Morphologic and Molecular Heterogeneity of Cervical Neuroendocrine Neoplasia

Abstract

Neuroendocrine neoplasms (NENs) of the cervix are rare aggressive tumors associated with poor prognosis and only limited treatment options. Although there is some literature on molecular underpinnings of cervical small cell neuroendocrine carcinomas (SCNECs), detailed morphologic and associated molecular characteristics of cervical NENs remains to be elucidated. Herein, 14 NENs (SCNEC: 6, large cell neuroendocrine carcinoma [LCNEC]: 6, neuroendocrine tumor [NET]: 2), including 5 admixed with human papillomavirus (HPV)-associated adenocarcinoma (carcinoma admixed with neuroendocrine carcinoma) were analyzed. All except 3 SCNECs were HPV16/18 positive. TP53 (3) and/or RB1 (4) alterations (3 concurrent) were only seen in SCNECs (4/6) and were enriched in the HPV16/ 18-negative tumors. The other most common molecular changes in neuroendocrine carcinomas (NECs) overlapping with those reported in the literature for cervical carcinomas involved PI3K/ MAPK pathway (4) and MYC (4) and were seen in both SCNECs and LCNECs. In contrast, the 2 NETs lacked any significant alterations. Two LCNECs admixed with adenocarcinoma had enough material to sequence separately each component. In both pathogenic alterations were shared between the 2 components, including ERBB2 amplification in one and an MSH6 mutation with MYC amplification in the other. Overall, these findings suggest that cervical HPV-associated NETs are genomically silent and high-grade NECs (regardless of small or large cell morphology) share molecular pathways with common cervical carcinomas as it has been reported in the endometrium and are different from NECs at other sites. Molecular analysis of these highly malignant neoplasms might inform the clinical management for potential therapeutic targets.

Multiomics sequencing and immune microenvironment characteristics define three subtypes of small cell neuroendocrine carcinoma of the cervix

“…RB1 mutations were not consistent in all the studies. Only one study showed a 66.7% RB1 alteration in SCCC; others varied from 0% to 10% [13,17,18,20,21,28–30,58]. RB1 alterations decreased overall survival in a recent study [59].…”

The impact of neo/adjuvant treatment choices on prognosis for surgically treated small-cell neuroendocrine carcinoma of the cervix

“…Cervical small cell neuroendocrine carcinoma has similar HPV infection status [16] and gene mutations [17][18][19] compared to more common cervical epithelial tumors but it has a higher proportion of lymph node metastasis, poorer treatment response, and survival prognosis. A large population-based analysis from NCDB revealed patients with cervical neuroendocrine carcinoma were younger and more often diagnosed with metastatic disease at presentation compared to patients with squamous cancer.…”

Mixed mucinous adenocarcinoma/large cell neuroendocrine carcinoma of the uterine cervix: case report and molecular characterization of a rare entity

“…The molecular profile of uterine cervix MiNEN is also poorly studied; to the best of our knowledge, there are no systematic studies on larger number of patients and only few reported cases in small series are available [ 6 , 8 , 12 , 15 , 16 ]. Our molecular analysis found that the adenocarcinomatous component of the neoplasm carried GNAS mutation,in fact GNAS mutations have been reported in numerous tumors of the gastrointestinal tract and also in endocervical mucinous adenocarcinoma [ 14 ].…”

“…In 2020 Eskander and colleagues [ 7 ] studied a large cohort of patients with high-grade cervical neuroendocrine carcinomas; they found that the most frequent altered genes were PIK3CA , MYC, TP53 , and PTEN and that the main interested pathways were PIK3CA/AKT/mTOR and RAS/MEK . In a recent work, Ordulu and colleagues found a similar set of mutations in a series of 14 NEN of the cervix, also including RB1 and MSH6 genes mutations [ 16 ]. However, ERBB2 mutations involving cervical neuroendocrine carcinomas are rarely reported in literature [ 5 , 21 ].…”