Abstract
Renal cell carcinoma is a heterogeneous disease with diverse phenotypes. Renal cell carcinoma classification is based on morphological and molecular characteristics and falls into 2 main categories: clear cell renal cell carcinoma and non-clear cell renal cell carcinoma. Clear cell renal cell carcinoma is the predominant subtype, accounting for approximately 70%-80%, while non-clear cell renal cell carcinoma constitutes 20%-30%. Non-clear cell renal cell carcinoma comprises multiple histologic types, each with distinct clinicopathologic features. The fifth edition of the World Health Organization classification of urinary and male genital tumors, published in 2022, introduced significant updates and revisions in kidney tumor classification. The new classification incorporated molecular biological factors into the existing framework and introduced additional tumor subtypes. Most clinical trials have excluded or included only small numbers of patients with non-clear cell renal cell carcinoma. Due to the scarcity of prospective studies focusing on this population, data on response rates and survival outcomes remain limited. However, recent evidence suggests the efficacy of combination therapy with immune checkpoint inhibitors and tyrosine kinase inhibitors in non-clear cell renal cell carcinoma. This review examines immunotherapy and tyrosine kinase inhibitor outcomes across non-clear cell renal cell carcinoma subtypes and highlights opportunities for enhanced care through novel therapies, biomarker-driven approaches, and more inclusive clinical trial designs.