What is the treatment for gastric round cell carcinoma, likely a Gastrointestinal Stromal Tumor (GIST)?

Treatment of Gastric Round Cell Carcinoma (Gastrointestinal Stromal Tumor)

For gastric GIST, complete surgical excision with negative margins (R0 resection) is the cornerstone of treatment, followed by risk-stratified adjuvant imatinib therapy for 3 years in high-risk patients, with imatinib 400 mg daily as the standard first-line treatment for unresectable or metastatic disease. 1, 2

Initial Diagnostic and Surgical Management

Small Gastric Nodules (<2 cm)

• Perform endoscopic ultrasound (EUS) assessment initially, with active surveillance if biopsy yields inadequate material 2
• Reserve surgical excision for tumors that increase in size or become symptomatic 2
• Short-term first assessment at 3 months, then increase follow-up intervals if no growth is evident 2

Resectable Gastric GIST (≥2 cm)

• Complete surgical excision with macroscopic and microscopic negative margins (R0 resection) is mandatory 1, 3
• Laparoscopic wedge resection is preferred for gastric GISTs ≤5 cm, offering reduced morbidity with equivalent oncological outcomes 3
• For tumors >5 cm, open surgery is recommended due to higher rupture risk with laparoscopy 3
• Critical surgical principles include avoiding tumor rupture and pseudocapsule injury, as rupture dramatically increases peritoneal recurrence risk 3
• No lymph node dissection is required, as lymphatic spread is extremely rare in standard GISTs 3

Unresectable or Locally Advanced Gastric GIST

• Neoadjuvant imatinib 400 mg daily is standard when immediate resection would be highly morbid or R0 resection is not feasible 1, 2
• Perform mutational analysis before starting neoadjuvant therapy to exclude resistant genotypes (PDGFRA D842V) and identify KIT exon 9 mutations requiring 800 mg daily 1
• Surgery should be performed after 6-12 months of treatment when maximal tumor response is achieved 1
• Imatinib can be stopped 1-2 days before surgery and resumed promptly when the patient recovers 1

Mutational Analysis and Risk Stratification

• Mutational analysis for KIT and PDGFRA is mandatory for all GISTs to confirm diagnosis, guide treatment sensitivity, and inform prognosis 2, 3
• Risk stratification is based on tumor size, mitotic index (expressed as mitoses per 5 mm²), tumor location, and tumor rupture 2, 3
• Gastric location confers lower risk compared to small intestinal GISTs 1

Adjuvant Therapy

High-Risk Patients

• Adjuvant imatinib 400 mg daily for 3 years is standard treatment for patients with high risk of relapse 1, 2
• For KIT exon 9 mutations, consider 800 mg daily for 3 years, though this is not universally approved by regulatory agencies 1
• High-risk criteria include: large tumor size (>5 cm), high mitotic count (>5 per 5 mm²), and tumor rupture 2

Tumor Rupture

• Adjuvant imatinib is mandatory after resection of ruptured GISTs due to very high risk of peritoneal recurrence, with consideration for lifelong treatment 2, 3

Contraindications to Adjuvant Therapy

• PDGFRA exon 18 D842V-mutated GISTs should not receive adjuvant imatinib, as they are insensitive to this agent 1
• NF1-related and SDH expression-negative GISTs should avoid adjuvant therapy 1

Advanced/Metastatic Disease

First-Line Treatment

• Imatinib 400 mg daily is the standard treatment for inoperable and metastatic disease, continued indefinitely as interruption leads to rapid tumor progression 1, 2, 4
• For KIT exon 9 mutations, 800 mg daily is standard due to superior progression-free survival 1, 5
• Treatment should continue indefinitely, even after complete response, as discontinuation accelerates disease progression 1

Disease Progression on Imatinib

Limited Progression:

• Continue imatinib and consider resection of progressing lesions if feasible 1
• Radiofrequency ablation or embolization for isolated lesions (category 2B) 1
• Dose escalation to 800 mg daily as tolerated is particularly useful for KIT exon 9 mutations 1

Generalized Progression:

• Change to sunitinib 50 mg daily for 4 weeks every 6 weeks, or 37.5 mg daily continuously (category 1) 1, 4
• Both sunitinib schedules are acceptable, with the continuous dosing potentially better tolerated 1

Second-Line Treatment Failure

• Regorafenib is standard third-line treatment after progression on imatinib and sunitinib 1, 6
• Regorafenib dose is 160 mg daily for 21 days of each 28-day cycle 6

PDGFRA D842V Mutations

• Avapritinib is the most active treatment for PDGFRA D842V-mutant GIST, achieving >90% response rate 1
• This agent may require individual funding requests in some healthcare systems 1

Response Assessment and Monitoring

• Tumor response should be assessed by both size and density on CT scan, as decreased density may precede tumor shrinkage 1
• Some increase in tumor size with decreased density indicates response, not progression 1
• FDG-PET scan is highly sensitive for early response assessment and useful when CT/MRI are ambiguous 1
• The "nodule within the mass" pattern (hyperdense area in responding lesion) indicates true progression 1

Follow-Up Protocol

• High-risk gastric GISTs require contrast-enhanced CT scans every 3-4 months for the first 2-3 years 7
• Then every 6 months for years 4-5, and annually thereafter up to 10 years 7
• Relapses most commonly occur in the liver and/or peritoneal cavity 1

Critical Pitfalls to Avoid

• Never discontinue tyrosine kinase inhibitor therapy, even with progressive disease, as this accelerates progression and worsens symptoms 1
• Do not perform lymph node dissection routinely, as it provides no benefit and increases morbidity 3
• Avoid direct tumor handling with forceps during laparoscopic surgery; use plastic bags for specimen removal to prevent tumor seeding 3
• Do not treat PDGFRA D842V mutations with imatinib, as they are inherently resistant 1
• Ensure mutational analysis is performed before starting any systemic therapy to guide appropriate drug selection 1, 2