Endothelial p16 expression identifies a subgroup of clear cell renal cell carcinoma with favorable prognosis

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is characterized by extensive angiogenesis and marked architectural heterogeneity. While vascular density has been investigated as a prognostic parameter in ccRCC, little is known about the biological characteristics of intratumoral endothelial cells. METHODS: In this study, we analyzed the p16 expression in a tissue microarray cohort comprising 347 ccRCC cases with clinicopathological and survival data and related the vascular p16 expression to previously described tumor architecture subtypes. RESULTS: Tumor architecture could be assessed in 315 cases and was classified into nine predominant growth patterns. Tumors with thick trabecular/insular or solid sheet architecture were grouped as high-risk patterns and were associated with higher tumor grade and shorter overall survival (p < 0.001). Tumor cell p16 expression was infrequent and showed no association with clinicopathological parameters or survival. In contrast, endothelial p16 expression was commonly observed in intratumoral blood vessels, with a median of 35% positive vessels per case. Higher endothelial p16 expression, both in extent and intensity, was significantly associated with lower tumor grade, lower pT stage, favorable architectural patterns, and prolonged overall survival. Furthermore, the prognostic impact of architectural growth patterns was most pronounced in tumors with low endothelial p16 expression, whereas tumors with high endothelial p16 expression showed comparable survival independent of architectural subtype. CONCLUSION: Endothelial p16 expression is common in ccRCC and is associated with favorable clinicopathological characteristics and prolonged survival. These findings suggest that endothelial p16 expression may complement architectural tumor stratification in ccRCC, identifying cases with good prognosis.