[Update on the pathologic features of penile cancer]

Penile squamous cell carcinoma (SSC) accounts for almost 10% of male cancers in high-incidence areas, although the incidence in Europe is below 1%. About half of penile SCCs arise from a precancerous high-grade squamous intraepithelial lesion (HSIL) caused by a transforming infection with human papillomavirus (HPV), most often high-risk HPV16. The HPV E6/E7 oncoproteins bind to proteins of the p53 and retinoblastoma pathways. This cell cycle disruption results in cellular accumulation/overexpression of p16, which serves as surrogate biomarker for HPV-associated carcinogenesis. The majority of HPV-independent SCCs arise in lesions of lichenoid dermatoses (lichen sclerosus and lichen planus) via rapidly progressing precancerous differentiated penile intraepithelial neoplasms (d-PeIN). These inflammation-associated, generally highly differentiated keratinized lesions commonly carry mutations in the tumor suppressor genes TP53 and CDKN2A. Missense TP53 mutations lead to accumulation of p53/agerrant p53 in the nuclei of proliferating tumor cells (nuclear overexpression), which serves as a surrogate marker for a TP53 missense mutation. About one third of HPV-independent penile SCCs arise in the absence of dermatoses and mutations in tumor suppressor genes and lack p16 and p53 overexpression. They arise via verrucous/verruciform PeIN. Correct identification of the etiology of precursor lesions is of clinical significance, as HPV-associated SCCs have better prognoses and survival rates. Moreover, the etiology is particularly relevant to the choice of treatment for the precancerous lesion. The slow progression of HSIL to invasive cancers allows time-intense surgical, destructive, or drug-based treatment options. In contrast, the precursor lesion of dermatoses-associated SCC, d‑PeIN, calls for immediate surgical resection to exclude early invasion. Guideline-conform treatment of lichenoid dermatoses reduces the cancer risk.