Gastrinomas are neuroendocrine tumors characterized by the secretion of gastrin with resultant excessive gastric acid production causing severe peptic ulcer disease and diarrhea, a combination referred to as the Zollinger-Ellison syndrome (ZES).
These tumors along with other pancreatic endocrine tumors are thought to originate from endodermal pluripotent cells. Gastrinomas can be either sporadic (75% to 80%) or associated with multiple endocrine neoplasia type 1 (MEN-1) syndrome, an autosomal dominant inherited disorder (20% to 30%). MEN1 is caused by germline mutations in the tumor suppressor MEN1 gene located on chromosome 11q13. It has been proposed that the tumors arise in susceptible patients as a result of multiple independent second-hit mutations in the MEN1 gene.
The worldwide incidence of gastrinomas is about 0.5 to 3 cases/million per year. With improved techniques for tumor detection, the annual incidence has increased. About 80% to 90% of these tumors arise in the so-called “gastrinoma triangle,” an anatomical area in the abdomen with boundaries formed superiorly by the confluence of the cystic and common bile ducts, inferiorly by the second and third portions of the duodenum, and medially by the neck of the pancreas. Gastrinomas can also rarely occur in the stomach, peri-pancreatic lymph nodes, liver, bile duct, ovary, heart or be associated with small cell lung cancer. Duodenal gastrinomas are usually < 1 cm, multiple, occur predominantly in the first part of the duodenum, and comprise approximately 50% to 88% of gastrinomas associated with sporadic ZES and 70% to 100% of gastrinomas associated with MEN 1. Pancreatic gastrinomas are larger than their duodenal counterparts, may occur in any portion of the pancreas, and comprise 25% of these tumors. Gastrinomas are also the most common functional and malignant pancreatic endocrine tumors. They are commonly diagnosed between the ages of 20 and 50 and have a slightly higher incidence in men. In patients with MEN1, gastrinomas present at an earlier age, commonly between the ages of 10 and 30 years. Gastrinomas are slow-growing tumors, but about 60% are malignant and have metastasized at the time of diagnosis.
The gastrinoma tumor cells secrete excessive amounts of gastrin which leads to hyperplasia of the fundic parietal cells and increased basal gastric acid output. The excessive gastric acid output breaches the mucosal defenses of the gastric as well as the duodenal wall, causes ulceration, and inactivates pancreatic digestive enzymes with resultant fat malabsorption and diarrhea. Inhibition of absorption of sodium and water by the small intestine results in a secretory component of the diarrhea.
Histologically, well-differentiated neuroendocrine tumor (NET) has a typical organoid arrangement of cells with nesting, trabecular, or gyriform patterns. The tumor cells are round with regular bland nuclei and produce large amounts of secretory granules with diffuse immunoexpression of neuroendocrine markers. In contrast, the poorly differentiated NET has atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression. An important feature for the diagnosis of neuroendocrine tumors is immunostaining for chromogranin A and synaptophysin. Gastrin immunostaining can be used to differentiate from other neuroendocrine tumors. Gastrinomas express a high density of somatostatin receptors, thus making somatostatin scintigraphy an effective localizing tool.
The WHO (2010) classified all neuroendocrine tumors, including gastrinomas into three grades based on the mitotic rate, or Ki-67 index: (1) Low grade, well-differentiated endocrine tumors with benign or uncertain behavior at the time of diagnosis with a mitotic rate of < 2 and Ki-67 index of < 3% (10% to 30%); (2) well-differentiated endocrine carcinomas with low-grade malignant behavior with a mitotic rate of 2 to 20 and Ki-67 index of 3% to 20% (50% to 80%), and (3) High grade, poorly differentiated endocrine carcinomas with high-grade malignant behavior with a mitotic rate of > 20 and Ki-67 index of > 20% (1% to 3%).
The most common clinical manifestations include abdominal pain and chronic diarrhea. Other manifestations may include dyspepsia, gastroesophageal reflux, gastrointestinal bleeding and weight loss. In patients with refractory/recurrent peptic ulcers (especially multiple and duodenal) and diarrhea, a diagnosis of gastrinoma must be considered. It is important to remember that ZES is the underlying cause in only about 0.1% to 1% of patients with peptic ulcer disease, so widespread screening is not recommended. Characteristically, diarrhea with ZES improves with administration of proton pump inhibitors (PPIs).
Diagnosis is established by demonstration of an elevated fasting serum gastrin concentration in association with increased basal gastric acid secretion and or low gastric PH. A normal fasting serum gastrin level excludes ZES. Hypergastrinemia also can be seen in patients with PPI therapy, hypercalcemia, atrophic gastritis or gastric outlet obstruction; therefore analysis of gastric acid secretion is useful. The majority of patients with gastrinomas have elevations in gastrin less than 10-fold above the upper limit of normal and may need confirmatory testing. A secretion stimulation test can be used to differentiate from other causes of gastrinomas, but access to secretin is limited. Chromogranin A is a non-specific serum biomarker of neuroendocrine tumors that correlates with tumor volume and may provide prognostic information and be useful for follow-up. Chromogranin A should be measured fasting, and exercise should be avoided before testing. Multiphasic CT, MRI, nuclear medicine imaging: somatostatin receptor scintigraphy with SPECT/CT, gallium-somatostatin analog PET-CT imaging are non-invasive imaging modalities that can be used for localizing the tumor and evaluating the extent of metastatic spread. The presence of enlarged peripancreatic lymph nodes or liver metastases suggests malignancy. CT is relatively insensitive for small liver lesions for which MRI is better. Endoscopy with endoscopic ultrasound is useful for small tumors that may be missed and has the added benefit of obtaining fine needle aspiration for histology. Due to low proliferative activity, FDG-PET scan is not useful. In some patients, tumor localization can only be achieved during laparotomy by direct palpation by the surgeon or by use of intra-operative ultrasound.
All patients with ZES will need to be evaluated for MEN 1 syndrome by history (hypercalcemia, nephrolithiasis, pituitary tumors) including family history and biochemical assessment including serum ionized calcium, parathyroid hormone levels, and prolactin.
Goal of medical management is to treat symptoms and prevent complications from peptic ulcer disease. The preferred medical therapy is the use of high doses of proton pump inhibitors. PPI’s are preferred over H2 receptor blockers due to their higher potency and longer duration of action.
Surgery is the only curative treatment for gastrinomas. All patients with sporadic gastrinoma in the absence of unresectable metastatic disease should be referred for surgery. In contrast, medical therapy is the current standard of care for most patients with MEN1 associated ZES due to the multiplicity of tumors, extra-pancreatic location, co-existent metastatic disease and low chance of surgical cure. Surgical resection is recommended for MEN 1 associated gastrinomas > 2 cm.
Metastases and extent of metastatic spread are the most important determinant of mortality. The goal of surgery is to resect the primary tumor for a potential cure and reduce the risk of distant metastatic disease and improve survival. For a non-metastatic gastrinoma situated in the pancreas, surgical excision/enucleation is often effective. Duodenal gastrinomas are often multiple and often require duodenectomy. Regional lymph nodes should be sampled systematically. Patients undergoing surgery should receive PPI’s. Patients are followed yearly with fasting serum gastrin and chromogranin A levels and imaging as needed after resection.
Conservative treatment with PPIs is also recommended for patients who are unsuitable for surgery or patients with widespread metastasis.
Current treatment modalities for patients with metastatic disease have limited efficacy. Chemotherapy may be administered for patients with widespread metastasis. The first-line treatment is combined therapy with streptozotocin and 5-fluorouracil or doxorubicin. However, these treatments have been shown to result in limited responses and considerable toxicity. Hormonal therapy with octreotide or lanreotide, which are human somatostatin analogs, are known to decrease the gastric acid secretion but are not known to show any anti-tumor activity. In pancreatic neuroendocrine tumors, targeted therapies like antiangiogenic strategies, multi-kinase, or mTOR inhibition which specifically inhibit growth factor receptors and their related signaling pathways are promising new approaches and have provided clear clinical benefits in a few phase III clinical trials, including delayed tumor progression but are pending large-scale use and further clinical trials. Other treatment modalities include hepatic artery embolization for liver metastasis and administration of human leukocyte interferon. Radiotherapy is not generally recommended.
Liver metastases and the extent of liver involvement is the most important prognostic factor for survival. The effect of lymph node metastasis on patient survival is controversial.