Synchronous Epidermodysplasia Verruciformis and Intraepithelial Lesion of the Vulva is Caused by Coinfection with α-HPV and β-HPV Genotypes and Facilitated by Mutations in Cell-Mediated Immunity Genes

Abstract

Abstract There have been exceedingly few reports of epidermodysplasia verruciformis (EV) or EV-like lesions in the vulva. We describe the first case series featuring vulvar lesions displaying synchronous EV-like histologic changes and conventional high-grade intraepithelial lesion (VIN 3), a finding hitherto unreported in medical literature. We hypothesized that this could be caused by coinfection with α-HPV and β-HPV genotypes. Cases were retrospectively selected from our institutional archive. Detailed review of clinical information, histologic examination and whole genome sequencing (WGS) were performed in 5 samples from 4 different patients. Three of four patients had a history of either iatrogenic immune suppression or prior immune deficiency, and all featured classic VIN 3 and EV changes within the same lesion. The fourth patient had no history of immune disorders, presented with EV-like changes and multinucleated atypia of the vulva, and was the sole patient without conventional high-grade intraepithelial lesion. By WGS, several uniquely mappable reads pointed towards infection with multiple HPV genotypes including both α-HPVs and β-HPVs. Mutations in genes implicated in cell-mediated immunity, such as DOCK8, CARMIL2, MST1 and others, were also found. Our findings provide novel insight into EV and HPV pathogenesis, vulvar precancerous lesions and expand the clinicopathological spectrum of genetic alterations linked to unconventional immune deficiencies.