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Requests for reprints should be addressed to Nicholas L. Compton, MD, or Andy J. Chien, MD, PhD, Division of Dermatology, Department of Medicine, Box 358056, 850 Republican Street, Seattle, WA 98109
Requests for reprints should be addressed to Nicholas L. Compton, MD, or Andy J. Chien, MD, PhD, Division of Dermatology, Department of Medicine, Box 358056, 850 Republican Street, Seattle, WA 98109
Rash can signal any number of disorders, from the relatively minor to the life-threatening. For a 62-year-old woman, an unrelenting skin complaint proved to be evidence of an unusual disease. She presented with a 2.5-year history of an intermittent pruritic rash in her underarms and gluteal cleft and on her groin and legs. It had become persistent in the last 3 months and was refractory to treatment with high-potency topical steroids, topical antifungal agents, and topical antibiotics prescribed by her primary care providers. She had been diagnosed with diabetes mellitus 5 months prior to our evaluation. In addition, she described a 20-pound weight loss and associated fatigue. Over the preceding 3 months, the patient had also developed new-onset alopecia.
Assessment
Physical examination revealed widespread, circumscribed, bilateral and symmetric erythematous eroded plaques with scale, which were located primarily in the axilla and gluteal cleft and on the trunk, groin, and upper legs (Figure, A and B). Erythematous scaly plaques were also noted in continuity with the oral labial commissures, consistent with angular cheilitis (Figure, C). Examination of the mouth demonstrated swelling and redness of the tongue consistent with glossitis.
FigureA physical examination of the patient revealed widespread, circumscribed, bilateral and symmetric erythematous eroded plaques with scale. (A), Lesions were located primarily in the axilla. (B), Her trunk, groin, and gluteal cleft were affected, as were her upper legs. (C), Erythematous scaly plaques were also noted in continuity with the oral labial commissures, consistent with angular cheilitis.
Histologic sections stained with hematoxylin and eosin showed focal erosion, parakeratosis, irregular acanthosis, and necrotic keratinocytes, along with relative pallor of the upper third of the epidermis. A mixed inflammatory infiltrate was identified in the dermis. Periodic acid-Schiff staining for fungus was negative. Laboratory testing disclosed normocytic normochromic anemia, hyperglycemia, and hypoalbuminemia. Zinc and creatinine levels were normal, as were the results of a liver function panel. Her glucagon level was hugely elevated (1,700 pg/mL; normal, 0-60 pg/mL). Computed tomography (CT) uncovered a 3.5-cm mass in the tail of the pancreas with no evidence of metastatic lesions in the liver or enlarged lymph nodes. In addition, a 6.7-cm cystic mass was noted in the left ovary.
Diagnosis
Our patient's rash was necrolytic migratory erythema, which is characterized by erosive annular plaques that frequently involve the groin and buttocks and by angular cheilitis, glossitis, and alopecia. It was indicative of glucagonoma syndrome—her glucagon level confirmed the diagnosis. First described in 1942, glucagonoma syndrome is extremely rare with an estimated prevalence of 1 in 20 million.
Aside from necrolytic migratory erythema, glucagonoma syndrome classically presents with weight loss, diabetes mellitus, and anemia. Several other manifestations have been described, including depression, alopecia, ocular scotoma, and hypoproteinemia. Metastatic disease can be seen in 50-100% of patients at the time of diagnosis, likely because the rarity and protean manifestations of glucagon-secreting tumors results in delayed diagnosis.
Because cure relies on surgical resection of the primary tumor before metastatic disease develops, early recognition is extremely important. The tumors tend to be very slow growing, and despite the high rate of metastasis at diagnosis, the mean survival ranges from 3-7 years.
Treatment of metastatic disease is difficult but may include metastasectomy, chemotherapy, somatostatin analogues, and radiation.
While necrolytic migratory erythema is most commonly associated with glucagon-secreting α-cell tumors of the pancreas, it does occur in patients with other diseases; this is known as pseudoglucagonoma syndrome. The condition can occur in patients with hepatic cirrhosis, celiac disease, inflammatory bowel disease, and nonpancreatic malignancies, including small-cell lung cancer.
Prognosis is determined by the underlying systemic disease.
On physical and histologic examinations, necrolytic migratory erythema can resemble the skin findings seen with nutritional deficiencies of zinc, components of vitamin B-complex, particularly biotin and niacin, or essential fatty acids. Annular and eroded thin plaques develop in intertriginous regions and occur in conjunction with glossitis and angular cheilitis. Most strikingly, the histologic finding of epidermal pallor, necrolytic keratinocytes, and parakeratosis observed in necrolytic migratory erythema is seen primarily with zinc and niacin deficiency. Blistering disorders, such as pemphigus, might be included in the differential diagnosis, but these tend not to coincide with new-onset diabetes.
Most patients with necrolytic migratory erythema have systemic symptoms, although in many cases, the rash may be the first sign of the glucagonoma syndrome. In case series involving more than 20 patients, 22-38% of patients presented with diabetes mellitus; however, in 1 series, 80% of patients eventually developed diabetes during their clinical course.
For our patient, the recognized link between new-onset diabetes, weight loss, and the characteristic rash, led rapidly to the correct clinical diagnosis and work-up. This case further highlights the diagnostic value of a skin biopsy for a recalcitrant rash, since the distinctive histologic findings seen in our patient also led our dermatopathologists to the correct diagnosis.
The evaluation of a patient suspected of having necrolytic migratory erythema should include a thorough history and physical examination that focuses on possible causes of vitamin deficiency. Examples are prior gastrointestinal surgery, alcoholism, anorexia nervosa, and cystic fibrosis. Symptoms of fatigue, polyuria, polydipsia, polyphagia, and weight loss are important. Laboratory testing should consist of a complete blood count; evidence of anemia is noteworthy. Also essential are liver function tests, including alkaline phosphatase, because as a zinc-dependent enzyme, it is often low in patients with zinc deficiency.
Levels of vitamin B complex (especially biotin and niacin), zinc, amino acids, essential fatty acids, glucose (preferably fasting), and glucagon must also be checked. Any radiologic evaluation should be directed by signs or symptoms, but evaluation of the pancreas is necessary as well. A CT scan of the abdomen is often adequate, but if the results are negative despite strong suspicion, further evaluation can be performed with angiography—the tumors tend to be highly vascular—or radiolabeled octreotide scanning.
Although the exact pathogenesis of necrolytic migratory erythema remains speculative, a multifactorial model that involves glucagon excess, amino acid deficiency, zinc deficiency, and free fatty acid deficiency has been suggested based on its occurrence in a spectrum of diseases, and on similarities between the histological and clinical presentations of these illnesses.
Exactly how hyperglucagonemia triggers necrolytic migratory erythema is not known. Elevated glucagon levels might lead to hypovitaminosis B by spurring unchecked stimulation of carbohydrate metabolism.
Similarly, high levels of glucagon may stimulate lipid metabolism, reducing stores of essential fatty acids. Likewise, hyperglucagonemia causes a decrease in amino acids through increased gluconeogenesis.
Overlapping clinical and histological features exist among all of these deficiencies and between these and necrolytic migratory erythema. Thus, multiple etiologic factors are likely at work in the pathogenesis of this distinctive presentation. Additional supporting evidence stems from improvement of necrolytic migratory erythema when patients are treated with nutritional supplementation, regardless of whether the rash was associated with a glucagon-secreting tumor.
Complete surgical resection of the glucagon-secreting tumor before metastasis is curative, highlighting the importance of early recognition and diagnosis. Following resection of the tumor, the rash of necrolytic migratory erythema almost universally resolves within days. In those with metastatic and/or unresectable disease, medical therapy can be quite helpful in alleviating symptoms and controlling the cutaneous disease. Long-acting somatostatin analogues such as octreotide have been used with significant success.
Supplementation with zinc has also shown some promise.
Our patient underwent resection of the pancreatic tumor, which on pathologic examination was identified as an islet cell tumor. Her rash cleared completely within 6 days; the ovarian cyst was benign.
In summary, necrolytic migratory erythema is an uncommon skin condition with annular, eroded, intertriginous plaques, alopecia, angular cheilitis, and glossitis. It is most commonly associated with the glucagonoma syndrome of necrolytic migratory erythema, diabetes, and hypoaminoacidemia. The majority of patients have metastatic disease at the time of diagnosis. However, since resection can be curative, early identification is extremely important.
References
Becker W.S.
Kahn D.
Rothman S.
Cutaneous manifestations of internal malignant tumors.
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