IHC-based molecular classification in muscle-invasive urothelial bladder carcinoma: Prognostic and predictive value toward a clinically applicable IHC marker panel - A systematic review.

Urothelial bladder carcinoma (UBC) is a heterogeneous disease, characterized by variable treatment responses and outcomes, attributed to its underlying molecular diversity. Molecular classification has advanced our understanding of UBC, but remains limited by cost and complexity. Immunohistochemistry (IHC) offers an accessible, cost-effective alternative for routine subtype classification. We aimed to evaluate the predictive role of IHC-based classification of UBC on oncological outcomes and response to treatment, as well as to identify key IHC markers for routine use. A systematic literature search of PubMed and Scopus was conducted in January 2025, following PRISMA guidelines. Using the PICOS framework, we included post-2020 observational studies on muscle-invasive UBC patients classified by IHC into molecular subtypes, correlating these subtypes with oncological outcomes and treatment responses. Luminal subtypes generally exhibit better PFS, DSS and OS, although some studies report mixed results. The basal subtype shows better RFS compared to double-negative subtype and demonstrates a significantly better response to neoadjuvant chemotherapy (NAC). Double-positive subtypes often have improved OS, while double-negative subtypes consistently show the worst outcomes. Commonly used IHC markers include GATA3 and CK5/6 for identifying luminal and basal subtypes, respectively. Additionally, p16 helps distinguish Luminal Unstable from Luminal Papillary or Genomically Unstable (GU) subtypes, EGFR refines basal subtype classification and vimentin differentiates rare mesenchymal-like subtypes. We showed that IHC-based classification is a practical, promising tool for UBC patient stratification, outcome and response to treatment prediction. By identifying key IHC markers, we proposed a standardized panel to improve consistency and reproductibility in clinical practice and research.