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Updated: May 7, 2026
Robotic Duodenal Sleeve Resection for Gastrointestinal Stromal Tumor with Rare Exon 8 KIT Mutation Following Neoadjuvant Imatinib
Published on: April 3, 2026
Gastrointestinal stromal tumours: from KIT to succinate dehydrogenase
Leona A Doyle1, Jason L Hornick
1Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, MA, USA.
Abstract:
The discovery of activating mutations in the tyrosine kinase receptor genes KIT and PDGFRA has led to the development of effective targeted therapies for gastrointestinal stromal tumours (GISTs). Specific genotypes, in part, predict the response to treatment with tyrosine kinase inhibitors. However, ~10% of GISTs lack such mutations (often referred to as 'wild-type' GISTs). Recent insights into the biology of 'wild-type' GISTs have resulted in clinically significant subclassification of this heterogeneous group of tumours, a large subset of which are now known to represent succinate dehydrogenase-deficient GISTs. Recognition of this distinctive class of tumours has critical implications for prognosis, therapy, clinical follow-up, and genetic counselling. Other uncommon genetic groups include neurofibromatosis type I-associated and BRAF-mutant GISTs. This review provides an update on the diagnosis and pathogenesis of these less common classes of GISTs, summarizes the clinical and pathological features associated with particular genotypes, and discusses mechanisms of resistance to targeted therapies.
Insights
Gastrointestinal stromal tumours (GISTs) with specific mutations respond to targeted therapies. This review focuses on rare wild-type GISTs, including succinate dehydrogenase-deficient subtypes, and their clinical implications.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Activating mutations in KIT and PDGFRA drive targeted therapy for gastrointestinal stromal tumours (GISTs).
- Approximately 10% of GISTs lack these common mutations, presenting as 'wild-type' GISTs.
- Wild-type GISTs are a heterogeneous group, with succinate dehydrogenase-deficient GISTs being a significant subgroup.
Purpose of the Study:
- To review the diagnosis and pathogenesis of uncommon GIST subtypes.
- To summarize clinical and pathological features of genotype-specific GISTs.
- To discuss resistance mechanisms in targeted GIST therapies.
Main Methods:
- Literature review of GIST diagnosis, pathogenesis, and treatment.
- Analysis of clinical and pathological data associated with GIST genotypes.
- Review of molecular mechanisms underlying targeted therapy resistance.
Main Results:
- Wild-type GISTs, particularly succinate dehydrogenase-deficient GISTs, have distinct prognostic and therapeutic implications.
- Neurofibromatosis type I-associated and BRAF-mutant GISTs represent other uncommon genetic classifications.
- Genotype significantly influences GIST response to tyrosine kinase inhibitors.
Conclusions:
- Subclassification of wild-type GISTs is crucial for accurate prognosis, therapy, and follow-up.
- Understanding rare GIST genotypes informs genetic counseling and treatment strategies.
- Further research into resistance mechanisms is needed for improved GIST management.
