Eosinophilic Pattern of Chromophobe Renal Cell Carcinoma is More Aggressive Than the Classic Pattern: A Comprehensive Morphologic and Genomic Analysis.

Abstract

Chromophobe renal cell carcinoma (chRCC) is generally considered an indolent malignancy; however, studies have produced conflicting results regarding the differences among its histologic patterns. The prognostic significance of eosinophilic morphology in chRCC remains controversial, in part due to inconsistent diagnostic criteria and inclusion of morphologic mimickers. Cases were classified by 3 expert genitourinary pathologists into eosinophilic, classic, and mixed chRCC patterns based on strict morphologic and immunohistochemical criteria (n=110). Clinicopathologic features, copy number variations (CNVs), and targeted sequencing of TP53 , PTEN , and RB1 were assessed, along with pathway analyses using RNAseq and multiplex gene expression profiling. Clinicopathological and survival analysis were assessed using GraphPad Prism. The final cohort included 24 eosinophilic, 47 classic, and 39 mixed chRCC. CNV frequencies were similar across patterns, while RB1 aberrations and enrichment of oncogenic pathways (TP53, PTEN, RB1, DNA repair, mTOR, and cell cycle) were increased in both mixed and eosinophilic chRCC, with the greatest prominence in eosinophilic chRCC. Clinically, eosinophilic chRCC and mixed chRCC were associated with larger tumour size, more advanced clinical stage, and significantly worse disease-free survival (DFS) and overall survival (OS) compared with classic chRCC. On multivariate analysis, histologic pattern and stage remained prognostic of DFS. Therefore, eosinophilic chRCC showed a distinct molecular phenotype with enriched oncogenic pathways and poorer outcomes, while mixed chRCC displayed an intermediate but similarly aggressive profile. These findings indicate that eosinophilic morphology has potentially more aggressive biology than classic chRCC, underscoring the need for the introduction of specific diagnostic criteria for eosinophilic chRCC and its differentiation clinically.