Context.—

Penile squamous cell carcinomas (PSCCs) are divided into tumors that are human papillomavirus (HPV) associated and those that are non–HPV associated. HPV and non-HPV PSCCs each display unique pathogenic mechanisms, histologic subtypes, and clinical behaviors. Treatment of localized PSCC tumors is linked to significant physical and psychological morbidity, and management of advanced disease is often treatment refractory. The identification of novel actionable mutations is of critical importance so that translational scientists and clinicians alike can pursue additional therapeutic options.

Objective.—

To provide an update on the molecular pathogenesis associated with PSCC. A special emphasis is placed on next-generation sequencing data and its role in identifying potential therapeutic targets.

Data Sources.—

A literature review using the PubMed search engine to access peer-reviewed literature published on PSCC.

Conclusions.—

Our understanding of the genetic and molecular mechanisms that underlie PSCC pathogenesis continues to evolve. PSCC tumorigenesis is mediated by multiple pathways, and mutations of oncogenic significance have been identified that may represent targets for personalized therapy. Preliminary results of treatment with immune checkpoint inhibition and tyrosine kinase inhibitors have produced variable clinical results. Further insight into the pathogenesis of PSCC will help guide clinical trials and develop additional precision medicine approaches.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.