Next-Generation Immunohistochemical and RNA in Situ Hybridization Assays for Renal Neoplasia: Which Biomarkers Are Ready for Prime Time?

The expanding molecular classification of renal neoplasia has created a growing need for biomarkers that translate biologic insights into practical diagnostic tools. This review focuses on recently introduced immunohistochemical (IHC) and RNA in situ hybridization (RNA-ISH) assays with potential relevance to routine kidney tumor pathology. Biomarkers were selected based on their applicability to conventional formalin-fixed, paraffin-embedded tissue; commercial accessibility and potential for cost-effective implementation; evaluation in substantial tumor cohorts; comparison with established or gold-standard methods; and, where available, validation in independent and/or multi-institutional studies. The reviewed biomarkers encompass markers of cellular lineage and differentiation (L1CAM, FOXI1, and LINC01187); markers of tumor identity, molecular alterations, and metabolic pathway dysregulation (GPNMB, AKR1B10, 2SC, VSTM2A, TRIM63, and Merlin); and prognostic or therapeutically relevant biomarkers (BAP1, HER2, ABCC2, and PD-L1). We critically evaluate their biologic rationale, diagnostic, prognostic, and predictive applications, technical limitations, and current level of validation. By distinguishing biomarkers supported for broader or selective clinical implementation from those requiring additional validation or remaining primarily relevant to defined therapeutic contexts, this review provides a practical framework for their integration into contemporary renal tumor pathology.