Answer: Clear cell carcinoma

Histology: The slides show a malignant neoplastic proliferation composed of polygonal tumor cells with well-defined cellular borders and clear, slightly granular, ample cytoplasm. Nuclear atypias are readily evident with nuclear pleomorphism, coarse chromatin, irregular nuclear membrane, and prominent nucleoli. Tumor nests are irregular with jagged contours. Foci of necrosis are easily found, mainly in the center of tumor nests.

Discussion: Clear cell carcinoma of the penis is a recently described HPV-related type of penile carcinoma with only a few cases reported in the literature. Is a distinctive clinicopathological entity characterized by a preferential foreskin location, a high metastatic rate, and a dismal prognosis compared to the usual variant of penile squamous cell carcinoma (SCC). The tumor cells are PAS/dPAS positive and also stain positively with MUC-1, EMA, and CEA. Clear cell carcinomas can be confused with other penile tumors depicting clear cell features, such as usual SCC and verruciform carcinomas, among others. Foci of clear cell changes can be found in an otherwise typical penile SCC but usually they are focal and limited to the superficial layers or central portions of an infiltrative nest. In these cases, nuclei do not show the atypical features of clear cell carcinomas and tend to be of low-grade. Verrucous, papillary, and pseudohyperplastic carcinomas can and do show focal clear cells with centrally located pyknotic nuclei, most frequently in tumor surface. Koilocytes, especially the pleomorphic ones observed in warty carcinomas, can also be taken as clear cells and, if extensive, suggest a clear cell carcinoma. To avoid this, morphological criteria for diagnosing koilocytes should be stringent: nuclear hyperchromasia, nuclear wrinkling, frequent bi or multinucleation, and presence of perinuclear halos. Also, papillomatosis is not a common finding in clear cell carcinomas while is a defining feature of warty SCC. In addition, foci of necrosis are extremely unusual in penile primary tumors except in sarcomatoid and, to a lesser extent, basaloid carcinomas, tumors in which clear cell features are not frequently found.

Other tumors with clear cell features that should be considered include sebaceous carcinoma, clear cell urothelial carcinoma of the distal urethra, and metastatic clear cell renal cell carcinoma. In cases of clear cell urothelial carcinoma there is usually a previous/concurrent history of urothelial carcinoma elsewhere, tumors are located in the meatal/perimeatal region (in contrast with the peripheral location of clear cell carcinomas), and areas of urothelial in situ carcinoma can be found. Urothelial markers such as uroplakin-III and thrombomodulin may be helpful in difficult cases. Metastatic clear cell renal cell carcinomas tend to be located in the penile shaft. An isolated and exclusively located foreskin location would be exceedingly rare for any secondary penile tumor. A concurrent/previous history of renal malignancy is common. In problematic cases immunohistochemistry for CD10, RCC, PAX2, PAX8 and CA9 (all positive in clear cell renal cell carcinomas) may be useful. Finally, sebaceous carcinomas originate in the outer foreskin, nuclei are smaller, and there is no evidence of HPV infection. In limited biopsies the clinical data, anatomical location of the tumor, and the positivity for PAS/dPAS, HPV and MUC-1 are useful in the differential diagnosis of clear cell carcinomas of the penis.