Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma.
OBJECTIVE
Because lymphatic vessels are absent from the normal eye and because uveal melanomas are presumed to spread by a hematogenous route in the absence of tumor exposure to conjunctival lymphatics, this study was undertaken to investigate the presence of lymphatic vessels in primary uveal melanomas.


METHODS
The presence of lymphatics in 2 control eyes and in 33 primary uveal, 10 primary cutaneous, and 3 metastatic cutaneous melanomas was evaluated by using a double-immunostaining protocol that differentially highlights blood and lymphatic vasculature. In addition, 14 uveal melanomas were immunostained for the lymphatic growth factor vascular endothelial growth factor (VEGF)-C (with anti-VEGF-C polyclonal antibodies [pAbs]), its receptors Flt-4 (with monoclonal antibody [mAb] 9D9) and KDR (with anti-KDR mAb [Clone KDR-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 coexpression of VEGF-C with Flt-4 and KDR in 6 (43%) of the 14 melanomas. Staining for VEGF-A was completely negative in 25 uveal melanomas analyzed.


CONCLUSIONS
The strictly hematogenous metastasis of primary uveal melanomas is explained by the absence of lymphatics in and around the tumor. The current data suggest that, in the presence of endothelial Flt-4, VEGF-C expression is not sufficient to induce lymphangiogenesis from preexisting blood vessels in human cancer.
Clarijs
R
R
Department of Pathology, University Medical Centre St. Radboud, Nijmegen, The Netherlands. r.clarijs@pathol.azn.nl
Schalkwijk
L
L
Ruiter
D J
DJ
de Waal
R M
RM
D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016228:Endothelial Growth Factors / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008208:Lymphatic System / Q000378:metabolism*; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D012878:Skin Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D014604:Uveal Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
D016228:Endothelial Growth Factors; D017978:Receptors, Growth Factor; D042582:Vascular Endothelial Growth Factor C; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3