Glucagonoma Workup

• 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 syndrome, also check serum levels of fasting insulin, glucagon, prolactin, calcium, and VIP.
• Performing a study of the nutritional status of the patient is important in order to correct nutritional deficits; this test must evaluate the level of serum concentration 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.
  • 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. 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.

• 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).

  • The selective angiographic study of the coeliac tripod localizes with high reliability the center of the tumor, which usually appears as a prominent, hypervascular area, and simultaneously characterizes hepatic metastases.
  • A CT scan and an MRI study of the pancreas help to characterize the precise site of the tumor (localized in the pancreatic tail in 86-88% of cases).^[7] In 95% of cases, the tumor appears as a single mass, with a diameter varying from 1-30 cm.
  • Abdominal CT scanning is helpful in localizing the tumor and metastases. Thus, the combination of CT scanning and angiography provides an acceptable preoperative assessment.^[7]
  • 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 (¹¹¹ In-D-Phe1-octreotide) or C-11 L-dihydroxyphenylalanine (¹¹ C-L - DOPA) have been used, but, because of the small number of patients with glucagonoma, estimating the real reliability of these imaging techniques has not been possible. However, because the lymph node metastasizes and the primary tumor in the pancreatic tail cannot be observed with ultrasonography, CT scanning, or angiography, this diagnostic tool might be useful only in selected patients. Practically all glucagonomas studied have been somatostatin receptor positive.^{[8, 9]}
• Endoscopic ultrasonography is another useful modality that can be used in early localization of the tumor.

• Correctly performing a 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.

Usually, glucagonomas arise from alpha-2 cells of the pancreatic islets and grossly appear as a single mass (80%). In approximately 80% of cases, glucagonoma is a carcinoma, and it is an adenoma in 20% of cases. 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 the whole pancreas is interested with multiple foci). 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 capsulated, 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. 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.

No detailed or generally accepted staging system for glucagonoma exists.