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Since 1995 it has been known that tumors harboring human papillomavirus (HPV) preferentially show basaloid or condylomatous histological features, while HPV-negative tumors have a different morphology. New classification models separate subtypes of penile squamous cell carcinomas in two groups, non–HPV- and HPV-related. It is purported that HPV-related tumors have better prognosis. Other features such as inflammatory cell–rich medullary, clear-cell, and lymphoepithelioma-like patterns are also strong predictors of the presence of HPV. These tumors are morphologically distinctive and with some experience, pathologists may recognize them after routine hematoxylin and eosin staining. Occasionally, p16 immunostaining may aid in differential diagnosis. The gold standard for HPV detection is polymerase chain reaction, but this technique is expensive and not available in most pathology laboratories. In …