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Specific clinical syndromes associated with the various islet cell tumors result from overproduction of a hormonally active polypeptide. Insulinomas, gastrinomas, glucagonomas, somatostatinomas, vipomas, and ACTH-producing tumors are the most important tumors that cause a clinical syndrome. Signs and symptoms unrelated to excessive hormone elaboration, including local invasion, vascular invasion, and metastatic disease, may be seen with both clinically silent and functioning islet cell tumors. As a group, islet cell tumors occur in young to middle-aged patients and have no significant sex predilection.
Insulinoma
Insulinomas classically manifest with symptomatic hypoglycemia and inappropriately elevated plasma levels of insulin. The Whipple triad (ie, symptoms of hypoglycemia, low blood levels of glucose, and resolution of symptoms with glucose administration) is a classic sign of insulinoma. Hypoglycemia may cause headaches, confusion, or even coma; these are referred to as neuroglycopenic symptoms. Sweating, palpitations, and tremor may occur secondary to catecholamine release in response to the hypoglycemia.
Symptoms of hypoglycemia are exacerbated by fasting. Patients often eat frequent meals to avoid the symptoms (4,9). A dramatic example of this behavior is recorded in the AFIP archives in the case of a 49-year-old woman who regularly set her alarm clock for 2:00 AM in order to eat. An electrical outage one night precluded her nocturnal snack, and she was brought to the hospital the next morning by ambulance, hypoglycemic and semicomatose.
Gastrinoma
Patients with gastrinomas present with signs and symptoms of peptic ulcer disease and elevated serum levels of gastrin. Peptic ulcer disease is seen in over 90% of patients with gastrinomas (4), but it often does not conform to the original description by Zollinger and Ellison of severe peptic ulcerations in multiple locations (such as the second and third portions of the duodenum) (5). Many patients have diarrhea because of gastric hypersecretion, and this may be the dominant symptom. Up to one-third of patients have mild peptic symptoms attributed to gastroesophageal reflux or ordinary peptic ulcer disease (10,11). Conversely, only one in 1,000 patients with peptic ulcer disease has a gastrinoma (4).
The diagnosis of Zollinger-Ellison syndrome is made when a patient has a fasting serum gastrin concentration greater than 1,000 pg/mL (1,000 ng/L) or positive results for a secretin test (11). In the latter test, the serum level of gastrin is measured before and after the administration of secretin (2 IU/kg). An increase in serum gastrin level of more than 200 pg/mL (200 ng/L) allows a confident diagnosis of a gastrinoma. The presence of hypergastrinemia alone is not diagnostic, because elevated gastrin levels may be seen in other disorders, such as pernicious anemia. A gastric pH of 3.0 or higher virtually excludes the diagnosis of gastrinoma (11).
Glucagonoma
The classic symptoms of glucagonoma syndrome include diabetes mellitus, dermatitis, and painful glossitis. The glucagonoma syndrome has been labeled the diabetes mellitus-dermatitis syndrome. The diagnosis is often made by a dermatologist because the patient presents with a skin rash. This characteristic rash, necrolytic migratory erythema, is seen in more than 70% of patients (12). Deep vein thrombosis and pulmonary emboli may also occur. Plasma glucagon levels are markedly elevated (over 1,000 pg/mL [1,000 ng/L]) (12).
Somatostatinoma
Elevated serum levels of somatostatin, diabetes mellitus, gallbladder disease, and steatorrhea are the hallmarks of the somatostatinoma syndrome (13). This condition has also been called the inhibitory syndrome, because all the clinical features are secondary to the inhibitory action of somatostatin on other pancreatic and bowel peptides. The nonspecific nature of these signs and symptoms, however, means that the disorder is rarely diagnosed early in its course.
Vipoma
Excessive quantities of vasoactive intestinal polypeptide act directly on cyclic adenosine monophosphate within the epithelial cells of the bowel and result in massive watery diarrhea similar to that seen in cholera. This disorder is also called the Verner-Morrison syndrome or the watery diarrhea, hypokalemia, achlorhydria syndrome. Hypokalemia, acidosis, and dehydration may result from the massive diarrhea, which often exceeds 1 L/day (14).
ACTH-producing Tumors
ACTH-producing tumors are a rare cause of Cushing syndrome. Excessive levels of ACTH result in increased cortisol levels and produce a number of signs and symptoms, including (from most common to least common) impaired glucose tolerance, central obesity, hypertension, oligomenorrhea, osteoporosis, purpura and striae, and muscle atrophy (6,15,16).
Clinically Silent Tumors
Patients with clinically silent tumors most commonly present with abdominal pain caused by local extension of disease or by metastatic disease. Masses located within the head of the pancreas may obstruct the common bile duct and cause jaundice. Vascular invasion of the splenic vein may cause gastric varices. In contrast to the clinical characteristics of functioning islet cell tumors, clinically silent tumors are not accompanied by an endocrine syndrome (3,6).
Multiple Endocrine Neoplasia
Multiple endocrine neoplasia (MEN) type I (also known as Wermer syndrome) is frequently associated with pancreatic islet cell tumors. Pituitary adenoma and parathyroid hyperplasia are the other components of the syndrome. MEN type I is an autosomal dominant disorder caused by a genetic defect in chromosome 11 (17). Islet cell tumors in patients with MEN type I are more likely to be multiple and to behave in a more malignant fashion than are sporadic islet cell tumors. In patients with MEN type I, gastrinomas are the most frequent tumors, occurring in approximately half of these patients; insulinomas are the next most common tumor (18,19).
Clinical Features