Comparison of Histologic Parameters and Predictive Gene Signatures in Clear Cell Renal Cell Carcinoma Response to Systemic Therapy.

Growing experience has correlated the histomorphological characteristics of clear cell renal cell carcinoma (ccRCC), ranging from cytoplasmic features to architectural patterns and tumor immune microenvironment, with clinical outcomes. However, further assessment is needed to determine which of these histologic parameters best correlate with outcomes of interest, especially response to tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Herein, we evaluated four histologic parameters: (i) World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grade; (ii) clear and eosinophilic cytological phenotypes; (iii) immunophenotypes; and (iv) vascularity-based architectural classification, using hematoxylin and eosin-stained whole slide images for The Cancer Genome Atlas (TCGA) ccRCC cohort (n = 433). We then correlated these parameters with gene expression signatures associated with TKI and ICI response. Multivariate analysis found that the cytological phenotype and vascularity-based architectural classification were independently associated with an angiogenesis-related gene signature (both p < 0.05). Conversely, WHO/ISUP grade and immunophenotype were independently associated with effector T-cell and immune checkpoint gene signatures (both p < 0.05). In conclusion, histologic parameters, including cytological features, architectural patterns, and tumor immune microenvironment, are associated with gene signatures related to therapy response, with different parameters informative for TKIs versus ICIs. These findings may help guide prospective validation studies.