Gastrinoma

Etiology

Gastrinomas arise from enteroendocrine G-cells, most commonly within the gastrinoma triangle. While the majority of these tumors occur sporadically, approximately 20% to 30% are associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by mutations in the MEN1 tumor suppressor gene. The precise mechanisms of tumorigenesis remain unclear; however, dysregulation of the MEN1 pathway, chromosomal instability, and alterations in key signaling pathways are thought to contribute to tumor development and progression.[2][7][8]

Epidemiology

Gastrinomas are rare neuroendocrine tumors with an estimated annual incidence of 0.5 to 2 cases per million individuals. Approximately 80% of gastrinomas occur sporadically and are typically diagnosed in patients approximately 50 years old, with a slight male predominance. The remaining cases are associated with MEN1 and present earlier in life, often between the ages of 20 and 30.[9]

Gastrinomas have been reported in various anatomic sites, primarily known as the “gastrinoma triangle,” which is an anatomic 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. Approximately 70% to 90% of gastrinomas arise in the duodenum, while 10% to 30% occur in the pancreas. Duodenal tumors, though, are generally smaller in size and more likely to metastasize to regional lymph nodes compared to pancreatic gastrinomas. Unfortunately, despite their indolent growth, the majority of gastrinomas are malignant, and approximately 60% have metastasized at the time of diagnosis.[4][5]

Pathophysiology

Gastrinomas originate from enteroendocrine G-cells and autonomously secrete markedly elevated levels of gastrin, culminating in the clinical syndrome of ZES. The resultant hypergastrinemia stimulates gastric parietal cells via cholecystokinin B (CCK-B) receptor activation to augment hydrochloric acid production. This acid hypersecretion precipitates severe peptic ulcer disease, gastroesophageal reflux, and diarrhea—mainly attributable to the acid-mediated inactivation of pancreatic enzymes and bile salts, which impairs lipid digestion and absorption. In contrast to gastrin's tightly regulated physiologic secretion, which is modulated by negative feedback from intragastric acid levels, gastrinomas secrete gastrin independent of luminal pH, thereby sustaining persistent acid hypersecretion.[10][11]

In MEN1, gastrinomas typically arise secondary to loss-of-function mutations in the MEN1 tumor suppressor gene, which disrupts the menin pathway and promotes neoplastic transformation. Over time, chronic acid hypersecretion induces hyperplasia of the fundic parietal cells, and the overwhelming acid output compromises the mucosal defenses of the gastric and duodenal walls. This breach predisposes patients to refractory ulceration, peptic ulcer perforation, gastrointestinal hemorrhage, and, in some instances, facilitates tumor metastasis.[12][13][14]

Histopathology

Histopathologically, gastrinomas exhibit features akin to other well-differentiated neuroendocrine neoplasms, often demonstrating an organoid architecture with cells arranged in nested, trabecular, or gyriform patterns. The neoplastic cells are typically round with uniform, bland nuclei and are replete with cytoplasmic secretory granules. They characteristically exhibit diffuse immunoreactivity for neuroendocrine markers (eg, chromogranin A and synaptophysin). In addition to their capacity to synthesize and secrete gastrin, gastrinomas frequently overexpress somatostatin receptors, rendering somatostatin receptor scintigraphy an invaluable modality for tumor localization. Nonetheless, the mere presence of gastrin within secretory granules or the tumor’s morphologic attributes in isolation is insufficient for establishing a definitive diagnosis. A diagnosis of gastrinoma is substantiated by the presence of ZES in conjunction with biochemical evidence of gastrin hypersecretion or positive immunohistochemical staining for gastrin.

Most gastrinomas are well-differentiated neuroendocrine tumors, predominantly classified as grade 1 or grade 2. Grading is determined per the World Health Organization (WHO) criteria, which integrate proliferative indices—specifically the Ki-67 labeling index and mitotic count—with the degree of cellular differentiation. Neuroendocrine tumors, including gastrinomas, are stratified into 3 the following grades based on mitotic rate and Ki-67 index:

• Grade 1: Low-grade, well-differentiated endocrine tumors exhibiting benign or uncertain behavior at diagnosis, characterized by a mitotic count of <2 per 10 high-power fields (HPF) and a Ki-67 index of <3%.
• Grade 2: Low-grade, well-differentiated endocrine tumors with intermediate proliferative activity, evidenced by a mitotic count of 2 to 20 per 10 HPF and a Ki-67 index of 3% to 20%.
• Grade 3: High-grade, poorly differentiated neuroendocrine carcinomas with aggressive clinical behavior, defined by a mitotic count of >20 per 10 HPF and a Ki-67 index of >20%.

This grading system (Table. World Health Organization 2022 Classification of Neuroendocrine Tumors) provides critical prognostic information and guides therapeutic decision-making in managing gastrinomas.[15][16][17]

Table. World Health Organization 2022 Classification of Neuroendocrine Tumors

History and Physical

Clinical Features of Gastrinomas

Patients with gastrinomas typically manifest with the clinical syndrome of ZES, characterized by refractory peptic ulcer disease, gastroesophageal reflux, and secretory diarrhea secondary to gastrin-induced acid hypersecretion. This acid excess precipitates mucosal injury and inactivates pancreatic enzymes and bile salts, thereby contributing to malabsorption and steatorrhea. Additional clinical features can include dyspepsia, gastrointestinal hemorrhage, and weight loss. Notably, the initial amelioration of symptoms with PPIs may obscure the underlying pathology, leading to a diagnostic delay.

Endoscopic findings, eg, multiple ulcers, particularly duodenal ulcers, in conjunction with refractory or recurrent diarrhea, should heighten clinical suspicion for gastrinoma. In patients with MEN1, gastrinomas frequently coexist with primary hyperparathyroidism; hence, the presence of unexplained hypercalcemia coupled with peptic ulcer disease warrants a comprehensive endocrine evaluation to assess for MEN1-related ZES.[18]

Physical examination findings are often nonspecific but may reveal epigastric tenderness, signs of malnutrition, or hepatomegaly indicative of metastatic involvement. Given the high malignant potential and the propensity for distant metastases in gastrinomas, a thorough clinical assessment—including detailed family history and endocrine screening—is essential to facilitate early diagnosis and guide appropriate management strategies.

Evaluation

The diagnostic evaluation of gastrinomas necessitates an integrative approach combining biochemical assays, functional assessments to confirm ZES, and advanced imaging techniques for precise tumor localization and metastatic evaluation. Discontinuing PPIs for at least 1 week and H2-receptor antagonists for 48 hours before laboratory testing is critical to prevent pharmacologic interference with gastrin levels.

Biochemical Testing

Fasting serum gastrin 

A fasting serum gastrin (FSG) assay is the initial screening modality due to its high sensitivity for detecting hypergastrinemia. An FSG level exceeding 1,000 pg/mL, approximately 10 times the normal upper limit, is diagnostic of a gastrinoma. Conversely, mildly elevated FSG levels (100–1,000 pg/mL) may be observed in conditions (eg, atrophic gastritis or chronic PPI therapy), while a normal FSG effectively excludes ZES.[5]

Gastric pH measurement

A gastric pH of ≤2 is indicative of acid hypersecretion and aids in differentiating gastrinomas from other etiologies of elevated serum gastrin.

Secretin stimulation test

Employed when fasting serum gastrin levels are equivocal, this test evaluates the paradoxical increase in gastrin secretion in response to secretin. An incremental rise in gastrin of >120 pg/mL following secretin administration is considered diagnostic for gastrinoma.

Chromogranin A

Elevated chromogranin A levels can support the diagnosis as a general neuroendocrine tumor marker; however, their lack of specificity limits their standalone diagnostic utility.

Screening for MEN1

Given the association of gastrinomas with MEN1, all patients with ZES should undergo a comprehensive endocrine evaluation. This includes a detailed personal and family history and biochemical assessments, including serum calcium, parathyroid hormone, prolactin, and pancreatic polypeptide levels.[19][20]

Imaging Studies for Localization and Staging

Advanced imaging techniques for precise tumor localization and metastatic evaluation include:

• Somatostatin receptor imaging (SRI): The ⁶⁸Ga-dotatate PET/CT scan is the preferred imaging modality due to its high sensitivity and specificity. The Gallium-68 dotatate tracer avidly binds to somatostatin receptors, which are overexpressed on gastrinoma cells, enabling the accurate detection of both primary and metastatic lesions.

• Cross-sectional imaging: Multiphasic CT and magnetic resonance imaging (MRI) are instrumental in identifying the primary tumor and assessing metastatic spread. While CT may be less sensitive for detecting lesions smaller than 3 cm, MRI demonstrates superior sensitivity, particularly for identifying hepatic metastases.[21]

• Endoscopic ultrasound (EUS): This modality is highly effective for detecting small duodenal or pancreatic gastrinomas, especially when cross-sectional imaging yields negative results. In addition, EUS facilitates tissue acquisition via fine needle aspiration, allowing for histopathologic confirmation.

Treatment / Management

The management of gastrinomas requires a comprehensive, multimodal approach that combines surgical, medical, and targeted therapies, each tailored to the tumor’s anatomical extent, functional status, and individual patient factors.[22]

Surgical Management

Localized disease

Surgical resection is the primary treatment modality for localized gastrinomas. Cure rates can exceed 70% to 80% in cases where complete excision is feasible. Options for small, well-demarcated lesions in the duodenum or pancreas include enucleation or segmental resection. Conversely, larger or more invasive lesions may require extensive procedures such as pancreaticoduodenectomy. Data suggest that for patients undergoing curative resection, the 5-year survival rate can approach 90% in the absence of metastatic disease.[5](B3)

Hepatic metastases

Hepatic metastases are detected when complete (R0) resection is achieved. Studies have demonstrated that this approach is associated with a significant improvement in long-term survival, with median survival times extending beyond 5 years in select cohorts. However, resectability is often limited by the number and distribution of liver lesions.[23]

MEN1-associated disease

In patients with MEN1, gastrinomas are typically multifocal and located in extra-pancreatic sites, complicating surgical management. In this setting, surgery is often reserved for tumors larger than 2 cm, as data indicate that lesions exceeding this size have a markedly increased risk (up to 60% to 80%) of metastasis compared to tumors smaller than 2 cm (<20% risk). Additionally, concomitant parathyroidectomy is recommended in MEN1 patients presenting with ZES and primary hyperparathyroidism, as hypercalcemia may exacerbate acid secretion.

Medical Management

Acid suppression

Given that uncontrolled acid hypersecretion underlies many of the complications of ZES, high-dose PPIs are the cornerstone of medical therapy. Regimens typically involve doses 2 to 3 times higher than standard gastroesophageal reflux disease (GERD) protocols, eg, omeprazole 60 mg/day or equivalent, to reduce gastric acid output by >90%. This level of suppression not only alleviates symptoms (with improvement reported in up to 80% of patients) but also prevents complications, eg, ulcer perforation and gastrointestinal bleeding.[24]

Somatostatin analogs

Somatostatin analogs (eg, octreotide and lanreotide) reduce gastrin secretion and control hormone-mediated symptoms. Their use is particularly advantageous in patients with positive somatostatin receptor imaging, where symptomatic relief and disease stabilization have been observed in 30% to 50% of cases. In some series, somatostatin analogs have also been associated with prolonged progression-free survival (PFS) in patients with well-differentiated neuroendocrine tumors.

Chemotherapy

In metastatic or unresectable cases, cytotoxic chemotherapy using agents such as streptozocin, 5-fluorouracil, or temozolomide-based regimens may be considered. However, the response rates are modest (typically 20% to 30%), and significant toxicity often limits these regimens. As such, chemotherapy is generally reserved for patients with widespread disease and symptomatic progression.

Targeted and Novel Therapies

Molecular targeted agents

Targeted therapies such as everolimus and sunitinib have emerged as important options for advanced neuroendocrine tumors, including gastrinomas. In pivotal trials such as RADIANT-3 and a phase III study for sunitinib, these agents have demonstrated an approximate doubling of median PFS, from around 5 to 6 months with placebo to 11 months or more with treatment, thereby offering a viable strategy for disease control in progressive metastatic cases.[25][26][27](A1)

Peptide receptor radionuclide therapy

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs (eg, ¹⁷⁷Lu-dotatate) provides a targeted approach for patients with progressive metastatic disease expressing high levels of somatostatin receptors. Typically administered in 4 cycles (approximately 7.4 GBq every 8 weeks), PRRT has shown objective response rates in the 30% to 40% range and can extend PFS significantly. However, long-term data indicate that recurrence is common, and PRRT is associated with potential adverse effects, including renal toxicity (observed in 10% to 15% of patients) and bone marrow suppression.[28][29]

Long-Term Management and Surveillance

Given the potential for recurrence and progression, long-term follow-up is essential. Serial monitoring with biochemical markers, notably fasting serum gastrin levels, and periodic imaging using modalities, eg, ⁶⁸Ga-dotatate PET/CT, CT, or MRI) are recommended to detect early disease recurrence. The frequency of monitoring is typically tailored based on initial tumor burden, grade, and response to therapy, with more intensive surveillance (every 6 to 12 months) advised in patients with high-risk features.[7]

Differential Diagnosis

The differential diagnosis for gastrinoma and ZES includes various conditions that can cause hypergastrinemia, gastric acid hypersecretion, or peptic ulcer disease. Chronic PPI use is a common cause of hypergastrinemia, as long-term acid suppression leads to compensatory gastrin elevation; however, the elevated gastrin level occurs without the acid hypersecretion and subsequent symptoms seen in ZES. Atrophic gastritis and autoimmune gastritis can also cause hypergastrinemia due to gastric parietal cell loss and subsequent hypochlorhydria, distinguishing these conditions from gastrinoma by a gastric pH >4.

Helicobacter pylori infection has been associated with increased gastrin levels, but the gastrin elevation is typically mild and resolves with eradication therapy. G-cell hyperplasia, a rare condition characterized by diffuse antral G-cell proliferation, can present with hypergastrinemia and acid hypersecretion but lacks a discrete tumor mass. Gastric outlet obstruction can lead to retained gastric contents and secondary hypergastrinemia. Renal failure may also impair gastrin clearance, leading to elevated serum levels.[30][31]

Staging

The staging of gastrinomas, like other neuroendocrine tumors of the pancreas or duodenum, is based on the Tumor-Node-Metastasis (TNM) grading system developed by the American Joint Committee on Cancer (AJCC) and the European Neuroendocrine Tumor Society (ENETS). This staging system considers tumor size, local invasion, lymph node involvement, and distant metastasis. Given that more than 60% of gastrinomas have metastasized at the time of diagnosis, many patients present with advanced disease (ie, stage IV).

The following criteria are utilized for TNM grading of gastrinomas:

1. Primary tumor (T):
   • T1: Tumor ≤2 cm, confined to the pancreas; tumor invades the mucosa or submucosa of the duodenum only and is ≤1 cm in greatest dimension
   • T2: Tumor >2 cm but ≤4 cm, confined to the pancreas; Tumor invades the muscularis propria of the duodenum or is >1 cm in greatest dimension
   • T3: Tumor >4 cm or invading adjacent structures (excluding major vessels); duodenal tumor invades the pancreas or peripancreatic adipose tissue
   • T4: Tumor invades adjacent organs, visceral peritoneum, or large vessels
2. Regional lymph nodes (N):
   • N0: No regional lymph node involvement
   • N1: Regional lymph node metastasis present
3. Distant metastasis (M): 
   • M0: No distant metastasis
   • M1: Distant metastasis present (commonly the liver, but may also include bones or lungs)

The following stages are based on established TNM grading criteria:

• Stage I: T1, N0, M0 (localized tumor, no lymph node or distant spread)
• Stage II: T2 or T3, N0, M0 (larger tumor, no metastasis)
• Stage III: T4, N0, M0 or Any T, N1, M0 (locally advanced or lymph node involvement)
• Stage IV: Any T, any N, M1 (presence of distant metastases) [NCCN Neuroendocrine Staging]

Prognosis

The prognosis of gastrinomas is heterogeneous and influenced by several factors, including tumor location, extent of metastasis, and the presence of MEN1. Patients with localized, surgically resectable gastrinomas generally have an excellent prognosis, with 5-year survival rates exceeding 90% when complete tumor excision is achieved. However, more than 60% of gastrinomas are malignant at diagnosis, frequently presenting with metastases to regional lymph nodes, the liver, or distant sites. In metastatic cases, 5-year survival rates drop significantly, ranging from 20% to 50%.

MEN1-associated gastrinomas typically manifest as multiple, small duodenal lesions that are often diagnosed at a later stage, resulting in a more guarded prognosis despite their usually indolent tumor biology. Although long-term survival can be achieved through effective acid suppression with high-dose PPIs and somatostatin analogs, these patients require close, ongoing surveillance. Regular biochemical monitoring (eg, serial fasting serum gastrin levels) and imaging studies are critical to detect disease progression early and guide subsequent management or imaging surveillance.[5][32]

Complications

Gastrinoma complications can be categorized by risks associated with the primary tumor, metastasis risk, and treatment risks. Gastrinomas can lead to significant complications, primarily due to excess gastrin secretion from the primary tumor causing elevated gastric acid levels, which results in severe peptic ulcer disease or, in extreme cases, intestinal bleeding or perforation. Metastatic disease can lead to organ dysfunction along with an increased risk of thromboembolic events. Treatment for gastrinoma also includes complications inherent to surgical and medical management of the disease process.[33]