Functional PETs usually present clinically with symptoms due to the hormone-excess state. 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 PETs are due to the tumor per se. The overall result of this is that some functional PETs 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 PET syndrome is 4–7 years. Therefore, the diagnoses frequently are missed for extended periods.
TREATMENT: Pancreatic Endocrine Tumor
Treatment of PETs 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 49-2); 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.
GASTRINOMA (ZOLLINGER-ELLISON SYNDROME)
A gastrinoma is a neuroendocrine tumor that secretes gastrin; the resultant hypergastrinemia causes gastric acid hypersecretion (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, 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% 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 peptic ulcer disease (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 gastrinoma.
Approximately 20–25% of patients with ZES have MEN 1, and in most cases, hyperparathyroidism is present before the gastrinoma. These patients are treated differently from those without MEN 1; therefore, MEN 1 should be sought in all patients by family history and by measuring plasma ionized calcium and prolactin levels and plasma hormone levels (parathormone, growth hormone).
Most gastrinomas (50–70%) are present in the duodenum, followed by the pancreas (20–40%) and other intraabdominal sites (mesentery, lymph nodes, biliary tract, liver, stomach, ovary). Rarely, the tumor may involve extraabdominal sites. In MEN 1 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 49-2) with metastatic spread to the lymph nodes and liver. Distant metastases to bone occur in 12–30% of patients with liver metastases.
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 gastrinomas have fasting hypergastrinemia, although in 40–60% the level may be elevated less than 10-fold. Therefore, when the diagnosis is suspected, a fasting gastrin should be determined first. It is important to remember that potent gastric acid suppressant drugs such as proton pump inhibitors (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 discontinued for a week before the gastrin determination. Withdrawal of proton pump inhibitors (PPIs) should be performed carefully 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 peptic disease (without ZES) and lead to a false-negative diagnosis because at routine doses used to treat patients with idiopathic peptic disease, 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 gastrinoma patients have a fasting pH ≤2 when the patient is off antisecretory drugs. If the fasting gastrin is >1000 pg/mL (increased 10-fold) and the pH is ≤2.0, which occurs in 40–60% of patients with gastrinoma, 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 and gastric pH ≤2.0, other conditions, such as H. pylori infections, antral G-cell hyperplasia or 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 result is usually positive, with the criterion of a >120-pg/mL increase over the basal level having the highest sensitivity (94%) and specificity (100%).
Gastric acid hypersecretion in patients with gastrinomas 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 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, more frequently develop gastric 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.
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. 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 or liver metastases (40% of all patients) and in 30% of patients long-term. In patients with MEN 1, long-term surgical cure is rare because the tumors are multiple, frequently with lymph node metastases. Therefore, all patients with gastrinomas without MEN 1 or a medical condition that limits life expectancy should undergo surgery by a surgeon experienced in the treatment of these disorders.
An insulinoma is an endocrine tumor 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.
Insulinomas are generally small (>90% <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.
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 can be elevated.
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. 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 than the 6 μU/mL 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.
Only 5–15% of insulinomas are malignant; therefore, after appropriate imaging (see later), 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 later discussion).
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.
A glucagonoma is an endocrine tumor 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.
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.
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 past decade. A plasma glucagon level >1000 pg/mL is considered diagnostic of glucagonoma. Other diseases causing increased plasma glucagon levels include 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.
Necrolytic migratory erythema is not pathognomonic for glucagonoma and occurs in myeloproliferative disorders, hepatitis B infection, malnutrition, short-bowel syndrome, inflammatory bowel disease, and malabsorption disorders.
In 50–80% of patients, hepatic metastases are present, so curative surgical resection is not possible. Surgical debulking in patients with advanced disease or other antitumor treatments may be beneficial (see later discussion). 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.
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 small-intestinal 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%.
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.
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. 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.
Pancreatic tumors are frequently (70–92%) metastatic at presentation, whereas 30–69% of small-intestinal 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.
VIPomas are endocrine tumors that secrete excessive amounts of vasoactive intestinal peptide, 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.
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 of 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%).
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 small-intestinal 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.
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%).
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. 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 or 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.
TREATMENT: Vasoactive Intestinal Peptidomas
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 embolization, chemoembolization, chemotherapy, radiotherapy, radiofrequency ablation, and peptide receptor radiotherapy may be helpful (see later discussion).
NONFUNCTIONAL PANCREATIC ENDOCRINE TUMORS
Nonfunctional PETs (NF-PETs) are endocrine tumors that originate in the pancreas and secrete no products, or their products do not cause a specific clinical syndrome. The symptoms are due entirely to the tumor per se. NF-PETs secrete chromogranin A (90–100%), chromogranin B (90–100%), PP (58%), α-HCG (human chorionic gonadotropin) (40%), and β-HCG (20%). Because the symptoms are due to the tumor mass, patients with NF-PETs 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-PETs 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 tumors by immunocytochemistry. In MEN 1, 80–100% of patients have microscopic NF-PETs, but they become large or symptomatic in only a minority (0–13%) of cases. In VHL, 12–17% develop NF-PETs, and in 4%, they are ≥3 cm in diameter.
The most common symptoms are abdominal pain (30–80%); jaundice (20–35%); and weight loss, fatigue, or bleeding. About 10–30% are found incidentally. The average time from the beginning of symptoms to diagnosis is 5 years.
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-PET from a nonendocrine pancreatic tumor, which is more common. 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 PETs, carcinoids, and other neuroendocrine disorders. Plasma PP is increased in 22–71% of patients and 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, and diabetes. A positive somatostatin receptor scan in a patient with a pancreatic mass should suggest the presence of PET or NF-PET rather than a nonendocrine tumor.
TREATMENT: Nonfunctional Pancreatic Endocrine Tumors
Overall survival in patients with sporadic NF-PET 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 metastatic disease. Treatment needs to be directed against the tumor per se using the various modalities discussed later for advanced disease. The treatment of NF-PETs 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-PETs, with most recommending careful surveillance of these patients.
GRFomas are endocrine tumors that secrete excessive amounts of growth hormone–releasing factor (GRF) that cause acromegaly. GRF is a 44-amino-acid peptide, and 25–44% of PETs have GRF immunoreactivity, although it is uncommonly secreted. GRFomas are lung tumors in 47–54% of cases, PETs in 29–30%, and small-intestinal 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) levels 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.
OTHER RARE PANCREATIC ENDOCRINE TUMOR SYNDROMES
Cushing's syndrome (ACTHoma) due to a PET 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 PETs 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. PETs occasionally can cause the carcinoid syndrome. PETs secreting calcitonin have been proposed as a specific clinical syndrome. Half of the patients have diarrhea, which disappears with resection of the tumor. The proposal that this could be a discrete syndrome is supported by the finding that 25–42% of patients with medullary thyroid cancer with hypercalcitonemia develop diarrhea, probably secondary to a motility disorder. This is classified in Table 49-2 as a possible specific disorder because so few cases have been described. Similarly classified with only a few cases described are a renin-producing PET in a patient presenting with hypertension; PETs secreting luteinizing hormone, resulting in masculinization or decreased libido; a PET-secreting erythropoietin resulting in polycythemia; and PETs secreting insulin-like growth factor II causing hypoglycemia (Table 49-2). Ghrelin is a 28-amino-acid peptide with a number of metabolic functions. Even though it is detectable immunohistochemically in most PETs, no specific syndrome is associated with release of ghrelin by the PET.