Intraepithelial Penile Lesions

Intraepithelial penile lesions encompass non-neoplastic and preneoplastic lesions. Non-neoplastic lesions comprise condyloma acuminatum, including giant condyloma acuminatum, also known as Buschke-Löwenstein tumor. It is usually the low-risk human papillomavirus (HPV) types 6 and 11 that are most prevalent in penile condylomas. However, high-risk HPV types can be detected along with low-risk types in a subset of patients. Penile intraepithelial neoplasia (PeIN) is a preneoplastic lesion that is either HPV-associated or HPV-independent. HPV-associated PeIN represents the majority of PeIN in regions where the incidence of penile cancer is lower, as in North America and Europe. HPV-associated PeIN is subdivided into basaloid, warty, and mixed subtypes and, less commonly, into pagetoid, clear-cell, and spindle-cell subtypes based on morphologic characteristics. HPV-associated PeIN is positive for immunohistochemical stain p16 and high-risk HPV in situ hybridization (ISH). Immunohistochemical stain p53 usually exhibits a wild-type staining pattern. HPV-independent PeIN/differentiated PeIN is more frequent in countries with a high incidence of penile cancer and an uncircumcised population. It is usually associated with predisposing factors like lichen sclerosus and chronic inflammatory conditions such as lichen planus, lichen simplex chronicus, and phimosis. The degree of atypia in differentiated PeIN ranges from subtle to full-thickness proliferation of markedly atypical pleomorphic cells. Many cases are associated with TP53 mutations and other alterations involving PIK3CA and HRAS. Recently, it has been proposed to further subclassify differentiated PeIN. Extramammary Paget disease (EMPD) can involve the skin of the penis and glans mucosa in elderly men. It is either primary or secondary, and when secondary, it can be associated with prostate or urothelial carcinoma. Lastly, rare case reports of primary penile melanoma in situ have been reported. The lesions can involve either the skin or mucosa, with the glans penis being the most commonly reported site.