Neoplasms of the Endocrine Pancreas

Synonyms and related keywords: pancreatic cancer, pancreas cancer, pancreatic neoplasm, pancreas neoplasm, pancreatic islet cell tumor, pancreatic islet cell adenoma, pancreatic endocrine tumor, pancreatic neuroendocrine tumor, insulinoma syndrome, insulinoma, Zollinger-Ellison syndrome, ZES, gastrinoma syndrome, gastrinoma, Verner-Morrison syndrome, WDHA syndrome, watery diarrhea, hypokalemia, achlorhydria, pancreatic cholera, vasoactive intestinal peptide-releasing tumor, VIPoma, glucagonoma syndrome, somatostatinoma syndrome, calcitoninoma, parathyrinoma, growth hormone releasing facto-secreting tumor, GRFoma, adrenocorticotropin hormone-secreting tumor, ACTHoma, neurotensinoma, pancreatic endocrine neoplasm, pancreatic polypeptidomas, PPomas, islet cell tumor, pancreatic cholera, MEN 1 syndrome, MEN-I syndrome, MEN-1 syndrome, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type I, MEN syndrome, APUDomas


INTRODUCTION

Background: Neoplasms of the endocrine pancreas can be divided into functional and nonfunctional varieties. Most pancreatic endocrine neoplasms discovered clinically are functional; ie, they secrete one or more hormonal products into the blood, which leads to a recognizable clinical syndrome. In 1927, Wilder et al described the first hormone-producing pancreatic tumor syndrome in a patient with hypoglycemia and a metastatic islet cell tumor, extracts of which caused hypoglycemia.

Subsequent to this initial description of insulinoma syndrome, 4 other classic pancreatic endocrine tumor syndromes have been described. The first is Zollinger-Ellison syndrome (also termed gastrinoma syndrome), described by Zollinger and Ellison in 1955. The second types comprise a group of 3 tumor syndromes, termed Verner-Morrison syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, and pancreatic cholera (also termed vasoactive intestinal peptide [VIP]–releasing tumor or VIPoma) and were described by Verner and Morrison in 1958. The third is glucagonoma syndrome, described by Mallinson et al in 1974. The fourth is somatostatinoma syndrome, described by Ganda et al and Larsson et al in 1977.

Several other rare clinical syndromes have been proposed as possible functional endocrine syndromes associated with pancreatic neoplasms. These include calcitoninoma (Howard, 1989; McLeod, 1992), parathyrinoma (Mao, 1995), growth hormone-releasing factor–secreting tumor (GRFoma), adrenocorticotropin hormone–secreting tumor (ACTHoma), and neurotensinoma (Meko, 1994).

Patients with pancreatic neoplasms that have the histologic characteristics of a pancreatic endocrine tumor but no associated elevation in plasma hormone levels, excluding the pancreatic polypeptide level, and those without a recognizable clinical syndrome are considered to have nonfunctional pancreatic endocrine tumors. A subset of these patients have nonfunctional pancreatic endocrine neoplasms that secrete pancreatic polypeptide (ie, PPomas). Pancreatic polypeptide (PP) is a product that appears to be a marker for pancreatic endocrine tumors, but it is not a mediator of any specific PP-related clinical syndrome (Langstein, 1990). Other nonfunctional pancreatic endocrine tumors likely secrete unknown products that are of little or no clinical significance.

Each of the classic pancreatic endocrine tumor syndromes is discussed in detail in other eMedicine articles. See Insulinoma, Gastrinoma, Zollinger-Ellison Syndrome, VIPomas, WDHA Syndrome, Glucagonoma, and Somatostatinomas.

Further, eMedicine articles are available on Wermer Syndrome (MEN Type 1) and von Hippel-Lindau Disease, conditions with which pancreatic endocrine tumors are associated.

Finally, Pancreatic Islet Cell Tumor discusses techniques used to localize and image these frequently elusive neoplasms.

Pathophysiology: The cells in pancreatic endocrine neoplasms are termed amine precursor uptake and decarboxylation (APUD) cells because they have a high amine content, are capable of amine precursor uptake, and contain an amino acid decarboxylase (Yeo, 2001). Pearse first used the term APUD in 1968 to unify a group of functionally and structurally similar neuroendocrine cells that are present throughout the body. APUD cells were once believed to originate from the embryologic neural crest, but current evidence suggests that these cells—and thus endocrine tumors of the pancreas and other endocrine tumors of the upper gastrointestinal tract (eg, carcinoid tumors)—actually develop from the embryologic endoderm (Andrew, 1998).

Although the term islet cell tumor is often used to identify neoplasms of the endocrine pancreas, this is a misnomer because many pancreatic neuroendocrine tumors do not develop directly from islet cells (Kloppel, 1988). Instead, the tumors arise from APUD stem cells, which are pluripotential neuroendocrine cells located within the ductular epithelium of the exocrine pancreas and elsewhere in the distal foregut (Heitz, 1982). The fact that many gastrinomas and somatostatinomas are found close to, but not within, the pancreatic parenchyma supports the notion of the possible extrapancreatic development of these neoplasms (Metz, 1995).

Patients with functional pancreatic endocrine neoplasms have physiologic derangements related to the normal action of the hormonal product that the tumors overproduce. Thus, patients with an insulin-secreting tumor (ie, insulinoma) have pathophysiologic findings of hypoglycemia; patients with a gastrin-secreting tumor (ie, gastrinoma) have hypersecretion of gastric acid, which often leads to the development of peptic ulcers (ie, Zollinger-Ellison syndrome); and so on. In contrast, patients with nonfunctional pancreatic endocrine neoplasms typically present later in the course of their disease, when their tumors begin to cause symptoms related to a mass effect.

Frequency:

• In the US: Neoplasms of the endocrine pancreas occur in 2 distinct epidemiologic groups. Solitary tumors that develop in patients without a significant personal or family history of endocrine disorders are characterized as the sporadic form. The second form affects kindreds with the multiple endocrine neoplasia type 1 (MEN 1) syndrome in a pattern of autosomal dominant inheritance (Norton, 1993). Approximately 80% of individuals with MEN 1 syndrome have one or more pancreatic neoplasms in their lifetime; gastrinoma and insulinoma are the most commonly identified lesions (Helmrath, 1997).

  Clinically recognized neoplasms of the endocrine pancreas are rare, with an overall annual incidence in the United States of 3-10 cases per million persons (Buchanan, 1986; Eriksson 1989). However, the much higher prevalence of these tumors in unselected autopsy specimens, ie, 0.5-1.5%, reflects the indolent nature of many of these tumors (Weil, 1985; Jensen, 1998).

  Insulinomas and gastrinomas occur with roughly equal annual incidences; together they account for more than half of all clinically apparent pancreatic endocrine tumors (Jensen, 1998). VIPomas are one-eighth and glucagonomas are one-seventeenth as common, whereas somatostatinomas are even more rare (Buchanan, 1986). Nonfunctional tumors account for 14-48% of all recognized neoplasms of the endocrine pancreas (Eriksson, 1995; Phan 1998).

Mortality/Morbidity: Because of the relative rarity of pancreatic endocrine tumors in the general population, accurate rates of morbidity and mortality for persons with these lesions are difficult to determine. However, both the survival and the quality of life of patients with neoplasms of the endocrine pancreas are generally improving secondary to improvements in the modalities used to diagnose and treat these lesions (also see Complications and Prognosis).

Race: Sporadic and inherited forms of pancreatic endocrine tumors appear to occur with equal frequency among the different racial groups in the United States.

Sex: Although neoplasms of the endocrine pancreas occur in men and women, these tumors seem to have a slightly higher incidence in women (Menegaux, 1993; Norton, 1993; Thompson, 1993). As would be expected in patients with a genetic disorder of autosomal dominant inheritance, no significant sex predilection is observed among patients with pancreatic endocrine tumors as part of MEN 1 syndrome (Metz, 1995).

Age: Patients with sporadic pancreatic endocrine tumors present most commonly when aged 30-50 years (Metz, 1994). In contrast, patients with pancreatic endocrine tumors that develop as part of MEN 1 syndrome tend to present when younger, commonly at age 10-30 years (Norton, 1993).

CLINICAL

History:

• Insulinoma

• Insulinomas are insulin-secreting tumors associated with the Whipple triad. The triad includes (1) symptoms of fasting hypoglycemia, (2) documented fasting hypoglycemia with a serum glucose level less than 50 mg/dL, and (3) relief of hypoglycemic symptoms after glucose administration (Whipple, 1935).

• Autonomous insulin secretion from insulinomas produces symptoms classified into 2 broad categories. Virtually all patients with an insulinoma who seek medical attention present with a subset of 1 of these 2 groups of symptoms, and more than half present with symptoms from both groups (Fajans, 1989).
  • First, the direct physiologic effect of hypoglycemia is neuroglycopenia, which may cause headache, light-headedness, confusion, visual disturbances, seizures, personality changes, obtundation, and even coma (Metz, 1995).
  • Second, in response to neuroglycopenic stress, the body generates a compensatory state of catecholamine excess, which can lead to palpitations, weakness, trembling, diaphoresis, tachycardia, and irritability (Yeo, 2001).

• Because insulinoma syndrome is rare and because the associated symptoms are relatively nonspecific, the physician with clinical acumen who encounters a patient with the symptoms of neuroglycopenic stress and/or catecholamine excess may think of insulinoma; however, the patient should be examined first for other more common conditions in the differential diagnosis (DDX) of hypoglycemia (see Other Problems to be Considered).
• Reactive hypoglycemia is the most common form of noniatrogenic hypoglycemia. Reactive hypoglycemia can be differentiated from insulinoma syndrome by a history of symptom onset 3-4 hours after meals, rather than after extended periods of fasting (Service, 1995).

• Gastrinoma

• The classic triad of Zollinger-Ellison syndrome includes (1) severe gastrointestinal ulcerative disease, (2) gastric acid hypersecretion, and (3) nonbeta islet cell tumors of the pancreas (Zollinger, 1955).
• Zollinger and Ellison rightly proposed that these pancreatic tumors released a stimulatory secretagogue into the circulation that induced gastric acid hypersecretion, resulting in ulcer disease. This substance is the polypeptide hormone now called gastrin.
• Currently, 1 patient in 1000 with primary duodenal ulcer disease and 2 patients in 100 with recurrent ulcers after ulcer surgery are estimated to have a gastrinoma (Wolfe, 1987).
• The clinical symptoms of patients with gastrinoma are a direct result of excessive levels of circulating gastrin.
• Abdominal pain and peptic ulceration of the upper gastrointestinal tract are the most common symptoms and are observed in 90-95% of patients with Zollinger-Ellison syndrome (Way, 1968; Orloff, 1995).
• Peptic ulcer symptoms in patients found to have gastrinomas are similar to those of patients with a common peptic ulcer. The symptoms may be more protracted than those of a common peptic ulcer, and they are frequently refractory to standard medical and surgical therapies.
• Although the symptoms of gastroesophageal reflux disease are rarely the only symptoms, they occur in approximately one third of the patients with Zollinger-Ellison syndrome. As many as 60% of patients with Zollinger-Ellison syndrome report dysphagia or odynophagia or have endoscopic findings consistent with reflux esophagitis (Miller, 1990; Bieligk, 1995).
• Diarrhea occurs in more than a third of patients with gastrinoma; it is secondary to both the high volume of hydrochloric acid in the upper gastrointestinal tract and the direct effects of circulating gastrin on the secretory and absorptive properties of the small intestine. Occasionally, diarrhea may be the only presenting symptom of a gastrinoma (Stabile, 1976; Vinik, 1993).
• Steatorrhea occurs in some people with gastrinoma syndrome secondarily; acid in the duodenum and proximal jejunum irreversibly denatures the pancreatic lipase, inactivating it. The denatured lipase is unable to hydrolyze intraluminal triglycerides to their respective diglycerides, monoglycerides, and fatty acids for absorption (Shimoda, 1968).

• Because the clinical history of patients with Zollinger-Ellison syndrome is often indistinguishable from that of patients with ordinary peptic ulcers, certain clinical conditions should alert clinicians to the possibility of gastrinoma syndrome. Many consider the following conditions to be indications for the initial measurement of a serum gastrin level (Yeo, 2001):
  • Postbulbar ulcers
  • Multiple ulcers
  • Ulcers refractory to standard medical therapy
  • Ulcer recurrence after antiulcer surgery
  • Ulcer and diarrhea
  • Prolonged unexplained diarrhea
  • Family history of peptic ulcer
  • Family history suggestive of MEN 1 syndrome
  • Ulcers in patients who are negative for Helicobacter pylori infection who have no history of nonsteroidal anti-inflammatory drug (NSAID) use
  • Nongastrinoma pancreatic endocrine tumor, ie, because of the high association of secondary elevations in hormone levels (Wynick, 1988; Chiang, 1990)
  • Prominent gastric rugal folds on images from upper endoscopy or a gastrointestinal series (reflecting the trophic effect of gastrin on the gastric fundus)

• VIPoma

• Symptoms of Verner-Morrison or WDHA syndrome (ie, watery diarrhea, hypokalemia, achlorhydria, acidosis) are the result of the physiologic effects of overproduction of VIP by pancreatic endocrine neoplasms.
• The primary and ubiquitous symptom of patients with a VIPoma is watery diarrhea, the occurrence of which may be constant, episodic, or intermittent (Jensen, 1998). Because diarrhea production in persons with Verner-Morrison syndrome is due to cyclic adenosine monophosphate–mediated prosecretory gastrointestinal stimulation by VIP, the term pancreatic cholera has been used to emphasize the physiologic mechanism of this disease (Metz, 1995].
• Abdominal cramps are common among patients with VIPoma syndrome, and flushing episodes occur in a small percentage of patients (O'Dorisio, 1989).
• The remaining symptoms associated with VIPomas are secondary to hypokalemia, which occurs because of fecal potassium losses that can reach 400 mEq/d. These symptoms may include muscular weakness, lethargy, and nausea (Yeo, 2001).

• Glucagonoma

• Glucagonomas secrete excessive amounts of glucagon and cause a syndrome characterized by dermatitis, stomatitis, weight loss, and anemia (Higgins, 1979).
• The dermatitis associated with glucagonoma syndrome is termed necrolytic migratory erythema. This dermatitis is characterized by the cyclic migration of erythematous patches that spread serpiginously and then reveal central points of healing (Wilkinson, 1973).

• Hyperglucagonemia in patients with glucagonomas results in glucose intolerance (ie, diabetes) and cachexia (secondary to anorexia and the catabolic effects of glucagon) that can be significant, even when the tumors are small and not metastatic (Stacpoole, 1981).

• As many as a third of patients with glucagonoma syndrome have secondary thromboembolic phenomena; therefore, they may have a history consistent with deep venous thrombosis and/or pulmonary embolism (Leichter, 1980). This feature of glucagonomas is unique among the different neoplasms of the endocrine pancreas.

• Patients with glucagonoma syndrome may have fatigue, which is the result of the normochromic normocytic anemia that occurs in approximately half the patients with this disease (Guillausseau, 1982).

• Somatostatinoma

• The symptoms of somatostatinoma syndrome reflect the general inhibitory action of somatostatin on global gastroenteropancreatic function.
• Patients with somatostatinomas often have history findings consistent with diabetes mellitus, which is probably secondary to the inhibitory action of somatostatin on insulin and glucagon release (Vinik, 1987).
• Inhibition of the action of cholecystokinin by somatostatin (Brodish, 1995) likely causes relative biliary stasis and the formation of gallbladder calculi. This inhibition may be responsible for the symptoms of biliary colic that often occur in patients with somatostatinomas (Boden, 1985).
• Patients with somatostatinoma syndrome may also have diarrhea and/or steatorrhea, both of which are likely to be caused by the inhibition of pancreatic enzyme and bicarbonate secretion (Jensen, 1998).
• When examining patients who present with the aforementioned features, the astute clinician should keep in mind that the triad of hyperglycemia, gallstones, and steatorrhea is not specific for somatostatinoma syndrome. Therefore, patients with these findings should be examined for more common disease entities prior to a comprehensive workup for somatostatinoma.

• Carcinoid tumor: The symptoms of carcinoid tumor are related to hypersecretion of serotonin (5-HT) and include flushing, diarrhea, heart valvular lesions, cramping, telangiectasia, peripheral edema, wheezing, cyanosis, and arthritis.

• Miscellaneous: Additional functional tumors of the endocrine pancreas have been reported, with secretion of GRF, neurotensin, parathyroid hormone-related peptide, PP, ACTH, and MSH.
  • ACTHoma: Symptoms pertain to Cushing syndrome depicted as facial and torso obesity, high blood pressure, stretch marks on the abdomen, generalized weakness, osteoporosis, and facial hair growth in females.
  • MSHoma: This causes skin hyperpigmentation.
  • GRFomas: These primarily result in acromegaly but can also present with other symptoms. They are frequently associated with MEN 1 syndrome and can be accompanied by ZES and/or Cushing syndrome in 40% of the cases.
  • Neurotensinomas can cause hypotension, hypokalemia, weight loss, flushing, and diabetes. These tumors are usually malignant.
  • PPomas have no characteristic symptoms and are associated with high circulating PP levels, although high PP levels can also be seen with other islet cell tumor syndromes.

Physical: Physical examination in patients with pancreatic endocrine tumors generally reveals nonspecific findings. However, visual identification of glucagonoma-associated necrolytic migratory erythema, stomatitis, angular chelitis, and VIPoma-associated flushing are important diagnostic clues.

• Patients with functional neoplasms of the endocrine pancreas usually present when their tumors are small; however, a mass may be found after abdominal palpation if the patient has a large, nonfunctional tumor.

• Large, nonfunctional neoplasms in the head of the pancreas may occasionally cause biliary obstruction, which can lead to jaundice.

Causes:

• Genetics

• Fundamental understanding of pancreatic endocrine tumors has increased greatly because of recent observations in the fields of classic and molecular genetics.

• In one small series of malignant pancreatic endocrine tumors analyzed by genetic karyotyping, clonal chromosomal abnormalities were identified in more than half the specimens (Long, 1994).

• Amplification of the HER-2/neu proto-oncogene has been demonstrated in gastrinomas (Evers, 1994), and a high level of mRNA expression for the alpha subunit of the cell cycle protein Gs is observed in insulinomas (Zeiger, 1993).

• Loss of heterozygosity at band 11q13 that results in the inactivation of a tumor suppressor gene in this region has been demonstrated in sporadic pancreatic endocrine tumors and in tumors of patients with MEN 1 syndrome or of those with von Hippel-Lindau syndrome (Eubanks, 1997).

• Recent genetic studies of endocrine tumors of the pancreas have suggested novel loci for tumor suppressor genes 3p25, 3p27, and 11p13, and others. Loss of alleles in these regions may serve as markers for malignant endocrine tumors of the pancreas. Also recently demonstrated is the fact that cyclin-dependent kinase inhibitor, p27kip1, is abundantly present in well-differentiated tumors but scant or absent in more aggressive tumors.

• MEN 1 syndrome

• MEN 1 syndrome, Wermer syndrome, is a genetic disorder with an autosomal dominant pattern of inheritance. The syndrome is characterized by hyperparathyroidism, adenomas of the pituitary, and neoplasms of the endocrine pancreas (Miller, 1997).

• As many as 97% of patients with MEN 1 syndrome have hyperparathyroidism. Between one third and one half of patients with MEN 1 syndrome have pituitary adenomas; prolactin-secreting tumors are the most common type.

• Approximately 80% of patients with MEN 1 syndrome have pancreatic endocrine neoplasms. The pancreatic tumors in these patients tend to be multiple and usually secrete multiple hormonally active products.

• Nearly all patients with pancreatic endocrine tumors associated with MEN 1 syndrome have one or more nonfunctional lesions, and the majority also have functional neoplasms, including gastrinomas (54%), insulinomas (21%), glucagonomas (3%), and VIPomas (1%) (Jensen, 1998).

• Environment

• No well-established environmental factors are known to be associated with the development of neoplasms of the endocrine pancreas.

• This lack is in stark contrast to knowledge about the development of neoplasms in the exocrine pancreas, for which cigarette smoking, specific diets, and exposure to industrial toxins are known risk factors (Nakeeb, 2001).

• Medications

• Leuprolide acetate (Lupron), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone, has been shown to cause significant but not dose-related increase of pancreatic islet cell adenomas in female mice in a 2-year study conducted by the FDA (2004).

• A 2-year study performed in the United Kingdom demonstrated a dose-related increase in pancreatic islet cell tumors in female rats exposed to high doses of medroxyprogesterone acetate (MPA) (2005).

DIFFERENTIALS

Gastrinoma
Glucagonoma
Insulinoma
Neoplasms of the Endocrine Pancreas
Somatostatinomas
VIPomas
WDHA Syndrome
Zollinger-Ellison Syndrome

Other Problems to be Considered:

The DDX of hypoglycemia includes reactive hypoglycemia, functional hypoglycemia associated with gastrectomy or gastroenterostomy, nonpancreatic tumors, pleural mesothelioma, sarcoma, adrenal carcinoma, hepatocellular carcinoma, carcinoid, hypopituitarism, chronic adrenal insufficiency, extensive hepatic insufficiency, and surreptitious self-administration of insulin or ingestion of oral hypoglycemic agents (Yeo, 2001). See the review article by Service for an exhaustive list.

The DDX of peptic ulcer includes Helicobacter pylori infection, NSAID use, gastric cancer, duodenal cancer, pancreatic cancer, ischemic gastric injury, and postoperative marginal ulcer.

The DDX of hypergastrinemia due to nonulcerogenic causes (ie, with normal-to-low acid secretion) includes atrophic gastritis, pernicious anemia, previous vagotomy, renal failure, and short-gut syndrome (Yeo, 2001).

The DDX of hypergastrinemia due to ulcerogenic causes (ie, with excessive acid secretion) includes antral G cell hyperplasia or hyperfunction, gastric outlet obstruction, retained excluded antrum, and Zollinger-Ellison syndrome (Yeo, 2001).

The DDX of watery diarrhea includes villous adenoma, laxative abuse, celiac disease, parasitic and infectious diseases, inflammatory bowel disease, carcinoid syndrome, and gastrinoma (Yeo, 2001).

WORKUP

Lab Studies:

• Insulinoma

• Monitored fasting test: Blood is sampled to determine glucose and insulin levels every 4-6 hours and when symptoms appear. Hypoglycemic symptoms typically occur when glucose levels are less than 50 mg/dL; concurrent serum insulin levels often exceed 25 mU/mL. The diagnosis of insulinoma is additionally supported by insulin-to-glucose ratios, which are calculated at different times during the monitored fast. After a prolonged fast, healthy persons have insulin-to-glucose ratios less than 0.3, whereas patients with insulinomas typically have ratios much higher than 0.4 (Yeo, 2001).

• Proinsulin and C peptide test: The physiologically active form of insulin is produced in vivo when C peptide is cleaved from proinsulin in the beta cells of the pancreas. Therefore, insulin and C peptide are secreted in equimolar amounts, and the levels of all 3 proteins, namely, proinsulin, C peptide, and insulin, are increased in patients with insulinoma. The surreptitious administration of insulin should be considered when elevated insulin levels are present in a background of normal proinsulin and C peptide levels.

• Anti-insulin antibody test: The presence of serum antibodies against insulin is strongly suggestive of the surreptitious administration of insulin and not insulinoma.

• Gastrinoma

• Fasting serum gastrin test: Levels greater than 200 pg/mL are suggestive of gastrinoma, and levels greater than 1000 pg/mL are virtually diagnostic of gastrinoma. Serum gastrin levels are also elevated in patients with pernicious anemia because of a lack of negative feedback from parietal cell secretion of hydrochloric acid; thus, hypergastrinemia in the absence of hyperchlorhydria and peptic ulcer is not attributable to a gastrinoma.

• Gastric acid analysis: Basal acid secretion at a rate higher than 15 mEq/h or a basal-to-maximal acid output ratio that exceeds 0.6 supports the diagnosis of gastrinoma (Yeo, 2001).

• Secretin stimulation test: A baseline fasting serum sample is drawn, after which secretin at 2 U/kg is administered as an intravenous bolus. Blood is drawn every 5 minutes for 30 minutes, and the serum gastrin level is determined in each sample. An increase in the gastrin level of more than 200 pg/mL above the basal level supports the diagnosis of gastrinoma (Wolfe, 1987).

• VIPoma

• Serum VIP test: Determined during periods of ongoing diarrhea, the level of serum VIP in patients with Verner-Morrison syndrome ranges from 225-1850 pg/mL. The normal serum VIP level is less than 170 pg/mL (Mekhjian, 1987).

• Serum electrolyte analysis: Patients with WDHA syndrome generally have low serum potassium and bicarbonate levels secondary to fecal loss.

• Gastric acid analysis: Patients with WDHA syndrome have low basal gastric acid output.

• Stool analysis: VIPoma-associated diarrhea is secretory diarrhea; therefore, it has a low fecal fat content and a normal stool osmolar gap (Krejs, 1987).

• Glucagonoma: Serum glucagon test levels greater than 1000 pg/mL are diagnostic of glucagonoma, levels less than 150 pg/mL are normal, and levels of 150-1000 pg/mL are equivocal (Guillausseau, 1982). Most patients with serum glucagon levels that are marginally elevated above 150 pg/mL do not have glucagonoma.

• Somatostatinoma: With a fasting serum somatostatin evaluation, the normal level is below 100 pg/mL but patients with somatostatinoma syndrome have elevated levels on the order of nanograms per milliliter (Ganda, 1977; Krejs 1979). This test in available only in select centers.

Imaging Studies:

• Computed tomography

• High-resolution contrast-enhanced spiral CT scanning with thin sections (ie, 3- to 5-mm section) through the pancreas is the initial imaging technique used to localize and stage most neoplasms of the endocrine pancreas.

• CT scan is noninvasive; however, it fails to help identify as many as 70% of these lesions; therefore, most patients must be examined with additional, more expensive, or more invasive localization techniques (Pelley, 1997).

• Magnetic resonance imaging

• Significant technical advances have recently brought MRI to the forefront as a useful technique for the localization of neoplasms of the endocrine pancreas.

• Because of the marked edema of the stromal tissue separating nests of endocrine cells, islet cell tumors present with exceptionally high relaxation times, resulting in greater enhancement on T1- and T2-weighted images than most pancreatic adenocarcinomas. Also, findings from 3 recent studies have demonstrated the usefulness of contrast-enhanced T1-weighted MRI studies in the evaluation of small primary and metastatic pancreatic endocrine tumors (Moore, 1995; Berger, 1996; Gibril, 1996). With the advent of hybrid fast-spin echo T2 sequences, small lesions that depend on minimization of motion-induced artifacts and maximization of resolution can be more accurately visualized (Mitchell, 1998).

• Somatostatin receptor scintigraphy

• This novel nuclear medicine imaging modality takes advantage of the fact that pancreatic endocrine tumors, with the notable exception of somatostatinomas, express large numbers of somatostatin receptors on their cell surfaces.

• Radiolabeled octreotide is a somatostatin analogue that preferentially binds to somatostatin receptors; the intravenous administration of octreotide can be used to identify such tumors (Krausz, 1998).

• Although the limited resolution of the images from this technique does not provide the detail necessary to determine the exact location of a primary tumor, somatostatin receptor scintigraphy is particularly helpful in diagnosing small extrapancreatic metastases (Frilling, 1998).

• Endoscopic ultrasonography

• In experienced hands, transduodenal endoscopic ultrasonography (EUS) can be helpful in localizing pancreatic endocrine tumors and in assessing lymph node metastases (Glover, 1992; Rosch, 1992).

• The major disadvantage of this imaging modality is that it cannot be used to evaluate hepatic and distant spread. EUS is most useful in identifying small intraduodenal and pancreatic tumors.

• Angiography

• Because of improvements in the techniques of CT, MRI, and EUS, visceral angiography currently has no role in the selective visualization of the arterial supply to the pancreas and peripancreatic regions (Yeo, 2001).

• Provocative angiography is a localization technique that takes advantage of the responsiveness of certain pancreatic endocrine tumors to specific biochemical stimulants and knowledge of the arterial supply of the pancreas and peripancreatic regions to map the location of occult gastrinomas and insulinomas.
  • In the selective arterial secretin stimulation test, secretin is selectively injected into the splenic, gastroduodenal, and inferior pancreaticoduodenal arteries (the last is a branch of the superior mesenteric artery) with concomitant and subsequent hepatic venous sampling for gastrin (Imamura, 1987; Thom, 1992). Based on the level of gastrin in each hepatic venous sample, the location of the gastrinoma is arterially mapped.
  • An analogous method is used in the selective arterial calcium stimulation test to determine the location of occult insulinomas, which respond to calcium stimulation by secreting insulin (Pereira, 1998).

Other Tests:

• Selective transhepatic portal venous sampling: In this invasive test, blood samples are obtained from different locations within the portion of the portal venous system into which the pancreas and pancreatic bed drain (Vinik, 1991). Serum levels of the tumor hormone product in question are determined from the blood samples to help localize the tumor based on anatomic venous drainage. The presumption is that the sample with the highest serum hormone level was drawn closest to the venous drainage point of the tumor.

Procedures:

• Endoscopy: Endoscopic evaluation of the upper gastrointestinal tract in patients with possible gastrinoma can be used to identify the location and number of peptic ulcers. The examination may reveal evidence of reflux esophagitis. Intraoperative endoscopic transduodenal illumination may be helpful in the localization of small pancreatic endocrine tumors located within the wall of the duodenum (Fraker, 1995).

• Intraoperative ultrasonography (IOUS): It is the study of choice for localization of insulinomas and is more effective than any other preoperative diagnostic imaging study, with a sensitivity of 90% (Gooding, 1993). Real-time IOUS images can provide additional information about the location and number of pancreatic endocrine tumors, and IOUS can be used to detect small lymph node and hepatic metastases (Norton, 1985; Grant, 1988). This technique should always be used in patients who undergo exploration for tumors that could not be definitively localized before surgery.

Histologic Findings: When visualized with light microscopy, all pancreatic endocrine tumors appear similar and resemble carcinoid tumors, the most common type of APUDomas (Norton, 1993). Routine histologic examination cannot be used to predict the biologic behavior of these neoplasms. Malignancy is typically determined by the presence of tumor spread to regional lymph nodes or by the existence of hepatic or distant metastases (Yeo, 2001).

Immunofluorescence techniques and the peroxidase-antiperoxidase procedure allow the demonstration of specific hormones within neoplastic cells, but positive findings with immunohistochemical staining for neuroendocrine products (eg, insulin, gastrin, pancreatic polypeptide) only confirm that a particular tumor can synthesize these products; such findings provide no information about whether the synthesized products are actually released into the blood stream (Heitz, 1982).

Staging:

• The staging system for islet cell cancer is still being developed. These tumors are most often divided into 1 of 3 groups:

• Islet cell cancers occurring in 1 site within the pancreas
• Islet cell cancers occurring in several sites within the pancreas

• Islet cell cancers that have spread to lymph nodes near the pancreas or to distant sites

• Unlike pancreatic adenocarcinoma, in which the tumoral stage, resectability, and prognosis are determined by using the tumor, nodes, and metastasis classification, the prognosis of patients with pancreatic endocrine tumors is predicted with the presence or absence of liver metastases. The prognosis of patients with regional lymph node metastases is similar to that of patients with only a primary tumor (Somogyi, 2000).

TREATMENT

Medical Care: Treatment must be individualized in patients with a neoplasm of the endocrine pancreas, in order to balance management of the effects of hormone production with management of the symptoms related to the bulk of the tumor (Macdonald, 2000). Many pancreatic endocrine tumor syndromes are potentially life-threatening upon presentation; therefore, initial medical therapy is aimed at stabilization of the patient adequate enough for a complete preoperative evaluation (Metz, 1995).

With the exception of the administration of the somatostatin analogue octreotide, of which either the original short-acting form or the newer long-acting form can be helpful in the treatment of all functional pancreatic endocrine neoplasms except somatostatinoma, the specific therapy for each syndrome depends on the action of the particular hormone product secreted (Vinik, 1989). The use of specific pharmacologic agents (including chemotherapeutic agents) in the treatment of patients with endocrine neoplasms of the pancreas is discussed in Medication. Treatments for specific syndromes may include the following:

• Upon initial presentation, patients with insulinoma may require immediate potassium replacement and dextrose administration. Hypoglycemia can often be managed in the preoperative period by administering diazoxide, which inhibits insulin release from both normal beta cells and insulinoma cells (Boden, 1989; Fajans, 1989).

• The 2 main goals in the initial treatment of a patient with a gastrinoma are (1) to stabilize the general hemodynamic condition of the patient and control bleeding from gastrointestinal ulcers and (2) to establish a nonacidic gastric pH with the use of proton pump inhibitors, eg, omeprazole (Yeo, 2001).
• The primary initial concern in the treatment of a patient who presents first with VIPoma-associated diarrhea is the replacement of volume losses and the correction of acid-base and electrolyte abnormalities (O'Dorisio, 1989).

• Patients with glucagonomas generally have nutritional depletion and often require blood transfusions, total parenteral nutrition, and preoperative control of hyperglycemia (Metz, 1995).

• Nutritional repletion and control of hyperglycemia are important aspects of good medical care in patients with somatostatinoma syndrome.

• Extralymphatic metastatic spread of pancreatic endocrine neoplasms primarily involves the liver. Therefore, cytoreductive techniques that lower serum levels of the offending gastroenteropancreatic hormone by decreasing hepatic tumor bulk often improve the patient's quality of life. Similar to surgical resection of hepatic metastases (discussed below), hepatic arterial embolization with or without chemotherapy yields impressive results in terms of tumor, hormone, and symptom regression (Moertel, 1994). Cryosurgery is reported to ameliorate symptoms in patients with hepatic metastases that are resistant to chemotherapy (Bilchik, 1997), and the treatment of these lesions with radiofrequency ablation has also been proposed (Brentjens, 2001).

Surgical Care: At the time of surgical exploration for pancreatic endocrine neoplasms, the pancreas and peripancreatic regions are completely evaluated. Dividing the gastrocolic ligament exposes the body and tail of the pancreas. This portion of the pancreas can be partially elevated out of the retroperitoneum by dividing the inferior retroperitoneal attachments to the gland. After the second portion of the duodenum is elevated out of the retroperitoneum by means of the Kocher maneuver, the pancreatic head and uncinate process are palpated bimanually. The liver is carefully assessed for evidence of metastatic disease. Potential extrapancreatic sites of tumoral involvement are evaluated in all cases, with particular attention to the duodenum; splenic hilum; small intestine and its mesentery; peripancreatic lymph nodes; and, in women, the reproductive tract (Yeo, 2001).

The goals of surgical therapy for pancreatic endocrine neoplasms include (1) controlling the symptoms of hormone excess, (2) safely resecting the maximal amount of tumor mass possible, and (3) preserving the maximal amount of pancreatic parenchyma possible (Yeo, 2001). Surgical management of the primary tumor is similar for the different types of pancreatic endocrine neoplasms. Surgical treatments may include the following:

• Small benign lesions remote from the main pancreatic duct can be enucleated (Menegaux, 1993; Yeo, 2001).

• Tumors deep in the substance of the pancreatic gland, and therefore close to the main duct, have ill-defined capsules, and tumors larger than 2 cm in diameter should be treated with regional pancreatectomy.

• Tumors in the body or tail of the pancreas can be managed with distal pancreatectomy (Lillemoe, 1999).

• Lesions in the head or uncinate process of the pancreas can be resected with pancreaticoduodenectomy (Phan, 1997; Udelsman, 1993).

• Tumors in the neck of the pancreas can now be managed with middle-segment pancreatectomy by oversewing the proximal pancreatic stump and draining the distal pancreatic duct via a pancreaticogastrostomy or pancreaticojejunostomy.

• When a preoperatively occult gastrinoma is not found during surgical exploration, despite the use of intraoperative ultrasonography and endoscopic transduodenal illumination, longitudinal duodenotomy can be performed at the level of the second portion of the duodenum to allow eversion of the duodenum to assess duodenal microgastrinomas (Sugg, 1993). Then, the localized microgastrinomas can be resected and the duodenal defect closed (Farley, 1994).

• Rather than performing a blind regional pancreatectomy for an occult insulinoma or gastrinoma, selective provocative angiography (see Other Tests) should be performed so that the appropriate pancreatic segment can be resected, eg, distal pancreatectomy versus pancreaticoduodenectomy (Thompson, 1993).

• Metastatic disease to the liver should be resected when possible. If facing unresectable disease, radiofrequency or cryosurgical ablation should be considered.

• In the past, most patients with metastatic neoplasms of the endocrine pancreas died of the hormone-excess states, but with the development of increasingly effective medical therapies to control this pathophysiologic condition (ie, proton pump inhibitors for gastrinomas; octreotide for other endocrine tumors), the major determinant of long-term patient survival is becoming the malignant nature of the tumors. For this reason, hepatic metastases are debulked with cytoreductive surgical resection. However, most surgeons believe that this aggressive approach should be reserved for patients in whom near 100% tumor removal can be achieved with reasonable safety (Gibril, 1995).

Consultations:

• Endocrinologist

• Gastroenterologist

• Pancreatic or oncologic surgeon

• Medical oncologist

Diet: Patients with unresectable insulinoma may have some symptomatic relief by eating frequent small meals with a high starch and complex carbohydrate content (Fajans, 1989). In contrast to the symptoms of routine dyspepsia, diet modification rarely ameliorates the symptoms or complications of gastrinoma-associated hyperchlorhydria. Patients with VIPomas, glucagonomas, and somatostatinomas frequently have fluid, electrolyte, and nutritional deficits, and they often require parenteral supplementation (Metz, 1995).

Activity: Exercise often exacerbates the symptoms of insulinoma syndrome secondary to relative substrate deficiency such as hypoglycemia (Stefanini, 1974). Therefore, patients with insulinoma may need to avoid exercise until their tumor is successfully resected.

MEDICATION

The goals of palliative medical therapy for pancreatic endocrine neoplasms are (1) the reduction of symptoms related to hormonal excess and (2) the control of tumor cell proliferation.

Recently, studies from a group in Sweden demonstrated that the combination of alpha-interferon and somatostatin analogs for the treatment of patients with advanced malignant endocrine pancreatic tumors resulted in radiological response in 3 (19%) of 16 patients (median duration, 23 mo) and biochemical response in 10 (62.5%) of 16 (median duration, 22 mo) (Fjallskog, 2002).

Drug Category: Antisecretory agents -- Used to modulate the release of gastroenteropancreatic hormones from both normal and neoplastic APUD cells in the treatment of pancreatic endocrine tumor syndromes to reduce specific symptoms related to hormonal excess.

Drug Name	Octreotide (Sandostatin) -- Somatostatin analogue that binds somatostatin receptors on pancreatic endocrine tumor cells and inhibits release of many gastroenteropancreatic hormones. Useful adjunct in palliative treatment of patients with most functional metastatic pancreatic endocrine tumors. Evidence suggests that it may also have antiproliferative effects in rare cases. However, symptomatic and antiproliferative effects last only months and are probably of short duration secondary to down-regulation of cell-surface somatostatin receptors (Maton, 1989). Because octreotide is a somatostatin agonist, it is not useful in the treatment of patients with somatostatinoma syndrome (Pless, 1986). Doses of 300-600 mcg/d or higher seldom result in additional biochemical benefit.
Adult Dose	50 mcg SC tid initially; may increase to 500 mcg tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May reduce effects of cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse effects are primarily related to altered GI tract motility and include nausea, abdominal pain, diarrhea, and increased incidence of gallstones and biliary sludge; hypoglycemia or hyperglycemia possible (due to alteration in counter-regulatory hormones [eg, insulin, glucagon, GH]); bradycardia, cardiac conduction abnormalities, and arrhythmias; hypothyroidism (due to inhibition of TSH secretion) caution in renal impairment; cholelithiasis; patients receiving insulin, oral hypoglycemics, beta-blockers, or calcium channel blockers may require dose adjustments

Drug Category: Immunotherapeutics -- Used to modulate host immune responses to neoplastic cells. Control of tumor cell proliferation is the goal when these agents are used to treat patients with pancreatic endocrine tumor syndromes.

Drug Name	Interferon alfa-2a (Roferon-A) and alfa-2b (Intron A) -- Protein product manufactured by using recombinant DNA technology. Pancreatic endocrine tumor patients treated with human leukocyte interferon have objective response rates of 77%, with effects lasting >1 year in some cases. Responses represent primarily decreased hormone production rather than objective reduction in tumor bulk (Oberg, 1989). Mechanisms of hormone reduction and antitumor activity are not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response likely have important roles.
Adult Dose	2 million U/m2 SC 3 times/wk for 30 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, and compromised CNS

Drug Category: Chemotherapeutics -- Primarily reserved for patients with pancreatic endocrine neoplasms that are metastatic and/or unresectable.

While most experts agree that chemotherapy is indicated in patients who have symptoms from tumor bulk or uncontrolled syndromes of hormone excess that cannot be palliated with other means (eg, cytoreductive surgery, cryosurgery, radiofrequency ablation, hepatic artery embolization), no consensus exists on when therapy should be started in asymptomatic patients with metastatic or recurrent disease. One common practice is to reassess patients at 3- to 6-month intervals after diagnosis of metastatic or recurrent disease. Patients with clear tumoral progression are treated with chemotherapy, whereas those with stable lesions are monitored. No benefit from chemotherapy has been demonstrated in patients with metastases to only lymph nodes.

Studies of patients with advanced islet cell carcinomas in which streptozocin alone was compared with streptozocin plus 5-fluorouracil (5-FU) have overall response rates as high as 63%, and survival rates increased by as much as 1 year with combination therapy, although single-agent therapies have generally yielded lower response rates (Moertel, 1980). A study of streptozocin plus doxorubicin compared with streptozocin plus 5-FU revealed a better response rate of 69% and an increased survival rate for patients treated with streptozocin plus doxorubicin (Moertel, 1992). In a study of patients with all types of GI neuroendocrine tumors, streptozocin was found to be more effective in patients with islet cell tumors than in those with carcinoid tumors (Moertel, 1994). However, a small study of patients with islet cell carcinomas treated with the combination of streptozocin, doxorubicin, and 5-FU had a response rate of only 54% and no complete responses (Rivera, 1998).

A number of other chemotherapeutic drugs, such as the taxanes, platinum compounds, gemcitabine, camptothecin analogues, targeted receptor antagonists, and antiangiogenesis/antiendothelial agents, have demonstrated activity against pancreatic endocrine tumors, but none has been adequately evaluated in these neoplasms or has demonstrated results as good as those of various combinations of streptozocin, doxorubicin, and 5-FU (Macdonald, 2000).

Drug Name	Streptozocin (Zanosar) -- Has diabetogenic action in some animals that is correlated with selective uptake of the drug by pancreatic beta cells (Schein, 1973). As a result, streptozocin is uniquely helpful in the treatment of insulinoma. Also inhibits cell proliferation and is cytolytic. Interferes with normal DNA function by means of alkylation and protein modification.
Adult Dose	1-1.5 g/m2 IV qwk for 6 wk, followed by 4-wk observation period
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Aminoglycosides, loop diuretics, and doxorubicin may increase nephrotoxicity; phenytoin may decrease effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Severe nausea and vomiting common; liver dysfunction and myelosuppression can occur; renal toxicity is dose-related and cumulative; closely monitor renal, hepatic, and hematologic function

Drug Name	Doxorubicin (Adriamycin, Rubex) -- Inhibits topoisomerase II and produces free radicals that may destroy DNA. Combination of these events can inhibit growth of neoplastic cells.
Adult Dose	60-75 mg/m2 IV as a single dose; repeat q21d Alternatively, 20-30 mg/m2/d IV for 2-3 d; repeat in 4 wk
Pediatric Dose	35-75 mg/m2 IV as a single dose; repeat q21d Alternatively, 20-30 mg/m2 qwk
Contraindications	Documented hypersensitivity; severe heart failure, cardiomyopathy, and impaired cardiac function; preexisting myelosuppression
Interactions	May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in impaired hepatic function

Drug Name	Fluorouracil (Adrucil) -- Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase and interferes with RNA synthesis and function. Has some effect on DNA.
Adult Dose	15 mg/kg/d IV continuous infusion (24 h) for 5 consecutive d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression; serious infection
Interactions	Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents
Pregnancy	D - Unsafe in pregnancy
Precautions	Nausea, oral and GI tract ulcers, immune system depression, and bone marrow suppression may occur; adjust dose in renal impairment

FOLLOW-UP

Further Inpatient Care:

• Patients who have complications from chemotherapy (eg, myelosuppression, renal failure, hepatic failure, severe gastrointestinal toxicity) may require inpatient treatment.

• Patients with tumor recurrences that lead to the recurrence of symptomatic hormone-excess states may again require inpatient care to correct fluid, electrolyte, and nutritional disturbances.

Further Outpatient Care:

• Patients who have undergone surgical resection of neoplasms of the endocrine pancreas require close follow-up with an endocrinologist or medical oncologist, and surveillance serum hormone levels should be tested regularly to ensure that recurrence is diagnosed early and treated appropriately.

• Proper outpatient treatment of patients with unresectable pancreatic endocrine tumors requires regular follow-up with endocrinologists and medical oncologists.

In/Out Patient Meds:

• Although octreotide is administered parenterally, usually via a subcutaneous injection, patients who have received the proper instruction can self-administer the medication.

• Interferon and cytotoxic chemotherapeutic agents are generally administered in a well-controlled outpatient or inpatient setting.

• Patients can also consider enrollment in some clinical trials conducted by the National Cancer Institute, if they meet criteria.

• The NCT00003514 Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Metastatic or Incurable Neuroendocrine Tumors (Verified by National Cancer Institute [NCI] October 2003)

• The NCT00075439 Phase II Study of Gefitinib in Patients with Progressive Metastatic Neuroendocrine Tumors (Verified by National Cancer Institute [NCI] December 2004)

Transfer:

• Neoplasms of the endocrine pancreas are rare, their diagnosis and localization often require advanced technologies, and their successful treatment requires a careful multidisciplinary approach.

• For these reasons, the patient with a possible or confirmed pancreatic endocrine tumor is best treated at a large referral center where endocrinologists, gastroenterologists, pancreatic surgeons, and medical oncologists are available.

Complications:

• Late in the course of pancreatic endocrine tumors, patients can have morbidity related to the mass effects of the disease.

• Patients with tumors in the pancreatic head occasionally have biliary obstruction, pancreatic obstruction, or both.
• Chronic abdominal pain can occur because of the compressive effects of a large intra-abdominal mass or obstructive pancreatitis.

• Morbidity resulting from the effects of excess hormonal production by functional neoplasms of the endocrine pancreas occurs sooner than the mass effects in the course of the disease.

• If untreated, patients with insulinoma can have hypoglycemic seizures and even frank coma (Welbourne, 1981).

• Prior to the development of effective antisecretory medications (eg, H2 blockers, proton pump inhibitors), patients with gastrinoma often had life-threatening gastrointestinal bleeding from peptic ulcers.

• Untreated patients with VIPoma can become severely dehydrated from diarrhea, and fatal cardiac arrhythmias can develop secondary to associated hypokalemia.

• The morbidity associated with the hormonal effects of glucagonoma can be striking; patients can have diabetes, wasting, stomatitis, and other features similar to severe nutritional deficiency.

• A study of 125 patients who underwent surgical resection of pancreatic neuroendocrine tumors between 1949 and 1996 had complications that included pancreatic fistula (16%), wound infection (15%), delayed gastric emptying (8%), and death (2.8%) (Phan, 1998):

• Permanent diabetes mellitus can mandate extended pancreatic tumor resection.

• Complications of medical therapies are discussed in Medication.

Prognosis:

• Endocrine tumors of the pancreas typically have indolent growth; nevertheless, the rate of tumor growth is still a major determinant of survival in patients with these lesions (Metz, 1995).
• Because these tumors usually grow slowly and have a relatively low metastatic potential and because no specific criteria have been defined to predict their behavior, the distinction between benign and malignant neoplasms is based on the presence of metastatic disease; therefore, long-term clinical follow-up is often required (Norton, 1993; Metz, 1994).
• Neoplasms of the endocrine pancreas have patterns of initial tumor spread that are similar to those of other gastrointestinal carcinomas.

• The neoplasms spread first to regional lymph nodes and then to the liver.
• Bone metastases may occur late in the course of the disease and indicate a poor prognosis (Kloppel, 1988).
• In rare cases, pancreatic endocrine tumors metastasize to the lungs or brain.

• Currently, the most important prognostic factor that determines the survival of patients with neoplasms of the endocrine pancreas is the presence or absence of metastatic disease.

• Because even metastatic pancreatic endocrine neoplasms typically grow slowly, the prognosis associated with these tumors is relatively good compared with nonendocrine pancreatic cancers.
• More than 90% of patients with insulinomas have benign neoplasms without evidence of metastases, and as many as 97% of these patients can be cured with surgical resection (Rothmund, 1990).
• Patients with gastrinomas have a poorer prognosis; 60% of these tumors are malignant (McGuigan, 1998). However, survival rates are strikingly different between patients in whom gastrinoma metastasis is limited to the lymph nodes and those with hepatic metastases.
  • Patients in whom gastrinoma metastasis involves only the lymph nodes can live a quarter decade or longer, and their life expectancy is indistinguishable from that of patients with gastrinoma in whom no tumor is identified at surgery (Stabile, 1985; Fraker, 1994; Weber, 1995).
  • Patients with hepatic gastrinoma metastases have a 5-year survival rate of 20-30%, compared with approximately 90% in patients without liver metastasis (Jensen, 1994).

• Among pancreatic endocrine tumors, glucagonomas tend to be relatively large (5-10 cm) at diagnosis. Also, as many as 80% are invasive or metastatic; this frequency rate is higher than that of the other tumors (Leichter, 1980; Stacpoole, 1981; Holst, 1985).

• Because glucagonoma syndrome is recognized relatively late in most patients, surgical cure is likely in fewer than 20% of all patients (Jensen, 1998).

• Approximately half of all VIPomas are metastatic at the time of diagnosis or surgery (Jensen, 1998), and approximately one third of patients are cured with surgery (Verner, 1974; Long, 1981).

• Most somatostatinomas (84%) are metastatic at the time of presentation, but a number of patients survive 5 years after combination surgery and chemotherapy (Boden, 1985; Vinik, 1987).

• The malignancy rate of nonfunctioning pancreatic endocrine tumors varies from 64-92% in different series (Jensen, 1998).
• One series of 25 patients with nonfunctioning neoplasms of the endocrine pancreas had 3- and 5-year survival rates of 60% and 44%, respectively, although most patients (92%) had metastatic disease (Kent, 1981).

• Finally, radical surgery continues to have a central role in the therapeutic approach to endocrine tumors of the pancreas. Tumor resection, the absence of liver and lymph node metastases, and the presence of MEN 1 syndrome are related to a better survival rate (Tomassetti, 2005).

MISCELLANEOUS

Medical/Legal Pitfalls:

• Because neoplasms of the pancreas are rare and because their heralding signs and symptoms are often nonspecific, delays in diagnosis of as long as 4 years are reported (Welbourne, 1981; Norton, 1993; Metz, 1994). Because these tumors can be cured if identified early, such errors in clinical judgment can be profoundly devastating for patients.

• As discussed in the Introduction, some patients, especially those with multiple lesions, have neoplasms of the endocrine pancreas as part of MEN 1 syndrome. If unrecognized, the hypercalcemia that results from hyperparathyroidism in these patients can lead to disastrous surgical complications; therefore, all patients who undergo surgical exploration for pancreatic endocrine tumors should be screened preoperatively for MEN 1.

• Unnecessary surgical exploration in patients who surreptitiously use insulin can be avoided in those patients with possible insulinoma by first measuring serum levels of proinsulin, C peptide, and anti-insulin antibodies.