Pancreatic Endocrine Tumours

These are rare endocrine tumours which originate from pancreatic islet cells. They are classified as neuroendocrine tumours (NET) but were previously described as apudomata.

• NETs can also arise from gastroenteric tissue, respiratory epithelial cells or parafollicular cells of the thyroid (medullary carcinoma of the thyroid).
• The tumours may be functional (exhibiting a distinct clinical syndrome due to hormone hypersecretion) or non-functional, and benign or malignant. 90% of non-functional tumours are malignant.

• Population based studies have assessed the incidence of pancreatic NETs as 0.2-0.4 per 100,000.¹
• The majority of pancreatic endocrine tumours are non-functional.²
• Insulinomas and gastrinomas are the commonest pancreatic endocrine tumours and are associated with multiple endocrine neoplasia (MEN 1).
• In MEN1, pancreatic neuroendocrine tumours occur in 40-80% of patients and are mostly non-functioning tumours or gastrinomas.³
• Insulinomas are benign in approximately 90%; all other types of pancreatic endocrine tumour are malignant in over 50% of cases.³

• Functional tumours exhibit metabolic and clinical characteristics depending upon the pancreatic islet cell type they arise from.
• Non functional tumours typically present due to tumour bulk or symptoms derived from metastases.

• If a pancreatic NET is suspected, investigations should include measurement of chromogranin A and 5 hydroxy indole acetic acid.
• Measurement of serum calcium, calcitonin, prolactin and parathyroid hormone can help to assess the presence of MEN 1.
• The measurement of other tumour markers may be indicated depending on the possible differential diagnosis.
• Hormonal radioimmunoassay can be used to confirm the diagnosis of the various tumour syndromes.

The appropriate imaging technique to localise a tumour is dependant on the tumour type:

• Functional tumours such as pancreatic vipomas, glucagonomas, somatostatinomas and non functional tumours are usually large (>2cm) at presentation and can be identified by CT scanning.
• A functional tumour secreting more active hormones, for example an insulinoma or gastrinoma, typically produces symptoms when less than 1cm in size. Magnetic resonance imaging, somatostatin receptor scintigraphy (SRS) digital subtraction angiography or endoscopic ultrasound may be used for localisation in these cases.¹

A very rare tumour (incidence 1 in 20 million) originating from glucagon secreting alpha cells.

Presentation

• Weight loss, impaired glucose tolerance, venous thrombosis, normocytic normochromic anaemia, bowel disturbance, nail dystrophy, depression and paraneoplastic neurological syndromes.
• Necrolytic migratory erythema is an erythematous rash associated with glucagonomas. The rash typically begins in the groins and perineum and migrates to distal extremities forming bullae which heal with hyperpigmentation.

Diagnosis

Raised fasting plasma glucagon.

Management

• 70% of patients have metastases at the time of presentation making a surgical cure difficult. However liver metastases may be resected or treated by liver transplant.
• Surgery can be complicated by the increased risk of thrombosis associated with glucagonomas. This is refractory to anticoagulation.
• Tumours may respond to chemotherapy with streptozotocin and 5-fluorouracil.
• Dacarbine or hepatic embolectomy can be used in resistant cases. Octreotide (a somatostatin analogue) is useful for controlling necrolytic migratory erythema but resistance to the treatment usually develops after about 6 months of use.

• These beta cell derived insulin secreting tumours are usually slow growing and only 10% are malignant.
• 10% of tumours are multiple and 50% of these occur in patients with MEN1.
• The median age at diagnosis is about 50 years but patients with MEN1 related insulinomas typically present in their mid twenties.

Presentation

Episodic hypoglycaemia, usually in the early morning or after missing a meal, and central nervous system dysfunction (confusion, personality change, blurred vision, weakness, convulsion, coma), which is immediately reversed by glucose administration.

Diagnosis

• Fasting hypoglycaemia (<2.5 mmol/l) associated with an elevated insulin level (in the absence of exogenous administration of insulin).
• Measurement of plasma proinsulin may be helpful for diagnosing insulin-secreting carcinomas.

Differential diagnosis

• Endocrine disorders such as hypopituitarism , Addison's disease , myxoedema, liver or renal failure may present with hypoglycaemia as a secondary feature.
• Insulinomas are the most common cause of hypoglycaemia resulting from hyperinsulinism but extrapancreatic insulin-producing tumours should also be considered as well as self-induced hypoglycaemia due to the administration of insulin or sulphonylureas.⁴

Management

• Diazoxide can be used to reduce insulin secretion. When used with hydrochlorothiazide its hyperglycaemic effect is increased.
• Octreotide may also prevent hypoglycaemia.
• Glucagon must not be used as it stimulates insulin secretion leading to severe hypoglycaemia.
• Surgery can be curative in 90% of patients and resection is often feasible even when metastases are present.
• Chemotherapy with streptozotocin in combination with doxorubicin or 5-fluorouracil is used in progressive disease.

This is an extremely rare malignant tumour (incidence 1 in 40 million). 50% 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).

Presentation

Pancreatic tumours present late with hepatic metastases. They are associated with diabetes mellitus, malabsorption, anaemia, weight loss and post prandial fullness.

Diagnosis

• Elevated somatostatin.
• Somatostatin receptor scintigraphy has been used to demonstrate hepatic involvement.⁵

Management

Curative resection may be attempted but most cases are managed by palliation with chemotherapy and hepatic embolisation.

Although the majority of tumours are found in the pancreas, up to 40% occur in the duodenum or stomach and up to 30% are associated with MEN1. 75% of tumours associated with MEN-1 are malignant with metastases present at the time of diagnosis.

Presentation

• Increased gastrin production causes hypersecretion of acid and multiple peptic ulcers (Zollinger-Ellison syndrome).
• Excessive acid secretion can also cause diarrhoea and steatorrhoea due to the inactivation of small bowel enzymes. This may precede ulcer disease by more than 12 months.

Diagnosis

• Raised fasting gastrin concentration (>1000 pg/ml) associated with increased basal gastric acid secretion, (when not taking H2-blockers or PPI's).
• A secretin test is sometimes used to exclude hypergastrinaemia secondary to G-cell hyperplasia or retained antrum post gastrectomy.

Management

• Resection of localised non metastatic tumours.
• Proton pump inhibitors will almost completely inhibit acid secretion and are highly effective for palliation in metastatic disease.

90% of tumours occur in the pancreas and 50% of these have metastasised to the liver and lymph nodes at the time of diagnosis.

Presentation

Severe diarrhoea with up to 10 litres of stool per day causing severe dehydration, weakness, hypotension, abdominal colic, flushing and weight loss (Verner Morrison Syndrome).

Diagnosis

• Fasting plasma vasoactive intestinal polypeptide (VIP) >500 pg/ml.
• 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%.
• In addition to the presence of watery diarrhoea, hypokalaemia and achlorhydria are also seen hence the synonym WDHA Syndrome.
• Hypomagnesaemia, hypercalcaemia (probably due to PTHrP), and glucose intolerance are other common biochemical disturbances.
• VIPomata are usually large and consequently localisation is usually straightforward.

Management

• Non metastatic disease is treated by surgical resection.
• VIPoma crisis can occur with severe electrolyte disturbance and requires fluid and electrolyte support with central venous pressure monitoring.
• Patients frequently respond dramatically to small doses of somatostatin analogues with cessation of diarrhoea.¹

• The majority of non functional pancreatic endocrine tumours present late with bulk effects such as obstructive jaundice and bowel obstruction.
• Immunocytochemical analysis aids distinction of these tumours from adenocarcinomas.
• The prognosis is generally poor as they are resistant to chemotherapy but palliation can be achieved by the use of hepatic embolisation.

Most pancreatic NETs are sporadic but they occur in approximately 75% of cases of multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant familial endocrine cancer syndrome.

• Pancreatic NETs are very rare tumours with a variable prognosis.
• Patients with completely resected tumours generally have a good prognosis, and aggressive surgical therapy in patients with advanced disease may also prolong survival.²
• The overall 10 year survival rate for malignant tumours is approximately 50%.
• Long-term survival has been reported even in the presence of widespread metastases.