Dermatologic Manifestations of Glucagonoma Syndrome Workup
- Author: Sara Flores, MD; Chief Editor: William D James, MD more...
Since glucagonoma may arise in the context of a polyfunctional endocrine tumor, assessing serum glucagon, in addition to serum insulin, corticotropin, pancreatic polypeptide (PP), parathyroid hormone (PTH), gastrin, serotonin and vasoactive intestinal peptide levels, is important. A glucose tolerance test may help in delineating the degree of glucagon excess relative to insulin. Glucose intolerance may relate to tumor size and hepatic metastases.
A nutritional profile, consisting of amino acid, zinc, and essential fatty acid levels, is essential because necrolytic migratory erythema (NME) may respond to a correction of a nutrient deficit.
CBC count with differential is indicated to evaluate for a possible anemia.
Blood chemistry testing may help in detecting liver metastases.
Localization of the pancreatic primary tumor and metastatic disease is performed primarily with CT scanning, MRI, and ultrasonography. In selected cases, positron emission tomography scanning may be useful. Celiac axis angiography is considered the criterion standard for diagnosis and localization of the glucagonoma. Determination of metastatic spread can be achieved by imaging with a somatostatin analogue that identifies both the primary lesion and the tumor extent.[11, 12]
Finding the glucagonoma, if one exists, is important. Depending on the radiographic workup results, either laparotomy with tumor resection or needle biopsy may be appropriate to obtain a histologic specimen.
A punch biopsy can demonstrate NME if the skin is sampled appropriately. Multiple biopsies from the edges of early lesions are most helpful in establishing a diagnosis.
Glucagonomas are tumors of the alpha cells of the pancreas. These tumors tend to arise in the tail of the pancreas, although they can be found anywhere within the organ. Many case reports describe the tumors as solid, well circumscribed, and encapsulated. The tumors show organized nests, islands, and occasional trabeculae. They are usually hypervascular, in contrast to pancreatic adenocarcinomas. Immunocytochemistry may be positive for glucagon, although the intensity of the stain may not correlate with the serum glucagon levels. If this method does not detect glucagon production, in situ hybridization to glucagon mRNA may be definitive. Electron microscopy shows neurosecretory granules and a well-developed, rough endoplasmic reticulum and Golgi complex.
The histologic findings of NME correlate with the clinical state of evolution of the lesion. NME initially manifests as a mild perivascular dermal lymphocytic infiltrate and epidermal spongiosis. It is helpful to take more than one biopsy, as early lesions may easily be mistaken for spongiotic dermatitis. In older lesions, The epidermis classically shows hyperparakeratosis, acanthosis, an absent granular layer, and pallor of keratinocytes in the upper layers of the epidermis (note the image below). Vacuolar degeneration and necrosis in the superficial layers result in a characteristic cleftlike detachment from the deeper epidermis. The infiltrate may also include neutrophils and eosinophils. In one study, keratinocytes in NME stained positive for Ki-67, K16, and K10, supporting changes in both differentiation and proliferation of keratinocytes.
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].
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].
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].
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].
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].
Fang S, Li S, Cai T. Glucagonoma syndrome: a case report with focus on skin disorders. Onco Targets Ther. 2014. 7:1449-53. [Medline].
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].
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].
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].
Lewis RB, Lattin GE Jr, Paal E. Pancreatic endocrine tumors: radiologic-clinicopathologic correlation. Radiographics. 2010 Oct. 30(6):1445-64. [Medline].
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].
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].
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].
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].
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].
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].
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].
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].