Human Papilloma Virus 18-Positive Submucosal Small Cell Neuroendocrine Carcinoma of the Vagina: An Immunohistochemical and Genomic Study

Abstract

Primary vaginal neuroendocrine carcinoma (NEC) is extremely rare among female genital tract tumors. Here, we report 2 cases of vaginal small cell NEC (SCNEC) using immunohistochemistry and next-generation sequencing (NGS) analysis. The 2 patients were in their mid-to-late 70s, presented with abnormal vaginal bleeding and had a vaginal submucosal mass. The biopsied or resected tumors showed a typical neuroendocrine morphology consisting of solid nests of atypical tumor cells, with no specific organoid patterns, and proliferating in the vaginal submucosa. Immunohistochemical analysis showed strong and diffuse expression of chromogranin A, synaptophysin, and p16, but no thyroid transcription factor 1 expression. Additionally, both cases were positive for human papillomavirus (HPV) 18. An NGS-based cancer panel analysis revealed that the tumors carried NF1 and AR mutations, but no major driver mutations were detected. The results of this study suggested that HPV18 infection is linked to vaginal SCNEC.

Small Cell Carcinoma of the Vagina: First Systematic Review of Case Reports and Proposal of a Management Algorithm

“…The 3 cases HPV18+ positive were reported to be p16+ with a diffuse pattern in the immunochemistry study. Moreover, 2 of them 6 were studied by next-generation sequencing analysis of a panel of 60 major cancer-related genes, finding low tumour mutational burden (TMB), low microsatellite instability score, and no TP53 (tumor protein p53) or retinoblastoma gene mutations in both cases. One of them harbored a mutation in NF1 (neurofibromatosis type 1) gene (NF1 p.T4671) and the other case harbored a mutation in AR (androgen receptor) gene (AR p.C327Y).…”

“…Only 5 cases were reported to be tested for HPV: 1 negative, 7 1 positive for a high-risk type different to 16–18 (not specified), 13 and 3 positive for 18 type (2 cases reported in 2021 6 and our case). The 3 cases HPV18+ positive were reported to be p16+ with a diffuse pattern in the immunochemistry study.…”

“…The first communicated attempt analyzed 2 HPV18-related SmCCV with a limited next-generation sequencing panel and found mutations only in NF1 gene (case 1) and AR gene (case 2) and showed TMB-low and microsatellite stability in both cases. 6 On the contrary, molecular studies of limited series of SmCCC found driver mutations in MAPK, PI3K/AKT/mTOR, TP53, ATRX, ERBB4, and BRCA pathways. 56 , 57 On the other hand, the partial molecular profile overlap found between SmCCC and SmCLC 58 , 59 revealed different but convergent pathogenesis 60 and strongly supports the development of similar therapeutic strategies for both entities.…”

“…A comprehensive molecular characterization of SmCCV would also be of interest to discover potential druggable targets. The first communicated attempt analyzed 2 HPV18-related SmCCV with a limited next-generation sequencing panel and found mutations only in NF1 gene (case 1) and AR gene (case 2) and showed TMB-low and microsatellite stability in both cases 6 . On the contrary, molecular studies of limited series of SmCCC found driver mutations in MAPK, PI3K/AKT/mTOR, TP53, ATRX, ERBB4, and BRCA pathways 56,57 .…”

“…First reported case dates from 1984 5 and the last one was reported in December 2021. 6 Data regarding pathological and clinical features, as well as medical management approaches and outcomes, were extracted. Progression-free survival (PFS) was lacking in many reports.…”