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

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.

TERT Promoter Mutations in Penile Squamous Cell Carcinoma: High Frequency in Non-HPV-related Type and Association With Favorable Clinicopathologic Features

“…However, in contrast to these previous reports, we found a correlation between TERT-p mutation with favorable clinicopathologic parameters in penile SCC, including a low histologic grade, low mitotic count, absence of necrosis, and low MIB-1 index. These results are in line with the fact that TERT-p mutations were more frequently detected in non-HPV-related tumors, which are generally low-grade tumors with low mitotic activities [48]. Similarly, the tumors in non-HPV-related penile SCC tend to be larger than those in the HPV-related type, which may explain the correlation between TERT-p mutant type and larger tumor size.…”

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

“…Several risk factors have been identified in PeCa etiology, including poor penile hygiene, phimosis and human papillomavirus (HPV) infection [4, 5]. A recent analysis of cancer registries showed that PeCa patient survival has not improved in Europe nor United States in the last 20 years [6].…”

Bedeutung von p16(INK4A) hinsichtlich des Nachweises von HPV-DNA und in der Stratifizierung der tumorspezifischen Mortalität bei 34 Patienten mit invasivem Peniskarzinom in Langzeit-Nachbeobachtung

“…Als entscheidender Nachteil der ISH in der Detektion von HPV-DNA wird die eingeschränkte Sensitivität angegeben [15]. Die Hochregulation des Tumorsuppressorproteins p16 INK4a (und der damit verbundene immunhistochemische Nachweis) wird als ein Versuch der Tumorabwehr gesehen, die mit der HPV-Infektion einhergehende unkontrollierte Zellproliferation zu unterbinden (u. a. durch Hemmung der onkogenen Transkription) [7,16]. Der immunhistochemische Nachweis von p16 INK4a wird demnach als Surrogatmarker für eine HPV-Infektion des Hochrisikotyps bei Patienten mit Peniskarzinom genutzt [7,10,16].…”

“…Die Hochregulation des Tumorsuppressorproteins p16 INK4a (und der damit verbundene immunhistochemische Nachweis) wird als ein Versuch der Tumorabwehr gesehen, die mit der HPV-Infektion einhergehende unkontrollierte Zellproliferation zu unterbinden (u. a. durch Hemmung der onkogenen Transkription) [7,16]. Der immunhistochemische Nachweis von p16 INK4a wird demnach als Surrogatmarker für eine HPV-Infektion des Hochrisikotyps bei Patienten mit Peniskarzinom genutzt [7,10,16]. Durch unsere Arbeitsgruppe wurde in einer früheren Arbeit für PSCC-Patienten mit p16 INK4a -Expression eine vergleichsweise geringere karzinomspezifische Mortalität (CSM) beschrieben; insgesamt sind die verfügbaren Daten hierzu jedoch inkonsistent [8 -11, 16].…”

“…Durch unsere Arbeitsgruppe wurde in einer früheren Arbeit für PSCC-Patienten mit p16 INK4a -Expression eine vergleichsweise geringere karzinomspezifische Mortalität (CSM) beschrieben; insgesamt sind die verfügbaren Daten hierzu jedoch inkonsistent [8 -11, 16]. Neben dem histologischen Subtyp wurdenin Analogie zu den Patienten mit HPV-bedingtem Oropharynx-und Zervixkarzinomdie histologischen Kriterien Tumorinvasionsfront und Koilozytose-Status in den Kontext einer HPV-Karzinogenese gesetzt [6,10,16,17].…”