Prognostic Factors of Survival in Patients with Surgically Treated Penile Squamous Cell Carcinoma: A Retrospective Cohort Analysis

<b>Background/Objectives</b>: Penile squamous cell carcinoma (PSCC) is a rare malignancy with a potential major impact on survival. Prognostic assessment remains challenging, particularly in underrepresented eastern European populations, where region-specific evidence is lacking. This paper aimed to identify independent predictors of overall survival in surgically treated patients with PSCC from a Romanian high-volume tertiary center. <b>Methods</b>: This retrospective cohort study analyzed 60 patients who were surgically treated for PSCC between October 2020 and December 2024. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors. <b>Results</b>: The mean patient age was 62 ± 12 years. T-stage distribution showed 30% pT1, 35% pT2, 31.67% pT3, and 3.33% pT4, with 55% of patients presenting with nodal metastases. Univariate analyses demonstrated significant associations between lymphovascular invasion (<i>p</i> < 0.001), perineural invasion (<i>p</i> = 0.022), and positive surgical margins (<i>p</i> = 0.030) and risk of death. Multivariate analysis identified three independent prognostic factors: absence of histologically documented urethral invasion (HR 0.32; <i>p</i> = 0.027), T3-T4 disease (HR 8.26; <i>p</i> = 0.005 vs. T1), and N3 stage (HR 3.53; <i>p</i> = 0.030 vs. N0-N1). Patients without urethral invasion demonstrated significantly longer median overall survival (63 months vs. 11 months). The final three-variable prognostic model demonstrated good discrimination (C-index 0.78), providing a potential practical risk stratification tool. <b>Conclusions</b>: Urethral invasion, advanced T-stage, and N3 disease independently predict poor survival in surgically treated PSCC. The identification of urethral invasion as an independent prognostic factor warrants consideration in clinical practice. This is the first study of a Romanian cohort to provide critical data for risk-adapted treatment strategies in underrepresented eastern European populations.