Pancreatic neuroendocrine tumours: insulinoma and VIPoma

• Pancreatic neuroendocrine tumours are rare epithelial neoplasms arising from the pancreatic islets. Only a minority are "functioning", secreting a hormone that produces a recognisable clinical syndrome.
• Insulinoma is the commonest functioning pancreatic NET. It is usually small, solitary and benign, and presents with hypoglycaemia; surgical removal is curative in most patients.
• VIPoma is far rarer. It secretes vasoactive intestinal peptide, causing the WDHA syndrome of profuse watery diarrhea, hypokalaemia and achlorhydria. Most are malignant and already metastasised at diagnosis.
• Functional pancreatic NETs are graded as other pancreatic NETs using mitotic count and the Ki-67 proliferation index.
• A significant minority arise in inherited syndromes, especially MEN1, with important roles for VHL disease, NF1 and tuberous sclerosis complex.

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

1. Distinguish functioning from non-functioning pancreatic NETs and outline WHO grading of pancreatic NETs.
2. Describe the hereditary syndromes predisposing to pancreatic NETs and the functional syndromes each can produce.
3. Recognise an insulinoma, explain its symptoms and confirm it with a supervised 72-hour fast.
4. Localise an insulinoma with imaging and plan surgical or medical treatment.
5. Recognise the WDHA syndrome, confirm a VIPoma and manage its fluid, electrolyte and tumour complications.
6. Adapt care when specialist tests or drugs are unavailable.

Pancreatic neuroendocrine tumours arise from the endocrine cells of the pancreas. Most are non-functioning: they may produce hormones detectable in tissue but they cause no clinical hormone syndrome. A minority are functioning, releasing a hormone in excess and producing a clinical syndrome. Functioning tumours are usually identified earlier because of their effects, but many are metastatic at diagnosis. Non-functioning tumours more often present with mass effect or as incidental findings.

Functioning tumours are named by the predominant hormone. The principal functioning pancreatic NETs are:

Insulinoma and gastrinoma are the most frequent functioning pancreatic NETs; glucagonoma, VIPoma, somatostatinoma and the ectopic hormone syndromes are progressively rarer.

Pancreatic NETs are graded by proliferative activity. Well-differentiated tumours are graded 1 to 3 using mitotic count and the Ki-67 proliferation index. Grade 1 tumours have under 2 mitoses per 2 mm squared and a Ki-67 index under 3%. Grade 2 tumours have 2 to 20 mitoses per 2 mm squared or a Ki-67 index of 3 to 20%. Grade 3 well-differentiated tumours have over 20 mitoses per 2 mm squared or a Ki-67 index over 20%. Poorly differentiated neuroendocrine carcinomas share the same thresholds but are recognised by morphology. Insulinomas are usually well-differentiated grade 1 tumours, whereas large VIPoma cohorts more often contain grade 2 tumours.^[4][2] Ki-67 is measured on tissue; a grade from the primary tumour can underestimate the grade of metastases, so re-biopsy is sensible if behaviour changes.

About 17% of pancreatic NETs occur in an inherited syndrome.^[3] The most important associations are:

• Multiple endocrine neoplasia type 1 (MEN1). The commonest inherited cause of pancreatic NET. It presents with parathyroid hyperplasia, pituitary adenoma, and pancreatic or duodenal NETs. Pancreatic NETs in MEN1 are often multiple and frequently non-functioning. Among functioning pancreatic NETs in MEN1, insulinoma and gastrinoma predominate; glucagonoma, VIPoma and somatostatinoma each occur in roughly 1% of patients. Conversely, 4 to 8% of all insulinomas, 15 to 30% of gastrinomas, 6 to 11% of VIPomas, 5 to 20% of glucagonomas and 2 to 7% of somatostatinomas are associated with MEN1.
• Multiple endocrine neoplasia type 4 (MEN4). A rare, MEN1-like syndrome caused by CDKN1B mutations; reported pancreatic NETs have mostly been non-functioning.
• von Hippel-Lindau (VHL) disease. Pancreatic NETs occur in 11 to 17% of patients, but they are almost exclusively non-functioning, so hormone syndromes are not expected; surveillance imaging matters instead.
• Neurofibromatosis type 1 (NF1). Functioning pancreatic NETs are rare. Duodenal somatostatinomas occur in the periampullary region and often present with biliary or pancreatic duct obstruction rather than with the full somatostatinoma syndrome.
• Tuberous sclerosis complex (TSC). Pancreatic NETs are uncommon, but more frequent than in the general population, and insulinoma is the predominant functioning tumour.^[3][1]

A functioning pancreatic NET in a patient under 40 years, or with multiple lesions, a family history of endocrine tumours, or tumours at more than one site, should prompt assessment for a hereditary syndrome, genetic counselling and screening of relatives.

Insulinoma has an incidence of roughly 3 to 4 cases per million people per year in the cited review (older guidance gives a lower figure).^[1] About 90% are sporadic and only 5 to 10% are malignant.^[1] VIPoma is much rarer, with an estimated incidence of roughly 0.1 new cases per million per year, accounting for only about 1 to 3% of pancreatic NETs.^[2][5][2][5]

Sporadic insulinomas have no established predisposition apart from being more common in women in some series, and MEN1. VIPomas are sporadic in most cases (about 90% in the cited review) and about 5% occur in MEN1, though some cohorts report higher shares.^[1][2] Pancreatic NETs in inherited syndromes usually present at a younger age, are often multiple, and may be accompanied by tumours in other organs. VHL-related pancreatic NETs are smaller, cystic and indolent, and are managed by surveillance with surgery reserved for lesions of at least a few centimetres. MEN1-related disease is often managed with serial imaging of the pancreas and stomach; operative intervention follows the same oncological principles as sporadic disease.

Insulinoma. Insulin is normally released by pancreatic beta cells only when blood glucose is high. An insulinoma secretes insulin autonomously and suppresses hepatic glucose output even while the patient is fasting. The resulting hypoglycaemia starves the brain of glucose and triggers a catecholamine surge. The tumour is usually a well-differentiated small lesion, often discovered only by high-resolution imaging, and may occur anywhere in the pancreas, most often in the body or tail. Its size does not reliably predict behaviour; very small tumours can produce severe hypoglycaemia.

VIPoma. Vasoactive intestinal peptide attaches to receptors on intestinal epithelial cells, activates adenylate cyclase and raises intracellular cyclic AMP. The bowel epithelium then secretes electrolytes and water into the lumen instead of absorbing them, producing a secretory diarrhea that continues during fasting. VIP is a vasodilator (causing flushing), a glycogenolytic agent (causing hyperglycaemia in up to 50% of patients), and an inhibitor of gastric acid (causing hypochlorhydria or achlorhydria in most patients). Dehydration, hypokalaemia and bicarbonate wasting follow; hypercalcaemia occurs in up to 50% of patients from dehydration and/or bone resorption. Tumours are usually solitary, larger than 3 cm at diagnosis and more often in the pancreatic body or tail.^[1][5]

Insulinomas present with hypoglycaemia. Symptoms divide into autonomic and neuroglycopenic:

• Autonomic: tremor, sweating, palpitations, hunger, anxiety.
• Neuroglycopenic: confusion, behavioural change, visual disturbance, focal neurological deficits, seizures, coma.

In longstanding or recurrent hypoglycaemia the autonomic warning symptoms become blunted and neuroglycopenic symptoms predominate. About 42.5% of patients become symptomatic within the first 12 hours of a supervised fast, 67% within 24 hours and 95% within 48 hours. Weight gain is common (roughly half of patients) because hypoglycaemia drives carbohydrate intake and many symptoms occur at night or before breakfast. The classical description is the Whipple triad: symptoms consistent with hypoglycaemia, a documented low plasma glucose, and relief of symptoms after administration of glucose.^[1]

VIPoma presents with the WDHA syndrome. The cardinal feature is profuse watery diarrhea that continues during fasting and that may reach over 3,000 mL per day. Dehydration, lethargy, nausea, vomiting, muscle cramps, tetany, cardiac arrhythmias and collapse follow. Flushing occurs in most patients, and hyperglycaemia, hypercalcaemia, achlorhydria and metabolic acidosis complete the picture. Between 60 and 70% of patients already have metastases at diagnosis, most often in the liver.^[2][5]

The broad differentials are:

For hypoglycaemia: factitious insulin use produces hypoglycaemia with very low or undetectable C-peptide because exogenous insulin lacks C-peptide; sulfonylurea or meglitinide use produces hypoglycaemia with detectable C-peptide and can be uncovered by a urinary or plasma sulfonylurea screen; non-insulinoma pancreatogenous hypoglycaemia (adult nesidioblastosis, often after bariatric surgery); insulin autoimmune syndrome; non-islet cell tumour hypoglycaemia due to IGF-2; disorders of counter-regulation (adrenal insufficiency, hypopituitarism); glycogen storage disease; liver failure and malnutrition.

For watery diarrhea: osmotic diarrhea (laxative, malabsorption), secretory diarrhea from other tumours (gastrinoma, glucagonoma, carcinoid, medullary thyroid cancer), infectious diarrhea, chronic inflammatory bowel disease, idiopathic secretory diarrhea. The low stool osmotic gap and the failure of fasting to stop the diarrhea point to a secretory cause.

The table below summarises the imaging side. On imaging, the main mimics of a pancreatic NET are chronic pancreatitis with a mass, serous or mucinous cystic neoplasm, metastatic disease, accessory splenic tissue and focal fat.

A plasma glucose under 45 mg/dL (older guidance uses 40 mg/dL or less) in a non-diabetic, symptomatic patient should be drawn during symptoms and assayed immediately, together with insulin, C-peptide, proinsulin and beta-hydroxybutyrate. Spontaneous hypoglycaemia is often not seen in the clinic; a supervised 72-hour fast is then performed. The diagnostic criteria during the fast are:

• plasma glucose under 45 mg/dL
• plasma insulin above 3 microIU/mL (older guidance uses 6 or more)
• plasma C-peptide above 200 pmol/L
• plasma proinsulin above 5 pmol/L
• plasma beta-hydroxybutyrate below 2.7 mmol/L^[1]

If fasting hypoglycaemia is absent but symptoms follow meals, a mixed meal test is the alternative. Correction of the blood glucose before sampling, a high insulin with low C-peptide, or a positive sulfonylurea screen points away from insulinoma.

The diagnosis rests on suggestive symptoms with an elevated stool volume (less than 700 mL per day virtually excludes VIPoma; fasting volumes are at least 20 mL/kg/day and often exceed 3 litres per day) and a VIP serum level three times above the upper limit of normal, above 60 nmol/L, with a low stool osmotic gap under 50.^[5] VIP is secreted episodically, so sampling must be repeated when the patient is symptomatic and after fasting. Hypokalaemia, non-anion-gap metabolic acidosis, hyperchlorhydria's absence (achlorhydria), and hypercalcaemia complete the picture. If the clinical picture is suggestive but VIP is normal, repeat fasting and symptomatic testing is warranted; other tumours can secrete VIP weakly.^[5]

• Multiphasic CT. Required to localise insulinomas, which are small hypervascular lesions; sensitivity is 83 to 88% in the arterial phase and 11 to 76% in the portal venous phase, and 94% for typical hypervascular lesions. VIPomas are larger and usually hypervascular masses.
• EUS. Sensitivity around 87% and specificity 98% for pancreatic NETs, can detect lesions of 2 to 5 mm, and gives the distance to the main duct for enucleation planning.
• MRI. Useful for pancreatic and liver disease, with reported sensitivity and specificity of 54 and 65% for insulinomas.
• Somatostatin receptor imaging (SRI). Important for staging and for peptide receptor radionuclide therapy (PRRT) selection. Insulinoma detection with somatostatin analogues is suboptimal because insulinomas often have low SSTR2, are small, and because there is physiological uptake in the uncinate process; sensitivity and specificity with DOTATOC PET/CT in one recent study were 58 and 89%.
• GLP-1 receptor PET (gallium-68 exendin-4). Has a pooled sensitivity of 94% for localised insulinoma and outperforms somatostatin-based imaging, because most insulinomas express GLP-1 receptors.^[1]
• Arterial calcium stimulation with hepatic venous sampling (ASVS). The gold standard invasive test for occult insulinomas that cannot be localised by imaging, with sensitivity 93% and specificity 86% in a meta-analysis; calcium is injected into the gastroduodenal, splenic and superior mesenteric arteries and insulin is sampled from the hepatic vein.
• EUS-guided biopsy confirms histology and Ki-67 grade when management changes on grade.

Insulinoma is diagnosed biochemically and on imaging; histology is usually confirmed at surgery. VIPoma requires the characteristic syndrome, elevated VIP and exclusion of other causes of secretory diarrhea. VIP above five times the upper limit of normal carries a worse prognosis.^[1] The grade (Ki-67) guides treatment intensity. Stage and grade together guide surgery and systemic therapy. WHO stage for pancreatic NETs follows the standard TNM categories.

Acute control. Frequent carbohydrate-rich meals, nocturnal snacks and, when needed, intravenous glucose control acute hypoglycaemia. Glucagon (intramuscular, subcutaneous or intranasal) reverses acute hypoglycaemia. Diazoxide 50 to 600 mg daily is the first-line medical therapy for advanced insulinoma, acting on ATP-sensitive potassium channels in the tumour, with about 50% efficacy. Somatostatin analogues reduce insulin secretion in advanced insulinoma with 50 to 60% efficacy, but a trial of short-acting octreotide under glucose monitoring is advisable first because SSA can also suppress glucagon and paradoxically worsen hypoglycaemia; everolimus and pasireotide have additional value in refractory disease. Glucocorticoids are rarely used. Verapamil, beta-blockers and diphenylhydantoin have been used with inconsistent results. EUS-guided radiofrequency ablation is an option for small, localised insulinomas in patients unfit for surgery.

Definitive treatment. Curative surgery is the standard for localised insulinoma.^[1] Parenchyma-sparing resection, laparoscopic or open, with intraoperative ultrasound, is first line; enucleation is suitable for insulinomas under 2 cm located at least 3 mm from the main pancreatic duct.^[1] Formal lymphadenectomy is not routinely required because nodal metastases are uncommon. Outcomes in metastatic insulinoma are worse, but individual patients may do well with cytoreduction.

Malignant or metastatic disease. Cytoreductive surgery is considered when 70 to 90% of visible disease can be removed with safe liver function. Liver-directed therapy, PRRT and systemic therapy (everolimus, sunitinib, chemotherapy) are used for metastatic disease under multidisciplinary care; sunitinib in particular should be used with caution because it may worsen hypoglycaemia.

Acute stabilisation. Resuscitation with intravenous fluids and electrolyte replacement is the first step because patients may be severely dehydrated and hypokalaemic. Potassium, magnesium and acid-base status must be corrected. Once stabilised, somatostatin analogues are the first-line medical therapy for both preoperative control and advanced disease, because they effectively control excessive VIP and prolong progression-free survival.^[1] Glucocorticoids may be used if secretory diarrhea does not respond to somatostatin analogues. PRRT, chemotherapy, molecular targeted therapy and liver-directed therapy are further options for metastatic disease.

Definitive and cytoreductive treatment. Surgery is the only potentially curative treatment,^[1] but only about a third of patients have resectable disease at diagnosis. Curative intent removal (distal pancreatectomy, enucleation or pancreaticoduodenectomy) resolves the hormone syndrome. In metastatic disease, resection of the primary and debulking of metastases can give good symptom control and long survival; about half of patients with metastatic disease survive at least ten years in expert centre series.^[2] Liver transplantation has been used in selected patients.

Follow-up. Recurrence is frequent in VIPoma, so long-term surveillance of symptoms, imaging and VIP levels is required.

• Insulinoma: severe hypoglycaemia, traumatic injury from blackouts, permanent neurological damage, death if unrecognised. Surgical risks include pancreatic fistula and exocrine or endocrine insufficiency; recurrence is more common in syndromic disease.
• VIPoma: dehydration, renal failure, arrhythmia, cardiac arrest, Wernicke syndrome from prolonged deficiency, fracture from osteomalacia, thromboembolism. Post-operative complications follow pancreatic surgery. Metastases to liver, lymph nodes, lung, bone and (rarely) skin.

Insulinoma is benign in 90% of cases in most series and surgery is usually curative. Incidental and syndromic cases need screening for new or recurrent tumours. VIPoma has a high metastatic rate, yet in specialist centre cohorts the median overall survival is about 15 years, including about 12 years for patients with stage IV disease at diagnosis, with better outcomes when the primary tumour is resected.^[2]

There is no primary prevention of sporadic insulinoma. Screening is reserved for families with MEN1 or other hereditary syndromes. In MEN1, endoscopic ultrasound or MRI of the pancreas and stomach begins in adolescence or early adulthood and continues at intervals, along with measurement of fasting glucose, gastrin, VIP and chromogranin where indicated. Patients found to have a small non-functioning pancreatic NET are increasingly managed with active surveillance rather than immediate surgery. Genetic counselling should precede testing.

In insulinoma, multiple or recurrent lesions, or presentation in childhood or young adulthood, raise MEN1 or TSC. VIPoma in a child is usually a ganglioneuroma or neuroblastoma rather than a pancreatic tumour. Tumours are managed in specialist centres with multidisciplinary care. Pregnancy data are limited and management is individualised.

• A supervised 72-hour fast needs an inpatient bed and repeated glucose measurements; if only an overnight stay is possible, a 24- or 48-hour fast still catches the majority (about two-thirds within 24 hours and 95% within 48 hours).^[1] Whipple triad, low fasting glucose with inappropriately high insulin and C-peptide, and resolution after glucose are diagnostic.
• If GLP-1 receptor PET and EUS are unavailable, multiphasic CT with careful arterial phase imaging, ultrasound or basic MRI, plus intraoperative palpation and ultrasound, still allows curative resection in most insulinomas.
• Diazoxide may not be on formulary; frequent meals, uncooked cornstarch at bedtime, and glucagon for emergencies provide partial control. Surgical removal, where expertise exists, remains the cure.
• For VIPoma, the life-threatening problem is dehydration and hypokalaemia. Rapid isotonic fluid replacement with potassium and base is essential and costs little. Octreotide is expensive and may be unavailable; loperamide, fluid replacement and glucocorticoids provide partial control. Referral to a centre with pancreatic surgery and somatostatin receptor imaging should be early.
• Histology and Ki-67 grading should be obtained wherever pathology is available; where it is not, clinical behaviour guides treatment.

Pancreatic exocrine disease; acute and chronic hypoglycaemia; diabetes mellitus; multiple endocrine neoplasia type 1; pancreatic surgery; liver metastases and liver-directed therapy; peptide receptor radionuclide therapy; somatostatin analogues.

• Insulinoma has an incidence of roughly 3 to 4 cases per million people per year in the cited review (older guidance gives a lower figure). ^[1]
• About 90% of insulinomas are sporadic and only 5 to 10% are malignant. ^[1]
• VIPoma has an estimated incidence of roughly 0.1 new cases per million per year and accounts for about 1 to 3% of pancreatic neuroendocrine tumours. ^[2][5][2][5]
• About 17% of pancreatic neuroendocrine tumours occur in an inherited syndrome. ^[3]
• The classic presentation of insulinoma is the Whipple triad: symptoms consistent with hypoglycaemia, a documented low plasma glucose, and relief after glucose administration. ^[1]
• A supervised 72-hour fast supports insulinoma when plasma glucose is under 45 mg/dL with insulin above 3 microIU/mL, C-peptide above 200 pmol/L, proinsulin above 5 pmol/L, and beta-hydroxybutyrate below 2.7 mmol/L. ^[1]
• VIPoma produces secretory diarrhea that continues during fasting, flushing from vasoactive intestinal peptide's vasodilation, hyperglycaemia in up to 50% of patients, achlorhydria in most, and hypercalcaemia in up to 50%. ^[1][5]
• Between 60 and 70% of patients with VIPoma already have metastases at diagnosis, most often in the liver. ^[2][5]
• VIPoma is supported by fasting watery diarrhea, a VIP level three times the upper limit of normal (above 60 nmol/L), and a stool osmotic gap under 50. ^[5]
• GLP-1 receptor (gallium-68 exendin-4) PET has a pooled sensitivity of 94% for localised insulinoma and outperforms somatostatin-based imaging. ^[1]