What is Glucagonoma Syndrome?
Glucagonomas are a type of tumor that grows in the pancreas and releases a hormone called glucagon. Glucagonoma syndrome is the result of too much glucagon in the body caused by the tumor. The first case of this condition was reported in 1942, involving a 45-year-old woman who had widespread skin inflammation, unexplained weight loss, tongue inflammation, and unusual reactions to sugar. They found that she had a tumor in her pancreas after examining her tissues after her death.
In 1966, another group of researchers identified classic signs of the syndrome, including mild diabetes and skin inflammation, in relation to elevated glucagon levels due to a tumor spread from the pancreas. This write-up focuses on how glucagonomas present in patients and how they are managed.
What Causes Glucagonoma Syndrome?
Glucagonomas are a type of tumor that start from a certain kind of stem cell that originated from the innermost layer of an embryo. These tumors usually grow from particular cells called alpha cells, located in small areas within the pancreas called islets. Most of the time, people only get one glucagonoma. However, in rare cases (less than 10%), these tumors have been linked with a condition called Multiple Endocrine Neoplasia 1 Syndrome (MEN1), which involves tumors in more than one gland in the body’s hormone-producing endocrine system.
Risk Factors and Frequency for Glucagonoma Syndrome
Glucagonomas are uncommon, with rates of new cases per year ranging from 0.01 to 0.1 per 100,000 people. These tumors tend to be large, usually exceeding 3 cm, and are most often found in the tail or body of the pancreas because that’s where most alpha cells are located. More than half of these tumors are already spread to other parts of the body when they’re diagnosed. Both males and females have an equal chance of having a glucagonoma, with most patients being diagnosed between the ages of 50 and 60.
- Glucagonomas are rare, with 0.01 to 0.1 new cases per 100,000 people each year.
- The tumors are generally large (greater than 3 cm).
- They are often found in the tail or body of the pancreas where most alpha cells are.
- Over 50% of cases have already spread by the time they are diagnosed.
- Both men and women get it equally.
- Most patients are between ages 50 and 60 when they get diagnosed.
Signs and Symptoms of Glucagonoma Syndrome
Glucagonoma syndrome is also known as 4D syndrome, referring to the main symptoms it causes. These symptoms include skin conditions (dermatosis), high blood sugar (diabetes), blood clots in deep veins (deep vein thrombosis), and feelings of sadness (depression).
The most common skin problem associated with glucagonoma syndrome, called necrolytic migratory erythema (NME), affects up to 90% of patients. This begins as little red bumps or patches that can be itchy and painful. These patches grow and merge together to form larger, blister-like spots. NME tends to occur mostly around the mouth, the genital area, and on the arms and legs. Other symptoms linked to NME can include soreness in the mouth, eyes, and lips, as well as hair loss and abnormal nails.
- Weight loss, experienced by about 90% of patients
- High blood sugar, seen in nearly 80% of patients
- Deep vein thrombosis, or blood clots in the veins, affecting about 50% of patients
- Depression, which affects about 50% of patients, possibly due to the chronic skin condition
- Other psychiatric symptoms may include memory loss, psychosis, restlessness, abnormal reflexes, poor coordination, paranoid thoughts, and muscle weakness
- Chronic diarrhea, seen in about 30% of patients
If someone has an unexplained blood clot, they should be checked for possible glucagonoma. This condition can sometimes lead to a blood clot in the lungs, which can be life-threatening.
Testing for Glucagonoma Syndrome
If you’re experiencing Necrolytic Migratory Erythema (NME), a skin rash typically associated with glucagonoma, along with or without other symptoms, your doctor may suspect you have this type of tumor. Glucagonoma is a rare tumor that grows in your pancreas and can cause various symptoms due to the excessive production of a hormone called glucagon.
One of the tests your doctor may order is a fasting plasma glucagon level test. This helps measure the amount of glucagon hormone in your bloodstream. Typically, if the glucagon levels exceed 500 pg/mL while you’ve been fasting, it may suggest glucagonoma. However, this test requires careful interpretation because various types of the glucagon molecule can interfere with the results. Your doctor will always use the same type of test to ensure accurate tracking of glucagon levels over time.
Your doctor might also recommend some tests to measure the levels of amino acids (components of proteins) and zinc in your blood. These tests help assess your nutritional status, as glucagonoma patients tend to have low levels due to the disease’s metabolic impact.
In addition, a complete blood count (CBC) might be requested to check for anemia, a condition where you don’t have enough red blood cells that can carry adequate oxygen to your body’s tissues. A comprehensive metabolic panel (CMP) which checks for various bodily functions like liver, kidney, electrolyte and acid/base balance, and blood sugar may also be conducted to identify other possible metabolic disturbances.
In some rare instances, glucagonoma could be linked with a condition called MEN1 syndrome (a condition characterized by multiple endocrine tumors). Therefore, it might be useful to check the levels of certain hormones like parathyroid hormone, gastrin, insulin, and others in your blood. A skin biopsy (a test where a small piece of skin is taken for laboratory examination) of the NME rash may also be performed. This can reveal specific changes in the skin cells that can suggest glucagonoma.
When it comes to imaging tests, a type of CT scan, called a helical multiphasic contrast-enhanced CT scan, is usually the first step for locating the tumor. This test is quite reliable and has a success rate of over 80% for spotting these tumors within the pancreas.
In cases where the findings from the CT scan are not clear, an MRI scan might be performed as it can be better at identifying liver metastases (spread of the tumor to the liver). Glucagonomas typically express abundant somatostatin receptors (protein molecules on the cell surface that respond to the hormone somatostatin), making them a good candidate for a test procedure called somatostatin receptor scintigraphy (SRS). SRS is a type of imaging test that uses a radioactive version of the hormone somatostatin, which binds to the receptors on the tumor cells, allowing them to be visualized.
In certain instances, PET imaging with specific injectable substances (such as DOTA peptides like DOTATATE, DOTANOC, DOTATOC) can be used to identify non-metastatic tumors. This provides a higher resolution image compared to SRS and is particularly helpful in detecting smaller lesions.
Treatment Options for Glucagonoma Syndrome
For some cancer cases where the tumor hasn’t spread, the only way to cure the person is through a surgery known as surgical resection. This involves removing part of the pancreas. The decision on which part to remove is very careful and depends on where exactly the tumor is and how big it is.
As many people with this condition lose weight due to the effects of a hormone called glucagon, they might also need special medical diets supplemented with nutrients and zinc to help counter these effects. The doctors may also prescribe nutrients injected into the veins, known as total parenteral nutrition.
Physicians also often recommend a group of medications called somatostatin analogs, examples of which are octreotide and lanreotide. These can help control glucagon levels in the body, improving symptoms like weight loss, high blood sugar, diarrhea, and neurological symptoms like confusion or mood swings.
If the disease spread to other parts of the body (most commonly the liver), treatment might vary. If the disease only involves a small part of the liver, physicians might remove that part in a procedure known as hepatic resection. If that’s not possible, they might use a less invasive method, like injecting a substance to block the blood supply to the liver tumors (known as hepatic arterial embolization) or using a probe to heat up and destroy small liver tumors (called radiofrequency ablation).
If liver treatments are not enough, physicians might also recommend chemotherapy drugs to kill the cancer cells throughout the body. Some these drugs are often taken together with somatostatin analogs. Patients with large tumors or particularly aggressive disease will be the ones most likely to need this type of treatment.
Another advanced neuroendocrine tumor treatment option is the use of drugs that act on specific parts of the cancer cells, like sunitinib and everolimus. Last, a novel method being used for the management of neuroendocrine tumors is known as Peptide receptor radionuclide therapy (PRRT), a type of therapy that uses radioactive material to kill cancer cells.
Ultimately, the goal of all these treatments is to control the size of the tumor, manage symptoms, and improve the patient’s quality of life.
What else can Glucagonoma Syndrome be?
Blood tests can reveal high levels of the hormone glucagon in various conditions – not just in response to a glucagonoma. These conditions include serious bodily damage or shock, diabetes, injuries caused by burns, severe infections throughout the body, kidney failure, liver disease, inflammation of the pancreas, and Cushing syndrome, among others. Usually, however, these conditions do not elevate glucagon levels beyond 500 pg/mL. There’s also a rare medical condition known as Mahvash disease, caused by a genetic mutation, that elevates glucagon levels without causing any symptoms.
Similarly, a skin condition called necrolytic migratory erythema (NME) is not exclusive to glucagonoma. NME can also occur with chronic liver disease, inflammatory bowel disease, pancreatitis, drug misuse (specifically heroin), certain types of cancer in the intestine and rectum, and a blood cell disorder called myelodysplastic syndrome.
There are also NME-like skin lesions that occur due to deficiencies in essential fatty acids or zinc, or due to malnourishment that leads to inadequate protein intake.
What to expect with Glucagonoma Syndrome
Glucagonomas, a rare type of tumor, often grow slowly, but they’re generally pretty advanced by the time they’re diagnosed. Factors that predict how well a person with a glucagonoma will do – called survival predictors – include the person’s age, the grade of the tumor, and whether the tumor has spread to other parts of the body (metastasized). Unfortunately, once the tumor has metastasized, or spread, it’s generally not possible to cure it.
The National Comprehensive Cancer Network has guidelines for what doctors should do after they’ve removed a glucagonoma. These guidelines recommend checking the patient’s medical history and doing a physical examination, measuring their blood glucagon level (since glucagonomas release this hormone), and performing a CT scan or MRI. These checks should be done in the first 3 to 12 months after surgery. After the first year, it’s recommended to do these checks every 6 to 12 months for up to 10 years.
