Practice Essentials
Neoplasms of the endocrine pancreas can be divided into functional and nonfunctional varieties. Most pancreatic endocrine neoplasms discovered clinically are functional—that is, they secrete one or more hormonal products into the blood, which leads to a recognizable clinical syndrome. [1]
The first report of a hormone-producing pancreatic tumor syndrome was published in 1927, when Wilder et al described insulinoma syndrome in a patient with a metastatic islet cell tumor who had hyperinsulinism and hypoglycemia. [2] Subsequently, four 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. [3]
The second type comprises a group of three tumor syndromes: Verner-Morrison syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, and pancreatic cholera (also termed vasoactive intestinal peptide [VIP]–releasing tumor or VIPoma); these were described by Verner and Morrison in 1958. [4]
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. [5, 6]
Several other rare clinical syndromes have been proposed as possible functional endocrine syndromes associated with pancreatic neoplasms. These include the following:
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Parathyrinoma [9]
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Growth hormone–releasing factor–secreting tumor (GRFoma)
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Adrenocorticotropin hormone–secreting tumor (ACTHoma)
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Neurotensinoma [10]
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 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. [11] 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 the following articles:
For discussion of other conditions with which pancreatic endocrine tumors are associated, see the following:
Background
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. [12] 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. [13] 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. [14]
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. [15] 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. [16] 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. [17]
Functional pancreatic endocrine neoplasms cause 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 the pathophysiologic manifestations 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.
Epidemiology
United States
Neoplasms of the endocrine pancreas occur in two 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. [18] 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. [19]
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. [20, 21] However, the much higher prevalence of these tumors in unselected autopsy specimens, 0.5-1.5%, reflects the indolent nature of many of these tumors. [22, 23]
Insulinomas and gastrinomas occur with roughly equal annual incidences; together they account for more than half of all clinically apparent pancreatic endocrine tumors. [23] VIPomas are one-eighth and glucagonomas are one-seventeenth as common, whereas somatostatinomas are even more rare. [20] Nonfunctional tumors account for 14-48% of all recognized neoplasms of the endocrine pancreas. [24, 25]
Mortality/Morbidity
Functional neoplasms of the endocrine pancreas can produce the following morbidity as a result of their excess hormonal production:
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If untreated, patients with insulinoma can have hypoglycemic seizures and even frank coma. [26]
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Prior to the development of effective antisecretory medications (eg, histamine 2 blockers, proton pump inhibitors), patients with gastrinoma often had life-threatening gastrointestinal bleeding from peptic ulcers.
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Untreated patients with VIPoma can become severely dehydrated from diarrhea, and fatal cardiac arrhythmias can develop secondary to associated hypokalemia.
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Glucagonomas can cause diabetes, wasting, stomatitis, and other features similar to severe nutritional deficiency.
Late in the course of pancreatic endocrine neoplasms, the growth of the tumor can result in the following morbidity related to the mass effects of the disease:
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Patients with tumors in the pancreatic head occasionally have biliary obstruction, pancreatic obstruction, or both.
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Chronic abdominal pain can occur because of the compressive effects of a large intra-abdominal mass or obstructive pancreatitis.
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 as a result of improvements in the modalities used to diagnose and treat these lesions (also see Prognosis).
Race-, Sex-, and Age-related Demographics
Sporadic and inherited forms of pancreatic endocrine tumors appear to occur with equal frequency among the different racial groups in the United States.
Neoplasms of the endocrine pancreas seem to have a slightly higher incidence in women than in men. [27, 18, 28] 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 MEN1 syndrome. [17]
Patients with sporadic pancreatic endocrine tumors present most commonly at the age of 30-50 years. [29] In contrast, patients with pancreatic endocrine tumors that develop as part of MEN1 syndrome tend to present when younger, commonly at age 10-30 years. [18]
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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).
