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NTRK expression is common in xanthogranuloma and is associated with the solitary variant
B Umphress1, M Kuhar1,2, R Kowal1,2
1Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Background:
Previously identified mutually-exclusive driver genes in juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG) include mutations in MAP kinase pathway genes such as MAP2K1, BRAF, ARAF, KRAS, NRAS, PIK3CD as well as fusions in BRAF and ALK, with a subset of cases with no identified driver yet. NTRK fusion has been identified in rare cases.
Methods:
We identified two consecutive index cases of localized JXG or AXG with NTRK1 fusion by next-generation sequencing (NGS) and confirmed by pan-NTRK immunostain. We expanded the study to a total of 50 cases of JXG and AXG using screening by pan-NTRK immunostain. We confirmed the specificity of our approach with negative results in 5 cases of histiocytic neoplasia lacking an NTRK fusion by NGS and 14 cases of non-neoplastic histiocytic disease.
Results:
We found 23 cases of JXG or AXG with overexpression of NTRK by immunostain, and these cases were restricted to localized disease (23 of 43 cases, 53.5%) rather than disseminated disease (zero of seven cases).
Conclusions:
NTRK expression is common in JXG or AXG and associated with localized rather than disseminated disease. We speculate that the potential importance of this in JXG and AXG has not been previously appreciated due to the tendency to focus sequencing studies on disseminated disease. We confirm the presence of an NTRK1 fusion in two positive cases by NGS, however, additional genetic studies are necessary to further explore this.
Insights
NTRK expression is common in juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG), particularly in localized cases. This finding may have been overlooked due to a focus on disseminated disease in genetic studies.
Area of Science:
- Oncology
- Genetics
- Dermatology
Background:
- Juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG) are histiocytic disorders with known driver genes in the MAP kinase pathway and rare NTRK fusions.
- A subset of JXG and AXG cases lack identified genetic drivers, suggesting other pathways may be involved.
Purpose of the Study:
- To investigate the prevalence and clinical significance of NTRK expression in JXG and AXG.
- To determine if NTRK expression is associated with specific disease presentations, such as localized versus disseminated forms.
Main Methods:
- Next-generation sequencing (NGS) and pan-NTRK immunostaining were used to identify NTRK1 fusions in two initial cases.
- A cohort of 50 JXG and AXG cases were screened using pan-NTRK immunostaining.
- Specificity was confirmed by testing cases with known NTRK status and non-neoplastic histiocytic conditions.
Main Results:
- NTRK overexpression was detected in 53.5% (23 of 43) of localized JXG/AXG cases.
- No NTRK overexpression was observed in disseminated JXG/AXG cases (zero of seven).
- NTRK1 fusions were confirmed by NGS in two positive cases.
Conclusions:
- NTRK expression is a frequent finding in JXG and AXG, predominantly in localized disease.
- The association of NTRK expression with localized disease may explain why it was previously underappreciated.
- Further genetic studies are warranted to fully elucidate the role of NTRK in JXG and AXG pathogenesis.
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