Are You Confident of the Diagnosis?

What you should be alert for in the history

History may include involvement of perineum, face, trunk, and lower extremities, with glossitis, angular cheilitis, and blepharitis in the setting of weight loss, new diabetes, diarrhea, and neuropsychiatric symptoms.

Characteristic findings on physical examination

Characteristic findings include superficial red erosions, with or without crusting, which can be annular or geographic, with central clearing (See Figure 1).

Expected results of diagnostic studies

Diagnostic findings include epidermal pallor with psoriasiform epidermal hyperplasia on histopathology, increased plasma glucagon level, and pancreatic tumor (with or without liver metastasis), which can be seen by ultrasound or imaging.

Diagnosis confirmation

Diagnosis confirmation is by fasting plasma glucagon level and abdominal (pancreatic and liver) imaging.

Clinical appearance includes differential of pseudoglucogonoma (necrolytic migratory erythema without pancreatic tumor) seen in liver cirrhosis, chronic pancreatitis, Crohn’s disease, celiac sprue, malabsorption syndrome, acrodermatitis enteropathica (check zinc level), glucagon-secreting bronchial carcinoma, and necrolytic acral erythema (check for hepatitis C). May also resemble dermatophyte infection, candidiasis, dermatitis, Hailey-Hailey disease, and pemphigus.

Who is at Risk for Developing this Disease?

Peak incidence is between 45 and 60 years old, and 60% of patients are female. Occurrence is sporadic, although there is a rare autosomal dominant familial form, reported in multiple endocrine neoplasia syndromes (MEN).

What is the Cause of the Disease?

Etiology

Glucogonoma syndrome is associated with slow-growing alpha-islet cell tumor of the pancreas, often with metastasis to liver or lymphatics.

Pathophysiology

Glucogonoma syndrome is of unknown pathophysiology, although metabolic abnormalities including deficiencies in zinc, essential fatty acids, and proteins have been implicated.

Systemic Implications and Complications

Other results seen include fasting plasma glucagon of greater than 500pg/mL (normal 50-150), hyperglycemia, normochromic normocytic anemia, increased erythrocyte sedimentation rate, increased liver function tests, and decreased plasma amino acids, fatty acids, and zinc.

Work-up should include skin biopsy, fasting plasma glucagon level, fasting blood glucose, serum zinc level, liver function tests, and pancreatic and hepatic imaging by ultrasound or computed tomography (CT) scan.

Treatment Options

Treatment is by surgical excision of pancreatic tumor, otherwise treat symptoms.

Optimal Therapeutic Approach for this Disease

Once the diagnosis is made, the patient needs to be referred to a surgical and medical oncologist.

Surgical excision of the non-metastatic pancreatic tumor provides a cure. Skin finding can reverse within 1 week. Metabolic changes (normalization of blood glucose) may take longer.

Surgical debulking may provide temporary symptomatic improvement.

Medical treatment with dacarbazine, doxorubicin, streptozotocin, octreotide, zinc, essential fatty acid supplementation, amino acid infusion, and pancreatic enzyme replacement may be of some temporary benefit.

Patient Management

Once diagnosed, patients should be managed in conjunction with a surgeon and oncologist. Skin finding will reverse quickly if surgery of non-metastatic pancreatic tumor is successful. At best, 40% are diagnosed before metastasis. Once metastatic, all treatment is palliative.

Unusual Clinical Scenarios to Consider in Patient Management

The most common clinical scenario is that of making the correct diagnosis, which is often missed for months to years, reflecting the high number of cases that are metastatic at the time of diagnosis. This is a rare diagnosis with only several hundred cases reported in the literature.

What is the Evidence?

Mullans, EA, Cohen, PR. “Iatrogenic necrolytic migratory erythema: a case report and review of non-glucagonoma-associated necrolytic migratory erythema”. J Am Acad Dermatol. vol. 38. 1998. pp. 866-73. (A patient with non-glucagonoma-associated necrolytic migratory erythema is presented. The authors review the literature on previously reported cases where an islet-cell pancreatic tumor was not present. These associations include liver disease, malabsorptive states, and non-islet cell tumors.)

Schwartz, RA. “Glucagonoma and pseudoglucagonoma syndromes”. Int J Dermatol. vol. 63. 1997. pp. 81-90. (A review of glucagonoma and pseudoglucagonoma syndromes. The author provides a thorough review of the literature with 119 references, and outlines twenty-three case reports from 1974-1995.)

Adams, DR, Miller, JJ, Seraphin, KE. “Glucogonoma syndrome”. J Am Acad Dermatol. vol. 53. 2005. pp. 690-1. (An outline of clinical pearls, radiological pearls, and differential diagnosis. The article summarizes the most important points of glucagonoma syndrome from a clinical and diagnostic perspective.)

Huang, W, Williams, CM, McNeely, MC. “A persistent periorifacial eruption. Diagnosis: Necrolytic migratory erythema (glucagonoma)”. Arch Dermatol. vol. 133. 1997. pp. 909-12. (A patient with necrolytic migratory erythema is presented, with clinical photos and histology. A short, practical discussion of the history, terminology, and important points of glucagonoma syndrome is provided.)

Mallinson, C, Bloom, S, Warin A Salmon, PR, Cox, B. “Glucogonoma syndrome”. Lancet. vol. 2. 1974. pp. 1-5. (A review of nine patients presenting with necrolytic migratory erythema, all with pancreatic tumors and glucagonoma syndrome. Each case is discussed, with one patient having complete resolution after surgical resection of his pancreatic tumor.)

El Rassi, Z, Partensky, C, Valette, PJ, Berger, F, Chayvialle, JA. Eur J Surg Oncol. vol. 24. 1998. pp. 562-7. (Three cases of glucagonoma syndrome are discussed. Skin findings resolved in all three cases with a combination of surgical resection of the tumor and administration of a long-acting somotostatin analog.)

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Glucogonoma Syndrome (Necrolytic Migratory Erythema, NME)