Immunohistochemistry-Based Molecular Classification of Muscle-Invasive Bladder Urothelial Carcinoma: Survival Trends Across Molecular Subtypes

Abstract

Muscle-invasive bladder urothelial carcinoma (MIBUC) is a heterogeneous disease, presenting variable clinical outcomes and therapeutic responses. Although molecular classification provides important prognostic information, its clinical use is limited by cost and technical complexity, making immunohistochemistry (IHC) a practical and reliable surrogate approach. We aimed to investigate the association between IHC-based molecular subtypes and overall survival (OS). We conducted a retrospective study including 75 newly diagnosed MIBUCs over a 4-year period. Tumours were stratified into seven molecular subtypes (LumP, LumNS, LumU, Ba/Sq, NE-like, stroma-rich, and double-positive) using a five-antibody IHC panel (GATA3, CK5/6, p16, FGFR3, and EpCAM). Marker expression was evaluated based on staining intensity and the proportion of positive tumour cells, using predefined, marker-specific cut-off values. OS was assessed for each subtype and compared across groups. Median OS ranged from 5 months (NE-like) to 26 months (stroma-rich and double-positive). LumU demonstrated the highest 1-year survival rate, while the double-positive subtype exhibited the most favourable long-term outcomes, at 2 and 5 years. Conversely, NE-like had the lowest 1-year survival rate, whereas the stroma-rich subtype demonstrated the lowest 2- and 5-year survival rates. No statistically significant difference in OS was identified across molecular subtypes (p = 0.714). Patients ≤65 years experienced significantly longer OS than older patients (p = 0.024). OS was comparable between sexes (p = 0.626) and did not differ significantly according to tumour morphology (p = 0.884). IHC-based molecular classification represents a feasible approach to characterize molecular heterogeneity in MIBUC, with further studies needed to clarify its prognostic significance.