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Summary: Angiogenesis in clear cell renal cell carcinoma has received recent focus with the development of antiangiogenic therapies. Although tumor progression is known to be correlated with intratumoral and plasma levels of vascular endothelial growth factor-A, the role of tumor induced-angiogenesis remains unclear in these tumors. We analyzed the vascular network in a cohort of 73 clear cell renal cell carcinoma cases using endothelial immunostaining. We studied protein expression of vascular endothelial growth factor, Von Hippel Lindau, and carbonic anhydrase IX by immunohistochemistry, Von Hippel Lindau gene alteration by sequencing, deletion- and methylation-specific Multiplex Ligation-dependent Probe Amplification, and gene expression by pangenomic microarray and quantitative polymerase chain reaction in a subcohort of 39 clear cell renal cell carcinoma cases. We described 2 distinct angiogenic phenotypes in comparison with the normal kidney vasculature: low and high angiogenic phenotypes. The low angiogenic phenotype was associated with more aggressive prognostic factors such as T3 to T4 (62% versus 31%, P = .002), N+ (29% versus 3% P = .004), M+ (53% versus 21%, P = .004) stages, Fuhrman grade (grade 3-4: 91% versus 36%, P < .001), and intratumoral vascular endothelial growth factor expression (74% versus 28%, P < .001); was less associated with Von Hippel Lindau inactivation (56% versus 80%, P = .03); and was a predictor of poor prognosis in terms of progression-free, cancer-specific, and overall survival (log-rank test, P = .002, P = .011, and P = .035, respectively). The low angiogenic phenotype was also associated with a relative down-regulation of gene expression (platelet-derived growth factor D, N-acetyl transferase 8, and N-acetyl transferase 8 B). In conclusion, the histologic and molecular distinction between these 2 angiogenic phenotypes could help to better understand the biologic behavior of clear cell renal cell carcinoma angiogenesis and could be analyzed in a prospective study of the effects of antiangiogenic drugs. [Copyright &y& Elsevier]