Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries - Podoplanin as a specific marker for lymphatic endothelium

Angiosarcomas apparently derive from blood vessel endothelial cells; howeve r, 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 n ot been possible, Here we provide evidence by light and electron microscopi c immunohistochemistry that podoplanin, a similar to 38-kd membrane glycopr otein of podocytes, is specifically expressed in the endothelium of lymphat ic 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 immuno staining 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 en dothelia 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 p aradigms of malignant vascular tumors, poorly differentiated (G3) common an giosarcomas (n = 8), epitheloid angiosarcomas (n = 3), and intestinal Kapos i's sarcomas (n = 5) were examined for their podoplanin content in relation to conventional endothelial markers. The relative number of tumor cells ex pressing podoplanin was estimated and, although the number of cases in this preliminary study was limited to 16, an apparent spectrum of podoplanin ex pression 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 angiosarcoma s and all Kaposi's sarcomas showed mixed expression of both lymphatic and b lood vascular endothelial phenotypes. By double labeling, most podoplanin-p ositive tumor cells coexpressed endothelial markers of blood vessels, where as few tumor cells were positive for individual markers only, From these re sults we conclude that (1) podoplanin is a selective marker of lymphatic en dothelium; (2) G3 angiosarcomas display a quantitative spectrum of podoplan in-expressing tumor cells; (3) in most angiosarcomas, a varying subset of t umor cells coexpresses podoplanin and endothelial markers of blood vessels; and (4) all endothelial cells of Kaposi's sarcomas expressed the lymphatic marker podoplanin.