease is characterized by cystic lung disease, at times leading to respiratory compromise, abdominal tumors (in particular, renal angiomyolipomas), and involvement of the axial lymphatics (e.g., adenopathy, lymphangioleiomyomas). Disease results from the proliferation of neoplastic cells (LAM cells), which, in many cases, have a smooth muscle cell phenotype, express melanoma antigens, and have mutations in one of the tuberous sclerosis complex genes (TSC1 or TSC2). In the lung, LAM cells found in the vicinity of cysts are, at times, localized in nodules and may be responsible for cyst formation through the production of proteases. Lymphatic channels, expressing characteristic lymphatic endothelial cell markers, are found within the LAM lung nodules. LAM cells may also be localized within the walls of the axial lymphatics, and, in some cases, penetrate the wall and proliferate in the surrounding adipose tissue. Consistent with extensive lymphatic involvement in LAM, the serum concentration of VEGF-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers.

The Natural History of Lymphangioleiomyomatosis: Markers of Severity, Rate of Progression and Prognosis

“…31 Patients who present with chylothorax, with or without ascites, thoraco-abdominal lymphadenopathy, and lymphangioleiomyomas may have a more severe form of disease. 70 There was a correlation between the extent of lymphangiogenesis, expression of VEGF-C, and LHS. 71 LAM tissue with greater reactivity with anti-VEGF-C antibodies also contained more VEGFR-3.…”

Perivascular epithelioid cell neoplasms: pathology and pathogenesis

“…PEComa express both typical smooth muscle cell markers and proteins normally expressed in the melanosome. In addition, these tumors appear to specifically recruit the in-growth of lymphatic vascular channels, through the secretion of VEGF-C and VEGF-D [117,118]. The presence of melanosome proteins in these tumors suggests the possibility of a neural crest lineage origin, which is congruent with the generation of many smooth muscle cells from this lineage during development.…”

Lymphangioleiomyomatosis andTSC2-/-Cells

“…[65][66][67] Fibroblast-like cells are interspersed among increased amounts of collagen and dilated vessels, including blood and lymphatic endothelial cells. 68,69 The epithelium overlying the tumors is often thickened due to a proliferation of keratinocytes. 70 Once the genetic basis for TSC was uncovered and antibodies were generated against human TSC1 and TSC2 proteins, it was possible to test for aberrant expression of these proteins in TSC tumors.…”