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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Gastrinoma
Authors

Shashank R. Cingam1; Mahesh Botejue2; Gilles J. Hoilat3; Harsha Karanchi4.

Affiliations
1 University of New Mexico Comprehensive Cancer Center
2 Riverside Community, UC Riverside School of Medicine
3 University of Iowa Hospital & Clinics
4 Louisiana State University HSC

Last Update: September 26, 2022.

Continuing Education Activity

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). Gastrinomas are 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. Unfortunately, at
least 60 percent of gastrinoma cases have already metastasized by the time of diagnosis, hastening death. Improving
the interprofessional team's knowledge regarding when to consider gastrinomas on differential diagnosis as well as
how to promptly evaluate patients for this condition will allow for earlier management and improved outcomes. This
activity reviews the evaluation and treatment of patients with gastrinomas and the importance of ruling out multiple
endocrine neoplasias. This activity highlights the role of the interprofessional team in caring for affected patients.

Objectives:

Identify the etiology of gastrinomas.

Review the physical presentation of a patient with a gastrinoma.

Describe the management options available for gastrinomas.

Outline interprofessional team strategies for improving care coordination and communication to advance
treatment and improve outcomes for patients with gastrinomas.

Access free multiple choice questions on this topic.

Introduction
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).[1][2][3]

Etiology
These tumors, along with other pancreatic endocrine tumors, appear 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 results from germline mutations in the
tumor suppressor MEN1 gene located on chromosome 11q13. Researchers have proposed that the tumors arise in
susceptible patients as a result of multiple independent second-hit mutations in the MEN1 gene.[4][5]

Epidemiology
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.

Pathophysiology
The gastrinoma tumor cells secrete excessive amounts of gastrin, which leads to hyperplasia of the fundic parietal
cells and increases 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. The inhibition of absorption of sodium and water by the small intestine results in a
secretory component of diarrhea.[6][7]

Histologically, a 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 essential feature for the diagnosis of neuroendocrine tumors is
immunostaining for chromogranin A and synaptophysin. Gastrin immunostaining can help 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%).

History and Physical

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
merit consideration. 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 the administration of proton pump inhibitors (PPIs).

Evaluation
The clinician can confirm the diagnosis is through an elevated fasting serum gastrin concentration associated 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 help 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 localize the tumor and help to evaluate 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, the FDG-PET scan is not
useful. In some patients, tumor localization can only be achieved during laparotomy by direct palpation by the
surgeon or intra-operative ultrasound.[8][9][10]

All patients with ZES will require 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. Patients can also have non-endocrine findings, including angiofibromas and
collagenomas.[11][12][13][14][15]

Treatment / Management
The 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. PPIs are preferable to 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 receive a referral 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 the 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 undergo systematic
sampling. 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 the recommendation for patients who are unsuitable for surgery or patients with
widespread metastasis.

Current treatment modalities for patients with metastatic disease have limited efficacy. Chemotherapy is an option for
patients with widespread metastasis. The first-line treatment is combined therapy with streptozotocin and 5-
fluorouracil or doxorubicin. However, these treatments have shown to result in limited responses and considerable
toxicity. Hormonal therapy with octreotide or lanreotide, which are human somatostatin analogs, are known to
decrease 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.

Differential Diagnosis

Achlorhydria

Atrophic gastritis

Gastric outlet obstruction

Peptic ulcer disease

 Pernicious anemia

Zollinger-Ellison syndrome

Prognosis
Patients who receive a complete tumorectomy can expect greater than 90% 5- to 10-year survival rate. With
incomplete tumor removal, this drops to a 43% chance of 5-year survival, and only a 25% chance for ten years.[16]

Complications
Complications may include:

The surgeon's inability to locate the tumor during surgery

Failure to remove all of the cancerous tissue

Intestinal bleeding or perforation from duodenal or gastric ulcers

Wright loss and/or severe diarrhea

Metastases

Deterrence and Patient Education

Patients need to understand that these tumors can have a high survival rate if caught early, and that medication
compliance is crucial to therapeutic successregarding complications form these tumors.

Pearls and Other Issues

Liver metastases and the extent of liver involvement are the most important prognostic factors for survival. The effect
of lymph node metastasis on patient survival is controversial.

Enhancing Healthcare Team Outcomes

The diagnosis and management of gastrinomas are complex and require an interprofessional team that includes a
general surgeon, endocrinologist, radiologist, pathologist, internist, and an oncologist. While the symptoms are
manageable with PPIs, localized lesions can ve cured with surgery. All patients with sporadic gastrinoma in the
absence of unresectable metastatic disease should receive a referral for surgery. In contrast, medical therapy is the
current standard of care for most patients with MEN1 associated ZES due to the number of tumors, extra-pancreatic
location, co-existent metastatic disease, and low chance of surgical cure. The recommendation os for surgical
resection for MEN 1 associated gastrinomas > 2 cm.

The outcomes for patients with localized lesions that are excisable are good. Patients with metastatic disease have a
poor outcome.[17][18]

Review Questions

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Comment on this article.

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