eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

Glucagonoma: Differential Diagnoses & Workup

Author: Luigi Santacroce, MD, Assistant Professor, Medical School, State University at Bari, Italy
Coauthor(s): Laura Diomede, University of Bari School of Medicine, Italy; Mini R Abraham, MD, Consulting Staff, Saint Luke's Medical Group
Contributor Information and Disclosures

Updated: Nov 20, 2008

Differential Diagnoses

Acrodermatitis Enteropathica
Diabetes Mellitus, Type 2
Bacteremia
Paraneoplastic Syndromes
Cirrhosis
Pellagra
Diabetes Mellitus, Type 1
Psoriasis

Other Problems to Be Considered

Burn injury
Essential fatty acid deficiency
Herpetic dermatitis
Kwashiorkor
Renal failure
Zinc deficiency
Prolonged fasting
Hepatic failure
Use of danazol or oral contraceptive

Workup

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 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.

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).
    • 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.

Procedures

  • 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.

Histologic Findings

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%).

Staging

No detailed or generally accepted staging system for glucagonoma exists.

More on Glucagonoma

Overview: Glucagonoma
Differential Diagnoses & Workup: Glucagonoma
Treatment & Medication: Glucagonoma
Follow-up: Glucagonoma
Multimedia: Glucagonoma
References
Further Reading
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References

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Keywords

glucagonoma, glucagon, glucagonoma syndrome, alpha-cell tumor, alpha-cell adenoma, alpha cell, alpha cells, alpha-2 cell, alpha-2 cells, diabetes, diabetes mellitus, diabetes mellitus type 2, pancreas, hyperglycemia, hyperglycemic, neuroendocrine, 4D syndrome, neuroendocrine tumor, islet cell, islet cells, islet cell pancreatic tumor, pancreatic tumor, pancreas tumor, insulin, insulinoma, glucagon overproduction, hypoaminoacidemia, weight loss, normochromic and normocytic anemia, necrolytic migratory erythema, NME, hyperglucagonemia, pancreas, octreotide, Sandostatin, peptide hormone, bioactive peptide, tumor of the pancreas, multiple endocrine neoplasia type1, MEN I, islet celltumor

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Contributor Information and Disclosures

Author

Luigi Santacroce, MD, Assistant Professor, Medical School, State University at Bari, Italy
Disclosure: Nothing to disclose.

Coauthor(s)

Laura Diomede, University of Bari School of Medicine, Italy
Disclosure: Nothing to disclose.

Mini R Abraham, MD, Consulting Staff, Saint Luke's Medical Group
Mini R Abraham, MD is a member of the following medical societies: American Association of Clinical Endocrinologists and Endocrine Society
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Novo Nordisk Honoraria Speaking and teaching; Eli Lilly Honoraria Speaking and teaching

Medical Editor

Frederick H Ziel, MD, Associate Professor of Medicine, David Geffen School of Medicine at UCLA; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group
Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Romesh Khardori, MD, Chief, Division of Endocrinology, Metabolism and Molecular Medicine, Professor, Department of Internal Medicine, Southern Illinois University School of Medicine
Romesh Khardori, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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