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Glucagonoma

  • Author: Luigi Santacroce, MD; Chief Editor: George T Griffing, MD  more...
 
Updated: May 14, 2015
 

Background

A glucagonoma is a rare neuroendocrine tumor with nearly exclusive pancreatic localization. Malignant glucagonomas are islet cell pancreatic tumors that are discovered because of glucagonoma syndrome (in which the glucagonoma autonomously secretes glucagon), because of local mass effects, or incidentally. Glucagonomas originate from the alpha-2 cells of the pancreas.

In 1942, Becker and colleagues first described glucagonomas. Fewer than 250 cases of glucagonomas have been described in the literature. Unregulated production (overproduction) of peptide hormones and growth factors, which are not normally expressed in the tissue of origin, is characteristic of neuroendocrine tumors. Abnormal production of these bioactive peptides can lead to significant systemic toxic consequences and to the promotion of further tumor growth. The origin of this pathology remained unknown until 1966, when McGavran and colleagues assessed the radioimmunoassay (RIA) technique for glucagon.[1, 2]

In 75-80% of cases, the glucagonoma starts in malignant form, and in 50% of these cases, metastasis exists at diagnosis. The tumor's presence is characterized by glucagon overproduction, weight loss, diabetes mellitus, hypoaminoacidemia, normochromic and normocytic anemia, and necrolytic migratory erythema (NME), which is the most characteristic clinical sign (as opposed to symptom) of this pathology. NME presents as phlogistic damage to tissues in areas exposed to friction and pressure.

Another noteworthy feature of glucagonoma syndrome is a high rate of thromboembolic complications and consequent pulmonary embolisms; this is dangerous for many patients who can succumb to it. The correct recognition of NME is very important, because it may allow early detection either of glucagonoma or of extrapancreatic, glucagon-secreting tumors.[3, 4, 5]

Glucagonomas that are not associated with glucagonoma syndrome are diagnosed in various ways. The tumor may appear as a malignant pancreatic tumor discovered because of local growth, with or without metastases, or the tumor may be associated with insulinoma or gastrinoma. Glucagonoma may also occur as a single microadenoma found incidentally at autopsy in elderly patients. Glucagonoma very rarely is part of multiple endocrine neoplasia (MEN) type 1 syndrome (also called Wermer syndrome), and in such cases, the glucagonoma appears as a single, biologically inactive lesion. Similar to other islet cell tumors, the primary and metastatic lesions are slow growing.

However, it is noteworthy that some cases of NME without glucagonoma have been reported.[6, 7] It has been suggested that in such patients, hyponutrition, especially that resulting from a lack of vitamins and minerals, causes differentiation/proliferation modifications of keratinocytes.

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Pathophysiology

Although the relationship between hyperglucagonemia and necrolytic migratory erythema (NME) is not clear, elevated glucagon serum levels can be found at the same time as this cutaneous manifestation of the disease. Glucagon is a peptidic hormone mostly produced from alpha-2 cells of the pancreas and, in smaller amounts, from amine precursor uptake and decarboxylation (APUD) cells in gastric and duodenal mucosa. Three known forms of this hormone exist. The pancreatic form contains 29 amino acids and has a molecular weight of 3485 daltons, the gastric form contains 29 amino acids and has a molecular weight of 3500 daltons, and the enteric form, or enteroglucagon, contains a polypeptidic chain, has a high molecular weight, and is biologically and chemically different from other hormones, although it cross-reacts with them.

Glucagon is secreted under the influence of various factors. The most important of these is the reduced blood concentration of glucose. Acetylcholine and catecholamines elevate serum levels of glucagon and somatostatin; serotonin reduces these levels. Physiologic glucagon activity includes the following:

  • Glycogenolysis activation with contemporary glycolysis inhibition and activation of the gluconeogenesis
  • Stimulation of lipolysis and catecholamine secretion
  • Inhibition of gastric secreting activity, pancreatic secreting activity, and GI motility
  • Stimulation of urinary excretion of water and phosphates, as well as of sodium, calcium, and magnesium ions

Hyperglycemia linked to glucagonoma is a consequence of the glycogenolytic and gluconeogenic effects of glucagon. Similarly, glucagon excess (or relative glucagon excess) can be observed in diabetes mellitus and its complication, diabetic ketoacidosis.

When glucagon is secreted by a tumor, it becomes independent and is no longer influenced by feedback control mechanisms; the subsequent increase in glucagon concentration in the blood produces characteristic symptoms. Diabetes mellitus occurs in patients with glucagonoma because of the lack of equilibrium between insulin production and glucagon production (which occurs when high serum levels of glucagon and normal levels of insulin exist or when insulin production is reduced and a normal glucagon level is present). However, glucagon may not induce hyperglycemia directly unless the metabolism of glucose by the liver is directly compromised.

Another factor affecting glucagon secretion may be variation in the molecular species of glucagon that is present in each case, and the biologic potency of these molecular species of glucagon. Weight loss is due to the action of glucagon on lipid and protein metabolism; increased caloric expenditure, as determined by the proteic catabolism; and the consequent increase of gluconeogenesis and ureagenesis. This mechanism is probably also responsible for the cases of anemia and hypoaminoacidemia observed in patients with glucagonoma. Thromboembolism, occasionally observed in patients, is attributable to the production of a molecule similar to coagulative factor X from tumoral cells.

Although many theories about the pathogenesis of NME exist, the process of pathogenesis is not explained with certainty. According to one theory, NME can be caused by a tryptophan loss in cutaneous tissues because of the excess circulating glucagon. The amino acid tryptophan is responsible for niacin (pellagra prevention vitamin) function, which regulates cell turnover, capillary tone, and the maturation of the epidermis and mucosal epithelia.

According to another theory, NME is related to the hypoalbuminemia due to glucagon excess; in fact, albumin acts as a carrier for zinc and essential fatty acids. Zinc carries out a fundamental role in the maintenance of cutaneous trophism. The mineral is also responsible for the linoleic acid desaturation and is therefore involved in prostaglandin synthesis, which could determine phlogistic damage to tissues in areas exposed to friction and pressure if it occurs in excess. NME may also occur in areas of cutaneous trauma.

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Epidemiology

Frequency

United States

A study by Yao and colleagues, based on an analysis of the Surveillance, Epidemiology, and End Results (SEER) program database, reported the occurrence of a total of 2705 cases of endocrine pancreatic tumors in the United States over a period of 28 years, ending Jan 1, 2003.[8] According to these authors, the incidence of glucagonoma is very low, with islet cell neoplasms accounting for 1.3% of pancreatic cancers.

International

A rare pathology, glucagonoma probably accounts for 1% of all neuroendocrine tumors. Between 1942 and the beginning of the 21st century, approximately 250 cases were described in the literature. Incidence of this pathology is estimated on an annual basis, with 1 case occurring in every 20 million people. This number is probably an underestimation of the actual occurrence because of the relative lack of specificity of the symptoms. The fact that the tumors are, for a time, clinically silent also contributes to this underestimation.

Mortality/Morbidity

Glucagonomas have a slow rate of growth. Most cases start with nonspecific symptoms. In a report on patients with functional pancreatic tumors, the average delay in diagnosis was 3 years. Approximately 50% of cases have metastases at diagnosis; for patients in whom metastasis has occurred, the prognosis is poor.

Because of the small number of cases of glucagonoma, the rate of survival after 5 years has not been determined. However, one study reported an average survival time of 3.7 years in a group of 12 patients and an average survival period of 4.9 years in another group, consisting of 9 patients.

Like other islet cell neoplasms, glucagonomas may overproduce multiple hormones, each of which can have clinical manifestations. Insulin is the second-most common hormone secreted by these tumors. Others include (in order of frequency) adrenocorticotropic hormone (ACTH), pancreatic polypeptide, and parathyroid hormone (PTH) or substances with activity similar to PTH, such as gastrin, serotonin, vasoactive intestinal polypeptide (VIP), and melanocyte-stimulating hormone (MSH).

Race

No race prevalence is known for glucagonoma.

Sex

The frequency of glucagonoma in males and females is nearly equal, although a greater incidence has been reported in females.

Age

Most patients with glucagonoma are in the sixth decade of life, with a mean age of 55 years and an age range of 19-84 years.

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Contributor Information and Disclosures
Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

Mini R Abraham, MD Consulting Staff, Overland Park Medical Specialists

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.

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 Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, 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 the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

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.

References
  1. 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. [Medline].

  2. 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. [Medline].

  3. Pujol RM, Wang CY, el-Azhary RA, et al. Necrolytic migratory erythema: clinicopathologic study of 13 cases. Int J Dermatol. 2004 Jan. 43(1):12-8. [Medline].

  4. Remes-Troche JM, Garcia-de-Acevedo B, Zuniga-Varga J, et al. Necrolytic migratory erythema: a cutaneous clue to glucagonoma syndrome. J Eur Acad Dermatol Venereol. 2004 Sep. 18(5):591-5. [Medline].

  5. 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. [Medline].

  6. 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. [Medline].

  7. 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. [Medline].

  8. Yao JC, Eisner MP, Leary C, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007 Dec. 14(12):3492-500. [Medline]. [Full Text].

  9. Fang S, Li S, Cai T. Glucagonoma syndrome: a case report with focus on skin disorders. Onco Targets Ther. 2014. 7:1449-53. [Medline]. [Full Text].

  10. 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. [Medline].

  11. 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. [Medline].

  12. 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. [Medline].

  13. O'Grady HL, Conlon KC. Pancreatic neuroendocrine tumours. Eur J Surg Oncol. 2008 Mar. 34(3):324-32. [Medline].

  14. 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. [Medline].

  15. 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. [Medline].

  16. 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. [Medline].

  17. 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. [Medline].

  18. 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. [Medline]. [Full Text].

  19. 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. [Medline].

  20. Akerstrom G, Hellman P, Hessman O, et al. Surgical treatment of endocrine pancreatic tumours. Neuroendocrinology. 2004. 80 Suppl 1:62-6. [Medline].

  21. Montenegro F, Lawrence GD, Macon W, et al. Metastatic glucagonoma. Improvement after surgical debulking. Am J Surg. 1980 Mar. 139(3):424-7. [Medline].

  22. 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. [Medline].

  23. Clouse ME, Perry L, Stuart K, et al. Hepatic arterial chemoembolization for metastatic neuroendocrine tumors. Digestion. 1994. 55 Suppl 3:92-7. [Medline].

  24. 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. [Medline].

  25. Radny P, Eigentler TK, Soennichsen K, et al. Metastatic glucagonoma: treatment with liver transplantation. J Am Acad Dermatol. 2006 Feb. 54(2):344-7. [Medline].

  26. Adam DN, Cohen PD, Ghazarian D. Necrolytic migratory erythema: case report and clinical review. J Cutan Med Surg. 2003 Jul-Aug. 7(4):333-8. [Medline].

  27. Baton O, Eggenspieller P, Bechade D, et al. [Median pancreatectomy for early glucagonoma]. Gastroenterol Clin Biol. 2005 Mar. 29(3):308-10. [Medline].

  28. Bhathena SJ, Higgins GA, Recant L. Glucagonoma and glucagonoma syndrome. Unger RH, Orci L, eds. Glucagon. New York, NY: Elsevier Science; 1981. 413.

  29. Cruz-Bautista I, Lerman I, Perez-Enriquez B, et al. Diagnostic challenge of glucagonoma: case report and literature review. Endocr Pract. 2006 Jul-Aug. 12(4):422-6. [Medline].

  30. Du Jardin P, Cools P, Van der Stighelen Y. Necrolytic migratory erythema: first symptom of a glucagonoma. A case report. Acta Chir Belg. 2004 Aug. 104(4):468-70. [Medline].

  31. Echenique-Elizondo M, Elorza JL, De Delas JS. Migratory necrolytic erythema and glucagonoma. Surgery. 2003 Apr. 133(4):449-50. [Medline].

  32. Grant CS. Surgical management of malignant islet cell tumors. World J Surg. 1993 Jul-Aug. 17(4):498-503. [Medline].

  33. Jabbour SA, Davidovici BB, Wolf R. Rare syndromes. Clin Dermatol. 2006 Jul-Aug. 24(4):299-316. [Medline].

  34. Koike N, Hatori T, Imaizumi T, et al. Malignant glucagonoma of the pancreas diagnoses through anemia and diabetes mellitus. J Hepatobiliary Pancreat Surg. 2003. 10(1):101-5. [Medline].

  35. Kovacs RK, Korom I, Dobozy A, et al. Necrolytic migratory erythema. J Cutan Pathol. 2006 Mar. 33(3):242-5. [Medline].

  36. Krause W. Skin diseases in consequence of endocrine alterations. Aging Male. 2006 Jun. 9(2):81-95. [Medline].

  37. Marko PB, Miljkovic J, Zemljic TG. Necrolytic migratory erythema associated with hyperglucagonemia and neuroendocrine hepatic tumors. Acta Dermatovenerol Alp Panonica Adriat. 2005 Dec. 14(4):161-4, 166. [Medline]. [Full Text].

  38. Moertel CG, Johnson CM, McKusick MA, et al. The management of patients with advanced carcinoid tumors and islet cell carcinomas. Ann Intern Med. 1994 Feb 15. 120(4):302-9. [Medline].

  39. Schanz S, Schaefer J, Fierlbeck G. Glucagonoma presenting with necrolytic migratory erythema: the glucagonoma syndrome. Gastroenterology. 2005 Dec. 129(6):1816, 2131. [Medline].

  40. Tomita T, Masuzaki H, Noguchi M, et al. GPR40 gene expression in human pancreas and insulinoma. Biochem Biophys Res Commun. 2005 Dec 30. 338(4):1788-90. [Medline].

  41. Vinik AI, Perry RR. Neoplasms of the gastroenteropancreatic endocrine system. Holland JF, Frei E III, Bast RC Jr, et al, eds. Cancer Medicine. 4th ed. Baltimore, Md: William & Wilkins; 1997.

  42. Wang L, Zhao YP, Lee CI, et al. Diagnosis and treatment of malignant pancreatic endocrine tumour. Chin Med Sci J. 2004 Jun. 19(2):130-3. [Medline].

  43. Zhang M, Xu X, Shen Y, et al. Clinical experience in diagnosis and treatment of glucagonoma syndrome. Hepatobiliary Pancreat Dis Int. 2004 Aug. 3(3):473-5. [Medline].

 
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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.
 
 
 
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