What is the treatment approach for gastric stromal tumors (GISTs)?

Treatment Approach for Gastric Stromal Tumors (GISTs)

For localized gastric GISTs, complete surgical excision with negative margins via wedge resection is the definitive treatment, while metastatic or unresectable disease requires imatinib 400 mg daily as first-line therapy. 1

Size-Based Management Algorithm

Small Gastric Nodules (<2 cm)

• Perform endoscopic ultrasound assessment followed by active surveillance, reserving excision for tumors that increase in size or become symptomatic 1
• If biopsy confirms GIST and resection is feasible without major morbidity, proceed with surgical or endoscopic resection 1
• Active surveillance is acceptable as an alternative, with short-term reassessment at 3 months, then extended intervals if no growth is detected 1
• Many of these small nodules represent low-risk or very low-risk GISTs with unclear clinical significance 1

Medium to Large Gastric Tumors (≥2 cm)

• Standard approach is biopsy or excision, as these tumors carry higher progression risk 1
• For large masses requiring multivisceral resection, obtain multiple core needle biopsies through EUS or CT guidance before surgery 1
• This allows surgical planning, consideration of neoadjuvant therapy, and avoids unnecessary surgery for non-GIST diagnoses 1

Surgical Principles for Localized Disease

Standard Surgical Approach

• Wedge resection of the stomach is adequate treatment since GISTs are typically exophytic and do not involve regional lymph nodes 1, 2
• Achieve complete macroscopic and microscopic resection (R0) with negative margins 1, 2
• Avoid tumor rupture and pseudocapsule injury, as rupture dramatically increases peritoneal recurrence risk and automatically places patients in high-risk category 3, 2
• Do not perform routine lymph node dissection, as lymphatic spread is extremely rare (except in SDH-mutated GISTs) 2
• Avoid direct tumor handling with forceps; use plastic bags for specimen removal to prevent tumor seeding 2

Laparoscopic vs. Open Surgery

• Laparoscopic wedge resection is preferred for gastric GISTs ≤5 cm, offering reduced morbidity with equivalent oncological outcomes 2
• GISTs >5 cm have limited data for laparoscopic approach and carry higher rupture risk 2

Margin Status Considerations

• While positive microscopic margins have not been definitively proven to compromise survival, re-excision should be considered for intramural, intralesionally excised tumors without serosal infiltration 1

Medical Therapy

Adjuvant Therapy for Localized Disease

• High-risk GISTs require 3 years of adjuvant imatinib 400 mg daily 2
• Consider 800 mg daily for KIT exon 9 mutations 2
• Tumor rupture or perforation mandates adjuvant imatinib due to very high peritoneal recurrence risk, with consideration for lifelong treatment 3, 2
• Risk stratification is based on tumor size, mitotic index (expressed per 5 mm² area), tumor location, and tumor rupture 1, 2

Neoadjuvant Therapy

• Preoperative imatinib for cytoreduction should be given for inoperable tumors or when function-sparing surgery is the goal 1
• Consider neoadjuvant imatinib after initial emergency management of perforated GISTs if the tumor is large or in a difficult location requiring extensive surgery 3

First-Line Therapy for Metastatic/Unresectable Disease

• Imatinib 400 mg daily is the standard first-line treatment for advanced disease 1
• Start treatment immediately even if the tumor is not evaluable 1
• No overall survival improvement has been demonstrated with 800 mg vs. 400 mg dosing, though progression-free survival may be superior with 800 mg in patients with KIT exon 9 mutations 1
• Imatinib interruption is associated with high risk of relapse, even in patients with complete remission 1

Second and Third-Line Therapy

• Sunitinib is indicated after imatinib failure 4, 5, 6
• Regorafenib 160 mg orally once daily for days 1-21 of each 28-day cycle is indicated for locally advanced, unresectable, or metastatic GIST previously treated with imatinib and sunitinib 7
• Regorafenib requires dose modifications for toxicity, with reductions in 40 mg increments to a minimum of 80 mg daily 7

Diagnostic Requirements

Pathological Diagnosis

• Diagnosis relies on morphology and immunohistochemistry, typically positive for CD117 (KIT) and/or DOG1 1
• Approximately 5% of GISTs are CD117-negative 1
• Mitotic count has prognostic value and should be expressed as number of mitoses per 5 mm² area 1

Mutational Analysis

• Mutational analysis for KIT and PDGFRA should be standard practice for all GISTs except <2 cm non-rectal GISTs unlikely to need medical treatment 2
• Mutational analysis confirms diagnosis in doubtful cases (particularly CD117/DOG1-negative GISTs) and has predictive and prognostic value 1
• 85% of GISTs exhibit KIT or PDGFRA mutations: KIT exon 11 (66%), exon 9 (13%), exon 13 (1%), exon 17 (0.6%); PDGFRA exon 18 (5%), exon 12 (1.5%) 1

Imaging and Staging

Initial Staging

• Contrast-enhanced CT scan is the imaging modality of choice for staging and surgical planning 1
• For rectal GISTs, MRI provides better preoperative staging information than CT 1
• Most metastases arise in the liver and peritoneal cavity; pleural, lung, or lymph node metastases are rare (<10%) 1
• FDG-PET is recommended only when early detection of tumor response to imatinib is required for surgical planning or when response evaluation is equivocal 1

Follow-Up for Perforated GISTs

• More intensive surveillance is required due to high recurrence risk 3
• Contrast-enhanced CT scans every 3-4 months for the first 2-3 years 3
• Every 6 months for years 4-5, then annually thereafter up to 10 years 3

Critical Pitfalls to Avoid

• Never perform tumor enucleation or allow tumor rupture during surgery, as this leaves tumor-seeded pseudocapsule behind and dramatically increases peritoneal recurrence risk 3, 2, 8
• Do not underestimate the significance of tumor rupture in risk stratification, as it mandates aggressive adjuvant therapy 3
• Avoid Bouin fixative for tissue samples, as it prevents molecular analysis 1
• Do not perform routine lymphadenectomy, as it provides no benefit in standard GISTs 2
• Do not fail to obtain mutational analysis, as it determines sensitivity to targeted therapy and informs prognosis 2