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Complications and Comorbidities> Endocrine>
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Glucagonoma

Nestoras Mathioudakis, M.D. and Douglas Ball, M.D.
01-13-2011

DEFINITION

  • A rare tumor originating from the alpha cells of the pancreas that results in hypersecretion of glucagon.
  • Mild diabetes mellitus is a classic presenting feature of glucagonoma.
  • Hyperglycemia results from the glycogenolytic and gluconeogenic effects of glucagon and low insulin-to-glucagon ratio.

EPIDEMIOLOGY

  • Prevalence of glucagonoma: 13.5 per 20 million people (Echenique-Elizondo).
  • Glucagonomas are exceedingly rare, ~7% of all pancreatic endocrine tumors (Kindmark).
  • Males and females equally affected.
  • Most tumors (80%) occur sporadically, while remainder associated with MEN-1 syndrome (pituitary, pancreatic islet cell tumors, or parathyroid tumors).
  • Typical age at presentation is 40-50 years.
  • Most glucagonomas (75%) malignant and have metastasized by the time of diagnosis.
  • Prevalence of diabetes mellitus in glucagonoma: 38-94% (Chastain).  
  • Generally, the diabetes is mild to moderate. Mean HbA1C reported at 9.8% in one series (Wermers).

DIAGNOSIS

  • Necrolytic migratory erythema (NME) (described below): pathognomonic skin rash associated with glucagonoma, and generally the only clue to make the diagnosis. Skin biopsy diagnostic of NME:  superficial necrolysis at edge of lesion with separation of outer epidermal layers and perivascular infiltration with lymphocytes and histiocytes (Chastain). Also seen in other disorders.
  • If considered, measure glucagon. Glucagon levels >500 pg/ml strongly suggestive, and levels >1000 virtually diagnostic.   
  • Moderately elevated glucagon levels seen in hypoglycemia, fasting, sepsis, renal or hepatic failure, or acute pancreatitis. Modest elevations in glucagon seen with other pancreatic neuroendocrine tumors (Zollinger-Ellison syndrome, insulinoma, carcinoid).
  • Less specific findings: normochromic, normocytic anemia; hypoaminoacidemia (due to amino acid oxidation and gluconeogenesis from amino acid substrates).
  • If patient has classic clinical findings and/or elevated glucagon levels, then image for pancreatic mass. Abdominal CT scan with IV contrast preferred initial imaging study to localize pancreatic tumor. Unlike insulinomas, glucagonomas generally large at the time of diagnosis and more readily localizable.
  • Endoscopic ultrasound (EUS) to detect tumors that are too small to be visualized by CT. Tumors as small as 2-3 mm can be seen on EUS.
  • Fine needle biopsy using EUS confirms the diagnosis. Histopathology demonstrates an islet-cell tumor with positive glucagon staining by immunohistochemistry.
  • Although octreotide scan has high sensitivity for glucagonomas, not usually necessary since most glucagonomas very large at presentation and easily detected by CT.
  • Liver lesions suggestive of metastasis should be biopsied under CT guidance.

SIGNS AND SYMPTOMS

  • 4D's: dermatitis, diabetes, deep vein thrombosis, depression.
  • Symptoms: weight loss, polyuria, polydypsia, abdominal pain, diarrhea, constipation, low mood
  • Signs: angular cheilitis, glossitis, stomatitis, blepharitis, hair thinning, dystrophic nails, anemia, ataxia, optic atrophy, proximal muscle weakness, dementia, depression
  • NLD rash: erythematous papules or plaques, usually beginning in groin and perineum, then extending to buttocks, extremities, and face. Lesions enlarge and coalesce over 1-2 weeks, leaving behind blistering lesions with central clearing and psoriatic-like scaling. Lesions are often painful and pruritic.
  • Related to venous thrombosis: pain, swelling, tenderness, redness/discolored skin in affected extremity, visible surface veins.
  • Dilated cardiomyopathy (rare)

CLINICAL TREATMENT

Surgical therapy

  • Depends on the extent of disease at the time of diagnosis. Most common metastases: liver, regional lymph nodes, bone, adrenals, kidney, and lung. If tumor localized to pancreas at time of diagnosis, resection (simple enucleation, focal resection, Whipple) can be curative, but only successful in 30% of patients (Morgan
  • If metastatic disease with positive octreotide scan and hyperglucagonemia, options include surgical resection of liver metastases, hepatic artery chemoembolization, radiofrequency or cryoablation, and liver transplantation.
Medical therapy 

  • Somatatostatin analogues (i.e.octreotide) highly effective at controlling symptoms. Typical starting dose of octreotide: 50 mcg subcutaneously three times daily, increasing dose gradually to control symptoms (diarrhea, NME, neurologic symptoms), then transition to a long-acting depot formulation (Sandostatin LAR).
  • For extra-hepatic metastases, systemic chemotherapy (streptozosin, doxorubicin) may be considered, although response rate is low (Chastain).
  • Interferon alfa (IFNa) may have biochemical, radiographic, or clinical efficacy in a minority of patients (Kindmark). Use is limited by uncertain efficacy data and poor side effect profile.
  • Nutritional support often needed perioperatively for associated malnutrition related to chronic hypercatabolic state. Total parental nutrition, enteral feeding, or supplements may be offered. NME may respond to infusions of amino and fatty acids.
  • Radiation therapy may give symptomatic palliation to patients who are not surgical candidates.
  • Diabetes usually mild and easily controlled by diet, oral agents, or insulin. Since beta cell function preserved, insulin secretion normal, and diabetic ketoacidosis rare.
  • Glycemic control for diabetes best achieved by treatment of underlying disease (i.e. tumor resection).
  • In patients with metastatic disease who cannot be cured, treat hyperglycemia as standard type 2 diabetes.

FOLLOW UP

  • Yearly measurement of glucagon levels and other gastrointestinal hormones (i.e. gastrin) indefinitely, as this will allow early detection of any recurrence and detection of secondary endocrine disorders, such as Zollinger-Ellison syndrome, that may develop many years later.
  • Evaluate patients regularly for development of other endocrine tumors in the setting of MEN syndrome.
  • Monitored for typical complications of diabetes (retinopathy, proteinuria, neuropathy) and treated to usual lipid and blood pressure targets.

EXPERT COMMENTS

  • Glucagonoma is an extremely rare cause of diabetes; the diagnosis requires a high level of suspicion.
  • A patient with diabetes, weight loss, and the typical rash of NME should raise suspicion for this condition.
  • Diabetes generally mild, but common among patients with glucagonoma.
  • Glycemic control best achieved with treatment of underlying state of glucagon excess but, if not successful, can be treated with diet, oral agents, or (rarely) insulin.

Basis for Recommendations

  • Kindmark H, Sundin A, Granberg D, et al.; Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years.; Med Oncol; 2007; Vol. 24; pp. 330-7;
    ISSN: 1357-0560;
    PUBMED: 17873310
    Rating: Basis for recommendation
    Comments:A more recent series of glucagonoma patients showing slightly lower prevalence of diabetes in this population than previously described.

  • Chastain MA; The glucagonoma syndrome: a review of its features and discussion of new perspectives.; Am J Med Sci; 2001; Vol. 321; pp. 306-20;
    ISSN: 0002-9629;
    PUBMED: 11370794
    Rating: Basis for recommendation
    Comments:An excellent clinically-oriented review of the glucagonoma syndrome, with comprehensive differential diagnoses of both the NME rash and hyperglucagonemia in general.

  • Wermers RA, Fatourechi V, Wynne AG, et al.; The glucagonoma syndrome. Clinical and pathologic features in 21 patients.; Medicine (Baltimore); 1996; Vol. 75; pp. 53-63;
    ISSN: 0025-7974;
    PUBMED: 8606627
    Rating: Basis for recommendation
    Comments:One of a few case series of glucagonoma patients.

REFERENCES


 
 
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