Mixed Adenoneuroendocrine Carcinomas of the Gastrointestinal Tract: Targeted Next-Generation Sequencing Suggests a Monoclonal Origin of the Two Components

Abstract

Background: Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract are rare neoplasms characterized by coexisting exocrine and neuroendocrine neoplastic components. MANECs' histogenetic classification and molecular characterization remain unclear, significantly affecting the identification of innovative therapeutic options for these tumors. Methods: The exocrine and neuroendocrine components of 6 gastrointestinal MANECs were microdissected and subjected to the simultaneous mutation assessment in selected regions of 54 cancer-associated genes using Ion Torrent semiconductor-based next-generation sequencing. Sanger sequencing and immunohistochemistry were used as validation of the mutational status. Results: A total of 20 driver gene somatic mutations were observed among the 12 neoplastic components investigated. In 11 of 12 (91.7%) samples, at least one mutation was detected; 7 samples (58.3%) were found to have multiple mutations. TP53 gene mutations were the most frequent genetic alterations observed in the series, occurring in 11/12 samples (91.7%). Somatic mutations in other genes were detected at lower frequencies: ATM, CTNNB1, ERBB4, JAK3, KDR, KRAS, RB1. Conclusions: Five of the 6 MANECs presented an overlapping mutational profile in both components, suggesting a monoclonal origin of the two MANEC components.

Clinicopathological features and outcome for neuroendocrine neoplasms of gastroesophageal junction: A population‐based study

“…Because inadequate understanding of GEJ‐NENs, it is controversial of the prognostic value of their histologic classification. Compared with the adenocarcinoma, NEC was more aggressive with poorly differentiated morphology . Shia et al reported the absence of an associated adenocarcinoma component was predictive of a worse outcome; however, previous studies about gastric or colorectal MANEC reported that there was no statistically significant difference in survival between MANECs and NEC .…”

“…Compared with the adenocarcinoma, NEC was more aggressive with poorly differentiated morphology. 16 Shia et al reported 17 the absence of an associated adenocarcinoma component was predictive of a worse outcome; however, previous studies about gastric or colorectal MANEC reported that there was no statistically significant difference in survival between MANECs and NEC. 18,19 In our cohort, a number of GEJ-NECs were mixed with high grade adenocarcinoma, the outcome of which was better than pure NECs.…”

Digestive System Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms

“…PDNEC mutational signature seems more specific of their primary locations and similar to that of adenocarcinomas of same site, rather than a common neuroendocrine signature [66,67,[70][71][72][73][75][76][77] . For instance, the molecular study of 867 PDNEC of various origins showed that CDKN2A/B and APC mutations were present in 27 and 3% of pancreatic PDNEC (28.3 and 2.5% in pancreatic adenocarcinomas [78] ), respectively, compared to 6 and 47% of colon PDNEC (9.8 and 49.3% in colon adenocarcinomas [78] ), respectively [79] .…”

Primary Mixed Adenoneuroendocrine Carcinoma of the Gallbladder in a 55-Year-Old Female Patient

“…10 Also, next-generation sequencing could demonstrate the clonal origin of both components in 5 of 6 digestive MANEC cases, but none of these originated in the biliary tract. 11 Furthermore, expression of cancer stem cell marker CD133 has been demonstrated in many gastrointestinal NETs, including MANECs. 12 Finally, the neometaplasia theory poses that an original monophasic biliary adenocarcinoma is amenable to metaplastic transformation, giving rise to secondary tumoral patterns.…”