Glucagonoma

A glucagonoma is a glucagon-secreting neuroendocrine tumor that originates from the α-cells in the pancreatic islets. Most glucagonomas are malignant, and many of them are part of the autosomal dominant condition known as multiple endocrine neoplasia syndrome type 1 (MEN 1). Elevated levels of glucagon lead to increased gluconeogenesis and glycogenolysis, resulting in an increase in free glucose in the bloodstream and the depletion of fat and amino acid stores. Patients often present with diabetes, a characteristic rash called necrolytic migratory erythema, weight loss, anemia, deep vein thrombosis, and neuropsychiatric symptoms. Laboratory findings demonstrate an elevated glucagon level, and imaging shows a pancreatic mass. Management is usually supportive and includes glucagon inhibition with octreotide (a somatostatin analog). Surgical resection is attempted if disease is localized, though this is frequently palliative. Chemotherapy and targeted molecular agents are also used in advanced disease.

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Definition and Epidemiology

Definition

A glucagonoma is a glucagon-secreting tumor arising from the α cells in the pancreatic islets and is sometimes seen in the context of MEN 1.

Epidemiology

  • Incidence: 
    • 1 in 10 million to 10 in 10 million
    • Male:female ratio = 1:1
  • Peak age at diagnosis: 45–70 years 
  • 50%–80% metastatic at diagnosis
  • Size and location:
    • 50%–80% occur in pancreatic tail (↑ number of α cells).
    • Usually > 3 cm  
  • Association with MEN 1: 
    • 10%–20% of glucagonomas associated with MEN 1
    • Glucagonomas occur in only 3% of MEN 1 patients.
  • Sporadic cases: 80%–90%

Pathophysiology

Normal physiology of glucagon

Secreted by the α cells in the pancreatic islets, glucagon’s role is to make energy readily available by producing glucose and halting its storage.

  • Stimulates:
    • Glycogenolysis: breakdown of glycogen → glucose
    • Gluconeogenesis: glucose production from amino acids and fats
    • Lipolysis: breakdown of lipids → fatty acids + glycerol → energy production
      • Fatty acids → ketogenesis
      • Glycerol → pyruvic acid → citric acid cycle
    • End effect: ↑ glucose
  • Inhibits:
    • Glycogenesis: glycogen production
    • Fatty acid synthesis
    • Cholesterol synthesis
  • Other glucagon effects:
    • GI smooth muscle relaxation → used in some GI radiologic imaging
    • Positive inotropic effects → used to treat beta blocker and calcium channel blocker toxicity
  • Normally secreted in response to:
    • Hypoglycemia and fasting
    • Gastric inhibitory peptide
    • Ghrelin
  • Secretion is inhibited by:
    • Hyperglycemia
    • Insulin
    • Somatostatin

Pathophysiology of glucagonomas

  • Unregulated ↑ glucagon:
    • Hyperglycemia
    • ↓ Amino acids (used to produce glucose)
    • ↓ Fat stores (used to produce glucose)
  • Pancreatic β-cell function preserved:
    • Insulin secretion remains under normal control.
    • ↑ Glucose → ↑ insulin → diabetes mellitus 
  • Express abundant somatostatin receptors (inhibitory) 
  • Metastasis is common in: 
    • Liver (1st)
    • Regional lymph nodes
    • Bone
    • Adrenal glands
    • Kidneys
    • Lungs

Pathophysiology of MEN 1

Glucagonomas are uncommon, but 10%–20% of those that are found are associated with MEN 1.

  • Autosomal dominant defect in MEN 1 gene (tumor suppressor)
  • Predisposes patients to tumors in:
    • Parathyroid glands
    • Pancreatic islet cells
    • Pituitary
  • Parathyroid tumors:
    • Primary hyperparathyroidism → ↑ calcium
    • Almost universal in MEN 1
    • Symptoms of hypercalcemia: 
      • ↓ Bone mineral density
      • Kidney stones
      • Polyuria and polydipsia
      • Constipation
  • Pancreatic tumors:
    • Gastrinoma/Zollinger–Ellison syndrome (most common): ↑ gastrin → multiple peptic ulcers
    • Insulinoma (common): ↑ insulin → ↓ glucose
    • Glucagonoma: ↑ glucagon → ↑ glucose
    • Somatostatinoma: inhibits a variety of GI processes
    • VIPoma: ↑ vasoactive intestinal peptide (VIP) → regulates smooth muscle activity and blood flow in GI tract
    • Nonfunctioning tumors
  • Pituitary adenomas (anterior pituitary):
    • Prolactinoma (most common) → ↑ prolactin
    • Others may secrete: 
      • Growth hormone (GH)
      • Adrenocorticotropic hormone (ACTH)
      • Thyroid stimulating hormone (TSH)

Clinical Presentation

The presentation of glucagonomas can be confused with that of many other conditions, and the ultimate diagnosis of most cases is not confirmed until there has been metastatic spread of the disease.

Diabetes mellitus

  • 75%–95% of cases
  • Usually no diabetic ketoacidosis (β-cell function and insulin secretion preserved)
  • Symptoms:
    • Polyuria 
    • Polydipsia
    • Blurred vision
    • Weight loss

Necrolytic migratory erythema (NME)

  • 70% of cases
  • Not specific to glucagonomas
  • Painful, pruritic rash
  • Lesions wax and wane
  • Location: 
    • Starts in intertriginous (areas where skin touches) and periorificial sites
    • Ultimately widespread: groin, perineum, buttocks, lower abdomen, extremities, and face
  • Progression of appearance: 
    • Erythematous plaques and papules 
    • Lesions enlarge and coalesce 
    • Central clearing and erosion 
    • Central induration with blistering, crusting, and scaling borders (can resemble impetigo)
  • Mucosal manifestations:
    • Stomatitis (inflammation of mouth)
    • Cheilitis (inflammation of lips)
    • Glossitis (inflammation of tongue)
  • Thought to be caused by:
    • ↓ Amino acids
    • Poor nutrition
Necrolytic migratory erythema

Necrolytic migratory erythema (NME) is a cutaneous manifestation often (but not exclusively) seen with glucagonomas. NME is described as areas of well-demarcated erythematous plaques, with fragile blisters and erosions.

Image: “Necrolytic Migratory Erythema” by Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, No, 277, Yanta West Road, 710061 Xi’an, Shaanxi, P,R, China. License: CC BY 4.0

Other common findings

  • Weight loss:
    • Most common presenting feature (80% of cases)
    • Due to ↑ lipolysis and gluconeogenesis from fats
  • Chronic diarrhea
  • Anemia
  • Deep vein thrombosis (DVT)/thromboembolic events 
  • Neuropsychiatric manifestations:
    • Depression
    • Dementia
    • Psychosis

Mnemonic

To recall the clinical manifestations of a glucagonoma, remember the 6 Ds:

  • Diabetes (or insulin resistance due to hyperglycemia)
  • Dermatitis (NME)
  • Declining weight
  • Diarrhea
  • Deep vein thrombosis 
  • Depression

Diagnosis

The diagnosis of glucagonoma is made on the basis of a combination of history, exam, elevated glucagon levels, and imaging showing a pancreatic mass. Staging malignant disease is also an important part of the diagnostic process, since metastases are often present at diagnosis.

Laboratory

  • ↑ Glucagon levels: usually > 500 pg/ml 
  • ↑ Glucose
  • CBC: normocytic anemia
  • CMP: 
    • Chronic diarrhea → electrolyte abnormalities
    • Hyperparathyroidism in MEN 1 → ↑ calcium
  • Skin biopsy:
    • Acantholytic epidermal cells
    • Lymphocytic and neutrophilic infiltrate

Imaging

  • Purpose:
    • Accurately localize tumor
    • Determine extent of disease
  • CT scan with IV contrast:
    • Best initial diagnostic method 
    • High sensitivity and specificity 
    • Findings: 
      • Pancreatic mass, often in tail
      • Typically > 3 cm in size
  • MRI:
    • May have higher sensitivity for liver metastasis than CT
    • Findings: 
      • ↓ Intensity on T1-weighted images
      • ↑ Intensity on T2-weighted images
  • Somatostatin-receptor scintigraphy:
    • Scans for radiolabeled uptake of somatostatin analog octreotide
    • Glucagonomas have ↑ somatostatin receptors and readily bind octreotide.
    • Allows for tumor localization and detection of metastases
    • Being replaced by functional PET scans
  • Functional PET:
    • Used for tumor localization and detection of metastases
    • Better resolution, quantification, specificity, and sensitivity than somatostatin-receptor scintigraphy

Staging and prognosis

  • Staged using TNM system:
    • Size of tumor
    • Extent of local invasion
    • Lymph node involvement
    • Presence and location of metastasis
  • Prognosis is determined according to stage.
  • Cure is rarely possible once metastasis occurs.
  • 5-year survival rates:
    • Stage I: 61%
    • Stage II: 52%
    • Stage III: 41%
    • Stage IV: 15%

Management

Initial management

  • Control diabetes.
  • Nutritional support (may require total parenteral nutrition)
  • Somatostatin analogs:
    • Octreotide
    • Inhibit glucagon secretion.
    • Improve NME, diabetes, diarrhea, and neurologic symptoms
  • DVT prophylaxis:
    • Lovenox
    • Heparin

Advanced management

  • Pancreatic resection (if localized to pancreas)
  • Hepatic resection (limited liver involvement)
  • Hepatic artery embolization (more extensive metastases):
    • Palliative technique
    • Can infuse chemotherapeutic drugs into hepatic artery during procedure
  • Radiofrequency ablation of small liver lesions
  • Chemotherapy
  • Molecular targeted agents for advanced disease:
    • Sunitinib (tyrosine kinase inhibitor)
    • Everolimus (mammalian target of rapamycin (mTOR) inhibitor)

Differential Diagnosis

  • Diabetes mellitus: a condition caused by an impairment in insulin secretion and/or function leading to hyperglycemia: Patients typically present with classic symptoms of hyperglycemia, including polyuria, polydipsia, blurred vision, and weight loss. Both diabetes mellitus and glucagonomas show persistent hyperglycemia, but glucagonoma should be suspected if there are dermatologic findings or chronic diarrhea or a DVT is also present. Glucagonoma can be confirmed with a glucagon level and imaging.
  • Cirrhosis: chronic progressive fibrosis of the liver, ultimately leading to hepatic failure: Cirrhosis is commonly caused by chronic viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease. The condition presents with jaundice, pruritus, upper GI bleeding, ascites, and/or weight loss. Although rare, NME can occur with cirrhosis, but spider telangiectasias are much more common skin manifestations. Cirrhosis can also cause elevated glucagon levels, although in cirrhosis these levels are usually < 500 pg/ml, as compared with glucagonomas, in which levels are often > 500 pg/ml. Cirrhosis is diagnosed with ultrasonography.
  • Acute pancreatitis: acute inflammation of the pancreas, typically presenting with severe epigastric pain and elevated serum lipase or amylase (2–3 times the upper limit of normal): Glucagon may be increased in acute pancreatitis, and imaging with CT or MRI shows focal or diffuse enlargement of the pancreas. Unlike acute pancreatitis, however, glucagonomas are not typically painful. 
  • Malnutrition or nutritional deficiencies: Zinc deficiency, pellagra, and kwashiorkor can all present with an NME-like rash. Primary management involves correcting the underlying deficiencies. However, none of the conditions listed are commonly associated with hyperglycemia and elevated glucagon levels, which is how they can be distinguished from glucagonomas (in addition to differences in history).
    • Zinc deficiency is associated with diseases of malabsorption (e.g., inflammatory bowel disease) and can cause hypogonadism, immune dysfunction, impaired wound healing, alopecia, loss of taste, and various skin lesions, including an NME-like rash. 
    • Pellagra is caused by niacin deficiency and may present with an NME-like rash, diarrhea, and dementia. 
    • Kwashiorkor is a disease of acute malnutrition. This disease is typically seen in children and results in symmetrical peripheral edema, beginning in the most dependent regions.

References

  1. Bergsland, E. (2019). Glucagonoma and the glucagonoma syndrome. In Grover, S. (Ed.), UpToDate. Retrieved February 12, 2021, from https://www.uptodate.com/contents/glucagonoma-and-the-glucagonoma-syndrome
  2. Sandhu, S. (2020) Glucagonoma syndrome. In Jialal, I. (Ed.), StatPearls. Retrieved February 12, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/22304/ 
  3. Arnold, A. (2019). Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis. In Mulder, J. E. (Ed.), UpToDate. Retrieved February 12, 2021, from https://www.uptodate.com/contents/multiple-endocrine-neoplasia-type-1-clinical-manifestations-and-diagnosis 
  4. Maitra, A., Abbas, A. K. (2005). The Endocrine System. In Kumar, V., Abbas, A. K., Fausto, N. (Eds). Robbins and Cotran Pathologic Basis of Disease (7th ed., p. 1207).
  5. Jensen, R. T. (2008). Endocrine tumors of the gastrointestinal tract and pancreas. In Fauci, A. S., Braunwald, E., Kasper, D. L., et al. (Eds.) Harrisons Internal Medicine (17th Ed., p. 2355).

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