Diagnostic, Prognostic, and Predictive Tissue Biomarkers in Urothelial Carcinoma In Situ: A Narrative Review.

Urothelial carcinoma in situ (UCIS) is a high-grade non-muscle-invasive neoplasm with significant clinical implications due to its potential for progression to muscle-invasive disease. Accurate diagnosis and risk stratification are crucial for appropriate management, particularly given the variability in response to intravesical Bacillus Calmette-Guérin (BCG) therapy. While the diagnosis of UCIS primarily relies on morphological criteria, immunohistochemical (IHC) markers serve as valuable ancillary tools, particularly in challenging cases. Markers such as CK20, CD44, p53, and Ki-67 have been extensively studied, though none demonstrate complete sensitivity or specificity. Additionally, molecular classification has identified luminal and basal subtypes, with potential prognostic and therapeutic implications. Recent studies have also explored predictive biomarkers for BCG response, including PD-L1, whose expression correlates with recurrence and potential responsiveness to immune checkpoint inhibitors. Emerging targeted therapies, such as enfortumab vedotin, have shown promise, with nectin-4 overexpression observed in most UCIS cases. Despite these advancements, challenges remain, including interobserver variability in morphological assessment, heterogeneous IHC methodologies, and the need for standardized molecular testing. This review highlights the current understanding of diagnostic, prognostic, and predictive tissue biomarkers in UCIS, underscoring the potential role of molecular profiling in guiding personalized treatment strategies. Future research should focus on refining biomarker-driven classification systems to improve risk stratification and therapeutic decision-making in UCIS patients.