DIAGNOSTIC DILEMMA

Aimee K. Zaas, MD, Section Editor

A Rare but Revealing Sign: Necrolytic Migratory ErythemaNicholas L. Compton, MD, Andy J. Chien, MD, PhD

Division of Dermatology, Department of Medicine, University of Washington School of Medicine, Seattle.

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PRESENTATIONRash can signal any number of disorders, from the relativelyminor to the life-threatening. For a 62-year-old woman,an unrelenting skin complaint proved to be evidence of anunusual disease. She presented with a 2.5-year history of anintermittent pruritic rash in her underarms and gluteal cleftand on her groin and legs. It had become persistent in thelast 3 months and was refractory to treatment with high-potency topical steroids, topical antifungal agents, and top-ical antibiotics prescribed by her primary care providers.She had been diagnosed with diabetes mellitus 5 monthsprior to our evaluation. In addition, she described a 20-pound weight loss and associated fatigue. Over the preced-ing 3 months, the patient had also developed new-onsetalopecia.

ASSESSMENTPhysical examination revealed widespread, circumscribed, bi-lateral and symmetric erythematous eroded plaques with scale,which were located primarily in the axilla and gluteal cleft andon the trunk, groin, and upper legs (Figure, A and B). Ery-thematous scaly plaques were also noted in continuity with theoral labial commissures, consistent with angular cheilitis (Fig-ure, C). Examination of the mouth demonstrated swelling andredness of the tongue consistent with glossitis.

Histologic sections stained with hematoxylin and eosinshowed focal erosion, parakeratosis, irregular acanthosis,and necrotic keratinocytes, along with relative pallor of theupper third of the epidermis. A mixed inflammatory infil-trate was identified in the dermis. Periodic acid-Schiff stain-ing for fungus was negative. Laboratory testing disclosednormocytic normochromic anemia, hyperglycemia, and hy-poalbuminemia. Zinc and creatinine levels were normal, as

Funding: None.Conflict of Interest: None.Authorship: Both authors had access to the data and a role in writing

the manuscript.Requests for reprints should be addressed to Nicholas L. Compton,

MD, or Andy J. Chien, MD, PhD, Division of Dermatology, Department ofMedicine, Box 358056, 850 Republican Street, Seattle, WA 98109.

iE-mail address: ncompton@uw.edu or andchien@u.washington.edu

0002-9343/$ -see front matter © 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.amjmed.2013.01.012

were the results of a liver function panel. Her glucagon levelwas hugely elevated (1,700 pg/mL; normal, 0-60 pg/mL).Computed tomography (CT) uncovered a 3.5-cm mass inthe tail of the pancreas with no evidence of metastaticlesions in the liver or enlarged lymph nodes. In addition, a6.7-cm cystic mass was noted in the left ovary.

DIAGNOSISOur patient’s rash was necrolytic migratory erythema,which is characterized by erosive annular plaques that fre-quently involve the groin and buttocks and by angularcheilitis, glossitis, and alopecia. It was indicative of gluca-gonoma syndrome—her glucagon level confirmed the di-agnosis. First described in 1942, glucagonoma syndrome isextremely rare with an estimated prevalence of 1 in 20million.1 In 1 large series of endocrine pancreatic tumors,% were characterized by glucagon hypersecretion.2

Aside from necrolytic migratory erythema, glucagonomasyndrome classically presents with weight loss, diabetesmellitus, and anemia. Several other manifestations havebeen described, including depression, alopecia, ocular sco-toma, and hypoproteinemia. Metastatic disease can be seenin 50-100% of patients at the time of diagnosis, likelybecause the rarity and protean manifestations of glucagon-secreting tumors results in delayed diagnosis.3,4 Mortalityaries, depending on time of diagnosis.

Because cure relies on surgical resection of the primaryumor before metastatic disease develops, early recognitions extremely important. The tumors tend to be very slowrowing, and despite the high rate of metastasis at diagno-is, the mean survival ranges from 3-7 years.4 There are,

however, reports of patients living as long as 21 years withmetastatic disease to the liver.5 Treatment of metastaticdisease is difficult but may include metastasectomy, che-motherapy, somatostatin analogues, and radiation.

While necrolytic migratory erythema is most commonlyassociated with glucagon-secreting �-cell tumors of theancreas, it does occur in patients with other diseases; thiss known as pseudoglucagonoma syndrome. The conditionan occur in patients with hepatic cirrhosis, celiac disease,

nflammatory bowel disease, and nonpancreatic malignan-

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388 The American Journal of Medicine, Vol 126, No 5, May 2013

cies, including small-cell lung cancer.6 Prognosis is deter-mined by the underlying systemic disease.

On physical and histologic examinations, necrolytic mi-gratory erythema can resemble the skin findings seen withnutritional deficiencies of zinc, components of vitamin B-complex, particularly biotin and niacin, or essential fattyacids. Annular and eroded thin plaques develop in intertrig-inous regions and occur in conjunction with glossitis andangular cheilitis. Most strikingly, the histologic finding ofepidermal pallor, necrolytic keratinocytes, and parakeratosisobserved in necrolytic migratory erythema is seen primarilywith zinc and niacin deficiency. Blistering disorders, such aspemphigus, might be included in the differential diagnosis,but these tend not to coincide with new-onset diabetes.

Most patients with necrolytic migratory erythema havesystemic symptoms, although in many cases, the rash maybe the first sign of the glucagonoma syndrome. In caseseries involving more than 20 patients, 22-38% of patientspresented with diabetes mellitus; however, in 1 series, 80%of patients eventually developed diabetes during their clin-ical course.2,4 For our patient, the recognized link betweenew-onset diabetes, weight loss, and the characteristic rash,ed rapidly to the correct clinical diagnosis and work-up.his case further highlights the diagnostic value of a skiniopsy for a recalcitrant rash, since the distinctive histologicndings seen in our patient also led our dermatopathologists

o the correct diagnosis.The evaluation of a patient suspected of having necro-

ytic migratory erythema should include a thorough historynd physical examination that focuses on possible causes ofitamin deficiency. Examples are prior gastrointestinal sur-ery, alcoholism, anorexia nervosa, and cystic fibrosis.ymptoms of fatigue, polyuria, polydipsia, polyphagia, andeight loss are important. Laboratory testing should consistf a complete blood count; evidence of anemia is notewor-hy. Also essential are liver function tests, including alkalinehosphatase, because as a zinc-dependent enzyme, it isften low in patients with zinc deficiency.

Levels of vitamin B complex (especially biotin and nia-in), zinc, amino acids, essential fatty acids, glucose (pref-rably fasting), and glucagon must also be checked. Anyadiologic evaluation should be directed by signs or symp-oms, but evaluation of the pancreas is necessary as well. AT scan of the abdomen is often adequate, but if the resultsre negative despite strong suspicion, further evaluation cane performed with angiography—the tumors tend to beighly vascular—or radiolabeled octreotide scanning.

Figure A physical examination of the patient revealed wide-spread, circumscribed, bilateral and symmetric erythematouseroded plaques with scale. (A), Lesions were located primarily inthe axilla. (B), Her trunk, groin, and gluteal cleft were affected,as were her upper legs. (C), Erythematous scaly plaques werealso noted in continuity with the oral labial commissures, con-

sistent with angular cheilitis.

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389Compton and Chien Diabetes and Recalcitrant Rash

Although the exact pathogenesis of necrolytic migratoryerythema remains speculative, a multifactorial model thatinvolves glucagon excess, amino acid deficiency, zinc de-ficiency, and free fatty acid deficiency has been suggestedbased on its occurrence in a spectrum of diseases, and onsimilarities between the histological and clinical presenta-tions of these illnesses.7 Exactly how hyperglucagonemiariggers necrolytic migratory erythema is not known. Ele-ated glucagon levels might lead to hypovitaminosis B bypurring unchecked stimulation of carbohydrate metabo-ism.8 Similarly, high levels of glucagon may stimulate lipid

metabolism, reducing stores of essential fatty acids. Like-wise, hyperglucagonemia causes a decrease in amino acidsthrough increased gluconeogenesis.

Overlapping clinical and histological features existamong all of these deficiencies and between these andnecrolytic migratory erythema. Thus, multiple etiologic fac-tors are likely at work in the pathogenesis of this distinctivepresentation. Additional supporting evidence stems fromimprovement of necrolytic migratory erythema when pa-tients are treated with nutritional supplementation, regard-less of whether the rash was associated with a glucagon-secreting tumor.9

TREATMENTComplete surgical resection of the glucagon-secreting tu-mor before metastasis is curative, highlighting the impor-tance of early recognition and diagnosis. Following resec-tion of the tumor, the rash of necrolytic migratory erythemaalmost universally resolves within days. In those with met-astatic and/or unresectable disease, medical therapy can bequite helpful in alleviating symptoms and controlling thecutaneous disease. Long-acting somatostatin analoguessuch as octreotide have been used with significant success.10

Supplementation with zinc has also shown some promise.

Our patient underwent resection of the pancreatic tumor,which on pathologic examination was identified as an isletcell tumor. Her rash cleared completely within 6 days; theovarian cyst was benign.

In summary, necrolytic migratory erythema is an uncom-mon skin condition with annular, eroded, intertriginousplaques, alopecia, angular cheilitis, and glossitis. It is mostcommonly associated with the glucagonoma syndrome ofnecrolytic migratory erythema, diabetes, and hypoaminoaci-demia. The majority of patients have metastatic disease atthe time of diagnosis. However, since resection can becurative, early identification is extremely important.

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malignant tumors. Arch Dermatol Syphilol. 1942;45:1069-1080.2. Kindmark H, Sundin A, Granberg D, et al. Endocrine pancreatic

tumors with glucagon hypersecretion: a retrospective study of 23 casesduring 20 years. Med Oncol. 2007;24:330-337.

3. Stacpoole PW. The glucagonoma syndrome: clinical features, diagno-sis, and treatment. Endo Rev. 1981;2:347-361.

4. Wermers RA, Fatourechi V, Wynne AG, Kvols LK, Lloyd RV. Theglucagonoma syndrome, Clinical and pathologic features in 21 pa-tients. Medicine (Baltimore) 1996;75:53-63.

5. Dourakis SP, Alexopoulou A, Georgousi KK, Delladetsima JK, TolisG, Archimandritis AJ. Glucagonoma syndrome: survival 21 years withconcurrent liver metastases. Am J Med Sci. 2007; 334:225-227.

6. Mignogna MD, Fortuna G, Satriano AR. Small-cell lung cancer andnecrolytic migratory erythema. N Engl J Med. 2008;359:2731-2732.

7. Tierney EP, Badger J. Etiology and pathogenesis of necrolytic migra-tory erythema: review of the literature. Med Gen Med. 2004;6:4.

8. van Beek AP, de Haas ER, van Vloten WA, Lips CJ, Roijers JF,Canninga-van Dijk MR. The glucagonoma syndrome and necrolyticmigratory erythema: a clinical review. Eur J Endocrinol. 2004;151:531-537.

9. Nakashima H, Komine M, Sasaki K, et al. Necrolytic migratory ery-thema without glucagonoma in a patient with short bowel syndrome. JDermatol. 2006;33:557-562.

10. Altimari AF, Bhoopalam N, O’Dorsio T, Lange CL, Sandberg L, PrinzRA. Use of a somatostatin analog (SMS 201-995) in the glucagonoma

syndrome. Surgery. 1986;100:989-996.