Human Papilloma Virus, Histopathological, and Molecular Subtyping in Penile Cancer: Relevance for Prognosis and Therapy

Context: Based on the new 2016 World Health Organization classification, penile carcinomas are subdivided into several histopathological subtypes which are associated with human papilloma virus (HPV) infection status. Objective: The primary objective of this review is to describe the subtyping of penile carcinomas according to the new World Health Organization classification based on HPV infection status and histopathological features and to correlate this to patient outcome. In addition, the current knowledge about the role of HPV infection in tumorigenesis as well as relevant molecular alterations will be presented. Evidence acquisition: A systematic literature search was conducted using PubMed to identify original articles, review articles regarding penile cancer/carcinoma, HPV, histopathological subtypes, prognosis, and molecular alterations. Articles published between 1989 and 2017 were reviewed and selected with the consensus of all the authors. Evidence synthesis: Penile squamous cell carcinomas (SCC) are the most common penile tumours. They are divided into HPV-related and HPV-unrelated subtypes based on the frequency of high-risk HPV infection. Histopathological subtype but not the HPV-status alone is associated with clinical outcome. High-risk HPV infection occurs in about 50% of penile SCC and varies worldwide. Although some specific molecular alterations including copy number alterations or mutations (most frequently CDKN2A and p53) and changes in signalling pathways could be identified, molecular pathogenesis considering HPV infection is not fully understand. Conclusions: The histopathological subtype should be documented and considered for prognostic evaluation in patients with penile SCC. The prognostic value of HPV infection has to be investigated in larger cohorts considering the histopathological subtype. Further molecular studies have to identify relevant molecular subtypes and to develop type-specific targeted therapies. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.