History
The presentation in patients with neoplasms of the endocrine pancreas reflects the hormone secreted by the tumor. Thus, signs and symptoms vary with the different syndromes.
Insulinoma
Insulinomas are insulin-secreting tumors associated with the Whipple triad. The triad includes the following [30] :
- Symptoms of fasting hypoglycemia
- Documented fasting hypoglycemia with a serum glucose level less than 50 mg/dL
- Relief of hypoglycemic symptoms after glucose administration
Autonomous insulin secretion from insulinomas produces symptoms classified into two broad categories. Virtually all patients with an insulinoma who seek medical attention present with a subset of at least one of these two groups of symptoms, and more than half present with symptoms from both groups. [31]
First, the direct physiologic effect of hypoglycemia is neuroglycopenia, which results in the following symptoms [17] :
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Headache
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Light-headedness
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Confusion
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Visual disturbances
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Seizures
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Personality changes
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Obtundation, or even coma
Second, in response to neuroglycopenic stress, the body generates a compensatory state of catecholamine excess, which can lead to the following [12] :
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Palpitations
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Weakness
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Trembling
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Diaphoresis
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Tachycardia
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Irritability
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 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. [32]
Gastrinoma
The classic triad of Zollinger-Ellison syndrome includes the following [3] :
- Severe gastrointestinal ulcerative disease
- Gastric acid hypersecretion
- Non-beta islet cell tumors of the pancreas
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, one patient in 1000 with primary duodenal ulcer disease and two patients in 100 with recurrent ulcers after ulcer surgery are estimated to have a gastrinoma. [33]
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. [34, 35]
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. [36, 37]
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. [38, 39]
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. [40]
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 [12] :
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Postbulbar ulcers
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Multiple ulcers
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Ulcers refractory to standard medical therapy
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Ulcer recurrence after antiulcer surgery
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Ulcer and diarrhea
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Prolonged unexplained diarrhea
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Family history of peptic ulcer
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Family history suggestive of MEN 1syndrome
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Ulcers in patients who are negative for Helicobacter pylori infection and have no history of nonsteroidal anti-inflammatory drug (NSAID) use
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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. [23] 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. [17]
Abdominal cramps are common among patients with VIPoma syndrome, and flushing episodes occur in a small percentage of patients. [43]
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. [12]
Glucagonoma
Glucagonomas secrete excessive amounts of glucagon and cause a syndrome characterized by the following [44] :
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Dermatitis
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Stomatitis
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Weight loss
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Anemia
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. [45]
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. [46]
In addition, 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. [47] This feature of glucagonomas is unique among the different neoplasms of the endocrine pancreas.
Normochromic normocytic anemia occurs in approximately half the patients with glucagonoma, and may manifest as fatigue. [48]
Somatostatinoma
The symptoms of somatostatinoma syndrome reflect the general inhibitory action of somatostatin on global gastroenteropancreatic function, as follows:
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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 [49]
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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 [23]
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 signs and symptoms of carcinoid tumor are related to hypersecretion of serotonin (5-HT) and include the following:
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Flushing
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Diarrhea
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Heart valvular lesions
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Cramping
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Telangiectasia
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Peripheral edema
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Wheezing
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Cyanosis
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Arthritis
Miscellaneous
Additional functional tumors of the endocrine pancreas have been reported, with secretion of growth hormone–releasing factor (GRF), neurotensin, parathyroid hormone-related peptide, pancreatic polypeptide (PP), adrenocorticotropin hormone (ACTH), and melanocyte-stimulating hormone (MSH), as follows:.
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ACTHomas cause Cushing syndrome, with manifestations that include facial and torso obesity, high blood pressure, stretch marks on the abdomen, generalized weakness, osteoporosis, and facial hair growth in females
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MSHomas cause skin hyperpigmentation
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GRFomas primarily result in acromegaly but can also present as other symptoms; they are frequently associated with MEN 1 syndrome and can be accompanied by Zollinger-Ellison syndrome and/or Cushing syndrome in 40% of the cases
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Neurotensinomas can cause hypotension, hypokalemia, weight loss, flushing, and diabetes; these tumors are usually malignant
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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 on 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
Fundamental understanding of pancreatic endocrine tumors has increased greatly because of recent observations in the fields of classic and molecular genetics, as follows:
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In one small series of malignant pancreatic endocrine tumors analyzed by genetic karyotyping, clonal chromosomal abnormalities were identified in more than half the specimens. [52]
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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. [53]
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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. [54]
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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.
Multiple endocrine neoplasia type 1 (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. [55]
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%). [23]
Environmental factors
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. [56]
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Neoplasms of the endocrine pancreas. CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).
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Celiac axis angiography illustrating neoplasms of the endocrine pancreas. Contrast is seen opacifying the common hepatic artery (CHA) and splenic artery (SA). The superior pancreatic artery (arrow) is seen as an early U-shaped branch of the splenic artery.
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Highly selective distal angiography illustrating neoplasms of the endocrine pancreas. With the arterial catheter now advanced into the superior pancreatic artery, the contrast blush of this vascular tumor is easily seen (arrows).
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Neoplasms of the endocrine pancreas. Intravenous and oral contrast-enhanced CT scan image in a patient with chronic diarrhea and elevated levels of serum vasoactive intestinal peptide. In the venous phase of this scan, the splenic vein (SV) is clearly seen draining the 5-cm tumor (T) located anteromedial to the spleen (S) in the tail of the pancreas.
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Neoplasms of the endocrine pancreas. Schematic diagram of provocative angiography. Access to the central venous and arterial systems is obtained through cannulation of a femoral vein and a femoral artery. In the selective arterial secretin stimulation test, secretin is injected selectively into the splenic, gastroduodenal (a branch of the common hepatic), and inferior pancreaticoduodenal (a branch of the superior mesenteric) arteries with concomitant and subsequent hepatic venous sampling for gastrin. Based on the level of gastrin in each hepatic venous sample, the location of the gastrinoma is arterially mapped. An analogous method can be used in the selective arterial calcium stimulation test to determine the location of occult insulinomas that respond to calcium stimulation by secreting insulin.
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Neoplasms of the endocrine pancreas. Graphic depiction of the results of a selective arterial secretin stimulation test in a patient with an occult gastrinoma. The gastrin gradient (the rise in hepatic vein gastrin concentration divided by the basal value) is plotted over time. An increase in gastrin gradient from 0 to 2 thus represents a 200% rise compared to the basal level. A significant rise in hepatic vein gastrin concentration is observed both after the injection of secretin into the superior mesenteric artery (SMA) and after secretin injection into the gastroduodenal artery (GDA), but no such increase occurs following secretin injection into the splenic artery (SPL). This patient's neoplasm is thus localized to the head of the pancreas or the duodenum
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Neoplasms of the endocrine pancreas. Octreotide scan (anterior view) in a patient with a pancreatic endocrine tumor. The large pancreatic-tail neoplasm is seen retaining tracer in the patient's left upper quadrant. Several tracer-enhancing hepatic metastases are seen in the patient's right upper quadrant and epigastrium. Tracer is also seen in the bladder following renal excretion (round density in the hypogastrium) (Yeo, 2001).
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Neoplasms of the endocrine pancreas. CT scan with oral and intravenous contrast in a patient with a glucagon-secreting neoplasm. This 10-cm contrast-enhancing tumor (T) is seen obliterating the normal appearance of the tail of the pancreas (Yeo, 2001).
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Neoplasms of the endocrine pancreas. Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).
