The role of histologic subtype, p16INK4a expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma

Background: Up to 50% of penile squamous cell carcinomas (pSCC) develop in the context of high-risk human papillomavirus (HR-HPV) infection. Most of these tumours have been reported to show basaloid differentiation and overexpression of tumour suppressor protein p16(INK4a). Whether HPV-triggered carcinogenesis in pSCC has an impact on tumour aggressiveness, however, is still subject to research. Methods: In tissue specimens from 58 patients with surgically treated pSCC between 1995 and 2012, we performed p16(INK4a) immunohistochemistry and DNA extraction followed by HPV subtyping using a PCR-based approach. The results were correlated with histopathological and clinical parameters. Results: 90.4% of tumours were of conventional (keratinizing) subtype. HR-HPV DNA was detected in 29.3%, and a variety of p16(INK4a) staining patterns was observed in 58.6% of samples regardless of histologic subtype. Sensitivity of basaloid subtype to predict HR-HPV positivity was poor (11.8%). In contrast, sensitivity and specificity of p16(INK4a) staining to predict presence of HR-HPV DNA was 100% and 57%, respectively. By focussing on those samples with intense nuclear staining pattern for p16(INK4a), specificity could be improved to 83%. Both expression of p16(INK4a) and presence of HR-HPV DNA, but not histologic grade, were inversely associated with pSCC tumour invasion (p = 0.01, p = 0.03, and p = 0.71). However, none of these correlated with nodal involvement or distant metastasis. In contrast to pathological tumour stage, the HR-HPV status, histologic grade, and p16(INK4a) positivity failed to predict cancer-specific survival. Conclusions: Our results confirm intense nuclear positivity for p16(INK4a), rather than histologic subtype, as a good predictor for presence of HR-HPV DNA in pSCC. HR-HPV/p16(INK4a) positivity, independent of histological tumour grade, indicates a less aggressive local behaviour; however, its value as an independent prognostic indicator remains to be determined. Since local invasion can be judged without p16(INK4a)/HPV-detection on microscopic evaluation, our study argues against routine testing in the setting of pSCC.