Penile squamous cell carcinoma (PSCC) is a rare malignancy that may develop following persistent infection with human papillomavirus (HPV). The prognostic value of HPV status remains controversial.

To evaluate the impact of p16 status, a surrogate marker of high-risk HPV-driven carcinogenesis, and selected histopathological features on survival outcomes in PSCC, and to assess their interrelationships.

This retrospective single-center study included 87 patients treated for PSCC at Saint-Louis Hospital (Paris, France) between 2015 and 2024.

Associations between p16 status and histopathological features (pT stage, pN stage, tumor grade, lymphovascular invasion, and perineural invasion) were assessed using Chi-squared tests. Their impact on disease-specific survival (DSS) and overall survival (OS) was analyzed using Kaplan-Meier curves and log-rank tests.

Thirty-seven patients (43%) had p16-positive tumors. p16 status was not associated with tumor stage, nodal status, lymphovascular invasion, or perineural invasion. p16-positive tumors were significantly associated with higher histological grade ( P < 0.001). Factors associated with poorer 3-year DSS included nodal involvement (54.4 vs. 100%, P < 0.001), lymphovascular invasion (52.5 vs. 90.9%, P = 0.024), and perineural invasion (59.9 vs. 91.4%, p < 0.01). p16 status was not associated with DSS ( P = 0.68).

In this retrospective single-center cohort, p16 status was not significantly associated with DSS in univariate analysis. Nodal involvement, lymphovascular invasion, and perineural invasion were the variables most strongly associated with prognosis in the univariate analyses.

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