Gastrointestinal Stromal Tumours (GIST)

What Are GISTs?

Gastrointestinal Stromal Tumours (GIST) are a type of tumour that can appear in the digestive tract. They most commonly occur in the stomach or small intestine. GISTs develop from special cells in the digestive system wall called interstitial cells of Cajal, which help move food through the digestive tract.

GISTs are relatively rare, making up only about 1-2% of all gastrointestinal (GI) cancers. The global incidence rate is 10-15 cases per million people each year. They are most frequently diagnosed in individuals over the age of 50, with the average age of presentation being 60-65 years old. However, GISTs can occur at any age.

GISTs are different from other types of gastrointestinal cancers. Stomach cancer starts at the stomach lining while GIST starts at the muscle layer of the stomach or intestinal wall. GISTs have unique origins, behaviours, and treatment requirements. 

Where Are GISTs Found?

GISTs can be found anywhere along the gastrointestinal tract, but they are most often located in:

• Stomach: 60%
• Small intestine: 35%
• Rectum: 5%
• Colon: 2-3%
• Oesophagus: less than 1%

The symptoms of Gastrointestinal Stromal Tumours (GISTs) can vary depending on the size and location of the tumour. However, some common symptoms include:

• Abdominal pain or discomfort
• A palpable mass or lump in the abdomen
• Fatigue or weakness due to anaemia
• Nausea or vomiting
• Unintended weight loss
• Blood in stool or vomit, which may appear as black or tarry stools
• Early satiety (feeling full after eating only a small amount of food)

It's important to note that these symptoms can also be associated with other, less serious conditions. Therefore, if you experience any of these symptoms, it is crucial to consult with a healthcare provider for a proper diagnosis and appropriate treatment.

The symptoms of GIST and stomach cancer:

Imaging Studies

• CT Scan: It helps to detect the size, location, and extent of the tumour, and can also reveal if the tumour has spread to other organs.
• PET-CT Scan: Positron Emission Tomography (PET) is used to determine if there has been any spread to other parts of the body (metastasis). 
• Endoscopy: An endoscope is a flexible tube with a light and camera used to visualize the gastrointestinal tract. It allows for direct observation of the tumour and enables tissue biopsy.
• Biopsy: The biopsy samples are analysed for specific markers, particularly the KIT protein (CD117), which is present in approximately 95% of GISTs. Immunohistochemistry is used to detect this protein and other markers that can help differentiate GIST from other types of tumours.

Genetic Testing

• Mutation Analysis: Identifies mutations in genes such as KIT and PDGFRA, which are commonly associated with GIST. The presence of certain mutations can guide treatment decisions and provide prognostic information.
• Next-Generation Sequencing (NGS): GIST without a KIT or PDGFR mutation should be tests for other rare biomarkers, e.g. DHC-deficiency, BRAF mutations, NF1 mutation, NRTK fusions, and FGFR fusions. NGS can provide detailed information about the genetic profile of the tumour.

Risk Classification of GIST

The management of GIST depends on the size of the tumour, its location, the patient's fitness for treatment, and the absence of evidence of spread.

Active Surveillance

For very small stomach GIST (size < 2cm) without high-risk features, active surveillance may be recommended. This approach involves regular monitoring using imaging studies such as CT scans or endoscopy to check for any changes in the size of the tumour.

Surgical Resection

Surgery is the primary treatment for localized gastrointestinal stromal tumours (GISTs), with the goal of complete tumour removal and recurrence prevention. A wide local resection with clear margins while preserving function is advised. Extended lymphadenectomy is typically unnecessary. Small tumours may be removed laparoscopically. However, in patients with large tumours, laparoscopic/robotic approach is discouraged because of the risk of tumour rupture. If adjacent organs are involved, en bloc resection is recommended.

If complete removal of the tumour is not feasible, physicians may administer targeted therapy prior to surgery. This approach is particularly advantageous when the tumour exhibits specific mutations that are responsive to such treatment. Pre-treatment with imatinib serves to reduce the size of the tumour, thereby enhancing surgical safety and minimizing the risk of complications such as rupture or bleeding. Typically, this therapy is administered over a period of 6-12 months before the surgical procedure. Beyond 12 months, further tumour shrinkage is uncommon, and there is a potential for the development of resistance to the treatment.

Adjuvant Therapies

Adjuvant imatinib is a medication used to help prevent the recurrence of gastrointestinal stromal tumours (GIST) after surgery. It works by targeting KIT mutations in the tumour cells, which can stop the cancer from growing and spreading. For patients with a higher risk of recurrence, imatinib is typically recommended at a dosage of 400 mg per day for a period of three years. 

Common side effects of imatinib include:

• Nausea and vomiting
• Diarrhoea
• Muscle cramps
• Fatigue
• Skin rash
• Fluid retention
• Abdominal pain
• Headache

Less common but more serious side effects can include:

• Hepatotoxicity (liver damage)
• Cardiotoxicity (heart issues)
• Severe fluid retention, leading to oedema
• Gastrointestinal bleeding
• Low blood cell counts

Follow-Up Care

Post-treatment follow-up care is important for monitoring recurrence and managing long-term treatment effects. This includes:

• Regular imaging studies to detect any signs of recurrence.
• The frequency of imaging is based on the risk of recurrence.
• Patients receiving adjuvant therapy with imatinib should have CT scans 3 months after surgery, then every 6 months for 2 years, followed by annual scans up to 5 years (as per intermediate risk patients).

For managing advanced and metastatic GIST, different treatments are recommended based on the specific mutation of the tumour:

C-KIT mutation:

• Imatinib is the standard first-line treatment.
  • For Exon 11 mutation: The usual starting dose is 400 mg daily.
  • For Exon 9 mutation: The usual starting dose is 800 mg daily.
  • If the disease progresses on 400 mg daily imatinib, the dose may be increased to 800 mg daily. 
• If there is confirmed progression or if the patient cannot tolerate imatinib, the second-line standard treatment is sunitinib.
• Sunitinib administration: 
  • 50 mg daily for 4 weeks on/2 weeks off or 37.5 mg once daily, taken orally
  • Side effects of sunitinib: fatigue, nausea/ vomiting, hypertension, diarrhoea, hand-foot syndrome, skin discoloration, mouth sores, bleeding etc.
• If progression continues or there is no response to imatinib and sunitinib, the third-line treatment is regorafenib.
• Regorafenib administration: 
  • 160 mg daily for 3 out of every 4 weeks, taken orally
  • Side effects of regorafenib: fatigue, hand-foot skin reaction, diarrhoea, hypertension, rash, decreased appetite, mucositis, liver function impairment, protein in urine, etc.
• If the disease progresses or there is intolerance to imatinib, sunitinib, and regorafenib, the fourth-line treatment is ripretinib.
• Administration of ripretinib: 
  • 150mg daily, taken orally
  • Side effects of ripretinib: fatigue, alopecia, myalgia, nausea, diarrhoea, abdominal pain, arrythmia, bleeding, etc.

SDH-deficient:

• For patients with SDH-deficient GISTs, the usual treatments may not work as well. If you didn't respond to imatinib before, doctors might try sunitinib or regorafenib. In some cases, doctors might even try imatinib again if you previously had a good response to it, or they might keep you on the same treatment even if the cancer is progressing.

PDGFRA exon 18 D842V mutations:

• Avapritinib is the standard treatment.
• Administration: 300mg daily po
• Side effects of Avapritinib: Fatigue, nausea/vomiting, diarrhoea, oedema, decreased appetite, anaemia, cognitive impairment, liver impairment

NTRK-fusion:

• Larotrectinib: 
  • Administered orally at a dose of 100 mg twice daily.
  • Side effects: Fatigue, dizziness, nausea, anaemia, increased liver enzymes, constipation, and weight gain.
• Entrectinib:
  • Administered orally at a dose of 600 mg once daily
  • Side effects: Fatigue, constipation, dizziness, oedema, dysgeusia (altered taste), and increased liver enzymes

BRAF-mutation:

• Dabrafenib and Trametinib
• Administration: Dabrafenib at 150mg twice daily; Trametinib at 2mg daily 
• Side effects: fatigue, fever, join pain, nausea, skin rashes, headache, high glucose level, arrhythmia, lower limb swelling

The only known risk factors for gastrointestinal stromal tumours (GISTs) are older age and certain rare inherited genetic conditions. Unfortunately, these factors cannot be changed. Since there are no lifestyle or environmental causes linked to GISTs, there is no particular way to prevent GIST.

NCCN guideline for GIST

European Society for Medical Oncology: Gastrointestinal Stromal Tumours - Sarcoma and GIST

Special thanks to Dr. Wendy Wing-Lok Chan, Department of Clinical Oncology, the University of Hong Kong for authoring and editing this article. 

Last updated on 18th Mar, 2025.