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Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Gastrointestinal stromal tumors
Bernadette Liegl-Atzwanger1, Jonathan A Fletcher, Christopher D M Fletcher
1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Abstract:
Gastrointestinal stromal tumors (GISTs) have emerged from being poorly defined, treatment-resistant tumors to a well-recognized, well-understood, and treatable tumor entity within only one decade. The understanding of GIST biology has made this tumor a paradigm for molecularly targeted therapy in solid tumors and provides informative insights into the advantages and limitations of so-called targeted therapeutics. Approximately 85% of GISTs harbor activating mutations in KIT or the homologous receptor tyrosine kinase PDGFRA gene. These mutations are an early event in GIST development and the oncoproteins serve as a target for the small molecule tyrosine kinase inhibitors imatinib and sunitinib. The existing and emerging treatment options demand exact morphologic classification and risk assessment. Although, KIT (CD117) immunohistochemistry is a reliable diagnostic tool in the diagnosis of GIST, KIT-negative GISTs, GISTs showing unusual morphology as well as GISTs which progress during or after treatment with imatinib/sunitinib can be a challenge for pathologists and clinicians. This review focuses on GIST pathogenesis, morphologic evaluation, promising new immunohistochemical markers, risk assessment, the role of molecular analysis, and the increasing problem of secondary imatinib resistance and its mechanisms.
Insights
Gastrointestinal stromal tumors (GISTs) are now treatable due to understanding their biology and targeted therapies. Research explores GIST pathogenesis, diagnosis, and resistance to treatments like imatinib.
Area of Science:
- Oncology
- Molecular Biology
- Pathology
Background:
- Gastrointestinal stromal tumors (GISTs) have transformed from poorly understood to treatable entities.
- GISTs serve as a model for molecularly targeted therapy in solid tumors.
- Activating mutations in KIT or PDGFRA genes drive GIST development in ~85% of cases.
Purpose of the Study:
- To review GIST pathogenesis, morphologic evaluation, and diagnostic tools.
- To discuss risk assessment, molecular analysis, and emerging treatments.
- To address challenges in diagnosing KIT-negative GISTs and managing imatinib resistance.
Main Methods:
- Literature review focusing on GIST biology, targeted therapies, and diagnostic advancements.
- Analysis of diagnostic challenges including immunohistochemistry and molecular testing.
- Examination of mechanisms of secondary imatinib resistance.
Main Results:
- Understanding GIST mutations (KIT/PDGFRA) enables targeted therapies like imatinib and sunitinib.
- KIT (CD117) immunohistochemistry is crucial but has limitations.
- Secondary resistance to imatinib is an increasing clinical challenge.
Conclusions:
- GISTs are a paradigm for targeted therapy, highlighting both successes and limitations.
- Accurate diagnosis, risk assessment, and molecular analysis are vital for effective GIST management.
- Further research is needed to overcome treatment resistance and improve patient outcomes.
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