"Wild type" GIST: Clinicopathological features and clinical practice

Area of Science:

• Gastrointestinal Oncology
• Molecular Pathology
• Genetics

Background:

• Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms of the GI tract, often driven by KIT or PDGFRA gene mutations.
• Approximately 10% of GISTs are "wild type," lacking these common mutations, and require further classification.
• Wild type GISTs are categorized into succinate dehydrogenase (SDH)-deficient and non-SDH-deficient groups, each with distinct genetic underpinnings and clinical features.

Purpose of the Study:

• To delineate the classification and characteristics of wild type GISTs.
• To highlight the genetic heterogeneity beyond KIT and PDGFRA mutations in GIST tumorigenesis.
• To emphasize the importance of genetic analysis and clinical evaluation for diagnosing and managing wild type GISTs.

Main Methods:

• Review of GIST classification based on genetic mutations.
• Categorization of wild type GISTs into SDH-deficient and non-SDH-deficient groups.
• Identification of associated genetic alterations (e.g., BRAF, KRAS, PIK3CA, ETV6-NTRK3) and syndromic associations (e.g., Carney triad, Carney Stratakis syndrome, neurofibromatosis type 1).

Main Results:

• SDH-deficient GISTs are associated with Carney triad/Stratakis syndrome, often affecting young women with epithelioid tumors in the gastric antrum.
• Non-SDH-deficient GISTs include those with neurofibromatosis type 1 (spindle cells, small intestine), BRAF mutations, or other genetic alterations.
• Tumor location, morphology, cellular features, and lymphovascular invasion are important diagnostic clues.

Conclusions:

• Accurate diagnosis of wild type GIST requires thorough clinical assessment (age, gender, family history) and comprehensive genetic analysis.
• KIT expression determination is essential, and suspicion of wild type GIST necessitates intensive genetic investigation.
• Long-term patient observation is recommended due to the specific characteristics of wild type GISTs.