Related Experiment Video
Updated: May 21, 2025
Radionuclide-fluorescence Reporter Gene Imaging to Track Tumor Progression in Rodent Tumor Models
Published on: March 13, 2018
Refining NTRK Fusion Detection in Papillary Thyroid Carcinoma Through Pan-TRK Immunohistochemistry and
Hyun Lee1, Sue Youn Kim1, Ji Min Park1
1Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
Abstract:
NTRK fusions are rare but recurrent driver alterations in papillary thyroid carcinoma (PTC), with therapeutic significance due to the availability of targeted TRK inhibitors. Pan-TRK immunohistochemistry (IHC) provides a practical approach for the identification of NTRK fusions; however, its application and reliability in routine pathology require further exploration. This study is aimed at evaluating the diagnostic utility of pan-TRK IHC for detecting NTRK fusions in PTC, assessing its correlation with histopathologic features, and developing a diagnostic algorithm. We analyzed 107 BRAF p.V600E-negative PTC cases using pan-TRK IHC, correlating staining patterns with molecular data and histopathologic features. RNA-based targeted sequencing confirmed gene fusions. NTRK fusion-positive tumors were enriched in distinct histopathologic features, including BRAF-like PTC with predominant follicular architecture, clear cells, and secretory-like cells. Findings such as tumor cell stratification, glomeruloid structures, and papillae with subfollicle formation (microfollicles within papillary structures) were associated with both NTRK and RET fusion-positive PTCs. Correlation of pan-TRK IHC and molecular testing results identified non-specific reactivity or false positivity in 62% of pan-TRK IHC-positive PTCs, including cases with RET fusions, BRAF fusion, or no detectable fusion. However, pan-TRK IHC with high H-scores (≥ 110) was observed exclusively in cases with NTRK fusions. For cases with lower H-scores (< 110), integrating histopathologic features improved the identification of fusion-driven PTCs. While our series further supports the limitations of pan-TRK IHC, a diagnostic algorithm that combines pan-TRK IHC H-scores and histopathologic patterns improved the triaging of NTRK molecular testing of BRAF p.V600E-negative PTCs when a stepwise approach is undertaken. This study also demonstrated that TRK protein localization may vary with tumor progression and dedifferentiation.
Insights
Pan-TRK immunohistochemistry (IHC) can help identify NTRK fusions in papillary thyroid carcinoma (PTC). However, combining IHC with histopathology improves accuracy in detecting these rare but targetable driver alterations.
Area of Science:
- Oncology
- Molecular Pathology
- Genetics
Background:
- Neurotrophic tyrosine receptor kinase (NTRK) fusions are rare but significant driver alterations in papillary thyroid carcinoma (PTC).
- Targeted TRK inhibitors offer therapeutic options for NTRK fusion-positive PTC.
- Pan-TRK immunohistochemistry (IHC) is a potential method for identifying NTRK fusions, but its diagnostic utility needs validation in routine pathology.
Purpose of the Study:
- To evaluate the diagnostic utility of pan-TRK IHC for detecting NTRK fusions in PTC.
- To assess the correlation between pan-TRK IHC staining patterns and histopathologic features.
- To develop a diagnostic algorithm for improved identification of fusion-driven PTC.
Main Methods:
- Analysis of 107 BRAF p.V600E-negative PTC cases using pan-TRK IHC.
- Correlation of IHC staining patterns with molecular data (RNA-based targeted sequencing for gene fusions) and histopathologic features.
- Development and assessment of a diagnostic algorithm integrating IHC scores and histopathologic patterns.
Main Results:
- NTRK fusion-positive PTCs exhibited distinct histopathologic features, including follicular architecture, clear cells, and secretory-like cells.
- Pan-TRK IHC showed non-specific reactivity or false positivity in 62% of positive cases, including those with RET or BRAF fusions.
- High pan-TRK IHC H-scores (≥110) were exclusively observed in NTRK fusion-positive PTCs; lower scores benefited from histopathologic feature integration.
Conclusions:
- Pan-TRK IHC has limitations in specificity for detecting NTRK fusions in PTC.
- A diagnostic algorithm combining pan-TRK IHC H-scores and histopathologic patterns enhances the accuracy of triaging NTRK molecular testing.
- TRK protein localization may vary with tumor progression and dedifferentiation in PTC.
