Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2021; 27(35): 5890-5907
Published online Sep 21, 2021. doi: 10.3748/wjg.v27.i35.5890
Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies
Roberta Elisa Rossi, Alessandra Elvevi, Davide Citterio, Jorgelina Coppa, Pietro Invernizzi, Vincenzo Mazzaferro, Sara Massironi
Roberta Elisa Rossi, Davide Citterio, Jorgelina Coppa, Vincenzo Mazzaferro, HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
Roberta Elisa Rossi, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
Alessandra Elvevi, Pietro Invernizzi, Sara Massironi, Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
Alessandra Elvevi, Pietro Invernizzi, Sara Massironi, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza 20033, Italy
Vincenzo Mazzaferro, Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy
Author contributions: Rossi RE designed the research; Rossi RE, Elvevi A, Citterio D, and Massironi S performed the literature search and wrote the first draft of the paper; Rossi RE, Massironi S, Coppa J, Invernizzi P, and Mazzaferro V revised the manuscript for important intellectual content; Rossi RE and Massironi S wrote the final version of the paper; All of the authors approved the final version for publication.
Conflict-of-interest statement: The authors declare no conflict of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Roberta Elisa Rossi, MD, PhD, HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), via Giacomo Venezian, Milan 20133, Italy.
Received: March 15, 2021
Peer-review started: March 15, 2021
First decision: April 17, 2021
Revised: April 29, 2021
Accepted: August 10, 2021
Article in press: August 10, 2021
Published online: September 21, 2021

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: Gastrinoma, Zollinger-Ellison syndrome, Neuroendocrine neoplasms, Pancreatic neuroendocrine neoplasm, Duodenal neuroendocrine neoplasm, Diagnosis, Therapy

Core Tip: As symptoms of Zollinger-Ellison syndrome are nonspecific and overlap with other gastrointestinal disorders, most of these patients are usually referred to general gastroenterologists, leading to a diagnostic delay. A better disease awareness together with the maintenance of a high index of suspicion are necessary to make the final diagnosis. The proper management of Zollinger-Ellison syndrome due to a gastrinoma include both the medical treatment for symptom’s relief and surgery whenever feasible with curative intent; the multidisciplinary approach, with close cooperation between gastroenterologists and surgeons, and the referral to tertiary centers with great expertise in the neuroendocrine field are mandatory.