AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

A gastrinoma is a gastrin-secreting tumor that can occur in the pancreas, although it is most commonly found in the duodenum. Duodenal wall gastrinomas have been identified in 40-50% of patients. These duodenal wall tumors are frequently small and multiple. Sporadic tumors occurring in the pancreas tend to be solitary and have greater malignant potential as compared to duodenal gastrinomas.

More than 80% of gastrinomas arise within the triangle defined as the confluence of the cystic and common bile duct superiorly, the second and third portions of the duodenum inferiorly, and the neck and body of the pancreas medially.

Rarely, primary tumors also occur in a variety of ectopic sites, including the body of the stomach, jejunum, peripancreatic lymph nodes, splenic hilum, omentum, liver, gallbladder, common bile duct, and the ovary.

Over 50% of gastrinomas are malignant and can metastasize to regional lymph nodes and the liver. One fourth of gastrinomas are related to multiple endocrine neoplasia (MEN) type I and are associated with hyperparathyroidism and pituitary adenomas. These MEN I associated tumors have been observed to occur at an earlier age than sporadic tumors and often follow a more benign course.

The triad of nonbeta islet cell tumors of the pancreas (gastrinomas), hypergastrinemia, and severe ulcer disease was described by Zollinger and Ellison in 1955, hence the eponym Zollinger-Ellison syndrome (ZES).

Pathophysiology

Enormous secretion of gastrin from the tumor cells leads to hyperplasia of fundic parietal cells and increased basal acid secretion. This results in severe ulcer disease. Ulceration might even extend into the small intestine. The acidic content of the small intestine causes the release of secretin, which is responsible for the diarrhea, in part, caused by the outpouring of water and bicarbonate from the pancreas and small intestine.

Frequency

International

The true incidence of ZES is not known. ZES constitutes 0.1% or more of cases of peptic ulcer disease. Although rare, gastrinomas are the most common pancreatic islet cell tumors.

Mortality/Morbidity

With the advent of antiulcer medications, the number of deaths secondary to ulcer complications decreased significantly. The primary determinants of survival for patients with gastrinomas are the size of the primary tumor and the occurrence of tumor metastasis.

• Patients with hepatic metastases may have a remaining life span of less than 1 year.
• In patients with liver metastasis, the 5-year survival rate is 20-30%.
• In patients with localized disease or metastasis to local lymph nodes without liver metastasis, the 5-year survival rate is 90%.

Sex

Gastrinomas are more common in males than in females, with ratios from 1.5:1 to 2:1.

Age

Although gastrinomas can occur at any age, the initial clinical manifestation usually appears in people aged 30-50 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The symptoms in 90-95% of patients with gastrinomas are similar to the symptoms of common peptic ulcer disease. Usually, persistent abdominal pain exists that is less responsive to medical treatment.
• Sometimes, symptoms may relate to a complication of peptic ulcer disease, such as bleeding (eg, melena, hematemesis), gastric outlet obstruction (eg, vomiting), and perforation (eg, peritoneal irritation).
• Other symptoms include gastroesophageal reflux, diarrhea, steatorrhea, and weight loss, all of which are secondary to acid hypersecretion. Vitamin B-12 malabsorption, which is not correctable by oral intrinsic factor, may also be observed.
• Chronic acid reflux may lead to esophageal complications (eg, esophagitis, stricture formation, Barrett esophagus) in up to two thirds of patients with Zollinger-Ellison syndrome.

Physical

• Epigastric tenderness is the most frequent abnormal physical finding. Depending on the possible ulcer complications, signs may vary.
• Nearly 75% of ulcers in patients with gastrinomas are present in the first portion of the duodenum. These ulcers usually are single or multiple and are indistinguishable from peptic ulcer disease.
• Nearly 10% of patients with ZES have no demonstrable ulcer. Ulcers located in the second, third, or fourth portion of the duodenum or jejunum should increase the possibility of gastrinoma.
• The other factors that alert one to the presence of underlying gastrinomas are the following:
• • Ulcers that are refractory to standard therapy
  • Multiple ulcers
  • Giant ulcers, larger than 2 cm
  • Recurrent ulcers
  • Ulcers with unexplained diarrhea
  • Strong family history of ulcers
  • Hypercalcemia
  • Duodenal ulcer that is not related to Helicobacter pylori infection or nonsteroidal anti-inflammatory drug use

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Antral G-cell hyperfunction
Massive small intestine resection

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Due to the elusive nature of the neoplasm, the diagnosis is based on the following 3 criteria:
• • Fasting hypergastrinemia is present (>150 pg/mL with levels >100,000 pg/mL in some patients; a serum gastrin level >1,000 pg/mL in the appropriate clinical setting is virtually diagnostic of Zollinger-Ellison syndrome).
  • Basal acid output (BAO) is greater than 10 mEq/h.
  • Results from a secretin stimulation test are positive.
• Fasting serum gastrin measurement is discussed as follows:
• • This is the most sensitive test for the diagnosis of ZES.
  • This screening test is indicated for patients strongly considered to have gastrinoma (see History).
  • Stop histamine 2 (H2) blockers 1 day or omeprazole 6 days prior to performing the study.
  • The reference range for fasting serum gastrin usually is 50-60 pg/mL, with an upper limit as high as 150 pg/mL.
  • Levels higher than 1000 pg/mL with acid hypersecretion are highly suggestive of ZES.
• Because low gastric acid output (eg, in atrophic gastritis, pernicious anemia, or postvagotomy state) can lead to hypergastrinemia, check patients for the following:
• • A gastric pH level higher than 3.0 excludes gastrinoma.
  • A BAO of greater than 15 mEq/h and even as high as 150 mEq/h is indicative of gastrinoma.
• In patients with intermediate gastrin levels (150-1000 pg/mL) and acid secretion, the secretin stimulation test can help diagnose the presence of gastrinoma. Intravenous secretin (2 U/kg) raises serum gastrin levels to higher than 200 pg/mL within 2 minutes and, virtually always, within 10 minutes in patients with gastrinomas.

Imaging Studies

• Imaging studies are helpful to help localize the tumor. They also are helpful for assessing surgical resectability by helping reveal liver metastasis.
• Somatostatin receptor scintigraphy (SRS) is very useful for helping identify the primary lesions preoperatively. SRS is the most sensitive noninvasive method for localizing primary tumors and metastases. It also is helpful for detecting the presence of liver or bone metastasis. The findings from this technique can be used to differentiate small liver metastases from small liver hemangiomas. Occasionally, false-positive SRS localization results can occur.
• Endoscopic ultrasound also has been found to be useful in helping detect primary tumor, with a reported overall sensitivity and accuracy of higher than 90% for intrapancreatic gastrinomas. For extrapancreatic gastrinomas in the duodenal wall, endoscopic ultrasound is useful but somewhat less sensitive.
• CT scan and selective angiogram also are helpful for detecting gastrinoma.
• MRI can be used as an adjunct to the imaging studies already discussed. MRI has great value in identifying liver metastases but has not been shown to be useful in detecting extrahepatic tumors less than 1 cm in diameter.
• Because of the large proportion of primary gastrinomas in the proximal duodenum, upper endoscopy may also be a useful tool in the localization of tumors in these patients.

Other Tests

• Selective arterial secretin injection, involving gastroduodenal, splenic, and superior mesenteric arteries, with hepatic vein serum gastrin concentrations is one among some other diagnostic procedures proposed for helping identify gastrinomas. However, this test has been shown to be of value primarily in localizing gastrinomas to the head of the pancreas and proximal duodenum and, therefore, is infrequently recommended.
• The calcium infusion test, calcium gluconate, is infused intravenously over 180 minutes with serum gastrin levels obtained at set intervals. In most patients with gastrinomas, this should substantially increase serum gastrin levels (>400 pg/mL increase).
• Serum chromogranin A, a nonspecific marker for neuroendocrine tumors, has been shown to be increased in gastrinoma patients with serum levels correlating with tumor burden.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Individualize the selection of treatment. Base treatment on factors related to ulcer disease, diarrhea, and malignant properties of the tumor. Antisecretory medications are helpful for controlling the manifestations of peptic acid disease and secretory diarrhea (secondary to hyperacidity).

• Proton pump inhibitors (eg, omeprazole, lansoprazole)
• • These are highly effective drugs and are the drugs of choice for suppressing acid secretion. Long duration of action, fewer adverse effects, and high potency make them superior to H2 blockers.
  • In 60% of patients, ulcer healing occurs within 2 weeks. In 90-100% of patients, healing occurs within 4 weeks.
  • The recommended initial dose of omeprazole is 60 mg/d. Divided, twice-a-day dosing is suggested for doses greater than 80 mg/d. Once an effective maintenance dose is achieved, tapering of the medication, while monitoring symptoms and acid output, is suggested.
• H2-receptor antagonists
• • The dose usually is 4-8 times higher than the dose administered to patients with peptic ulcer disease.
  • Although a good success rate exists, this treatment has been reported to fail in 50% of patients.
• Chemotherapy
• • This is indicated in patients with metastatic disease and in patients who are not candidates for surgery; however, it is not indicated for metastatic disease confined to the lymph nodes.
  • Chemotherapy reduces tumor size and improves the symptoms secondary to metastatic effects of the tumor.
  • A combination of streptozocin, 5-fluorouracil, and doxorubicin has been used, with the response rate reported to be as high as 65%.

Surgical Care

• Surgical care is indicated for localized disease. Surgical resection of localized disease leads to a complete cure without any recurrence in 20-25% of patients with gastrinomas.
• Patients who have an isolated lesion or patients in whom the preoperative workup fails to localize the tumor should undergo laparotomy (by an experienced surgeon) with the intent to resect.
• It has been reported that Whipple pancreaticoduodenectomy affords the greatest probability for cure, particularly for MEN I associated gastrinomas, though also for sporadic tumors, since it results in removal of the entire gastrinoma triangle. However, the excellent long-term survival in patients with less complicated surgeries and the increased morbidity and mortality associated with the Whipple procedure make its general utility still unclear and recommended primarily for large, advanced tumors.

Consultations

• Gastroenterologist
• Endocrinologist
• Oncologist
• Surgeon

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Immediate and sustained control of gastric acid hypersecretion is the most important aspect of disease management in patients with ZES because acid hypersecretion is the cause of essentially all symptoms and early morbidity and mortality.

Once ZES is considered and while appropriate diagnostic tests are conducted, acute acid secretion usually is best controlled with oral administration of a proton pump inhibitor (eg, omeprazole, lansoprazole, rabeprazole, esomeprazole). However, continuous infusion of an H2 antagonist (eg, ranitidine, cimetidine, famotidine), often at high doses, may be necessary for a small proportion of patients requiring rapid control of acid secretion who are unable to take oral medication.

Long-term management of acid secretion with a high dose of a proton pump inhibitor (or H2 blocker) is safe and effective.

Drug Category: Proton pump inhibitors

These agents bind to the proton pump of the parietal cell, inhibiting secretion of hydrogen ions into the gastric lumen. These agents are more effective than H2 blockers in relieving pain and healing ulcers. They are the drugs of choice in ZES. Although the drugs in this class are equally effective, omeprazole is used most commonly. Efficacy and tolerability of parenterally administered proton pump inhibitors in the acute treatment of patients with suspected ZES have not been established.

Drug Category: H2-receptor antagonists

Inhibit the action of histamine on the parietal cell, which inhibits acid secretion. All agents in this class are equally effective. Intravenous administration may be helpful in patients who are unable to take oral medication.

Drug Category: Chemotherapeutic agents

Indicated in metastatic disease and in patients who are not candidates for surgery. Reduce tumor size and improve symptoms secondary to metastatic effects of the tumor. A combination of streptozocin, 5-fluorouracil, and doxorubicin has been used, with a response rate of as high as 65%.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Follow-up of patients with gastrinomas that have been resected is directed at the diagnosis and treatment of recurrence.
• • Measurement of the fasting serum gastrin level is the best screening test to monitor these patients.
  • Disease recurrence might present as a recurrent peptic ulceration, diarrhea, or abdominal pain.
  • If recurrent disease is identified, reoperation may be considered and undertaken if no evidence of metastasis exists.
  • Metastatic disease can be managed with chemotherapy and long-term acid suppression.

Prognosis

• The primary determinants of survival for patients with gastrinomas are the size of the primary tumor and the development of tumor metastasis.
• • Patients with hepatic metastases may have a remaining life span of less than 1 year.
  • In patients with liver metastasis, the 5-year survival rate is 20-30%.
  • In patients with localized disease or metastasis to local lymph nodes without liver metastasis, the 5-year survival rate may be 90%.
• Surgical resection of localized disease leads to a complete cure without any recurrence in 20-25% of patients with gastrinomas.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Gastrinoma can be a difficult diagnosis. However, delay in diagnosis or misdiagnosis can lead to incorrect treatment or less successful treatment secondary to any such delay. Thus, gastrinoma always should be included in the differential diagnosis in those patients with the appropriate symptoms (see Clinical).
• Risks exist regarding medication-induced adverse effects and the surgical procedures associated with the treatment of this disease.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Campana D, Piscitelli L, Mazzotta E. Zollinger-Ellison syndrome. Diagnosis and therapy. Minerva Med. Jun 2005;96(3):187-206. [Medline].
• Del Valle J, Scheiman J. Zollinger-Ellison Syndrome. Textbook of Gastroenterology, 4th Edition. 2003;1377-1388.
• Delvalle J, Yamada T. Zollinger-Ellison Syndrome. Textbook of Gastroenterology. 1995;1430.
• Feldman M, Sleisenger MW, McGuigan JE. Zollinger-Ellison syndrome and other hypersecretory states. In: Feldman M, Scharschmidt BF, Sleisenger M, Zorab R, eds. Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 6th ed. Philadelphia, Pa: WB Saunders; 1998:. 679-90.
• Hirschowitz BI. Zollinger-Ellison syndrome: pathogenesis, diagnosis, and management. Am J Gastroenterol. Apr 1997;92(4 Suppl):44S-48S; discussion 49S-50S. [Medline].
• Jensen RT, Gibril F. Somatostatin receptor scintigraphy in gastrinomas. Ital J Gastroenterol Hepatol. Oct 1999;31 Suppl 2:S179-85. [Medline].
• Mignon M, Cadiot G. Natural history of gastrinoma: lessons from the past. Ital J Gastroenterol Hepatol. Oct 1999;31 Suppl 2:S98-103. [Medline].
• Nobels FR, Kwekkeboom DJ, Coopmans W. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. J Clin Endocrinol Metab. Aug 1997;82(8):2622-8. [Medline].
• Norton JA. Gastrinoma: advances in localization and treatment. Surg Oncol Clin N Am. Oct 1998;7(4):845-61. [Medline].
• Norton JA. Surgical treatment and prognosis of gastrinoma. Best Pract Res Clin Gastroenterol. Oct 2005;19(5):799-805. [Medline].
• Norton JA, Fang TD, Jensen RT. Surgery for gastrinoma and insulinoma in multiple endocrine neoplasia type 1. J Natl Compr Canc Netw. Feb 2006;4(2):148-53.
• Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol. Oct 2005;19(5):753-81.
• Passaro E, Howard TJ, Sawicki MP. The origin of sporadic gastrinomas within the gastrinoma triangle: a theory. Arch Surg. Jan 1998;133(1):13-6; discussion 17. [Medline].
• Pellicano R, De Angelis C, Resegotti A. Zollinger-Ellison syndrome in 2006: concepts from a clinical point of view. Panminerva Med. Mar 2006;48(1):33-40.
• Sugg SL, Norton JA, Fraker DL. A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas. Ann Surg. Aug 1993;218(2):138-44. [Medline].

Article Last Updated: Jun 27, 2006