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PANCREATIC NEUROENDOCRINE TUMORS

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Functional pNETs usually present clinically with symptoms due to the hormone-excess state (Table 113-2). Only late in the course of the disease does the tumor per se cause prominent symptoms such as abdominal pain. In contrast, all the symptoms due to nonfunctional pNETs are due to the tumor per se. The overall result of this is that some functional pNETs may present with severe symptoms with a small or undetectable primary tumor, whereas nonfunctional tumors usually present late in the disease course with large tumors, which are frequently metastatic. The mean delay between onset of continuous symptoms and diagnosis of a functional pNET syndrome is 4–7 years. Therefore, the diagnoses frequently are missed for extended periods.

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TREATMENT

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TREATMENT Pancreatic Neuroendocrine Tumor (General Points)

Treatment of pNETs requires two different strategies. First, treatment must be directed at the hormone-excess state such as the gastric acid hypersecretion in gastrinomas or the hypoglycemia in insulinomas. Ectopic hormone secretion usually causes the presenting symptoms and can cause life-threatening complications. Second, with all the tumors except insulinomas, >50% are malignant (Table 113-2); therefore, treatment must also be directed against the tumor per se. Because in many patients these tumors are not surgically curable due to the presence of advanced disease at diagnosis, surgical resection for cure, which addresses both treatment aspects, is often not possible.

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GASTRINOMA (ZOLLINGER-ELLISON SYNDROME)

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A gastrinoma is an NET that secretes gastrin; the resultant hypergastrinemia causes gastric acid hypersecretion (Zollinger-Ellison syndrome [ZES]). The chronic hypergastrinemia results in marked gastric acid hypersecretion and growth of the gastric mucosa with increased numbers of parietal cells and proliferation of gastric ECL cells. The gastric acid hypersecretion characteristically causes peptic ulcer disease (PUD), often refractory and severe, as well as diarrhea. The most common presenting symptoms are abdominal pain (70-100%), diarrhea (37-73%), and gastroesophageal reflux disease (GERD) (30-35%); 10-20% of patients have diarrhea only. Although peptic ulcers may occur in unusual locations, most patients have a typical duodenal ulcer. Important observations that should suggest this diagnosis include PUD with diarrhea; PUD in an unusual location or with multiple ulcers; PUD refractory to treatment or persistent; PUD associated with prominent gastric folds; PUD associated with findings suggestive of MEN 1 (endocrinopathy, family history of ulcer or endocrinopathy, nephrolithiases); and PUD without Helicobacter pylori present. H. pylori is present in >90% of idiopathic peptic ulcers but is present in <50% of patients with gastrinomas. Chronic unexplained diarrhea also should suggest ZES.

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Approximately 20-25% of patients with ZES have MEN 1 (MEN1/ZES), and in most cases, hyperparathyroidism is present before the ZES develops. These patients are treated differently from those without MEN 1 (sporadic ZES); therefore, MEN 1 should be sought in all patients with ZES by family history and by measuring plasma ionized calcium and prolactin levels and plasma hormone levels (parathormone, growth hormone).

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Most gastrinomas (50–90%) in sporadic ZES are present in the duodenum, followed by the pancreas (10–40%) and other intraabdominal sites (mesentery, lymph nodes, biliary tract, liver, stomach, ovary). Rarely, the tumor may involve extraabdominal sites (heart, lung cancer). In MEN 1/ZES the gastrinomas are also usually in the duodenum (70–90%), followed by the pancreas (10–30%), and are almost always multiple. About 60–90% of gastrinomas are malignant (Table 113-2) with metastatic spread to lymph nodes and liver. Distant metastases to bone occur in 12–30% of patients with liver metastases.

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Diagnosis
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The diagnosis of ZES requires the demonstration of inappropriate fasting hypergastrinemia, usually by demonstrating hypergastrinemia occurring with an increased basal gastric acid output (BAO) (hyperchlorhydria). More than 98% of patients with ZES have fasting hypergastrinemia, although in 40–60% the level may be elevated less than tenfold. Therefore, when the diagnosis is suspected, a fasting gastrin is usually the initial test performed. It is important to remember that potent gastric acid suppressant drugs such as proton pump inhibitors (PPIs) (omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole) can suppress acid secretion sufficiently to cause hypergastrinemia; because of their prolonged duration of action, these drugs have to be tapered or frequently discontinued for a week before the gastrin determination. Withdrawal of PPIs should be performed carefully because PUD complications can rapidly develop in some patients and is best done in consultation with GI units with experience in this area. The widespread use of PPIs can confound the diagnosis of ZES by raising a false-positive diagnosis by causing hypergastrinemia in a patient being treated with idiopathic PUD (without ZES) and lead to a false-negative diagnosis because at routine doses used to treat patients with idiopathic PUD, PPIs control symptoms in most ZES patients and thus mask the diagnosis. If ZES is suspected and the gastrin level is elevated, it is important to show that it is increased when gastric pH is ≤2.0 because physiologically hypergastrinemia secondary to achlorhydria (atrophic gastritis, pernicious anemia) is one of the most common causes of hypergastrinemia. Nearly all ZES patients have a fasting pH ≤2 when off antisecretory drugs. If the fasting gastrin is >1000 pg/mL (increased tenfold) and the pH is ≤2.0, which occurs in 40–60% of patients with ZES, the diagnosis of ZES is established after the possibility of retained antrum syndrome has been ruled out by history. In patients with hypergastrinemia with fasting gastrins <1000 pg/mL (<10-fold increased) and gastric pH ≤2.0, other conditions, such as H. pylori infections, antral G-cell hyperplasia/hyperfunction, gastric outlet obstruction, and, rarely, renal failure, can masquerade as ZES. To establish the diagnosis in this group, a determination of BAO and a secretin provocative test should be done. In patients with ZES without previous gastric acid–reducing surgery, the BAO is usually (>90%) elevated (i.e., >15 mEq/h). The secretin provocative test is usually positive, with the criterion of a >120-pg/mL increase over the basal level having the highest sensitivity (94%) and specificity (100%). Unfortunately the diagnosis of ZES is becoming increasing more difficult. This is due not only to the widespread use of PPIs (leading to false-positive results as well as masking ZES presentation), but also recent studies demonstrate than many of the commercial gastrin kits that are used by most laboratories to measure fasting serum gastrin levels are not reliable. In one study, 7 of the 12 tested commercial gastrin kits inaccurately assessed the true serum concentration of gastrin primarily because the antibodies used had inappropriate specificity for the different circulating forms of gastrin and were not adequately validated. Both underestimation and overestimation of fasting serum gastrin levels occurred using these commercial kits. To circumvent this problem, it is either necessary to use one of the five reliable kits identified or, alternatively, to refer the patient to a center with expertise in making the diagnosis in your area, or if this is not possible, to contact such a center and use the gastrin assay they recommend. An accurate gastrin assay is essential for accurate measurement of fasting serum gastrin level as well as for assessing gastrin levels during the secretin provocative test, and thus, the diagnosis of ZES cannot reliably be made without one.

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TREATMENT

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TREATMENT Zollinger-Ellison Syndrome

Gastric acid hypersecretion in patients with ZES can be controlled in almost every case by oral gastric antisecretory drugs. Because of their long duration of action and potency, which allows dosing once or twice a day, the PPIs (H+, K+-ATPase inhibitors) are the drugs of choice. Histamine H2-receptor antagonists are also effective, although more frequent dosing (q 4–8 h) and high doses are required. In patients with MEN 1/ZES with hyperparathyroidism, correction of the hyperparathyroidism increases the sensitivity to gastric antisecretory drugs and decreases the basal acid output. Long-term treatment with PPIs (>15 years) has proved to be safe and effective, without development of tachyphylaxis. Although patients with ZES, especially those with MEN 1/ZES, more frequently develop gastric NETs (carcinoids), no data suggest that the long-term use of PPIs increases this risk in these patients. With long-term PPI use in ZES patients, vitamin B12 deficiency can develop; thus, vitamin B12 levels should be assessed during follow-up. Epidemiologic studies suggest that long-term PPI use may be associated with an increased incidence of bone fractures; however, at present, there is no such report in ZES patients.

With the increased ability to control acid hypersecretion, more than 50% of patients who are not cured (>60% of patients) will die from tumor-related causes. At presentation, careful imaging studies are essential to localize the extent of the tumor to determine the appropriate treatment. A third of patients present with hepatic metastases, and in <15% of those patients, the disease is limited, so that surgical resection may be possible. Surgical short-term cure is possible in 60% of all patients without MEN 1/ZES or liver metastases (40% of all patients) and in 30% of patients long term. In patients with MEN 1/ZES, long-term surgical cure is rare because the tumors are multiple, frequently with lymph node metastases. Surgical studies demonstrate that successful resection of the gastrinoma not only decreases the chances of developing liver metastases but also increases the disease-related survival rate. Therefore, all patients with gastrinomas without MEN 1/ZES or a medical condition that limits life expectancy should undergo surgery by a surgeon experienced in the treatment of these disorders.

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INSULINOMAS

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An insulinoma is an NET of the pancreas that is thought to be derived from beta cells that ectopically secrete insulin, which results in hypoglycemia. The average age of occurrence is 40–50 years old. The most common clinical symptoms are due to the effect of the hypoglycemia on the CNS (neuroglycemic symptoms) and include confusion, headache, disorientation, visual difficulties, irrational behavior, and even coma. Also, most patients have symptoms due to excess catecholamine release secondary to the hypoglycemia, including sweating, tremor, and palpitations. Characteristically, these attacks are associated with fasting.

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Insulinomas are generally small (>90% are <2 cm) and usually not multiple (90%); only 5–15% are malignant, and they almost invariably occur only in the pancreas, distributed equally in the pancreatic head, body, and tail.

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Insulinomas should be suspected in all patients with hypoglycemia, especially when there is a history suggesting that attacks are provoked by fasting, or with a family history of MEN 1. Insulin is synthesized as proinsulin, which consists of a 21-amino-acid α chain and a 30-amino-acid β chain connected by a 33-amino-acid connecting peptide (C peptide). In insulinomas, in addition to elevated plasma insulin levels, elevated plasma proinsulin levels are found, and C-peptide levels are elevated.

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Diagnosis
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The diagnosis of insulinoma requires the demonstration of an elevated plasma insulin level at the time of hypoglycemia. A number of other conditions may cause fasting hypoglycemia, such as the inadvertent or surreptitious use of insulin or oral hypoglycemic agents, severe liver disease, alcoholism, poor nutrition, and other extrapancreatic tumors. Furthermore, postprandial hypoglycemia can be caused by a number of conditions that confuse the diagnosis of insulinoma. Particularly important here is the increased occurrence of hypoglycemia after gastric bypass surgery for obesity, which is now widely performed. A new entity, insulinomatosis, was described that can cause hypoglycemia and mimic insulinomas. It occurs in 10% of patients with persistent hyperinsulinemic hypoglycemia and is characterized by the occurrence of multiple macro-/microadenomas expressing insulin, and it is not clear how to distinguish this entity from insulinoma preoperatively. The most reliable test to diagnose insulinoma is a fast up to 72 h with serum glucose, C-peptide, proinsulin, and insulin measurements every 4–8 h. If at any point the patient becomes symptomatic or glucose levels are persistently below <2.2 mmol/L (40 mg/dL), the test should be terminated, and repeat samples for the above studies should be obtained before glucose is given. Some 70–80% of patients will develop hypoglycemia during the first 24 h, and 98% by 48 h. In nonobese normal subjects, serum insulin levels should decrease to <43 pmol/L (<6 µU/mL) when blood glucose decreases to <2.2 mmol/L (<40 mg/dL) and the ratio of insulin to glucose is <0.3 (in mg/dL). In addition to having an insulin level >6 µU/mL when blood glucose is <40 mg/dL, some investigators also require an elevated C-peptide and serum proinsulin level, an insulin/glucose ratio >0.3, and a decreased plasma β-hydroxybutyrate level for the diagnosis of insulinomas. Surreptitious use of insulin or hypoglycemic agents may be difficult to distinguish from insulinomas. The combination of proinsulin levels (normal in exogenous insulin/hypoglycemic agent users), C-peptide levels (low in exogenous insulin users), antibodies to insulin (positive in exogenous insulin users), and measurement of sulfonylurea levels in serum or plasma will allow the correct diagnosis to be made. The diagnosis of insulinoma has been complicated by the introduction of specific insulin assays that do not also interact with proinsulin, as do many of the older radioimmunoassays (RIAs), and therefore give lower plasma insulin levels. The increased use of these specific insulin assays has resulted in increased numbers of patients with insulinomas having lower plasma insulin values (<6 µU/mL) than levels proposed to be characteristic of insulinomas by RIA. In these patients, the assessment of proinsulin and C-peptide levels at the time of hypoglycemia is particularly helpful for establishing the correct diagnosis. An elevated proinsulin level when the fasting glucose level is <45 mg/dL is sensitive and specific.

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TREATMENT

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TREATMENT Insulinomas

Only 5–15% of insulinomas are malignant; therefore, after appropriate imaging (see below), surgery should be performed. In different studies, 75–100% of patients are cured by surgery. Before surgery, the hypoglycemia can be controlled by frequent small meals and the use of diazoxide (150–800 mg/d). Diazoxide is a benzothiadiazide whose hyperglycemic effect is attributed to inhibition of insulin release. Its side effects are sodium retention and GI symptoms such as nausea. Approximately 50–60% of patients respond to diazoxide. Other agents effective in some patients to control the hypoglycemia include verapamil and diphenylhydantoin. Long-acting somatostatin analogues such as octreotide and lanreotide are acutely effective in 40% of patients. However, octreotide must be used with care because it inhibits growth hormone secretion and can alter plasma glucagon levels; therefore, in some patients, it can worsen the hypoglycemia.

For the 5–15% of patients with malignant insulinomas, these drugs or somatostatin analogues are used initially. In a small number of patients with insulinomas, some with malignant tumors, mammalian target of rapamycin (mTOR) inhibitors (everolimus, rapamycin) are reported to control the hypoglycemia. If they are not effective, various antitumor treatments such as hepatic arterial embolization, chemoembolization, chemotherapy, and peptide receptor radiotherapy have been used (see below).

Insulinomas, which are usually benign (>90%) and intrapancreatic in location, are increasingly resected using a laparoscopic approach, which has lower morbidity rates. This approach requires that the insulinoma be localized on preoperative imaging studies.

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GLUCAGONOMAS

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A glucagonoma is NET of the pancreas that secretes excessive amounts of glucagon, which causes a distinct syndrome characterized by dermatitis, glucose intolerance or diabetes, and weight loss. Glucagonomas principally occur between 45 and 70 years of age. The tumor is clinically heralded by a characteristic dermatitis (migratory necrolytic erythema) (67–90%), accompanied by glucose intolerance (40–90%), weight loss (66–96%), anemia (33–85%), diarrhea (15–29%), and thromboembolism (11–24%). The characteristic rash usually starts as an annular erythema at intertriginous and periorificial sites, especially in the groin or buttock. It subsequently becomes raised, and bullae form; when the bullae rupture, eroded areas form. The lesions can wax and wane. The development of a similar rash in patients receiving glucagon therapy suggests that the rash is a direct effect of the hyperglucagonemia. A characteristic laboratory finding is hypoaminoacidemia, which occurs in 26–100% of patients.

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Glucagonomas are generally large tumors at diagnosis (5–10 cm). Some 50–80% occur in the pancreatic tail. From 50 to 82% have evidence of metastatic spread at presentation, usually to the liver. Glucagonomas are rarely extrapancreatic and usually occur singly.

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Two new entities have been described that can also cause hyperglucagonemia and may mimic glucagonomas. Mahvah disease is due to a homozygous P86S mutation of the human glucagon receptor. It is associated with the development of α-cell hyperplasia, hyperglucagonemia, and the development of nonfunctioning pNETs. A second disease called glucagon cell adenomatosis can mimic glucagonoma ­syndrome clinically and is characterized by the presence of hyperplastic islets staining positive for glucagon instead of a single glucagonoma.

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Diagnosis
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The diagnosis is confirmed by demonstrating an increased plasma glucagon level. Characteristically, plasma glucagon levels exceed 1000 pg/mL (normal is <150 pg/mL) in 90%; 7% are between 500 and 1000 pg/mL, and 3% are <500 pg/mL. A trend toward lower levels at diagnosis has been noted in the last decade. A plasma glucagon level >1000 pg/mL is considered diagnostic of glucagonoma. Other diseases causing increased plasma glucagon levels include cirrhosis, diabetic ketoacidosis, celiac disease, renal insufficiency, acute pancreatitis, hypercorticism, hepatic insufficiency, severe stress, and prolonged fasting or familial hyperglucagonemia, as well as danazol treatment. With the exception of cirrhosis, these disorders do not increase plasma glucagon >500 pg/mL.

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Necrolytic migratory erythema is not pathognomonic for glucagonoma and occurs in myeloproliferative disorders, hepatitis B infection, malnutrition, short-bowel syndrome, inflammatory bowel disease, zinc deficiency, and malabsorption disorders.

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TREATMENT

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TREATMENT Glucagonomas

In 50–80% of patients, hepatic metastases are present, and so curative surgical resection is not possible. Surgical debulking in patients with advanced disease or other antitumor treatments may be beneficial (see below). Long-acting somatostatin analogues such as octreotide and lanreotide improve the skin rash in 75% of patients and may improve the weight loss, pain, and diarrhea, but usually do not improve the glucose intolerance.

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SOMATOSTATINOMA SYNDROME

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The somatostatinoma syndrome is due to an NET that secretes excessive amounts of somatostatin, which causes a distinct syndrome characterized by diabetes mellitus, gallbladder disease, diarrhea, and steatorrhea. There is no general distinction in the literature between a tumor that contains somatostatin-like immunoreactivity (somatostatinoma) and does (11–45%) or does not (55–90%) produce a clinical syndrome (somatostatinoma syndrome) by secreting somatostatin. In a review of 173 cases of somatostatinomas, only 11% were associated with the somatostatinoma syndrome. The mean age is 51 years. Somatostatinomas occur primarily in the pancreas and small intestine, and the frequency of the symptoms and occurrence of the somatostatinoma syndrome differ in each. Each of the usual symptoms is more common in pancreatic than in intestinal somatostatinomas: diabetes mellitus (95% vs 21%), gallbladder disease (94% vs 43%), diarrhea (92% vs 38%), steatorrhea (83% vs 12%), hypochlorhydria (86% vs 12%), and weight loss (90% vs 69%). The somatostatinoma syndrome occurs in 30–90% of pancreatic and 0–5% of SI somatostatinomas. In various series, 43% of all duodenal NETs contain somatostatin; however, the somatostatinoma syndrome is rarely present (<2%). Somatostatinomas occur in the pancreas in 56–74% of cases, with the primary location being the pancreatic head. The tumors are usually solitary (90%) and large (mean size 4.5 cm). Liver metastases are common, being present in 69–84% of patients. Somatostatinomas are rare in patients with MEN 1, occurring in only 0.65%.

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Somatostatin is a tetradecapeptide that is widely distributed in the CNS and GI tract, where it functions as a neurotransmitter or has paracrine and autocrine actions. It is a potent inhibitor of many processes, including release of almost all hormones, acid secretion, intestinal and pancreatic secretion, and intestinal absorption. Most of the clinical manifestations are directly related to these inhibitory actions.

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Diagnosis
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In most cases, somatostatinomas have been found by accident either at the time of cholecystectomy or during endoscopy. The presence of psammoma bodies in a duodenal tumor should particularly raise suspicion. Duodenal somatostatin-containing tumors are increasingly associated with von Recklinghausen’s disease (NF-1) (Table 113-6). Most of these tumors (>98%) do not cause the somatostatinoma syndrome. The diagnosis of the somatostatinoma syndrome requires the demonstration of elevated plasma somatostatin levels.

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TREATMENT

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TREATMENT Somatostatinomas

Pancreatic tumors are frequently (70–92%) metastatic at presentation, whereas 30–69% of SI somatostatinomas have metastases. Surgery is the treatment of choice for those without widespread hepatic metastases. Symptoms in patients with the somatostatinoma syndrome are also improved by octreotide treatment.

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VIPOMAS

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VIPomas are NETs that secrete excessive amounts of vasoactive intestinal peptide (VIP), which causes a distinct syndrome characterized by large-volume diarrhea, hypokalemia, and dehydration. This syndrome also is called Verner-Morrison syndrome, pancreatic cholera, and WDHA syndrome for watery diarrhea, hypokalemia, and achlorhydria, which some patients develop. The mean age of patients with this syndrome is 49 years; however, it can occur in children, and when it does, it is usually caused by a ganglioneuroma or ganglioneuroblastoma.

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The principal symptoms are large-volume diarrhea (100%) severe enough to cause hypokalemia (80–100%), dehydration (83%), hypochlorhydria (54–76%), and flushing (20%). The diarrhea is secretory in nature, persisting during fasting, and is almost always >1 L/d and in 70% is >3 L/d. In a number of studies, the diarrhea was intermittent initially in up to half the patients. Most patients do not have accompanying steatorrhea (16%), and the increased stool volume is due to increased excretion of sodium and potassium, which, with the anions, accounts for the osmolality of the stool. Patients frequently have hyperglycemia (25–50%) and hypercalcemia (25–50%).

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VIP is a 28-amino-acid peptide that is an important neurotransmitter, ubiquitously present in the CNS and GI tract. Its known actions include stimulation of SI chloride secretion as well as effects on smooth-muscle contractility, inhibition of acid secretion, and vasodilatory effects, which explain most features of the clinical syndrome.

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In adults, 80–90% of VIPomas are pancreatic in location, with the rest due to VIP-secreting pheochromocytomas, intestinal carcinoids, and rarely ganglioneuromas. These tumors are usually solitary, 50–75% are in the pancreatic tail, and 37–68% have hepatic metastases at diagnosis. In children <10 years old, the syndrome is usually due to ganglioneuromas or ganglioblastomas and is less often malignant (10%).

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Diagnosis
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The diagnosis requires the demonstration of an elevated plasma VIP level and the presence of large-volume diarrhea. A stool volume <700 mL/d is proposed to exclude the diagnosis of VIPoma. When the patient fasts, a number of diseases can be excluded that can cause marked diarrhea because the high volume of diarrhea is not sustained during the fast. Other diseases that can produce a secretory large-volume diarrhea include gastrinomas, chronic laxative abuse, carcinoid syndrome, systemic mastocytosis, rarely medullary thyroid cancer, diabetic diarrhea, sprue, and AIDS. Among these conditions, only VIPomas caused a marked increase in plasma VIP. Chronic surreptitious use of laxatives/diuretics can be particularly difficult to detect clinically. Hence, in a patient with unexplained chronic diarrhea, screens for laxatives should be performed; they will detect many, but not all, laxative abusers. Elevated plasma levels of VIP should not be the only basis of the diagnosis of VIPomas because they can occur with some diarrheal states including inflammatory bowel disease, post small bowel resection, and radiation enteritis. Furthermore, nesidioblastosis can mimic VIPomas by causing elevated plasma VIP levels, diarrhea, and even false-positive location in the pancreatic region on somatostatin receptor scintigraphy.

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TREATMENT

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TREATMENT VIPomas

The most important initial treatment in these patients is to correct their dehydration, hypokalemia, and electrolyte losses with fluid and electrolyte replacement. These patients may require 5 L/d of fluid and >350 mEq/d of potassium. Because 37–68% of adults with VIPomas have metastatic disease in the liver at presentation, a significant number of patients cannot be cured surgically. In these patients, long-acting somatostatin analogues such as octreotide and lanreotide are the drugs of choice.

Octreotide/lanreotide will control the diarrhea short- and long-term in 75–100% of patients. In nonresponsive patients, the combination of glucocorticoids and octreotide/lanreotide has proved helpful in a small number of patients. Other drugs reported to be helpful in small numbers of patients include prednisone (60–100 mg/d), clonidine, indomethacin, phenothiazines, loperamide, lidamidine, lithium, propranolol, and metoclopramide. Treatment of advanced disease with cytoreductive surgery, embolization, chemoembolization, chemotherapy, radiotherapy, radiofrequency ablation, and peptide receptor radiotherapy may be helpful (see below).

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NONFUNCTIONAL PANCREATIC NEUROENDOCRINE TUMORS (NF-pNETs)

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NF-pNETs are NETs that originate in the pancreas and either secrete no products or their products do not cause a specific clinical syndrome. Their symptoms are due entirely to the tumor per se. NF-pNETs secrete chromogranin A (90–100%), chromogranin B (90–100%), α-HCG (human chorionic gonadotropin) (40%), neuron-specific enolase (31%), and β-HCG (20%), and because 40–90% secrete PP, they are also often called PPomas. Because the symptoms are due to the tumor mass, patients with NF-pNETs usually present late in the disease course with invasive tumors and hepatic metastases (64–92%), and the tumors are usually large (72% >5 cm). NF-pNETs are usually solitary except in patients with MEN 1, in which case they are multiple. They occur primarily in the pancreatic head. Even though these tumors do not cause a functional syndrome, immunocytochemical studies show that they synthesize numerous peptides and cannot be distinguished from functional pNETs by immunocytochemistry. In MEN 1, 80–100% of patients have microscopic NF-pNETs, but they become large or symptomatic in a minority (0–13%) of cases. In VHL, 12–17% develop NF-pNETs, and in 4%, they are ≥3 cm in diameter.

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The most common symptoms are abdominal pain (30–80%), jaundice (20–35%), and weight loss, fatigue, or bleeding; 10–35% are found incidentally. The average time from the beginning of symptoms to diagnosis is 5 years.

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Diagnosis
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The diagnosis is established by histologic confirmation in a patient without either the clinical symptoms or the elevated plasma hormone levels of one of the established syndromes. The principal difficulty in diagnosis is to distinguish an NF-pNET from a nonendocrine pancreatic tumor, which is more common, as well as from a functional pNET. Even though chromogranin A levels are elevated in almost every patient, this is not specific for this disease as it can be found in functional pNETs, GI-NETs (carcinoids), and other neuroendocrine disorders. Plasma PP elevations should strongly suggest the diagnosis in a patient with a pancreatic mass because it is usually normal in patients with pancreatic adenocarcinomas. Elevated plasma PP is not diagnostic of this tumor because it is elevated in a number of other conditions, such as chronic renal failure, old age, inflammatory conditions, alcohol abuse, pancreatitis, hypoglycemia, postprandially, and diabetes. A positive somatostatin receptor scan in a patient with a pancreatic mass should suggest the presence of pNET/NF-pNET rather than a nonendocrine tumor.

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TREATMENT

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TREATMENT Nonfunctional Pancreatic Neuroendocrine Tumors (NF-pNETs)

Overall survival in patients with sporadic NF-pNET is 30–63% at 5 years, with a median survival of 6 years. Unfortunately, surgical curative resection can be considered only in a minority of these patients because 64–92% present with diffuse metastatic disease. Treatment needs to be directed against the tumor per se using the various modalities discussed below for advanced disease. The treatment of NF-pNETs in either MEN 1 patients or patients with VHL is controversial. Most recommend surgical resection for any tumor >2–3 cm in diameter; however, there is no consensus on smaller NF-pNETs in these inherited disorders, with most recommending careful surveillance of these patients. The treatment of small sporadic, asymptomatic NF-pNETs (≤2 cm) is also controversial. Most of these are low- or intermediate-grade lesions, and <7% are malignant. Some advocate a nonoperative approach with careful, regular follow-up, whereas other recommend an operative approach with specially consideration for a laparoscopic surgical approach.

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GRFOMAS

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GRFomas are NETs that secrete excessive amounts of growth hormone–releasing factor (GRF) that cause acromegaly. GRF is a 44-amino-acid peptide, and 25–44% of pNETs have GRF immunoreactivity, although it is uncommonly secreted. GRFomas are lung tumors in 47–54% of cases, pNETs in 29–30%, and SI carcinoids in 8–10%; up to 12% occur at other sites. Patients have a mean age of 38 years, and the symptoms usually are due to either acromegaly or the tumor per se. The acromegaly caused by GRFomas is indistinguishable from classic acromegaly. The pancreatic tumors are usually large (>6 cm), and liver metastases are present in 39%. They should be suspected in any patient with acromegaly and an abdominal tumor, a patient with MEN 1 with acromegaly, or a patient without a pituitary adenoma with acromegaly or associated with hyperprolactinemia, which occurs in 70% of GRFomas. GRFomas are an uncommon cause of acromegaly. GRFomas occur in <1% of MEN 1 patients. The diagnosis is established by performing plasma assays for GRF and growth hormone. Most GRFomas have a plasma GRF level >300 pg/mL (normal <5 pg/mL men, <10 pg/mL women). Patients with GRFomas also have increased plasma levels of insulin-like growth factor type I (IGF-I) similar to those in classic acromegaly. Surgery is the treatment of choice if diffuse metastases are not present. Long-acting somatostatin analogues such as octreotide and lanreotide are the agents of choice, with 75–100% of patients responding.

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OTHER RARE PANCREATIC NEUROENDOCRINE TUMOR SYNDROMES

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Cushing’s syndrome (ACTHoma) due to a pNET occurs in 4–16% of all ectopic Cushing’s syndrome cases. It occurs in 5% of cases of sporadic gastrinomas, almost invariably in patients with hepatic metastases, and is an independent poor prognostic factor. Paraneoplastic hypercalcemia due to pNETs releasing parathyroid hormone–related peptide (PTHrP), a PTH-like material, or unknown factor, is rarely reported. The tumors are usually large, and liver metastases are usually present. Most (88%) appear to be due to release of PTHrP. pNETs occasionally can cause the carcinoid syndrome. A number of very rare pNET syndromes involving a few cases (less than five) have been described; these include a renin-producing pNET in a patient presenting with hypertension; pNETs secreting luteinizing hormone, resulting in masculinization or decreased libido; a pNET secreting erythropoietin, resulting in polycythemia; pNETs secreting IGF-II, causing hypoglycemia; and pNETs secreting enteroglucagon, causing small intestinal hypertrophy, colonic/SI stasis, and malabsorption (Table 113-2). A number of other possible functional pNETs have been proposed, but most authorities classify these as unclear or as a nonfunctional pNET because in each case numerous patients have been described with similar plasma hormone elevations that do not cause any symptoms. These include pNETs secreting calcitonin, neurotensin (neurotensinoma), PP (PPoma), and ghrelin (Table 113-2).

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