Zollinger-Ellison syndrome

Definition

Gastrinomas are tumors associated with a rare gastroenterological disorder known as Zollinger-Ellison syndrome (ZES). They occur primarily in the pancreas and duodenum (beginning of the small intestine) and secrete large quantities of the hormone gastrin, triggering gastric acid production that produces ulcers. They may be malignant (cancerous) or benign.

Description

Gastrinomas are an integral part of the Zollinger-Ellison syndrome (ZES). In fact, ZES is also known as gastrinoma. This syndrome consists of ulcer disease in the upper gastrointestinal tract, marked increases in the secretion of gastric acid in the stomach, and tumors of the islet cells in the pancreas. The tumors produce large amounts of gastrin that are responsible for the characteristics of Zollinger-Ellison syndrome, namely severe ulcer disease. Although usually located within the pancreas, they may occur in other organs.

Gastrinomas may occur randomly and sporadically, or they may be inherited as part of a genetic condition called multiple endocrine neoplasia type 1 (MEN-1) syndrome. About half of persons with MEN-1 have gastrinomas, which tend to be more numerous and smaller than tumors in sporadic cases.

About half of ZES patients have multiple gastrinomas, which can vary in size from 1-20 mm. Gastrinomas found in the pancreas are usually much larger than duodenal gastrinomas. About two thirds of gastrinomas are malignant (cancerous). These usually grow slowly, but some may invade surrounding sites rapidly and metastasize (spread) widely. Sometimes, gastrinomas are found only in the lymph nodes, and it is uncertain whether these malignancies have originated in the lymph nodes or have metastasized from a tumor not visible in the pancreas or duodenum.

There is some evidence that the more malignant form of gastrinomas is more frequent in larger pancreatic tumors, especially in females and in persons with a shorter disease symptom duration and higher serum gastrin levels.

Causes & symptoms

Most persons with gastrinomas secrete profound amounts of gastric acid, and almost all develop ulcers, mostly in the duodenum or stomach. Early in the course of the disease, symptoms are typical of peptic ulcers, however once the disease is established, the ulcers become more persistent and symptomatic, and may respond poorly to standard anti-ulcer therapy. Abdominal pain is the predominant symptom of ulcer disease. About 40% of patients have diarrhea as well. In some patients, diarrhea is the primary symptom of gastrinoma.

Diagnosis

Persons with gastrinomas have many of the same symptoms as persons with ulcers. Their levels of gastric acid, however, are usually far greater than those in common ulcer disease. Gastrinomas are usually diagnosed by a blood test that measures the level of gastrin in the blood. Patients with gastrinomas often have gastrin levels more than 200 pg/mL, which is 4-10 times higher than normal. Serum gastrin levels as high as 450,000 pg/mL have occurred.

When the serum gastrin test does not show these extremely high levels of gastrin, patients may be given certain foods or injections in an attempt to provoke a response that will help diagnose the condition. The most useful of these provocative tests is the secretin injection test (or secretin stimulation or provocative test), which will almost always produce a positive response in persons with gastrinomas but seldom in persons without them.

Surgically, gastrinomas are often difficult to locate, even with careful inspection. They may be missed in at least 10-20% of patients with ZES. Gastrinomas are sometimes found only because they have metastasized and produced symptoms related to the spread of malignancy. Such metastasis may be the most reliable indication of whether the gastrinoma is malignant or benign.

Diagnostic imaging techniques help locate the gastrinomas. The most sophisticated is an x-ray test called radionuclide octreotide scanning (also known as somatostatin receptor scintigraphy or 111In pentetreotide SPECT). A study by the National Institutes of Health (NIH) found this test to be superior to other imaging methods, such as computed tomography scan (CT) or magnetic resonance imaging (MRI), in pinpointing the location of tumors and guiding physicians in treatment.

Approximately half of all gastrinomas do not show up on imaging studies. Therefore, exploratory surgery is often recommended to try to locate and remove the tumors.

Treatment

Therapy for gastrinomas should be individualized, since patients tend to have varying degrees of disease and symptoms. Treatment is aimed at eliminating the overproduction of gastric acid and removing the gastrin-producing tumors.

Drugs

Gastrinomas may not be easily treated by the standard anti-ulcer approaches. The medical treatment of choice is with drugs called proton pump inhibitors, such as omeprazole or lansoprazole, daily. These drugs are potent inhibitors of gastric acid. High doses of H-2 receptor antagonists may also reduce gastric acid secretion, improve symptoms, and induce ulcer healing. These drugs must be continued indefinitely, since even a brief discontinuation will cause ulcer recurrence. Antacids may provide some relief, but it is usually not longlasting or healing.

Surgery

Because of the likelihood that gastrinomas may be malignant, in both sporadic tumors and those associated with the inherited MEN-1 syndrome, surgery to locate and remove gastrinomas is frequently advised. It is now known that complete surgical removal of gastrinomas can cure the overproduction of gastrin, even in patients who have metastases to the lymph nodes. Surgery in patients with MEN-1 and ZES, however, remains controversial since the benefit is less clear.

Freedom from disease after surgery is judged by improved symptoms, reduced gastric acid production, reduced need for drug therapy, normalization of serum gastrin levels, and normalization of results from the secretin stimulation test and imaging studies.

Prognosis

Medical therapy often controls symptoms, and surgery may or may not cure gastrinoma. About 50% of ZES patients in whom gastrinomas are not removed will die from malignant spread of the tumor. In patients with gastrinomas as part of MEN-1 syndrome, the cure rate is extremely low.

A NIH study of patients who had surgical removal of gastrinomas found that 42% were disease-free one year after surgery and 35% were disease-free at five years. Disease recurrences can often be detected with a serum gastrin test or secretin stimulation test.

When gastrinomas are malignant, they often grow slowly. The principal sites of metastasis are the regional lymph nodes and liver, but they may also spread to other structures. About one quarter of patients with gastrinomas have liver metastases at the time of diagnosis. This appears to be more frequent with pancreatic gastrinomas than duodenal gastrinomas.

Metastases of malignant gastrinomas to the liver is very serious. Survival five years after diagnosis is 20-30%, however patients with gastrinomas found only in the lymph nodes have been known to live as long as 25 years after diagnosis, without evidence of further tumor spread. In fact, the life expectancy of patients with gastrinomas that have spread to the lymph nodes is no different from that of patients with gastrinomas that cannot even be found at surgery for about 90%, five years after diagnosis.

Key Terms

Gastrin

A hormone secreted in the stomach that is involved in the production of gastric acid. Overproduction of gastric acid contributes to peptic ulcer formation.

Multiple endocrine neoplasia type 1 (MEN-1)

An inherited condition marked by multiple malignancies of the pituitary gland, parathyroid gland, and islet cells of the pancreas. About half of MEN-1 patients with pancreatic islet cell tumors will have gastrinomas, gastrin-producing tumors that lead to ulcer disease.

Peptic ulcer

An eroded area in the stomach lining or in the first part of the duodenum (beginning of the small intestine).

Serum gastrin test

A laboratory test that is performed on a blood sample to determine that level of the hormone gastrin. High levels of gastrin indicate the presence a duodenal ulcer or a gastrinoma.

Sporadic

Occurring at random or by chance, and not as a result of a genetically determined, or inherited, trait.

Further Reading

For Your Information

Books

• Friedman, Lawrence S., and Walter L. Peterson. "Peptic Ulcer and Related Diseases." In Harrison's Principles of Internal Medicine. Edited by Anthony S. Fauci, et al. New York: McGraw-Hill, 1998.

  Periodicals

• Delcore R., and S.R. Friesen. "The Place for Curative Surgical Procedures in the Treatment of Sporadic and Familial Zollinger-Ellison Syndrome." Current Opinion in General Surgery (1994): 69-76.
• Meko, J.B., and J.A. Norton. "Management of Patients with Zollinger-Ellison Syndrome." Annual Review of Medicine 46 (1995): 395-411.

  Organizations

• National Digestive Diseases Information Clearinghouse. 2 Information Way, Bethesda, MD 20892-3570. (301) 654-3810. http://www.niddk.nih.gov/health/digest/nddic.htm.

Gale Encyclopedia of Medicine. Gale Research, 1999.