Gastrinoma - Classification, Symptoms, Causes and, Treatment

Introduction: Gastrinomas are tumors of neuroendocrine origin, which means they arise from cells with traits similar to both nerve cells and hormone-producing cells. Gastrinomas are slow-growing tumors, but in approximately 60 % of cases, they metastasize and become malignant at diagnosis. There is excessive secretion of gastrin (a hormone that stimulates the secretion of HCL by the parietal cells of the stomach), leading to diarrhea and severe peptic ulcer diseases. Zollinger-Ellison syndrome is when one or more gastrinomas form in the duodenum (upper part of the small intestine) or pancreas and produce an excess of acid.

What Are the Causes of Gastrinomas?

Gastrinomas originate from endodermal pluripotent cells. They can be of two types:

• Irregular and haphazard in 75 % to 80 % of cases.

• Associated with multiple endocrine neoplasia type-1 (MEN-1). It is a hereditary disorder associated with endocrine gland tumors. It occurs due to mutation in the tumor suppressor MEN-1 gene on chromosome 11q13.

In Which Parts of the Body Gastrinoma Can Occur?

1. About 80 % to 90 % of cases arise in the ‘gastrinoma triangle.’ It is an anatomical area in the abdomen with the following boundaries:

• Superior: The collaboration of cystic ducts and common bile ducts.
• Inferior: Portions of the duodenum.
• Medial: The neck of the pancreas.

2. Gastrinoma can rarely occur in peripancreatic lymph nodes, liver, stomach, bile ducts, ovary, and lungs.

3. Duodenal gastrinomas occur predominantly in the first part of the duodenum and are approximately 50 % to 80 % associated with sporadic ZES (Zollinger-Ellison syndrome) and almost 70 % to 100 % linked with MEN-1 (multiple endocrine neoplasias). The size of gastrinoma is less than 1 cm.

4. Pancreatic gastrinomas can occur in any portion of the pancreas. These tumors are larger than duodenum gastrinomas and comprise approximately 25 % of tumors.

How Does Gastrinoma Damage Different Cells and Organs?

• The gastrinoma malignant cells stimulate secretion of gastrin which causes hyperplasia of fundic parietal cells and eventually increases gastric acid secretion.

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• HCL (gastric acid) secretion ruptures the mucosal defenses of the gastric and duodenal wall, causing ulcerations. It also causes malabsorption of fat and diarrhea due to the inactivation of pancreatic digestive enzymes.

• The diarrhea is caused due to inhibition in the absorption of sodium and water by the small intestine.

How Do Gastrinoma Cells Appear?

• Matured neuroendocrine tumor cells show an organoid arrangement with trabecular, pyriform, or nesting patterns. The tumor cells are round with regular nuclei and produce large amounts of secretory granules with diffused immunoexpression of neuroendocrine markers.

• Immature and poorly differentiated NET (neuroendocrine tumors) have sheet-like, irregular, and diffused nuclei with limited biomarkers immunoexpression.

What Is the WHO Classification of Gastrinomas?

The WHO (World Health Organization) classified (in 2010) neuroendocrine tumors, including gastrinomas, into three grades depending on the mitotic rate:

• Low-grade, well-differentiated tumors with uncertain nature at the time of diagnosis. It can be benign with a mitotic rate of less than 2.

• Well-differentiated carcinoma with low-level malignant behavior with a mitotic rate of 2 to 20.

• High-grade, poorly differentiated endocrine tumors with high-grade malignant nature with a mitotic rate of more than 20.

What Are the Symptoms of Gastrinomas?

The most common symptoms are chronic (from a long duration) diarrhea and abdominal pain.

• Dyspepsia: Pain or discomfort in the upper abdomen, often after eating or drinking.

• Gastrointestinal Bleeding: Bleeding from the gastrointestinal tract lining due to ulcerations.

• Gastroesophageal Reflux: Excessive gastric acid in the stomach can lead to acid reflexes.

• Weight Loss: Due to chronic diarrhea and altered digestion.

How to Diagnose Gastrinoma?

• Serum Gastrin Concentration: Elevated fasting serum gastrin concentration is associated with increased gastric secretion leading to low pH.

• Chromogranin A: It is an immunostaining biomarker used to diagnose neuroendocrine tumors. It should be measured during fasting, and any kind of heavy physical activity or exercise should be avoided before testing.

• Computed tomography (CT) scan, magnetic resonance imaging (MRI), somatostatin receptor scintigraphy with SPECT/CT, and gallium-somatostatin analogs PET-CT imaging are non-invasive imaging procedures that can help localize the tumor and evaluate the metastatic spread.

• In some cases, tumors can only be localized by laparotomy and direct palpation by the surgeon or intraoperative ultrasound.

• All cases with ZES (Zollinger- Ellison syndrome) will require proper family history and biochemical assessment such as parathyroid hormone levels, prolactin, and serum calcium levels.

What Is the Treatment of Gastrinoma?

• The medical approach is only helpful in preventing complications and treating the symptoms of peptic ulcer disease. The use of proton pump inhibitors at high doses is preferred as it has a higher potency than H2 receptors and a prolonged duration of action.

• Surgery is the treatment of choice for gastrinomas. All cases of sporadic gastrinoma without metastasis are suggested for surgery.

• However, cases of MEN-1 (multiple endocrine neoplasia-1) associated with ZES (Zollinger- Ellison syndrome) are referred to as medical therapy due to the multiplicity and metastasis nature of the tumor and a low chance of surgical cure. Surgical resection is recommended only for cases of MEN-1 with gastrinoma more than 2 cm in size.

• Chemotherapy is an option in cases of metastasis. The first-line treatment is a combined therapy with 5-Fluorouracil or Doxorubicin and Streptozotocin. These drugs show some limited results in some cases but are toxic in nature.

• Octreotide and Lanreotide are some human somatostatin analogs that can decrease gastric acid secretion but do not show any effect on tumors.

• In cases of pancreatic neuroendocrine tumors, therapies like multi-kinase, mTOR inhibitor, and antiangiogenic strategies can specifically inhibit growth factor receptors. These are new approaches showing some clinical benefits in trials.

• Other treatment procedures can be hepatic artery embolization in cases of liver metastasis.

Which Conditions Are Similar to Gastrinoma?

• Gastric Outlet Obstruction: It is a syndrome characterized by postprandial vomiting and abdominal pain in the epigastric region due to mechanical obstruction.

• Atrophic Gastritis: Chronic inflammation of gastric mucosa with replacement of gastric glandular cells with fibrous tissue and intestinal-type epithelium.

• Peptic Ulcer Diseases: Open sores on the inner lining of the stomach and duodenum.

Conclusion:

Gastrinoma is a neuroendocrine tumor that can become malignant if not diagnosed on time. It affects the absorption of water and sodium ions leading to chronic diarrhea (one of the common symptoms). Other signs can be gastrointestinal bleeding and abdominal pain. If the tumor shows metastasis, it can affect adjacent organs like the pancreas, liver, or intestines and cause more complications. The treatment of choice for the tumor is surgery, and however medical therapy can help to control the symptoms.