Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies

Abstract

Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to gastroesophageal reflux disease, recurrent peptic ulcers, and chronic diarrhea. As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders, the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years. The critical step for the diagnosis of ZES is represented by the initial clinical suspicion. Hypergastrinemia is the hallmark of ZES; however, hypergastrinemia might recognize several causes, which should be ruled out in order to make a final diagnosis. Gastrin levels > 1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma; some specific tests, including esophageal pH-recording and secretin test, might be useful in selected cases, although they are not widely available. Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES, particularly in the setting of multiple endocrine neoplasia type 1. Some controversies about the management of these tumors also exist. For the localized stage, the combination of proton pump inhibitory therapy, which usually resolves symptoms, and surgery, whenever feasible, with curative intent represents the hallmark of gastrinoma treatment. The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure. Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms, and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series. The multidisciplinary approach remains the cornerstone for the proper management of this composite disease. Herein, we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis, providing potential diagnostic and therapeutic algorithms.

Keywords: Diagnosis; Duodenal neuroendocrine neoplasm; Gastrinoma; Neuroendocrine neoplasms; Pancreatic neuroendocrine neoplasm; Therapy; Zollinger-Ellison syndrome.

Figure 1

A suggested diagnostic algorithm is depicted. GERD: Gastroesophageal reflux disease; H. pylori: Helicobacter pylori; MEN-1: Multiple endocrine neoplasia type 1; PPIs: Proton pump inhibitors; ULN: Upper limit of normal; ZES: Zollinger Ellison syndrome.

Figure 2

A proposed therapeutic algorithm is represented based on both evidence from literature and personal own experience. ¹Allocation driving prognostic factors are performance status, age, metastatic disease burden and pattern, comorbidities. CT: Computed tomography; dNEN: Duodenal neuroendocrine neoplasm; EUS: Endoscopic ultrasound; H2: Histamine receptor 2: LT: Orthotopic liver transplantation; MEN-1: Multiple endocrine neoplasia type 1; MRI: Magnetic resonance imaging; PET: Positron emission tomography; pNEN: Pancreatic NEN; PPIs: Proton pump inhibitors; PRRT: Peptide-radioreceptor therapy; SSAs: Somatostatin analogs; TACE: Transarterial chemoembolization; TARE: Transarterial radioembolization; ZES: Zollinger Ellison syndrome.