A gastrinoma is a gastrin-secreting tumor that can occur in the pancreas, although it is most commonly found in the duodenum.[1, 2] 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 a greater malignant potential as compared to duodenal gastrinomas.[3]
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,[1] splenic hilum, omentum, liver, gallbladder, common bile duct, and the ovary.
Over 50% of gastrinomas are malignant and can metastasize to the 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).
Enormous secretion of gastrin from the tumor cells leads to hyperplasia of the 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.
A small study by Kohan et al describes duodenal bulb mucosa with hypertrophic heterotopia in patients with Zollinger-Ellison syndrome (ZES).[4] The investigators evaluated the incidence of duodenal gastric oxyntic hypertrophic heterotopia in 7 patients with ZES over an average period of 5 years. The patients underwent endoscopic examinations with methylene blue staining and biopsy of the gastric and duodenal mucosa every 3-6 months.
Of the 7 patients with ZES and an intact stomach and duodenum, 2 had no evidence of duodenal mucosal hypertrophic heterotopia, but 5 did, in whom bowel mucosal biopsies revealed patchy replacement of the surface epithelium by gastric-type epithelium with hypertrophic oxyntic glands in the lamina propria.[4] In addition, patients with gastric oxyntic hypertrophic heterotopia had higher levels of average serum gastrin and basal acid output levels than those without gastric oxyntic hypertrophic heterotopia, a finding that Kohan et al suggest that not only could the hypertrophic and heterotopic gastric mucosa result from increased gastrin levels but that an increased incidence of postbulbar ulcers may result in affected patients.[4]
United States data
Gastric carcinoids or neuroendocrine tumors are reported to account for an estimated 0.6-2% of detected gastric polyps.[5] In the United States, the incidence of these tumors has greatly increased over the past several decades.[5]
International data
The true incidence of Zollinger-Ellison syndrome (ZES) is not known. ZES constitutes 0.1% or more of the cases of peptic ulcer disease. Although rare, gastrinomas are the most common pancreatic islet cell tumors.
In a 2013 German epidemiologic review of 2 time periods (1976-1988 and 1998-2006) comprising more than 10.8 million people, there was an approximately 5-fold increase in the cases of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) between 1976 and 2006, accompanied by a change in the anatomic distribution.[6]
Sex- and age-related demographics
Gastrinomas are more common in males than in females, with ratios from 1.5:1 to 2:1.
Although gastrinomas can occur at any age, the initial clinical manifestation usually appears in people aged 30-50 years.
Patients with hepatic metastases may have a remaining life span of less than 1 year; 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.
Mortality/Morbidity
With the advent of anti-ulcer medications, the number of deaths secondary to ulcer complications has decreased significantly. The primary determinants of survival for patients with gastrinomas are the size of the primary tumor and the occurrence of tumor metastasis.
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.
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.
Other factors that alert one to the presence of underlying gastrinomas include the following:
Due to the elusive nature of the neoplasm, the diagnosis is based on the following 3 criteria:
Fasting serum gastrin measurement is discussed as follows:
Because low gastric acid output (eg, in atrophic gastritis, pernicious anemia, or postvagotomy state) can lead to hypergastrinemia, check patients for the following:
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 the serum gastrin levels to higher than 200 pg/mL within 2 minutes and, virtually always, within 10 minutes in patients with gastrinomas.
Imaging studies are helpful in localizing the tumor. They also are helpful for assessing surgical resectability by helping reveal liver metastasis.
Somatostatin receptor scintigraphy (SRS) is very useful to identify the primary lesions preoperatively. SRS is the most sensitive noninvasive method for localizing the 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 ultrasonography has also been found to be useful in helping to detect the primary tumor, with a reported overall sensitivity and accuracy greater than 90% for intrapancreatic gastrinomas. For extrapancreatic gastrinomas in the duodenal wall, endoscopic ultrasound is useful but somewhat less sensitive.
Computed tomography (CT) scanning and selective angiogram also are helpful in detecting gastrinoma.
Magnetic resonance imaging (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.
Selective arterial secretin injection, involving the gastroduodenal, splenic, and superior mesenteric arteries, with assessment of the hepatic vein serum gastrin concentrations is one among several diagnostic procedures proposed for helping identify gastrinomas. However, this test has been shown to be of value primarily in localizing gastrinomas in 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).
Levels of serum chromogranin A (CgA), a nonspecific marker for neuroendocrine tumors, do not appear to have any value in the diagnosis of gastrinomas compared with alpha-amidated gastrin levels.[8] In a separate study that compared the sensitivity, specificity, and positive/negative predictive values of plasma CgA levels with a polymerase chain reaction (PCR) assay based on a 51-transcript signature to detect neuroendocrine tumors, the PCR-based assay was not only significantly superior to CgA on all performance metrics, but it was also not affected by proton pump inhibitor therapy.[9]
Individualize the selection of treatment.[2] Base the 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).
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.[10]
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.
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%.
Granberg et al described a patient with almost complete response to treatment with Sandostatin LAR, a long-acting somatostatin analog.[11]
Interferon or targeted radiotherapy may also be considered in patients who are not candidates for chemotherapy. Treatment of metastasized gastrinoma with targeted somatostatin-based radiotherapy with repeated cycles of 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([90Y-DOTA]-TOC) or with cycles alternating between [90Y-DOTA]-TOC and 177lutetium-labeled DOTA-TOC ([177Lu-DOTA]-TOC) appears to improve the overall survival.[12, 13]
Consult with the following specialists:
Surgical care is indicated for localized disease[14] ; resection is the treatment of choice for primary pancreatic neuroendocrine tumors (PNETs), because it is associated with increased survival.[2, 15] Indications for surgery include considerations of clinical symptom control, tumor size, location, extent, malignancy, and the presence of metastasis.[2]
Surgical resection of localized disease leads to a complete cure without any recurrence in 20-25% of patients with gastrinomas. The rate of recurrence-free survival is lower in patients whose symptoms do not improve following resection.[16]
The intraoperative use of a portable large field of view gamma camera (LFOVGC) and a handheld gamma detection probe (HGDP) may improve the localization and indium-111 (111In)-pentetreotide–radioguided gastrinoma resection and removal in patients with Zollinger-Ellison syndrome.[17]
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.
For patients with malignant pancreatic neuroendocrine tumors (PNETs), laparoscopy appears not to compromise oncologic resection and offers the advantages of reduced postoperative pain, improved cosmetic results, shorter hospital stay, and a shorter postoperative recovery period.[15]
It has been reported that Whipple pancreaticoduodenectomy affords the greatest probability for cure, particularly for multiple endocrine neoplasia type I (MEN I)-associated gastrinomas, although also for sporadic tumors, because it results in the 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 it is recommended primarily for large, advanced tumors.
Follow-up of patients with gastrinomas that have been resected is directed at the diagnosis and treatment of recurrence. Note the following:
Immediate and sustained control of gastric acid hypersecretion is the most important aspect of disease management in patients with Zollinger-Ellison syndrome (ZES), because acid hypersecretion is the cause of essentially all the 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.
Clinical Context: Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ -ATP pump.
Titrate dose to achieve a BAO of 10 mEq/h. Gastric acid hypersecretion usually is controlled with doses < 80 mg/d, but doses up to and even >200 mg/d have been used in some patients.
Clinical Context: Inhibits gastric acid secretion. Titrate dose to achieve a BAO of 10 mEq/h. Efficacy and tolerability of IV administration in acute treatment of patients with suspected ZES have not been established.
Clinical Context: Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ -ATP pump. Titrate dose to achieve a BAO of 10 mEq/h.
Clinical Context: S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H+/K+ -ATP pump at the secretory surface of gastric parietal cells. Titrate dose to achieve a BAO of 10 mEq/h.
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.
Clinical Context: Inhibits histamine stimulation of the H2 receptor in the gastric parietal cells, which, in turn, reduces gastric acid secretion, gastric volume, and hydrogen concentrations. Titrate dose to achieve BAO < 10 mEq/h.
Clinical Context: Inhibits histamine at H2 receptors of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations. Titrate dose to achieve BAO < 10 mEq/h.
Clinical Context: Competitively inhibits histamine at H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations. Titrate dose to achieve a BAO of 10 mEq/h.
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.
Clinical Context: Inhibits DNA synthesis without significantly affecting the bacterial or mammalian RNA or protein synthesis.
Clinical Context: Interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid, inhibiting thymidylate synthetase, and, subsequently, inhibiting cell proliferation.
Clinical Context: Inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can, in turn, inhibit the growth of neoplastic cells.
Indicated in metastatic disease and in patients who are not candidates for surgery. These drugs reduce the 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%.