Neuroendocrine tumours and carcinoid

• Neuroendocrine tumours (NETs) are well-differentiated neoplasms arising from the diffuse neuroendocrine system, which spans the gut, pancreas, lungs and, less often, other endocrine organs.
• They are graded by cell division: grade 1 tumours divide slowly (fewer than 2 mitoses per 2 mm2 and/or Ki-67 under 3%), grade 2 more quickly (2 to 20 mitoses and/or Ki-67 3 to 20%), and grade 3 rapidly (more than 20 mitoses and/or Ki-67 above 20%). Poorly differentiated neuroendocrine carcinomas are a separate, more aggressive category.
• Only a minority (roughly 20 to 30% of pancreatic and gut NETs) secrete hormones. Carcinoid syndrome is the classic one: serotonin from a gut NET causes flushing, watery diarrhoea, wheezing and, in the long term, right-sided heart and mesenteric fibrosis.
• The modern diagnostic backbone is cross-sectional imaging (contrast CT/MRI) plus somatostatin-receptor imaging, especially 68Ga-DOTATATE PET-CT. Biochemistry (24-hour urinary or plasma 5-HIAA) confirms carcinoid syndrome.
• Long-acting somatostatin analogues (octreotide LAR 20 mg intramuscularly every 4 weeks, raised to 30 mg if needed; lanreotide 60-120 mg deep subcutaneously every 4 weeks) are first-line for symptoms and slow tumour growth, with telotristat ethyl, everolimus, PRRT and liver-directed therapy for refractory or progressive disease.

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

1. Define a neuroendocrine tumour and separate NET (well-differentiated) from neuroendocrine carcinoma (poorly differentiated), using the WHO 2022 grading.
2. Recognise carcinoid syndrome and the other hormone-secreting syndromes a NET can cause.
3. Explain why symptoms appear only when venous drainage bypasses the liver.
4. Choose and interpret the imaging used to find and stage a NET, including 68Ga-DOTATATE PET-CT.
5. Treat carcinoid syndrome: short- and long-acting somatostatin analogues, dose escalation, telotristat ethyl, everolimus, PRRT and liver-directed therapy.
6. Spot and manage complications: carcinoid crisis, carcinoid heart disease, mesenteric fibrosis and niacin (vitamin B3) deficiency.
7. Plan follow-up and counsel patients, including families with multiple endocrine neoplasia type 1.

The word "carcinoid" was introduced by Oberndorfer in 1907 for small-bowel tumours that looked like cancer but behaved indolently. It is still used, but ambiguously: histology, not the name, determines behaviour. The World Health Organization now classifies all of these as neuroendocrine neoplasms (NENs), split into well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NECs), on the basis of morphology, mitotic count and the Ki-67 proliferation index. A third category, mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), contains both components. ^[1]

"Functional" NETs secrete hormones and produce a recognisable clinical syndrome; most NETs are non-functional. ^[3]

Gastroenteropancreatic (GEP) NETs account for roughly 55 to 70% of all neuroendocrine neoplasms, and GEP NENs overall are uncommon but increasingly recognised: in the United States the age-adjusted incidence rose from 1.05 per 100,000 in 1975 to 5.45 per 100,000 in 2015. ^[1] Improvement in cross-sectional and endoscopic imaging is a substantial part of the rise. Site distribution differs by region: in US series the commonest primary sites are rectum, small intestine and pancreas; in China and Japan rectal and pancreatic NETs predominate. ^[1] NETs occur at all ages; appendiceal tumours usually present after age 50, and hereditary syndromes present earlier. ^[1] Women have slightly higher reported survival rates than men in most series, but no large difference in treatment response. ^[1]

Carcinoid syndrome develops in about 20% of well-differentiated small-intestine NETs and, overall, in roughly 19% of patients with neuroendocrine neoplasms, most often with grade 1 or 2 tumours of small-intestine or bronchopulmonary origin. ^[2][4] It is diagnosed most often in the fifth and sixth decades, with slightly more women affected. ^[2]

Most GEP NETs are sporadic. Approximately 10% of NEN cases occur in inherited syndromes, principally multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau disease, neurofibromatosis type 1 and tuberous sclerosis. ^[1] MEN1 is the commonest inherited predisposition to pancreatic NET (PNET): by age 50 more than 90% of MEN1 carriers have at least one endocrine tumour, including pancreatic endocrine tumours in 80 to 100%. ^[1] Tuberous sclerosis (TSC1/TSC2 mutations) is associated particularly with pancreatic NETs. Von Hippel-Lindau disease also predisposes to pancreatic NETs through hypoxia-inducible factor dysregulation. ^[1] No ordinary environmental or lifestyle risk factor is well established for sporadic NETs. ^[1]

The WHO Classification of Endocrine Tumours, 5th edition, underlies the system below. ^[1] Grading relies on two proliferative measures, both reported on the histology: mitotic count per 2 mm2 and the Ki-67 index (the percentage of tumour cells staining for the proliferation marker Ki-67).

Three points matter in practice. First, the "and/or" rule: a tumour is placed in the higher of the two grades if mitotic count and Ki-67 disagree. Second, well-differentiated NET G3 is now recognised as distinct from NEC: NECs show small-cell or large-cell morphology and are usually driven by TP53 and RB1 inactivation, while NET G3 retains well-differentiated morphology. ^[1] Third, older reports still use the 2010 WHO scheme, in which what is now NET G3 was labelled NEC, so historical survival data need care. ^[1]

The diffuse neuroendocrine cells of the gut release peptides and amines into the lamina propria. A key physiological fact explains the clinical rule: substances released into the portal venous drainage reach the liver, which inactivates serotonin, tachykinins and catecholamines before they reach the systemic circulation. Carcinoid syndrome therefore usually appears when a tumour, most often ileal, has metastasised to the liver (or, rarely, sits outside portal drainage, for example an ovarian metastasis or a lung NET), so the vasoactive products bypass hepatic clearance. ^[2][3][4]

Pulmonary metabolism provides a second safeguard: serotonin is inactivated in the lungs, so carcinoid heart disease affects the right-sided valves (tricuspid, pulmonary), which are exposed to the venous return before pulmonary clearance. ^[4]

Serotonin is the best-established mediator: it causes intestinal secretion and motility (diarrhoea), fibroblast proliferation (mesenteric and valvular fibrosis) and acts as a vasoactive substance. Tachykinins (substance P, neurokinin A) and catecholamines contribute to flushing. Histamine underlies the "atypical" flushing of gastric NET. ^[4] Antagonists of the serotonin pathway help diarrhoea but not flushing reliably, implying other mediators in the flush. ^[4]

Functioning syndromes depend on the cell type the NET arises from: a pancreatic beta-cell NET causes hypoglycaemia (insulinoma); a gastrin-secreting tumour causes gastric acid hypersecretion and intractable peptic ulceration and diarrhoea (gastrinoma, Zollinger-Ellison syndrome); an alpha-cell NET causes diabetes, a rash (necrolytic migratory erythema), weight loss and diarrhoea (glucagonoma); VIP secretion causes watery diarrhoea, achlorhydria and hypokalaemia (VIPoma); somatostatin secretion causes diabetes, gallstones, steatorrhoea and hypochlorhydria (somatostatinoma); pancreatic polypeptide secretion can cause weight loss and jaundice. ^[3] In the chest, typical and atypical bronchial carcinoids can produce carcinoid syndrome through lung bypass, and ACTH ectopia or Cushing syndrome may occur. ^[3]

NETs are grey-pink, firm, submucosal or intrapancreatic masses, often yellow on cut surface because of lipid. They are composed of uniform cells in nests, trabeculae or glands, with a finely granular "salt and pepper" chromatin and scant mitoses in low-grade tumours. Immunohistochemistry confirms the neuroendocrine lineage with synaptophysin and chromogranin A, and grades the tumour with Ki-67. ^[1] Morphology alone cannot separate NET G3 from NEC reliably; immunohistochemistry and molecular markers (TP53, RB1) are needed. ^[1] Mitotic count and Ki-67 can differ between the primary and its metastases or within one tumour (intratumoural heterogeneity), so a single small biopsy may under-grade the disease. ^[3]

A majority of NETs are non-functional and present late with local effects or metastatic disease. Symptoms split into those of the tumour itself and those of hormone excess.

Carcinoid syndrome is the commonest hormonal syndrome in NETs and is caused mainly by serotonin. ^[4] It is present in roughly 19 to 20% of patients with small-intestine NENs. ^[2][4] The components, in descending frequency, are:

• Flushing: sudden warmth and redness, usually of the face and upper chest, short-lived, often provoked by alcohol, food or emotion; reported in over 90% of cases in ENETS 2022 guidance (Mulders review: 65 to 78%; ENETS jejunoileal consensus: 60 to 85%). ^[6][4]
• Diarrhoea: secretory, watery, often 3 to 30 bowel movements daily; prevalence as high as 60 to 80% in ENETS 2022 guidance (Mulders review: 67 to 73%). ^[6][4]
• Bronchospasm or wheezing in about 15% (ENETS 2022 guidance; about 8 to 10% in the Mulders review; under 10% in the ENETS jejunoileal consensus). ^[6][4]
• Mesenteric fibrosis in about 50%, with postprandial abdominal pain, bowel obstruction or ischaemia. ^[2]
• Carcinoid heart disease: thickened right-sided valves with tricuspid regurgitation and stenosis, leading to right heart failure; about 20% in modern series, 20 to 50% in ENETS 2022 guidance, and 17 to 21% in the Mulders review (older series up to 50 to 60%). ^[6][4]
• Pellagra (niacin deficiency) from diverted tryptophan: scaly rash, sore tongue, confusion. ^[2]
• Carcinoid crisis in 19 to 35%: acute haemodynamic collapse or severe bronchospasm during procedures or surgery. ^[4]

Patients with carcinoid syndrome have shorter overall survival (4.7 years versus 7.1 years in patients without the syndrome in one cohort) and worse quality of life. ^[2]

A firm hepatomegaly, a palpable right lower quadrant mass, or a systolic tricuspid murmur (carcinoid heart disease) may be present. Small-intestine mesenteric masses or desmoplastic reaction can produce a palpable abdominal mass and signs of bowel obstruction. ^[2] Gastric NETs may be asymptomatic and discovered incidentally.

The clinical picture divides into two questions: a flush (other causes include menopause, alcohol, rosacea, mastocytosis, pheochromocytoma, medullary thyroid cancer) and chronic watery diarrhoea with a vasoactive aetiology. For the more frequent mimics the following separators help.

For the imaging mass itself, the differential includes other small-bowel tumours, pancreatic neoplasms, metastases and adenocarcinoma, distinguished histologically. ^[3]

The workup has three parts: confirm hormone excess, find the primary and measure stage and grade. ^[3][5]

• Chromogranin A is the most useful general marker of well-differentiated NET, but is non-specific (raised by proton pump inhibitors, renal impairment, chronic atrophic gastritis). ^[2]
• For carcinoid syndrome: 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) is the standard; a level above 50 micromol in 24 hours is compatible with the diagnosis. Sensitivity 73 to 91%, specificity 100%. ^[2] Plasma (or serum) 5-HIAA correlates closely and can be used as a single-sample alternative, with a reported cut-off of 135 nmol/L (sensitivity 91%, specificity 62% against the urine assay). ^[2]
• Other specific tests as the syndrome suggests: fasting gastrin and gastric pH (gastrinoma); 72-hour fast with insulin, C-peptide, proinsulin (insulinoma); glucagon, vasoactive intestinal peptide, somatostatin, pancreatic polypeptide, ACTH/cortisol. ^[3]

Morphological imaging first: contrast-enhanced CT of the neck, thorax, abdomen and pelvis, including a three-phase liver study, is recommended by ENETS for diagnosis, staging, response assessment and surveillance. ^[3] MRI (with diffusion-weighted imaging) is preferred for liver, pancreatic, brain and bone assessment; ultrasound helps for liver metastases and biopsy guidance. ^[3]

Functional (somatostatin-receptor) imaging is the key step. 68Ga- (or 64Cu-) DOTA-somatostatin analogue PET-CT (for example 68Ga-DOTATATE) combines anatomical and receptor information and is the diagnostic tool of choice for staging and restaging most non-insulinoma NETs, for locating an unknown primary and for selecting patients for peptide receptor radionuclide therapy. Sensitivity is 86 to 100% and specificity 79 to 100%, except in insulinomas where sensitivity is only about 25%. ^[3] Somatostatin receptor scintigraphy (111In-pentetreotide, OctreoScan) is reserved for when PET-CT is unavailable. ^[3] 18F-FDG PET is optional: it images high-grade G3 and high G2 disease with increased glucose metabolism and is a marker of worse prognosis. ^[3] CT or MRI enterography/enteroclysis assesses small-bowel primaries and mesenteric desmoplastic reaction. ^[3] Endoscopic ultrasound is the most sensitive test for pancreatic NETs and allows fine-needle biopsy with Ki-67 assessment. ^[3]

Tissue diagnosis is mandatory, from resection or metastasis biopsy, with grade reported on mitotic count and Ki-67. ^[3] Re-biopsy metastases if behaviour changes, because tumours can evolve to a higher grade. ^[3]

Diagnosis of NET requires histological confirmation of neuroendocrine differentiation. The WHO grade (G1-G3, NEC, MiNEN) above serves as the severity classification; staging follows standard TNM. ^[1][3] Carcinoid syndrome is diagnosed clinically in a patient with a NET plus elevated 5-HIAA (urinary above 50 micromol/24 h) together with typical symptoms. ^[2] Severity of carcinoid syndrome is tracked with bowel-movement frequency, flushing counts and 5-HIAA, and with carcinoid heart disease markers (transthoracic echocardiography and NT-proBNP) every 6 to 12 months. ^[2] There is no single serum score; use WHO grade, stage and biochemical trajectory together. ^[1][2]

Surgery is the only curative treatment when complete resection is possible (primary and, where appropriate, metastases). ^[1] For inoperable or metastatic disease, somatostatin analogues control symptoms and delay progression, with escalation to telotristat ethyl, everolimus, peptide receptor radionuclide therapy (PRRT), chemotherapy or liver-directed therapy as the disease dictates. ^[2] Care should be coordinated by a multidisciplinary team. ^[2]

Carcinoid crisis is a medical emergency: sudden flushing, severe blood-pressure swing, profuse diarrhoea and bronchospasm, usually triggered by anaesthesia, surgery, biopsy or PRRT. ^[4] Prevention is better than cure: guidelines recommend prophylactic octreotide, 100 to 500 micrograms subcutaneously every 6 to 8 hours or an intravenous infusion starting at 50 micrograms per hour, increased to 100 to 200 micrograms per hour if needed, from 12 hours before the procedure through it and afterwards until stable. ^[2] An intravenous octreotide bolus and infusion, fluids, corticosteroids and vasopressors are used once a crisis begins. ^[2] Not all authors agree that prophylactic octreotide prevents crisis, so recognition and readiness matter more than the prescription. ^[2]

• Short-acting octreotide: 100 to 600 micrograms per day by subcutaneous injection in 2 to 4 divided doses (mean 300 micrograms daily; up to 1500 micrograms daily in some patients) for the first 2 weeks, both to control symptoms and to establish response before switching to long-acting. ^[5]
• Long-acting octreotide LAR: 20 mg intramuscularly into the gluteal region every 4 weeks; continue subcutaneous octreotide for at least 2 weeks during the switch. After 2 months raise to 30 mg every 4 weeks if symptoms remain uncontrolled, or trial 10 mg if well controlled; doses above 30 mg monthly are not recommended by the label. ^[5]
• Short-acting rescue therapy: 100 to 500 micrograms subcutaneously every 6 to 8 hours, or escalation of the long-acting dose/shorter interval, for breakthrough carcinoid syndrome. ^[2]
• Lanreotide: 60, 90 or 120 mg by deep subcutaneous injection every 4 weeks. ^[2]
• Telotristat ethyl: 250 mg orally three times a day in carcinoid syndrome refractory to somatostatin analogues, reducing bowel movements by at least 30% in roughly 43% of patients. ^[4]
• Everolimus: 10 mg daily with long-acting octreotide 30 mg every 28 days in progressive or metastatic disease, where it prolongs progression-free survival and lowers 5-HIAA. ^[2]
• Interferon-alpha is an older, poorly tolerated option for refractory syndrome. ^[2]
• Pasireotide, a broader somatostatin receptor agonist, reduced diarrhoea and flushing in refractory syndrome but is not approved for carcinoid syndrome because of higher glycaemic adverse effects and trial discontinuation. ^[2]

Somatostatin analogues commonly cause gallstones (about 24% of carcinoid patients), steatorrhoea and malabsorption (exocrine pancreatic insufficiency), hyperglycaemia, hypothyroidism, vitamin B12 reduction and QT effects. ^[5] They also slow gut motility, which worsens constipation in some patients. ^[5] Octreotide must be stopped at least 4 weeks before each 177Lu-DOTATATE dose because it competes for the somatostatin receptor. ^[5]

Somatostatin-receptor expression falls as proliferation (Ki-67) rises, so somatostatin imaging is brightest in low-grade disease; conversely FDG-PET uptake increases with grade. Using both together increases sensitivity and refines prognosis. ^[3]

177Lu-DOTATATE improves progression-free survival in progressive, receptor-positive, well-differentiated G1-2 midgut NETs. ^[2] In the NETTER-1 trial, diarrhoea improved equivalently (48% versus 43%) in the PRRT plus octreotide arm compared with high-dose octreotide alone, with delayed deterioration of quality of life; it did not significantly improve flushing. ^[2] A more recent cohort reported reduced bowel movements by 30% or more in many patients treated with PRRT. ^[2] Carcinoid crisis can occur during PRRT, so high-risk patients (large tumour burden, liver metastases, prior crisis) need prophylaxis with octreotide and corticosteroids, although this is debated. ^[2]

In liver-dominant disease, embolisation techniques (bland embolisation, chemoembolisation, radioembolisation/SIRT) give a symptomatic response in about 82% and a biochemical response in about 61%; post-embolisation syndrome occurs in roughly 40% and more serious complications are less common. ^[2] Cytoreductive surgery relieves carcinoid syndrome in the great majority of suitable patients. ^[2] Liver-only metastases with resected primary in selected young patients may be considered for transplantation (5-year recurrence-free survival about 20 to 30%). ^[2]

• Resect the primary whenever feasible, because metastatic progression is unpredictable and complete surgery is curative. ^[1]
• Small-bowel NETs: segmental resection with mesenteric lymphadenectomy; management of mesenteric fibrosis may require careful surgical relief. ^[2]
• Site-specific surgical management (appendiceal, rectal and small-bowel primaries) cross-checks with the gastrointestinal topic; follow site-specific surgical consensus and grading. ^[3]

Follow-up interval depends on grade and stage. Low-grade, fully resected localised disease is reviewed with periodic biochemical markers and imaging; metastatic disease needs closer surveillance determined by its behaviour, with echocardiography every 6 to 12 months in carcinoid syndrome. ^[2] Re-image if symptoms recur or markers rise.

• Carcinoid crisis: life-threatening; see above. ^[4]
• Carcinoid heart disease: about 20% in modern series, 20 to 50% in ENETS 2022 guidance, and 17 to 21% in the Mulders review of carcinoid syndrome patients (older series up to 50 to 60%); right-sided valvular disease with right heart failure. Echo and NT-proBNP monitoring every 6 to 12 months; valve replacement when severe. ^[6][4]
• Mesenteric fibrosis: about 50% of patients with carcinoid syndrome in clinicopathological series; postsurgical abdominal pain, obstruction, ischaemia. ^[2]
• Malnutrition and vitamin deficiency: niacin (vitamin B3) deficiency (pellagra), cobalamin deficiency after terminal ileal resection, steatorrhoea from somatostatin analogues (treat exocrine pancreatic insufficiency with enzymes, minimum 40,000 USP per meal). ^[2]
• Sarcopenia and electrolyte losses from chronic diarrhoea. ^[2]
• Cholelithiasis from somatostatin analogues (about 24% in prolonged treatment). ^[5]
• Serotonin and tachykinin-mediated fibrosis elsewhere: pulmonary fibrosis, ureteric obstruction rarely. ^[4]

Well-differentiated NET G1 and G2 have a comparatively indolent course, but more than half of patients already have lymph node metastases at diagnosis and the liver is the commonest metastatic site, involved in about 82% of metastatic cases. ^[1] Five-year outcomes depend strongly on grade and stage and on whether the primary can be removed. Carcinoid syndrome shortens survival (4.7 versus 7.1 years in one comparison). ^[2] High-grade (G3) NETs and NECs behave aggressively and need chemotherapy-based regimens. ^[1] Pancreatic NET has more favourable survival in some surgical series; midgut NETs often have long natural histories even with metastases. ^[1] Markers that predict worse outcome include high Ki-67, FDG uptake on PET, and high 5-HIAA in carcinoid syndrome. ^[3][4]

No population screening exists for sporadic NETs. Patients with MEN1, von Hippel-Lindau disease, neurofibromatosis type 1 or tuberous sclerosis benefit from periodic biochemical and imaging surveillance for pancreatic and duodenal NETs according to syndrome-specific guidance; this is implied by the genetics above but follow the inherited-tumour protocols in your centre. ^[1] Because appendiceal NETs are the commonest incidental finding at appendicectomy, ensure the base and margin status are reported. ^[3] For carcinoid heart disease, screen with echocardiography every 6 to 12 months in all patients with carcinoid syndrome. ^[4] Try to prevent niacin deficiency in carcinoid syndrome with adequate nutrition; nicotinamide 200 to 250 mg where deficient. ^[2]

• Pregnancy: NETs in pregnancy are rare. Somatostatin analogues have limited safety data; management of any functioning or progressive NET is by a combined obstetric-endocrine-oncology team. ^[5] (Octreotide pregnancy data are insufficient to confirm safety.) ^[5]
• Children: small-bowel NETs are very uncommon in children; hereditary syndromes present earlier. Tuberous sclerosis predisposes to pancreatic NET. ^[1]
• Older adults: polypharmacy, renal and hepatic impairment change octreotide dosing (reduce to 10 mg monthly in dialysis or cirrhosis). ^[5]
• Immunocompromised and patients on PRRT: watch for marrow suppression and renal toxicity.

• A multiphase contrast CT (and a biopsy) is usually the most available staging tool when 68Ga-PET-CT is not present; somatostatin receptor scintigraphy, although less sensitive, may be available. ^[3]
• Functional assessment then relies on 24-hour urinary 5-HIAA (or plasma 5-HIAA), chromogranin A and serum syndrome-specific markers, which are easier to obtain than PET. ^[2][3]
• Long-acting somatostatin analogues are expensive; where they are unavailable, short-acting octreotide (100 to 600 micrograms daily subcutaneously) or dietary measures for diarrhoea may be used, with surgery for control of the primary and cytoreduction when possible. ^[5]
• Value for money lies in finding primaries and resecting early, plus avoiding unnecessary chemotherapy for low-grade disease. ^[1][3] Check your local formulary for available drugs and doses.

• Gastrointestinal neuroendocrine tumours (cross-check for site-specific surgery and follow-up)
• Multiple endocrine neoplasia type 1
• Pancreatic endocrine tumours and Zollinger-Ellison syndrome
• Cardiac valve disease, heart failure
• Malabsorption and steatorrhoea
• Serotonin pharmacology