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Gastrointestinal Stromal Tumour

Disease Details

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Description: A gastrointestinal stromal tumor (GIST) is a rare type of tumor that occurs in the digestive tract, most commonly in the stomach or small intestine, arising from specialized cells known as interstitial cells of Cajal.
Type: A gastrointestinal stromal tumor (GIST) is a type of mesenchymal tumor that occurs primarily in the gastrointestinal tract, most commonly in the stomach or small intestine.

Genetic transmission of GISTs is generally sporadic, meaning they occur randomly and are not usually inherited. However, a small percentage of GISTs can be familial, often associated with hereditary syndromes such as neurofibromatosis type 1 (NF1) or familial GIST syndrome due to mutations in the KIT or PDGFRA genes.
Signs And Symptoms: GISTs may present with trouble swallowing, gastrointestinal bleeding, or metastases (mainly in the liver). Intestinal obstruction is rare, due to the tumor's outward pattern of growth. Often, there is a history of vague abdominal pain or discomfort, and the tumor has become rather large by time the diagnosis is made.
Prognosis: Gastrointestinal stromal tumors (GISTs) are a type of tumor that occurs in the digestive tract, most commonly in the stomach or small intestine. The prognosis for patients with GIST varies depending on several factors such as the size of the tumor, its location, the mitotic rate (how quickly the tumor cells are dividing), and whether the cancer has metastasized.

Generally, patients with GISTs that are small, have a low mitotic rate, and are localized tend to have a better prognosis and higher survival rates. The introduction of targeted therapies, such as imatinib (Gleevec), has significantly improved the outlook for many patients, especially those with metastatic or high-risk tumors. However, the specific prognosis should be individualized based on a thorough medical evaluation.
Onset: Gastrointestinal stromal tumors (GISTs) can occur at any age but are most commonly diagnosed in adults between the ages of 40 and 70. Although rare, they can also occur in younger individuals, including children and adolescents.
Prevalence: The prevalence of gastrointestinal stromal tumor (GIST) in the general population is relatively low. It is estimated to occur in about 10 to 20 people per million annually. While it is a rare type of cancer, it is the most common mesenchymal tumor of the gastrointestinal tract.
Epidemiology: GISTs occur in 10-20 per one million people. The true incidence might be higher, as novel laboratory methods are much more sensitive in diagnosing GISTs. The estimated incidence of GIST in the United States is approximately 5000 cases annually.: 1063 This makes GIST the most common form of sarcoma, which constitutes more than 70 types of cancer.
The majority of GISTs present at ages 50–70 years. Across most of the age spectrum, the incidence of GIST is similar in men and women.: 1122 Adult GISTs are rare before age 40. Pediatric GISTs are considered to be biologically distinct. Unlike GISTs at other ages, pediatric GISTs are more common in girls and young women. They appear to lack oncogenic activating tyrosine kinase mutations in both KIT and PDGFRA. Pediatric GISTs are treated differently from adult GISTs. Although the generally accepted definition of pediatric GIST is a tumor that is diagnosed at the age of 18 years or younger, "pediatric-type" GISTs can be seen in adults, which affects risk assessment, the role of lymph node resection, and choice of therapy.
Intractability: Gastrointestinal stromal tumors (GISTs) are not inherently intractable, but their manageability depends on various factors such as the size, location, and metastatic nature of the tumor. They can often be treated effectively with surgery if detected early and localized. Additionally, targeted therapies such as imatinib (Gleevec) have significantly improved outcomes for many patients, especially for those with advanced or metastatic GISTs. However, some cases may be more challenging due to drug resistance or recurrence.
Disease Severity: Gastrointestinal stromal tumors (GISTs) are generally considered serious and potentially life-threatening. Their severity depends on factors such as tumor size, location, rate of growth (mitotic rate), and whether they have metastasized (spread to other parts of the body). Early detection and treatment improve the prognosis, but advanced or metastatic GISTs can be more challenging to treat.
Healthcare Professionals: Disease Ontology ID - DOID:9253
Pathophysiology: GISTs are tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are nonepithelial. About 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. Small tumors are generally not aggressive, especially when cell division rate is slow. GIST tumors commonly metastasize to the liver (in 28% of cases) and/or to the greater omentum, lesser omentum, or mesentery (in 30% of cases). Less common areas of metastasis include the lungs, subcutaneous tissue, lymph nodes or bones.GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility.
Carrier Status: Gastrointestinal stromal tumors (GIST) are primarily caused by mutations in specific genes, most commonly in the KIT gene or PDGFRA gene, but GIST is not inherited in a way that would involve a carrier status like autosomal recessive traits. The occurrence is usually sporadic, meaning it is not typically passed from parents to offspring.
Mechanism: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in specific genes that are crucial for normal cellular functions. The primary mechanisms and molecular mechanisms involved in GISTs include:

1. **KIT Gene Mutations**:
- About 75-80% of GISTs have mutations in the KIT gene, which encodes a type of receptor tyrosine kinase (RTK) known as KIT.
- These mutations lead to constitutive activation of the KIT protein, independent of its ligand, known as stem cell factor (SCF). This continuous activation promotes uncontrolled cell proliferation and survival.

2. **PDGFRA Gene Mutations**:
- Approximately 5-10% of GISTs harbor mutations in the PDGFRA gene, coding for another RTK, the platelet-derived growth factor receptor alpha (PDGFRA).
- Similar to KIT mutations, these lead to constitutive activation of the PDGFRA protein, driving tumorigenesis.

3. **Secondary Genetic Alterations**:
- Additional genetic alterations, such as secondary mutations in KIT or PDGFRA, can occur and contribute to drug resistance and disease progression.
- Loss of function in tumor suppressor genes (e.g., SDH, NF1) can also play a role in the pathogenesis of GISTs.

4. **Signaling Pathways**:
- The constitutive activation of KIT or PDGFRA mutations leads to the downstream activation of several key signaling pathways, including PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, and JAK/STAT pathways.
- These pathways collectively contribute to cell proliferation, survival, and anti-apoptotic mechanisms within GIST cells.

5. **SDH-deficient GISTs**:
- Some GISTs lack mutations in KIT or PDGFRA but have deficiencies in the succinate dehydrogenase (SDH) complex, leading to mitochondrial dysfunction and accumulation of succinate.
- This metabolic alteration causes pseudo-hypoxia and activation of oncogenic pathways.

6. **Epigenetic Changes**:
- Alterations in DNA methylation and histone modifications have been observed in GISTs, which can influence gene expression patterns and contribute to tumorigenesis.

Understanding these molecular mechanisms is crucial for the diagnosis, treatment, and development of targeted therapies for GISTs, including the use of tyrosine kinase inhibitors (e.g., imatinib, sunitinib) that specifically target aberrant KIT and PDGFRA signaling.
Treatment: Treatment for a gastrointestinal stromal tumor (GIST) typically involves the following approaches:

1. **Surgery**: The primary treatment for GISTs, especially if the tumor is resectable. The goal is to remove the tumor completely.

2. **Targeted Therapy**: Imatinib (Gleevec) is the most common targeted therapy used, particularly for tumors that are not amenable to surgical removal or have metastasized. Other targeted drugs include sunitinib (Sutent) and regorafenib (Stivarga).

3. **Monitoring**: For small, asymptomatic GISTs, active surveillance with regular follow-ups and imaging may be recommended.

4. **Radiation Therapy**: Rarely used, as GISTs are generally resistant, but may be considered in specific cases for symptom relief.

5. **Chemotherapy**: Generally not effective against GISTs and is rarely used.

Patients should discuss their specific case with an oncologist to determine the most appropriate treatment plan.
Compassionate Use Treatment: Compassionate use treatment and off-label or experimental treatments for gastrointestinal stromal tumors (GIST) can include:

1. **Avapritinib (Ayvakit)**: Primarily approved for PDGFRA exon 18 mutations, it may be considered for other scenarios under compassionate use.

2. **Ripretinib (Qinlock)**: A fourth-line treatment option, it might be used earlier under certain compassionate use programs.

3. **Larotrectinib (Vitrakvi) and Entrectinib (Rozlytrek)**: These drugs target NTRK gene fusions and might be used experimentally if such mutations are present in GIST.

4. **Immunotherapies**: Drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) are being studied as experimental treatments for GIST, especially in cases resistant to standard therapies.

5. **Combination therapies**: Combining existing treatments like imatinib (Gleevec) with other agents, although experimental, is being explored in clinical trials.

Clinical trials often provide access to these experimental treatments, and physicians can sometimes obtain them through compassionate use programs for patients who have exhausted other options.
Lifestyle Recommendations: For gastrointestinal stromal tumour (GIST), lifestyle recommendations include:

1. **Healthy Diet**: Emphasize fruits, vegetables, whole grains, and lean proteins. This helps maintain overall health and supports the body's ability to withstand treatments.

2. **Regular Exercise**: Engage in regular physical activity, as tolerated. Consult with a healthcare provider to create a suitable exercise plan.

3. **Quit Smoking**: If you smoke, seek resources to help you quit, as smoking can negatively affect treatment outcomes and overall health.

4. **Limit Alcohol**: Drink alcohol in moderation, if at all, as excessive consumption can impact liver function and overall health.

5. **Manage Stress**: Practice stress-reducing techniques like meditation, yoga, or hobbies to support mental well-being.

6. **Regular Medical Follow-Ups**: Attend all scheduled appointments to monitor the condition and adjust treatments as necessary.

7. **Adherence to Treatment Plans**: Follow all prescribed treatments and medications as directed by healthcare providers.

8. **Support Networks**: Engage with support groups, whether online or in-person, for emotional support and shared experiences.

These recommendations can help improve quality of life and complement medical treatments for GIST.
Medication: For gastrointestinal stromal tumor (GIST), the primary medication used is imatinib (Gleevec). It is a tyrosine kinase inhibitor that targets the specific mutations commonly found in GIST. Other medications that may be used include sunitinib (Sutent) and regorafenib (Stivarga) in cases where imatinib is not effective or if the patient develops resistance. These medications help by inhibiting the growth and proliferation of cancer cells. Regular monitoring and follow-up with a healthcare provider are essential to adjust the treatment plan as necessary.
Repurposable Drugs: For gastrointestinal stromal tumor (GIST), some drugs originally developed for other conditions have shown potential for repurposing. These include:

1. **Imatinib (Gleevec)**: Originally developed for chronic myeloid leukemia, it is now a first-line treatment for GIST.
2. **Sunitinib (Sutent)**: Initially used for kidney cancer, it is an alternative for patients who do not respond to imatinib.
3. **Regorafenib (Stivarga)**: Approved for colorectal cancer, it is used for GIST patients who have failed previous treatments with imatinib and sunitinib.

These repurposable drugs target specific mutations and pathways involved in GIST, offering additional therapeutic options.
Metabolites: Gastrointestinal stromal tumors (GISTs) can affect various metabolic pathways, but there are no specific metabolites identified exclusively for GISTs. Diagnostic and therapeutic approaches generally focus on imaging studies, histopathology, and molecular testing for mutations, particularly in KIT and PDGFRA genes. Changes in general cancer metabolism, such as altered glucose and amino acid metabolism, may be observed in GISTs, similar to other tumors.
Nutraceuticals: Nutraceuticals have not been conclusively shown to be effective in the treatment of gastrointestinal stromal tumors (GISTs). The primary treatment for GISTs is typically surgical resection, possibly combined with targeted therapies such as tyrosine kinase inhibitors. Nutraceuticals, which are food-derived products with potential health benefits, may support general health but should not be relied upon as a primary treatment for GISTs. Always consult healthcare providers before adding any supplements to your treatment regimen.
Peptides: Gastrointestinal stromal tumors (GISTs) can be treated using targeted therapies, some of which may involve inhibitory peptides that target specific mutations. Imatinib (Gleevec) is a well-known example of a tyrosine kinase inhibitor used for treating GISTs. Research continues into the development of novel peptide-based therapies to improve outcomes for patients with this disease. Nanotechnology is also being explored for its potential to enhance drug delivery systems, making treatment more effective by targeting tumor cells more precisely and reducing side effects.