Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma

PURPOSE. Because lymphatic vessels are absent from the normal eye and becau se uveal melanomas are presumed to spread by a hematogenous route in the ab sence of tumor exposure to conjunctival lymphatics, this study was undertak en to investigate the presence of lymphatic vessels in primary uveal melano mas. METHODS. The presence of lymphatics in 2 control eyes and in 33 primary uve al, 10 primary cutaneous, and 3 metastatic cutaneous melanomas was evaluate d by using a double-immunostaining protocol that differentially highlights blood and lymphatic vasculature. In addition, 14 uveal melanomas were immun ostained for the lymphatic growth factor vascular endothelial growth factor (VEGF)-C (with anti-VEGF-C polyclonal antibodies [pAbs]), its receptors Fl t-4 with monoclonal antibody [mAb] 9D9) and KDR (with anti-KDR mAb [Clone K DR-2]), and the hemangiogenic factor VEGF-A (with anti-VEGF pAbs). RESULTS. Lymphatics were not detected in normal eyes or in uveal melanoma. As a consequence, signs of lymphangiogenesis were not present. There was co expression of VEGF-C with Flt-4 and KDR in G (43%) of the 14 melanomas. Sta ining for VEGF-A was completely negative in 25 uveal melanomas analyzed. CONCLUSIONS. The strictly hematogenous metastasis of primary uveal melanoma s is explained by the absence of lymphatics in and around the tumor. The cu rrent data suggest that, in the presence of endothelial Flt-4, VEGF-C expre ssion is not sufficient to induce lymphangiogenesis from preexisting blood vessels in human cancer.