International Society of Urological Pathology (ISUP) Multidisciplinary Consensus on Premalignant and Putative Precursor Lesions of Penile Cancer: Working Group 5 report on Terminology, Grading, and Molecular Testing Practices

The classification and diagnosis of penile intraepithelial neoplasia (PeIN) remains inconsistent among pathologists, despite its recognized role and understanding as a precursor to penile squamous cell carcinoma (PSCC). The International Society of Urological Pathology (ISUP) convened a consensus group of multidisciplinary thought leaders to assess current global practices regarding the usage of terminology, grading, and molecular testing in penile cancer precursor lesions. A preconference survey was distributed to ISUP members in 2024, collecting responses from 112 pathologists, predominantly genitourinary specialists, to evaluate the use of penile cancer precursor lesion classification systems, grading approaches, and diagnostic biomarkers. The results were presented at the ISUP Multidisciplinary Consensus Conference on Cancer Precursor Lesions in September 2024, where further consensus was achieved through electronic voting. The survey revealed that 89.4% of respondents classify PeIN based on HPV association, with 76% supporting further subtyping into basaloid, warty, and differentiated subtypes. Grading of PeIN remains controversial; 51.3% initially favored grading, but 82% finally voted that PeIN should not be graded. p16 immunohistochemistry (IHC) was widely utilized (91.5%) to distinguish HPV-associated from HPV-independent PeIN, whereas p53 IHC and HPV genotyping lacked consensus for routine use. Reporting practices for PeIN margins and their association with lichen sclerosis were widely endorsed, while the value and concordance of subtyping HPV-independent PeIN remains an area for further investigation. This ISUP consensus paper guides PeIN classification, confirming the importance of HPV-related stratification and p16 IHC staining and reporting as standard practice. However, significant variability persists in PeIN grading and molecular testing strategies. These findings highlight the need for further research and standardization to optimize diagnostic accuracy and clinical relevance in PeIN.