Consultant 0

Gastrointestinal Stromal Tumors (GISTs)

Gastrointestinal stromal tumors (GISTs)

  • Definition and Origin
    • Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchymal (connective tissue) tumors of the GI tract.
    • They typically arise from the interstitial cells of Cajal (or related stem cells), which are involved in regulating peristalsis.
  • Location
    • GISTs can occur anywhere along the GI tract, but most frequently appear in the stomach (60–70%) and the small intestine (20–30%). Less commonly, they can occur in the esophagus, colon, or rectum.
  • Genetic Mutations
    • About 80% of GISTs have activating mutations in the KIT (CD117) gene.
    • Around 5–10% have mutations in the PDGFRA (platelet-derived growth factor receptor alpha) gene.
    • A small subset of GISTs lack both KIT and PDGFRA mutations (“wild-type GISTs”), which may have other driver mutations (e.g., SDH-deficient).
  • Risk Factors
    • Most GISTs are sporadic, with no clear environmental risk factor.
    • Rare familial syndromes (e.g., Neurofibromatosis Type 1 [NF1]) can predispose to GIST.
    • A few inherited conditions involve germline mutations in KIT or PDGFRA, but these are uncommon.
  • Presentation and Symptoms
    • Early stages often cause few or no symptoms.
    • Possible signs include GI bleeding (black, tarry stools or occult blood in stool), abdominal discomfort, a palpable mass, or anemia (fatigue, weakness).

Disease Progression

  • Local Growth
    • GISTs can grow into the lumen or outward from the GI wall.
    • Symptoms often arise as tumors enlarge and cause bleeding, obstruction, or pain.
  • Potential for Malignancy
    • GISTs were historically all considered potentially malignant.
    • Risk of aggressive behavior is stratified based on tumor size, mitotic rate (how rapidly cells are dividing), and location (e.g., gastric vs. small bowel).
    • High-risk GISTs have a greater likelihood of metastasis.
  • Common Sites of Metastasis
    • Liver and peritoneum (abdominal lining) are the most common sites for metastatic spread.
    • Metastasis to lymph nodes is less frequent in GISTs compared to other GI malignancies.

Screening*

  • General Population
    • No standardized screening guidelines exist for sporadic GISTs in the general population.
    • GISTs are relatively rare, and most do not produce early symptoms that would prompt routine testing.
  • High-Risk Individuals
    • Those with familial GIST syndromes or Neurofibromatosis Type 1 may undergo periodic imaging (e.g., endoscopy, CT/MRI) based on their genetic counseling and medical advice.
    • Screening, if done, is individualized, as the incidence in these groups is higher compared to the general population.

Treatment Approaches

           Treatment strategy depends on tumor size, location, risk classification, and whether the disease is localized or metastatic.

   Localized/Resectable Disease

  • Surgical Resection
    • Mainstay of curative treatment for localized GIST.
    • Goal is complete removal of the tumor with negative margins, typically without routine lymph node dissection (as nodal spread is relatively uncommon).
  • Adjuvant Therapy
    • Imatinib (Gleevec)—a tyrosine kinase inhibitor (TKI)—is often used post-surgery for high-risk GISTs (large tumors, high mitotic rate, etc.) to reduce recurrence.
    • Duration of adjuvant imatinib typically 3 years for high-risk patients, though durations can be individualized based on emerging data.

   Advanced/Metastatic Disease

  • Tyrosine Kinase Inhibitors (TKIs)
    • Imatinib is the first-line therapy for most metastatic or unresectable GISTs. It targets mutations in KIT/PDGFRA, controlling tumor growth.
    • Resistance can develop over time, leading to use of second-line (e.g., Sunitinib) and third-line (e.g., Regorafenib) TKIs.
    • Newer agents include Avapritinib (especially for PDGFRA D842V mutant GIST) and Ripretinib, used for advanced or resistant cases.
  • Surgery in Metastatic Disease
    • Resection of metastatic lesions may be considered in select cases (e.g., limited liver metastases) to prolong disease control in combination with targeted therapy.
  • Palliative/Supportive Care
    • For symptomatic relief (pain control, managing GI bleeding).
    • Can include endoscopic or interventional radiology procedures if needed.

Summary

Gastrointestinal stromal tumors (GISTs) are unique mesenchymal neoplasms of the GI tract, most frequently found in the stomach or small intestine. While no routine screening is recommended for the general population, early detection in symptomatic or high-risk individuals can lead to surgical cure of localized disease. The introduction of tyrosine kinase inhibitors—particularly imatinib—has dramatically changed the natural history of advanced GIST, converting it into a more chronic, controllable disease for many patients. Prognosis varies based on tumor factors (size, mitotic rate, mutation type) and stage, but with proper surgical and medical management, long-term survival has significantly improved.

 

* Please note that screening programs may vary among different countries.