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From the Department of Clinical Pathology,*
the
Department of Dermatology
Division of
Immunology, Allergy and Infectious Diseases, and the Department of
Internal Medicine III,
Division of
Nephrology and Dialysis, University of Vienna, Vienna, Austria, and the
Department of Pathology,§
Haartman Institute,
Molecular/Cancer Biology Laboratory, University of Helsinki,
Helsinki, Finland
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 ~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.
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R. B. Colvin Emphatically Lymphatic J. Am. Soc. Nephrol., March 1, 2004; 15(3): 827 - 829. [Full Text] [PDF]
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O. Straume, D. G. Jackson, and L. A. Akslen Independent Prognostic Impact of Lymphatic Vessel Density and Presence of Low-Grade Lymphangiogenesis in Cutaneous Melanoma Clin. Cancer Res., January 1, 2003; 9(1): 250 - 256. [Abstract] [Full Text] [PDF]
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P. Salven, S. Mustjoki, R. Alitalo, K. Alitalo, and S. Rafii VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells Blood, January 1, 2003; 101(1): 168 - 172. [Abstract] [Full Text] [PDF]
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S. Podgrabinska, P. Braun, P. Velasco, B. Kloos, M. S. Pepper, D. G. Jackson, and M. Skobe Molecular characterization of lymphatic endothelial cells PNAS, December 10, 2002; 99(25): 16069 - 16074. [Abstract] [Full Text] [PDF]
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M. E. Akerman, W. C. W. Chan, P. Laakkonen, S. N. Bhatia, and E. Ruoslahti Nanocrystal targeting in vivo PNAS, October 1, 2002; 99(20): 12617 - 12621. [Abstract] [Full Text] [PDF]
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S. F. Schoppmann, P. Birner, J. Stockl, R. Kalt, R. Ullrich, C. Caucig, E. Kriehuber, K. Nagy, K. Alitalo, and D. Kerjaschki Tumor-Associated Macrophages Express Lymphatic Endothelial Growth Factors and Are Related to Peritumoral Lymphangiogenesis Am. J. Pathol., September 1, 2002; 161(3): 947 - 956. [Abstract] [Full Text] [PDF]
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