Metachronous nodal metastases from HPV-associated penile carcinoma in situ.

Penile intraepithelial neoplasia (PeIN) is a premalignant precursor of squamous cell carcinoma (SCC) with a 5-15 % risk of progression. Nodal metastasis without histologic invasion is exceedingly rare. We describe a 40-year-old man with recurrent, HPV-positive basaloid PeIN of the glans and distal urethra who developed right inguinal and pelvic nodal metastases despite serial resections consistently showing carcinoma in situ. Genomic profiling revealed EGFR and JUN amplifications with NCOR1 and PRKAR1A losses, alterations linked to aggressive tumor biology. This case highlights the paradoxical metastatic potential of high-grade PeIN and underscores the need for molecular risk stratification in surveillance and management.