Molecular landscape of vulvar squamous cell caricnoma: review of the literature

Introduction/Background* Molecular landscape and carcinogenesis of vulvar squamous cell carcinoma (VSCC) have been poorly explored and lack a biomarker-driven targeted therapy. In this non-systematic review we aimed to summarize findings of studies exploring molecular landscape of VSCC. Methodology Key word search was conducted (PubMed, Scopus) in January 2021, using the terms (“vulvar” and “cancer” or “carcinoma”) and (“molecular” or “genomic” or “mutation”). Observational studies evaluating molecular alterations in VSCC were deemed eligible. Pre-specified data were extracted from the selected articles, including the number of samples analyzed, DNA sequencing technique, number and frequency of identified mutations, HPV prevalence and prognostic data. Result(s)* Fourteen studies published between 2005 and 2020 were identified, including a total of 747 VSCC samples. Selected studies were highly heterogeneous in terms of DNA sequencing and HPV testing strategies and included small samples. Twelve studies performed next generation sequencing (NGS), nine of whom used targeted approach, two used whole exome sequencing and one used whole genome sequencing. The two remaining studies used multiplex ligation-dependent probe amplification assay and Sanger sequencing. The most frequently studies and mutated genes were TP53 and CDKN2A, followed by PIK3CA, HRAS and PTEN (table 1). Evidence on genomic differences between HPV-associated and -independent VSCC is particularly scarce and variable between studies. Only a single, targeted NGS study showed notorious differences in molecular profiles based on HPV status. Accumulated evidence indicates that in HPV-associated VSCC more frequently involves PI3K/AKT/mTOR pathway, involving HRAS, KRAS, PIK3CA, KMT2D, PTEN and FBXW7 mutations. On the other hand, HPV-independent VSCC involve alterations in TP53, CDKN2A, CCND1. The prognostic role of molecular alterations in VSCC was assessed in seven articles, with discordant results. Some articles suggest that TP53 alterations are associated to worse prognosis in patients with VSCC, particularly when combined with PIK3CA, HRAS or CDKN2A. Conclusion* Limitations and heterogeneity of available molecular series contribute to a limited view of the molecular landscape of VSCC. Prognostic or therapeutic roles of identified mutations and pathways in VSCC remain to be elucidated. Large-scale, genome or exome-wide studies with robust HPV testing are necessary to expand the knowledge on molecular landscape in VSCC.