Macroscopic Color Variation in Clear Cell Renal Cell Carcinoma: A Novel Prognostic Indicator Reflecting the Tumor Microenvironment

Abstract [Background] Clear cell renal cell carcinoma (ccRCC) exhibits heterogeneous macroscopic colors, ranging from golden yellow to pale tan or white, demonstrating intratumoral heterogeneity in cellular composition. This study aimed to establish a macroscopic color scoring system for ccRCC and evaluate its correlation with pathological prognostic factors and previously reported histological parameters linked to treatment response-related gene signatures. [Methods] We retrospectively analyzed macroscopic color variation in 309 localized ccRCC cases, categorizing it into three levels: score 1 (golden yellow), score 2 (yellow to pale tan), and score 3 (grey to white). The prognostic significance of macroscopic color scores and their associations with pathological prognostic features were evaluated. [Results] Macroscopic color score was significantly correlated with TNM stage (p = 0.009), tumor size (p = 0.001), World Health Organization (WHO)/International Society of Urologic Pathology (ISUP) grade, sarcomatoid/rhabdoid features, tumor-type necrosis, cytological phenotype, vascularity-based architectural classification, and immunophenotype (p < 0.001). Higher scores were associated with adverse histological parameters, decreased vascularity, and increased immune infiltration, with the strongest correlations observed for WHO/ISUP grade and vascularity-based architectural classification. Although the C-index, a measure of predictive accuracy, of macroscopic score was lower than that of histological parameters, it effectively stratified recurrence-free survival into three distinct groups (hazard ratio, 2.69; p = 0.022 for score 2; hazard ratio, 6.53; p < 0.001 for score 3). [Conclusion] Macroscopic color variation in ccRCC may reflect underlying morphological and molecular heterogeneity. The macroscopic color scoring system may be valuable for guiding tissue sampling and risk stratification, potentially informing treatment strategies and diagnostic imaging approaches.