NTRK Fusion in a Cohort of BRAF p. V600E Wild-Type Papillary Thyroid Carcinomas

Seung Eun Lee; Mi-Sook Lee; Heejin Bang; Mi Young Kim; Yoon-La Choi; Young Lyun Oh

doi:10.1016/j.modpat.2023.100180

NTRK Fusion in a Cohort of BRAF p. V600E Wild-Type Papillary Thyroid Carcinomas

Mod Pathol. 2023 Aug;36(8):100180. doi: 10.1016/j.modpat.2023.100180. Epub 2023 Mar 30.

Authors

Seung Eun Lee¹, Mi-Sook Lee², Heejin Bang¹, Mi Young Kim³, Yoon-La Choi⁴, Young Lyun Oh⁵

Affiliations

¹ Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.
² Laboratory of Molecular Pathology and Theranostics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
³ Department of Radiology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.
⁴ Laboratory of Molecular Pathology and Theranostics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea; Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: ylachoi@skku.edu.
⁵ Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: bijou@skku.edu.

PMID: 37003481
DOI: 10.1016/j.modpat.2023.100180

Abstract

Owing to the availability of a potent tropomyosin receptor kinase (TRK) inhibitor, it is necessary to develop an effective strategy to identify an enriched population of NTRK fusions in papillary thyroid carcinoma (PTC) in routine diagnostic practice. The reported prevalence of NTRK fusion in a large cohort of PTC is ∼3%. We performed an analysis to refine the characteristic histologic features of PTCs harboring NTRK fusions and further validate the diagnostic utility of pan-TRK immunohistochemistry as a screening tool. In this study, 450 PTCs known to harbor no BRAF p. V600E mutations were screened by pan-TRK immunohistochemistry, and the cases with TRK expression were confirmed by RNA-based next-generation sequencing assay. Eleven NTRK fusion cases were detected (2.4%), and all PTCs were classical subtypes. NTRK1 and NTRK3 were involved in the fusion with 9 different partner genes. Most cases showed similar characteristic histologic findings. Nodular permeative border, multinodular growth with a predominantly follicular pattern, extensive lymphatic invasion, and prominent internodular and intratumoral fibrosis were the characteristic histologic features of NTRK-rearranged PTCs. The ill-defined margins in the ultrasonography findings, which could not be clearly distinguished from the adjacent nontumorous thyroid tissue, were nodular permeative margins in histologic findings. Therefore, preoperative ultrasonographic findings in nodule margins were consistent with the final histologic findings. NTRK1/3 fusion in PTCs showed an overall sensitivity of 100% (95% CI, 71.51%-100%) and specificity of 100% (95% CI, 71.51%-100%) in the 22 cases examined, as confirmed with next-generation sequencing. Our study provides an integrative report of the preoperative ultrasonographic, histologic, immunohistochemical, and molecular features of NTRK-rearranged PTCs. Based on these findings, we propose an algorithmic approach for the stepwise assessment of NTRK fusions in PTCs.

Keywords: NTRK fusion; RNA-based NGS assay; TRK inhibitors; pan-TRK immunohistochemistry; papillary thyroid carcinoma (PTC).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Oncogene Proteins, Fusion / genetics
Receptor, trkA* / analysis
Receptor, trkA* / genetics
Thyroid Cancer, Papillary / genetics
Thyroid Neoplasms* / genetics
Thyroid Neoplasms* / pathology

Substances

Receptor, trkA
Oncogene Proteins, Fusion