A heterogeneous spectrum of epithelial alterations and atypical lesions affect the squamous epithelium of penile mucosal anatomical compartments. Analogous to other genital sites, the terminology utilized to define the lesions is variable. The few pathologic studies of penile precancerous lesions are mostly related to carcinoma in situ and human papilloma Virus (HPV), and the information on low-grade atypical lesions is limited. The objective of this study was to comprehensively describe the morphologic features of all epithelial alterations, benign and atypical, low grade and high grade, associated with invasive squamous cell carcinoma of the penis and to investigate their relation with each other and with subtypes of invasive carcinoma. We also propose herein a simple and reproducible nomenclature for penile precancerous abnormalities until more biological, molecular, or epidemiologic information on the lesions is available. Two hundred and eighty-eight penectomy and circumcision specimens with invasive squamous cell carcinoma were pathologically evaluated. Carcinomas were classified as usual, verrucous, papillary not otherwise specified, warty (condylomatous), basaloid, and mixed. Associated lesions were classified as squamous hyperplasia and squamous intraepithelial lesions of low and high grade (LGSIL and HGSIL). In LGSIL, atypia was confined to the lower third, and in HGSIL, atypical cells affected at least two thirds of the squamous epithelium. Subtypes of SIL were squamous, warty, basaloid, warty-basaloid, and papillary. Squamous hyperplasia, the most common lesion, was found in 83% of the cases, followed by LGSIL (59%) and HGSIL (44%). In 62% of the cases more than 1 associated lesion was present per specimen. A sequence from squamous hyperplasia to low-grade to high-grade SIL was seen frequently. Squamous hyperplasia was more commonly associated with usual squamous, papillary, and verrucous than with warty and basaloid invasive carcinomas. LGSIL was associated with all types of squamous cell carcinoma but was rarely present adjacent to basaloid or verrucous tumors. HGSIL was present in two thirds of invasive warty, basaloid, and mixed warty-basaloid tumors, in about half of usual squamous cell carcinomas, and was absent in papillary and verrucous carcinomas. Correlation of special types of invasive carcinomas with subtypes of SIL revealed morphologic correspondence of invasive tumor and the associated intraepithelial lesion. Squamous LGSIL was preferentially associated with verrucons, papillary, an usual squamous cell carcinomas; warty LGSIL, with invasive warty and mixed warty-basaloid carcinomas. High-grade SIL of the squamous type was frequently found in squamous cell carcinoma of usual type but was rarely present with warty or basaloid carcinomas. Basaloid HGSIL was associated with basaloid carcinoma, and HGSIL of warty type, with either warty or mixed warty-basaloid carcinomas. The high frequency of squamous hyperplasia and LGSIL and preferential association with usual, verrucous, and papillary carcinomas plus the subtle morphologic differences of the 2 lesions suggest that, despite its benign appearance, squamous hyperplasia is a precursor of the aforementioned carcinomas. The association and histologic similarities between high-grade SIL of the basaloid, warty, or mixed forms with their invasive counterparts indicate these lesions are their likely precursors.
