Gastrinomas

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Overview

Gastrinomas are a type of pancreatic endocrine tumor that arises from islet cells but can also arise from the gastrin-producing cells in duodenum and other sites in the body. Gastrinomas occur in the pancreas or duodenal wall 80 to 90% of the time. The remainder occur in the splenic hilum, mesentery, stomach, lymph node, or ovary. About 50% of patients have multiple tumors.

Gastrinomas usually are small (< 1 cm in diameter) and grow slowly. About 50% are malignant.

About 40 to 60% of patients with gastrinoma have multiple endocrine neoplasia, a syndrome that is associated with neuroendocrine tumors of the pancreas (eg, gastrinoma), pituitary adenomas, and parathyroid hyperplasia.

 

Symptoms

Zollinger-Ellison syndrome typically manifests as aggressive peptic ulcer disease, with ulcers occurring in atypical locations (up to 25% are located distal to the duodenal bulb). However, as many as 25% of patients do not have an ulcer at diagnosis. Typical ulcer symptoms and complications (eg, perforation, bleeding, obstruction) can occur. Diarrhea is the initial symptom in 25 to 40% of patients.

Diagnosis

Gastrinoma is suspected by history, particularly when symptoms are refractory to standard acid suppressant therapy.

Serum gastrin level is the most reliable test. All patients have levels > 150 pg/mL (> 72 pmol/L); markedly elevated levels of > 1000 pg/mL (> 480 pmol/L) in a patient with compatible clinical features and gastric acid hypersecretion of > 15 mEq/hour establish the diagnosis. However, moderate hypergastrinemia can occur with hypochlorhydric states (eg, pernicious anemia, chronic gastritis, use of proton pump inhibitors), in renal insufficiency with decreased clearance of gastrins, in massive intestinal resection, and in pheochromocytoma.

A secretin provocative test may be useful in patients with gastrin levels < 1000 pg/mL (< 480 pmol/L). An IV bolus of secretin 2 mcg/kg is given with serial measurements of serum gastrin (10 minutes and 1 minute before, and 2, 5, 10, 15, 20, and 30 minutes after injection). The characteristic response in gastrinoma is a paradoxical increase in gastrin levels, the opposite of what occurs in patients with antral G-cell hyperplasia or typical peptic ulcer disease. Patients also should be evaluated for Helicobacter pylori infection, which commonly results in peptic ulceration and moderate excess gastrin secretion.

Once the diagnosis of gastrinoma has been established, the tumor or tumors must be localized. The first test is abdominal CT or somatostatin receptor scintigraphy, which may identify the primary tumor and metastatic disease. PET or selective arteriography with magnification and subtraction is also helpful. If no signs of metastases are present and the location of the primary tumor is uncertain, endoscopic ultrasonography should be done. Selective arterial secretin injection is an alternative.

Prognosis

Five- and 10-year survival are > 90% when an isolated tumor is removed surgically vs 43% at 5 years and 25% at 10 years with incomplete removal

Treatment

Acid suppression

Proton pump inhibitors are the medications of choice (eg, omeprazole or esomeprazole 40 mg orally 2 times a day). The dose may be decreased gradually once symptoms resolve and acid output declines. A maintenance dose is needed; patients need to take these medications indefinitely unless they undergo surgery.

Octreotide injections, 100 to 500 mcg subcutaneously twice a day to 3 times a day, may also decrease gastric acid production and may be palliative in patients who are not responding well to proton pump inhibitors. A long-acting form of octreotide (20 to 30 mg IM once a month) can be used.

Surgery

Surgical removal should be attempted in patients without apparent metastases because of the high risk of underlying cancer. At surgery, duodenotomy and intraoperative endoscopic transillumination or ultrasonography help localize tumors.

Surgical cure is possible in 20% of patients if the gastrinoma is not part of a multiple endocrine neoplasia syndrome.

Chemotherapy

In patients with metastatic disease, streptozocin in combination with 5-fluorouracil or doxorubicin is the preferred chemotherapy for islet cell tumors. The combination may reduce tumor mass (in 50 to 60%) and serum gastrin levels and is a useful adjunct to omeprazole.

Newer chemotherapies under investigation for insulinoma include temozolomide-based regimens, everolimus, or sunitinib. Patients with metastatic disease are not cured by chemotherapy.