Gastrointestinal Stromal Tumors (GIST)

Background:

• Most common mesenchymal tumors of GI tract

• Risk assessment uses:

  • Tumor size

  • Mitotic rate

  • Anatomic location

  • Tumor rupture

    • Significantly increases recurrence risk.

• Gastric GIST generally have better prognosis than non-gastric GIST.

  • For example, a >10 cm gastric tumor with >5 mitoses/50 HPF has 34% metastasis risk, while the same parameters in small bowel GIST carry 71-90% risk.

Work up:

• Histology + IHC:

  • Confirm GIST with positive KIT and/or DOG1 immunostaining.

• Imaging:

  • CAP CT scan

  • MRI as needed for liver/rectal lesions

• Mutational testing:

  • Essential to guide systemic therapy

  • Common mutations:

    • KIT mutation (~80%)

      • KIT exon 11 mutations: Best response to imatinib 400 mg daily

      • KIT exon 9 mutations: Better PFS with imatinib 400 mg BID

    • PDGFRA mutations (~5-10%)

      • Resistant to imatinib; use avapritinib as first-line

    • Wild-type:

      • Test for alternative drivers (BRAF, NF1, NTRK, FGFR fusions) via NGS

Treatment:

Localized resectable disease:

• Surgery

  • Segmental resection with negative margins

    • Extended resections rarely needed

  • Preserve pseudocapsule (avoid tumor rupture)

  • Lymphadenectomy usually unnecessary

• Neoadjuvant therapy:

  • Indicated for tumors requiring high-morbidity surgery:

    • Rectal

    • Esophagogastric junction

    • Duodenum

    • Requiring multivisceral resection

  • Preferred medications:

    • Imatinib for KIT and PDGFRA mutations (except PDGFRA D842V)

    • Avapritinib for PDGFRA D842V mutation (resistant to imatinib)

    • Sunitinib for imatinib progression/intolerance

    • Larotrectinib/entrectinib (NTRK inhibitors) if NTRK fusion present

• Adjuvant therapy:

  • If moderate-high risk disease with imatinib-sensitive mutations:

    • Adjuvant Imatinib for 3-6 years

• Surveillance:

  • CT/MRI every 3-6 months for 5 years, then annually.

    • Individualized approach after 10 years.

Metastatic/unresectable disease:

• Life-long systemic therapy is recommended for TKI-sensitive GIST.

• Treatment options:

  • 1st line:

    • Imatinib for KIT/PDGFRA-mutation

    • Avapritinib for PDGFRA D842V mutation

  • 2nd line:

    • Sunitinib if imatinib fails

      • For limited/focal progression on imatinib, consider dose escalation or local therapy (resection, ablation, radiation) while continuing imatinib.

  • 3rd line:

    • Regorafenib

  • 4th line:

    • Ripretinib

• Surveillance:

  • CAP CT scan every 3–6 months during stable disease

  • MRI every 3–6 months if:

    • Liver-dominant disease

    • Rectal GIST

    • Patients with contrast allergy

    • Assessing tumor density and necrosis

  • FDG-PET/CT to assess TKI efficacy after 2-4 weeks if rapid assessment is necessary

    • Increase in tumor size with decreased density is consistent with drug efficacy (myxoid degeneration), not progression.