Spectrum of Human Papillomavirus (HPV)-Related Penile Cancer

Penile squamous cell carcinomas (pSCC) are broadly divided into two subgroups based on their etiopathogenesis: Human Papillomavirus (HPV)-associated and HPV-independent. HPV-associated pSCC is driven by high-risk HPV and commonly overexpresses p16 by immunohistochemistry (IHC), making it a widely used surrogate for HPV presence. HPV-associated pSCC encompasses multiple histologic subtypes, including basaloid, warty, mixed (warty-basaloid), clear cell, lymphoepithelioma-like, and medullary carcinomas. Although most of these have a distinct morphology, a "block" or "diffuse" staining pattern of p16 IHC is recommended for categorically classifying them as HPV-associated pSCC. Molecular diagnostics (e.g., HPV DNA or RNA assays) are rarely employed for the classification of pSCC. The prognostic relevance of HPV status and p16 overexpression remains under investigation, but preliminary findings suggest that HPV-associated / p16-positive tumors may have a more favorable prognosis, with better survival outcomes, and may also dictate the choice of therapy in advanced cases. Larger multicentric datasets from regions of higher incidence, harmonized criteria for p16 IHC interpretation, and standardized HPV detection methods are needed to further understand the utility of these biomarkers in pSCC. Finally, the relevance and impact of HPV vaccination on HPV-associated pSCC are not well documented, largely because male vaccination is not yet accepted globally.