Glucagonoma (Glucagon-Secreting Tumor)

Definition

A glucagonoma is a tumor that secretes glucagon, a hormone normally produced in the pancreas and responsible for raising blood sugar (glucose) levels. Glucagonomas are almost entirely found in the pancreas, arising from the alpha-2 cells of the gland, and about 80% of these tumors are malignant (cancerous). The tumor can cause elevated blood glucose levels known as glucagonoma syndrome but this is not present in every case.

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The elevated blood glucagon level (hyperglucagonemia) along with raised blood glucose levels (hyperglycemia) lead to a host of complications, marked by the 4Ds – diabetes mellitus, dermatitis (skin rash), deep vein thrombosis (DVT) and depression. The prognosis for glucagonomas are poor, especially once the cancerous cells spread to adjacent organs.

Incidence

Overall glucagonomas are rare neuroendocrine tumors. It only accounts for about 1% of all neuroendocrine tumors. The incidence of glucagonomas is estimated to be about 1 in 20 million people. The high risk age group is between 40 to 70 years with the average age of onset being 55 years. Women seem to be more likely than men to develop glucagonomas.

Pathophysiology

Glucagon and insulin are two pancreatic hormones that regulate the blood glucose levels. Insulin lowers blood glucose while glucagon elevates it. Glucagon is mainly secreted by the alpha-2 cells of the pancreas. Small amounts are also secreted by the inner lining (mucosa) of the stomach and duodenum of the small intestine. Normally glucagon is secreted in response to low blood glucose levels.

It stimulates the liver to release glucose that is stored in the form of glycogen within the liver. Apart from the blood glucose level, glucagon secretion may also be stimulated by other factors like acetylcholine and adrenal hormones like epinephrine. Serotonin is one hormone that can decrease the glucagon levels.

A glucagonoma secretes glucagon independently of the stimulating factors. The elevated levels of glucagon in the blood stream, referred to as hyperglucagonemia. Apart from recruiting the glycogen stores in the liver, glucagon also breaks down protein and fat in order to yield glucose. An elevated level of glucagon would increase glucose levels in the blood but not unless the metabolism in the liver is affected.

Insulin is unable to curb the rise in the blood glucose and this eventually leads to hyperglycemia. Apart from the effects of the hyperglucagonemia, glucagonomas are usually cancerous tumors. These cancers are slow growing and the survival rate is significantly longer after diagnosis when compared to other cancers. Diagnosis of a glucagonoma is often late and at this point there is often spread to other organs (metastasis), often the liver.

Symptoms

The symptoms of a glucagonoma are not always immediately obvious. Initially there is generalized symptoms and often the complications of hyperglucagonemia, like diabetes mellitus, may first be diagnosed. It is only with the collective presentation of certain of these complications, known as the 4 D’s, that a glucagonoma is considered as a possible diagnosis.

Generalized Symptoms

  • Unintentional weight loss
  • Inflamed mouth
  • Diarrhea
  • Increased appetite
  • Anemia

Diabetes Mellitus Symptoms

  • Increased thirst (polydipsia)
  • Frequent urination (polyuria)
  • Nighttime urination (nocturia)

There are a host of other symptoms of diabetes mellitus that becomes apparent over time.

Dermatitis Symptoms

A characteritic skin symptom develops in most cases of a glucagonoma and is known as necrolytic migratory erythema (NME). Initially the rash appears as red bumps and raised patches (plaques). It tends to start in the groin and spread to the buttocks. It then migrates to the abdomen and limbs. These lesions tend to coalesce over a 1 to 2 week period to form large continuous patches. These patches are itchy and often painful.

Gradually the rash starts to scale and clears from the center leaving behind a bronze to brown colored darkening of the skin. The edges of the rash become blistered and crusts over. There is a risk of a bacterial infection which can worsen the condition and need aggressive antibiotic treatment to prevent cellulitis. The mouth may also be involved with cracks at the corner of the lips.

Deep Vein Thrombosis Symptoms

  • Swelling of the leg
  • Skin color changes from a red to pale or even blue color. Dermatitis symptoms may also be present on the leg.
  • Leg pain with warmth over the affected area.

Often there are no symptoms present at the outset. Should the clot in the leg vein dislodge, it can travel through the blood stream and reach the lung where it causes an occlusion – pulmonary embolism. This is potentially fatal.

Depression Symptoms

  • Sadness
  • Apathy
  • Episodes of irritability, anger and frustration
  • Sleeping problems
  • Low sex drive

The presentation of depression can be complex and vary to some degree from one patient to another.

Causes

The causes of a glucagonoma are unknown. Patients may have a family history of glucagonoma. The condition is also associated with multiple endocrine neoplasia (MEN) type I which is a known risk factor. A glucagonoma is a neuroendocrine tumor that is localized to the pancreas in almost all cases. Secretion of glucagon arises either as a result of the mass apply pressure on the glucagon-secreting alpha-2 pancreatic cells or the tumor cells itself producing and secreting glucagon independently.

Diagnosis

A diagnosis of glucagonoma is often missed as these tumors are rare. The presence of the 4 D’s – diabetes, dermatitis (necrolytic migratory erythema), deep vein thrombosis and depression – should raise the concern about a glucagonoma. It is often the necrolytic migratory erythema that is the characteristic feature of the glucagonoma. The confirmation of the diagnosis involves several investigations such as :

  • Blood tests :
    – Glucagon level : normal is 50 to 200 pg/mL but in a glucagonoma it may be as high as 1,000 pg/mL or more.
    – Glucose level : fasting or glucose tolerance test (GTT) to confirm diabetes mellitus.
    – Liver function test (LFT) and bilirubin levels to detect cancer spread (metastasis) to the liver.
  • Scans :
    –  Computed tomography (CT)
    – Magnetic resonance imaging (MRI)
    – Metaiodobenzylguanidine (MIBG) scintigraphy
    – Positron emission tomography (PET)

Treatment

The medical treatment of glucagonoma is limited and surgery is the preferred option.

  • Octreotide is a drug that inhibits the secretion of glucagon. It can help relieve some of the symptoms associated with a glucagonoma but may worsen diabetes.
  • Chemotherapy is reserved for cases where surgery is not possible or the cancer has already spread (metastasis). However, chemotherapy has a very limited use in the treatment of glucagonomas.

Surgery is ideal in that the tumor can be removed and all symptoms will resolve thereafter. Due to the high chance of spread and often late diagnosis, some of the healthy tissue surrounding the tumor and regional lymph nodes are resected as well.

Patients should consult with a dietitian for further advice on a suitable eating plan. The aim is to replenish proteins and fats that are broken down due to the increased gluconeogenesis. Vitamin and mineral supplementation may also be advisable.

Survival Rate

The survival rate for a glucagonoma is poor. The tumor grows very slowly so there are cases where patients live for 15 years or more after diagnosis. The 5 year survival rate is about 85% after surgery where the tumor was localized to the pancreas and successfully removed.

References :

emedicine.medscape.com/article/118899-overview

www.nlm.nih.gov/medlineplus/ency/article/000326.htm

www.endocrinediseases.org/neuroendocrine/glucagonoma.shtml

www.diabetes.co.uk/glucagonoma.html

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