Pancreatic endocrine tumours (PETs) are classified as neuroendocrine tumours (NETs). PETs arise from amine precursor uptake and decarboxylation (APUD) stem cells, which are pluripotent neuroendocrine cells within the ductular epithelium of the exocrine pancreas and elsewhere in the distal foregut. PETs can be divided into functional (exhibit a distinct clinical syndrome due to hormone hypersecretion) and non-functional tumours. The main syndromes caused by hormone secretion are:¹

• Insulinoma syndrome: insulin-secreting tumours and present with fasting hypoglycaemia and relief of hypoglycaemic symptoms after glucose administration.
• Zollinger-Ellison syndrome: high levels of gastrin secreted from a gastrinoma causing severe peptic ulceration.
• Verner-Morrison syndrome (vasoactive intestinal polypeptide-secreting tumour (VIPoma)): watery diarrhoea, hypokalaemia, and achlorhydria (deficiency of hydrochloric acid in the stomach)
• Glucagonoma syndrome: high levels of glucagon are secreted from pancreatic alpha cells.
• Somatostatinoma syndrome: 50% of these tumours originate in the delta cells of the pancreas and the remainder originate in the duodenum. Half of tumours in the duodenum are associated with neurofibromatosis type 1 (Von Recklinghausen's disease).
• Other rare clinical syndromes may occur, e.g. calcitoninoma, parathyroid tumour, growth hormone-releasing factor-secreting tumour (GRFoma), adrenocorticotrophic hormone-secreting tumour (ACTHoma), neurotensinoma and serotonin (5-hydroxytryptamine) secreting tumours (which are classified as carcinoid tumours).

The majority of PETs are non-functional.² Non-functional tumours may secrete pancreatic polypeptide (PP), which appears to be a marker of PETs but is not a mediator of any specific PP-related clinical syndrome.

Liver metastases are the most common secondaries beyond spread to regional lymph nodes. Bone metastases may occur late in the course of the disease and indicate a poor prognosis. In rare cases, pancreatic endocrine tumours metastasise to the lungs or brain.

Epidemiology

• Population-based studies have assessed the incidence of pancreatic neuroendocrine tumours (NETs) as 0.2-0.4 per 100,000.³ However, there is a much higher prevalence of 0.5-1.5% in unselected autopsy specimens.¹
• Most pancreatic endocrine tumours (PETs) are sporadic but they occur in approximately 75% of cases of multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant familial endocrine cancer syndrome.
• Insulinomas and gastrinomas are equally common and account for more than half of all clinically apparent PETs. VIPomas are one-eighth and glucagonomas are one-seventeenth as common. Somatostatinomas are even more rare. Non-functional tumours account for 14-48% of all recognised PETs.
• Currently, 1 patient in 1,000 with primary duodenal ulcer disease and 2 patients in 100 with recurrent ulcers after ulcer surgery are estimated to have a gastrinoma.
• Pancreatic NETs occur in 40-80% of patients with MEN 1 syndrome and are mostly non-functioning tumours or gastrinomas.⁴
• PETs appear to have a slightly higher incidence in women than in men. Patients with sporadic PETs present most often between 30-50 years of age. Patients with PETs as part of MEN 1 syndrome tend to present between 10-30 years of age.

Presentation¹

• Functional tumours exhibit metabolic and clinical characteristics depending upon the pancreatic islet cell type they arise from.
• Non-functional pancreatic endocrine tumours (PETs) typically present later in the course of their disease, when their tumours begin to cause symptoms related to tumour bulk or symptoms derived from metastases. An abdominal mass may be felt if there is a large, non-functional tumour. Large, non-functional neoplasms in the head of the pancreas may occasionally cause jaundice as a result of biliary obstruction.
• Physical examination in patients with pancreatic endocrine tumours generally reveals nonspecific findings.
• Insulinomas are benign in approximately 90%; all other types of PET are malignant in over 50% of cases.⁴

Insulinoma

• Episodic hypoglycaemia, usually in the early morning or after missing a meal, presenting with headache, light-headedness, confusion, visual disturbances, seizures, personality changes and even coma.
• Compensatory catecholamine excess can lead to palpitations, weakness, trembling, tachycardia, and irritability.
• Insulinomas are the most common cause of hypoglycaemia resulting from hyperinsulinism but extrapancreatic insulin-producing tumours and self-induced hypoglycaemia due to the administration of insulin or sulphonylureas should be considered.⁵

Gastrinoma

See separate Zollinger-Ellison Syndrome article.

• Abdominal pain and peptic ulceration of the upper gastrointestinal tract are the most common symptoms. The symptoms tend to be protracted and refractory to standard medical and surgical therapies.
• Symptoms of gastro-oesophageal reflux disease and dysphagia may occur.
• Diarrhoea occurs in more than a third of patients and steatorrhoea may also occur.

VIPoma

• The main symptom is severe watery diarrhoea causing weakness, hypotension, lethargy and weight loss. Abdominal cramps and nausea are common and flushing episodes may occur.
• Faecal potassium loss causes hypokalaemia.

Glucagonoma

• Dermatitis (necrolytic migratory erythema), nail dystrophy and stomatitis. Necrolytic migratory erythema is an erythematous rash, which typically begins in the groins and perineum and migrates to distal extremities, forming bullae which heal with hyperpigmentation.⁶
• Hyperglucagonaemia in patients with glucagonomas results in glucose intolerance (including diabetes) and weight loss (secondary to anorexia and increased catabolism).
• As many as a third of patients have secondary thromboembolic phenomena, with a history of deep venous thrombosis and/or pulmonary embolism.
• Normochromic normocytic anaemia may occur.

Somatostatinoma

• Somatostatinomas are associated with diabetes mellitus and anaemia.
• Postprandial fullness
• Relative biliary stasis with gallbladder calculi and symptoms of biliary colic.
• Diarrhoea and/or steatorrhoea, with malabsorption and weight loss.
• May present late with hepatic metastases.

Investigations

Diagnosis of clinical presentation

• Non-functioning pancreatic tumours:
  • It is recommended that serum chromogranin A and pancreatic polypeptide should be tested in patients with possible non-functioning pancreatic tumours.¹
• Insulinoma:
  • Fasting hypoglycaemia (<2.5 mmol/L) associated with an elevated insulin level (in the absence of exogenous administration of insulin).
  • Proinsulin and C-peptide test: proinsulin, C-peptide, and insulin are all increased in patients with insulinoma. Administration of insulin causes elevated insulin levels but normal or low proinsulin and C-peptide levels.
  • Anti-insulin antibodies strongly suggest administration of insulin rather than insulinoma. Insulin antibodies, especially at high titres, may also indicate the presence of autoimmune hypoglycaemia.
• Gastrinoma:
  • Fasting serum gastrin levels.
  • Basal and maximal gastric acid secretion.
  • Secretin stimulation test: a large increase in the gastrin level of more than 200 pg/mL above the basal level supports the diagnosis of gastrinoma.
• VIPoma:
  • Serum vasoactive intestinal polypeptide (VIP) Since VIP has a very short half life, the diagnosis is confirmed by the finding of elevated circulating histidine methionine, which is produced from the prepro-VIP molecule and co-secreted by VIPomata.
  • Pancreatic polypeptide levels are elevated in 75% of cases and neurotensin in 10%.
  • Low serum potassium and bicarbonate levels secondary to faecal loss. Hypomagnesaemia, hypercalcaemia and glucose intolerance are other common biochemical disturbances.
  • Low basal gastric acid output.
• Glucagonoma:
  • Serum glucagon levels greater than 1,000 pg/mL are diagnostic of glucagonoma.¹
• Somatostatinoma:
  • Raised fasting serum somatostatin levels.
  • Somatostatin receptor scintigraphy has been used to demonstrate hepatic involvement.⁷

Localising the tumour¹

• High-resolution contrast-enhanced spiral CT scanning is the initial imaging technique used to localise and stage most pancreatic endocrine tumours (PETs).
• MRI, somatostatin receptor scintigraphy or transduodenal endoscopic ultrasound may be useful for localisation of small tumours.³
• Provocative angiography can be used to map the location of occult gastrinomas and insulinomas.
• Selective transhepatic portal venous sampling: to help localise the tumour.
• Endoscopy: location and number of peptic ulcers. May reveal reflux oesophagitis.
• Intraoperative endoscopic transduodenal illumination may be helpful in the localisation of small PETs located within the wall of the duodenum.
• Intraoperative ultrasonography is the study of choice for localisation of insulinomas and is more effective than any preoperative diagnostic imaging study.

Management

Initial management

Many pancreatic endocrine tumour (PET) syndromes are potentially life-threatening at presentation. Initial treatments for specific syndromes may include:

• Insulinoma: may initially require immediate potassium replacement and dextrose administration. Hypoglycaemia can often be managed in the preoperative period by administering diazoxide.
• Gastrinoma: treatment is directed at stabilising the general haemodynamic condition of the patient, controlling bleeding from gastrointestinal ulcers and establishing a non-acidic gastric pH with the use of proton pump inhibitors.
• VIPoma-associated diarrhoea: replacement of volume losses and the correction of acid-base and electrolyte abnormalities.
• Glucagonomas: often require blood transfusions, total parenteral nutrition and preoperative control of hyperglycaemia.
• Somatostatinoma syndrome: nutritional support and control of hyperglycaemia are important aspects of care.

Subsequent management

• Somatostatin analogues:
  • The only effective medication for functional pancreatic endocrine neoplasms is a long-acting somatostatin analogue (e.g. octreotide), which is effective for all functional PETs except somatostatinoma.
  • Octreotide is also a useful adjunct in palliative treatment of patients with most functional metastatic PETs.
  • Patients with VIPoma frequently respond dramatically to small doses of somatostatin analogues with cessation of diarrhoea.³
  • Somatostatin analogues are not useful in the treatment of patients with somatostatinoma syndrome.
• Interferon alfa:
  • Interferon alfa-2a and alfa-2b: patients with PETs have shown good response with human leukocyte interferon.
  • The combination of alfa-interferon and somatostatin analogues has been shown to be beneficial for the treatment of patients with advanced malignant PETs.
• Insulinoma:
  • Diazoxide can be used to reduce insulin secretion for patients with insulinomas. When used with hydrochlorothiazide, its hyperglycaemic effect is increased.
  • Patients with unresectable insulinoma may gain benefit by eating frequent small meals with a high starch and complex carbohydrate content.
  • Exercise often exacerbates the symptoms of insulinoma syndrome secondary to relative substrate deficiency such as hypoglycaemia. Therefore, patients with insulinoma may need to avoid exercise until their tumour is successfully resected.

Chemotherapy

• Primarily reserved for patients with PETs that are metastatic and/or unresectable. No benefit from chemotherapy has been demonstrated in patients with metastases to only lymph nodes.
• Agents used include doxorubicin and 5-fluorouracil.

Surgery

Radical surgery has a central role in the therapy of endocrine tumours of the pancreas. Surgical management of the primary tumour is similar for the different types of pancreatic endocrine neoplasms. Surgical treatments may include:

• Small benign lesions remote from the main pancreatic: resection of the tumour.
• Tumours deep in the substance of the pancreatic gland and tumours larger than 2 cm in diameter: regional pancreatectomy. Lesions in the head or uncinate process of the pancreas can be resected with pancreaticoduodenectomy. Permanent diabetes mellitus can occur following extensive pancreatic tumour resection.
• When a preoperatively occult gastrinoma is not found during surgical exploration, despite the use of intraoperative ultrasonography and endoscopic transduodenal illumination, longitudinal duodenotomy can be performed to assess for duodenal microgastrinomas. The localised microgastrinomas can be resected and the duodenal defect closed.
• Selective provocative angiography should be performed for an occult insulinoma or gastrinoma so that the appropriate pancreatic segment can be resected.
• Metastatic disease to the liver should be resected when possible. Aggressive surgical therapy in patients with advanced disease may prolong survival.² Surgical resection or hepatic arterial embolisation of hepatic metastases, with or without chemotherapy, are effective. In patients with unresectable disease, radiofrequency or cryosurgical ablation should be considered.
• Liver transplant or splenectomy may be required for metastatic disease.

Prognosis

• Tumour resection, the absence of metastases, and the presence of MEN 1 syndrome are related to a better survival rate. The prognosis of patients with metastases only to regional lymph nodes is often similar to that of patients with only a primary tumour.
• Insulinomas: more than 90% of patients have benign neoplasms without evidence of metastases. As many as 97% of these patients can be cured with surgical resection.
• Glucagonoma:
  • Glucagonomas tend to present later and be larger than other pancreatic endocrine tumours (PETs) (5-10 cm) at diagnosis and as many as 80% are invasive or metastatic by the time of diagnosis. Surgical cure is possible in fewer than 20% of all patients.
  • Patients with hepatic gastrinoma metastases have a 5-year survival rate of 20-30%, compared with approximately 90% in patients without liver metastasis.
• VIPoma: approximately half are metastatic at the time of diagnosis or surgery. Approximately one third of patients are cured with surgery.
• Somatostatinomas: most are metastatic at the time of presentation but a number of patients survive 5 years after combination surgery and chemotherapy.
• The rate of metastases for non-functioning PETs varies from 64-92% in different series.¹

Document references

1. Ong SE; Neoplasms of the Endocrine Pancreas, Medscape, Dec 2009
2. Halfdanarson TR, Rubin J, Farnell MB, et al; Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer. 2008 Jun;15(2):409-27. [abstract]
3. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours, British Society of Gastroenterology & BMJ (2005); (Gut 2005;54(Supplement 4):iv1-iv16; doi:10.1136/gut.2004.053314 )
4. Alexakis N, Neoptolemos JP; Pancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2008;22(1):183-205. [abstract]
5. Perros P, Henderson AK, Carter DC, et al; Lesson of the week. Are spontaneous hypoglycaemia, raised plasma insulin and C peptide concentrations, and abnormal pancreatic images enough to diagnose insulinoma? BMJ. 1997 Feb 15;314(7079):496-7.
6. Necrolytic migratory erythema, DermNet NZ Website
7. Angeletti S, Corleto VD, Schillaci O, et al; Use of the somatostatin analogue octreotide to localise and manage somatostatin-producing tumours. Gut. 1998 Jun;42(6):792-4. [abstract]

Internet and further reading

• Islet Cell Cancer; US National Cancer Institute

Acknowledgements