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Gastrointestinal Stromal Tumors (GISTs)

Gastrointestinal stromal tumors (GISTs) are rare tumors that start in special cells found in the wall of the GI tract, called the interstitial cells of Cajal (ICCs). ICCs are part of the autonomic nervous system, and coordinate the automatic movements of the GI tract. ICCs are sometimes called the "pacemakers" of the GI tract because they send signals to the muscles of the digestive system, telling them to move food and liquid through the GI tract.

GISTs may occur anywhere along the length of the digestive tract from the esophagus to the anus. 

Statistics

Although the exact incidence is still somewhat unclear, the American Cancer Society estimates that each year between 4,000 and 5,000 Americans develop GISTs. It is slightly more common in men. Although GISTs are most often diagnosed in people 50 years of age or older, they can occur in any age group. GIST appears to occur with increased frequency in patients with a history of neurofibromatosis (NF1 disease).

Approximately 50 to 70 percent of all GISTs develop in the stomach, while around 20 to 30 percent will arise in the small intestine. The rest arise in the esophagus, colon, and rectum. 

Risk factors

The most substantial risk factor for GIST is the presence of neurofibromatosis. There are rare instances of familial GIST where several family members have the condition.

Screening

Unfortunately there is no general screening test to check for GISTs. However, the earlier any tumor is discovered and treated, the better the chance of survival. For this reason, people who notice signs or symptoms of GIST should discuss this with their doctor right away.

Symptoms

People with early stage GIST often do not have any symptoms of the disease. Most GISTs are diagnosed after a person develops symptoms. These may include:

  • Abdominal discomfort or pain

  • Vomiting

  • Blood in stools or vomit

  • Fatigue due to anemia (low blood counts)

  • Feeling full after eating only a small amount (early satiety)

  • Loss of appetite

 

These symptoms may be the result of GIST or of other less serious causes. A person with these symptoms should discuss them with their doctor.

Why does GIST develop?

The way in which GIST grows, or the route the tumor takes when it spreads through the body, is called its pathophysiology.

Scientists are beginning to unravel some of the processes that go on inside cells that cause them to develop into GISTs. Normally these cells, like other cells in the body, grow and divide in a controlled fashion. But sometimes things can go wrong, allowing these cells to grow out of control and ultimately become cancerous.

Scientists have discovered that cells may grow in an uncontrolled manner as the result of an abnormality in their DNA. In GIST, a specific mutation causes a cellular enzyme known as KIT to be switched "on" all the time. KIT is an enzyme (called a "tyrosine kinase") responsible for sending growth and survival signals inside the cell. If it is ON, the cell stays alive and grows or proliferates. The overactive, uncontrolled mutant KIT enzyme triggers the runaway growth of GIST tumor cells. This insight into the way GISTs develop has already helped to identify new treatments for this sarcoma.

How is GIST diagnosed?

If a person feels a lump or experiences symptoms that may indicate the presence of a GIST, he or she should discuss them with a doctor. The doctor will take a detailed history of the patient and ask questions about the symptoms.

After a careful physical exam the doctor may perform tests such as an ultrasound, a computed tomography (CT or CAT) scan, or magnetic resonance imaging (MRI) to gain more information about whether there is an abnormal growth, where the growth is located, and whether it has spread.

In some cases a tissue sample, called a biopsy, may be needed. A doctor might perform one of three types of biopsies: fine needle aspiration; core needle biopsy; and excisional or incisional biopsy.

After the biopsy is taken, the sample is examined under a microscope by a pathologist. One of the things the pathologist will look for is whether there are detectable amounts of the KIT enzyme. KIT can be identified by looking for a portion of the enzyme called the "CD117" antigen (this is a bit of the enzyme that can be detected by a special diagnostic test). Most GISTs produce KIT, and detection of CD117 (called "expression of CD117" or "CD117 positivity") helps prove that the growth is a GIST.

Once a GIST has been identified, it is important to determine the best way to treat it. Ideally, surgery should be considered, to be performed by an expert surgeon who has experience in GIST management. GISTs grow differently in each patient. The size of the tumor and the rate at which they grow are important in determining the risk the tumor presents. Specifically, the risk of spread to other parts of the body (a process called metastasis) can vary greatly, with some very small GISTs (< 1 cm in size) essentially never spreading, whereas larger GISTs (> 15 cm) virtually always spread. 

Distinguishing benign from malignant tumors can be difficult. It is important to recognize that current consensus notes all GISTs as being at some risk of malignant behavior. In some cases even small tumors that are not growing rapidly may spread or metastasize. The location of the tumor seems to affect the tumor's behavior. For example, a small GIST from the small intestine may grow more quickly and be more likely to spread than a large tumor from the stomach. When a GIST metastasizes it usually spreads to the liver or peritoneal cavity (the lining of the abdominal wall).

How is GIST is treated?

Conventional approaches

Until recently, the only treatment for GIST had been surgery. The goal of surgery is to remove the tumor completely. However, surgery alone for larger GISTs, or for GISTs that have spread, yielded disappointing results.

Because there is a chance that malignant tumors can recur or come back after surgery, chemotherapy or radiation is used with many types of cancer. This is called adjuvant therapy. However, in the case of GIST, using either chemotherapy or radiation after surgery has not been shown to work in preventing the tumor from coming back. For this reason researchers have sought new effective therapies for GIST.

New treatments

A new drug previously used to treat a type of leukemia has been shown to be effective in treating GIST. The drug, called Gleevec (imatinib mesylate, Novartis Pharmaceuticals Corp, East Hanover, NJ), is used for patients with advanced-stage GIST, and it may also help patients with earlier-stage tumors. It doesn't seem to cure advanced GISTs, but it can help people with them live longer and feel better.

The way Gleevec works against cancer is unique. Most anticancer therapies developed in the past kill both tumor cells and normal cells, but Gleevec is able to disable the tumor cells while leaving healthy cells unharmed. Gleevec blocks the overactive KIT enzyme in the tumor cells. This disables the GIST cells so that many of them are destroyed. Although the drug also inhibits the KIT enzyme in normal cells, it does not seem to damage them.

By selectively killing tumor cells while allowing healthy cells to survive, Gleevec represents a new approach in cancer therapy called targeted therapy.

Gleevec is taken as an oral capsule and it is usually recommended that it be taken with a meal and a large glass of water to reduce irritation to the intestinal tract. Side effects of Gleevec are mostly mild to moderate. The most common side effect is mild nausea. Other side effects, usually mild as well, include diarrhea, fluid retention and swelling (often around the eyes), indigestion, muscle cramps, bleeding from the GIST tumor, fatigue, and a skin rash.

Sutent (Sunitinib) is another targeted therapy drug that is useful in treating GIST. It targets the KIT protein and several other proteins that Gleevec does not target. It is used in patients when Gleevec doesn't work or if they can't take it because of side effects. It seems to help about one out of three patients who can't take Gleevec. Sutent can cause tumors to shrink and often stops them from growing for a time. More important, patients getting the drug may live longer.

Sutent is also taken as a pill. The most common side effects are diarrhea, mouth irritation, and skin color changes. More serious side effects can include high blood pressure, increased risk of bleeding, and swelling.

FYH

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