Beyond clear cell: Rare histologic and molecular variants of renal cell carcinoma.

Renal cell carcinoma (RCC) represents a complex and heterogeneous group of renal malignancies, encompassing the predominant clear cell RCC (ccRCC) as well as a broad spectrum of nonclear cell RCC (non-ccRCC) subtypes. Advances in histopathology and genomic profiling have significantly refined RCC classification, enabling integration of morphological, immunohistochemical, and molecular features to enhance diagnostic precision, prognostication, and individualized treatment planning. While the 2022 5th edition of the WHO Classification continues to prioritize histopathologic assessment, it introduces a novel category of molecularly defined renal carcinomas, classifying tumors based on specific genetic and molecular features and reflecting advances in tumor biology. Herein, non-ccRCC includes different subtypes of papillary, chromophobe, tubulocystic, oncocytoma, eosinophilic solid and cystic, and collecting duct carcinomas, as well as several molecularly defined entities. Rare histological subtypes and molecularly characterized tumors, including ALK-rearranged, FH-deficient, SDH-deficient, TFEB/TFE3-rearranged, ELOC-mutated, and SMARCB1-deficient RCCs, demonstrate distinct clinical behavior, variable aggressiveness, and specific therapeutic vulnerabilities, underscoring the importance of accurate molecular diagnosis. Non-ccRCC subtypes remain a clinical challenge due to their relative rarity, histological heterogeneity, and underrepresentation in clinical trials, often necessitating the extrapolation of treatment paradigms from ccRCC. Emerging targeted therapies and immunotherapeutic strategies show promise for these rare RCCs, emphasizing the need for subtype-specific clinical research. This review provides a comprehensive overview of the histological and molecular rare variants of RCC, highlights diagnostic innovations, and discusses the implications of these insights for precision medicine and future therapeutic development in kidney cancer.