Neuroendocrine tumors (NETs) are tumours (neoplasms) that arise from the cells of the endocrine (hormonal) and nervous systems. Many are benign, while some are malignant. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the lung and the rest of the body. Although there are many kinds of neuroendocrine tumor, they are treated as a group of tissue disease because the cells of these neoplasms share common features, such as a similar appearance, having special secretory granules, and often producing biogenic amines (such as serotonin) and polypeptide hormones.
Neuroendocrine tumours in detail - technical
Neuroendocrine tumors are a group of neoplasms arising from neuroendocrine cells of the diffuse endocrine system. They comprise approximately 2% of all malignant tumors of the gastrointestinal tract, and are usually sporadic, but they may occur as part of multiple endocrine neoplasia 1 syndrome (MEN1), von Hippel–Lindau syndrome, neurofibromatosis, and tuberous sclerosis.
Most have relatively slow tumor growth, but malignant potential, and most are diagnosed when distant (mainly liver) metastases have developed. Gastrointestinal neuroendocrine tumors (carcinoids) and neuroendocrine pancreatic tumours (islet cell tumours) make up the majority.
Surgery of the primary and metastasis, where possible, remains the only chance of cure. Somatostatin analogues control symptoms in cases of functional tumors, and peptide receptor treatment, transarterial hepatic embolization (or chemoembolization), chemotherapy are options for palliative therapy.
The term Karzinoide was originally used by Obendorfer in 1907 to describe a carcinoma-like lesion without malignant qualities. It has now come to refer to tumours capable of producing serotonin (5-hydroxytryptamine, 5-HT). However, several different cell types either synthesize or take up 5-HT and so the term carcinoid is applied to a variety of malignant tumours with different biological behaviour grouped by their similar histological appearances. This section focuses primarily on those tumours associated with the classic carcinoid syndrome.
Primary gastrointestinal carcinoid tumours are derived from the embryonic foregut (thyroid, bronchus, stomach, common bile duct, and pancreas), midgut or hindgut. The most common sites for carcinoid tumours are the appendix and rectum, but these tumours, often found incidentally on histological examinations of appendicectomy and rectal biopsy specimens, are almost always benign. Rectal neuroendocrine tumours generally produce glucagon-like peptides and PYY rather than 5-HT and are not usually associated with a clinical syndrome, even when they metastasize.
The carcinoid syndrome occurs in about 10% of patients with carcinoid tumours. It does not develop when the tumour drains through a normal liver, and so midgut tumours have almost always metastasized, usually to the liver, before symptoms develop. The carcinoid syndrome is most commonly due to a metastatic midgut tumour, about 50% of which metastasize to the liver. Primary carcinoid tumours are bronchial in origin in about 10% of cases, and rarely occur in the ovary and testis. Tumours in these sites may be associated with the syndrome in the absence of metastases. The annual incidence of the carcinoid syndrome is about 1 in 500 000.
The cardinal feature of the classic carcinoid syndrome is the flush. The carcinoid flush predominantly involves the head and upper thorax, and is usually associated with tachycardia, hypotension, increased skin temperature and, sometimes, wheezing. Rarely, flushing extends to the trunk and limbs, and may be associated with lacrimation, facial oedema, and great distress. Attacks are paroxysmal and usually unprovoked, although precipitating factors include alcohol or food ingestion, stress, emotion, or exertion. Flushing initially lasts for only a few minutes, but as the disease progresses may become almost continuous, and such patients often develop a chronically reddened and cyanotic facial hue, with widespread telangiectasia, the ‘leonine facies’. This fixed flush is more commonly seen with bronchial carcinoids, which are often metabolically inactive, but when associated with flushing can cause severe attacks lasting for hours or days, occasionally with profound hypotension and even anuria. Gastric carcinoids are often associated with raised, localized, wheal-like areas of flushing, which are usually pruritic and may migrate.
The other characteristic feature of the syndrome is secretory diarrhoea, which may be profuse and accompanied by electrolyte disturbance, cramping abdominal pain, nausea, and vomiting. Rarely these symptoms may result from small-bowel obstruction by a large ileal carcinoid tumour, but the majority of primary tumours are small, usually being less than 1% of total body tumour weight. Hepatic metastases may cause right hypochondrial pain, particularly if the liver capsule is involved or stretched, and acute exacerbations may occur if metastases become ischaemic and undergo autonecrosis. Weight loss and, in the later stages, cachexia are common as a result of poor dietary intake, malabsorption, and increased catabolism. Pellagra with dermatitis of sun-exposed areas may occur, the increased conversion of 5-hydroxytryptophan into 5-HT causing nicotinamide deficiency.
Cardiac valve abnormalities affect about 50% of patients. They occur as a result of endocardial fibrosis, with plaques of smooth muscle in a collagenous stroma deposited on the valves. Lesions are almost always on the right-hand side, left-sided valve damage occurring only in association with bronchial carcinoids, which drain into the left atrium, or atrioseptal defects with right to left shunting. The most common lesions are tricuspid incompetence and pulmonary stenosis, and the usual clinical outcome is oedema and breathlessness due to right ventricular failure, which can be fatal. The other causes of breathlessness in association with the carcinoid syndrome are bronchospasm, which affects a small number of patients, often occurring with flushing attacks, and metastatic involvement of the lung and pleura. Arthritis occurs in a small number of patients, and sclerotic bone metastases may be seen, usually in association with foregut tumours.
Carcinoid tumours, in common with other gastroenteropancreatic tumours, have the potential to produce a variety of peptide products and may be associated with other syndromes, with or without the carcinoid syndrome. The most common of these associated syndromes is Cushing’s, due to an ectopic ACTH-secreting, bronchial or pancreatic carcinoid. Carcinoid tumours may also be a feature of multiple endocrine neoplasia type 1.
The biologically active metabolite characteristically produced by metastatic carcinoid tumours is 5-HT, synthesized from the amino acid tryptophan. 5-HT probably plays a part in the pathogenesis of some of the symptoms of the carcinoid syndrome, particularly the diarrhoea and bronchoconstriction. It is metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which accounts for 95% of the urinary excretion of 5-HT.
A variety of vasoactive substances may be secreted by carcinoid tumours and have been implicated in the pathogenesis of the flush. Flushing can be provoked by intravenous noradrenaline, which has been shown to activate kallikrein in the tumour, leading to synthesis and release of bradykinin. Other possible mediators of the flush include histamine, the tachykinins substance P and neurokinin A, and prostaglandins, although the flush is rarely affected by inhibitors of prostaglandin synthesis, such as indomethacin. Gastric carcinoids are derived from histamine-producing enterochromaffin-like cells and histamine is possibly the cause of the characteristic wheal-like flush seen with gastric tumours.
The diagnosis of carcinoid syndrome is made on the basis of elevated concentrations of 5-HIAA in a 24-h urine collection, and urinary 5-HIAA acts as a marker of disease progression. Various foods, including avocados, bananas, aubergines, pineapples, plums, and walnuts, should be avoided while collecting specimens, to prevent false-positive results. A number of drugs and other substances interfere with the spectrophotometric assay: paracetamol, fluorouracil, methysergide, and caffeine give false-positive results, and ACTH, phenothiazines, methyldopa, monoamine oxidase inhibitors, and tricyclic antidepressants false negatives. The other products of carcinoid tumours are not routinely assayed.
Topographic localization of carcinoid tumours can be done by Octreoscan, CT scan, or endoscopy/ultrasound and is rarely a problem, as most have gross hepatic metastases, visible on CT scan or abdominal ultrasonography, at the time of diagnosis. In those rare cases where the syndrome occurs in the absence of metastases, tumour localization may offer the prospect of cure. These tumours are unlikely to be in the gastrointestinal tract and so chest radiographs and CT scans of the chest and pelvis should be taken. Angiography may be of value in assessing suitability for hepatic embolization. Carcinoid tumours have characteristic histological features being composed of regular polygonal cells arranged in nests. The capacity of 5-HT to reduce silver salts (so-called argentaffinity) led to the development of a classical diagnostic histochemical stain, although immunostaining for 5-HT is also used to identify the tumours.
The realistic aim of therapy in patients with the carcinoid syndrome is to relieve the symptoms. Simple treatments such as codeine phosphate, diphenoxylate, and loperamide may help to control the diarrhoea. Many of the symptoms can be controlled with the peripheral 5-HT antagonists: cyproheptadine, a 5-HT type 2 receptor blocker, often helps the diarrhoea; ketanserin may be effective in reducing flushing; and the 5-HT type 3 receptor antagonist ondansetron can alleviate nausea and anorexia. Parachlorphenylalanine, an inhibitor of tryptophan hydroxylase, and chlorpromazine block synthesis of 5-HT, but are rarely used. Histamine may mediate some of the features of the syndrome, especially in patients with gastric carcinoids, and in these cases H1- and H2-receptor blockade may be useful. With the exception of simple antidiarrhoeal agents, these treatments have been largely superseded by the long-acting, subcutaneously administered, somatostatin analogue octreotide. This inhibits the release of the mediators of the syndrome by the tumour and antagonizes their peripheral effects.
Octreotide is effective in alleviating symptoms in more than 90% of patients. It is rarely associated with significant side effects: the acidic solution can cause pain at the injection site; gallstones often develop, but are rarely of clinical significance; and a few patients develop steatorrhoea, which can be prevented by giving pancreatic enzyme supplements. Octreotide is now the first-line treatment for most patients and may be life-saving in the carcinoid crisis, when symptoms become severe and continuous. In addition to octreotide, during crises patients usually need close monitoring of fluid and electrolytes, often by measurement of central venous pressure, and appropriate replacement therapy. Minor injury, including overenthusiastic clinical examination of large carcinoid masses in the liver, may induce a life-threatening state akin to the tumour lysis syndrome characterized by pain, fever, shock, and renal failure compounded by hyperuricaemia and hyperphosphataemia. Allopurinol, and the judicious use of infusions of sodium bicarbonate to make the urine more alkaline, as well as antimicrobials, may reduce the threat of renal failure in this condition. Corticosteroids may improve shock.
The principal disadvantage of octreotide is that patients develop resistance with time, and most become refractory to any form of treatment after about 4 years. Vitamin supplements containing nicotinamide are necessary when patients have pellagra, and these can be given prophylactically. The treatment of cardiac manifestations is the same as for valve disease and cardiac failure of other causes. Patients with painful bony metastases may benefit from palliative radiotherapy.
In patients who fail to respond to octreotide or are intolerant to it, tumour debulking may provide palliative relief. Surgery is rarely indicated, although enucleation of large metastases may give some benefit. Carcinoid tumours rarely respond to any form of chemotherapy. The most effective means of debulking is hepatic embolization, which devascularizes the tumour while the blood supply to the normal liver is maintained by the portal vein. Octreotide should be given in high dose during this intervention, as the necrotic metastases release large quantities of vasoactive mediators that can cause a severe carcinoid crisis with profound hypotension, leading to acute renal failure (see tumour lysis syndrome, above).
Carcinoid tumours behave like other gastroenteropancreatic tumours, with the majority following an indolent course. Estimates given for 5-year survival rates for carcinoids are; appendiceal 98%, gastric (types I/II) 81%, rectal 87%, small intestinal 60%, colonic carcinoids 62%, and gastric type III/IV 33%. Palliation is very worthwhile in these patients, allowing them to lead a normal life until the terminal stages of the disease.
Pancreatic endocrine disorders and multiple endocrine neoplasia
Pancreatic neuroendocrine tumours (islet cell tumours) are rare and usually sporadic, but they may be associated with complex familial endocrine cancer syndromes. Recognized types of pancreatic neuroendocrine tumours are those that are nonfunctioning (often advanced at diagnosis due to the absence of symptoms attributable to hormone hypersecretion), insulinoma (the most frequent type, see the article on hypoglycaemia), and others including:
Gastrinoma—90% located in the pancreatic region; present with severe, multiple peptic ulcers that are often associated with complications such as haemorrhage, perforation, and stricture formation (Zollinger–Ellison syndrome); diagnosis requires demonstration of a raised fasting plasma gastrin concentration associated with increased basal gastric acid secretion; symptomatic treatment is with high-dose proton pump inhibitors.
VIPoma—90% occur in the pancreas; present with large-volume diarrhoea without steatorrhoea (Verner–Morrison syndrome, pancreatic cholera); hypokalaemia may be profound; diagnosis can be confirmed by finding of an elevated plasma level of peptide histidine–methionine (PHM, produced from the prepro-VIP molecule); diarrhoea responds well to somatostatin analogues (octreotide, lanreotide).
Glucagonoma—rare α-cell tumours of the pancreas; presenting features include weight loss, diarrhoea, anorexia, abdominal discomfort (hepatomegaly from metastases), and diabetes, also necrolytic migratory erythema; diagnosis is made on the basis of an elevated fasting plasma glucagon in association with characteristic clinical features; skin rash and other symptoms may respond to somatostatin analogues; oral zinc sulphate supplementation may be of benefit and is usually given.
Management—the following should be considered in addition to the symptomatic treatments for pancreatic neuroendocrine tumours described above: (1) surgical resection—the only curative treatment, but not possible in many cases; (2) interferon-α and systemic chemotherapy (streptozotocin and either doxorubicin or 5-fluorouracil)—evidence of efficacy is limited, but some improvement in about 50% of cases; and—for patients with liver metastases—(3) surgical resection or other local ablative techniques; (4) radiopharmaceutical therapy—e.g. 90Y-octreotide or 90Y-lanreotide.
Multiple endocrine neoplasia (MEN)
There are two main MEN syndromes, which are rare hereditary conditions characterized by a predisposition to cancer development within two or more endocrine organs.
MEN 1—typical features are parathyroid adenomas, pancreatic neuroendocrine tumours (gastrinomas > insulinomas > others) and pituitary adenomas; caused by mutation of the MEN1 gene, which encodes a nuclear protein (menin) that is presumed to be a tumour suppressor gene, with diagnosis confirmed by genetic analysis; following identification of an index case, genetic analysis in first-degree relatives allows identification of affected family members; minimal surveillance programme for individuals with MEN1 syndrome or a family-specific mutation of the MEN1 gene should include annual measurement of serum prolactin (from age 5 years), fasting serum calcium and PTH (from age 8 years), and fasting serum gastrin concentration (from age 20 years).
MEN 2—there are three variants: (1) MEN 2A (Sipple’s syndrome)—medullary thyroid carcinoma, phaeochromocytoma, and parathyroid hyperplasia/adenomas; (2) MEN 2B—medullary thyroid carcinoma and phaeochromocytoma, with other features including marfanoid habitus and mucosal neuromas; (3) familial medullary thyroid carcinoma. Caused by mutation in the RET oncogene, with diagnosis confirmed by genetic analysis and strong genotype–phenotype correlation informing management of index cases and affected family members, e.g. prophylactic thyroidectomy is recommended for those with mutations conferring the highest risk of aggressive medullary thyroid carcinoma; annual measurement of urinary catecholamines for those with high risk of phaeochromocytoma.
Other syndromes of MEN include (1) Carney complex, (2) McCune–Albright syndrome, (3) neurofibromatosis type 1, (4) von Hippel–Lindau syndrome.
Pancreatic neuroendocrine tumours
Pancreatic neuroendocrine tumours (islet cell tumours) are rare tumours representing 1 to 2% of all pancreatic neoplasms and have an incidence of approximately 1 per 100 000 per year. Although pancreatic neuroendocrine tumours may be associated with complex familial endocrine cancer syndromes such as multiple endocrine neoplasia (MEN), the majority are nonfamilial (sporadic) cases. Pancreatic neuroendocrine tumours have a wide range of clinical manifestations. Between 15 and 30% are clinically silent (nonfunctioning) and usually present with mass effect or metastatic disease. Those pancreatic neuroendocrine tumours associated with a specific endocrine hyperfunction syndrome are termed ‘functional’, with insulinomas and gastrinomas being the most common. The pancreas is an extremely rare site of carcinoid tumours, and the majority of carcinoids arise from extrapancreatic sites (carcinoid tumours are described above). This section will consider biochemical confirmation and localization of pancreatic neuroendocrine tumours, specific clinical presentations of functional tumour types, management options, and discussion of the clinical features of MEN types 1 and 2 (MEN1 and MEN2).
Introduction and definition
The gastrointestinal tract is the largest endocrine organ in the body, which includes endocrine cells of the gut and pancreas. The ability of these enteroendocrine cells to take up amine precursor substances and perform their decarboxylation to produce peptide hormones and biogenic amines led to their original description as APUD (amine precursor uptake and decarboxylation) cells. APUD cells were initially believed to arise from the embryological neural crest. However, this theory has been disproved, with current evidence suggesting that these cells are derived from endodermal, omnipotent stem cells. Since these enteroendocrine cells share many of the properties exhibited by neural cells, this has led to their description as neuroendocrine cells. Criteria for defining neuroendocrine cells include production of bioactive substances that provide transmitter functions, release of hormones via exocytosis from dense-core secretory vesicles following an external stimulus, and an absence of axons or synapses. These cells also share certain histological features with neural cells, including the presence of chromogranin-A, synaptophysin, and neuron-specific enolase.
Aetiology and genetics
Pancreatic neuroendocrine tumours are associated with complex familial endocrine neoplasia syndromes, including MEN1 and MEN2, von Hippel–Lindau (VHL) syndrome as well as the phacomatoses neurofibromatosis type 1 (NF-1) and tuberous sclerosis. Nevertheless, the majority of pancreatic neuroendocrine tumours are actually sporadic (i.e. non-inherited). Pancreatic neuroendocrine tumours are a principal feature of multiple endocrine neoplasia type 1. Over 95% of patients with MEN1 display germline-inactivating mutations in the MEN1 gene, a presumed tumour suppressor gene located on chromosomes 11q13 which encodes for the menin protein. Of all these familial endocrine neoplasia syndromes, it is MEN1 that has the strongest association with pancreatic neuroendocrine tumours and these occur in up to 80% of MEN1 patients. Somatic mutations of the MEN1 gene together with loss of heterozygosity on 11q13 have been associated with nonfamilial malignant pancreatic neuroendocrine tumours. Approximately 14% of patients with VHL have pancreatic neuroendocrine tumours, which are usually nonfunctioning and often multiple. Products of the VHL gene inhibit transcription elongation, but the VHL gene does not appear to be involved in the pathogenesis of sporadic pancreatic neuroendocrine tumours.
Pancreatic neuroendocrine tumour markers
The chromogranins are acidic glycoproteins occurring in the dense-core secretory granules of neuroendocrine cells (see article about: Hormones and the gastrointestinal tract). Chromogranin A is released into the circulation and, to date, is considered to be the most useful nonspecific neuroendocrine tumour marker. Several commercial radioimmunoassays (RIAs) for the measurement of chromogranin A have been developed. Chromogranin A concentrations may correlate with tumour burden and can be also useful in monitoring response to treatment or recurrence of disease. Chromogranin A is elevated in patients with kidney, liver, or heart failure as well as with hypergastrinaemia, most notably due to the use of proton pump inhibitors. Chromogranin B coexists with chromogranin A, yet differs in its amino acid sequence and has been reported to be less influenced by renal failure and proton pump inhibitors. Chromogranin B may be more useful than chromogranin A in the diagnosis of insulinomas. The 74 amino acid C-terminal fragment of chronogranin B, known as GAWK, has been described as a particularly useful marker for pancreatic neuroendocrine tumours. Pancreatic polypeptide is produced by the F cells of the normal pancreas, although levels of pancreatic polypeptide may also be significantly increased in patients with pancreatic neuroendocrine tumours. Pancreatic polypeptide alone is a less sensitive neuroendocrine tumour marker than chromogranin A, yet its diagnostic sensitivity may be significantly increased when combined with chromogranin A. Pancreastatin, a cleavage product of chromogranin A, can also be measured by commercially available RIA, although it has been largely superseded by the measurement of chromogranin A. Although non- pancreatic neuroendocrine tumours are not associated with hypersecretion of a specific hormone, these tumours commonly secrete chromogranin A, pancreatic polypeptide, and α and β subunits of human chorionic gonadotrophin (hCG).
In addition to general pancreatic neuroendocrine tumour marker, specific gut hormones produced by these tumours can be measured by RIA using a single fasting plasma sample, and for certain syndromes a small number of confirmatory tests. As with chromogranins, several non-neoplastic conditions are associated with increased levels of specific circulating gut hormones (Table 1). Gut hormone RIAs are not well standardized, and there is considerable variation between laboratories. However, concentrations are usually of the same order of magnitude in all assays and show a similar percentage increase above normal.
Assessment of pancreatic neuroendocrine tumours using immunohistochemistry involves general neuroendocrine tumour markers derived either from the cytosol such as neuron-specific enolase and the protein gene product 9.5 (PGP9.5), or granular markers such as chromogranin A and synaptophysin. The tumour should be stained for Ki-67 protein, to generate a proliferative index. Malignant neuroendocrine tumours are usually poorly differentiated, with cellular atypia, a high mitotic index, and a high proliferative status.
|Table 1 Causes of elevated gut hormones other than pancreatic endocrine tumours|
|All hormones||Nonfasting sample|
|Achlorhydria (most commonly proton pump inhibitor or other antacid therapy)|
|Antral gastrin cell hyperfunction|
|Oral contraceptives and danazol|
PP, pancreatic polypeptide; VIP, vasoactive intestinal polypeptide.
Imaging in pancreatic neuroendocrine tumours
Investigations used in the radiographic localization of pancreatic neuroendocrine tumours include ultrasonography, CT and MRI. Transabdominal ultrasonography may have limited use in the detection of small pancreatic neuroendocrine tumours, but can be used to take biopsies from metastases for histopathological analysis. In experienced hands, endoscopic ultrasonography may be more sensitive than conventional imaging, with a resolution of 2 mm and a detection rate of over 75% for tumours in the pancreatic head. However, visualization using ultrasound is poorer for lesions in the pancreatic tail. Intraoperative ultrasonography may be particularly effective in identifying pancreatic neuroendocrine tumours, especially when it is combined with palpation by the surgeon. Neuroendocrine tumour cells express somatostatin receptors, and hence somatostatin receptor scintigraphy with radiolabelled somatostatin analogues is the mainstay of imaging in most neuroendocrine tumours, particularly those arising from the pancreas.
There are five somatostatin receptor subtypes (SSTRs 1–5) which all avidly bind endogenous somatostatin. The clinically used somatostatin analogues, octreotide and lanreotide, used for diagnosis and treatment, bind to SSTR-2 and SSTR-5. Only 50% of nonmetastatic insulinomas express SSTR-2, yet insulinomas with metastatic spread may be more likely to be positive for these receptors. Therefore, although somostatin receptor scintigraphy is recognized as the most sensitive imaging modality for pancreatic neuroendocrine tumours (80–90%), its role in nonmetastatic insulinomas is often limited. In cases of nonfunctioning pancreatic neuroendocrine tumours, somostatin receptor scintigraphy may be helpful in differentiating these from pancreatic adenocarcinomas. Somostatin receptor scintigraphy is also useful in detecting metastatic disease, although the standard 99Tc bone scan is the most sensitive imaging modality for bony metastases.
Somostatin receptor scintigraphy may be more limited in detecting small tumours, which is significant since 40% of gastrinomas and insulinomas are microadenomas (<1 cm). Such small pancreatic neuroendocrine tumours may be detected by selective angiography with secretagogue injection into the main pancreatic arteries (gastroduodenal, superior mesenteric, inferior pancreaticoduodenal, and splenic). In addition to anatomical localization, this enables biochemical localization. Previously, secretin was the secretagogue of choice, but this has now been replaced by calcium. Injection of calcium into the artery supplying the tumour causes a marked rise in hormone levels in the hepatic vein, and hence allows equivocal lesions to be verified. Visualization of a tumour blush on angiography prior to calcium stimulation further increases the sensitivity of this investigation. Furthermore, since the hepatic artery is cannulated at the end of the procedure, hepatic metastases may also be detected. Positron emission tomography (PET) utilizes uptake of certain radiolabelled tracers. The role of PET in pancreatic neuroendocrine tumours remains to be fully elucidated since most pancreatic neuroendocrine tumours do not show uptake with fluorodeoxyglucose PET owing to low metabolic activity.
The spontaneous course of disease in pancreatic neuroendocrine tumours is difficult to ascertain because of their low incidence, heterogeneous behaviour, and an absence of controlled prospective clinical trials to assess the efficacy of different therapeutic strategies. Nonfunctioning pancreatic neuroendocrine tumours are often more advanced at diagnosis because of the absence of symptoms attributable to hormone hypersecretion. Poorly differentiated, large (>3 cm) tumours associated with metastases are indicators of a poor prognosis. Early in the disease, morbidity and mortality result from the effects of peptide hypersecretion rather than tumour bulk. Metastatic spread to liver and bone is a major cause of death in patients with pancreatic neuroendocrine tumours. The overall 5-year survival for pancreatic neuroendocrine tumours is 50 to 80%, with insulinomas and gastrinomas having up to 94% 5-year survival. Pancreatic neuroendocrine tumours associated with familial disease such as MEN1 may have a less favourable outcome than sporadic tumours, since these are frequently multiple and diffuse, which may limit surgical cure.
Specific tumour syndromes
Insulinomas are the most frequent functional pancreatic neuroendocrine tumours and are discussed in the article about hypoglycaemia
Overall, gastrinomas are the second most frequent functionally active pancreatic neuroendocrine tumour. At the time of diagnosis, 50 to 60% are malignant. Over 90% of gastrinomas are in the pancreatic region of the ‘gastrinoma triangle’, an area bounded by the junction between the cystic duct and the common bile duct, the junction between the second and third parts of the duodenum, and the junction between the head and neck of pancreas. Those gastrinomas arising in the pancreas are most frequently situated in the pancreatic head. In MEN1 patients, gastrinomas are the most common functional pancreatic neuroendocrine tumour. Approximately 25% of gastrinomas are associated with MEN1, although these tend to be situated in duodenum rather than the pancreas and are usually small and multifocal. The gastrinoma syndrome was first described in 1955 by Zollinger and Ellison, who reported the triad of fulminating ulcer diathesis, recurrent ulceration with a poor response to therapy, and pancreatic non-β-cell islet tumours. The syndrome, also known as Zollinger–Ellison syndrome, is the result of excess gastrin-stimulated gastric acid secretion. This causes severe, multiple peptic ulcers, which are usually duodenal, but may occur in the oesophagus and jejunum, and are often associated with complications such as haemorrhage, perforation, and stricture formation. The excess gastric acid secretion inactivates pancreatic enzymes and damages the intestinal mucosa, resulting in diarrhoea and steatorrhoea, which may be prominent features and may precede symptoms of peptic ulcer disease.
The diagnosis of the gastrinoma syndrome requires the demonstration of a raised fasting plasma gastrin concentration (>40 pmol/litre), associated with increased basal gastric acid secretion. Hypercalcaemia may increase plasma gastrin concentrations, which may be of consequence in patients with MEN1 and coexistent primary hyperparathyroidism. Since plasma gastrin levels in gastrinomas overlap with those seen with the use of antacids such as proton pump inhibitors, ideally patients should not take H2-blockers for 3 days or proton pump inhibitors for 2 weeks before gastrin measurement. However, patients with true gastrinomas may be at risk of peptic ulcer perforation if anatacids are stopped for plasma gastrin measurements. Hypergastrinaemia and raised acid output may also arise from retained antrum following partial gastrectomy or the rare condition of antral gastrin cell hyperfunction.
The intravenous secretin test distinguishes these conditions from gastrinoma and can aid diagnosis when other investigations are equivocal. Under normal physiological conditions, secretin inhibits serum gastrin. In contrast, secretin provokes a paradoxical rise in serum gastrin in patients with gastrinoma. Alternatively, an intravenous calcium infusion can be used diagnostically with a rise in plasma gastrin observed in gastrinoma patients. Since ingestion of food is a stimulus for gastrin secretion from the antral and duodenal mucosa, it has been proposed that a standard test meal may differentiate hypergastrinaemia of antral and tumoral origin. However, more recently the usefulness of this test has been questioned. If gastric acid output studies are not possible, a basal gastric pH above 2 virtually excludes the diagnosis of Zollinger–Ellison syndrome. Endoscopy may be valuable in demonstrating oesophageal and duodenal ulceration and hypertrophy of the gastric mucosa. Localization of microgastrinomas may be aided preoperatively by endoscopic ultrasound or selective visceral angiography and venous sampling. Survival depends on the presence of hepatic metastases at presentation, which is more commonly seen with pancreatic rather than duodenal gastrinomas. Overall, the 5-year survival rate is about 65%.
Tumours secreting vasoactive intestinal polypeptide (VIP) are termed VIPomas. Ninety per cent of VIPomas occur in the pancreas, most frequently arising from the pancreatic tail. Extrapancreatic VIPomas may be of neural origin, such as gangliomas or ganglioneuroblastomas which arise from the sympathetic chain or adrenal medulla, and these tumours are especially common in children. Most extrapancreatic tumours are benign, but more than 50% of pancreatic VIPomas have metastasized at the time of diagnosis, usually to local lymph nodes and the liver. Approximately 9% of VIPomas are associated with MEN1.
The features of the VIPoma (Verner–Morrison, pancreatic cholera) syndrome reflect the known biological actions of VIP. Large-volume diarrhoea without steatorrhoea is the cardinal symptom, with most patients excreting more than 3 litres per day. It is often intermittent at first, but in severe crises the volume loss coupled with the vasodilatory effects of VIP and the associated hypokalaemia may precipitate cardiovascular collapse. Hypokalaemia in the VIPoma syndrome may be profound, resulting from gastrointestinal losses and activation of the renin–angiotensin system. The loss of bicarbonate in the stool leads to a paradoxical acidosis, which may mask the true potassium deficit. Achlorhydria or hypochlorhydria occurs in more than 50% of patients and distinguishes this diarrhoeal syndrome from that associated with gastrinoma. Nevertheless, the absence of this feature in a significant proportion of VIPoma patients makes the acronym WDHA (watery diarrhoea, hypokalaemia, and achlorhydria) syndrome inappropriate. In up to 50% of cases there is glucose intolerance as a result of the glucagon-like actions of VIP. Other biochemical abnormalities include hypercalcaemia, probably due to secretion of parathyroid hormone-related peptide (PTHrP) and exacerbated by the dehydration and hypomagnesaemia, due to loss in stools. The vasodilatory action of VIP may cause flushing of the head and neck and, particularly on tumour palpation, may be associated with a marked fall in systemic blood pressure. In advanced cases, extreme weight loss may occur.
VIPomas are usually associated with markedly raised plasma VIP concentrations (>30 pmol/litre). Since the half-life of circulating VIP is only 2 min it may be difficult to always confirm an elevation in circulating VIP. Peptide histidine–methionine (PHM) produced from the prepro-VIP molecule, is more stable in plasma than VIP, and is cosecreted by VIPomas. Therefore, in patients with features consistent with VIPoma syndrome, the finding of an elevated PHM may confirm the diagnosis. Pancreatic polypeptide concentrations levels are elevated in 75% of cases and neurotensin in 10%. Primary pancreatic VIPomas are usually large (>2 cm) and so localization is rarely a problem. Occasionally, selective visceral angiography and venous sampling may be necessary to detect small pancreatic lesions. In those with nonmetastatic VIPomas, the 5-year survival rate is more than 90%; when metastases are present it is about 60%.
Glucagonomas are rare α-cell tumours of the pancreas which secrete various forms of glucagon and other peptides derived from the preproglucagon molecule. Primary glucagonomas most commonly arise in the pancreatic tail and extrapancreatic glucagonomas are rare. Glucagonomas are usually more than 2 cm in diameter at presentation. Smaller glucagonomas tend to be benign and increased tumour size correlates with risk of malignancy. In the majority of cases of sporadic glucagonomas, metastases have occurred at presentation. Up to 17% of glucagonomas are associated with MEN1 and these patients tend to present at a younger age.
Common presenting features of glucagonoma syndrome are weight loss, diarrhoea, anorexia, and abdominal discomfort, with the latter often reflecting tumour bulk from hepatomegaly. Necrolytic migratory erythema is a frequent presenting feature of glucagonoma syndrome; it is cyclical in nature, consisting of macules, central bulla formation, and crusted plaques occurring mainly at friction sites such as perineum, buttocks, groin, lower abdomen, and lower extremities. The exact pathogenesis of this unusual skin eruption remains unclear and is likely to be multifactorial. Hypoaminoacidaemia, zinc deficiency, hypovitaminosis B, and hepatic dysfunction have all been implicated.
Diabetes mellitus is present in approximately two thirds of those with the glucagonoma syndrome and this may predate neurolytic migratory erythema. Other common presentations in glucagonoma syndrome include glossitis, angular cheilitis, and neurological and psychiatric symptoms. Thromboembolism has been described in up to 30% of all cases of glucagonoma syndrome, which is not a feature of other pancreatic neuroendocrine tumours and is a significant cause of death in glucagonoma syndrome.
The diagnosis of glucagonoma is made on the basis of an elevated fasting plasma glucagon (>50 pmol/litre), in association with characteristic clinical features and a demonstrable neuroendocrine tumour and/or metastatic deposits. Glucagonomas are usually of significant size at presentation to be identified by contrast-enhanced CT or MRI. Endoscopic ultrasonography may be of limited use in glucagonomas, as these are usually located in the pancreatic tail. Glucagonomas and their metastases are commonly hypervascular, making selective visceral angiography and venous sampling particularly useful in localizing the tumour and identifying small hepatic metastases. Although the majority of patients with glucagonoma syndrome present with evidence of metastases, the slow-growing nature of these tumours can result in a relatively good prognosis. The 5-year survival ranges from 66 to 85%.
Somatostatinomas are extremely rare, with an estimated annual incidence of about 1 in 40 million per year. Fifty per cent of these tumours are pancreatic, the remainder arising in the duodenum. Unlike other functional pancreatic neuroendocrine tumours, somatostatinomas are rarely associated with MEN1. Pancreatic somatostatinomas are usually large, more than 2 cm at diagnosis, and thus present with local symptoms or features relating to excess somatostatin secretion. Somatostatin has been described as ‘endocrine cyanide’ because of its inhibitory effects on gut motility, transit and absorption, gallbladder contraction and secretion, and endocrine and exocrine pancreatic functions. The so-called somatostatin or ‘inhibitory’ syndrome resulting from somatostatin hypersecretion therefore consists of diarrhoea, steatorrhoea, cholelithiasis, hyperglycaemia, and hypochlorhydria.
Hypoglycaemia has occasionally been described, possibly due to larger molecular forms of somatostatin having a greater inhibitory effect on counter-regulatory hormones than on insulin. In comparison to pancreatic somatostatinomas, duodenal somatostatinomas are smaller, frequently associated with neurofibromatosis type 1, seldom associated with a recognizable ‘somatostatin syndrome’ and often contain psammoma bodies. Duodenal somatostatinomas usually present with obstructive jaundice, pancreatitis, intestinal obstruction, or gastrointestinal haemorrhage.
Diagnosis of a somatostatinoma is secured by demonstrating elevated plasma somatostatin levels (>150 pmol/litre) in the context of a relevant clinical history and the presence of a pancreatic mass. Multiple molecular weight forms of somatostatin may be demonstrated by column chromatography of plasma or tumour extracts, and these may explain unusual clinical features. Localization is rarely a problem due to the large size at presentation. Pancreatic and duodenal somatostatinomas appear to have similar rates of metastases and malignancy. The overall 5-year survival rate is 75%, or 60% if metastases are present.
Rare pancreatic neuroendocrine tumours
Ectopic ACTH production by pancreatic neuroendocrine tumours, resulting in Cushing’s syndrome, is well documented in the literature and virtually all cases are highly malignant with a poor prognosis. Neurotensinomas are rare and truly difficult to separate from the symptom complex produced by VIP excess. There are reports of patients with acromegaly and gigantism as a result of ectopic GHRH secretion by pancreatic neuroendocrine tumours. Secretion of PTHrP by pancreatic neuroendocrine tumours resulting in hypercalcaemia has been rarely described. Other peptides produced by islet-cell tumours include neuropeptide Y, neuromedin B, calcitonin gene-related peptide, bombesin, and motilin, but these are not associated with recognized clinical syndromes.
Nonfunctioning pancreatic neuroendocrine tumours and pancreatic polypeptide-secreting tumours (PPomas)
Nonfunctional tumours represent 15 to 30% of pancreatic neuroendocrine tumours. These most frequently arise in the pancreatic head and are most often diagnosed in the fifth to sixth decades of life. Twenty to thirty per cent of these tumours are associated with MEN1. They usually present late with symptoms attributable to either tumour bulk, such as anorexia and weight loss, or to effects on local structures, such as obstructive jaundice or intestinal obstruction. Despite pancreatic polypeptide (PP) being secreted by up to 75% of pancreatic neuroendocrine tumours, PP itself has no recognized physiological role or associated tumour syndrome. Therefore, pure PPomas can also be regarded effectively as nonfunctioning tumours. Although diarrhoea may be a feature, PPomas are usually silent and present with pressure effects such as abdominal pain. Their malignant potential has not yet been defined. The clinical silence of these nonfunctioning pancreatic neuroendocrine tumours may also reflect secretion of neuropeptides at low circulating concentrations, biologically inactive molecular forms, down-regulation of peripheral receptors or simultaneous production of an inhibitor such as somatostatin. Nonfunctioning pancreatic neuroendocrine tumours are often mistakenly diagnosed as adenocarcinomas, but the presence of elevated circulating gut hormones, such as PP or neurotensin, negative uptake on somatostatin receptor scintigraphy and the use of immunocytochemical analysis can establish the correct diagnosis. The overall 5-year survival is about 50%.
Management of pancreatic neuroendocrine tumours
Surgery is the only curative treatment for pancreatic neuroendocrine tumours. In sporadic pancreatic neuroendocrine tumours, small isolated insulinomas or gastrinomas may be removed by enucleation. Larger functioning and nonfunctioning sporadic tumours may be removed by either a distal pancreatectomy or pancreato-duodenectomy depending on the location of the tumour. Surgical management of pancreatoduodenal neuroendocrine tumours in MEN1 remains controversial because of the multifocal nature of the associated pancreatic disease. In patients with MEN1, surgical cure rates are high for insulinomas, but significantly lower for gastrinomas. Some centres advocate an aggressive surgical approach to MEN1-associated pancreatoduodenal neuroendocrine tumours, including distal subtotal pancreatectomy combined with preservation of the pancreatic head, enucleation of any neuroendocrine tumours remaining in the pancreatic head and in the duodenal wall. This approach may significantly reduce morbidity and mortality associated with pancreatic neuroendocrine tumours in MEN1 patients.
The inhibitory effects of somatostatin have therapeutic implications in pancreatic neuroendocrine tumours, although the clinical effectiveness of native somatostatin is limited by its short half-life of only minutes in the circulation. This necessitated the development of somatostatin analogues, which are the only proven treatment for control of symptoms in pancreatic neuroendocrine tumours and also control tumour growth, presumably because of their antiproliferative effects. The clinically available somatostatin analogues, octreotide and lanreotide, bind most avidly to SSTR-2 and -5 with a lower affinity for SSTR-3. SSTR-2 is believed to mediate the biochemical responses to somatostatin analogues, whereas both SSTR-2 and -5 subtypes are believed to mediate their antiproliferative effects.
Octreotide has a half-life of several hours in the circulation and is usually administered two to three times a day. Depot injections of somatostatin analogues have been developed more recently, allowing sustained release over a few weeks. Therefore, patients may be stabilized on short acting octreotide before converting to longer acting depot preparations. Tachyphylaxis often occurs with time which may necessitate dose escalation to control the clinical symptoms. Imaging using somatostatin scintigraphy can not only identify those who would benefit from somatostatin analogues, but also can be used to monitor the effects of treatment.
Specific tumour syndromes
Treatment of insulinomas is discussed in the article about hypoglycaemia
Short- or long-term treatment with proton pump inhibitors, which inhibit gastric acid secretion, is highly effective for symptomatic relief and tachyphylaxis does not occur. Somatostatin analogues may be superfluous if symptomatic relief occurs with high-dose proton pump inhibitors, although these may be effective in metastatic disease.
VIPomas are usually exquisitely sensitive to somatostatin analogues, with small doses often significantly reducing diarrhoeal symptoms. During acute crises, patients require aggressive intravenous rehydration combined with potassium and bicarbonate replacement if necessary.
Octreotide is particularly useful as a prompt and effective treatment of necrolytic migratory erythema, providing improvement within 48 to 72 h of initiating treatment. Similarly, other symptoms such as diarrhoea and weight loss may also improve. Somatostatin analogues have a variable effect on glucose intolerance and adjuvant glucose-lowering therapy with oral hypoglycaemic agents or insulin may be required. Most patients with glucagonoma syndrome are treated empirically with oral zinc sulphate supplementation, regardless of plasma zinc levels. Patients should be anticoagulated because of the high incidence of thromboembolic disease.
There are a small number of cases reported demonstrating improvements of symptoms by administration of somatostatin analogues. Pancreatic enzyme supplementation and insulin for diabetes mellitus may also be necessary.
Nonfunctioning pancreatic neuroendocrine tumours
These may also benefit from somatostatin analogues if somatostatin receptor imaging is positive and there is evidence of progressive disease.
Interferon-α and systemic chemotherapy
Interferon-α has been used in the treatment of carcinoids and pancreatic neuroendocrine tumours with varying degrees of success and its efficacy may be improved by combining it with a somatostatin analogue. However, use of interferon-α may be limited by side effects including fatigue and flu-like symptoms. The efficacy of systemic chemotherapy in pancreatic neuroendocrine tumours is limited by the restricted number of prospective studies. The combination of streptozotocin and doxorubicin has been shown to be superior to a regimen of streptozotocin and 5-fluorouracil, although the use of doxorubicin may be limited by cardiotoxicity. These combinations produce symptomatic improvement in about 50% of cases and significant tumour regression is seen in up to a third of patients.
Management options for hepatic metastases
Where hepatic metastases are confined to one lobe, surgical resection may be possible, aiming either at cure or at a significant reduction in tumour burden. Other local ablative techniques involve cryosurgery using liquid nitrogen and radiofrequency ablation using a slow-wave diathermy technique to destroy the tumour cells. In the presence of extensive hepatic metastases, debulking surgery may lead to palliation of symptoms. Although orthoptic liver transplantation has been performed for metastatic pancreatic neuroendocrine tumours, outcome is variable and hence it role has not been fully elucidated. Hepatic embolization exploits the fact that hepatic metastases are supplied by the hepatic artery, yet the liver parenchyma has a dual blood supply from the hepatic artery and portal vein. Embolization of these metastases can therefore occur via the hepatic arterial blood supply, resulting in devascularization and necrosis, while portal blood supply to the hepatic parenchyma is preserved. Hepatic artery embolization is achieved using polyvinyl alcohol or microspheres. Administration of somatostatin analogues is necessary before and after the procedure, since necrosis of hepatic metastases may be associated with massive release of neuropeptides. Hepatic chemoembolization combines this approach with the targeted local delivery of chemotherapy agents such as doxorubicin and cisplatin.
Following the introduction of radiolabelled somatostatin analogues for diagnostic purposes, the next step was to develop radiopharmaceuticals as therapies. Such targeted radiotherapy acts systemically and is particularly useful palliative option for patients with inoperable or multisite disease. Prerequisites for treatment success include demonstration of high tumour uptake relative to nontarget tissues on quantitative diagnostic radionuclide imaging and stable haematological and biochemical function. Toxicity is generally low, being limited to reversible myelosuppression and nephrotoxicity. Radiopeptides emitting β-radiation rather than γ-radiation are superior in their therapeutic potential, since they emit particles with sufficient energy to cause cell damage without penetrating very far into surrounding tissue. Yttrium-90 (90Y) is a pure β-emitter which is well suited to internal radiotherapy and may be coupled with octreotide or lanreotide. Administration of 90Y-octreotide or 90Y-lanreotide has been associated with regression of liver metastases and substantial symptomatic improvement.
External beam radiotherapy
This may be effective in relieving pain from bone metastases and, in a small number of cases, has been curative in patients with locally unresectable pancreatic neuroendocrine tumours.
Multiple endocrine neoplasia
MEN refers to rare hereditary cancer syndromes characterized by a predisposition to tumour development within two or more endocrine organs. The two major forms of MEN, namely MEN1 and MEN2, are caused by germ-line mutations which display an autosomal dominant pattern of inheritance and a high degree of penetrance. MEN1 is associated with mutations in the MEN1 gene, whereas MEN2 results from a RET (REarranged during Transfection) gene mutation. These MEN subtypes can either be sporadic, or more commonly, familial. Recent advances in our understanding of the molecular and clinical genetics of these syndromes have significantly altered the approach to diagnosis and management of these patients.
Multiple endocrine neoplasia type 1 (MEN1)
Clinical features and classification
The major components of MEN1 are parathyroid adenomas, pancreatic neuroendocrine tumours, and pituitary adenomas (see Table 2). Underdahl first described the association of these tumours in 1953, and Wermer subsequently proposed their autosomal dominant inheritance in 1954, with the latter providing the eponym for this syndrome. MEN1 occurs in approximately 1 in 30 000 individuals, with an equal sex distribution and may be defined as a case in which two of the three main MEN1-related endocrine tumours occur. Two different forms of MEN1, sporadic and familial, have been described. Familial MEN1 (OMIM 131100) is more prevalent, with an autosomal dominant pattern of inheritance, and is defined as an MEN1 case with at least one first-degree relative with one of these three characteristic endocrine tumours. More than 95% of MEN1 mutation carriers manifest clinical features of the syndrome by the age of 40 years.
|Table 2 Clinical features of MEN1 (Wermer’s syndrome) with estimated prevalence in parentheses|
|Endocrine features||Associated nonendocrine features|
Primary hyperparathyroidism is the most common presenting feature of MEN1, reaching almost 100% penetrance by age 50 years. The typical age of onset of primary hyperparathyroidism in MEN1 is 20 to 25 years, which is 30 years earlier than that of sporadic primary hyperparathyroidism. Patients present either with asymptomatic hypercalcaemia on biochemical screening or with features similar to those of sporadic primary hyperparathyroidism. In MEN1, hyperparathyroidism reflects hyperplasia of multiple parathyroid glands and supernumerary glands are common. There is a consensus that minimally invasive parathyroidectomy is not advisable, since it prevents the routine identification of all four glands. However, controversy exists regarding the most appropriate surgical approach. Subtotal parathyroidectomy with near total thymectomy (to remove ectopic parathyroid tissue in the thymus) is the most common approach. Some centres advocate total parathyroidectomy with autotransplantation of a fresh parathyroid gland into the forearm to avoid reoperative neck surgery if recurrent primary hyperparathyroidism in the transplanted hyperplastic gland occurs. An alternatively approach is a total parathyroidectomy followed by immediate replacement therapy with 1α-hydroxycholecalciferol.
Pancreatic neuroendocrine tumours
Pancreatic neuroendocrine tumours are the second most common clinical manifestation of MEN1, occurring in about 30 to 80% of MEN1 patients, with gastrinomas accounting for 60% of cases. Insulinomas represent about 30% of MEN1-associated pancreatic neuroendocrine tumours and coexist with gastrinomas in 10% of cases. Other functional tumour types such as VIPomas, glucagonomas, and somatostatinomas are rare. MEN1 patients with pancreatic neuroendocrine tumours usually manifest with symptoms of hormone hypersecretion by the age of 40 years, although these tumours may be detected earlier if asymptomatic carriers are having routine biochemical or imaging screening. The MEN1 pancreas characteristically contains numerous microadenomas which have the potential to grow to clinically relevant lesions. Tumours arise in any part of the pancreas, although MEN1 associated gastrinomas frequently arise within the duodenal submucosa. Surgical management of MEN1 associated pancreatic neuroendocrine tumours is described earlier in this chapter. Despite surgical options, MEN1-associated gastrinomas are associated with a high risk of recurrence and hence some centres advocate medical management with proton pump inhibitors. Pancreatic neuroendocrine tumours associated with MEN1 are less malignant than sporadic tumours and carry a better prognosis, with a median survival of 15 years compared to 5 years in patients with sporadic tumours. This may reflect more indolent disease or—since MEN1 patients usually participate in a surveillance programme—earlier diagnosis.
The incidence of pituitary adenomas in MEN1 patients varies from 10 to 60%. These adenomas are detected by screening in 30% of patients, but are found at autopsy in more than 50% of patients. The majority of these tumours are microadenomas (diameter <1 cm). Prolactinomas are the most common type of pituitary adenoma in MEN1 (60%), although tumours secreting growth hormone or ACTH are not uncommon. Double and even triple pituitary adenomas, which may secrete different pituitary hormones, have been described in MEN1. Imaging and treatment is the same as for sporadic pituitary tumours.
Other manifestations of MEN1
Carcinoid tumours occur in 3 to 4% of patients with MEN1. These originate in the foregut and are rarely associated with hypersecretion of hormones. MEN1 thymic carcinoid is seen mainly in men, whereas bronchial carcinoid is commoner in women. Gastric carcinoids in MEN1 are small and multiple, and their malignant potential remains uncertain. Adrenal cortical adenomas are present in up to 40% of patients with MEN1. These are often nonfunctioning and bilateral. Other forms of adrenal pathology associated with MEN1 are diffuse adrenal hyperplasia, adrenal nodular hyperplasia, and adrenal carcinoma. The presence of multiple facial angiofibromas, which consist of acneiform papules, is highly suggestive of MEN1. Collagenomas are another common feature and are multiple, skin-coloured, or occasionally hypopigmented cutaneous nodules, on the trunk, neck, and upper limbs. Subcutaneous or, rarely, visceral lipomas occur in 10 to 30% of MEN1 patients. Furthermore, MEN1 gene mutations have been demonstrated in individuals with atypical familial endocrine syndromes including phaeochromocytoma.
Genetics of MEN1
The MEN1 gene was identified in 1997 by positional cloning and is a putative tumour suppressor gene, in keeping with the ‘two-hit’ model of hereditary cancer as originally postulated by Knudson for retinoblastoma. Knudson proposed that affected family members inherited a ‘first hit’ as an inactivating germ-line mutation in one allele of a tumour suppressor, resulting in a predisposition to tumour development. The ‘second hit’ is acquired as a stochastic somatic event in a susceptible cell type. The inactivation of the remaining functional allele results in progression to neoplasia. Therefore, to explain the apparent paradox of an autosomal dominant disease that is clearly recessive at the cellular level, there must be a relatively high frequency of such stochastic somatic events.
Sporadic cases of MEN1 involve distinct first and second ‘hits’ in somatic cells. There is an enormous diversity of mutations occurring in the MEN1 gene, with over 400 different germ-line or somatic mutations currently reported in MEN1 families and sporadic cases. These mutations are dispersed throughout the entire coding region. Unlike the RET gene in MEN2, there is no significant correlation between the nature or position of the mutation in the MEN1 gene and clinical status. Sequencing of the MEN1 gene detects a germ-line mutation in about 70% of index cases for familial MEN1. The remaining 30% are mostly false negatives, reflecting mutations in the MEN1 gene which are not detected by current gene sequencing techniques. More than 10% of MEN1 mutations arise de novo and may be transmitted to subsequent generations. The MEN1 gene encodes a 610 amino acid nuclear protein, menin, which has been shown to interact with several proteins, including the activator protein 1 transcription factor JunD. It has been proposed that menin may act in DNA repair or synthesis, although its exact function remains to be established.
Genetic screening and management
Mutational analysis of the MEN1 gene is recommended for those in whom a diagnosis of MEN1 is suspected and requires a single blood sample. Following identification of an MEN1 mutation in an index case, genetic analysis in first-degree relatives allows identification of affected family members. Such early identification of MEN1 in asymptomatic carriers is particularly useful to allow subsequent periodic surveillance. This screening may detect the onset of the disease about 10 years before symptoms develop and thus provide an opportunity for earlier treatment. This early detection and treatment of the potential malignant neuroendocrine tumours should reduce the morbidity and mortality associated with MEN1 syndrome. Current guidelines suggest that the minimal surveillance programme for individuals known to have MEN1 syndrome or to have a family-specific mutation of the MEN1 gene should include annual measurement of: serum prolactin (from age 5 years), fasting serum calcium and PTH (from age 8 years), and fasting serum gastrin concentration (from age 20 years). Onset of MEN1 is rare before the age of 5 years, so screening does not need to occur before that age. Periodic radiological screening may include brain MRI, upper gastrointestinal endoscopy, abdominal CT, and somatostatin receptor scintigraphy imaging. In the 10 to 20% of cases of MEN1 where genetic analysis fails to detect a mutation, periodic biochemical testing is an alternative.
Multiple endocrine neoplasia type 2 (MEN2)
Clinical features and classification
MEN2 has at least three distinct variants: MEN2A, MEN2B and familial medullary thyroid carcinoma, and their clinical features are outlined in Table 3. Although MEN2 can arise sporadically, familial cases are more common. Familial MEN2 is defined as an MEN2 case with at least one of the characteristic endocrine tumours in a first degree relative. MEN2 has an estimated prevalence of 1:30 000. Each variant of MEN2 is caused by germline mutations in the RET proto-oncogene, which is located on chromosome 10.
MEN2A (OMIM 171400)
This may also be referred to as Sipple’s syndrome and is characterized by medullary thyroid carcinoma, phaeochromocytoma and parathyroid hyperplasia/adenomas. MEN2A accounts for 80% of MEN2 cases. Medullary thyroid cancer is usually the first neoplastic manifestation in MEN2, appearing between the ages of 5 and 25 years. Phenotypic variants of MEN2A include MEN2A plus megacolon and aganglionosis of the colon (Hirschprung’s MEN2B disease) and MEN2A plus cutaneous lichen amyloidosis, a pruritic rash located on the upper back which usually arises before the onset of the thyroid cancer.
|Table 3 Clinical features of MEN2 with estimated prevalence in parentheses|
|MEN2Aa||Medullary thyroid carcinoma (99%)|
|Parathyroid hyperplasia/adenoma (15–30%)|
|MEN2B||Medullary thyroid carcinoma (100%)|
|Intestinal ganglioneuromatosis and mucosal neuromas (40%)|
|Familial medullary thyroid carcinoma||Thyroid tumour is sole manifestation|
MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma.
a MEN2A accounts for >80% of all MEN2 cases.
MEN2B (OMIM 162300)
Endocrine features of this subtype are medullary thyroid cancer and phaeochromocytoma, but not primary hyperparathyroidism. Medulary thyroid cancer associated with MEN2B occurs about 10 years earlier than MEN2B. Patients with this syndrome have a marfanoid habitus, skeletal abnormalities (kyphoscolisos or lordosis), mucosal neuromas, intestinal ganglioneuromas (which may cause chronic megacolon) and myelinated corneal nerves. This variant represents about 5% of all cases of MEN2, and although MEN2B is often diagnosed earlier than MEN2A because of the characteristic associated physical features, it exhibits a higher morbidity and mortality than MEN2A.
Familial medullary thyroid carcinoma (OMIM 155240)
Medullary thyroid carcinoma (MTC) is the only clinical feature in this MEN2 subtype, although this may sometimes be associated with Hirschprung’s disease. Since MTC is usually the first neoplasm to manifest in MEN2, because of its earlier and overall higher penetrance, it is essential to correctly classify familial medullary thyroid carcinoma. Misdiagnosis of familial medullary thyroid carcinoma in situations where the correct diagnosis is actually MEN2A may unintentionally exclude future screening for phaeochromocytoma, which may have catastrophic consequences. FMTC may be diagnosed where there are at least 10 carriers in the kindred, multiple carriers or affected members above the age of 50 years, and an family history adequate to exclude hyperparathyroidism and phaeochromocytoma.
Medullary thyroid carcinoma
Medullary thyroid carcinoma originates from the parafollicular cells (C cells) of the thyroid. These cells secrete calcitonin, which serves as a tumour marker. In MEN2, familial medullary thyroid carcinoma is the most benign, indolent form, whereas medullary thyroid carcinoma in association with MEN2B represents the most malignant form of the disease. C-cell hyperplasia is the precursor to hereditary MTC, with a variable progression to nodular hyperplasia and finally, through clonal progression, to malignancy. MTC occurs at a younger age in patients with MEN2 than does the sporadic form. Local invasion is common, with metastatic spread to lymph nodes in the neck and mediastinum occurring in up to 50% of cases. Distant metastases to liver, bone, and lung are seen in 15 to 25% of cases. Presentation in MTC may be with a neck mass, or symptoms from distant metastases (diarrhoea, flushing, weight loss, or bone pain). Rarely, ectopic ACTH secretion from MTC may cause Cushing’s syndrome.
Calcitonin is elevated in all cases of clinically palpable MTC. In smaller tumours or cases of C-cell hyperplasia, basal calcitonin levels may be normal and stimulation with a secretagogue such as pentagastrin may be necessary to confirm the diagnosis. Genetic screening in MEN2-associated MTC has now largely replaced biochemical screening for MTC using the pentagastrin-stimulated calcitonin test. Cytological diagnosis using fine needle aspiration may be useful where MTC manifests in previously unidentified MEN2 carriers as a neck mass. Cross-sectional imaging of MTC using CT or MRI may be useful when planning surgery, and radioisotopes such as 131I- metaiodobenzylguanidine (MIBG) and pentavalent 99mTc-dimercaptosuccininc acid are often valuable in detecting metastatic disease. As the tumour stage at presentation is the major prognostic factor, early diagnosis and surgical intervention before cervical lymph node metastases appear is necessary to improve survival. Current practice involves total thyroidectomy with central node dissection. Postoperatively, in addition to a diagnostic role, calcitonin is used to establish the presence of metastases or disease recurrence.
Phaeochromocytomas are neuroendocrine neoplasias of neural crest origin. These occur in approximately 50% of patients with MEN2A or MEN2B, are usually benign, and are invariably confined to the adrenal glands. Phaeochromocytomas associated with MEN2A or MEN2B are bilateral in 50 to 80% of cases. Features and management of phaeochromocytomas are outlined in Chapter 16.17.3. Earlier detection and improved management has resulted in a significant reduction in the morbidity associated with phaeochromocytoma in MEN2. If MTC and phaeochromocytoma are diagnosed simultaneously in MEN2A or MEN2B individuals, adrenalectomy should be performed before thyroidectomy.
Primary hyperparathyroidism is a feature in 20 to 30% of MEN2A patients and is usually asymptomatic. Compared to MEN1, parathyroid disease in MEN2A is usually milder and has a later onset. Surgical management of primary hyperparathyroidism in MEN2A is similar to that in MEN1. During thyroidectomy in MEN2A, enlarged parathyroid glands in a normocalcaemic individual should be evaluated and removed if necessary.
Genetics of MEN2
In contrast to MEN1, which is a tumour suppressor gene, RET is an oncogene. RET has 21 exons and encodes a membrane tyrosine kinase receptor protein called RET. Normal RET is expressed mainly in developing and adult neural ectoderm and comprises extracellular, transmembrane, and intracellular regions. The extracellular region contains four cadherin-like domains and a juxtamembrane cysteine-rich region. Two tyrosine kinase domains located in the intracellular region are involved in the activation of numerous intracellular signal transduction pathways. Mutations involving exons 8, 10, 11, 13, 14, 15, and 16 have been identified in patients with MEN2A, MEN2B, and familial MTC. These exons should therefore be routinely screened for RET mutations. MEN2A and FMTC mutations usually affect the extracellular cysteine-rich domain, whereas those associated with MEN2B most frequently involve the intracellular tyrosine kinase domains of RET. In 85% of cases of MEN2A, codon 634 is affected and more than 95% of cases of MEN2B result from a mutation at codon 918. Generally, mutations associated with FMTC are distributed among the six cysteine codons. In contrast to MEN1, MEN2 displays a strong genotype–phenotype correlation and mutations are identified in more than 95% of patients.
Genetic screening and management
Early recognition of carriers of RET mutations can prevent and cure medullary thyroid cancer, by enabling prophylactic thyroidectomy before the clinical manifestation of the tumour. Genetic testing for germ-line RET mutations is performed in blood leucocytes. Since there is a strong correlation between the specific RET codon mutation and the aggressiveness of the tumour, decision regarding prophylactic thyroidectomy is based on the RET mutation identified. Genetic testing for germ-line RET mutations is recommended in all children with a parent known to have MEN2. Those children carrying MEN2B mutations (codon 883, 918, 922) have the highest risk of aggressive MTC and total thyroidectomy with central node dissection is recommended within the first 6 months of life. This surgery should be performed by age 5 years in carriers of RET codon mutations 611, 618, 620, and 634. Mutations affecting codons 609, 768,790, 791, 804, and 891 are associated with more indolent disease and may have prophylactic surgery by age 5 to 10 years or following first detection of abnormal stimulated calcitonin.
Genetic screening may also be useful in the management of MEN2-associated phaeochromocytoma. Individuals with RET mutations associated with a high risk of developing phaeochromocytoma should have annual measurement of urinary catecholamines.
Other MEN syndromes
In addition to MEN1 and MEN2, there are four other MEN syndromes. Carney complex (OMI 160980) is a rare syndrome characterized by myxomas (cutaneous, mucosal, and cardiac), spotty skin pigmentation (lentiginosis), primary pigmented adrenocortical disease, and pituitary adenomas. A diagnosis of McCune–Albright syndrome (OMIM 174800) requires at least two features of the triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and autonomous endocrine hyperfunction. Patients with Carney complex or McCune–Albright syndrome have mild hypersomatomammotropinemia (excess growth hormone secretion) starting in adolescence. In both disorders, pituitary hyperplasia appears to precede tumour development. Patients with neurofibromatosis type 1 (NF1; OMIM 162200) are predisposed to neuroendocrine tumours including phaeochromocytomas and duodenal somatostatinomas. Finally, as previously described, VHL syndrome (OMIM 193300) is associated with phaeochromoytomas and pancreatic neuroendocrine tumours.
Carcinoid syndrome, hormones and the gastrointestinal tract
Besterman HS, et al. (1978). Gut hormone profile in coeliac disease. Lancet, i, 785–8.
Bishop AE, Polak JM (1997). Classification of neuroendocrine tumours. In: Sheaves R, Jenkins P, Wass JAH (eds). Clinical endocrine oncology, pp. 369–376. Blackwell Scientific Publications, Oxford.
Bishop AE, Polak JM (1999). The gut and the autonomic nervous system. In: Bannister R, Mathias C (eds) Autonomic failure, pp. 117–25. Oxford University Press, Oxford.
Bloom SR, Long RG (eds) (1982). Radioimmunoassay of gut regulatory peptides. Saunders, London. Coll AP, Farooqi IS, O’Rahilly S (2007). The hormonal control of food intake. Cell, 129, 252–62.
Cook GC, et al. (1979). Gut hormone responses in tropical malabsorption. Br Med J, i, 1252–5.
Cummings DE, Overduin J (2007). Gastrointestinal regulation of food intake. J Clin Invest, 117, 13–23.
Drucker DJ (2007). The role of gut hormones in glucose homeostasis. J Clin Invest, 117, 24–32.
Gorden P, et al. (1989). NIH conference. Somatostatin and somatostatin analogue (SMS 201–995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann Intern Med, 110, 35–50.
Gutniak M, et al. (1992). Antidiabetogenic effect of glucagon-like peptide-1 (7–36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med, 326, 1316–22.
Hodgson HJ, Maton PN (1987). Carcinoid and neuroendocrine tumours of the liver. Baillière’s Clin Gastroenterol, 1, 35–61.
Jensen RT (ed.) (1989). Gastrointestinal endocrinology. Gastroenterol Clin N Am, 18, 671–931.
Pancreatic endocrine disorders and multiple endocrine neoplasia
Akerstrom G, et al. (2005). Pancreatic tumours as part of the MEN-1 syndrome. Best Pract Res Clin Gastroenterol, 19, 819–30.
Barakat MT, Meeran K, Bloom SR (2004). Neuroendocrine tumours. Endocr Relat Cancer, 11, 1–18.
Brandi ML, et al (2001). Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab, 86, 5658–71.
Doherty GM (2005). Rare endocrine tumours of the GI tract. Best Pract Res Clin Gastroenterol, 19, 807–17.
de Groot JW, et al. (2006). RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumours. Endocr Rev, 27, 535–60.
Dhillo WS, et al. (2006). Plasma gastrin measurement cannot be used to diagnose a gastrinoma in patients on either proton pump inhibitors or histamine type-2 receptor antagonists. Ann Clin Biochem, 43(Pt 2), 153–5.
Kaltsas GA, Besser GM, Grossman AB (2004). The diagnosis and medical management of advanced neuroendocrine tumours. Endocr Rev, 25, 458–511.
Lewington VJ (2003). Targeted radionuclide therapy for neuroendocrine tumours. Endocr Relat Cancer, 10, 497–501.
Marini F, et al. (2006). Multiple endocrine neoplasia type 1. Orphanet J Rare Dis, 1, 38.
Marini F, et al. (2006). Multiple endocrine neoplasia type 2. Orphanet J Rare Dis, 1, 45.
Marx SJ (2005). Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer, 5, 367–74.
Oberg K, Eriksson B (2005). Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol, 19, 753–81.
Ramage JK, et al (2005). Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut, 54 Suppl IV, iv1–16.
Taupenot L, Harper KL, O’Connor DT (2003). The chromogranin-secretogranin family. N Engl J Med, 348, 1134–49.
Van Eeden S and Offerhaus GJ (2005). Historical, current and future perspectives on gastrointestinal and pancreatic endocrine tumours. Virchows Arch, 448, 1–6.