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Dermatologic Manifestations of Glucagonoma Syndrome

  • Author: Sara Flores, MD; Chief Editor: William D James, MD  more...
 
Updated: May 12, 2016
 

Background

Glucagonoma syndrome was first described by Becker, Kahn, and Rothman in 1942. Glucagonoma syndrome is an uncommon clinicopathologic entity.[1] It is characterized by a glucagon-secreting tumor associated with hyperglucagonemia; necrolytic migratory erythema (NME)[2] ; diabetes mellitus; hypoaminoacidemia; cheilosis; a normochromic, normocytic anemia; venous thrombosis; weight loss; and neuropsychiatric features. The finding of NME was once considered pathognomonic for glucagonoma syndrome. However, publications have reported that neither glucagonoma nor hyperglucagonemia is necessary for NME.[3] Pseudoglucagonoma syndrome refers to NME in the absence of a glucagon-secreting tumor.[4, 5]

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Pathophysiology

Although the pathogenesis of NME is poorly understood, high serum levels of glucagon have been implicated in most cases. Often, NME resolves rapidly with surgical resection of a glucagonoma or with a potent inhibitor of glucagon release and glucagon action, such as somatostatin. However, abnormal serum glucagon levels alone do not explain the skin manifestations. Typically, levels of glucagon do not correlate well with the episodic course of the skin manifestations.

Various metabolic abnormalities and nutritional deficiencies also have been implicated in the pathogenesis of NME. Supplementation with both zinc and essential fatty acids has been shown to resolve NME in a small number of patients with demonstrable deficiencies of these nutrients. The role of zinc is intriguing because acrodermatitis enteropathica and acquired zinc deficiency manifest lesions similar to NME. NME also may resolve with parenteral nutrition to correct amino acid deficiencies.

In an attempt to unify these conflicting findings, some have proposed a multifactorial origin for NME. One theory asserts that the pathogenesis of NME may relate to glucagon-induced hypoalbuminemia because albumin functions as a carrier of zinc and essential fatty acids. Others suggest that zinc-dependent delta-6 desaturation of linoleic acid or poor hepatic breakdown of glucagon may contribute to an excessive prostaglandin-mediated inflammatory response in the epidermis. This theory may help to explain the distribution of the cutaneous eruption, which is more prominent in areas of increased friction and pressure.

Diabetes mellitus usually develops in the hyperglucagonemic state of glucagonoma syndrome. Because glucagon is glycogenolytic and gluconeogenic, an excess of glucagon relative to insulin elevates serum glucose levels. Therefore, the onset of diabetes occurs when insulin production fails to match glucagon production. This can be seen when either glucagon levels are very high and insulin production continues normally or insulin production is impaired and glucagon is only mildly elevated. Patient factors, such as preexisting insulin resistance, pancreatic tumor burden, and hormonal milieu (eg, tumor-derived somatostatin, other endocrine products secreted by the tumor), also modulate glucose tolerance.

Most likely, the catabolic effects of glucagon on protein and fat metabolism are the major factor causing weight loss. Increased caloric expenditure also occurs from increased gluconeogenesis and ureagenesis from glucagon-induced protein catabolism. Tumor burden and the associated cachexia probably play a minor role in weight loss. Similar catabolic effects with respect to protein metabolism probably cause the normochromic, normocytic anemia and hypoaminoacidemia that often are seen at initial presentation.

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Epidemiology

Frequency

Glucagonomas are quite rare; since 1942, more than 300 cases have been reported worldwide. Their annual incidence has been estimated at 1 in 20 million. Pseudoglucagonoma syndrome has been described in an even smaller group of patients; data on incidence and prevalence are not currently available for this syndrome.

Sex

Males and females appear to be equally affected.

Age

Glucagonoma usually develops in patients aged 50-59 years. However, one report describes a case of glucagonoma syndrome occurring in a 15-year-old girl in the setting of multiple endocrine neoplasia.[6]

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Prognosis

Glucagonomas are slow-growing tumors that typically present with nonspecific symptoms. At least 50% of these tumors are metastatic at the time of diagnosis and, therefore, generally carry a poor prognosis. The 5-year survival rate is unknown because of the small patient population, but one study reported that tumor-related death occurred in 9 out of 21 patients at an average of 4.9 years from diagnosis. The remaining 12 patients were alive after an average follow-up interval of 3.7 years. Prolonged survival (>20 y) has been reported.

The mortality rate associated with pseudoglucagonoma syndrome generally follows that of the underlying pathologic diagnosis. Some cases resulting from celiac sprue are completely reversible by dietary modification. Others, such as those resulting from hepatic cirrhosis or other neoplasm, generally have a poor outcome.

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Contributor Information and Disclosures
Author

Sara Flores, MD Resident Physician, Department of Dermatology, University of Cincinnati College of Medicine

Sara Flores, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, Cincinnati Dermatological Society, Ohio Dermatological Association

Disclosure: Nothing to disclose.

Coauthor(s)

Ali Alikhan, MD Clinical Assistant Professor, Director of Clinical Trials, Residency Program Co-Director, Department of Dermatology, University of Cincinnati College of Medicine

Ali Alikhan, MD is a member of the following medical societies: American Academy of Dermatology, National Psoriasis Foundation, Cincinnati Dermatological Society, National Psoriasis Foundation, Ohio Dermatological Association

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

David P Fivenson, MD Associate Director, St Joseph Mercy Hospital Dermatology Program, Ann Arbor, Michigan

David P Fivenson, MD is a member of the following medical societies: American Academy of Dermatology, Michigan State Medical Society, Society for Investigative Dermatology, Photomedicine Society, Wound Healing Society, Michigan Dermatological Society, Medical Dermatology Society

Disclosure: Nothing to disclose.

Nathalie C Zeitouni, MDCM, FRCPC Chair of Dermatology, Associate Professor of Dermatology, Roswell Park Cancer Institute

Nathalie C Zeitouni, MDCM, FRCPC is a member of the following medical societies: American Academy of Cosmetic Surgery, American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery, Women's Dermatologic Society, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Nishikant Harvey, MD Clinical Assistant Instructor, Department of Anesthesiology, SUNY at Buffalo Graduate Medical-Dental Consortium

Nishikant Harvey, MD is a member of the following medical societies: American Society of Anesthesiologists

Disclosure: Nothing to disclose.

References
  1. Vinik A, Feliberti E, Perry RR, De Groot LJ, Beck-Peccoz P, Chrousos G, et al. Glucagonoma Syndrome. 2000. [Medline]. [Full Text].

  2. Cardoso Filho Fde A, Feitosa RG, Fechine CO, de Matos CM, Cardoso AL, Cardoso DL. Glucagonoma syndrome associated with necrolytic migratory erythema. Rev Assoc Med Bras. 2015 May-Jun. 61 (3):203-6. [Medline].

  3. Nakashima H, Komine M, Sasaki K, Mitsui H, Fujimoto M, Ihn H, et al. Necrolytic migratory erythema without glucagonoma in a patient with short bowel syndrome. J Dermatol. 2006 Aug. 33(8):557-62. [Medline].

  4. Doyle JA, Schroeter AL, Rogers RS 3rd. Hyperglucagonaemia and necrolytic migratory erythema in cirrhosis--possible pseudoglucagonoma syndrome. Br J Dermatol. 1979 Nov. 101(5):581-7. [Medline].

  5. Echenique-Elizondo M, Tuneu Valls A, Elorza Orúe JL, Martinez de Lizarduy I, Ibáñez Aguirre J. Glucagonoma and pseudoglucagonoma syndrome. JOP. 2004 Jul. 5(4):179-85. [Medline].

  6. Luber AJ, Ackerman LS, Culpepper KS, Buschmann CM, Koep LJ. Pediatric Necrolytic Migratory Erythema as a Presenting Sign of Glucagonoma Syndrome. Br J Dermatol. 2015 Nov 20. [Medline].

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

  8. Chao SC, Lee JY. Brittle nails and dyspareunia as first clues to recurrences of malignant glucagonoma. Br J Dermatol. 2002 Jun. 146(6):1071-4. [Medline].

  9. Coughlin CC, Roy SM, Arkin LM, Adzick NS, Yan AC, De León DD, et al. Iatrogenic Necrolytic Migratory Erythema in an Infant with Congenital Hyperinsulinism. Pediatr Dermatol. 2016 Mar. 33 (2):e43-e47. [Medline].

  10. Stavropoulos PG, Papafragkaki DK, Avgerinou G, Papafragkakis H, Katsavou A, Katsambas AD. Necrolytic migratory erythema: a common cutaneous clue of uncommon syndromes. Cutis. 2013 Nov. 92 (5):E1-4. [Medline].

  11. Lewis RB, Lattin GE Jr, Paal E. Pancreatic endocrine tumors: radiologic-clinicopathologic correlation. Radiographics. 2010 Oct. 30(6):1445-64. [Medline].

  12. 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. [Medline].

  13. van der Loos TL, Lambrecht ER, Lambers JC. Successful treatment of glucagonoma-related necrolytic migratory erythema with dacarbazine. J Am Acad Dermatol. 1987 Feb. 16(2 Pt 2):468-72. [Medline].

  14. Nitta N, Ohta S, Tanaka T, Takazakura R, Toyama T, Sonoda A, et al. An initial clinical study on the efficacy of cisplatin-releasing gelatin microspheres for metastatic liver tumors. Eur J Radiol. 2009 Sep. 71(3):519-26. [Medline].

  15. Melen-Mucha G, Lawnicka H, Kierszniewska-Stepien D, Komorowski J, Stepien H. The place of somatostatin analogs in the diagnosis and treatment of the neuoroendocrine glands tumors. Recent Pat Anticancer Drug Discov. 2006 Jun. 1(2):237-54. [Medline].

  16. Eldor R, Glaser B, Fraenkel M, Doviner V, Salmon A, Gross DJ. Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour. Clin Endocrinol (Oxf). 2011 May. 74(5):593-8. [Medline].

  17. Mir O, Coriat R, Goldwasser F. Advances in pancreatic neuroendocrine tumor treatment. N Engl J Med. 2011 May 12. 364(19):1871; author reply 1873-4. [Medline].

  18. Virani S, Prajapati V, Devani A, Mahmood MN, Elliott JF. Octreotide-responsive necrolytic migratory erythema in a patient with pseudoglucagonoma syndrome. J Am Acad Dermatol. 2013 Feb. 68(2):e44-6. [Medline].

  19. Poggi G, Villani L, Bernardo G. Multimodality treatment of unresectable hepatic metastases from pancreatic glucagonoma. Rare Tumors. 2009 Jul 22. 1(1):e6. [Medline]. [Full Text].

  20. Blackford S, Wright S, Roberts DL. Necrolytic migratory erythema without glucagonoma: the role of dietary essential fatty acids. Br J Dermatol. 1991 Nov. 125(5):460-2. [Medline].

 
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Necrolytic migratory erythema in a patient with glucagonoma syndrome. Annular erythematous plaques, vesicles, and erosions involving the whole perineal area are shown.
Necrolytic migratory erythema involving the entire buttock and perineal region in a patient with glucagonoma syndrome.
Close-up view of an annular plaque showing necrolytic migratory erythema in a patient with glucagonoma syndrome.
Acanthosis with upper epidermal necrolysis from a patient with necrolytic migratory erythema and glucagonoma syndrome. Note prominent intracellular edema and loss of granular cell layer (X10).
 
 
 
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