Navigating prognostic uncertainty in non-muscle invasive urothelial bladder cancer with focal squamous differentiation

Objectives Transitional cell carcinoma (TCC), or urothelial carcinoma, represents the predominant histological type of bladder cancer. While the majority of TCC cases are characterized by conventional urothelial features, a significant subset exhibits variant histologies, such as focal squamous differentiation (SD). This variant is clinically noteworthy, given its association with more aggressive disease behavior and potential resistance to standard therapies, particularly intravesical Bacillus Calmette–Guérin (BCG) therapy. It raises critical challenges in prognosis and treatment. Materials and Methods This single-center prospective cohort study enrolled patients with histopathologically confirmed TCC of the bladder, with or without focal SD, following transurethral resection of bladder tumor. Participants, devoid of deep muscle invasion and residual growth, received intravesical BCG therapy consisting of six weekly induction doses followed by 12 months of maintenance therapy. Outcomes were assessed through regular follow-up, utilizing clinical evaluations, imaging, urine cytology, and cystoscopy. The primary endpoints included recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). Results Of the 131 patients evaluated, 35 exhibited focal SD. Statistically significant differences were observed between TCC with and without SD groups, with the former demonstrating poorer PFS (68.6% vs. 82.6%) and DSS (88.6% vs. 98%) after 1 year. However, RFS rates were comparable. Subgroup analysis revealed no significant differences in outcomes based on the extent of SD (>50% vs. <50%). Conclusion Focal SD within TCC of the bladder portends a worse prognosis, particularly in terms of PFS and DSS, underscoring the necessity for tailored therapeutic approaches.