Systematic Reviews
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 14, 2020; 26(30): 4537-4556
Published online Aug 14, 2020. doi: 10.3748/wjg.v26.i30.4537
Differential diagnosis of diarrhoea in patients with neuroendocrine tumours: A systematic review
Mohid S Khan, Thomas Walter, Amy Buchanan-Hughes, Emma Worthington, Lucie Keeber, Marion Feuilly, Enrique Grande
Mohid S Khan, Department of Gastroenterology and Neuroendocrine Tumours, University Hospital of Wales, Cardiff CF14 4XW, United Kingdom
Thomas Walter, Department d'Oncologie Médicale, Hospices Civils de Lyon, Lyon 69003, France
Amy Buchanan-Hughes, Emma Worthington, Evidence Development, Costello Medical, Cambridge CB1 2JH, United Kingdom
Lucie Keeber, Medical Affairs, Ipsen, Slough SL1 3XE, United Kingdom
Marion Feuilly, Health Economics and Outcomes Research, Ipsen, Boulogne-Billancourt 92100, France
Enrique Grande, Oncology Department, MD Anderson Cancer Center, Madrid 28033, Spain
Author contributions: Khan MS, Walker T, Buchanan-Hughes A, Worthington E, Keeber L, Feuilly M and Grande E each made substantial contributions to study conception and design, analysis and interpretation of the data, drafting the article or revising it critically for important intellectual content, and final approval of the version of the article to be published.
Supported by Ipsen.
Conflict-of-interest statement: MK has received sponsorship for meeting attendance, and honoraria for advisory boards from Novartis, Ipsen, Pfizer and BMS. TW has received honoraria for advisory boards and lectures from Keocyt, Ipsen, Novartis, and Adacap. TW has received research grants from Roche, Ipsen and Novartis. EG has received honoraria for advisory boards, meetings and/or lectures from Pfizer, BMS, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Sanofi-Genzyme, Adacap, Novartis, Pierre Fabre, Lexicon and Celgene. EG has received unrestricted research grants from Pfizer, Astra Zeneca, MTEM/Threshold, Roche, Ipsen and Lexicon. ABH and EW are employees of Costello Medical. LK and MF are employees of Ipsen.
PRISMA 2009 Checklist statement: This is study followed PRISMA guidelines.
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: Mohid S Khan, BSc, FRCP, MBBS, PhD, Doctor, Department of Gastroenterology and Neuroendocrine Tumours, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, United Kingdom.
Received: March 5, 2020
Peer-review started: March 5, 2020
First decision: March 13, 2020
Revised: May 22, 2020
Accepted: June 23, 2020
Article in press: June 23, 2020
Published online: August 14, 2020

Approximately 20% of patients with neuroendocrine tumours (NETs) develop carcinoid syndrome (CS), characterised by flushing and diarrhoea. Somatostatin analogues or telotristat can be used to control symptoms of CS through inhibition of serotonin secretion. Although CS is often the cause of diarrhoea among patients with gastroenteropancreatic NETs (GEP-NETs), other causes to consider include pancreatic enzyme insufficiency (PEI), bile acid malabsorption and small intestinal bacterial overgrowth. If other causes of diarrhoea unrelated to serotonin secretion are mistaken for CS diarrhoea, these treatments may be ineffective against the diarrhoea, risking detrimental effects to patient quality of life.


To identify and synthesise qualitative and quantitative evidence relating to the differential diagnosis of diarrhoea in patients with GEP-NETs.


Electronic databases (MEDLINE, Embase and the Cochrane Library) were searched from inception to September 12, 2018 using terms for NETs and diarrhoea. Congresses, systematic literature review bibliographies and included articles were also hand-searched. Any study designs and publication types were eligible for inclusion if relevant data on a cause(s) of diarrhoea in patients with GEP-NETs were reported. Studies were screened by two independent reviewers at abstract and full-text stages. Framework synthesis was adapted to synthesise quantitative and qualitative data. The definition of qualitative data was expanded to include all textual data in any section of relevant publications.


Forty-seven publications (44 studies) were included, comprising a variety of publication types, including observational studies, reviews, guidelines, case reports, interventional studies, and opinion pieces. Most reported on PEI on/after treatment with somatostatin analogs; 9.5%-84% of patients with GEP-NETs had experienced steatorrhoea or confirmed PEI. Where reported, 14.3%–50.7% of patients received pancreatic enzyme replacement therapy. Other causes of diarrhoea reported in patients with GEP-NETs included bile acid malabsorption (80%), small intestinal bacterial overgrowth (23.6%-62%), colitis (20%) and infection (7.1%). Diagnostic approaches included faecal elastase, breath tests, tauroselcholic (selenium-75) acid (SeHCAT) scan and stool culture, although evidence on the effectiveness or diagnostic accuracy of these approaches was limited. Assessment of patient history or diarrhoea characteristics was also reported as initial approaches for investigation. From the identified evidence, if diarrhoea is assumed to be CS diarrhoea, consequences include uncontrolled diarrhoea, malnutrition, and perceived ineffectiveness of CS treatment. Approaches for facilitating differential diagnosis of diarrhoea include improving patient and clinician awareness of non-CS causes and involvement of a multidisciplinary clinical team, including gastroenterologists.


Diarrhoea in GEP-NETs can be multifactorial with misdiagnosis leading to delayed patient recovery and inefficient resource use. This systematic literature review highlights gaps for further research on prevalence of non-CS diarrhoea and suitability of diagnostic approaches, to determine an effective algorithm for differential diagnosis of GEP-NET diarrhoea.

Keywords: Carcinoid syndrome, Diarrhea, Differential diagnosis, Neuroendocrine tumours, Serotonin, Systematic review

Core tip: Patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) often experience diarrhoea, which may have multiple synchronous causes. Although this has a considerable impact on patient quality of life, differential diagnosis of diarrhoea in patients with GEP-NETs is a relatively unexplored topic, and there is currently no formal clinical guidance. This systematic literature review provides valuable insight on the prevalence of causes of diarrhoea in patients with GEP-NETs, evidence on how these cause are diagnosed in this patient population specifically, the consequences if the true cause(s) of diarrhoea are not ascertained, and suggestions for improving differential diagnosis of GEP-NET diarrhoea.