Abstract
BackgroundUp 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 p16INK4a. Whether HPV-triggered carcinogenesis in pSCC has an impact on tumour aggressiveness, however, is still subject to research.MethodsIn tissue specimens from 58 patients with surgically treated pSCC between 1995 and 2012, we performed p16INK4a immunohistochemistry and DNA extraction followed by HPV subtyping using a PCR-based approach. The results were correlated with histopathological and clinical parameters.Results90.4% of tumours were of conventional (keratinizing) subtype. HR-HPV DNA was detected in 29.3%, and a variety of p16INK4a 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 p16INK4a staining to predict presence of HR-HPV DNA was 100% and 57%, respectively. By focussing on those samples with intense nuclear staining pattern for p16INK4a, specificity could be improved to 83%. Both expression of p16INK4a 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 p16INK4a positivity failed to predict cancer-specific survival.ConclusionsOur results confirm intense nuclear positivity for p16INK4a, rather than histologic subtype, as a good predictor for presence of HR-HPV DNA in pSCC. HR-HPV / p16INK4a 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 p16INK4a/HPV-detection on microscopic evaluation, our study argues against routine testing in the setting of pSCC.
Highlights
Up to 50% of penile squamous cell carcinomas develop in the context of high-risk human papillomavirus (HR-Human papillomavirus (HPV)) infection
Integration of high-risk human papillomavirus (HR-HPV) DNA into the host cell genome leads to overexpression of viral oncoproteins E6 and E7 that exert a dysregulating effect on cell cycle control [6]; upregulation of tumour suppressor protein p16INK4a is understood as an attempt to stop uncontrolled cell proliferation in response to HPV infection [7]
On the other hand, published data suggests a role for HPV-16 E6/E7 oncoproteins in the induction of epithelial-mesenchymal transition which may contribute to cell migration and metastasis [13,14]
Summary
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 p16INK4a. We did not detect HPV DNA in 29 samples of urothelial carcinoma in situ despite diffuse intense confluent staining pattern for p16INK4a [10]. Concerning prognosis, HPV-driven squamous cell carcinomas of the head and neck region (HNSCCs) are associated with significantly improved progression-free survival and disease-free survival [12]. We analysed pSCC tissue samples for expression of p16INK4a and presence of HPV DNA and correlated the results with tumour- and patient-specific characteristics as well as cancer-specific survival. We analysed the impact of HPVdriven tumourigenesis on cancer-specific survival in pSCC patients
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