Medicine chapters
Neuroendocrine tumours and multiple endocrine neoplasia
Neuroendocrine tumours of the gut and pancreas (carcinoid syndrome, insulinoma, gastrinoma, VIPoma, glucagonoma) and the inherited multiple endocrine neoplasia syndromes MEN 1, MEN 2A and MEN 2B.
- Neuroendocrine tumours (NETs) arise from hormone-making cells of the gut, pancreas and lung; they stain for chromogranin A and most carry somatostatin receptors, so octreotide both images and treats them.
- Carcinoid syndrome (flushing, diarrhoea, wheeze, right-sided valve disease) usually means liver metastases; diagnose with 24-hour urinary 5-HIAA. Pancreatic NETs: insulinoma (Whipple triad), gastrinoma (Zollinger–Ellison), VIPoma (watery diarrhoea, low K), glucagonoma (rash, diabetes).
- MEN is autosomal dominant: MEN 1 (menin) = parathyroid, pituitary, pancreas; MEN 2 (RET) = medullary thyroid cancer + phaeochromocytoma, with hyperparathyroidism in 2A and marfanoid habitus and mucosal neuromas in 2B.
On this page
Overview
Neuroendocrine tumours (NETs) come from cells that make peptide hormones and amines. They occur mostly in the gut (small bowel, appendix, rectum), pancreas and lung (bronchial carcinoid, small cell carcinoma). Many grow slowly; some secrete hormones and cause dramatic syndromes.
Multiple endocrine neoplasia (MEN) syndromes are inherited conditions in which tumours arise in several endocrine glands, at the same time or one after another. Recognising one tumour should prompt a search for the others and screening of the family.
Neuroendocrine tumours: general features
- Markers: tumour cells and blood show chromogranin A (a storage-granule protein); synaptophysin on histology.
- Somatostatin receptors on most NETs allow:
- imaging with radiolabelled octreotide scintigraphy or 68Ga-DOTATATE PET-CT;
- treatment with somatostatin analogues (octreotide, lanreotide) and radiolabelled analogues (peptide receptor radionuclide therapy).
- Grade (Ki-67 index) and stage guide prognosis. Many are found by chance on scans.
- Functioning tumours present with hormone excess; non-functioning tumours present with mass effects or liver metastases.
Carcinoid tumours and carcinoid syndrome
Carcinoid tumours
- Arise from enterochromaffin cells. In the gut, the commonest sites are the appendix and terminal ileum; they also occur in the rectum, stomach and bronchus.
- An appendiceal carcinoid may present as acute appendicitis and be found on histology.
- Most do not cause hormone symptoms.
Carcinoid syndrome
Occurs in only a small minority (about 5% of gut carcinoids) and, for gut tumours, only once there are liver metastases. Normally the liver inactivates the amines drained from the gut in the portal blood; liver deposits release them directly into the systemic circulation. Bronchial and ovarian carcinoids drain directly into the systemic veins, so they can cause the syndrome without liver spread.
Mediators: serotonin (5-HT) (diarrhoea, heart fibrosis), bradykinin and other kinins (flushing), histamine, tachykinins, prostaglandins.
| Feature | Details |
|---|---|
| Flushing | Episodic, purple-red, face and neck; triggered by alcohol, food, stress; later permanent telangiectasia |
| Diarrhoea | Watery, with abdominal cramps |
| Bronchospasm | Wheeze |
| Heart | Right-sided valve fibrosis: tricuspid regurgitation and pulmonary stenosis, right heart failure (left side is spared because the lung inactivates serotonin) |
| Liver | Hepatomegaly from metastases |
| Pellagra | Tryptophan is used up making serotonin, so less niacin is made: dermatitis, diarrhoea, dementia |
Carcinoid crisis: severe flushing, bronchospasm, hypotension or hypertension and arrhythmia, often triggered by anaesthesia, surgery, biopsy or embolisation. Prevent and treat with IV octreotide.
In gut carcinoids the syndrome means the tumour has already reached the liver; the diagnostic test is 24-hour urinary 5-HIAA and symptoms respond to octreotide.
Carcinoid syndrome is "FDR": Flushing, Diarrhoea, Right heart lesions (plus wheeze).
Investigations
- 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA), the main breakdown product of serotonin: the key diagnostic test. Avoid serotonin-rich foods (bananas, tomatoes, avocados, walnuts, pineapple) and some drugs before the collection, as they cause false results.
- Plasma chromogranin A: raised in most.
- Imaging: ultrasound, CT or MRI of the liver; somatostatin receptor imaging (octreotide scan, DOTATATE PET) to find the primary and metastases.
- Echocardiography for carcinoid heart disease.
Management
- Surgery: resection of the primary (and of liver metastases where possible) is the only cure; right hemicolectomy for larger appendiceal or ileal tumours.
- Somatostatin analogues (octreotide, lanreotide): control flushing and diarrhoea, slow tumour growth, and cover surgery.
- Liver-directed treatment: hepatic artery embolisation, ablation.
- Peptide receptor radionuclide therapy, interferon-alfa, targeted drugs (mTOR and tyrosine kinase inhibitors), chemotherapy in selected cases.
- Valve replacement for severe carcinoid heart disease; niacin supplements.
Many patients live 5–10 years or more even with metastases because these tumours grow slowly.
Pancreatic neuroendocrine tumours
Arise from islet cells. Most are non-functioning. About 10–15% are part of an inherited syndrome (MEN 1, von Hippel–Lindau). Endoscopic ultrasound is the most sensitive test for small pancreatic tumours and allows biopsy.
| Tumour | Cell / hormone | Key features | Diagnosis | Treatment |
|---|---|---|---|---|
| Insulinoma (commonest functioning) | β cell, insulin | Fasting or exercise hypoglycaemia; confusion, odd behaviour, seizures, weight gain; most benign, single and small | 72-hour supervised fast: low glucose with high insulin, C-peptide and proinsulin | Surgical removal; diazoxide or somatostatin analogues if inoperable |
| Gastrinoma (Zollinger–Ellison syndrome) | G cell, gastrin | Severe, recurrent, multiple or unusually sited peptic ulcers (beyond the duodenal bulb), diarrhoea (acid inactivates pancreatic lipase), GORD; tumours in pancreas or duodenum | Raised fasting gastrin with high gastric acid; secretin stimulation test | High-dose proton pump inhibitor; surgery if localised |
| VIPoma (Verner–Morrison, WDHA) | Vasoactive intestinal peptide | Profuse watery (secretory) diarrhoea, hypokalaemia, achlorhydria or hypochlorhydria, dehydration, metabolic acidosis | High plasma VIP | Fluids and K+; octreotide; surgery |
| Glucagonoma | α cell, glucagon | Necrolytic migratory erythema (rash), diabetes, weight loss, DVT, anaemia, glossitis, low albumin | High glucagon | Surgery; octreotide |
| Somatostatinoma | δ cell, somatostatin | Diabetes, gallstones, steatorrhoea | High somatostatin | Surgery |
Somatostatinoma "inhibits everything": no insulin (diabetes), no CCK (gallstones), no pancreatic enzymes (steatorrhoea).
Insulinoma is the commonest functioning pancreatic NET; most are small, single and benign, and removal cures the patient.
Whipple's triad (for insulinoma and any true hypoglycaemia)
- Symptoms of hypoglycaemia (often fasting or after exercise).
- Low blood glucose proven at that time.
- Relief of symptoms when glucose is given.
Separating causes of hypoglycaemia with high insulin
| Cause | Insulin | C-peptide | Sulphonylurea screen |
|---|---|---|---|
| Insulinoma | High | High | Negative |
| Secret insulin injection (factitious) | High | Low (injected insulin has no C-peptide) | Negative |
| Sulphonylurea misuse | High | High | Positive |
C-peptide is made in equal amounts with the body's own insulin. High insulin with low C-peptide means insulin is being injected. Factitious hypoglycaemia is commoner than insulinoma, often in people with health-care access.
In a patient with peptic ulcers plus hypercalcaemia (and perhaps a pituitary tumour), think gastrinoma in MEN 1. Check calcium in every patient with Zollinger–Ellison syndrome.
Multiple endocrine neoplasia
All MEN syndromes are autosomal dominant. Affected people inherit one faulty copy of a tumour suppressor gene (MEN 1) or a gain-of-function oncogene (MEN 2). In MEN 1, tumours appear when the second normal copy is lost in a cell (the "two-hit" model), so they arise at different ages.
| Feature | MEN 1 (Wermer) | MEN 2A (Sipple) | MEN 2B (MEN 3) |
|---|---|---|---|
| Gene | MEN1 (menin), tumour suppressor | RET proto-oncogene | RET (different mutation) |
| Chromosome | 11 | 10 | 10 |
| Parathyroid | Hyperplasia/adenomas, about 95% (usually first) | Hyperplasia, about 60% | Absent |
| Pituitary | Adenomas, about 70% (prolactinoma commonest; GH, ACTH) | – | – |
| Pancreas/duodenum | NETs, about 50% (gastrinoma, insulinoma, non-functioning) | – | – |
| Thyroid | Adenomas (occasional) | Medullary thyroid carcinoma (nearly all) | Medullary carcinoma, early and aggressive |
| Adrenal | Cortical adenomas | Phaeochromocytoma, often bilateral | Phaeochromocytoma |
| Other | Carcinoids, lipomas, angiofibromas | – | Marfanoid habitus, mucosal neuromas (lips, tongue), intestinal ganglioneuromas |
MEN 1 = 3 Ps: Parathyroid, Pituitary, Pancreas. MEN 2A = 2 Ps + M: Parathyroid, Phaeochromocytoma, Medullary thyroid cancer. MEN 2B = 1 P + M + marfanoid + mucosal neuromas.
Primary hyperparathyroidism is usually the first and commonest feature of MEN 1; in MEN 2 the key tumour is medullary thyroid carcinoma, with calcitonin as its marker.
Medullary thyroid carcinoma (MTC) in brief
- From parafollicular C cells; secretes calcitonin (tumour marker), sometimes CEA and ACTH; amyloid stroma on histology.
- About a quarter of patients with MTC carry a RET mutation, even when no other MEN 2 tumour is present, so every case needs genetic testing.
- Calcium is usually normal despite high calcitonin.
- Treatment: total thyroidectomy with neck node dissection; radioiodine does not work (C cells do not take up iodine).
Management and screening
- Treat each tumour much as in sporadic cases. In MEN 1 hyperparathyroidism, all four glands are usually involved, so subtotal or total parathyroidectomy is done.
- Genetic testing of first-degree relatives once the family mutation is known, ideally in childhood.
- MEN 1 carriers: yearly calcium and PTH (simplest first screen), prolactin, IGF-1, gut hormones (gastrin, insulin and glucose), with periodic pituitary and pancreatic imaging. Pancreatic NETs can metastasise silently.
- MEN 2 carriers (RET): prophylactic total thyroidectomy in early childhood (around 5 years of age or earlier; earliest in MEN 2B), calcitonin monitoring, yearly metanephrines and calcium.
Before any thyroid or other surgery in MEN 2, exclude a phaeochromocytoma with metanephrines; if present, it is removed first under alpha-blockade.
Related inherited syndromes
| Syndrome | Endocrine and other features |
|---|---|
| Von Hippel–Lindau (VHL gene, chromosome 3) | Phaeochromocytoma, pancreatic NETs and cysts, cerebellar and retinal haemangioblastomas, renal cell carcinoma, renal cysts |
| Neurofibromatosis type 1 | Phaeochromocytoma, café-au-lait spots, neurofibromas |
| McCune–Albright (GNAS mosaic, not inherited) | Precocious puberty, other gland overactivity, polyostotic fibrous dysplasia, café-au-lait patches |
Do not mix up MEN (tumours, gland overactivity) with autoimmune polyendocrine syndromes (gland failure: Addison disease, hypothyroidism, type 1 diabetes, hypoparathyroidism).
Expect: carcinoid sites (appendix, ileum), why the syndrome needs liver metastases, flushing and diarrhoea, right-sided valve lesions, pellagra, 24-hour urinary 5-HIAA, octreotide for symptoms and crisis; insulinoma with Whipple triad, 72-hour fast and high C-peptide, and factitious insulin with low C-peptide; gastrinoma with resistant or distal ulcers and diarrhoea; VIPoma with watery diarrhoea and hypokalaemia; glucagonoma with necrolytic migratory erythema; somatostatinoma with gallstones and steatorrhoea; MEN 1 (menin, 3 Ps, hyperparathyroidism first, prolactinoma, gastrinoma); MEN 2A and 2B (RET, medullary thyroid cancer, phaeochromocytoma, marfanoid habitus, mucosal neuromas); calcitonin as the MTC marker; prophylactic thyroidectomy.
Quick revision
- NETs: chromogranin A; somatostatin receptors → octreotide scan, DOTATATE PET, octreotide therapy.
- Carcinoid syndrome: liver metastases; flushing, diarrhoea, wheeze, tricuspid regurgitation/pulmonary stenosis; urinary 5-HIAA; octreotide.
- Insulinoma: commonest functioning pancreatic NET; low glucose, high insulin and C-peptide; surgery or diazoxide.
- Gastrinoma: severe ulcers + diarrhoea; high gastrin; high-dose PPI; check calcium (MEN 1).
- VIPoma: watery diarrhoea, low K, achlorhydria. Glucagonoma: rash, diabetes, DVT. Somatostatinoma: diabetes, gallstones, steatorrhoea.
- MEN 1: menin, chromosome 11, parathyroid > pituitary > pancreas.
- MEN 2A: RET, MTC + phaeochromocytoma + parathyroid. MEN 2B: MTC + phaeochromocytoma + marfanoid + mucosal neuromas.
- RET carriers: early prophylactic thyroidectomy; exclude phaeochromocytoma before any surgery.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
Why does carcinoid heart disease affect the right side of the heart?
Serotonin from liver metastases reaches the right heart first; the lungs then break it down, so the left-sided valves are usually spared.
What is the best test for carcinoid syndrome?
A 24-hour urine collection for 5-HIAA, the main breakdown product of serotonin, taken after avoiding serotonin-rich foods.
How do you tell an insulinoma from someone injecting insulin?
Both have low glucose and high insulin, but C-peptide is high with an insulinoma and low when insulin is injected.
Which MEN syndrome has no hyperparathyroidism?
MEN 2B, which instead has a marfanoid build, mucosal neuromas of the lips and tongue and gut ganglioneuromas.
Why are children with a RET mutation offered thyroidectomy?
Nearly all carriers develop medullary thyroid cancer, which can spread early, so removing the thyroid in childhood prevents it.