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Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybridization, and Next-Generation Sequencing

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Abstract

NTRK1/3 rearrangements have been reported in 2.3–3.4% of papillary thyroid carcinoma (PTC) and are regarded as potential therapeutic targets. Recently, the application of immunohistochemistry (IHC) to detect NTRK rearrangements has been widely discussed. The current study aimed to characterize the clinicopathological features of PTC with NTRK1/3 fusions, to examine the utility of pan-TRK IHC, and to compare IHC with fluorescent in situ hybridization (FISH) and next-generation sequencing (NGS). In a cohort of 525 consecutive PTC cases, 60 BRAFV600E-negative cases underwent complete analyses of FISH, and 12 (2.3%) cases with NTRK1/3 break-apart were found. A novel ERC1-NTRK3 fusion was identified by NGS in one case. Pathological features of non-infiltrative tumor border, clear cell change, and reduced nuclear elongation and irregularity were significantly more common in NTRK1/3-rearranged PTC when compared with 48 BRAFV600E-negative non-NTRK1/3 PTC cases. In whole tissue sections, pan-TRK IHC was positive in 3/7 (42.9%) cases with an ETV6-NTRK3 rearrangement including 2 cases with low percentage of stained tumor cells, 2/3 (66.7%) with non-ETV6 NTRK3 rearrangements, and 2/2 (100%) with NTRK1 rearrangements. All FISH-negative cases were negative for pan-TRK in tissue microarray sections. As a result, pan-TRK IHC showed a sensitivity of 58.3% and specificity of 100% for NTRK1/3 rearrangements in BRAFV600E-negative PTC. In conclusion, NTRK1/3-rearranged PTC shared some unique morphologic features. Pan-TRK IHC showed high specificity and moderate sensitivity for NTRK1/3-rearranged PTC and should be interpreted with caution due to staining heterogeneity. Based on the above findings, we propose an algorithm integrating morphology, IHC, and molecular testing to detect NTRK1/3 rearrangements in PTC.

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Acknowledgments

The authors would like to thank Ms. Shu-Ying Wang and Ms. Yun-Hsin Liang for technical assistance and the Biobank, Taipei Veterans General Hospital for the assistance with sample preparation in this study.

Funding

The study was supported by the research grants from Taipei Veterans General Hospital (Grant No.: V109B-029), Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program (Grant No.: 109-V-B-002 and 109-V-B-003), and Taipei Institute of Pathology (Grant No.: TIP-108-004).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Taipei, 11217, Taiwan

    Yu-Cheng Lee, An-Hang Yang & Jen-Fan Hang

  2. Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

    Jui-Yu Chen

  3. National Yang-Ming University School of Medicine, Taipei, Taiwan

    Jui-Yu Chen, Chun-Jui Huang, Harn-Shen Chen, An-Hang Yang & Jen-Fan Hang

  4. Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan

    Jui-Yu Chen

  5. Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chun-Jui Huang & Harn-Shen Chen

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  1. Yu-Cheng Lee
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Correspondence to Jen-Fan Hang.

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This study was approved by the IRB of Taipei Veterans General Hospital, which granted exemption of informed consent for tissue procurement through the Biobank of Taipei Veterans General Hospital after an unlinked anonymous process (IRB no.: 2019-07-001BC, Biobank no.: 10818).

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Lee, YC., Chen, JY., Huang, CJ. et al. Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybridization, and Next-Generation Sequencing. Endocr Pathol 31, 348–358 (2020). https://doi.org/10.1007/s12022-020-09648-9

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