Macroscopic Tumor Color as a Surrogate for Biological Diversity in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) exhibits marked intratumoral heterogeneity, reflected in its macroscopic color variation. As limited tissue sampling often underrepresents aggressive tumor components, macroscopic appearance may serve as an accessible, integrative indicator of intratumoral heterogeneity. However, its oncologic relevance has not been systematically investigated. This study evaluated a macroscopic color scoring system and its correlation with pathological prognostic factors and histological parameters linked to therapeutic response-related gene signatures.

Macroscopic color in 309 surgically treated ccRCC cases was retrospectively analyzed and scored as 1 (golden yellow), 2 (yellow/pale tan), or 3 (grey/white). Correlations with pathological prognostic factors, histological features (cytological phenotype/vascularity-based architectural classification/immunophenotype), and recurrence-free survival (RFS) were evaluated. Survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards regression models.

Macroscopic color score was significantly correlated with TNM stage (p=0.009), tumor size (p=0.001), and histological parameters, including World Health Organization (WHO)/International Society of Urologic Pathology (ISUP) nucleolar 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. The strongest correlations were observed with WHO/ISUP grade and vascularity-based architectural classification. Although its C-index was lower than that of histological parameters, macroscopic color score effectively stratified RFS into three distinct groups [hazard ratio (HR)=2.69; p=0.022 for score 2; HR=6.53; p<0.001 for score 3].

Macroscopic intratumoral heterogeneity in ccRCC may offer a readily accessible surrogate for biological diversity and tumor microenvironmental features linked to therapeutic response. Systemic gross evaluation may improve tissue sampling, reduce pathological underestimation, and support personalized treatment strategies.