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Gastrointestinal Stromal Tumors [Chapter 81 SKF]

Gastrointestinal Stromal Tumor (GIST)

Epidemiology

  • Most common mesenchymal (nonepithelial) neoplasms of the GI tract.
  • Locations:
    • Stomach: 56%
    • Small intestine: 32%
    • Colon and rectum: 6%
    • Esophagus: <1%
  • Extragastrointestinal lesions (EGISTs): Rare occurrences in mesentery, pelvis, pancreas, liver, omentum, genitourinary tract.
  • Incidence:
    • Ranges from 7 to 15 cases per million people.
    • SEER data: Approximately 6.8 cases per million in the U.S. (~2,100 cases).
    • Underreporting possible due to classification issues.
  • Survival Rates:
    • 5-year overall survival: 65%
    • 5-year disease-specific survival: 79%

Pathology and Diagnosis

Histology

  • Diagnosis based on morphologic features and immunohistochemical (IHC) studies.
  • Histologic Types:
    • Spindle cell (≈70%)
    • Epithelioid
    • Mixed (combination of spindle and epithelioid cells)
  • Rare Variants:
    • Myxoid stroma
    • Neuroendocrine features
    • Signet ring variant
    • Marked lymphocytic infiltrate
  • Differential Diagnosis: Can be confused with fibromatosis and leiomyosarcomas.

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Identification of Cells of Origin

  • Interstitial Cells of Cajal (ICC):
    • Express CD34 and CD117 (KIT).
    • Located between nerve endings and smooth muscle cells in the gut wall.
    • Integral in gut peristalsis (slow-wave propagation).
    • Found primarily in the GI tract but also in other locations like the genitourinary system.

Molecular Mechanism of Carcinogenesis

  • Gain-of-function mutations in KIT tyrosine kinase receptor lead to increased cell proliferation.
  • Normal KIT Function:
    • Binds to stem cell factor (SCF).
    • Causes receptor dimerization and autophosphorylation.
  • Other Mutations:
    • PDGFRA (platelet-derived growth factor receptor A)
    • BRAF (proto-oncogene serine/threonine kinase)
    • These mutations account for about 10% of GISTs.

Immunohistochemical Staining

  • CD117 (KIT):
    • Primary marker for GIST diagnosis.
    • Sensitivity: >95%
    • Specificity: High
  • PDGFRA:
    • Used for GISTs lacking c-KIT mutation.
    • Positive in up to 15% of cases.
  • DOG1 (Discovered on GIST):
    • Useful for diagnosing KIT-negative GISTs.
    • Sensitivity: 95%

Clinical Presentation

  • Often asymptomatic; found incidentally.

  • Symptoms (when present):

    • Early: Mild pain, bloating, dyspepsia.
    • Advanced: Palpable mass, pressure, pain, compression symptoms.
    • GI bleeding: Due to mucosal ulceration.
    • Peritonitis: From tumor perforation.

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Imaging and Diagnosis

  • Contrast-enhanced CT and/or MRI:
    • Large GISTs: Hypervascular, enhancing, heterogeneous masses.
    • Small GISTs: Homogeneous, polypoid appearance.

  • Endoscopy:

    • Reveals submucosal mass, smooth luminal bulge.
    • Possible ulceration in bleeding lesions.

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  • Biopsy:

    • Not required if lesion is surgically resectable.
    • Needed for neoadjuvant therapy or unresectable/metastatic tumors.
    • Endoscopic biopsy preferred over percutaneous.
  • Endoscopic Ultrasound (EUS):
    • Differentiates submucosal mass from external compression.
    • Assesses high-risk features in small (<2 cm) gastric GISTs:
      • Irregular borders
      • Cystic spaces
      • Ulceration
      • Echogenic foci
      • Internal heterogeneity
  • PET Scans:
    • Useful for staging and assessing response to therapy.
    • Ring-shaped uptake indicates adverse prognosis.

Malignant Potential and Staging

  • Most GISTs have metastatic potential; rarely truly benign.
  • Staging Factors:
    • Tumor size
    • Presence of nodal metastases (rare)
    • Distant metastases (common in liver and peritoneum)
    • Grade: Mitotic rate (>5 mitoses/50 HPF indicates high grade)

  • Prognostic Criteria:

    • Fletcher Criteria: Tumor size and mitotic figures.
    • Joensuu Criteria: Adds tumor location and rupture.
    • Nomograms: Include patient sex, tumor site, size, mitotic rate.

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Treatment

Surgical Therapy

  • Complete surgical resection is the primary treatment.
  • Surgical Principles:
    • Aim for complete resection with 1–2 cm gross margins.
    • Avoid tumor pseudocapsule rupture to prevent peritoneal seeding.
    • Lymphadenectomy not routinely indicated.

  • Microscopically Positive Margins (R1):

    • May not worsen prognosis.
    • Re-resection often not necessary.

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Extent of Surgical Resection

  • Gastric GISTs:
    • Partial gastrectomy or wedge resection preferred.
    • Total gastrectomy usually unnecessary.
  • Small Bowel GISTs:
    • Segmental resection.
  • Rectal GISTs:
    • Treatment varies based on size and location.
    • Options: Radical resection or transanal excision.

Minimally Invasive Approaches

  • Laparoscopic resection is feasible and effective.
  • Benefits:
    • Decreased blood loss.
    • Shorter hospital stays.
  • Criteria:
    • Initially for tumors <2 cm, now used for larger tumors (<5 cm).
  • Techniques:
    • Tumor retrieval in a bag to prevent spillage.

    • Approach based on tumor location: [Privette et al.]

      • Type I: Fundus/greater curvature—laparoscopic partial gastrectomy.
      • Type II: Antrum/prepyloric—laparoscopic distal gastrectomy.
      • Type III: Lesser curvature/GE junction—laparoscopic transgastric resection.

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Management of Very Small Gastric GISTs

  • Definition: Gastric GISTs <2 cm without high-risk features.
  • Evaluation:
    • EUS to assess for high-risk features.
  • High-Risk Features:
    1. Irregular borders
    2. Cystic spaces
    3. Ulceration
    4. Echogenic foci
    5. Internal heterogeneity
  • Management:
    • Observation with serial EUS if no high-risk features.
    • Surgery if high-risk features present or progression observed.

Follow-Up and Recurrence

  • Monitoring Schedule:
    • History and physical every 3–6 months for 5 years, then annually.
    • CT scans every 3–6 months for 3–5 years, then annually.
  • Recurrence Rate: Approximately 40–50% after resection.
  • Adjuvant Therapy: Considered based on recurrence risk.

Systemic Therapy with Biologic Agents

  • Genotyping recommended to guide therapy.

Imatinib (Gleevec)

  • Mechanism: Inhibits KIT tyrosine kinase phosphorylation.
  • Indications:
    • Adjuvant therapy post-surgery for high-risk GISTs.
    • Neoadjuvant therapy for unresectable or large tumors.
    • First-line therapy for metastatic GISTs.
  • Efficacy:
    • Improves relapse-free survival (RFS) and overall survival (OS).
    • High response rates in metastatic cases.
  • Side Effects: Diarrhea, fatigue (generally well-tolerated).

Sunitinib (Sutent) and Regorafenib (Stivarga)

  • Used when imatinib is ineffective or not tolerated.
  • Sunitinib:
    • Targets multiple kinases (KIT, PDGFR, BRAF).
    • Improves time to progression and OS.
  • Regorafenib:
    • Effective as third-line therapy.
    • Extends progression-free survival (PFS) and OS.

Neoadjuvant Biologic Therapy Followed by Surgery

  • Benefits:
    • Reduces tumor size.
    • Enables organ-preserving surgeries.
    • Decreases risk of tumor rupture.
  • Treatment Duration: Typically 4–12 months preoperatively.
  • Postoperative Therapy: Continued imatinib for 1–2 years.

Role of Radiation Therapy

  • Historically considered resistant.
  • Current Use:
    • Mainly for palliation of bone metastases.
    • Potential role in treating intra-abdominal or liver metastases (requires more research).

Treatment of Recurrent and Metastatic Disease

  • Imatinib remains the primary treatment.
  • High-Dose Imatinib:
    • May be beneficial for specific mutations (e.g., KIT exon 9).
  • Duration of Therapy:
    • Indefinite continuation unless toxicity occurs.
  • Surgical Resection:
    • May improve survival when combined with imatinib.
    • Reserved for cases where complete gross resection is possible.

Pediatric GISTs

  • Rare and distinct from adult GISTs.
  • Characteristics:
    • More often epithelioid or mixed histology.
    • Predominantly affect females.
    • Higher metastasis and recurrence rates but more indolent.
  • Molecular Differences:
    • Wild-type GISTs lacking KIT and PDGFRA mutations.
    • Mutations in IGF1R, BRAF, SDH, NF1.
  • Treatment:
    • Surgery is primary.
    • Limited efficacy of tyrosine kinase inhibitors.
    • Individualized approach similar to pediatric cases.

Hereditary GISTs

  • Approximately 5% are familial.
  • Associated Syndromes:
    • Neurofibromatosis type 1 (NF1)
    • Carney Triad: GIST, pulmonary chondroma, pheochromocytoma/paraganglioma.
    • Familial GIST Syndrome: c-KIT/PDGFRA mutations.
    • Carney-Stratakis Syndrome: GIST and paraganglioma (SDH mutations).
  • Management:
    • Genetic testing and counseling.
    • Similar treatment approach as pediatric GISTs due to indolent nature.

Summary

  • GISTs are the most common mesenchymal tumors of the GI tract.
  • Often asymptomatic and discovered incidentally.
  • Complete surgical resection is the mainstay of treatment.
  • Very small gastric GISTs without high-risk features may be observed.
  • Imatinib is used in adjuvant, neoadjuvant, and metastatic settings.
  • Second-line (sunitinib) and third-line (regorafenib) therapies are available.
  • Multidisciplinary approach enhances patient outcomes significantly.

Note: Understanding the core concepts of GISTs—including their epidemiology, pathology, clinical presentation, diagnosis, and management—is crucial for optimal patient care. Advances in molecular biology have led to targeted therapies that have markedly improved survival rates and quality of life for patients with GISTs.