First described by Becker in 1942, glucagonoma tumors comprise a rare functional NET that typically presents in the fifth decade of life. Pathologically, they appear as well-encapsulated, firm tumors, and arise from the alpha cells of the pancreas.10,11 This allows for the detection of this particular tumor through immunoperoxidase staining or by in situ hybridization targeting glucagon mRNA.
Typically arising in the tail of the pancreas, these tumors may vary in size from 2 to 25 cm by the time of diagnosis. The majority acts in a malignant fashion, and they often already have metastasized at the time of diagnosis. Initially thought to have a female preponderance, recent reports show a more even distribution between the genders.10 Glucagonoma tumors are rarely encountered in patients with MEN type I, who typically have a family or personal history of primary hyperparathyroidism, pituitary tumors (adenomas), other PNETs, and carcinoid tumors.
Clinical Manifestations and Biochemical Evaluation
Patients typically present with findings of hyperglycemia and hyperglucagonemia. Glucagonoma tumors are classically associated with a clinical syndrome including NME (Fig. 49-1), chelitis, glossitis, diabetes mellitus, anemia, weight loss, cachexia, diarrhea, venous thrombosis, and neuropsychiatric symptoms. Weight loss and NME occur in 65% to 70% of patients at the time of diagnosis. Chelitis and glossitis are often pathognomonic for glucagonoma. Diabetes is seen in 75% to 95% of all patients with this syndrome, while venous thrombosis occurs in 30% of patients.12,13 Neurologic symptoms are rare, but can include ataxia, dementia, optic atrophy, and proximal muscle weakness.
The glucagonoma syndrome, necrolytic migratory erythema. Flaccid and papulovesicular lesions (A) with erosions, crusting, and fissures around the orifices, and (B) appearing as geographic, circinate “necrolytic migratory erythema” in the groin. (A and B are not the same patient.) (Reproduced with permission from Goldsmith LA, Katz SI, Gilchrest BA, et al. Fitzpatrick's Dermatology in General Medicine, 8th ed. New York: McGraw-Hill Education, Inc; 2012.)
A thorough history and physical examination are important for all patients. NME also can be seen in patients with liver disease, pancreatitis, celiac disease, and lung cancer. However, the presence of NME or glossitis and chelitis should elicit further evaluation for glucagonoma. If an NME diagnosis by clinical exam is not clear, punch biopsies taken from the edges of the active lesions often show characteristic epidermal necrosis (Fig. 49-1). Multiple biopsies of the NME lesions are recommended.14
Specific laboratory findings include normochromic, normocytic anemia, present in nearly 90% of patients, and an elevated fasting serum concentration of glucagon (>500 pg/mL, normal 50 to 200 pg/mL), which is diagnostic for glucagonoma.15 However, glucagonoma patients may have serum glucagon levels below 500 pg/mL; therefore, if clinical suspicion is high, additional testing should be undertaken. Performing a study of the nutritional status of the patient is important in order to correct nutritional deficits; this test must evaluate the serum level/concentration of amino acids, zinc, and essential fatty acids.
Determining the level of transaminases, bilirubins, and alkaline phosphatase is important in order to detect hepatic metastases. The serum level of chromogranin A (CgA) is sensitive but nonspecific for determining the presence of a glucagonoma. Stimulation tests with arginine, secretin, or tolbutamide, which rapidly stimulate plasma glucagon levels in patients affected by glucagonoma, offer little to the diagnostic evaluation.16
The detection of telomerase and the quantification of the human telomerase reverse transcriptase (hTERT) protein subunit have been proposed for distinguishing clinically benign from malignant endocrine tumors. In a few reported cases, malignant glucagonoma showed telomerase activity. The quantification of hTERT messenger ribonucleic acid (mRNA) has been used in clinical practice to exclude malignancy.17