What are the diagnosis and management options for gastrointestinal stromal tumors (GISTs)?

Gastrointestinal Stromal Tumor (GIST): Diagnosis and Management

Diagnostic Approach

For tumors >2 cm in size, biopsy or excision is the standard approach to establish diagnosis, while tumors ≤2 cm in gastric/duodenal locations should undergo endoscopic ultrasound with surveillance unless they demonstrate growth. 1

Initial Assessment by Tumor Size and Location

Small Gastric/Duodenal Nodules (≤2 cm):

• Perform endoscopic ultrasound (EUS) initially 1
• Follow with active surveillance, reserving excision for tumors that increase in size or become symptomatic 2
• First reassessment at 3 months, then increase intervals if no growth 2

Tumors >2 cm:

• Proceed directly to biopsy or excision due to higher malignancy risk 1
• For larger masses requiring multivisceral resection, obtain multiple core needle biopsies via endoscopic ultrasound, CT-guided, or laparoscopic approach 1
• This allows surgical planning and avoids unnecessary surgery for non-GIST entities (lymphomas, mesenteric fibromatosis) 1

Rectal Nodules (Any Size):

• All rectal nodules require biopsy or excision after endorectal ultrasound and pelvic MRI, regardless of size 2
• Higher progression risk and worse prognosis compared to gastric GISTs necessitate tissue diagnosis 2

Metastatic Disease:

• Biopsy the metastatic focus if more accessible than the primary tumor; laparotomy for diagnostic purposes is unnecessary 1

Pathological Diagnosis

Diagnosis relies on morphology plus immunohistochemistry showing CD117 (KIT) and/or DOG1 positivity, though approximately 5% of GISTs are CD117-negative. 1

Essential Pathological Elements:

• Mitotic count expressed as number of mitoses per 5 mm² total area (replaces the 50 high-power field measurement) 1
• Mutational analysis for KIT and PDGFRA mutations is standard practice for all GISTs (except <2 cm non-rectal GISTs unlikely to need medical treatment) 1
• Mutational analysis confirms diagnosis in CD117/DOG1-negative cases and has both predictive value for treatment sensitivity and prognostic relevance 1

Advanced Molecular Testing:

• In GISTs without KIT/PDGFRA mutations, perform SDHB immunohistochemistry to identify SDH-deficient GIST 1
• In quadruple-negative GIST (KIT/PDGFRA/BRAF/SDH), exclude underlying NF1 syndrome 1
• Rare BRAF mutations or NTRK gene rearrangements may have therapeutic implications 1

Tissue Handling:

• Fix tumor samples in 4% buffered formalin (never use Bouin fixative as it prevents molecular analysis) 1
• Collect fresh snap-frozen tissue when possible for future molecular assessments 1

Risk Stratification and Prognostic Factors

The three main prognostic factors are mitotic rate, tumor size, and tumor site—gastric GISTs have significantly better prognosis than small bowel or rectal GISTs. 1

Essential Prognostic Factors: 1

• Anatomical site (gastric > small bowel > rectal)
• Tumor size (continuous variable, not just threshold-based)
• Mitotic rate (continuous variable per 5 mm²)
• Tumor rupture (major adverse factor whether spontaneous or surgical) 1

Additional Prognostic Factors: 1

• KIT/PDGFRA mutation presence and specific mutation site
• Surgical resection margins (R0 vs R1)
• PDGFRA D842V mutation: generally good prognosis but imatinib-resistant 1
• KIT exon 11 deletions involving codons 557-558: high recurrence risk 1

Management of Localized Disease

Complete surgical excision with negative margins (R0 resection) is the cornerstone of treatment for localized GIST, without dissection of clinically negative lymph nodes. 1, 2

Surgical Principles

Primary Surgery:

• R0 excision is the goal; lymph node dissection is not indicated 1
• Laparoscopic approach acceptable for smaller tumors following oncologic surgery principles 1
• Laparoscopic approach is contraindicated for large tumors due to rupture risk, which carries very high recurrence risk 1

When R0 Surgery Not Immediately Feasible:

• Neoadjuvant imatinib is recommended when R0 surgery would require major functional sequelae or when cytoreduction enables less mutilating surgery 1, 2
• Treat for 6-12 months until maximal tumor response, then proceed to surgery 1
• Perform mutational analysis first to exclude imatinib-resistant mutations 1
• PET scan useful to assess rapid response (within weeks) and avoid delaying surgery in non-responders 1

Adjuvant Therapy

High-risk patients should receive 3 years of adjuvant imatinib 400 mg daily, which significantly improves both recurrence-free survival and overall survival compared to 1 year of therapy. 1, 2, 3

Adjuvant Imatinib Indications: 2, 3

• High-risk GISTs based on risk classification (tumor size >5 cm with mitotic count >5/50 HPF, or tumor >10 cm with any mitotic count, or any size with mitotic count >10/50 HPF)
• Mandatory for ruptured GISTs regardless of other risk factors—consider lifelong treatment due to very high peritoneal recurrence risk 2
• Standard dose: 400 mg daily for 3 years 2, 3
• For KIT exon 9 mutations: 800 mg daily due to superior outcomes 2

Key Trial Data:

• Study comparing 3 years vs 1 year adjuvant imatinib showed hazard ratio of 0.46 (95% CI: 0.32-0.65, p<0.0001) for recurrence-free survival 3
• Overall survival also significantly improved with 3-year treatment: hazard ratio 0.45 (95% CI: 0.22-0.89, p=0.02) 3

Management of Advanced/Metastatic Disease

Imatinib 400 mg daily is the standard first-line treatment for unresectable and metastatic GIST, continued indefinitely as interruption leads to rapid tumor progression. 2, 3

First-Line Therapy

Imatinib Dosing: 2, 3

• Standard dose: 400 mg daily
• KIT exon 9 mutations: 800 mg daily (superior progression-free survival and overall survival) 2
• Continue treatment indefinitely until disease progression or unacceptable toxicity 2, 3

Response Rates: 3

• Objective response rate: 46-49% (complete response 5%, partial response 46-49%)
• Median progression-free survival: 18.9-23.2 months
• Median overall survival: approximately 49 months

Second and Third-Line Therapy

After imatinib failure, sunitinib is the standard second-line treatment, followed by regorafenib as third-line therapy. 2, 4

Regorafenib (Third-Line): 4

• Indicated for locally advanced, unresectable, or metastatic GIST previously treated with imatinib and sunitinib
• Dose: 160 mg (four 40 mg tablets) orally once daily for 21 days of each 28-day cycle
• Take with low-fat meal (<600 calories, <30% fat)
• Monitor hepatic function closely—severe and sometimes fatal hepatotoxicity has occurred 4

Role of Surgery in Advanced Disease

Surgery plays a role in selected patients with advanced disease, particularly for limited disease progression on TKI therapy or complete cytoreductive surgery when feasible. 2

Multidisciplinary Management

Management must be carried out at reference centers for sarcomas and GISTs with multidisciplinary teams including pathologists, radiologists, surgeons, medical oncologists, gastroenterologists, and nuclear medicine specialists. 1

Staging and Follow-up Imaging:

• Contrast-enhanced abdominal and pelvic CT scan is the investigation of choice 1
• MRI provides better preoperative staging for rectal GISTs 1
• FDG-PET scan useful for early detection of tumor response to imatinib (within weeks) 1
• Most relapses affect peritoneum and liver 1

Critical Pitfalls to Avoid

Never use Bouin fixative for tissue samples—it prevents molecular analysis that is essential for treatment planning. 1

Do not perform lymph node dissection—GISTs do not metastasize to lymph nodes and dissection adds unnecessary morbidity. 1

Avoid laparoscopic surgery for large tumors—tumor rupture dramatically increases recurrence risk and may necessitate lifelong adjuvant therapy. 1, 2

Do not stop imatinib in responding metastatic patients—interruption leads to rapid tumor progression. 2

Recognize PDGFRA D842V mutations—these tumors are imatinib-resistant but have good prognosis when localized. 1