NORD gratefully acknowledges E. Christopher Ellison, MD, Academy Professor and The Robert M Zollinger Professor Emeritus, The Ohio State University, for assistance in the preparation of this report.
Zollinger-Ellison syndrome (ZES) is characterized by the development of a tumor (gastrinoma) or tumors that secrete excessive levels of gastrin, a hormone that stimulates production of acid by the stomach. Many affected individuals develop multiple gastrinomas, which are thought to have the potential to be cancerous (malignant). In most patients, the tumors arise within the pancreas and/or the upper region of the small intestine (duodenum). Due to excessive acid production (gastric acid hypersecretion), individuals with ZES may develop peptic ulcers of the stomach, the duodenum, and/or other regions of the digestive tract. Peptic ulcers are sores or raw areas within the digestive tract where the lining has been eroded by stomach acid and digestive juices. Symptoms and findings associated with ZES may include mild to severe abdominal pain; diarrhea; increased amounts of fat in the stools (steatorrhea); and/or other abnormalities. In most affected individuals, ZES appears to develop randomly (sporadically) for unknown reasons. In approximately 25 percent of patients, ZES occurs in association with a genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). All of the tumors are considered to have malignant potential. Prognosis is related to tumor size and the presence of distant metastases.
ZES is characterized by abnormally increased acid production (gastric hypersecretion), excessively high levels of gastrin in the blood (hypergastrinemia), and ulceration of the stomach or the upper region of the small intestine (duodenum) due to gastrin-producing tumors (gastrinomas). In most patients, gastrinomas arise within the wall of the duodenum or within the pancreas. The pancreas is a gland that functions as part of the digestive and endocrine systems. Certain pancreatic cells (exocrine cells) secrete digestive juice into ducts, while clusters of other pancreatic cells (pancreatic endocrine cells known as “islet cells”) secrete certain hormones directly into the bloodstream.
The gastrinomas associated with ZES are considered to have malignant potential. Evidence suggests that these malignancies are usually slow growing, although a small percentage may be rapidly invasive. The malignancies most commonly spread to regional lymph nodes and the liver. Malignant tumor growth and metastatic disease may result in potentially life-threatening complications.
In individuals with ZES, excessive acid secretion may erode the lining of the stomach, duodenum, or other regions of the digestive tract (peptic ulcers). Most affected individuals have single or, less commonly, multiple ulcers of the stomach or the upper region of the duodenum. In those with multiple ulcers, ulceration may extend to the lower duodenum or the middle region of the small intestine (jejunum). Particularly during early disease, ulcer symptoms associated with ZES are often similar to those seen in others with peptic ulcers from other causes. Such symptoms may include a “gnawing” or burning pain in the abdominal area, inflammation of the esophagus (esophagitis), appetite changes, nausea, vomiting, weight loss, and/or other abnormalities.
However, in some patients, symptoms associated with peptic ulcers may be more severe, persistent, and progressive and may be associated with potentially life-threatening complications, such as bleeding, perforation, or intestinal obstruction. Bleeding from peptic ulcers may result in vomiting of blood and/or the passage of blood in the stools. In some patients, ulcers may penetrate the wall of the digestive tract, creating an abnormal opening (perforation) into the abdominal cavity. Associated symptoms may include severe, persistent, piercing pain in the abdominal area; inflammation of the abdominal lining (peritonitis); and/or other symptoms and findings. In addition, inflammation and scarring from chronic ulceration may narrow the outlet from the stomach to the duodenum (pyloric stenosis), causing obstruction, a feeling of early fullness, lack of appetite, pain, vomiting, and/or other associated abnormalities. Such complications are considered medical emergencies that require immediate treatment.
In some individuals with ZES, diarrhea may be the initial symptom. Excessive acid levels within the digestive tract may also cause increased amounts of fat in the stools (steatorrhea).
In most individuals with ZES, the condition appears to occur spontaneously for unknown reasons (sporadically). However, in approximately 25 percent of affected individuals, ZES occurs in association with the genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). In most patients, MEN-1 is inherited as an autosomal dominant genetic condition.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Most individuals with a disease gene for MEN-1 will develop symptoms and findings associated with the disorder (high penetrance). However, the characteristics that are manifested may vary greatly in range and severity from case to case (variable expressivity).
MEN-1 is caused by changes (mutations) in the MEN1 gene. The MEN1 gene regulates production of a protein (termed “menin”) that appears to play some role in preventing tumor development (tumor suppressor). (For more information on MEN-1, please see the “Related Disorders” section of this report below.)
ZES may become apparent at any age. However, symptom onset usually occurs between ages 30 and 60 years. The exact frequency of ZES in the general population is unknown. However, some researchers estimate that ZES represents less than one percent of peptic ulcers.
The diagnosis of ZES is based upon a thorough clinical evaluation, a detailed patient history, and specialized tests, including certain laboratory studies and advanced imaging techniques. ZES may be suggested by various factors, including the development of frequent or multiple peptic ulcers that are resistant to certain standard ulcer treatments and/or that occur in unusual sites (e.g., the jejunum).
In individuals with suspected ZES, diagnostic studies may include blood testing to detect increased gastrin levels and evaluation of samples of gastric juice to detect increased acid levels. In some patients, additional laboratory tests may also be conducted to help confirm ZES. Such tests may include measuring levels of gastrin within the fluid portion of the blood (serum) before and after intravenous infusion of calcium; injection of the digestive hormone secretin, or feeding of a standard meal. Additional laboratory studies may also be conducted to help confirm or rule out MEN-1.
The U.S. Food and Drug Administration (FDA) has approved the use of synthetic porcine secretin for use in the diagnosis of gastrinoma associated with ZES. This biological is manufactured by ChiRhoClin, Inc.
When possible (e.g., if there is no evidence of metastasis of a single tumor), complete surgical removal of the gastrinoma may be considered the optimal treatment for ZES. Evidence suggests that complete and curative removal of gastrinoma is possible in approximately 20 to 30 percent of individuals with ZES.
Various advanced imaging techniques may be used before surgery to help localize and characterize the gastrinoma and exclude metastatic disease (e.g., endoscopic ultrasound, nuclear medicine studies, abdominal ultrasounds, computerized tomography [CT] scanning, abdominal angiography). Recent advances in imaging have led to 68G Ga-Dotatate PET CT replacing somatostatin scintigraphy for localization of neuroendocrine tumors including those causing ZES. This test has a high sensitivity and specificity. Gastrinomas are slow growing and hence 18F-FDG PET/CT is not commonly used for initial evaluation. Due to slow metabolic activity of gastrinoma in initial stages, they are not typically avid on 18F-FDG PET/CT. In contrast to FDG PET/CT, 68Ga-Dotatate PET demonstrates a high uptake because neuroendocrine tumors express significant numbers of somatostatin 2 receptors. In addition, in some patients, certain imaging techniques (e.g., intraoperative endoscopic transillumination or ultrasound) may be used during surgical exploration to aid in the localization and possible removal of tumors. Recent studies have shown that intraoperative localization may be facilitated by the intravenous administration of indocyanine- green (ICG) 0.1 mg/kg and within one minute of injection examination of the pancreas and duodenum with near infrared fluorescence visualization.
Surgery is the only treatment shown to potentially cure gastrinoma. Biochemical cure of sporadic gastrinoma is reported in 30% to 50% of patients. However, recurrence has been documented in nearly one-third of patients. The average time to recurrence is 5 to 10 years. Regardless of achieving biochemical cure, complete resection of all tumors is associated with improved survival. The 10-year disease-specific survival in patients having complete resection of sporadic gastrinoma is 85% compared to 40% for patients having incomplete resection and 25% for those having no resection.
In some studies, MEN-1 patients operated upon with a curative intent, cure was achieved in only 6% of patients. However, the 10-year survival with gastrinoma in MEN-1 with complete resection was 90%, compared with only 45% for patients having an R2 resection or no resection. As incomplete resections do not increase survival, MEN -1 patient with extensive metastatic disease or loco-regional spread that precludes complete resection receive little benefit from surgical resection and these patients are typically not offered surgery.
Pancreatic gastrinoma survival fairs well when compared to other pancreatic neuroendocrine tumors (PNETs). It has been reported that between histologic subtypes, there were significant differences in sex and age, and in tumor size, grade, location, and stage. Median survival time for insulinomas was 12.7 years; gastrinomas, 10.2 years; glucagonomas, 7.7 years; VIPomas, 7.9 years; and mixed tumors, 3.4 years. Multivariate analysis has shown that histology (insulinoma, gastrinoma, and VIPoma; p = .009), absence of distant metastases (p = .002), age < 50 years (p = .001), surgical intervention (p = .001), and stage I/II disease (p = .011) were associated with prolonged survival. Rarely, in severe cases in which other therapy is ineffective, surgical removal of the stomach (gastrectomy) may be considered.
Initial treatment commonly includes the use of certain medications called proton pump inhibitors, such as omeprazole. Such medications may reduce stomach acid production, relieve symptoms, and promote ulcer healing. In some patients, another type of acid-suppressing medication called H2 blockers may also be used, such as cimetidine or ranitidine.
In 2006, the FDA approved AstraZeneca’s proton pump inhibitor Nexium for management of acid hypersecretion in patients with ZES.
The FDA approved a proton pump inhibitor called Protonix (pantoprazole sodium), in the form of delayed-release tablets, for the long-term treatment of individuals with ZES. Protonix is marketed in the United States by Wyeth Pharmaceuticals.
Due to the effectiveness of the medications discussed above, serious complications associated with ulcers may often be prevented. However, some affected individuals may remain undiagnosed until developing such complications (e.g., perforation or obstruction). These complications are considered medical emergencies that require immediate treatment, potentially including surgery.
In some affected individuals with aggressively invasive gastrinoma, recommended treatment may include the use of certain anticancer drugs (chemotherapy) to help reduce tumor mass and blood gastrin levels.
Management of Metastatic Disease
Patients with malignant gastrinoma of the pancreas and duodenum not infrequently present with liver metastases. In these situations, it is essential for the surgeon to work collaboratively with a multidisciplinary team.
Liver directed therapy for patients with unresectable liver only or liver-dominant metastases, who present with symptomatic disease is beneficial for those with >25% liver burden. Transarterial chemoembolization (TACE), radionuclide-laden spheres (Yittrium-90) or local ablative therapy (radiofrequency or microwave ablation) are effective liver directed therapies. These modalities will not cure the patient, but they may provide effective cytoreduction of liver metastases, alleviate symptoms attributable to metastatic disease, and possibly extend survival. However, these treatments have not been compared to one another or to best supportive care. Hence, these patients are best served in the context of a multidisciplinary team and perhaps in the framework of a clinical trial.
Systemic Treatments/Cytotoxic Chemotherapy
Trials using chemotherapeutic drugs including doxorubicin, streptozocin, 5-fluorouracil (5-FU), temozolomide, and dacarbazine have established cytotoxic effects in PNETs. There have been limited numbers of patients with gastrinoma treated in these trials.
Capecitabine and temozolomide have been shown to have a high and durable response in PNETs in a small study with 70% of patients demonstrating a radiographic response with median progression free survival of 18 months. Given this radiographic response this regimen has also been reported in the neoadjuvant setting. Response rates specific to gastrinoma have not been reported.
Everolimus and sunitinib are both FDA approved treatments for advanced pancreatic neuroendocrine tumors. A randomized controlled trial of everolimus, an oral inhibitor of mammalian target of rapamycin (mTor) showed an increase in progression free survival from 4.6 months to 11.0 months. Sunitinib, a multi-targeted tyrosine kinase inhibitor has also been shown to increase progression free survival to 11.4 months from 5.5 months and increase in overall survival in patients with metastatic unresectable disease.
Both octreotide and l long acting octreotide (LAR) have been shown to prolong progression free survival however overall survival has not been significantly increased. These drugs are thought to stabilize tumor growth in addition to relieving symptoms associated with functional tumors.
Peptide receptor radionuclide therapy (PRRT) was approved by the FDA for treatment of neuroendocrine tumors in 2017. PRRT is a molecular therapy that uses octreotide combined with a small amount of radioactive material creating a radiopeptide. This is then injected into the bloodstream. The NETTER-1 study, a large phase III randomized clinical trial showed lutetium 177 (177Lu) dotatate improved progression free survival a median of 33 months when compared with LAR.
Genetic counseling is recommended for individuals with ZES and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
Information on cancer clinical trials is available through the Internet on www.cancer.gov or by calling: 1-800-4CANCER.
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