Carcinoid syndrome and neuroendocrine tumours of the gut

• A gut neuroendocrine tumour (NET) is a slow-growing tumour of the hormone-producing cells that line the digestive tract; it is often found in the small bowel, appendix or rectum.
• Carcinoid syndrome is the clinical picture produced by hormones (mainly serotonin) that these tumours release; it usually appears only when the tumour's hormones bypass the liver, which is why liver metastases (or a tumour draining outside the portal system) are required. ^[1]
• The classic features are flushing, secretory watery diarrhoea, bronchospasm and right-sided heart valve damage (tricuspid regurgitation and pulmonary stenosis).
• Appendiceal NETs found during appendectomy are usually harmless when under 1 cm, but a tumour larger than 2 cm prompts a right hemicolectomy. ^[5]
• Diagnosis rests on 24-hour urine 5-HIAA (or plasma 5-HIAA), imaging (CT or MRI and Ga-68 DOTATATE PET) and endoscopy; treatment combines surgery, somatostatin analogues, telotristat, liver-directed therapy, everolimus and peptide receptor radionuclide therapy. ^[1][9]

By the end of this page you should be able to:

1. Define a neuroendocrine tumour, place it among the common gut sites, and apply the Ki-67 / mitotic-rate grading scheme.
2. Explain why carcinoid syndrome needs liver metastases (or extra-portal drainage) and trace each symptom back to serotonin.
3. Recognise pellagra as a complication of tryptophan diversion, and name its four D features.
4. Apply the appendiceal size rules that follow appendectomy.
5. Choose first-line investigations and interpret a raised 24-hour urinary 5-HIAA.
6. Outline management, including somatostatin analogue doses, telotristat, everolimus, peptide receptor radionuclide therapy and perioperative octreotide.
7. Distinguish the main flushing mimics using a comparison table.
8. Recognise the link with MEN1 and the low-resource fallbacks.

Carcinoid syndrome is the systemic illness caused by hormones released by certain NETs: flushing, secretory diarrhoea, bronchospasm, right-sided heart valve disease, abdominal pain from mesenteric fibrosis and, by diverting tryptophan, pellagra. ^[1]

NETs occur at every level of the gut and beyond. The essential distinction for management is well-differentiated NET (G1-G3) versus poorly differentiated neuroendocrine carcinoma; neuroendocrine carcinomas are aggressive, need platinum-based chemotherapy and are not the tumours that usually cause carcinoid syndrome.

The small bowel (terminal ileum) is the classic site for midgut NETs and for carcinoid syndrome. The appendix holds 50 to 77% of all appendiceal neoplasms as NETs. ^[5] The rectum is a common colonic site, often found at screening colonoscopy. The stomach gives three types: type 1 (75 to 80%) linked to autoimmune atrophic gastritis and high gastrin; type 2 (about 5%) linked to Zollinger-Ellison syndrome and MEN1; type 3 (15 to 25%) sporadic and higher grade. ^[6] Lung (bronchial) carcinoids are divided into typical and atypical carcinoids. Pancreatic NETs are often non-functioning and are the commonest NET in MEN1.

Carcinoid syndrome affects about 19% of patients with neuroendocrine neoplasms, most often people with well-differentiated grade 1 or 2 tumours of small intestinal or bronchopulmonary origin. ^[2] CS is reported in 8% of pulmonary carcinoids. ^[7] Women and men are both affected; in gut NETs the presentation varies by site, and women report more severe symptoms in some series. ^[1]

• Age and genetics. Sporadic NETs dominate. Multiple endocrine neoplasia type 1 (MEN1) is the important inherited association: pancreatic and duodenal NETs, gastrinomas and (less commonly) thymic or bronchial NETs occur, and 2% of lung carcinoids carry germline MEN1 mutations. ^[7]
• Risk factors for gastric NETs are autoimmune atrophic gastritis (type 1) and gastrinoma/Zollinger-Ellison syndrome (type 2); type 3 arises sporadically.
• There are no firmly established modifiable risk factors for small bowel NETs.

NETs of the gut absorb tryptophan and convert it to serotonin. Serotonin, rather than histamine or bradykinin, is the mediator best supported for diarrhoea and the fibrotic complications, although flushing probably involves tachykinins and catecholamines as well. ^[2]

Why liver metastases matter. The liver inactivates serotonin and other vasoactive products released into the portal vein. Carcinoid syndrome therefore develops when tumour products reach the systemic circulation without that first pass: most often with liver metastases, but also with an extra-portal primary (for example a bronchial or ovarian tumour) or widespread disease. ^[1]

Symptoms follow the biology.

• Flushing reflects vasodilator release; in CS it is usually a dry, reddish-brown or bright-red flush of the head and neck, often short-lived. ^[1] Flushing occurs in 65% to 78% and diarrhoea in 67% to 73% of patients with carcinoid syndrome. ^[2] Other reviews give higher figures for flushing (over 90%) and a range of 60% to 80% for diarrhoea, so series differ. ^[1]
• Secretory diarrhoea comes from serotonin acting on the gut; stools are watery and persist during fasting.
• Bronchospasm is uncommon (about 8% to 10% in one review, around 15% in another), with wheeze and dyspnoea driven by histamine and serotonin. ^[1][2]
• Right-sided valvular disease is classic Thorson's syndrome: endocardial fibrosis thickens the tricuspid and pulmonary valves, producing tricuspid regurgitation and pulmonary stenosis (sometimes regurgitation too). Left-sided valves are usually spared because serotonin is inactivated in the lung vasculature; left-sided disease needs a right-to-left shunt or a pulmonary primary.
• Mesenteric fibrosis comes from prolonged serotonin release and occurs in about half of patients with carcinoid syndrome (up to 70% in some series); it puckers the mesentery, causing chronic abdominal pain, obstruction, ischaemia or intussusception. ^[1]
• Pellagra follows tryptophan diversion. Normally most tryptophan goes to nicotinamide; in carcinoid syndrome the shift to serotonin depletes niacin. ^[1] Biochemical sub-clinical deficiency may affect 30% to 45%. ^[1] Clinical pellagra presents with the four Ds - diarrhoea, dermatitis, dementia and death - plus scaly skin, glossitis, stomatitis, confusion, violent behaviour and language deficits; nicotinamide 200 to 250 mg is used when niacin deficiency is found. ^[1]
• Long-term 5-hydroxyindoleacetic acid exposure drives carcinoid heart disease, seen in roughly 20% to 50% of patients (17% to 21% in some series), with tricuspid regurgitation as the dominant lesion. ^[1] Tricuspid regurgitation can be monitored with transthoracic echocardiography and NT-proBNP every 6 to 12 months, with valve replacement in severe cases. ^[1]

History

• Flushing attacks: sudden warmth and redness of face and neck, sometimes with palpitations or blood pressure change, often triggered by alcohol, food, emotion or physical handling of the tumour.
• Watery diarrhoea, often nocturnal and unrelated to food, sometimes with urgency and steatorrhoea after bowel resection.
• Wheeze, dyspnoea, chest tightness.
• Weight loss, fatigue, abdominal pain or obstructive symptoms.
• Symptoms of carcinoid heart disease: exertional breathlessness, ankle swelling, ascites.

Examination

• The flushing itself may be visible during an attack; telangiectasia can develop.
• Right-sided heart failure signs: raised jugular venous pressure with a prominent v wave, pulsatile liver, peripheral oedema, a pansystolic murmur of tricuspid regurgitation and an ejection click or murmur of pulmonary stenosis.
• Abdominal mass or tenderness; signs of malabsorption or subacute obstruction.
• Skin changes of pellagra: a photosensitive rash, glossitis and stomatitis.
• Women report more severe symptoms in some series, with more abdominal pain, tachycardia and psychiatric symptoms.

A table comparing the common flushing disorders is the fastest way to separate them; note that carcinoid flushing is usually dry and reddish-brown, whereas menopausal flushing is often wet and whole-body.

Other neuroendocrine-related differentials are a pancreatic VIPoma (watery diarrhoea, hypokalaemia, achlorhydria), gastrinoma (peptic ulcer disease, raised gastrin), insulinoma (hypoglycaemia) and glucagonoma (diabetes, necrolytic migratory erythema).

Biochemistry

• 24-hour urinary 5-HIAA: sensitivity 73% to 91%, specificity 100%, with a cut-off above 50 micromol considered compatible with carcinoid syndrome. ^[1] Collect for 24 hours with dietary advice (avoid serotonin-rich foods).
• Plasma (or serum) 5-HIAA is a convenient alternative: single sample, no meal effect; a cut-off of 135 nmol/L gives 91% sensitivity and 62% specificity. ^[1]
• Chromogranin A is sensitive but non-specific: raised by proton pump inhibitors, chronic atrophic gastritis, inflammatory bowel disease, renal impairment and several other conditions. ^[8] It should never be used as a screening test, and a normal or raised value should not override the clinical picture. ^[8] In one comparison a 31 to 32 U/L cut-off gave 75% sensitivity and 84% specificity. ^[8]
• Routine screening tests as the site demands: gastrin, VIP, insulin, glucagon and others for functioning pancreatic NETs.

Imaging

• CT or MRI of abdomen, pelvis and chest, multiphasic CT for hypervascular liver metastases, MRI liver with hepatocyte-specific contrast when needed.
• Ga-68 DOTATATE PET (somatostatin receptor imaging) to stage disease, confirm receptor positivity and select patients for peptide receptor radionuclide therapy. ^[9]
• Somatostatin receptor imaging also helps in lung NET work-up; Ga-68 DOTATATE has been validated for preoperative nodal staging of lung carcinoids.
• Endoscopy and endoscopic ultrasound for gastric, duodenal and rectal NETs; colonoscopy for rectal lesions; capsule endoscopy only rarely needed.

How each tumour presents locally

• Appendix: found incidentally at appendectomy; size measured on the resected specimen.
• Rectum: usually a small submucosal nodule found at colonoscopy, often yellow and vascular; endoscopic resection is standard for small lesions.
• Stomach: types 1 and 2 need biopsy with assessment of atrophic gastritis or gastrinoma; type 3 is treated as cancer.
• Small bowel: may need CT enterography or capsule endoscopy, with mesenteric disease and fibrosis seen on CT.
• Lung: bronchoscopy and thoracic CT; typical and atypical carcinoids distinguished by mitotic count and necrosis.
• Pancreas: multiphasic CT/MRI and endoscopic ultrasound for small lesions.

The diagnosis of carcinoid syndrome is clinical plus biochemical (diarrhoea and/or flushing with elevated serotonin metabolite). There is no single staging score in common use; practical staging combines grade (G1-G3), tumour site, resectability, the burden of liver and other metastases and the presence of carcinoid heart disease.

Carcinoid heart disease is screened with transthoracic echocardiography and ECG in every patient with carcinoid syndrome, then monitored every 6 to 12 months, with NT-proBNP as a non-specific marker. Right-sided valve surgery is reserved for severe, symptomatic valve disease.

Surgery

• Resect the primary tumour and any accessible metastases when feasible; small bowel and appendix resections are often curative for small, localised tumours.
• For appendiceal NET found at appendectomy: tumours under 1 cm are adequately treated by appendectomy alone; tumours larger than 2 cm warrant right hemicolectomy; in the 1 to 2 cm group, completion surgery is debated and is usually reserved for risk factors such as high grade, mesoappendix invasion over 3 mm, angioinvasion or involved margins. ^[5]
• Rectal lesions are often resected endoscopically; larger or deeper lesions need surgical resection.
• Debulking of liver metastases, when the bulk is resectable, improves hormone control and may slow tumour growth.
• Prophylactic octreotide around surgery and procedures (see below).

Somatostatin analogues

Octreotide and lanreotide are the mainstay for flushing and diarrhoea.

• Octreotide is usually started with short-acting injections and then switched to long-acting octreotide LAR, typically 20 mg intramuscularly every 4 weeks, with an FDA-approved maximum of 30 mg every 4 weeks. ^[3] ENETS first-line guidance for lung and thymic carcinoids recommends octreotide LAR 30 mg or lanreotide autogel 120 mg every 28 days. ^[9] Guidelines therefore differ on the starting long-acting dose; follow the product label and local practice.
• Lanreotide autogel is given as 60 to 120 mg subcutaneously every 28 days. ^[3]
• Ongoing symptoms may respond to increased dose or more frequent injections; a short-acting octreotide top-up before known triggers helps.
• With refractory carcinoid syndrome, pasireotide 40 mg or octreotide 60 mg monthly helped roughly 20% to 27% of patients in randomised trials; ^[9] telotristat ethyl improved diarrhoea in about 42% to 44% of patients. ^[9]

Lanreotide and octreotide control symptoms in an estimated 65% to 75% of patients and give biochemical improvement in 40% to 50%. ^[9] They also have antiproliferative activity in randomised trials of well-differentiated NETs.

Telotristat ethyl

Telotristat ethyl 250 mg by mouth three times daily with food inhibits tryptophan hydroxylase and reduces serotonin production. ^[3] It is licensed for adults with carcinoid syndrome diarrhoea not controlled by a somatostatin analogue. Common adverse effects include nausea, abdominal pain and, rarely, depression. Monitor liver enzymes.

Everolimus

Everolimus 10 mg once daily is an mTOR inhibitor used for progressive well-differentiated NETs (notably pancreatic and lung primaries). ^[3] It is not primarily a symptom drug, though some patients gain symptom benefit.

Peptide receptor radionuclide therapy (PRRT)

177Lu-DOTATATE delivers beta radiation to somatostatin receptor-positive tumour cells. In NETTER-1, patients received 7.4 GBq intravenously every 8 weeks with octreotide LAR 30 mg every 4 weeks. ^[3] PRRT is used for progressive somatostatin receptor-positive GEP-NETs and, by extension, in some bronchial NETs, with haematologic and renal toxicity as the main cautions.

Liver-directed and other therapy

Transarterial embolisation, radioembolisation or ablation are useful for liver-dominant metastatic disease and carcinoid syndrome not controlled by drugs, especially where there is a liver-dominant pattern. Systemic cytotoxic chemotherapy is reserved for poorly differentiated neuroendocrine carcinoma or rapidly progressive disease.

Carcinoid crisis prevention and treatment

Carcinoid crisis is a life-threatening release of vasoactive hormones triggered by anaesthesia, tumour manipulation, biopsy, PRRT or liver-directed therapy; it causes abrupt flushing, severe blood pressure change, profuse diarrhoea and bronchospasm (systolic pressure under 80 or over 180 mmHg, heart rate over 120 beats per minute in one large series). ^[1] It is not fully preventable, so prompt recognition matters.

Prophylaxis: octreotide 100 to 500 micrograms subcutaneously every 6 to 8 hours, or an intravenous infusion starting at 50 micrograms per hour and increased to 100 to 200 micrograms per hour if needed, begun 12 hours before surgery and before anaesthesia, continued through the procedure and afterwards until the patient is stable. ^[1]

If a crisis occurs: intravenous octreotide, aggressive fluid resuscitation, corticosteroids, vasopressors and treatment of bronchospasm and arrhythmias.

• Carcinoid syndrome itself (see above).
• Carcinoid heart disease in 20% to 50%, with tricuspid regurgitation the dominant lesion.
• Mesenteric fibrosis in about half of patients, with obstruction, ischaemia or intussusception.
• Malnutrition from chronic diarrhoea, pancreatic insufficiency or post-surgical change (reported around 25%). ^[1]
• Pellagra from niacin deficiency.
• Biliary problems and gallstones with long-term somatostatin analogue use.
• Metastatic disease to liver, bone and ovary.

Outcome depends on differentiation grade, primary site, metastatic burden and the presence of carcinoid syndrome and carcinoid heart disease. Localised, well-differentiated NETs have an excellent prognosis after resection; metastatic small bowel NETs behave indolently, with survival often measured in years. The presence of carcinoid syndrome is associated with a worse prognosis (median overall survival about 4.7 years with CS compared with about 7.1 years without, in one series), mainly because it marks metastatic disease. ^[1]

There is no population screening for small bowel NETs. Screening is appropriate for mutation carriers in MEN1 (clinical, biochemical and imaging surveillance) and in families with hereditary syndromes. Detecting and treating niacin deficiency early avoids pellagra. Prophylactic octreotide is indicated for procedures that may trigger carcinoid crisis.

MEN1. Patients with MEN1 develop duodenal and pancreatic NETs, gastrinomas and, less often, bronchial or thymic NETs; gastric type 2 NETs occur in this setting. Screening and management follow MEN1 protocols; the pancreatic and duodenal lesions are often multiple and small.

Children and pregnancy. NETs are rare in children; MEN1-related disease should be considered. Management in pregnancy is by a multidisciplinary team.

• Measure 24-hour urinary 5-HIAA where the laboratory can run it; it is cheap relative to plasma panels and highly specific when raised.
• Use a careful clinical diagnosis of right-sided valve disease with a stethoscope and basic echocardiography if available; refer significant valve disease early.
• Surgery (appendectomy, resection of small bowel primary) and histology are achievable in most hospitals; measure the tumour size on the specimen and apply the 1 cm / 2 cm rules.
• When somatostatin analogues are unavailable, use loperamide, antihistamines and nutritional support; niacin or nicotinamide replaces what diversion depletes. Refer complex carcinoid syndrome and heart disease to a specialist centre.

• A NET is a hormone-secreting tumour of the gut; carcinoid syndrome occurs when its products bypass hepatic first-pass metabolism, usually via liver metastases.
• Grading by Ki-67 and mitotic count: G1 (under 3%, under 2), G2 (3-20%, 2-20), G3 (over 20%, over 20), and neuroendocrine carcinoma (poorly differentiated, over 20%).
• Classic features are flushing (65-78%), secretory diarrhoea (67-73%), bronchospasm (8-10%, up to 15%), and right-sided valvular disease.
• Right-sided valve involvement means tricuspid regurgitation and pulmonary stenosis; left-sided valves are usually spared.
• Mesenteric fibrosis occurs in about half of patients; carcinoid heart disease in 20% to 50%.
• Pellagra (diarrhoea, dermatitis, dementia, death) can complicate tryptophan diversion; nicotinamide 200 to 250 mg is used.
• Appendiceal NETs: under 1 cm treated by appendectomy, over 2 cm by right hemicolectomy, 1-2 cm individualised.
• Diagnosis: 24-hour urinary 5-HIAA (above 50 micromol), plasma 5-HIAA, chromogranin A with caution, CT/MRI, Ga-68 DOTATATE PET, endoscopy.
• First-line somatostatin analogues: octreotide LAR 20 to 30 mg every 4 weeks (guidance differs) or lanreotide 60 to 120 mg every 28 days; symptom control 65-75%.
• Specifics: telotristat 250 mg three times daily, everolimus 10 mg daily, 177Lu-DOTATATE 7.4 GBq every 8 weeks, perioperative octreotide 100 to 500 micrograms subcutaneously every 6-8 hours or IV at 50 rising to 100-200 micrograms per hour.
• Screen for and treat carcinoid heart disease; monitor valves every 6-12 months.
• Think MEN1 with pancreatic/duodenal NETs, gastrinoma or (2% of cases) lung carcinoids.

MEN1; appendicitis; small bowel obstruction; right-sided heart failure and tricuspid regurgitation; chronic diarrhoea; pellagra; neuroendocrine tumour grading; liver metastases.