Molecular Biomarker Testing in Kidney Cancer: Integrating Diagnosis, Prediction, and Emerging Renal Tumor Entities

Background: Kidney tumors comprise a biologically diverse and diagnostically challenging group of neoplasms. Many entities share overlapping morphologic features despite having distinct molecular profiles. Although histomorphology remains the cornerstone of diagnosis, molecular biomarker testing has become increasingly important for accurate classification, recognition of emerging entities, identification of hereditary cancer syndromes, and therapeutic decision-making. Focus of the Review: This narrative review provides a practical, pathology-oriented framework for molecular biomarker testing in kidney tumors. It integrates immunohistochemistry, fluorescence in situ hybridization, polymerase chain reaction-based methods, and next-generation sequencing with morphologic assessment. Particular attention is given to diagnostically relevant alterations involving VHL, TFE3, TFEB, MET, FH, ELOC, and ALK, genes encoding SDH subunits, and components of the mTOR signaling pathway, together with commonly used immunohistochemical surrogates. The prognostic and predictive roles of selected biomarkers, including their potential value in hereditary risk assessment and treatment selection, are also discussed. Practical limitations, such as limited biopsy material, intratumoral heterogeneity, and technical variability, are considered. Conclusions: Molecular biomarker testing is reshaping kidney tumor pathology by supporting an integrated diagnostic approach that complements, rather than replaces, careful morphologic evaluation. Its appropriate use can improve diagnostic accuracy, refine clinical stratification, and facilitate the recognition of emerging renal tumor entities with hereditary or therapeutic relevance. Future developments are expected to include methylation profiling, transcriptomic classifiers, liquid biopsy platforms, and artificial intelligence-assisted interpretation.