Angiosarcomas Express Mixed Endothelial Phenotypes of Blood and Lymphatic Capillaries

Abstract

Angiosarcomas apparently derive from blood vessel endothelial cells; however, occasionally their histological features suggest mixed origin from blood and lymphatic endothelia. In the absence of specific positive markers for lymphatic endothelia the precise distinction between these components has not been possible. Here we provide evidence by light and electron microscopic immunohistochemistry that podoplanin, a approximately 38-kd membrane glycoprotein of podocytes, is specifically expressed in the endothelium of lymphatic capillaries, but not in the blood vasculature. In normal skin and kidney, podoplanin colocalized with vascular endothelial growth factor receptor-3, the only other lymphatic marker presently available. Complementary immunostaining of blood vessels was obtained with established endothelial markers (CD31, CD34, factor VIII-related antigen, and Ulex europaeus I lectin) as well as podocalyxin, another podocytic protein that is also localized in endothelia of blood vessels. Podoplanin specifically immunolabeled endothelia of benign tumorous lesions of undisputed lymphatic origin (lymphangiomas, hygromas) and was detected there as a 38-kd protein by immunoblotting. As paradigms of malignant vascular tumors, poorly differentiated (G3) common angiosarcomas (n = 8), epitheloid angiosarcomas (n = 3), and intestinal Kaposi's sarcomas (n = 5) were examined for their podoplanin content in relation to conventional endothelial markers. The relative number of tumor cells expressing podoplanin was estimated and, although the number of cases in this preliminary study was limited to 16, an apparent spectrum of podoplanin expression emerged that can be divided into a low-expression group in which 0-10% of tumor cells contained podoplanin, a moderate-expression group with 30-60% and a high-expression group with 70-100%. Ten of eleven angiosarcomas and all Kaposi's sarcomas showed mixed expression of both lymphatic and blood vascular endothelial phenotypes. By double labeling, most podoplanin-positive tumor cells coexpressed endothelial markers of blood vessels, whereas few tumor cells were positive for individual markers only. From these results we conclude that (1) podoplanin is a selective marker of lymphatic endothelium; (2) G3 angiosarcomas display a quantitative spectrum of podoplanin-expressing tumor cells; (3) in most angiosarcomas, a varying subset of tumor cells coexpresses podoplanin and endothelial markers of blood vessels; and (4) all endothelial cells of Kaposi's sarcomas expressed the lymphatic marker podoplanin.

VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma

“…Recently, podoplanin, an B38 kDa membrane mucoprotein originally detected on the surface of rat podocytes, 13 was established as a specific marker for lymphatic endothelium. 23 This discovery changed the landscape for lymphatic studies, with podoplanin being used as a valuable marker for identifying lymph vessels and accurately evaluating lymph vessel density. 17,18,[24][25][26] In this study, we found that lymph node metastasis was statistically correlated with both increased lymph vessel density and VEGF-D expression of both mRNA and protein, and that VEGF-D immunoreactivity was significantly and positively correlated with increased lymph vessel density.…”

The potential role of podoplanin in tumour invasion

“…The extracellular domain is highly O-glycosylated, with sialic acid, a-2,3 linked to galactose, forming the main part of the protein's carbohydrate moieties. In normal human tissue, podoplanin is expressed in kidney podocytes (Breiteneder-Geleff et al, 1999), in skeletal muscle, placenta, lung and heart (Martin-Villar et al, 2005), in myofibroblasts of the breast and salivary glands, in osteoblasts and mesothelial cells (Ordonez, 2006b). It is also expressed on the apical surface of rat alveolar type I cells (Rishi et al, 1995).…”

Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx

“…Podoplanin is highly and specifically expressed in lymphatic endothelial cells, but not in blood vessel endothelium. 4,5 It has been shown that podoplanin deficiency disrupts normal lymphatic vasculature formation. As podoplanin is expressed on lymphatic but not on blood vessel endothelium, it is widely used as a specific marker for lymphatic endothelial cells and lymphangiogenesis in many species.…”