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