Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Surg. Mar 27, 2021; 13(3): 231-255
Published online Mar 27, 2021. doi: 10.4240/wjgs.v13.i3.231
Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot
Cornelius J Fernandez, Mayuri Agarwal, Biju Pottakkat, Nisha Nigil Haroon, Annu Susan George, Joseph M Pappachan
Cornelius J Fernandez, Mayuri Agarwal, Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
Biju Pottakkat, Department of Surgical Gastroenterology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry 605006, India
Nisha Nigil Haroon, Department of Endocrinology and Internal Medicine, Northern Ontario School of Medicine, Sudbury P3E 2C6, Ontario, Canada
Annu Susan George, Department of Medical Oncology, VPS Lakeshore Hospital, Cochin 682040, Kerala, India
Joseph M Pappachan, Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, PR2 9HT, Preston, The University of Manchester, Oxford Road M13 9PL, Manchester Metropolitan University, All Saints Building M15 6BH, Manchester, United Kingdom.
Author contributions: Fernandez CJ and Agarwal M performed majority of the initial drafting and prepared the figures and tables, and share the first authorship; Pottakkat B made critical revisions in the surgical aspects of the write up; Haroon NN provided substantial additional contributions to the endocrine aspects of the work; George AS contributed to the conception and design of the study and made critical revisions especially the oncological aspects; Pappachan JM conceived the study, made critical revisions and provided final approval of the final version of the manuscript to be published
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
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: Joseph M Pappachan, MD, MRCP, FRCP; Consultant, Senior Researcher, Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, PR2 9HT, Preston, The University of Manchester, Oxford Road M13 9PL, Manchester Metropolitan University, All Saints Building M15 6BH, Manchester, United Kingdom.
Received: December 11, 2020
Peer-review started: December 11, 2020
First decision: January 11, 2021
Revised: January 17, 2021
Accepted: March 2, 2021
Article in press: March 2, 2021
Published online: March 27, 2021

Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.

Keywords: Gastroenteropancreatic neuroendocrine neoplasms, Neuroendocrine tumours, Neuroendocrine carcinoma, Targeted molecular therapy, Octreoscan, Chemotherapy

Core Tip: Gut, the largest endocrine organ of the body, secretes several hormones through its specialised neuroendocrine cells. Neuroendocrine neoplasms (NENs) originating from these cells are collectively known as gastroenteropancreatic (GEP) NENs that pose significant challenges to clinicians in the diagnostic work up, prognostication and management. Rapid advancements in the molecular diagnostic and therapeutic strategies in the recent years revolutionised the options for clinical investigations and management of patients with these uncommon neoplasms. This review updates the pathophysiological aspects, diagnostic strategies, and management algorithms of GEP NENs with the best evidence currently available in the global scientific literature to enable clinicians to optimally manage these unusual disease entities.