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World J Gastroenterol. Feb 28, 2022; 28(8): 794-810
Published online Feb 28, 2022. doi: 10.3748/wjg.v28.i8.794
Mixed neuroendocrine–nonneuroendocrine neoplasms of the gastrointestinal system: An update
Gulsum Ozlem Elpek
Gulsum Ozlem Elpek, Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
Author contributions: Elpek GO performed the design of the article, obtained, analyzed and interpreted the data, and wrote the article.
Conflict-of-interest statement: All authors have no any conflicts of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Gulsum Ozlem Elpek, MD, Professor, Pathology , Akdeniz University Medical School, Dumlupınar bulvarı, Antalya 07070, Turkey.
Received: October 14, 2021
Peer-review started: October 14, 2021
First decision: December 3, 2021
Revised: December 15, 2021
Accepted: January 22, 2022
Article in press: January 22, 2022
Published online: February 28, 2022

Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) of the digestive tract are a rare heterogeneous group of tumors that present many challenges in terms of diagnosis and treatment. Over the years, the diagnostic criteria, classification, and clinical behavior of these tumors have been the subjects of ongoing debate, and the various changes in their nomenclature have strengthened the challenges associated with MiNENs. This review is performed to provide an understanding of the key factors involved in the evolution of the designation of these tumors as MiNEN, highlight the current diagnostic criteria, summarize the latest data on pathogenesis and provide information on available treatments. Moreover, this work seeks to increase the awareness about these rare neoplasms by presenting the clinicopathological features and prognostic factors that play important roles in their behavior and discussing their different regions of origin in the gastrointestinal system (GIS). Currently, the MiNEN category also includes tumors in the GIS with a nonneuroendocrine component and epithelial tumors other than adenocarcinoma, depending on the organ of origin. Diagnosis is based on the presence of both morphological components in more than 30% of the tumor. However, this value needs to be reconfirmed with further studies and may be a limiting factor in the diagnosis of MiNEN by biopsy. Furthermore, available clinicopathological data suggest that the inclusion of amphicrine tumors in the definition of MiNEN is not supportive and warrants further investigation. The diagnosis of these tumors is not solely based on immunohistochemical findings. They are not hybrid tumors and both components can act independently; thus, careful grading of each component separately is required. In addition to parameters such as the metastatic state of the tumor at the time of diagnosis and the feasibility of surgical resection, the aggressive potential of both components has paramount importance in the choice of treatment. Regardless of the organ of origin within the GIS, almost MiNENs are tumors with poor prognosis and are frequently encountered in the elderly and men. They are most frequently reported in the colorectum, where data from molecular studies indicate a monoclonal origin; however, further studies are required to provide additional support for this origin.

Keywords: Mixed neuroendocrine–nonneuroendocrine neoplasms, Mixed adeno neuroendocrine carcinoma, Gastrointestinal system, Liver, Pancreas, Gallbladder

Core Tip: Mixed neuroendocrine-nonneuroendocrine neoplasms of the gastrointestinal system are a rare heterogeneous group of tumors that present many challenges in terms of diagnosis and treatment. Current data indicate that they are more frequent in the colon and rectum and that most of them consist of aggressive tumors that have poor prognoses in older men. Their correct diagnosis with the proposed criteria and the separate assessment of the grade of each component are crucial in terms of determining the treatment. Although studies have indicated a monoclonal origin, further studies are needed to determine whether these molecular changes could become treatment targets.