Excess secretion (Figure 46-7) of any one or several of the hormones of the islets of Langerhans may be caused by islet cell neoplasms or hyperplasia.
Adenomas derived from the islet cells are relatively common. In 10–15% of cases, multiple adenomas are present. Islet cell carcinomas occur, but less frequently.
Grossly, islet cell neoplasms are firm nodules that typically have a yellowish-brown color. They vary in size from microscopic (microadenomas) to large masses that may weigh several kilograms. They may or may not show encapsulation.
Microscopically, islet cell neoplasms are composed of uniform small cells arranged in nests and trabeculae separated by endothelium-lined vascular spaces. The islet cell origin of a pancreatic neoplasm can be established (1) by the presence of membrane-bound, electron-dense neurosecretory granules in the cytoplasm on electron microscopy; and (2) by positive staining for neuron-specific enolase, chromogranin, or specific hormones by immunoperoxidase techniques.
Differentiation of adenomas from carcinomas of islet cells is difficult by light microscopic examination. Invasion of the capsule and cytologic atypia are common in neoplasms that show benign behavior and cannot be used as evidence of malignant change. Conversely, islet cell carcinomas may be well circumscribed and have little cytologic atypia. Features that favor a diagnosis of carcinoma are extensive invasion of the pancreatic stroma or peripancreatic tissue, venous involvement, and perineural invasion. The only definite evidence of malignancy is the presence of metastatic lesions.
Islet cell adenomas are cured by surgical excision; carcinomas tend to grow slowly but are difficult to control if surgery fails. Even in the presence of metastatic disease, patients may survive several years because of the slow growth rate of islet cell carcinoma.
Most islet cell neoplasms are composed of one cell type; less commonly, multiple cell types are involved. The diagnosis of the cell type is impossible by routine light microscopy and requires (1) electron microscopy, which demonstrates characteristic granules of the different cells; (2) serum assay for the different pancreatic hormones; and (3) demonstration of hormone in the tumor cells by immunoperoxidase techniques. Some islet cell neoplasms do not produce sufficient hormone to be detectable in serum (nonfunctional islet cell neoplasms).
Diffuse hyperplasia of the islets is a rare cause of hypersecretion of pancreatic hormones, and there is some doubt about whether it is a real entity. Islet cell hyperplasia is characterized by the presence of islets in the size range 300–700 μm. Islets measuring less than 300 μm are normal; those above 700 μm are microadenomas. Microscopically, hyperplastic islets resemble normal islets; immunohistochemical studies sometimes show a dominance of one cell type.
In adults, the most common situation in which hyperplastic islets are found is in the pancreas adjacent to an islet cell neoplasm. The finding of hyperplastic islets in a surgically removed pancreas should therefore lead to a careful search for an adenoma in the remaining pancreas. Marked islet cell hyperplasia (of insulin-producing B cells) is also seen in fetuses born of diabetic mothers as a fetal response to the high glucose environment.
Clinical Features of Pancreatic Hormone Excess
The clinical features of hypersecretion of the islets depend on which hormone is secreted in excess and to what degree. In most cases, hypersecretion is restricted to one hormone; rarely, two or more hormones are involved.
The most common clinical syndrome associated with hyperfunctioning islets is hyperinsulinism. Seventy percent of cases are caused by solitary B cell adenomas (insulinomas); 10% by multiple adenomas; 10% by carcinomas; and 10% by islet cell hyperplasia.
Increased insulin secretion is characterized (1) by hypoglycemia, precipitated by fasting or exercise and causing dizziness, confusion, and excessive sweating which, if sustained, are followed by convulsions, coma, and death; (2) by prompt relief of symptoms after glucose administration; and (3) by a plasma glucose level under 40 mg/dL during an attack. The fasting plasma glucose is also decreased to less than half of normal. This symptom complex is known as Whipple's triad.
The diagnosis is established by the finding of an inappropriately high serum insulin level during a period of hypoglycemia.
Glucagon stimulates glycogenolysis and gluconeogenesis, serving to maintain glucose levels between meals. Hyperfunction of A cells is rare and caused by an islet cell neoplasm (glucagonoma), 70% of which are carcinomas and 30% adenomas. Two thirds of patients with carcinomas present with evidence of metastases, commonly in the liver.
Clinically, patients have mild diabetes mellitus due to the insulin antagonistic action of glucagon and a typical erythematous necrotizing migratory skin eruption. Alopecia, increased skin pigmentation, and glossitis are less common manifestations.
The diagnosis is made by finding an elevated serum glucagon level.
Gastrin hypersecretion is second in frequency to hyperinsulinism among this group of diseases. It is usually caused by an islet cell neoplasm composed of G cells (gastrinoma), 70% of which are malignant. In 10% of cases, islet cell hyperplasia is present but no neoplasm is found in the pancreas. In 1% of cases, a microadenoma measuring about 1 mm in diameter is the cause. Gastrinomas rarely occur also in the duodenal and gastric wall.
Secretion of large amounts of gastrin leads to Zollinger-Ellison syndrome, characterized by continuous hypersecretion of gastric acid, causing a low pH of gastric juice. The resting acid secretion is greater than 60% of the maximum acid secretion in response to an injection of histamine or pentagastrin. Unrelenting, recurrent peptic ulcers occur in the stomach, duodenum, esophagus, and jejunum in 90% of patients. Severe diarrhea and hypokalemia—induced by the hyperacidity—are present in 30% of patients. Diarrhea may be associated with malabsorption of fat and steatorrhea due to inactivation of lipase by the low pH in the duodenum. Ten percent of patients with Zollinger-Ellison syndrome present with diarrhea and have no peptic ulcer disease. The gastric mucosal folds are commonly thickened.
The diagnosis of Zollinger-Ellison syndrome is made by demonstrating high serum gastrin levels. It can be distinguished from other causes of elevated serum gastrin by a paradoxic increase in gastrin levels in response to intravenous secretin and calcium injections.
D cell neoplasms of the pancreas (somatostatinomas) are very rare. Eighty percent are malignant. Clinically, mild diabetes mellitus resulting from impaired release of insulin is the most constant feature; diarrhea and gallstones also occur commonly.
Diagnosis by demonstration of an elevated serum level is difficult because of the short half-life of somatostatin.
Vasoactive Intestinal Polypeptide Excess
Excess secretion of vasoactive intestinal polypeptide (VIP) is rare and caused by a D1 cell neoplasm of the islets (VIPoma). Clinically, the polypeptide stimulates intestinal secretion by an unknown mechanism, causing watery diarrhea with hypokalemia and alkalosis (WDHA syndrome; Verner-Morrison syndrome). The diagnosis is established by demonstrating elevated VIP levels in the serum and in an extract of the tumor.
Pancreatic Polypeptide Excess
Pancreatic polypeptide (PP)-producing neoplasms are extremely rare. They may be present in patients with no clinical symptoms. Some patients have watery diarrhea and hypokalemia; others have peptic ulcer disease.