Zollinger-Ellison Syndrome: An Overview
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N\AAbstract
Zollinger-Ellison syndrome is characterized by severe manifestations, including abdominal pain associated with duodenal peptic ulcer disease, gastroesophageal reflux disease, diarrhea, and weight loss. The underlying cause of the disease is a gastrin-producing tumor, which increases gastric acid secretion. The use of proton pump inhibitors may alleviate symptoms but complicate the accurate diagnosis of the condition. As a result, the average diagnostic delay for Zollinger-Ellison syndrome is several years. By the time the correct diagnosis is established, many patients have advanced gastrinoma with metastases to the liver and lymph nodes. Treatment at this stage is challenging and involves various surgical and therapeutic approaches. The aim of this study is to review current methods for diagnosing and treating patients with Zollinger-Ellison syndrome.
Methods: A search of publications in the databases PubMed, CYBERLININKA, and Google Scholar was conducted.
Results: Advancements in surgical and conservative treatment strategies, as well as the introduction of new techniques such as vascular embolization, radiopharmaceutical therapy, and chemotherapy, have improved cure rates, increased overall survival, and prolonged recurrence-free survival in patients with Zollinger-Ellison syndrome.
Conclusions: 1) Since Zollinger-Ellison syndrome is based on gastrin hypersecretion by a tumor, essential diagnostic steps should include serum gastrin measurement, gastric juice pH analysis, and tumor localization.
2) Studies on the immunohistological characteristics of gastrinomas have led to the development of diagnostic and therapeutic methods based on somatostatin analogs.
3) Surgical treatment of sporadic gastrinomas in Zollinger-Ellison syndrome has a high success rate. However, in advanced cases with metastases, surgical intervention is supplemented by vascular embolization, chemotherapy, and radiopharmaceutical therapy.
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Zollinger R.M., Ellison E.H. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Annals of Surgery. 1955 April;142(4):709-723. PMID: 13259432.
Klimko A., Plotogea O., Constantinescu A., Constantinescu G. Delayed Management of Zollinger-Ellison Syndrome in a Noncompliant Patient. Cureus. 2020 Jun 6;12(6):e8471. doi: 10.7759/cureus.8471.
Cho M.S., Kasi A. Zollinger-Ellison Syndrome. 2022 Nov 21. In: StatPearls [Internet]. [cited 2025 January 10] Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 30726029. Available from: https://pubmed.ncbi.nlm.nih.gov/30726029/.
Shao Q.Q., Zhao B.B., Dong L.B., Cao H.T., Wang W.B. Surgical management of Zollinger-Ellison syndrome: classical considerations and current controversies. World J Gastroenterol. 2019;25:4673–4681. doi: 10.3748/wjg.v25.i32.4673.
Lorenzo M.V., Agel F.M. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome. Rev Esp Enferm Dig. 2024 Jul;116(7):390. doi: 10.17235/reed.2023.9815/2023.
Falconi M., Eriksson B., Kaltsas G., Bartsch D.K., Capdevila J., Caplin M., Kos-Kudla B., Kwekkeboom D., Rindi G., Klöppel G., Reed N., Kianmanesh R., Jensen R.T. ENETS Consensus Guidelines Update for the Management of Patient with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology. 2016 Jan;103(2):153-71. doi: 10.1159/000443171.
Norton J.A., Foster D.S., Ito T., Jensen R.T. Gastrinomas: Medical or Surgical Treatment. Endocrinol Metab Clin North Am. 2018 Sep;47(3):577-601. doi: 10.1016/j.ecl.2018.04.009.
Rossi R.E., Elvevi A., Citterio D., Coppa J., Invernizzi P., Mazzaferro V., Massironi S. Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies. World J Gastroenterol. 2021 Sep 21;27(35):5890-5907. doi: 10.3748/wjg.v27.i35.5890.
Maev I.V., Andreev D.N., Kucheryavy`j Yu.A., Dicheva D.T. Zollinger-Ellison syndrome: modern aspects of diagnostics and treatment. Rossijskij zhurnal gastroe`nterologii, gepatologii, koloproktologii. 2014;24(4):57-69. (In Russ.).
Osadchuk M.A., Osadchuk A.M., Sibryaev A.A. H.pylori-negative peptic ulcer disease: current state of the problem. Rossijskij zhurnal gastroe`nterologii, gepatologii, koloproktologii. 2014;24(1):4-9. (In Russ.).
Metz D.C., Cadiot G., Poitras P., Ito T., Jensen R.T. Diagnosis of Zollonger-Ellison syndrome in the era of PPIs, faulty gastrin assays, sensitive imaging and limited access to acid secretory testing. Int J Endocr Oncol. 2017 Oct;4(4):167-185. doi: 10.2217/ije-2017-0018.
Chatzipanagiotou O., Schizas D., Vailas M., Tsoli M., Sakarellos P., Sotiropoulou M., Papalambros A., Felekouras E. All you need to know about gastrinoma today | Gastrinoma and Zollinger-Ellison syndrome: A thorough update. J Neuroendocrinol. 2023 Apr;35(4):e13267. doi: 10.1111/jne.13267.
Giusti F., Cioppi F., Fossi C., Marini F., Masi L., Tonelli F., Brandi M.L. Secretin Stimulation Test and Early Diagnosis of Gastrinoma in MEN1 Syndrome: Survey on the MEN1 Florentine Database. J Clin Endocrinol Metab. 2022 Apr 19;107(5):e2110-e2123. doi: 10.1210/clinem/dgab903.
Bhattacharya S., Blau J.E., Cochran C., Auh S., Weinstein L.S., Jensen R.T., Wank S. Validity of Secretin Stimulation Testing on Proton Pump Inhibitor Therapy for Diagnosis of Zollinger-Ellison Syndrome. Am J Gastroenterol. 2021 Nov 1;116(11):2216-2221. doi: 10.14309/ajg.0000000000001487.
Gkolfinopoulos S., Tsapakidis K., Papadimitriou K., Papamichael D., Kountourakis P. Chromogranin A as a valid marker in oncology: Clinical application or false hopes? World J Methodol. 2017 Mar 26;7(1):9-15. doi: 10.5662/wjm.v7.i1.9.
Adamová Z., Chrostek M., Dvořák T., Rada E. Duodenal gastrinoma - case report. Rozhl Chir. 2023;102(12):464-469. doi: 10.33699/PIS.2023.102.12.464-469.
Declich P., Belloni J., Tavani E., Omazzi B., Bellone S., Bortoli A., Arena I., Devani M. The morphological and immunohistochemical spectrum of gastric biopsies of patients with absorptive hypercalciuria. BMJ Open Gastroenterol. 2015 Feb 6;1(1):e000004. doi: 10.1136/bmjgast-2014-000004.
Manoharan J., Anlauf M., Albers M.B., Denzer U.W., Mintziras I., Wächter S., Di Fazio P., Bollmann C., Bartsch D.K. Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf). 2021 Sep;95(3):439-446. doi: 10.1111/cen.14430.
Rehfeld J.F. The cckOMA syndrome and its relation to the Zollinger-Ellison syndrome: a diagnostic challenge. Scand J Gastroenterol. 2024 May;59(5):533-542. doi: 10.1080/00365521.2024.2308532.
Alshikho M.J., Noureldine S.I., Talas J.M., Nasimian A., Zazou S., Mobaed B., Nasser M. Zollinger-Ellison Syndrome Associated with von Recklinghausen Disease: Case Report and Literature Review. Am J Case Rep. 2016 Jun 13;17:398-405. doi: 10.12659/ajcr.898472.
Rafieian S., Vahedi M., Jahanbin B., Ghasemloee A. Primary thoracic gastrinoma causing Zollinger-Ellison syndrome. Indian J Thorac Cardiovasc Surg. 2021 Nov;37(6):706-709. doi: 10.1007/s12055-021-01211-3.
Roseland M.E., Francis I.R., Shampain K.L., Stein E.B., Wasnik A.P., Millet J.D. Gastric neuroendocrine neoplasms: a primer for radiologists. Abdom Radiol (NY). 2022 Dec;47(12):3993-4004. doi: 10.1007/s00261-022-03509-1.
Giusti F., Marini F., Brandi M.L. Multiple Endocrine Neoplasia Type 1. 2005 Aug 31 [updated 2022 Mar 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. (link active January 10 2025) Available at: https://www.ncbi.nlm.nih.gov/books/NBK1538/.
Ogawa S., Wada M., Fukushima M., Shimeno N., Inoue S., Chung H., Fujita M., Suginoshita Y., Okada A., Inokuma T., Yagi S., Ito K., Imai Y. Case of primary hepatic gastrinoma: Diagnostic usefulness of the selective arterial calcium injection test. Hepatol Res. 2015 Jul;45(7):823-6. doi: 10.1111/hepr.12404.
Shajmardanov R.Sh., Gubaev R.F., Gafurov K.D., Nuriev I.I., Bagautdinov E`.B., Sharafiev S.Z., Kurbanov R.R. Diagnosis and treatment of Zollinger-Ellison syndrome. Vestnik sovremennoj klinicheskoj mediciny`. 2018;11(5):177-180. doi: 10.20969/VSKM.2018.11(5).177-180. (In Russ.).
Mendelson A.H., Donowitz M. Catching the Zebra: Clinical Pearls and Pitfalls for the Successful Diagnosis of Zollinger-Ellison Syndrome. Dig Dis Sci. 2017 Sep;62(9):2258-2265. doi: 10.1007/s10620-017-4695-7.
Maev I.V., Andreev D.N., Kucheryavy`j Yu.A., Barkalova E.V. Evolution of clinical concepts of Zollinger-Ellison syndrome. Terapevticheskij arxiv. 2014;2:82-89. (In Russ.).
Anderson M.A., Carpenter S., Thompson N.W., Nostrant T.T., Elta G.H., Scheiman J.M. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol. 2000 Sep;95(9):2271-7. doi: 10.1111/j.1572-0241.2000.02480.x.
Trudgill N.J., Sifrim D., Sweis R., Fullard M., Basu K., McCord M., Booth M., Hayman J., Boeckxstaens G., Johnston B.T., Ager N., De Caestecker J. British Society of Gastroenterology guidelines for oesophageal manometry and oesophageal reflux monitoring. Gut. 2019;68:1731–1750. doi: 10.1136/gutjnl-2018-318115.
Norton J.A., Fraker D.L., Alexander H.R., Jensen R.T. Value of surgery in patients with negative imaging and sporadic Zollinger-Ellison syndrome. Ann Surg. 2012;256:509–517. doi: 10.1097/SLA.0b013e318265f08d.
Giovinazzo F., Butturini G., Monsellato D., Malleo G., Marchegiani G., Bassi C. Lymph nodes metastasis and recurrences justify an aggressive treatment of gastrinoma. Updates Surg. 2013;65:19–24. doi: 10.1007/s13304-013-0201-8.
Bartsch D.K., Waldmann J., Fendrich V., Boninsegna L., Lopez C.L., Partelli S., Falconi M. Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma. Br J Surg. 2012;99:1234–1240. doi: 10.1002/bjs.8843.
Pavel M., Öberg K., Falconi M., Krenning E.P., Sundin A., Perren A., Berruti A. ESMO Guidelines Committee. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31:844–860. doi: 10.1016/j.annonc.2020.03.304.
Machado M.C. Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. Clinics (Sao Paulo). 2012;67 Suppl 1(Suppl 1):145-8. doi: 10.6061/clinics/2012(sup01)24.
Jilesen A.P., Klümpen H.J., Busch O.R., van Gulik T.M., van Lienden K.P., Gouma D.J., Nieveen van Dijkum E.J. Selective Arterial Embolization of Liver Metastases from Gastrinomas: A Single-Centre Experience. ISRN Hepatol. 2013 Jul 29;2013:174608. doi: 10.1155/2013/174608.
Hanzawa S., Sadamori H., Kagoura M., Monden K., Hioki M., Hyodo T., Omonishi K., Takakura N. Primary hepatic gastrinoma being diagnosed preoperatively: a case report and literature review. Surg Case Rep. 2020 Nov 18;6(1):290. doi: 10.1186/s40792-020-01072-9.
Lee L., Ramos-Alvarez I., Ito T., Jensen R.T. Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome. Int J Mol Sci. 2019 Oct 16;20(20):5128. doi: 10.3390/ijms20205128.
Verdugo M.A.C., Soto R.M.R., Salgado D.L.N., Medrano M.E.B., León W.A. Clinical and Surgical Management of Zollinger-Ellison Syndrome: A Literature Review. International Journal of Medical Science and Clinical Research Studies. 2022;2(12):1508–1511. https://doi.org/10.47191/ijmscrs/v2-i12-27.
Ito T., Ramos-Alvarez I., Jensen R.T. Long-Term Proton Pump Inhibitor-Acid Suppressive Treatment Can Cause Vitamin B(12) Deficiency in Zollinger-Ellison Syndrome (ZES) Patients. Int J Mol Sci. 2024 Jul 2;25(13):7286. doi: 10.3390/ijms25137286.
Aamar A., Madhani K., Virk H., Butt Z. Zollinger-Ellison Syndrome: A Rare Case of Chronic Diarrhea. Gastroenterology Res. 2016 Dec;9(6):103-104. doi: 10.14740/gr734w.
Ito T., Igarashi H., Uehara H., Jensen R.T. Pharmacotherapy of Zollinger-Ellison syndrome. Expert Opin Pharmacother. 2013 Feb;14(3):307-21. doi: 10.1517/14656566.2013.767332.
Raymond E., Dahan L., Raoul J.L., Bang Y.J., Borbath I., Lombard-Bohas C., Valle J., Metrakos P., Smith D., Vinik A., Chen J.S., Hörsch D., Hammel P., Wiedenmann B., Van Cutsem E., Patyna S., Lu D.R., Blanckmeister C., Chao R., Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–513. doi: 10.1056/NEJMoa1003825.
Yao J.C., Shah M.H., Ito T., Bohas C.L., Wolin E.M., Van Cutsem E., Hobday T.J., Okusaka T., Capdevila J., de Vries E.G., Tomassetti P., Pavel M.E., Hoosen S., Haas T., Lincy J., Lebwohl D., Öberg K. RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523. doi: 10.1056/NEJMoa1009290.
Prakash L., Bhosale P., Cloyd J., Kim M., Parker N., Yao J., Dasari A., Halperin D., Aloia T., Lee J.E., Vauthey J.N., Fleming J.B., Katz M.H. Role of Fluorouracil, Doxorubicin, and Streptozocin Therapy in the Preoperative Treatment of Localized Pancreatic Neuroendocrine Tumors. J Gastrointest Surg. 2017;21:155–163. doi: 10.1007/s11605-016-3270-4.
Cives M., Ghayouri M., Morse B., Brelsford M., Black M., Rizzo A., Meeker A., Strosberg J. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016;23:759–767. doi: 10.1530/ERC-16-0147.
Kunz P.L., Catalano P.J., Nimeiri H., Fisher G.A., Longacre T.A., Suarez C.J., Yao J.C., Kulke M.H., Hendifar A.E., Shanks J.C., Shah M.H., Zalupski M., Schmulbach E.L., Reidy D.L., Strosberg J.R., O’Dwyer P.J., Benson A.B. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211) J Clin Oncol. 2018;36:4004–4004. doi: 10.1200/JCO.22.01013.
Bongiovanni A., Liverani C., Foca F., Fausti V., Di Menna G., Mercatali L., De Vita A., Riva N., Calpona S., Miserocchi G., Spadazzi C., Cocchi C., Ibrahim T. Temozolomide Alone or Combined with Capecitabine for the Treatment of Metastatic Neuroendocrine Neoplasia: a "Real World" data analysis. Neuroendocrinology. 2020 doi: 10.1159/000513218.
Jadhav A., Ayyat M., Serafini F.M. Presentation, Diagnosis, and Treatment of a Sporadic Gastrinoma With Liver Metastases. Cureus. 2024 May 31;16(5):e61426. doi: 10.7759/cureus.61426.
Van Adrichem R.C., Kamp K., Van Deurzen, C.H. Is there an additional value of using somatostatin receptor subtype 2a immunohistochemistry compared to somatostatin receptor scintigraphy uptake in predicting gastroenteropancreatic neuroendocrine tumor response? Neuroendocrinology. 2016; 103:560-566. doi: 10.1159/000441604.
Strosberg J., El-Haddad G., Wolin E., Hendifar A., Yao J., Chasen B. et al. Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376:125-135. doi: 10.1056/NEJMoa1607427.
Brabander T., Van der Zwan W.A., Teunissen, J.J.M., Kam B.L.R., Feelders R.A., de Herder W.W., et al. Long-term efficacy, survival, and safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017; 23:4617-4624. doi: 10.1158/1078-0432.CCR-16-2743.
Thang S.P., Lung M.S., Kong, G., Hofman M.S., Callahan J., Michael M., et al. Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis. Eur J Nucl Med Mol Imaging. 2018; 45:262-277. doi: 10.1007/s00259-017-3821-2.
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