TERT promoter mutations in penile squamous cell carcinoma: high frequency in non-HPV-related type and association with favorable clinicopathologic features

Sang Kyum Kim,Jae Ho Han,Ji Su Kim,Se Joong Kim,Ji Eun Kwon,Nam Hoon Cho,Seol Ho Choo,Bumhee Park,Jang-Hee Kim,Sun Il Kim

doi:10.1007/s00432-021-03514-9

Abstract

PurposePenile carcinoma is a rare malignant neoplasm with a largely unknown molecular pathogenesis. Telomerase reverse transcriptase promoter (TERT-p) mutations have been detected in several types of human malignancies. The aim of this study was to investigate the presence of TERT-p mutations in penile squamous cell carcinomas (SCCs) and their associations with clinicopathologic features.MethodsIn this retrospective study, Sanger sequencing was performed to detect TERT-p mutations in formalin-fixed paraffin-embedded tissue samples from 37 patients with penile SCC, 16 patients with cutaneous SCC, and 4 patients with non-neoplastic penile/skin tissue. The expression of p16INK4a and Ki-67 was investigated via immunohistochemistry. Associations of TERT-p mutation with clinicopathological factors, immunohistochemical results, and clinical outcome were statistically analyzed.ResultsRecurrent TERT-p mutations were identified in 18 out of 37 (48.6%) penile SCCs, including all 3 carcinoma in situ cases. TERT-p mutations were significantly more frequent in non-human papilloma virus (HPV)-related penile SCC types than in non-HPV-related penile SCC based on both histologic classification and p16INK4a immunoreactivity. Furthermore, TERT-p mutation was associated with a low histologic grade, low mitotic count, absence of necrosis, low Ki-67/MIB-1 labeling index, and absence of lymph node or distant metastasis.ConclusionOur study shows TERT-p mutations are the most frequent somatic mutations in penile SCC. In addition, TERT-p mutations are far more frequent in non-HPV-related penile SCC than in HPV-related penile SCC, indicating TERT-p mutations may have a role in tumorigenesis distinct from HPV-related penile SCC.

Highlights

Penile carcinoma is a rare malignant neoplasm with an incidence of 1–4 per 100,000 in developing countries and is even rarer in developed countries (Rubin et al 2001)
We here provide the first report of Telomerase reverse transcriptase promoter (TERT-p) mutation and its clinicopathologic significance in penile squamous cell carcinomas (SCCs)
TERTp mutations were detected at a high frequency (48.6%) in penile SCC, which, to our knowledge, are the most frequent mutations in penile SCC described to date (Ferrandiz-Pulido et al 2015)

Summary

Introduction

Penile carcinoma is a rare malignant neoplasm with an incidence of 1–4 per 100,000 in developing countries and is even rarer in developed countries (Rubin et al 2001). Penile carcinomas are classified into two distinct groups based on clinicopathologic characteristics and an association with HPV infection: human papilloma virus (HPV)-related and non-HPV-related type (Mannweiler et al 2013). HPV high-risk (HPV-HR) DNA is detected in 20–80% of penile carcinomas, and plays a role in the carcinogenesis of HPV-related penile SCC (Spiess et al 2016). The detection rates of HPV DNA vary depending on histologic subtypes (Cubilla et al 2016). The non-HPV-related penile SCC develops in the background of chronic inflammatory skin diseases such as lichen sclerosus and lichen planus. HPV-HR16 is known to be the most prevalent HPV DNA type in HPV-related penile SCC (Rubin et al 2001). p16INK4a protein, a cyclin-dependent kinase inhibitor, accumulates, which can be identified by p16INK4a immunohistochemistry (Aumayr et al 2013)

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