Molecular Analysis of an Intestinal Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) Reveals MLH1 Methylation-driven Microsatellite Instability and a Monoclonal Origin: Diagnostic and Clinical Implications

Abstract

Mixed neuroendocrine/non-neuroendocrine neoplasms (MiNEN) are rare mixed epithelial neoplasms in which a neuroendocrine component is combined with a non-neuroendocrine component. Here, we provide the clinical, pathologic, and molecular report of a 73-year-old-man presenting with an intestinal MiNEN. The lesion was composed of a well-differentiated G3 neuroendocrine tumor and a colloid adenocarcinoma. The molecular characterization was performed using a multigene nextgeneration sequencing panel. The neoplasm displayed microsatellite instability due to MLH1 promoter methylation. The extended molecular profile documented the same mutations affecting ARID1A, ASXL1, BLM, and RNF43 genes in both components, indicating a monoclonal origin of the tumor. Regarding component-specific gene mutations, BRCA2 was specifically altered in the neuroendocrine area. It may represent a new actionable target for precision oncology in MiNEN, but the lack of its alteration in the colloid component calls for further considerations on intratumor heterogeneity. The most important finding with potential immediate implications regards the presence of microsatellite instability: it indicates that this molecular alteration should become part of the diagnostic algorithm for these rare neoplasms.

From morphology to molecular targets—the pathologist’s view in diagnosing gastroenteropancreatic neuroendocrine neoplasms

“…The molecular features of MiNEN (at least of those with adenocarcinoma components) appear to be more closely related to those of non-neuroendocrine adenocarcinomas than to those of NECs, as BRAF, KRAS and APC mutations are common while RB1 mutations are sparse and TP53 mutations occur in lower frequency compared to NECs [35]. Recent publications have also described microsatellite instability and ATRX mutations in MiNEN [41][42][43]. However, the genetic landscape of MiNEN is heterogenous and complex and remains to be elucidated.…”

Mixed neuroendocrine–nonneuroendocrine neoplasms of the gastrointestinal system: An update

“…On the other hand, BRCA2 has been explicitly altered in the neuroendocrine area. Although the latter observation suggested that BRCA2 could be a potential new target for MiNEN, the lack of this alteration in the nonneuroendocrine part of the tumor requires further consideration concerning intratumor heterogeneity[ 90 ].…”