Pathogenesis of Penile Squamous Cell Carcinoma: Molecular Update and Systematic Review

Abstract

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.

Keywords: HPV; genomic landscape; molecular analysis; next generation sequencing; penile cancer; penile squamous cell carcinoma; whole-exome sequencing.

Figure 1

A characteristic example of each of the two types of penile squamous cell carcinoma, HPV-associated and HPV-independent. (A) Penile squamous cell carcinoma (H&E 40×) with positive p16 (B) and wild-type p53 immunohistochemical stainings (C) (40×); (D) Penile squamous cell carcinoma (H&E 40×) with negative p16 (E) and mutated pattern (diffuse overexpression) of p53 immunohistochemical stainings (F) (40×).

Figure 2

Flowchart with outline of search results and study selection process.

Figure 3

Geographical distribution of the selected study series and the number of patients from each country involved.