Gastrointestinal stromal tumors (GISTs): What are they, and how are they treated?

A gastrointestinal stromal tumor is a type of sarcoma that develops in the connective tissue of the gastrointestinal tract. It’s often referred to as GIST.

GISTs are usually found in adults between the ages of 30 and 50. Though rare, GISTs can also be found in children and young adults.

We spoke with sarcoma medical oncologist Neeta Somaiah, M.D., to learn more about this rare type of cancer, including how it develops, how it’s treated and if it’s curable.

Where do gastrointestinal stromal tumors develop?

Gastrointestinal stromal tumors form when interstitial cells of Cajal grow abnormally and turn into cancer. Interstitial cells of Cajal are special cells in the muscle of the digestive tract.

Most GISTs start in the stomach, but they can be found anywhere in the gastrointestinal tract. In very rare cases, GISTs can appear to start in the peritoneum, the tissue that lines the abdominal wall.

What causes a GIST?

Most GISTs arise because of a random mutation in a cell’s KIT or PDGFR gene that occurs sporadically, meaning there’s no known cause. They often start as one tumor. In rare cases, people can be prone to developing multiple tumors at a younger age, or multiple family members can have a GIST. This usually happens in patients who have certain inherited mutations in the KIT, PDGFRA or SDH genes, or have the inherited disorder neurofibromatosis type 1.

Is a GIST likely to spread?

This depends on several factors, including:

Size of the tumor

This also correlates with how long the tumor has been inside of your body. The longer it’s been in your body, the more likely it is to have spread to the bloodstream.

Growth rate of the tumor

The mitotic count of a tumor refers to how many cells are actively dividing in a defined area of tumor tissue when viewed under a microscope.

Location of the tumor

If the GIST is in a larger organ like the stomach, it can often grow larger without spreading to other organs, especially if the mitotic rate is low. But if the GIST is in the small intestine or rectum, a more vascular area with a lot of nearby structures, it’s more likely to metastasize or spread.

GISTs usually spread to the liver or peritoneal cavity. They mostly spread through the bloodstream.

A GIST can be life-threatening if left untreated. It can metastasize and lead to death.

What are the symptoms of GISTs?

Some GISTs are small and may not cause symptoms. Often, a person doesn’t show symptoms until the cancer is at a late stage.

The top three symptoms of GISTs are:

• Gastrointestinal bleeding or anemia
• Feeling full quickly or after eating only a little bit
• Pain near the tumor site

How are GISTs diagnosed?

Because people with gastrointestinal stromal tumors usually do not have any symptoms during the disease’s earliest stages, GISTs are often found when a doctor is looking for something else.

If your doctor suspects you may have GIST, they may order any of the following tests:

• Imaging tests: A CT scan is used to look for a mass, or an MRI is done on the abdomen and pelvis.
• Upper endoscopy or colonoscopy: These can detect a mass in the esophagus, stomach, parts of the small intestine, colon or rectum. 
• Biopsy: This is when tissue is removed and tested for cancer cells.

If the patient has a tumor large enough to where we’re considering systemic treatment, we will run genetic testing on the biopsied tissue. Usually, we look for mutations in the KIT and PDGFRA genes. If those are negative, we’ll do additional testing. If we plan to treat the patient using targeted therapy, it’s important to know the GIST’s mutation type because some rare GISTs don’t respond to certain drugs.

How are GISTs treated?

Treatment for GISTs usually involves surgery and/or targeted therapy.

For GISTs that have not spread to other parts of the body, surgery is used to remove all of the cancer.

Sometimes, targeted therapy is used to shrink the tumor(s) before surgery. Targeted therapy is also used to treat GISTs that are advanced or have spread to other parts of the body. The drugs used are oral tyrosine kinase inhibitors.

Imatinib works well in 60% to 70% of patients, so it is the first-line treatment for most GISTs. The type of mutation and location of the mutation in the KIT or PDGFR gene determines how well the GIST will respond to the drug. About 5% to 8% of GISTs have mutations in the PDGFRA gene in the exon 18 location, which doesn’t respond to imatinib. 10% to 15% of GISTs might have mutations in genes other than KIT or PDGFR that make them less responsive to imatinib. Often, GISTs that respond to imatinib might eventually stop responding. This resistance to imatinib occurs because the GIST can develop secondary mutations. These secondary mutations are important because they can determine a patient’s response to later lines of therapy. We can test for mutations on biopsied tissue or through a liquid biopsy in certain cases.

If initial treatment doesn’t work or stops working, patients may be given sunitinib, a second-line treatment. If those drugs don’t work, regorafenib may be given as a third-line treatment. And if none of those drugs work, ripretinib may be given as a fourth-line treatment. This treatment sequence is evolving as we learn more about the secondary mutations and as newer drugs are being tested. Avapritinib is the only drug approved to treat GIST patients with the PDGFRA exon 18 mutation.

If the cancer doesn’t respond to standard treatments, the patient may need to try other targeted therapy drugs or enroll in a clinical trial.

Before 2001, chemotherapy was used to treat GISTs, but it did not work in shrinking the tumors. The chemotherapy drug temozolamide has shown success in treating a small subset of gastrointestinal stromal tumors called SDH-deficient GIST and is being tested in clinical trials.    

Are GISTs curable?

GISTs can be cured if they’re caught early and can be removed by surgery. Often, patients with GISTs will also need to take imatinib if their risk of recurrence is high. The risk is calculated based on the GIST’s:

• size,
• mitotic count and
• location.

Even patients with metastatic disease can be cured if the tumor is not bulky or large. For these patients, it’s important to understand that ‘cured’ means we can get to no evidence of disease (NED), but you need to keep taking the medication. We have patients who remain NED for a long time by continuing to take treatment. GISTs can be managed by treatment, and it lowers the risk of recurrence.

It’s more challenging to treat large, bulky tumors that are getting bigger on imatinib because subsequent therapies may not offer long-lasting benefits. This is often due to the presence of new secondary mutations.

Localized treatments, like embolization, ablation or surgery are used on a case-by-case basis to manage residual cancer cells or a limited area of growth that develops in patients who have metastatic disease and are on oral targeted therapy.

Catching GISTs early and treating them based on the mutation type can improve your chances of survival. It’s important to seek care for these rare types of tumors at a center like MD Anderson that has specialists who focus on treating these tumors. We can personalize your treatment, so you get the best possible results.

What research is being done to advance GIST treatment? 

We are testing new treatments for GISTs through clinical trials.

Once imatinib stops working for a patient, we want to determine if we can sequence the next treatment based on the drug that works best for the specific secondary mutations that are causing resistance. This can help ensure the tumor better responds to subsequent treatment.

MD Anderson is participating in a clinical trial looking at combining sunitinib with bezuclastinib to block more mutations in GISTs. I’m also leading a study to see if regorafenib can be used as a second-line treatment in patients with certain genetic mutations. IDRX-42 and NB003 are promising new drugs being tested in clinical trials.

This new research should give hope to patients and caregivers who may soon have more options for GIST treatment.

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