Prognosis and Therapies in Non-Clear Cell Renal Cell Carcinomas

Background/Objectives: Non-clear cell renal cell carcinoma (nccRCC) comprises biologically heterogeneous renal malignancies with distinct molecular drivers, clinical behavior, and therapeutic responses. This review summarizes prognosis and systemic therapy and evaluates emerging histology-specific and biomarker-directed approaches. Methods: We analyzed overall survival by histology in the SEER 17 Registries database (2000–2022) and conducted a narrative review of trials, guidelines, and translational studies. The ICD-O-3-defined population included 43,966 adults; 43,789 with known survival time were included in survival analyses. Results: Median follow-up was 96 months. Compared with papillary RCC, adjusted HRs were 0.67 (95% CI 0.64–0.70) for chromophobe RCC, 3.73 (3.37–4.11) for collecting duct carcinoma, 0.97 (0.80–1.17) for oncocytic tumors, and 33.23 (27.47–40.20) for medullary carcinoma. VEGFR- and MET-directed therapies and immune checkpoint inhibitor combinations show activity that varies by histology. Conclusions: nccRCC should be studied and managed as a collection of distinct entities. Registry associations require cautious interpretation because of residual confounding, evolving classification, and non-proportional hazards; subtype-specific trials and molecular stratification remain priorities.