Gastrointestinal stromal tumors

Gastrointestinal stromal tumors

Gastrointestinal stromal tumors

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GIST 101 - The Gut's Odd Lump

  • What: Most common mesenchymal tumor of the GI tract; arises from the Interstitial Cells of Cajal (gut pacemaker cells).
  • Mutation: Gain-of-function mutation in the KIT gene (a receptor tyrosine kinase) is the primary driver.
  • Location: 60% Stomach > 30% Small Intestine > Esophagus/Colon/Rectum.
  • Presents: Often asymptomatic. Can cause GI bleeding (melena, hematemesis), abdominal pain, or a palpable mass.
  • Histo: Look for uniform spindle cells.
  • Diagnosis: Immunohistochemistry (IHC) is key-tumors are positive for KIT (CD117).

⭐ The presence of the KIT mutation is not just diagnostic; it's the target for specific chemotherapy (tyrosine kinase inhibitors like Imatinib).

GIST Histology: KIT and PDGFRA Mutations

Pathogenesis - KIT's Wild Ride

  • Origin: GISTs arise from the Interstitial Cells of Cajal (ICCs), the specialized pacemaker cells regulating GI motility.
  • Primary Driver: The vast majority are driven by activating (gain-of-function) mutations in the KIT proto-oncogene, a receptor tyrosine kinase.
  • A smaller subset involves mutations in the related PDGFRA gene.
  • 📌 KIT is the "key" that's stuck, turning the ignition on permanently for cell growth.

Exam Favorite: The specific KIT exon mutation predicts imatinib sensitivity. Exon 11 mutations (~70% of KIT mutations) are most common and show the best response, while exon 9 mutations often require higher doses.

KIT/PDGFRA signaling pathway in GIST and drug mechanisms

Diagnosis & Staging - The Stromal Reveal

  • Initial Workup:
    • Endoscopy/EUS reveals a submucosal mass, sometimes with ulceration.
    • Contrast-enhanced CT defines tumor size, location, and metastatic spread (liver, peritoneum).
  • Definitive Diagnosis: Biopsy & IHC
    • EUS-guided fine-needle aspiration (FNA) is the preferred method. ⚠️ Percutaneous biopsy risks peritoneal seeding.
    • Immunohistochemistry (IHC) is key:
      • KIT (CD117): Positive in ~95% of cases.
      • DOG1: Highly specific marker.
      • CD34: Positive in ~70%.

GIST: Spindle cells with positive c-KIT CD117 staining

  • Risk Stratification (NIH Criteria):
    • Mitotic Rate: High risk if >5 mitoses/50 HPF.
    • Tumor Size: High risk if >5 cm.
    • Location: Gastric GISTs have a better prognosis than those in the small intestine.

⭐ GISTs with a PDGFRA exon 18 D842V mutation are primarily resistant to imatinib therapy.

Management - The Imatinib Era

  • Primary Therapy: Imatinib mesylate, a tyrosine kinase inhibitor (TKI).
    • Targets gain-of-function mutations in c-KIT (CD117) and PDGFRA.
    • Standard dose: 400 mg daily.
  • Indications:
    • Unresectable, recurrent, or metastatic GIST.
    • Adjuvant therapy for resected GISTs with a high risk of recurrence.
  • Resistance:
    • Primary: Rare, e.g., PDGFRA D842V mutation.
    • Secondary (acquired): Sunitinib (2nd line), Regorafenib (3rd line).

Exam Favorite: Over 70% of GISTs have a KIT gene mutation. The most common, in exon 11, predicts a favorable response to imatinib therapy.

High‑Yield Points - ⚡ Biggest Takeaways

  • GISTs are the most common mesenchymal tumors of the GI tract, originating from the interstitial cells of Cajal.
  • Most are driven by gain-of-function mutations in the KIT gene (CD117), a receptor tyrosine kinase.
  • Histology typically shows bundles of spindle cells.
  • The stomach is the most frequent site (>50%), followed by the small intestine.
  • Imatinib, a tyrosine kinase inhibitor, is the cornerstone of targeted therapy.
  • Prognosis depends on tumor size, mitotic rate, and location.

Practice Questions: Gastrointestinal stromal tumors

Test your understanding with these related questions

A research team develops a new monoclonal antibody checkpoint inhibitor for advanced melanoma that has shown promise in animal studies as well as high efficacy and low toxicity in early phase human clinical trials. The research team would now like to compare this drug to existing standard of care immunotherapy for advanced melanoma. The research team decides to conduct a non-randomized study where the novel drug will be offered to patients who are deemed to be at risk for toxicity with the current standard of care immunotherapy, while patients without such risk factors will receive the standard treatment. Which of the following best describes the level of evidence that this study can offer?

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Flashcards: Gastrointestinal stromal tumors

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What GI pathology is associated with the rotavirus vaccine? _____

TAP TO REVEAL ANSWER

What GI pathology is associated with the rotavirus vaccine? _____

Intussusception

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