Diagnostic Considerations

The poorly defined symptoms of glucagonoma sometimes make it difficult to establish a correct differential diagnosis (eg, with a pancreatic adenocarcinoma that causes weight loss, the early stages of dyspepsia, and the later stages of jaundice).

As necrolytic migratory erythema (NME) may be the only manifestation during the development of malignant glucagonomas, clinicians often misdiagnose NME as eczema, psoriasis, or contact dermatitis.^[4]

In the absence of clinical signs and symptoms of glucagonomas, other conditions associated with elevated glucagon levels include the following^[14]:

Cirrhosis
Renal failure
Pancreatitis
Diabetes mellitus
Prolonged fasting
Familial hyperglucagonemia

Differential Diagnoses

Workup

Sandhu S, Jialal I. Glucagonoma Syndrome. 2022 Jan. [QxMD MEDLINE Link]. [Full Text].
McGavran MH, Unger RH, Recant L, et al. A glucagon-secreting alpha-cell carcinoma of the pancreas. N Engl J Med. 1966 Jun 23. 274(25):1408-13. [QxMD MEDLINE Link].
Yabe D, Rokutan M, Miura Y, Komoto I, Usui R, Kuwata H, et al. Enhanced glucagon-like peptide-1 secretion in a patient with glucagonoma: implications for glucagon-like peptide-1 secretion from pancreatic a cells in vivo. Diabetes Res Clin Pract. 2013 Oct. 102(1):e1-4. [QxMD MEDLINE Link].
Gao Y, Wang C, Gao Y, Chen H, Peng B, Chen W, et al. Glucagonoma syndrome with serous oligocystic adenoma: A rare case report. Medicine (Baltimore). 2017 Oct. 96 (43):e8448. [QxMD MEDLINE Link]. [Full Text].
Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chin J Cancer. 2013 Jun. 32 (6):312-24. [QxMD MEDLINE Link]. [Full Text].
Georgiou GK, Gizas I, Katopodis KP, Katsios CS. Non-secreting benign glucagonoma diagnosed incidentally in a patient with refractory thrombocytopenic thrombotic purpura: report of a case. Surg Today. 2014 Nov 6. [QxMD MEDLINE Link].
el Darouty M, Abu el Ela M. Necrolytic migratory erythema without glucagonoma in patients with liver disease. J Am Acad Dermatol. 1996 Jun. 34(6):1092-3. [QxMD MEDLINE Link].
Nakashima H, Komine M, Sasaki K, et al. Necrolytic migratory erythema without glucagonoma in a patient with short bowel syndrome. J Dermatol. 2006 Aug. 33(8):557-62. [QxMD MEDLINE Link].
Yao JC, Eisner MP, Leary C, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007 Dec. 14(12):3492-500. [QxMD MEDLINE Link]. [Full Text].
Öberg K. Neuroendocrine gastro-enteropancreatic tumors - from eminence based to evidence-based medicine - A Scandinavian view. Scand J Gastroenterol. 2015 Jun. 50 (6):727-39. [QxMD MEDLINE Link].
Song X, Zheng S, Yang G, Xiong G, Cao Z, Feng M, et al. Glucagonoma and the glucagonoma syndrome. Oncol Lett. 2018 Mar. 15 (3):2749-2755. [QxMD MEDLINE Link]. [Full Text].
Guimarães M, Rodrigues P, Pereira SS, Nora M, Gonçalves G, Albrechtsen NW, et al. GLP1 and glucagon co-secreting pancreatic neuroendocrine tumor presenting as hypoglycemia after gastric bypass. Endocrinol Diabetes Metab Case Rep. 2015. 2015:150049. [QxMD MEDLINE Link]. [Full Text].
Fang S, Li S, Cai T. Glucagonoma syndrome: a case report with focus on skin disorders. Onco Targets Ther. 2014. 7:1449-53. [QxMD MEDLINE Link]. [Full Text].
Wewer Albrechtsen NJ, Challis BG, Damjanov I, Holst JJ. Do glucagonomas always produce glucagon?. Bosn J Basic Med Sci. 2016 Feb 1. 16 (1):1-7. [QxMD MEDLINE Link]. [Full Text].
Granberg D. Biochemical Testing in Patients with Neuroendocrine Tumors. Front Horm Res. 2015. 44:24-39. [QxMD MEDLINE Link].
Vezzosi D, Bouisson M, Escourrou G, Laurell H, Selves J, Seguin P, et al. Clinical utility of telomerase for the diagnosis of malignant well-differentiated endocrine tumours. Clin Endocrinol (Oxf). 2006 Jan. 64 (1):63-7. [QxMD MEDLINE Link].
Corrias G, Horvat N, Monti S, Basturk O, Lin O, Saba L, et al. Malignant transformation of glucagonoma with SPECT/CT In-111 OctreoScan features: A case report. Medicine (Baltimore). 2017 Dec. 96 (50):e9252. [QxMD MEDLINE Link]. [Full Text].
Xu Q, Chen WH, Huang QJ. Spiral CT localization of pancreatic functioning islet cell tumors. Hepatobiliary Pancreat Dis Int. 2004 Nov. 3(4):616-9. [QxMD MEDLINE Link].
Lv WF, Han JK, Liu X, Wang SC, Pan BO, Xu AO. Imaging features of glucagonoma syndrome: A case report and review of the literature. Oncol Lett. 2015 Apr. 9 (4):1579-1582. [QxMD MEDLINE Link]. [Full Text].
Melen-Mucha G, Lawnicka H, Kierszniewska-Stepien D, et al. The place of somatostatin analogs in the diagnosis and treatment of the neuoroendocrine glands tumors. Recent Patents Anticancer Drug Discov. 2006 Jun. 1(2):237-54. [QxMD MEDLINE Link].
Kindmark H, Sundin A, Granberg D, et al. Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years. Med Oncol. 2007. 24(3):330-7. [QxMD MEDLINE Link].
Miyagawa J, Hanafusa O, Sasada R, Yamamoto K, Igarashi K, Yamamori K, et al. Immunohistochemical localization of betacellulin, a new member of the EGF family, in normal human pancreas and islet tumor cells. Endocr J. 1999 Dec. 46 (6):755-64. [QxMD MEDLINE Link].
O'Grady HL, Conlon KC. Pancreatic neuroendocrine tumours. Eur J Surg Oncol. 2008 Mar. 34(3):324-32. [QxMD MEDLINE Link].
Pautrat K, Bretagnol F, de Muret A, et al. [Recurrent glucagonoma 20 years after surgical resection]. Gastroenterol Clin Biol. 2003 Dec. 27(12):1163-5. [QxMD MEDLINE Link].
Akerstrom G, Hellman P, Hessman O, et al. Surgical treatment of endocrine pancreatic tumours. Neuroendocrinology. 2004. 80 Suppl 1:62-6. [QxMD MEDLINE Link].
Sansovini M, Severi S, Ianniello A, Nicolini S, Fantini L, Mezzenga E, et al. Long-term follow-up and role of FDG PET in advanced pancreatic neuroendocrine patients treated with ¹⁷⁷Lu-D OTATATE. Eur J Nucl Med Mol Imaging. 2017 Mar. 44 (3):490-499. [QxMD MEDLINE Link].
Moattari AR, Cho K, Vinik AI. Somatostatin analogue in treatment of coexisting glucagonoma and pancreatic pseudocyst: dissociation of responses. Surgery. 1990 Sep. 108(3):581-7. [QxMD MEDLINE Link].
Tomassetti P, Migliori M, Corinaldesi R, et al. Treatment of gastroenteropancreatic neuroendocrine tumours with octreotide LAR. Aliment Pharmacol Ther. 2000 May. 14(5):557-60. [QxMD MEDLINE Link].
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10. 364(6):514-23. [QxMD MEDLINE Link].
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10. 364(6):501-13. [QxMD MEDLINE Link].
Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlácková E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17. 371(3):224-33. [QxMD MEDLINE Link]. [Full Text].
Montenegro F, Lawrence GD, Macon W, et al. Metastatic glucagonoma. Improvement after surgical debulking. Am J Surg. 1980 Mar. 139(3):424-7. [QxMD MEDLINE Link].
Fernandez-Cruz L, Blanco L, Cosa R, Rendon H. Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors?. World J Surg. 2008 May. 32(5):904-17. [QxMD MEDLINE Link].
Wong KP, Tsang JS, Lang BH. Role of surgery in pancreatic neuroendocrine tumor. Gland Surg. 2018 Feb. 7 (1):36-41. [QxMD MEDLINE Link]. [Full Text].
Bruballa R, Fratantoni ME, Ardiles V, Mazza O. Laparoscopic Enucleation of Pancreatic Neoplasms: A Single-Center Experience and Outcomes. J Laparoendosc Adv Surg Tech A. 2022 Oct. 32 (10):1032-1037. [QxMD MEDLINE Link].
[Guideline] Howe JR, Merchant NB, Conrad C, Keutgen XM, Hallet J, Drebin JA, et al. The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors. Pancreas. 2020 Jan. 49 (1):1-33. [QxMD MEDLINE Link]. [Full Text].
Liu X, Pausch T, Probst P, Cui J, Wei J, Hackert T, et al. Efficacy of Pasireotide for Prevention of Postoperative Pancreatic Fistula in Pancreatic Surgery: a Systematic Review and Meta-analysis. J Gastrointest Surg. 2020 Jun. 24 (6):1421-1429. [QxMD MEDLINE Link].
[Guideline] Halfdanarson TR, Strosberg JR, Tang L, Bellizzi AM, Bergsland EK, O'Dorisio TM, et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors. Pancreas. 2020 Aug. 49 (7):863-881. [QxMD MEDLINE Link]. [Full Text].
Singh S, Moody L, Chan D, et al. Follow-up Recommendations for Completely Resected Gastroenteropancreatic Neuroendocrine Tumors. JAMA Oncol. 2018 Jul 26. 4:1597-1604. [QxMD MEDLINE Link]. [Full Text].
Clouse ME, Perry L, Stuart K, et al. Hepatic arterial chemoembolization for metastatic neuroendocrine tumors. Digestion. 1994. 55 Suppl 3:92-7. [QxMD MEDLINE Link].
King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. 2008 Sep 1. 113(5):921-9. [QxMD MEDLINE Link].
Radny P, Eigentler TK, Soennichsen K, et al. Metastatic glucagonoma: treatment with liver transplantation. J Am Acad Dermatol. 2006 Feb. 54(2):344-7. [QxMD MEDLINE Link].
[Guideline] National Comprehensive Cancer Network. NCCN Guidelines: Neuroendocrine and Adrenal Tumors. Available at https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Version 1.2022 — May 23, 2022; Accessed: October 22, 2022.

Media Gallery

A section of a glucagonoma mass with several fiber bundles and solid cellular strands (125 X). Courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
A section of a glucagonoma mass with irregular aspects of fiber bundles and cellular strands (400 X). Courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
Bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors: Part 1. Courtesy of Memorial Sloan-Kettering Cancer Center.
Bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors: Part 2. Courtesy of Memorial Sloan-Kettering Cancer Center.
Postprocedure computed tompgraphy scans after bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors. Courtesy of Memorial Sloan-Kettering Cancer Center.
Necrolytic migratory erythema over the back with areas of healing and hyperpigmentation. Courtesy of Case Reports in Surgery (https://www.hindawi.com/journals/cris/2016/1484089/).
Necrolytic migratory erythema. Courtesy of Rare Tumors (SAGE Publications Ltd) (http://www.pagepress.org/journals/index.php/rt/article/view/rt.2009.e6/1169).

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Author

Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT Associate Professor of Medicine, Program Director, Endocrinology, Diabetes and Metabolism Fellowship Program, Director for Diversity in Graduate Medical Education, University of Arizona College of Medicine-Phoenix; Assistant Professor of Medicine, Mayo College of Medicine, Mayo Clinic Arizona; Staff Endocrinologist, Phoenix Veterans Hospital (VAMC)

Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT is a member of the following medical societies: Academy of Physicians in Clinical Research, American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Healthcare Trustees, American College of Physicians, American Medical Association, American Thyroid Association, Association of Program Directors in Endocrinology, Endocrine Society, National Hispanic Medical Association, World Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Fabian Andres Wayar Ocampo, MD Primary and Urgent Care, Private Practice, Curare Centro Medico, Bolivia

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for Physician Leadership, American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society, International Society for Clinical Densitometry, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Frederick H Ziel, MD Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Luigi Santacroce, MD Assistant Professor, Medical School, State University at Bari, Italy

Disclosure: Nothing to disclose.

Mini R Abraham, MD Consultant, Blue Valley Endocrinology, PA

Mini R Abraham, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society

Disclosure: Nothing to disclose.

Laura Diomede University of Bari School of Medicine, Italy

Disclosure: Nothing to disclose.