Pathological features, differential diagnosis, prognosis, and diagnostic challenges in the classification of penile squamous neoplasia

Approximately 50% of penile squamous cell carcinomas are of the usual (conventional) type, resembling their counterparts in the skin or other organs. The remaining half comprises a heterogeneous group of histological variants, some of which exhibit highly distinctive morphological features. Current classification models recognize more than 14 subtypes of penile squamous cell carcinoma. Pathological guidelines recommend histological subtyping of penile carcinomas in diagnostic reports. This practice is clinically significant because specific subtypes carry distinct prognostic implications. However, diagnostic challenges may arise in certain cases due to overlapping histological features. While most subtypes of penile intraepithelial neoplasia (PeIN) are readily identifiable, a subset of cases presents diagnostic challenges. A notable example is distinguishing benign condylomas from low grade minimally atypical warty PeIN. Among invasive carcinomas, the most significant diagnostic difficulties arise in classifying verruciform tumours, due to their overlapping morphological features. Warty carcinomas may simulate giant condylomas; verrucous carcinoma may simulate giant condylomas or Papillary NOS carcinomas. Conversely, this tumour may be confused with low grade warty carcinomas. With some experience, histological classification using H&E stain is possible in about 70% of the cases. The remainder 30%, however, presents diagnostic difficulties even for experienced pathologists. The use of immunostaining and HPV genotyping are crucial aids in the differential diagnosis. By describing and illustrating in detail their morphological features, suggesting treatment options, and emphasizing diagnostic difficulties in the differential diagnosis, we aimed to assist our colleagues in improving their penile neoplasia classification skills.