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Gastrointestinal Stromal Tumor (GIST) [ small note]

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal (non-epithelial) neoplasms of the gastrointestinal (GI) tract. They can occur anywhere along the GI tract, from the esophagus to the internal anal sphincter. GISTs originate from the interstitial cells of Cajal (ICC), which are pacemaker cells responsible for gut motility.

Epidemiology

  • Incidence: Approximately 7 to 15 cases per million people annually.
  • Common Locations:
    • Stomach: ~56%
    • Small Intestine: ~32%
    • Colon and Rectum: ~6%
    • Esophagus: <1%
  • Extragastrointestinal GISTs (EGISTs): Rare, occurring in locations such as the mesentery, omentum, pancreas, and genitourinary tract.

Pathology and Diagnosis

Histology

  • Cell Types:
    • Spindle Cell Type: ~70% of cases.
    • Epithelioid Type.
    • Mixed Type: Combination of spindle and epithelioid cells.
  • Differential Diagnosis: Important to distinguish GISTs from other mesenchymal tumors like leiomyomas and schwannomas.

Identification of Cells of Origin

  • Origin: Interstitial cells of Cajal (ICC).
  • Markers:
    • CD117 (c-KIT): A tyrosine kinase receptor, positive in >95% of GISTs.
    • CD34: Positive in many GISTs.
    • DOG1: A sensitive marker, especially in c-KIT negative tumors.

Molecular Mechanism of Carcinogenesis

  • KIT Mutations:
    • Gain-of-function mutations leading to constitutive activation of the KIT receptor.
    • Results in uncontrolled cell proliferation.
  • PDGFRA Mutations:
    • Occur in approximately 10% of GISTs.
    • Similar mechanism to KIT mutations.
  • BRAF Mutations:
    • Less common but contribute to GIST development.

Immunohistochemical Staining

  • Primary Diagnostic Criterion: Positive staining for CD117.
  • Additional Markers:
    • PDGFRA: Useful when c-KIT is negative.
    • DOG1: Helps identify GISTs lacking KIT or PDGFRA mutations.

Clinical Presentation

  • Asymptomatic Cases: Often found incidentally during imaging or endoscopy.
  • Symptoms When Present:
    • Mild abdominal pain or discomfort.
    • Bloating or dyspepsia.
    • GI bleeding leading to anemia.
    • Palpable abdominal mass.
    • Symptoms from compression of adjacent organs.

Imaging and Diagnosis

  • Computed Tomography (CT):
    • Contrast-enhanced CT is the imaging modality of choice.
    • Large GISTs: Appear as hypervascular, heterogeneous masses.
    • Small GISTs: Homogeneous and polypoid.
  • Magnetic Resonance Imaging (MRI):
    • Alternative to CT, especially for liver metastases.
  • Endoscopy:
    • May reveal a submucosal mass with smooth appearance.
    • Ulceration may be present in bleeding tumors.
  • Endoscopic Ultrasound (EUS):
    • Useful for small (<2 cm) gastric GISTs.
    • Can assess high-risk features and guide biopsy.
  • Biopsy:
    • Not required for resectable tumors.
    • Indicated for unresectable, metastatic, or neoadjuvant therapy considerations.
    • Preferably performed endoscopically to reduce risks.

Malignant Potential and Staging

  • Malignancy Risk Factors:
    • Tumor Size: Larger tumors have higher risk.
    • Mitotic Index: Higher mitotic rate indicates aggressive behavior.
    • Tumor Location: Non-gastric GISTs tend to be more aggressive.
    • Tumor Rupture: Associated with poorer prognosis.
  • Staging Systems:
    • American Joint Committee on Cancer (AJCC) staging includes tumor size, nodal involvement, metastases, and mitotic rate.
    • Risk Stratification Criteria:
      • Fletcher Criteria.
      • Joensuu Criteria: Incorporates tumor rupture.
    • Nomograms: Predict recurrence risk based on multiple factors.

Treatment

Surgical Therapy

  • Primary Treatment: Complete surgical resection with negative margins.
  • Surgical Principles:
    • Avoid tumor rupture or pseudocapsule violation.
    • Lymphadenectomy not routinely performed due to rare nodal metastasis.
  • Extent of Resection:
    • Gastric GISTs: Wedge resection or partial gastrectomy.
    • Small Intestine GISTs: Segmental resection.
    • Rectal GISTs: Resection approach depends on tumor size and location.
  • Minimally Invasive Surgery:
    • Laparoscopic resection is feasible for select tumors, especially those <5 cm.
    • Ensure oncologic principles are maintained.

Management of Small Gastric GISTs

  • Very Small GISTs (<2 cm):
    • Often monitored with serial imaging.
    • Surgery reserved for lesions with high-risk features or growth.

Systemic Therapy with Biologic Agents

Imatinib Mesylate (Gleevec)

  • Mechanism: Tyrosine kinase inhibitor targeting KIT and PDGFRA.
  • Indications:
    • Adjuvant Therapy: Reduces recurrence risk post-surgery in high-risk patients.
    • Neoadjuvant Therapy: Shrinks tumors to facilitate resection.
    • Metastatic or Unresectable GISTs: First-line treatment.
  • Duration: Optimal duration varies; often continued for at least 3 years in high-risk cases.

Sunitinib (Sutent)

  • Mechanism: Multitargeted tyrosine kinase inhibitor.
  • Indications: Second-line therapy for imatinib-resistant or intolerant patients.

Regorafenib (Stivarga)

  • Mechanism: Multikinase inhibitor with activity against KIT.
  • Indications: Third-line therapy after failure of imatinib and sunitinib.

Neoadjuvant Therapy

  • Purpose: Reduce tumor size for surgical resectability and organ preservation.
  • Treatment Duration: Generally 4 to 12 months, until maximal response achieved.
  • Postoperative Therapy: Continued imatinib recommended.

Role of Radiation Therapy

  • Limited Use: Historically considered resistant.
  • Current Role: Palliative treatment for bone metastases; potential utility in controlling intra-abdominal or liver metastases.

Treatment of Recurrent and Metastatic Disease

  • Systemic Therapy: Imatinib remains the cornerstone.
  • Surgical Intervention:
    • Considered for resectable metastatic lesions.
    • May improve survival if complete (R0/R1) resection achievable.

Special Considerations

Pediatric GISTs

  • Characteristics:
    • Rare, often epithelioid or mixed histology.
    • Predominantly occur in females.
    • Frequently lack KIT or PDGFRA mutations.
  • Treatment:
    • Surgery is primary treatment.
    • Limited efficacy of tyrosine kinase inhibitors due to different molecular profile.

Hereditary GISTs

  • Associated Syndromes:
    • Neurofibromatosis Type 1 (NF1).
    • Carney Triad: GIST, paraganglioma, pulmonary chondroma.
    • Familial GIST Syndrome: Germline mutations in KIT or PDGFRA.
  • Management:
    • Similar to sporadic GISTs.
    • Genetic counseling recommended.

Follow-Up and Surveillance

  • Monitoring:
    • Regular imaging (CT scans) every 3 to 6 months for the first 3 to 5 years.
    • Annual scans thereafter.
  • Recurrence Risk:
    • Approximately 40% to 50% may recur post-surgery.
    • Risk stratification guides surveillance intensity.

Summary

GISTs are unique tumors of the GI tract with specific diagnostic and treatment considerations. Surgical resection remains the mainstay of curative treatment, with the goal of complete tumor removal while preserving organ function. The advent of tyrosine kinase inhibitors like imatinib has revolutionized the management of advanced, recurrent, and metastatic GISTs, significantly improving patient outcomes. Multidisciplinary care is essential to optimize treatment strategies and surveillance for these patients.