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ESSENTIALS OF DIAGNOSIS

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ESSENTIALS OF DIAGNOSIS

  • Peptic ulcer disease, abdominal pain, and diarrhea are common presentations.

  • Patients have marked gastric acid secretion arising from a gastrin-secreting non–β islet cell tumor.

  • Multiple endocrine neoplasia syndrome type 1 (MEN 1) is present in approximately 20–25% of patients.

  • Serum gastrin concentration >1000 pg/mL in combination with acidic stomach pH <2.0 is diagnostic.

  • Up to 40% of patients have elevated serum gastrin levels that are <500 pg/mL and warrant a secretin test.

  • Significant hypergastrinemia can occur with proton pump inhibitor (PPI) use, Helicobacter pylori infection, or chronic atrophic gastritis and hypochlorhydria.

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GENERAL CONSIDERATIONS

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Zollinger-Ellison syndrome (ZES) is characterized by peptic ulcers, diarrhea, and marked gastric acid hypersecretion in association with a gastrin-secreting non–β islet cell endocrine tumor (gastrinoma). The reported incidence of gastrinomas ranges from 0.1 to 3 cases per million of the population per year. ZES is a rare cause of peptic ulcer disease and accounts for only 0.1–1% of ulcers. The mean age of onset of symptoms is 41 years, and slightly more males than females are affected, with a ratio of about 3:2. The diagnosis of ZES is typically delayed by at least 6–9 years. Although the majority of gastrinomas develop as a sporadic tumor, approximately 20–25% of ZES patients have gastrinomas as part of the inherited MEN 1. MEN 1 is an autosomal-dominant inherited syndrome characterized by pancreatic neuroendocrine tumors, pituitary tumors, and hyperparathyroidism, and is caused by mutations of the MEN 1 tumor suppressor gene on chromosome 11q13.

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PATHOGENESIS

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Patients with ZES most often present with symptoms arising from excessive gastric acid secretion. The unregulated gastrin production from the gastrinoma binds to CCK-2 receptors located on enterochromaffin-like (ECL) cells causing the release of histamine. Histamine then binds to H2 receptors on parietal cells to stimulate the release of acid. In addition, gastrin also has trophic effects on gastric epithelial and ECL cells. Chronic hypergastrinemia increases parietal cell mass, which further augments acid hypersecretion. The enteroendocrine cells that make up the gastrinoma are well differentiated and round, with small nuclei and prominent nucleolus. They often contain neuroendocrine tumor markers, including chromogranin A, neurospecific enolase, and synaptophysin.

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CLASSIFICATION

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Gastrinomas are derived from the enteroendocrine cells that arise from the embryologic endoderm. Due to their origin, gastrinomas are considered to be neuroendocrine tumors (NETs). The World Health Organization further classifies NETs in different sites into poorly differentiated or well-differentiated endocrine tumors or carcinomas. Well-differentiated tumors are further divided into classes with different behavior depending on size, functionality, location, invasiveness, and proliferative indices. Accurate classification not only provides prognostic implications but also affects treatment. Most gastrinomas are well-differentiated pancreatic neuroendocrine tumors (pNETs) grade 1.

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Epelboym  I, Mazeh  H. Zollinger-Ellison syndrome: classical considerations and current controversies. Oncologist. 2014;19:44–50.
[PubMed: 24319020]  
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Ito  T, Igarashi  H, Jensen  RT. Zollinger-Ellison syndrome: recent advances and controversies. Curr Opin Gastroenterol. 2013;29:650–661. ...

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