Systematic Reviews
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 14, 2020; 26(34): 5181-5206
Published online Sep 14, 2020. doi: 10.3748/wjg.v26.i34.5181
Mixed epithelial endocrine neoplasms of the colon and rectum – An evolution over time: A systematic review
Rani Kanthan, Suresh Tharmaradinam, Tehmina Asif, Shahid Ahmed, Selliah C Kanthan
Rani Kanthan, Suresh Tharmaradinam, Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon S7N 0W8, SK, Canada
Tehmina Asif, Shahid Ahmed, Division of Oncology, Saskatoon Cancer Centre, Saskatoon S7N 0W8, SK, Canada
Selliah C Kanthan, Division of General Surgery, University of Saskatchewan, Saskatoon S7N 0W8, SK, Canada
Author contributions: All authors made a substantial contribution to the concept, design, acquisition of data and manuscript writing. Each author has participated sufficiently in the work to take public responsibility for the appropriate portions of the content. Preliminary drafts and revisions were undertaken for review of intellectual content and the final version is approved by all authors prior to submission for publication.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
PRISMA 2009 Checklist statement: The guidelines of the PRISMA 2009 statement have been adapted.
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: Suresh Tharmaradinam, MD, Department of Pathology and Laboratory Medicine, University of Saskatchewan, Royal University Hospital 2839 - 103 Hospital Dr, Saskatoon S7N 0W8, SK, Canada.
Received: May 22, 2020
Peer-review started: May 22, 2020
First decision: June 13, 2020
Revised: June 18, 2020
Accepted: August 20, 2020
Article in press: August 20, 2020
Published online: September 14, 2020
Processing time: 110 Days and 7.3 Hours

Mixed tumors of the colon and rectum, composed of a combination of epithelial and endocrine elements of benign and malignant potential are rare neoplasms. These can occur anywhere in the gastrointestinal tract and are often diagnosed incidentally. Though they have been a well-documented entity in the pancreas, where the exocrine-endocrine mixed tumors have been known for a while, recognition and accurate diagnosis of these tumors in the colon and rectum, to date, remains a challenge. This is further compounded by the different terminologies that have been attributed to these lesions over the years adding to increased confusion and misclassification. Therefore, dedicated literature reviews of these lesions in the colon and rectum are inconsistent and are predominantly limited to case reports and case series of limited case numbers. Though, most of these tumors are high grade and of advanced stage, intermediate and low grade lesions of these mixed tumors are also increasingly been reported. There are no established independent consensus based guidelines for the therapeutic patient management of these unique lesions.


To provide a comprehensive targeted literature review of these complex mixed tumors in the colon and rectum that chronicles the evolution over time with summarization of historical perspectives of terminology and to further our understanding regarding their pathogenesis including genomic landscape, clinicoradiological features, pathology, treatment, prognosis, the current status of the management of the primary lesions, their recurrences and metastases.


A comprehensive review of the published English literature was conducted using the search engines PubMed, MEDLINE and GOOGLE scholar. The following search terms [“mixed tumors colon” OR mixed endocrine/neuroendocrine tumor/neoplasm/lesion colon OR adenocarcinoma and endocrine/neuroendocrine tumor colon OR mixed adenocarcinoma and endocrine/neuroendocrine carcinoma colon OR Amphicrine tumors OR Collision tumors] were used. Eligibility criteria were defined and all potential relevant items, including full articles and/or abstracts were independently reviewed, assessed and agreed upon items were selected for in-depth analysis.


In total 237 full articles/abstracts documents were considered for eligibility of which 45 articles were illegible resulting in a total of 192 articles that were assessed for eligibility of which 139 have been selected for reference in this current review. This seminal manuscript is a one stop article that provides a detailed outlook on the evolution over time with summarization of historical perspectives, nomenclature, clinicoradiological features, pathology, treatment, prognosis and the current status of the management of both the primary lesions, their recurrences and metastases. Gaps in knowledge have also been identified and discussed. An important outcome of this manuscript is the justified proposal for a new, simple, clinically relevant, non-ambiguous terminology for these lesions to be referred to as mixed epithelial endocrine neoplasms (MEENs).


MEEN of the colon and rectum are poorly understood rare entities that encompass an extensive range of heterogeneous tumors with a wide variety of combinations leading to tumors of high, intermediate or low grade malignant potential. This proposed new revised terminology of MEEN will solve the biggest hurdle of confusion and misclassification that plagues these rare unique colorectal neoplasms thus facilitating the future design of multi institutional prospective randomized controlled clinical trials to develop and evaluate newer therapeutic strategies that are recommended for continued improved understanding and personal optimization of clinical management of these unique colorectal neoplasms.

Keywords: Mixed epithelial endocrine neoplasms, Mixed adeno-neuroendocrine carcinoma, Mixed adeno neuro endocrine tumors, Mixed neuroendocrine-non neuroendocrine neoplasms, Colorectal

Core Tip: This seminal manuscript provides a targeted review of these complex, rare neoplasms of the colon and rectum that should interest colorectal pathologists, surgeons, oncologists and gastroenterologists. This targeted review chronicles the evolution over time with summarization of historical perspectives of terminology with a proposal for a new-innovative, clinically-relevant, simple, non-ambiguous terminology for these lesions as mixed epithelial endocrine neoplasms. The pathogenesis including genomic landscape, clinico-radio-pathological features, treatment and prognosis, with gaps in knowledge are discussed. In keeping with our philosophy of a multidisciplinary management of these tumors, this manuscript has a multidisciplinary team (pathologists, oncologist and surgeon) of authorship.