Approach Considerations
If there is a clinical suspicion of glucagonoma, finding a markedly elevated serum glucagon level on a sample drawn in the morning will confirm the diagnosis. In most cases of glucagonoma, the glucagon level will be 2-3 times the upper limit of normal.
Laboratory Studies
Determining the level of glucagonemia by means of radioimmunoassay (RIA) testing is mandatory. A positive test result for glucagonoma exceeds 1000 pg/mL (reference range is 50-200 pg/mL).
Performing a fasting blood sugar and/or glucose tolerance test to establish the presence of diabetes is important. A complete blood count (CBC) with a differential count is important for evaluating whether anemia is present. Because glucagonoma can, in rare cases, be a part of multiple endocrine neoplasia type 1 (MEN1) syndrome, also check serum levels of fasting insulin, glucagon, prolactin, calcium, and vasoactive intestinal polypeptide (VIP).
Assessing the nutritional status of the patient is important in order to correct nutritional deficits resulting from glucagon excess. Tests performed must include serum concentrations of amino acids, zinc, and essential fatty acids.
Determining the level of transaminases, bilirubinemia, and alkaline phosphatase is important in order to detect hepatic metastases. The serum level of chromogranin A (CgA) has been proposed as and demonstrated to be a type of sensitivity marker (albeit a nonspecific one) for determining the presence of glucagonoma. [15] However, elevated levels of chromogranin A do not appear to assist in the diagnosis of recurrences. Stimulation tests with arginine, secretin, or tolbutamide, which rapidly stimulate plasmatic glucagon levels in patients affected by glucagonoma, are of little additional help.
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. [16] In reported cases, primary endocrine malignant tumor showed telomerase activity. The quantification of hTERT messenger ribonucleic acid (mRNA) has been used in clinical practice to exclude malignancy.
Imaging Studies
In patients with functioning islet cell tumors, the radiologist must localize the lesion. Knowing the tumor size and location, especially with hepatic metastases, is fundamentally important when deciding on treatment.
As with other endocrine tumors of the pancreas, the diagnosis requires localization by 1 of several modalities, including angiography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI). Ultrasonography is neither specific nor sensitive and has a low negative predictive value. The most frequent anatomical site is the distal pancreas (90% body and tail), making ultrasonographic identification even more difficult. [17] CT and MRI of the pancreas can help to characterize the precise site of the tumor (localized in the pancreatic tail in 86-88% of cases). [18] In 95% of cases, the tumor appears as a single mass, with a diameter varying from 1-30 cm.
Selective angiography of the celiac tripod can localize the center of the tumor with high reliability, and simultaneously characterizes hepatic metastases. The tumor usually appears as a prominent, hypervascular area. The combination of abdominal CT and angiography provides an acceptable preoperative assessment. [18]
MRI is useful in characterizing islet cell tumors, which have marked increased signal intensity on T2-weighted images. Gadolinium enhancement in the nonnecrotic or nondegenerated areas of the tumor shows a characteristic pattern that allows differentiation of islet cell tumors from the more common pancreatic adenocarcinoma, which is hypovascular and has lower signal intensity on T2 images.
Metaiodobenzylguanidine (MIBG) scintigraphy may be helpful in detecting the primary tumor.
Positron emission tomography (PET) scanning and scintigraphic study with indium-111 octreotide (111In-D-Phe1-octreotide) or C-11 L-dihydroxyphenylalanine (11C-L-DOPA) have been used, but, because of the small number of patients with glucagonoma, estimating the true reliability of these imaging techniques has not been possible. Because the lymph node metastases and the primary tumor in the pancreatic tail cannot be observed with ultrasonography, CT scanning, or angiography, this diagnostic tool might be useful in selected patients. [19] Practically all glucagonomas studied have been somatostatin receptor positive. [20, 21]
Procedures
Correctly performed biopsy of the skin during an advanced phase of the disease allows for a diagnosis of necrolytic migratory erythema. Different stages of the cutaneous lesions may be present simultaneously. Performing repetitive, multiple, and random sampling of the lesions is very helpful for diagnosis.
Based on radiologic features, a Tru-cut biopsy or laparotomy could be performed in order to obtain histologic samples.
Histologic Findings
Usually, glucagonomas arise from alpha-2 cells of the pancreatic islets and grossly appear as a single mass (80%). Approximately 80% of glucagonomas are carcinomas; the remainder are adenomas. Although the tumor is most frequently localized in the tail of the pancreas, finding it in other areas of the organ is not rare (24% in the body of pancreas, 10% in the head of the pancreas, and 20% in multiple foci throughout the pancreas). Glucagonoma is rarely found in a gastric or duodenal location.
The tumor appears as a solid, single mass of 5 cm or more that is well demarcated from the surrounding parenchyma and is encapsulated, with a rich vascular network that differentiates it from pancreatic adenocarcinomas. More rarely, a number of neoplastic lesions can be found. The tumor cells are occasionally organized in nests and strands and appear strongly glucagon positive on immunohistochemical staining. A strong cellular affinity for betacellulin, a member of the family of epidermal growth factors (EGFs), has been reported. [22] Electron microscopy shows secretory granules and an extended rough endoplasmic reticulum (RER).
The basic skin damage seems to consist of small blisters, which contain acantholytic epidermal cells, neutrophils, and lymphocytes. The surrounding epidermis is usually intact, and the dermis contains a lymphocytic perivascular infiltrate. Skin samples from the areas with early necrolytic migratory erythema show lymphocytic infiltration of the dermis, while examination of the epidermis shows focal dyskeratosis and lymphocytes. Later, lymphocytic infiltration of the dermis with neutrophils and eosinophils can be found, while the epidermis shows diffuse parakeratosis, acanthosis, loss of the granular layer, and necrosis of the superficial layers.
Metastases that are histologically similar to the primitive tumor may be in the liver (60-90%).
Images are included below.
A section of a glucagonoma mass with several fiber bundles and solid cellular strands (125 X). Courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
A section of a glucagonoma mass with irregular aspects of fiber bundles and cellular strands (400 X). Courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
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A section of a glucagonoma mass with several fiber bundles and solid cellular strands (125 X). Courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
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A section of a glucagonoma mass with irregular aspects of fiber bundles and cellular strands (400 X). Courtesy of Professor Pantaleo Bufo, University of Foggia, Italy.
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Bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors: Part 1. Courtesy of Memorial Sloan-Kettering Cancer Center.
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Bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors: Part 2. Courtesy of Memorial Sloan-Kettering Cancer Center.
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Postprocedure computed tompgraphy scans after bland embolization of the right hepatic artery in a patient with metastatic neuroendocrine tumors. Courtesy of Memorial Sloan-Kettering Cancer Center.
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Necrolytic migratory erythema over the back with areas of healing and hyperpigmentation. Courtesy of Case Reports in Surgery (https://www.hindawi.com/journals/cris/2016/1484089/).
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Necrolytic migratory erythema. Courtesy of Rare Tumors (SAGE Publications Ltd) (http://www.pagepress.org/journals/index.php/rt/article/view/rt.2009.e6/1169).
