Lymphangiogenesis in Lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lungs, lymph nodes, and/or other organs. We examined lymphangiogenesis using immunohistochemistry for Flt-4 (VEGFR-3), a new specific marker for lymphatic endothelial cells, as well as the expression of vascular endothelial growth factor (VEGF)-C in LAM. Specimens were obtained from 6 autopsy cases, a single lung transplant case, and 8 surgical cases for analyses. We demonstrated that lymphatics were extremely abundant in both pulmonary and extrapulmonary LAM and that lymphatic endothelial cells not only proliferated encompassing LAM foci but also infiltrated the intra-LAM foci, and that in advanced LAM, lymphangiogenesis involved vascular walls and interstitium surrounding the area where LAM cells proliferate. In contrast, angiogenesis, confirmed with CD31 immunostaining, was observed less in the LAM foci. LAM cells demonstrated positive reactivity against anti-VEGF-C antibody at varying intensities. Significant correlation (P < 0.001) was noted between the degree of lymphangiogenesis in LAM or VEGF-C expression on LAM cells and lymphagioleiomyomatosis histologic score (LHS), which represents the histologic severity of pulmonary LAM and has been reported to have prognostic significance. Our study is likely to provide a novel point of view on the pathophysiologic significance of lymphangiogenesis in LAM.

Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis

“…Slit-like channels, lined with lymphatic endothelial cells, traverse LAM foci or nodules in lung and extrapulmonary LAM-affected organs ( i.e . lymph node, uterus and ovaries) [23, 24] and appear to be lymphatic capillaries.…”

“…Immunohistochemical studies involving TSC neoplasms (kidney AMLs, cortical tumours and skin lesions) reported the expression and up-regulation of the angiogenic growth factor vascular endothelial growth factor (VEGF)-A [41, 42] and the vascular endothelial marker CD31 [41]. In contrast, evidence of angiogenesis (positive staining for CD31) was observed less in LAM lung foci [23], and serum levels of VEGF-A in LAM patients were no different from those of controls [43]. Collectively, data from these experiments suggest angiogenesis as a partial mechanism for pathogenesis of TSC.…”

“…LAM cells express VEGF-C [23] and VEGF-D [43]. Podoplanin, a lymphatic marker recognised by the monoclonal antibody, D2-40, is expressed in LAM lesions and lung nodules [44].…”

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

“…However, only 40% of patients with LAM have uterine leiomyomas [1]. Other putative sources of LAM cells are renal AML, axial lymphatics [67], and perivascular epithelioid cell tumors [66]. …”

“…LAM cells express the lymphangiogenic factors VEGF-C and VEGF-D and their receptors VEGFR-2 and VEGFR-3 [67]. In TSC2-deficient cells in vitro, VEGF secretion is markedly elevated and this effect is only partly reverted by sirolimus, suggesting that tuberin regulates VEGF through both mTOR-dependent and mTOR-independent pathways [76].…”