The prognostic role of HPV status in penile squamous cell carcinoma: a systematic review and meta-analysis

Penile squamous cell carcinoma (PSCC) is a rare but aggressive malignancy that can present as either Human papillomavirus (HPV)-associated or HPV-independent. Currently, there is no consensus on the prognostic value of HPV status in PSCC or its role in guiding treatment strategies. Therefore, in this systematic review and meta-analysis we aim to assess the impact of different methods of determining HPV status on cancer specific survival (CSS) and overall survival (OS) in patients with PSCC. Databases including MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched between 1980 and February 2025. Studies were eligible if they assessed HPV status using any method in PSCC patients and reported CSS or OS with a minimum follow-up of two years. Case reports, narrative reviews, expert opinions, and studies reporting less than 50 participants were excluded. Quality of included studies was assessed using the QUIPS tool. A total of 31 studies, published between 2001 and 2024, met the inclusion criteria, all of which were of retrospective design. High risk of bias (RoB) was noted for study attrition, prognostic factor measurement, and study confounding. Sample sizes ranged from 57 to 611 participants (median: 152 participants). HPV-status was assessed through DNA testing in 19 studies and 10 studies used p16 immunohistochemistry (IHC) as a surrogate marker of HPV-driven carcinogenesis. Four studies used both HPV DNA measurements and p16 IHC staining and two articles determined HPV status based on histological subtyping. Median follow-up was 49.9 months (range: 27-107.9 months). We identified 23 studies that reported sufficient data for inclusion in a meta-analysis, encompassing a total of 5291 men with various stages of PSCC. Of these, 1946 (36.8%) had HPV-associated disease. Positive p16 status was associated with improved CSS (HR = 0.40, 95% CI [0.20, 0.80], p = 0.009) and OS (HR = 0.49, 95% CI [0.29, 0.85], p = 0.01) in a pooled cohort of 1266 and 1189 patients respectively. HPV DNA positivity was associated with improved CSS (HR = 0.54, 95% CI [0.35, 0.83], p = 0.005), but not with OS (HR = 0.86 95% CI [0.70, 1.07], p = 0.17). In conclusion, p16 and HPV DNA positivity are associated with improved CSS in patients with PSCC. Positive p16 status was related to better OS, while HPV status based on DNA measurements was not. These findings underscore the prognostic value of p16 and HPV status.