PANCREATIC NEUROENDOCRINE TUMOURS

PANCREATIC NEUROENDOCRINE TUMOURS

Pancreatic neuroendocrine tumours (pNETs) are also called islet cell tumours, but because the cell of origin of most of these tumours is unknown, the general term pNET is preferred. This term is also a misnomer, however, because pNETs can occur outside the pancreas. Eleven pNETs are well established. Other functional pNET syndromes have been rarely reported: pNETs secreting renin causing hypertension, pNETs secreting erythropoietin causing polycythaemia, pNETs secreting luteinizing hormone that causes virilization, pNETs secreting insulin-like growth factor (IGF)-II or glucagon-like peptide (GLP)-1 causing hypoglycaemia, and pNETs secreting enteroglucagon causing small intestinal hypertrophy1. In addition, pNETs synthesizing neurotensin, calcitonin, and ghrelin have been reported, but no distinct syndromes related to them have been generally accepted).

PANCREATIC NEUROENDOCRINE TUMORS

NAME OF TUMOR NAME OF SYNDROME MAIN SIGNS OR SYMPTOMS LOCATION MALIGNANCY (%) HORMONE CAUSING SYNDROME
I. FUNCTIONAL pNET
Gastrinoma Zollinger-Ellison syndrome Abdominal pain, diarrhoea, oesophageal symptoms Pancreas—30%
Duodenum—60%
Other—10%
60-90 Gastrin
Insulinoma Insulinoma Hypoglycaemic symptoms Pancreas—100% 5-15 Insulin
Glucagonoma Glucagonoma Dermatitis, diabetes/glucose intolerance, weight loss Pancreas—100% 60 Glucagon
VIPoma Verner-Morrison, pancreatic cholera, WDHA Severe watery diarrhoea, hypokalaemia Pancreas—90%
Other—10% (neural, adrenal, periganglionic tissue)
80 Vasoactive intestinal peptide (VIP)
Somatostatinoma Somatostatinoma Diabetes mellitus, cholelithiasis, diarrhoea Pancreas—56%
Duodenum/jejunum—44%
60 Somatostatin
GRFoma GRFoma Acromegaly Pancreas—30%
Lung—54%
Jejunum—7%
Other—13% (adrenal, foregut, retroperitoneum)
30 Growth hormone–releasing factor (GRF)
ACTHoma ACTHoma Cushing’s syndrome Pancreas—4-16% of all ectopic Cushing’s cases >95 Adrenocorticotropic hormone (ACTH)
pNET causing carcinoid syndrome pNET causing carcinoid syndrome Diarrhoea, flushing Pancreas—<1% of all carcinoids 60-90 Serotonin, tachykinins
pNET causing hypercalcemia pNET causing hypercalcemia Signs/symptoms of hypercalcemia Pancreas (rare cause of hypercalcemia) >85 PTHrP, other unknown
CCKoma CCKoma Diarrhoea, peptic ulcer, gallbladder disease, Pancreas (1 case) 100 Cholecystokinin
II. NONFUNCTIONAL pNET
Nonfunctioning PPoma Nonfunctional PPoma Weight loss, abdominal mass, hepatomegaly Pancreas—100% 60-90 None: pancreatic polypeptide, chromogranin released, but no known symptoms due to hypersecretion

pNET = pancreatic endocrine tumour; PP = pancreatic polypeptide; PTHrP = parathormone-related peptide; WDHA = watery diarrhoea, hypokalaemia, and achlorhydria.

pNETs frequently are classified as functional or nonfunctional, depending on whether a clinical syndrome resulting from the autonomously released hormone is present). Nonfunctional pNETs frequently release hormones and peptides (pancreatic polypeptide, neurotensin, α- and β-subunits of human chorionic gonadotropin, neuron-specific enolase, chromogranin A and breakdown products) that cause no distinct clinical syndromes.

pNETs are uncommon, having a prevalence of less than 10 cases per 1 million population. Insulinomas, gastrinomas, and nonfunctional pNETs are the most common, with an incidence of 1 to 3 new cases per 1 million population.

All pNETs share certain features. pNETs are classified as APUDomas (amine precursor uptake and decarboxylation), which share cytochemical features with carcinoid tumours, melanomas, and other endocrine tumours (pheochromocytomas, medullary thyroid cancer). Except for insulinomas, these tumours are frequently malignant. All pNETs appear similar histologically, with few mitotic figures. Ultrastructurally, they have dense granules containing peptides, amines, and products of neuroendocrine differentiation (neuron-specific enolase, chromogranins, synaptophysin). The presence of chromogranin immunoreactivity in the tumour is now widely used to identify these tumours as endocrine tumours.

Molecular studies show that pNETs have a different pathogenesis than common gastrointestinal adenocarcinomas because they infrequently demonstrate mutations in common tumour suppressor genes (e.g., retinoblastoma gene) or common oncogenes (ras c-Jun c-Fos). Recent studies show important alterations are found in the MEN1 gene, gene alterations affecting p53 and retinoblastoma activity, mutations in the DAXX-ATRX complex (important for transcription/chromatin remodeling), and the mTOR pathway. Alterations in p16INK4a , the MEN1 gene, and the expression of growth factors, as well as chromosomal losses (1q, 3p, 3q, 6p, X) and gains (17p, 17q, 20q), have been associated with a worse prognosis in numerous studies. A number of other factors have prognostic significance, the most important of which is the presence of liver metastases. Recently, classification systems including a TNM classification and a grading system (World Health Organization, ENETS [European Neuroendocrine Tumour Society], AJCC/UICC [American Joint Committee on Cancer/Union for International Cancer Control]) have been proposed for pNETs based on tumour size, presence of metastases, invasiveness, and proliferative indices; these classification systems have been recently shown to have prognostic value in a number of studies. Furthermore, they are important in choosing the proper treatment approach.

Four autosomal dominant inherited disorders are associated with an increased occurrence of pNETs: multiple endocrine neoplasia type 1 (MEN 1; 80 to 100% develop pNETs), von Hippel-Lindau disease (VHL; 10 to 17% have pNETs), von Recklinghausen disease (neurofibromatosis [NF]-1; 12% develop duodenal somatostatinomas), and tuberous sclerosis (<1% develop pNETs).

Functional Pancreatic Neuroendocrine Tumour Syndromes

Zollinger-Ellison syndrome (ZES) is a clinical syndrome caused by a gastrin-releasing endocrine tumour usually located in the pancreas or duodenum and characterized by clinical symptoms and signs resulting from gastric acid hypersecretion (peptic ulcer disease, diarrhoea, oesophageal reflux disease). ZES is diagnosed most frequently between the ages of 35 and 65 years and is slightly more common in men (60%).

In recent surgical series, gastrinomas occur two to five times more frequently in the duodenum than in the pancreas. Duodenal gastrinomas are generally small (<1 cm), whereas pancreatic gastrinomas are generally larger. Occasionally ZES results from a gastrinoma in the splenic hilum, mesentery, stomach, or only in a lymph node or an ovary. Extrapancreatic gastrinomas producing ZES have been reported in the heart and as a result of small-cell lung cancer. As with other pNETs, malignancy can be reliably determined only by demonstrating the presence of metastatic disease, and no light microscopic or ultrastructural finding can clearly establish malignant behaviour.

Gastrin stimulates parietal cells to secrete acid and also has a growth effect on cells of the gastric mucosa. Chronic hypergastrinemia thus leads to increased gastric mucosal thickness, prominent gastric folds, and increased numbers of parietal cells and gastric enterochromaffin-like cells. Patients with gastrinomas have increased basal and maximal acid outputs. Helicobacter pylori appears not to be important in the pathogenesis of the ulcer disease in ZES, in contrast to that of routine peptic ulcers. Diarrhoea is common because the large-volume gastric acid output leads to structural damage to the small intestine (inflammation, blunted villi, edema), interference with fat transport, inactivation of pancreatic lipase, and precipitation of bile acids. These same mechanisms, if prolonged, can lead to steatorrhea. If acid hypersecretion is controlled, the diarrhoea will stop.

Twenty to 25% of ZES patients have MEN 1(MEN1/ZES). These patients have hyperplasia or tumours of multiple endocrine glands (parathyroid hyperplasia [>90%], pituitary tumours [60%], and pNETs [80 to 100%]). In 80 to 95% the gastrinomas are in the duodenum, frequently small (<0.5 cm), almost always multiple, and in 40 to 60% associated with lymph node metastases.

Abdominal pain resulting from a peptic ulcer is the most common symptom (>80%). Most ulcers occur in the duodenum (>85%), but they occasionally occur in the postbulbar area, jejunum, or stomach, or in multiple locations. Initially, the pain is usually similar to that of patients with typical peptic ulcers. With time, the symptoms become persistent and, in general, respond poorly to treatments aimed at eliminating H. pylori and to conventional doses of histamine-2 receptor antagonists, as well as to the now rarely used surgical treatments for ulcer disease. By comparison, conventional doses of proton pump inhibitors (PPIs) (e.g., omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole) can mask the symptoms of most patients with ZES and can also cause hypergastrinemia as seen in ZES. The widespread use of PPIs has delayed the diagnosis of ZES.

Heartburn is also common (20%). Diarrhoea (60 to 70%) occurs frequently and may be the first symptom (10 to 20%). In MEN1, ZES is the most common functional pNET syndrome (54%), although patients typically first develop renal stones related to hypercalcemia from hyperparathyroidism or have elevated prolactin levels resulting from pituitary tumours and only later develop ZES. However, studies show that 20 to 40% of patients with MEN1/ZES initially present with ZES symptoms.

In ZES patients, almost all the symptoms result from the effects of gastric acid hypersecretion, but late in the disease, patients can have tumour-related symptoms. Approximately one third of patients have metastatic liver disease at presentation, but less than 20% of other patients develop metastatic disease to the liver during a 10-year follow-up period.

Up to 5% of patients with ZES develop Cushing syndrome as a result of adrenocorticotropic hormone (ACTH) secretion by the gastrinoma. These patients usually have a metastatic gastrinoma in the liver, ZES without MEN 1, and a poor prognosis.

ZES should be suspected in any patient whose peptic ulcer disease is accompanied by diarrhoea, is recurrent, does not heal with treatment, is not associated with H. pylori infection, is associated with a complication (bleeding, obstruction, oesophageal stricture), is multiple or occurs in unusual locations, or is associated with a pancreatic tumour. ZES should also be suspected in patients with chronic secretory diarrhoea, peptic ulcer disease associated with large gastric folds, a family or personal history of renal stones or endocrinopathies, or the laboratory finding of hypercalcemia, hypergastrinemia, or gastric acid hypersecretion.

When suspected, the initial test is a fasting serum gastrin level, which is elevated in 99 to 100% of ZES patients. Recent studies report up to 60% of commercial gastrin assays are unreliable (over/underestimate true value), so a reliable assay should be used. Besides ZES, other causes of fasting hypergastrinemia include renal failure, H. pylori infections, and a physiologic response to achlorhydria or hypochlorhydria because of pernicious anaemia, atrophic gastritis, or the use of PPIs. If the serum gastrin level is elevated, the fasting gastric pH should be determined. If the serum gastrin is more than 1000 pg/mL (normal, <100) and the gastric pH is less than 2.0, the patient almost certainly has ZES; approximately 40% of patients have this combination. If the gastrin is increased less than 10-fold and the gastric pH is higher than 2.0, basal acid output and a secretin test should be performed. Basal acid output is increased in patients with ZES, and more than 95% have a value greater than 15 mEq/hour if no previous gastric acid–reducing surgery has been performed. Because of their long duration of action, PPIs must be stopped for at least 1 week, if possible, to ensure that the cause of the hypergastrinemia is not the drug itself. Stopping a PPI in an undiagnosed ZES patient can lead to complications, so it needs to be done with care, and it is best to consult a group well versed in making the diagnosis.

A secretin test can exclude H. pylori infection, retained gastric antrum syndrome, antral G-cell hyperfunction or hyperplasia, chronic renal failure, and gastric outlet obstruction that may mimic ZES. Physiologically normal individuals show a less than 120 pg/mL increase in the gastrin level after intravenous secretin, whereas 94% of ZES patients with a fasting gastrin level that is elevated less than 10-fold above normal have a positive test. No false-positive results are reported except in patients with achlorhydria. In all patients with ZES, evaluation must exclude MEN 1 syndrome by searching for other endocrinopathies and assessing family history.

All patients should have imaging studies to localize the tumour. A cross-sectional imaging study such as triphasic computed tomography (CT) or magnetic resonance imaging (MRI) with contrast is usually the initial study because of their widespread availability. Somatostatin receptor scintigraphy using single-photon emission CT (SPECT) after injection of indium-111–[diethylenetriamine pentaacetic acid- d -phenylalanine-1] octreotide is the most sensitive modality; it identifies 60% of primary gastrinomas and more than 90% of patients with metastatic liver disease, with a sensitivity equal to all conventional imaging studies (MRI, CT, ultrasound, angiography) combined. 14 For pancreatic gastrinomas, endoscopic ultrasound is particularly sensitive. Small duodenal gastrinomas (<1 cm) are frequently not detected by an imaging modality but can be found at surgery if routine duodenotomy is performed. Recent studies show that two new imaging techniques may be useful for small gastrinomas and other pNETs: the use of hybrid scanning with CT or MRI and somatostatin receptor scintigraphy (SRS) and the use of positron emission tomographic scanning, especially with gallium-68-labeled somatostatin analogues.

Patients need medical therapy directed at controlling the gastric acid hypersecretion and, if possible, surgical therapy to remove the gastrinoma. PPIs are now the drugs of choice. Because of their long duration of action, acid hypersecretion can be controlled in all patients with once- or twice-daily doses. The recommended starting dose for omeprazole is 60 mg once a day. In 30% of patients, higher doses are needed, particularly in patients with complicated disease (MEN 1), previous gastric surgery, or a history of severe oesophageal reflux. With time the omeprazole dose can be reduced in most patients with uncomplicated disease to 20 to 40 mg/day. Patients must be treated indefinitely unless surgically cured. Long-term therapy is safe, and patients have been treated for up to 20 years with omeprazole without loss of efficacy, although reduced vitamin B12 levels may occur and require vitamin B 12 supplementation. Histamine-2 receptor antagonists are also effective, but frequent (every 4 to 6 hours) high doses are needed. Total gastrectomy, the historical treatment, is now performed only for patients who cannot or will not take oral antisecretory medications. Selective vagotomy reduces acid secretion, but many patients continue to require a low dose of drug, and it is now rarely used. Parathyroidectomy should be performed in MEN 1 patients with hyperparathyroidism and ZES, because it reduces acid secretion and increases the sensitivity to antisecretory drugs.

Surgical exploration for cure is recommended in all patients without unresectable liver metastases, MEN 1, or complicating medical conditions that limit life expectancy. Tumors are found by experienced endocrine surgeons in 95% of patients at surgery. Surgical resection decreases the metastatic rate, increases survival, and results in a 5-year cure rate of 30%. Patients with metastatic gastrinoma in the liver have a poor prognosis, with a 5-year survival rate of 30%.

If the metastatic disease can be resected (>90%), surgery should be considered (5 to 15% of cases). If the metastatic disease is nonresectable and slowly increasing in size or is symptomatic, treatment with octreotide (100 to 450 µg two to three times daily) alone or in combination with interferon-α (1 to 5 million U, 3 to 7 days/week) is effective in inhibiting further tumour growth in 50 to 60% of patients. In a randomized multinational study, the somatostatin analog lanreotide was associated with significantly prolonged survival among patients with somatostatin-positive metastatic enteropancreatic neuroendocrine tumours of grade 1 or 2. If this treatment fails or if the tumour is rapidly growing, chemotherapeutic agents (streptozotocin, 5-fluorouracil, doxorubicin) or treatment with the mTOR inhibitor everolimus or the tyrosine kinase inhibitor sunitinib is recommended. Everolimus and sunitinib also have been shown in prospective randomized studies to more than double the progression-free survival time. For patients with extensive metastatic disease, somatostatin receptor–directed radiation therapy using analogues labelled with yttrium-90, lutetium-177, or indium-111 is increasingly used, but these therapies are still not approved. Newer chemotherapy treatments using temozolomide show some promise in a small number of gastrinomas and other pNET patients. In advanced cases where metastases are confined to the liver, liver-directed therapies (embolization, chemoembolization, radioembolization) and local ablative methodologies such as radio frequency ablation, are increasingly used. Liver transplantation is occasionally performed in the rare patient with metastases limited to the liver.

Approximately 25% of gastrinomas show aggressive growth. The most important prognostic predictor is the development of liver metastases. The presence of a large primary tumour, a pancreatic tumour, bone metastases, development of ectopic Cushing syndrome, or a high fasting gastrin level is associated with aggressive growth.

Glucagonomas are endocrine tumours of the pancreas that ectopically secrete glucagon, causing a specific syndrome.

Glucagon hypersecretion explains the glucose intolerance. The exact origin of the rash is unclear; some studies report that prolonged glucagon infusions can cause the characteristic skin lesions. A role for possible zinc deficiency has been proposed because of the similarity of the rash to that seen with zinc deficiency (acrodermatitis enteropathica) and because the rash improves in some patients who are given zinc. The hypoaminoacidemia is thought to be secondary to the effect of glucagon on amino acid metabolism by altering gluconeogenesis. The wasting and weight loss are intrinsic parts of the glucagonoma syndrome, and recent studies suggest that a novel anorectic substance distinct from glucagon is responsible.

The cardinal clinical features are a distinct dermatitis (necrolytic migratory erythema, seen in 70 to 90%), diabetes mellitus and glucose intolerance (40 to 90%), weight loss (70 to 96%), anaemia (30 to 85%), hypoaminoacidemia (80 to 90%) with deficiencies of essential fatty acids, thromboembolism (10 to 25%), diarrhoea (15 to 30%), and psychiatric disturbances (0 to 20%). The characteristic rash is usually found at intertriginous and periorificial sites, especially in the groin and buttocks. It is initially erythematous, becomes raised, and develops central bullae whose tops detach, with the eroded areas becoming crusty. Healing occurs with hyperpigmentation.

The diagnosis is established by demonstrating elevated plasma glucagon levels. Normal levels are 150 to 200 pg/mL; in patients with glucagonomas, levels usually (>90%) are higher than 1000 pg/mL. However, in some recent studies, up to 40% of patients had plasma glucagon values of 500 to 1000 pg/mL. Increased plasma glucagon levels also occur in renal insufficiency, acute pancreatitis, hypercorticism, hepatic diseases, celiac disease, severe stress and prolonged fasting, in patients treated with danazol, and in familial hyperglucagonemia. In these conditions, the level is usually less than 500 pg/mL except in patients with hepatic diseases or in those with familial hyperglucagonemia. Recently, two new glucagonoma-related syndromes have been described: Mahvash disease (characterized by mutations in the glucagon receptor, glucagon cell hyperplasia, hyperglucagonemia, but no symptoms of the glucagonoma syndrome) and glucagon cell adenomatosis (characterized by glucagon cell hyperplasia and occasional symptoms mimicking the glucagonoma syndrome).

Glucagonomas are generally large when discovered (mean, 5 to 10 cm), and they most frequently occur in the pancreatic tail (>50%). Liver metastases are commonly present at the time of diagnosis (45 to 80%).

Subcutaneous administration of the synthetic long-acting somatostatin analogue octreotide (100 to 400 µg two to three times daily) controls the rash in 80% of patients and improves weight loss, diarrhoea, and hypoaminoacidemia, but it usually does not improve the diabetes mellitus. Increasingly, long-acting depot formulations of octreotide (octreotide-LAR) or lanreotide autogel are being given by monthly injection. Zinc supplementation and infusions of amino acids or fatty acids, or both, can diminish the severity of the rash. After tumour localization, surgical resection is preferred; even debulking of metastatic tumour may be of benefit. For advanced disease, treatment is similar to outlined for advanced nonresectable gastrinomas.

The prognosis is now largely determined by the growth of the tumour per se, because the symptoms of glucagon excess can be largely controlled by somatostatin analogues. This is particularly true with glucagonomas; in many series, more than 50 to 80% are metastatic at presentation, and patients usually present late with large primary tumours. The mean 5-year survival rate is 50%; however, extended survivals (>15 years) are reported in some patients with treatment with somatostatin analogues and other tumour-directed therapies.

The VIPoma syndrome, also called the Verner-Morrison syndrome, pancreatic cholera, and the WDHA syndrome (for watery diarrhoea, hypokalaemia, and achlorhydria), results from an endocrine tumour, usually in the pancreas, that ectopically secretes vasoactive intestinal polypeptide (VIP).

VIPomas in adults are found in the pancreas in 80 to 90% of cases; rare cases result from intestinal carcinoids, ganglioneuromas, ganglioneuroblastomas, and pheochromocytomas. In children younger than 10 years and rarely in adults (<5%), the VIPoma syndrome is caused by ganglioneuromas or ganglioneuroblastomas at extrapancreatic sites. VIPomas are usually large and solitary; 50 to 75% of these tumours occur in the pancreatic tail, and 40 to 70% have metastasized at diagnosis. VIPomas frequently secrete both VIP and peptide histidine methionine, but VIP is responsible for the symptoms. VIP is a potent stimulant of secretion in the small and large intestine, which causes the cardinal clinical features of the VIPoma syndrome. VIP also causes relaxation of gastrointestinal smooth muscle, and this may contribute to the dilated loops of bowel that are common in this syndrome, as well as a dilated atonic gallbladder that is sometimes seen. Hypochlorhydria is thought to result from the inhibitory effect of VIP on acid secretion, the flushing is related to the vasodilatory effects of VIP, and the hyperglycaemia is caused by the glycogenolytic effect of VIP. The mechanism of the hypercalcemia remains unclear.

The cardinal clinical feature is severe, large-volume, watery diarrhoea (>1 L/day) (100%), which is secretory and occurs during fasting. Hypokalaemia (67 to 100%) and dehydration (83%) commonly occur because of the volume of the diarrhoea. Achlorhydria is occasionally noted, but hypochlorhydria is usually found (34 to 72% of cases). Flushing occurs in 20% of patients, hyperglycaemia in 25 to 50%, and hypercalcemia in 41 to 50%. Steatorrhea is uncommon (16%) despite the volume of diarrhoea.

The diarrhoea of VIPomas characteristically persists during fasting and is large in volume (>3 L/day in 70 to 80%); the diagnosis is excluded when fasting stool volume is less than 700 mL/day. To differentiate VIPomas from other causes of large-volume fasting diarrhoea, fasting plasma VIP levels should be determined. The normal value in most laboratories is less than 190 pg/mL, and elevated levels are present in 90 to 100% of patients in various series. The differential diagnosis of large-volume fasting diarrhoea (>700 mL/day) includes ZES, diffuse islet cell hyperplasia, surreptitious use of laxatives, the pseudopancreatic cholera syndrome, and rarely, HIV infection. Serum gastrin levels identify patients with ZES, and plasma VIP levels are normal in most patients who abuse laxatives, in 82% of patients with pancreatic islet cell hyperplasia, and in patients with HIV-induced secretory diarrhoea.

The symptoms caused by the VIP are controlled initially in more than 85% of patients by daily doses of octreotide (50 to 400 µg once to three times daily) or by monthly injections of the depot form, octreotide-LAR or lanreotide autogel, but increased doses may be needed over time. Before the availability of octreotide, small numbers of patients were reported to respond to a variety of agents, including high-dose prednisone (60 to 100 mg/day; 40 to 50%), clonidine, lithium carbonate, indomethacin, loperamide, metoclopramide, and phenothiazines. After tumour localization studies, surgical resection should be attempted if it is possible to remove all visible tumour; however, more than 50% of patients have generalized liver metastases at diagnosis, so complete resection may not be possible. For patients with unresectable advanced disease, treatment is similar to outlined for advanced nonresectable gastrinomas.

The prognosis is now largely determined by the growth of the tumour per se, because the symptoms of VIP excess can be largely controlled by somatostatin analogues. This is particularly true in patients with VIPomas, because they frequently (>50%) present with advanced metastatic disease. The mean 5-year survival is 50 to 70%.

Somatostatinomas are endocrine tumours that occur in the pancreas or upper small intestine and ectopically secrete somatostatin. In the gastrointestinal tract, somatostatin inhibits basal and stimulated acid secretion, pancreatic secretion, intestinal absorption of amino acids, gallbladder contractility, and release of numerous hormones, including cholecystokinin and gastrin.

Most reported somatostatinomas are diagnosed histologically as an endocrine tumour containing somatostatin-like immunoreactivity and are not associated with a distinct clinical syndrome (the somatostatinoma syndrome). The somatostatinoma syndrome includes diabetes mellitus, gallbladder disease, diarrhoea, steatorrhea, and weight loss. Sixty percent of somatostatinomas occur in the pancreas, and 40% are found in the duodenum or jejunum. Pancreatic somatostatinomas occur in the pancreatic head in 60 to 80% of cases; 70 to 92% will have metastasized at diagnosis, and they are usually large (mean, 5 cm) and solitary. In contrast, duodenal somatostatinomas are smaller (mean, 2.4 cm), frequently associated with psammoma bodies on histologic examination (11%), and less frequently have metastases at diagnosis (30 to 40%).

The somatostatinoma syndrome occurs much more commonly (80 to 95% of all cases) in patients with pancreatic than duodenal or intestinal somatostatinomas. Duodenal somatostatinomas occur in up to 10% of patients with von Recklinghausen disease and are usually asymptomatic.

Somatostatinomas are usually found by accident, particularly during exploratory laparotomy for cholecystectomy, during endoscopy, or on imaging studies. The presence of psammoma bodies on histologic examination of a duodenal endocrine tumour or any duodenal lesions in patients with von Recklinghausen disease should raise the suspicion of a duodenal somatostatinoma. The diagnosis of the somatostatinoma syndrome requires the demonstration of increased concentrations of somatostatin-like immunoreactivity in the plasma and the resected tumour. However, other tumours outside the pancreas or intestine, such as small-cell lung cancer, medullary thyroid carcinoma, pheochromocytomas, and paragangliomas, may also have elevated concentrations of somatostatin-like immunoreactivity. Somatostatinomas can be imaged using somatostatin receptor scintigraphy or, if needed, other conventional imaging studies to assess the tumour’s location.

Treatment with octreotide or lanreotide can improve symptoms. Surgery, if possible, should be performed. For patients with unresectable advanced disease, treatment is similar to outlined for advanced nonresectable gastrinomas.

Patients with intestinal somatostatinomas, which uncommonly cause the somatostatinoma syndrome and are less malignant, have an excellent prognosis (5-year survival rate, >80%), whereas those with pancreatic somatostatinomas, which frequently cause the somatostatinoma syndrome and present with metastatic disease (>70%), have a much reduced 5-year survival rate (<50%).

GRFomas are endocrine tumours that frequently originate in the pancreas but also occur in other extrapancreatic locations and ectopically release growth hormone–releasing factor (GRF). The GRF causes acromegaly that is clinically indistinguishable from that caused by a pituitary adenoma.

GRFomas most commonly occur in the lung (54%). Most of the remainder occur in the gastrointestinal tract, including 30% in the pancreas. Pancreatic GRFomas are usually large (mean, 6 cm), 39% are metastatic at diagnosis, 40% occur in combination with ZES, and 33% are in patients with MEN 1.

GRFomas are an uncommon cause of acromegaly. These tumours occurred in none of 177 unselected patients with acromegaly in one study. However, any patient with acromegaly and abdominal complaints, with acromegaly but no pituitary tumour, or with acromegaly and hyperprolactinemia (which occurs in 70% of GRFomas) should be suspected of having a GRFoma. The intra-abdominal features of GRFomas result from its metastases and are typical of any malignant pNET. The diagnosis is confirmed by performing a plasma assay for GRF and growth hormone.

The effects of the GRF can be controlled with octreotide or lanreotide in more than 90% of patients. Treatment should be directed at the GRFoma per se, as described for the other more common pNETs. For patients with unresectable advanced disease, treatment is similar to that outlined for advanced nonresectable gastrinomas.

Nonfunctional pNETs are endocrine tumours that originate in the pancreas and either secrete no peptides or secrete products that do not cause clinical symptoms.

Frequently secreted nonfunctional peptides include chromogranin A (100%), pancreatic polypeptide (60%), and the α-subunit (40%) and β-subunit of human chorionic gonadotropin. Immunocytochemically, even higher percentages contain these peptides as well as insulin (50%), glucagons (30%), and somatostatin (13%).

Nonfunctional pNETs are frequently diagnosed only late in the course of disease after the patient presents with symptoms or signs of metastatic disease and a liver biopsy reveals metastatic pNET. Any symptoms or signs result from the tumour per se and include abdominal pain (36 to 56%), abdominal mass or hepatosplenomegaly (8 to 40%), weight loss or cachexia (8 to 46%), and jaundice (27 to 40%). In 20% of asymptomatic patients, tumours are found incidentally at surgery.

Any patients with a long survival (>5 years) after a diagnosis of metastatic pancreatic adenocarcinoma should be suspected of having a nonfunctional pNET. Most primary tumours are large (70% are > 5 cm), and 70% occur in the pancreatic head. Liver metastases are frequent (38 to 62%) at presentation. An elevated plasma chromogranin A or pancreatic polypeptide level or a positive somatostatin receptor scintigraphic scan is strong evidence that a pancreatic mass is a pNET. Malignancy correlates with vascular or perineural invasion, a proliferative index of more than 2%, a mitotic rate of 2 or higher, a size of at least 4 cm, capsular penetration, nuclear atypia, lack of progesterone receptors, and the presence of calcitonin immunoreactivity in the tumour.

Tumour localization is needed in all patients. Survival is better in patients with smaller tumours, patients who are asymptomatic at presentation, patients with no metastases, and patients in whom surgical resection can be performed.

Surgical resection should be performed whenever possible. For patients with unresectable advanced disease, treatment is similar to that outlined for advanced nonresectable gastrinomas.

The overall 5-year survival rate varies in different series from 30 to 70%, but it is heavily dependent on the extent of the disease at diagnosis, with survival rates of 96% in patients without metastases at presentation, decreasing to 30 to 50% for those with metastatic disease.

pNETs that ectopically secrete ACTH cause 4 to 16% of the cases of ectopic Cushing syndrome. Cushing syndrome occurs in 5% of all cases of ZES, but in patients with sporadic ZES it is a late feature, occurring with metastatic liver disease. Its development is associated with a poor prognosis, and the response to chemotherapy is generally poor; however, occasional patients benefit from the use of long-acting somatostatin analogues (octreotide, lanreotide).

Paraneoplastic hypercalcemia can result from a pNET that releases parathormone-related peptide or an unknown hypercalcaemic substance. Tumors are generally large, with metastatic liver disease at diagnosis. Somatostatin analogues may help control the hypercalcemia, but surgery, chemotherapy, hepatic embolization, and chemoembolization are the mainstays of treatment.

pNETs causing the carcinoid syndrome are usually large, and 68 to 88% are malignant. Octreotide may control the symptoms. Surgery, chemotherapy, hepatic embolization, chemoembolization, or molecular targeted therapy (everolimus, sunitinib) may be helpful.

A single case of a pNET that secreted renin manifested with severe hypertension; the tumour was localized with somatostatin receptor scintigraphy, and the patient’s symptoms improved significantly after tumour reseA single case of an erythropoietin-secreting pNET resulting ipolycythaemiaia, and a single case of a pNET secreting IGF-II or GLP-1 causing hypoglycaemia have been described.

Two symptomatic cases of pNETs that secreted luteinizing hormone have been described; virilization occurred in the female patient, whereas the male patient had increased acne and a rash. In both cases, the tumours were resectable, and symptoms improved postop. A single case of a pNET secreting cholecystokinin (CCKoma) has been recently described, with the patients demonstrating peptic ulcer disease, gallbladder disease, diarrhoea, and weight loss. A case of a pNET secreting enteroglucagon causing small intestinal hypertrophy has also been described.

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