Differential diagnosis of diarrhoea in patients with neuroendocrine tumours: A systematic review

Table 1 Proportion of patients with non-carcinoid syndrome diarrhoea inferred from symptoms/treatment or prevalence estimates

Ref.	Population	Condition	Diagnosis	Data
Diagnosis method or clinical definition of condition not reported
Boudreaux[25], 2016	Patients with NETs and abdominal pain, weight loss, bloating and diarrhoea (n = 100)	Bowel obstruction	NR	“More than one-third of these patients had an occult bowel obstruction that was complete or nearly complete because their primary tumour had never been resected”
Boudreaux et al[24], 2010	NA (Guideline)	Bowel obstruction or ischaemia	Symptoms	“As many as 35% of patients with advanced carcinoid present with symptoms of obstruction, ischaemia, or both”
Iyer et al[23], 2017	NA (Monograph)	PEI	NR	“Somatostatin analogues lead to more diarrhea from exocrine suppression in up to 30% of patients”
Ruszniewski et al[26], 2016	Adults with NETs receiving lanreotide for at least 3 mo for relief of carcinoid syndrome (n = 273262 provided a cause of diarrhoea)	PEI	NR	“Note that the whole study population was selected based on a history of diarrhoea at some point prior to the study. Of those patients for whom a reason for diarrhoea was provided (n = 262), 30% (79) had another potential cause of diarrhoea in addition to CS. The most common were small bowel resection [44% (35/79), 13.4% (35/262)], pancreatic insufficiency [32% (25/79), 9.5% (25/262)], and ileocecal valve/colonic resection [24% (19/79), 7.3%a (19/262)]”
		Bowel resection	NR
		Ileocecal valve or colonic resection	NR
Saif et al[37], 2020	Patients with GEP-NETs (n = 110)	Motility disorders	NR	“13 received PPI concomitantly while 6 started when symptoms did not improve with PER. Nutrition recommended low fat diet, 14 of 19 had improvement in diarrhoea within 4–8 wk. Two were non-compliant and 3 (2.7%) were found to have motility disorders”
Inferred from symptoms and treatment
Chaudhry et al[40], 2017	Patients with NETs referred to a gastroenterology NET clinic (n = 39)	PEI	Steatorrhoea (faecal elastase used, but number of patients diagnosed with PEI using faecal elastase NR)	“78% (25/32) had been on long-acting SSA therapy and 81% (26/32) had steatorrhea”
Donnelly et al[33], 2017	Patients with NETs referred to a NET gastroenterologist service (n = 57)	PEI	Faecal elastase used but number diagnosed with PEI using this test NR	“19 (33.3%) patients were commenced on either creon or colesevelam.” Of the 20 patients who returned questionnaires: “95% of patients required treatment with creon or colesevelam for their steatorrhea or bile acid malabsorption respectively”
Fiebrich et al[39], 2010	Acromegaly and carcinoid patients receiving treatment with SSAs (n = 35)	PEI	Steatorrhoea, no tests reported	“8/35 (22.9%a) patients complained about steatorrhoea. 12/35 patients experienced increased stool frequency (1-10 times daily). 5/35 (14.3%) carcinoid patients received supplementation of pancreatic enzymes for steatorrhea.” It is inferred that 5/8 (62.5%) patients with steatorrhoea received supplementation of pancreatic enzymes
Khan et al[27], 2011	Patients with metastatic midgut NETs and carcinoids syndrome (n = 69 had complete data)	PEI	Steatorrhoea, no tests reported	“35 (50.7%a) patients experienced steatorrhoea which was controllable by pancreatic enzyme supplementation”
Lamarca et al[6,28]	Patients with NETs receiving treatment with SSAs (n = 50)	PEI	Steatorrhoea and/or bloated abdomen	"Twelve patients (24%) developed SSA-related PEI (4 clinical diagnosis, 8 FE-confirmed) at a median of 2.9 mo after starting SSA: 11/12 (92%) patients received enzyme replacement." “SSA-induced PEI occurs in 1 out of 4 patients”
Lim et al[29], 2017	Patients with NETs seen at gastroenterology and endocrinology clinics (n = 141)	PEI	Steatorrhoea, no tests reported	"27 patients reported steatorrhea, 26 of whom were prescribed somatostatin analogues. 26 (96%) of these patients were also prescribed Creon." “27/141 NET patients (19.2%a) complained of steatorrhoea. 26 were prescribed Creon”
Toumpanakis et al[30], 2009	Patients with metastatic NETs of midgut origin and symptoms of carcinoid syndrome who received octreotide LAR (n = 108)	PEI	Steatorrhoea, no tests reported	"Twenty-eight (25.9%) patients developed clinical features of steatorrhoea, which resolved after the initiation of pancreatic enzyme supplements"
Whyand et al[32], 2018	Patients with NETs receiving an SSA (n = 176)	PEI	Steatorrhoea, no tests reported	“Pancreatic enzyme insufficiency is one cause of fat loss in stools. When the fat is obvious, it causes greasy and frothy loose stools called steatorrhoea. Among the survey respondents, 84% stated they had this to varying degrees”
Proportion of patients with non-CS diarrhoea diagnosed by clinical tests
Donnelly et al[33], 2017	Patients with NETs referred to a NET gastroenterologist service (n = 57)	PEI	Faecal elastase test (< 200 abnormal), although PEI not specifically stated in the abstract or poster	17% of patients tested (n = 18) had abnormal faecal elastase. Median: 296.0; Range: 14.0-64.0 (approximate)
		BAM	SeHCAT scan (> 20% = Normal)	80% of patients tested (n = 20) were diagnosed with BAM
		SIBO	Hydrogen breath test	62% of patients tested (n = 13) had SIBO
Gorbunova et al[34], 2016	Patients with metastatic well-differentiated, functional NETs, on octreotide LAR for 5–6 mo (n = 5)	Colitis	CT scan	1 patient (20%a) diagnosed with colitis
Kiesewetter et al[35,36]	Patients given ondansetron as bridging therapy for refractory CS (n = 14)	Infectious diarrhoea (Campylobacter coli)a	Stool culture	1 patient (7.1%a) excluded after enrolment for infectious diarrhoea
Lamarca et al[6,28]	Patients receiving treatment with SSAs (n = 50)	PEI	Faecal elastase below the normal limit (200 µg/g)	“Twelve patients (24%) developed SSA-related PEI (4 clinical diagnosis, 8 FE-confirmed)”
Saif et al[38], 2010	Patients with histological diagnosis of NETs (n = 43)	PEI	Stool studies for faecal fat	“Overall, our cohort showed that 11.6% of patients on chronic octreotide analog therapy developed pancreatic insufficiency”
Saif et al[37], 2020	Patients with GEP-NETs following SSA therapy (n = 110)	PEI	Quantitative measurement of faecal fat and evidence of steatorrhoea	"19 (17.3%) had evidence of steatorrhea and received PER who received PER @ 500 units/kg/meal to a maximum of 10000 units/kg per day. 13 received PPI concomitantly while 6 started when symptoms did not improve with PER"
Whyand et al[32], 2017	Patients with NETs undergoing HBT (n = 55)	SIBO	Hydrogen breath test, using glucose or lactulose substrates	“Twenty-four (24/55, 44%) had prior right hemicolectomy. Ten (10/24, 42%) of those were SIBO positive. Ten patients were positive for HBT prior to being given the glucose substrate, they all had abdominal surgery in the past. Twelve patients who tested negative for glucose HBT had repeat testing using lactulose and measured both H2 and CH4 production. This led to an additional 3 (25%) positive results”. Overall, 23.6%a (13/55) of the overall study population were diagnosed with SIBO

^aValues were calculated by the reviewers from the available data. BAM: Bile acid malabsorption; CH₄: Methane; CS: Carcinoid syndrome; FE: Faecal elastase; CT: Computed tomography; GEP: Gastroenteropancreatic; H₂: Hydrogen; HBT: Hydrogen breath test; LAR: Long acting release; NA: Not applicable; NET: Neuroendocrine tumour; NR: Not reported; PEI: Pancreatic enzyme insufficiency; PER: Pancreatic enzyme replacement; PPI: Proton pump inhibitor; SeHCAT: Tauroselcholic [75 selenium]; SIBO: Small intestinal bacterial overgrowth; SSA: Somatostatin analogue.

Table 2 A summary of clinical tests used to confirm cause of diarrhoea

Condition or cause	Diagnostic test	Diagnostic criteria	Evaluation or opinion on accuracy of diagnostic test
Pancreatic enzyme insufficiency (PEI)	Faecal elastase[6,33,40,60-64]	Donnelly 2017 defined an abnormal test result as “< 200” but units were not specified[33]. Lamarca 2018: PEI defined as either an FE1 value below the normal limit (< 200 μg/g) or a reduction of ≥ 21%a[6]. Other articles only mentioned the test in passing, for example stating that FE was evaluated or presenting a proportion of patients with abnormal FE	Chaudhry 2017: 22/32 patients had steatorrhoea with a normal faecal elastase, sensitivity of FE test for detecting steatorrhoea in patients with NETs was 15.4%. The authors concluded that there is a lack of association between FE and steatorrhoea in patients with NETs[40]. Donnelly 2017 reported that only 17% of patients with NETs and steatorrhoea had abnormal faecal elastase[33]. Lamarca 2018 acknowledged that there is a risk of false positives from diarrhoea, but concluded that faecal elastase testing is feasible, accessible and recommended for patients who develop symptoms of PEI, and report it was the basis for diagnosis in 67% of patients who developed PEI[6]
	Faecal fat: 72-h stool fat testing[37,38,63]; Sudan stain of a spot stool measurement[38]	-	Faecal fat quantification is the cheapest and easiest way to confirm a diagnosis of PEI[38]. Sudan stain of a spot stool measurement is easier but a quantitative 72-h collection is more reliable (no clear evidence is provided to support this)[38]. Faecal fat test could be utilised for assessing response to PERT[38]
Bile acid malabsorption	SeHCAT scan[33,61]	SeHCAT < 20% retention	-
Colitis	CT scan[34]	-	-
Dumping syndrome	Provocative meal test[44]	-	-
Infectious diarrhoea	Bacterial: Stool culture for Salmonella, Campylobacter, Shigella and Yersinia, as well as Clostridium difficile, enteropathogenic Vibrio species, or Escherichia coli strains[50]; Viral: Stool analyses for cytomegaly virus[50]; Parasitical: Stool analysis for Entamoeba histolytica or Giardia lamblia[50]	-	-
Intestinal ischaemia	Angiography[44] (type of angiography was not further specified)	-	-
Laxative abuse	KOH stool preparation, intestinal secretion[42,43]	-	-
PCI (induced by sunitinib)	CT scan[46]	-	-
SBS	Urinary sodium (undetectable)[61]	-	-
SIBO	Breath tests: Hydrogen breath test[61], with glucose[33] or lactulose substrate[32]; Methane breath test[32,61]	-	Whyand et al[32] assessed the sensitivity of additional MBT and lactulose HBT testing on 12 (out of 55) patients who tested negative for SIBO with glucose HBT, but whose diarrhoea did not abate. This was under the rationale that patients with NETs are more likely to have distal SIBO (due to influences such as ileocoecal valve resection), whereas glucose HBT may be more sensitive to proximal SIBO as glucose rarely reaches the colon. This testing yielded an additional 3 positive results, and led the authors to conclude that lactulose HBT and MBT increase sensitivity for detecting SIBO in patients with NETs who have previously undergone hemicolectomy

^aA reduction in faecal elastase value by ≥ 21% was applied by the authors in this study, but is not a standard definition in clinical practice. BAM: Bile acid malabsorption; CS: Carcinoid syndrome; CT: Computed tomography; FE: Faecal elastase; FF: Faecal fat; GEP-NET: Gastroenteropancreatic neuroendocrine tumour; HBT: Hydrogen breath test; KOH: Potassium hydroxide; LAR: Long acting release; MBT: Methane breath test; PEI: Pancreatic enzyme insufficiency; PERT: Pancreatic enzyme replacement therapy; SeHCAT: Tauroselcholic [75 selenium] acid; SIBO: Small intestinal bacterial overgrowth; SSA: Somatostain analogue.