BACKGROUND: HPV infection is implicated in approximately half of global penile squamous cell carcinoma (PSCC) cases. Previous studies on HPV DNA and p16INK4a status in PSCC have yielded inconclusive prognostic findings. This meta-analysis aims to elucidate the prognostic role of HPV in PSCC by pooling data on disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). METHODS: We systematically searched Medline and Embase up to January 2023 for relevant human studies. Data from eligible publications reporting HPV DNA or p16INK4a status, along with and DFS, DSS, or OS outcomes, were extracted. A random-effects meta-analysis model was used to synthesize data, with study weights based on size and significance. The study protocol was registered with PROSPERO (CRD42019131355). RESULTS: Out of 544 studies screened, 34 publications were included, comprising a pooled sample size of 3,944 patients. p16INK4a-positive status was associated with improved OS (hazard ratio [HR], 0.54
95% CI, 0.39-0.75
I2=31%), DFS (HR, 0.52
95% CI, 0.29-0.94
I2=20%), and DSS (HR, 0.34
95% CI, 0.23-0.50
I2=18%). HPV DNA positivity was significantly associated with improved DFS (HR, 0.63
95% CI, 0.46-0.87
I2=13%) and DSS (HR, 0.46
95% CI, 0.29-0.75
I2=47%) but not OS (HR, 0.92
95% CI, 0.74-1.11
I2=0%). CONCLUSIONS: This meta-analysis, comprising the largest number of patients with PSCC to date, shows a notable correlation between p16INK4a immunohistochemistry positivity and survival outcomes. These findings support the understanding that penile cancer cases not associated with HPV tend to behave more aggressively. We support p16INK4a immunohistochemistry testing as part of the initial diagnostic evaluation of patients with PSCC.