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Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors
L Schirosi1, N Nannini2, D Nicoli3
1Section of Pathologic Anatomy, University Clinic Policlinico of Modena, Modena.
Background:
To analyze a multi-institutional series of type C thymic carcinomas (TCs) (including neuroendocrine tumors), focusing on the expression and mutations of c-KIT.
Materials And Methods:
Immunohistochemical expression of c-KIT/CD117, p63, CD5 and neuroendocrine markers, as well as mutational analysis of c-KIT exons 9, 11, 13, 14, 17 by direct sequencing of 48 cases of TCs. Immunohistochemical and molecular data were statistically crossed with clinicopathological features.
Results:
Overall, 29 tumors (60%) expressed CD117, 69% were positive for CD5 and 85% (41 cases) for p63. Neuroendocrine markers stained all six atypical carcinoids and five poorly-differentiated thymic squamous cell carcinomas. Overall, six CD117-positive cases (12.5%) showed c-KIT mutation. No mutation was detected in CD117-negative tumors and carcinoids. All the mutations were found in poorly-differentiated thymic squamous cell carcinomas expressing CD117, CD5, p63 and lacking neuroendocrine markers (6 of 12 cases with these features). Mutations involved exon 11 (four cases: V559A, L576P, Y553N, W557R), exon 9 (E490K) and exon 17 (D820E).
Conclusions:
All TCs need an immunohistochemical screening with CD117, while c-KIT mutation analysis is mandatory only in CD117-positive cases, particularly when coexpressing CD5 and p63, lacking neuroendocrine differentiation. The finding of c-KIT mutation can predict efficacy with different c-KIT inhibitors.
Insights
CD117 expression is common in type C thymic carcinomas (TCs). c-KIT mutations occur in a subset of CD117-positive TCs, particularly those lacking neuroendocrine markers, guiding targeted therapy selection.
Area of Science:
- Oncology
- Molecular Pathology
- Cancer Genetics
Background:
- Type C thymic carcinomas (TCs) are rare tumors.
- c-KIT (CD117) expression and mutations are implicated in various cancers.
- Understanding c-KIT in TCs is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the expression and mutation status of c-KIT in a multi-institutional series of type C thymic carcinomas.
- To correlate c-KIT findings with clinicopathological features.
- To identify potential therapeutic targets in TCs.
Main Methods:
- Immunohistochemistry for c-KIT (CD117), p63, CD5, and neuroendocrine markers on 48 TC cases.
- Direct sequencing of c-KIT exons 9, 11, 13, 14, and 17.
- Statistical analysis of immunohistochemical and molecular data with clinicopathological features.
Main Results:
- 60% of TCs expressed CD117; 69% were CD5-positive; 85% were p63-positive.
- c-KIT mutations were identified in 12.5% of CD117-positive cases, specifically in poorly differentiated thymic squamous cell carcinomas.
- Mutations were found in c-KIT exons 9, 11, and 17.
Conclusions:
- Immunohistochemical screening for CD117 is recommended for all TCs.
- c-KIT mutation analysis is essential in CD117-positive TCs, especially those coexpressing CD5 and p63 and lacking neuroendocrine markers.
- Identifying c-KIT mutations can predict response to c-KIT inhibitors.
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