Endocrine tumours of the pancreas
Physiology and pathology
Endocrine tumours of the pancreas are rare in comparison with tumours of the exocrine pancreas (see Benign and malignant diseases of the hepatobiliary system). Such tumours may be benign or malignant, single or multiple, functioning or nonfunctioning.
The islets of Langerhans contain at least five cell types:
- alpha cells, which produce glucagon
- beta cells, which produce insulin
- gamma cells, which produce somatostatin
- F-cells, which produce pancreatic polypeptide
- enterochromaffin cells, which produce serotonin.
However, it is important to note that individual islet cells are capable of producing more than one hormone and that these hormones may include peptides that are not normally associated with the pancreas, including gastrin, adrenocorticotropic hormone and vasoactive intestinal peptide.
Although the majority of cases occur sporadically, approximately 10% of patients with islet cell tumours are members of families demonstrating multiple endocrine neoplasia type I (MEN I; see Parathyroid).
Islet cell tumours may be functioning or nonfunctioning.
Non-functioning tumours, which form approximately 20% of islet cell tumours, produce symptoms related to their site and size, and in many ways are comparable to the more common adenocarcinoma of the pancreas. Most present in the head of the pancreas and most are malignant, so investigation and treatment is similar to those for adenocarcinoma. The differential features that declare these to be ‘APUDomas’ (APUD: amine precursor uptake and decarboxylation) are their capacity to take up radioactive iodine-labelled metaiodo-benzylguanidine (MIBG) and immunohistochemical staining for neurospecific enolase.
Functioning tumours produce a wide range of peptides as already defined. Rare forms are the glucagonoma, which produces the diabetes-dermatitis syndrome, the ‘VIPoma’ (VIP: vaso-active intestinal peptide), which stimulates cyclic AMP production by the gut leading to massive watery diarrhoea (pancreatic cholera), and the somatostatinoma, which produces diabetes and steatorrhoea.
The most common forms of functioning tumours of the islet cells, although themselves still rarities, are insulinoma and gastrinoma.
These are the most common forms of islet cell tumour of the pancreas. Seventy-five per cent of lesions are single adenomas, 10% are multiple and 10% are primarily malignant. The remaining 5% represent nesidioblastomas (diffuse micro-adenomatosis or nesidioblastosis hyperplasia of the B cells).
Patients usually present in middle age with Whipple's triad:
- Symptoms of confusion and bizarre behaviour, visual disturbance or transient motor defects following fasting, with the associated sympathetic discharge resulting in palpitations, sweating and tremor.
- Blood glucose levels during these episodes of less than 45 mmol/L.
- Rapid relief of symptoms and signs by the administration of glucose either orally or intravenously.
It is important to note that the neurological effects of hypoglycaemia are easily confused with a number of other conditions, including psychoses, and it is not unusual for there to be a significant delay in diagnosis if the classical features are not recognised.
Diagnosis can be established by fasting, with estimation of blood glucose levels and immunoreactive insulin every 6 hours. In the presence of an insulinoma, fasting stimulates hypoglycaemia and the presence of inappropriately high levels of insulin. The fasting is continued until either symptoms or hypoglycaemia result, although this may not occur for up to 72 hours. Very rarely, even such prolonged fasting will not result in hypoglycaemia, but vigorous exercise after 72 hours' fasting will invariably produce hypoglycaemia.
The tumours may be multiple and therefore localisation is necessary. Abdominal ultrasound, MRI and computed tomography (CT) scanning are all of value, but because the lesions are usually less than 2 cmin size at the time of diagnosis, the tumours are demonstrated in only 50% of cases. Recent studies have shown that endoscopic ultrasound may help in localisation of small tumours. As the tumours are hypervascular, arteriography will demonstrate tumours in half of the patients where the lesion has not been demonstrated by CT scanning. The most accurate technique for preoperative localisation is transhepatic portal venous sampling with measurement of insulin levels progressively at points along the portal vein. This technique demonstrates the site of the lesion in 95% of cases.
Acute hypoglycaemic episodes are easily treated by the administration of glucose, either intravenously or orally. Normal blood glucose can be maintained by frequent small meals.
Once the diagnosis has been established and the tumour localised, the treatment is surgical. Approach may be laparotomy or by laparoscopy. Localisation of the tumour is confirmed by the use of intra-operative ultrasound, using either technique.
Single tumours are removed by enucleation. If multiple tumours or nesidioblastomas are present, all involved tissue is removed as far as possible, usually with retention of the head of the pancreas to preserve both exocrine and endocrine function. This may still result in the development of diabetes. Where lesions are malignant, radical surgery, which may include resection of hepatic metastases, should be undertaken because of the difficulty of controlling hypoglycaemia in the presence of a large tumour burden. Diazoxide and longacting somatostatin analogues may be used to inhibit the production of insulin when there is residual malignancy and the tumours themselves can be treated by a combination of streptozotocin and 5-fluorouracil directed against the tumour, although the effect of these drugs is temporary and both have significant toxicity.
This is the second most common form of islet cell tumour, with the gastrin secretion resulting in Zollinger-Ellison syndrome. This is still a rare condition, with peptic ulcer disease being caused by a gastrinoma in less than 0.1% of patients with such ulcers. The lesions are most commonly single, in the form of either adenoma or carcinoma, with a small percentage resulting from multiple microadenomas or hyperplasia. Sixty per cent of the lesions are malignant and 40% benign. Ninety per cent of tumours are found in the ‘gastrinoma triangle’ (Gastrinoma triangle bounded by the cystic duct and the common bile duct, junction of the head and neck of the pancreas, and the second and third part of the duodenum. Ninety per cent of gastrinomas are found in this area.) Rarely, the lesions are in the submucosal region of the first or second parts of the duodenum. Lesions at that site are usually benign.
Three-quarters of patients present in a sporadic fashion, with the remaining 25% showing the features of MEN I. The diagnosis is suggested by the aggressive behaviour of peptic ulcers, with failure to respond to standard forms of medical therapy or rapid relapse after cessation of medical therapy for peptic ulcer. The gastric hypersecretion as a result of the inappropriate gastrin production may lead to profuse watery diarrhoea and indeed5%of patients present with diarrhoea alone and no evidence of peptic ulcer disease.
Patients presenting with the features described should have serum gastrin measured. Very high levels of gastrin suggest malignancy. To distinguish other causes of hypergastrinaemia a secretin test should be performed, as secretin acts as a stimulant for gastrin release from gastrinoma, while having little effect on other conditions. It is not necessary to carry out measurement of gastric acid levels, as was once thought to be important.
Upper gastrointestinal endoscopy will demonstrate the presence of an ulcer or ulcers that may be in unusual sites, such as the second part of the duodenum or in the jejunum after previous gastric surgery. Again endocopic ultrasonography may assist in detecting small tumours.
Dynamic CT scanning will demonstrate 80% of tumours, and because the tumours are not as vascular as insulinomas, arteriography has little additional role. Transhepatic portal venous sampling for measurement of gastrin levels after intra-arterial calcium gluconate injection may assist in tumour localisation.
There is now little role for extensive gastric surgery, including total gastrectomy, partly because medical therapy is now much more effective and partly because preoperative and intra-operative localisation of tumours has led to a much greater success rate for direct surgery to control the gastrinoma. Where tumours are small, localised and readily acccessible by open laparotomy or minimally invasive surgery, they should be removed, since this offers the only chance of cure.
Following recurrence after surgery or where surgery is not applicable, medical treatment should be undertaken.
This requires lifelong administration of H2-receptor antagonists or omeprazole to control acid secretion. However, because the risk of malignancy is relatively high, it is now usual to attempt cure of the syndrome. At laparotomy, intra-operative ultrasound is of major value, as it is with insulinomas, and this together with the pre-operative CT scanning should allow detection of most lesions. Single lesions or multiple small adenomas can be enucleated but, as with insulinoma, all involved tissue should be removed as far as possible. Again it is usual to leave the head of the pancreas, in an attempt to maintain endocrine and exocrine function. If no lesion is detected at operation, the duodenum should be opened to search for submucosal lesions, which although rare are easily treated by excisional surgery.Unresectable or metastatic gastrinoma is compatible with long survival, with either repeated resection of metastases or the administration of combined streptozoticin and 5-fluorouracil. These agents appear to be more effective with gastrinoma than with insulinoma, and although they may produce side-effects of nausea and vomiting, and renal and hepatotoxicity, their administration may produce several years of life of reasonable quality.