An etiology-focused overview of vulvar and penile squamous cell carcinoma and its precursors: similarities, differences and emerging concepts

Although rare, cancer of the vulva and penis have significant morbidity, mortality, and potentially psychologically distressing treatments. At both sites, squamous cell carcinoma (SCC) is the most common tumor type. Transitioning from classification systems reliant on histomorphology, two pathways of carcinogenesis are recognized in genital SCC based on human papillomavirus (HPV) infection status: HPV-associated and HPV-independent. Each pathway has unique etiology, pathology, molecular findings, and prognostic differences with clinically relevant outcomes. As more research comes to light, especially in vulvar pathology, a third potential pathway is emerging of HPV-independent, p53-wild type precursors and SCC. To familiarize pathologists with this group of diseases, we present an overview of HPV-associated and HPV-independent precursor lesions, as well as SCC, in both the vulva and penis.