The prognostic impact of squamous differentiation in bladder cancer after radical cystectomy: a propensity score-matched comparative analysis of pure urothelial carcinoma, urothelial carcinoma with squamous differentiation, and squamous cell carcinoma

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Objectives To evaluate the prognostic impact of squamous differentiation in bladder cancer by comparing clinicopathological characteristics and survival outcomes among patients with pure urothelial carcinoma (UC), urothelial carcinoma with squamous differentiation (UCSD), and pure squamous cell carcinoma (SCC) treated with radical cystectomy (RC). Methods A single-center, retrospective cohort analysis was conducted. Patients who underwent RC for bladder cancer between January 2015 and June 2024 were identified and stratified into three groups based on final pathology: pure UC, UCSD, and SCC. Clinicopathological features were compared, and overall survival (OS) was analyzed using Kaplan-Meier methods and multivariable Cox regression. To control for baseline imbalances, 1:1 propensity score matching (PSM) was performed, matching for age, sex, surgical approach, muscle invasion status, and lymph node status. Results Among 312 eligible patients, there were 236 with pure UC,60 with UCSD, and 16 with SCC.In unadjusted analysis,patients with UCSD and SCC presented with more advanced disease (higher rates of stage III+IV, muscle invasion, and lymph node metastasis; P < 0.05) and had significantly worse 5-year OS (42.1% and 38.9%, respectively) compared to the pure UC group (62.5%;log-rank P < 0.001). After 1:1 propensity score matching, baseline characteristics were well-balanced across the three groups. Pairwise log-rank comparisons demonstrated that overall survival was significantly worse in both the UCSD and SCC groups compared to the pure UC group (UC vs.UCSD: HR = 1.52,95% CI:1.18–1.96, P = 0.002; UC vs.SCC: HR = 1.78,95% CI:1.25–2.54, P = 0.001).However, no significant difference was observed between the UCSD and SCC groups (HR = 1.17,95% CI:0.79–1.73, P = 0.622).In the matched cohort,the 5-year OS rates were 59.5% for pure UC, 45.8% for UCSD, and 42.6% for SCC.In multivariable Cox regression (full cohort), older age(HR = 1.03,95% CI:1.02–1.04, P < 0.001), muscle invasion (HR = 2.25,95% CI: 1.75–2.89, P < 0.001), positive lymph node status (HR = 2.18,95% CI: 1.65–2.88, P < 0.001), and pathological subtype were independent predictors of worse OS. Specifically, compared to pure UC, UCSD (HR = 1.52, 95% CI: 1.18–1.96, P = 0.002) and SCC (HR = 1.78,95% CI: 1.25–2.54, P = 0.001) were independently associated with worse OS. Conclusions Patients with UCSD and SCC present with more advanced disease at diagnosis, leading to poorer unadjusted survival. After rigorous adjustment for key clinicopathological confounders, squamous differentiation remained an independent risk factor for worse overall survival following radical cystectomy, with both UCSD and pure SCC associated with significantly poorer prognosis compared to pure UC, whereas no significant difference existed between UCSD and SCC. These findings indicate that squamous differentiation confers an intrinsically more aggressive tumor biology that is not fully explained by stage or nodal status alone.

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