AIMS Angiosarcomas apparently derive from endothelia of the blood vasculature, however occasionally their histologic 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 was not possible so far. Here we provide evidence that podoplanin, a approximately 38 kD membrane glycoprotein of podocytes is a specific marker of lymphatic endothelium that was used to identify the relative fraction of tumor cells with lymphatic or blood vascular endothelial phenotype in vascular tumors. METHODS Podoplanin was localized in normal human skin and kidney cortex by immunohistochemistry on paraffin sections, double immunofluorescence on frozen sections with PAL-E, immunoelectron microscopy and by immunoblotting. 45 vascular tumors (29 benign lesions, 11 angiosarcomas and 5 gastrointestinal Kaposi's sarcomas) were evaluated for podoplanin expression. Complementary staining was obtained with established endothelial markers (CD 31, CD 34, Factor VIII related antigen, UEA I) and with podocalyxin, another podocytic protein mainly present in endothelia of blood vessels. RESULTS In human tissues podoplanin is specifically expressed in the endothelium of lymphatics, but not in blood vasculature or in hemangiomas. This expression is preserved in endothelia of all benign lymphatic tumorous lesions and all Kaposi's sarcomas examined. By contrast 10 out of 11 G3 angiosarcomas contained only variable fractions of podoplanin-expressing tumor cells. Most tumor cells coexpressed podoplanin and markers of blood vessel phenotype. CONCLUSIONS (1) Podoplanin is a selective marker of lymphatic endothelium; (2) G3 angiosarcomas display a quantitative spectrum of podoplanin-expressing tumor cells; (3) In the majority of angiosarcomas tumor cells coexpress podoplanin and endothelial markers of blood vessels; (4) All endothelial cells of Kaposi's sarcomas expressed the lymphatic marker podoplanin.