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Dermatologic Manifestations of Glucagonoma Syndrome Clinical Presentation

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

History

Patients usually present with nonspecific complaints, such as weight loss, diabetes, diarrhea, and stomatitis. Unexplained weight loss and the onset of necrolytic migratory erythema (NME), especially with new-onset diabetes mellitus, often hasten the correct diagnosis. Still, because mild early lesions may exhibit only subtle changes in histology and because inadequate sampling can miss the diagnostic changes, the skin eruption itself often is interpreted as a nonspecific dermatitis. It is not uncommon for several years to elapse before the correct diagnosis is found.[7]

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Physical

NME can be found anywhere on the body, although it has a predilection for the perineum, buttocks, groin, lower abdomen, and lower extremities, areas subject to greater pressure and friction. The lesions wax and wane in a cycle of about 10 days, beginning with an erythematous patch that blisters centrally, erodes, and then crusts over and heals with hyperpigmentation. The lesions are typically annular or polycyclic and may demonstrate confluence in severely affected areas. Patients report intense discomfort because these lesions are pruritic and painful. Other associated mucocutaneous findings include atrophic glossitis, cheilosis, onychoschizia, buccal mucosal inflammation, and, rarely, dyspareunia.[8] Note the images below.

Necrolytic migratory erythema in a patient with gl 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 Necrolytic migratory erythema involving the entire buttock and perineal region in a patient with glucagonoma syndrome.
Close-up view of an annular plaque showing necroly Close-up view of an annular plaque showing necrolytic migratory erythema in a patient with glucagonoma syndrome.
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Causes

Hyperglucagonemia can be found as part of a polyfunctional endocrine tumor or an exclusively glucagon-producing tumor. The tumor may be part of a clinical syndrome (eg, Zollinger-Ellison syndrome), or it may be asymptomatic. Although most glucagonomas appear to be sporadic, in about 3% of cases they occur in the setting of multiple endocrine neoplasia type 1. Glucagonoma syndrome typically manifests with very high levels of serum glucagon (up to 1000 times normal levels).

Pancreatic neuroendocrine tumors have also been associated in patients with Von Hippel-Lindau syndrome and p27 germline mutations.

Non-neoplastic pathologies can elevate glucagon levels that are high enough to produce cutaneous manifestations. Hepatic cirrhosis is an example. Since the liver is responsible for glucagon breakdown, cirrhosis may prolong the effective plasma half-life of glucagon and contribute to abnormally high serum levels. A single report describes a case of iatrogenic hyperglucagonemia resulting from glucagon administration for congenital hyperinsulinism.[9] However, markedly elevated levels of glucagon alone do not necessarily produce NME, diabetes mellitus, or hypoaminoacidemia, which are the defining criteria for this syndrome. NME in the context of pseudoglucagonoma may be associated with nonpancreatic malignancy, liver disease, inflammatory bowel disease, pancreatitis, celiac sprue, and zinc and other nutritional deficiencies. Glucagon levels in pseudoglucagonoma are elevated in up to half of patients, but not to the degree as those observed with glucagonoma.[10]

NME with normal glucagon levels has been reported in celiac sprue and pancreatitis; similar skin findings can present with cystic fibrosis. This may be mediated by enteroglucagon, a substance that is produced by the crypt cells of the small intestine in the malabsorptive state. Unabsorbed nutrients in the lumen are a potent stimulator of enteroglucagon, which can cause NME by an undetermined mechanism.

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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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