Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybri
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Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybridization, and Next-Generation Sequencing Yu-Cheng Lee 1 & Jui-Yu Chen 2,3,4 & Chun-Jui Huang 3,5 & Harn-Shen Chen 3,5 & An-Hang Yang 1,3 & Jen-Fan Hang 1,3 Accepted: 24 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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, panTRK 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. Keywords Papillary thyroid carcinoma (PTC) . NTRK1 . NTRK3 . Pan-TRK immunohistochemistry (IHC) . Fluorescent in situ hybridization (FISH) . Next-generation sequencing (NGS)
Introduction Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland and accounts for more than 80% * Jen-Fan Hang [email protected] Yu-Cheng Lee [email protected]
of thyroid carcinoma [1]. Although the prognosis of PTC is generally excellent, a small portion of cases may still develop an aggressive clinical course and become refractory to conventional radioiodine therapy. In such cases, novel targeted 1
Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Taipei 11217, Taiwan
2
Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
3
Nat
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