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Published on: July 5, 2019
Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ
Yu-Cheng Lee1, Jui-Yu Chen2,3,4, Chun-Jui Huang3,5
1Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Taipei, 11217, Taiwan.
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.
Insights
NTRK1/3 rearrangements in papillary thyroid carcinoma (PTC) present unique features and can be detected using pan-TRK immunohistochemistry (IHC). This IHC method shows high specificity but moderate sensitivity, suggesting an integrated approach for accurate diagnosis.
Area of Science:
- Oncology
- Molecular Pathology
- Genetics
Background:
- NTRK1/3 rearrangements occur in 2.3-3.4% of papillary thyroid carcinoma (PTC) and are significant therapeutic targets.
- Immunohistochemistry (IHC) for NTRK rearrangements is increasingly discussed, necessitating evaluation of its utility.
- BRAFV600E mutation is a common alteration in PTC, and NTRK rearrangements are typically found in BRAFV600E-negative cases.
Purpose of the Study:
- To characterize clinicopathological features of PTC with NTRK1/3 fusions.
- To assess the utility of pan-TRK IHC for detecting NTRK rearrangements.
- To compare IHC with fluorescent in situ hybridization (FISH) and next-generation sequencing (NGS).
Main Methods:
- Analysis of 525 consecutive PTC cases, with 60 BRAFV600E-negative cases undergoing FISH and NGS.
- Evaluation of pan-TRK IHC on whole tissue sections and tissue microarrays.
- Comparison of diagnostic performance of IHC, FISH, and NGS for NTRK1/3 rearrangements.
Main Results:
- NTRK1/3 rearrangements were identified in 2.3% of BRAFV600E-negative PTC cases (12/60 by FISH, 1 novel fusion by NGS).
- NTRK1/3-rearranged PTC cases showed distinct pathological features including non-infiltrative borders and clear cell changes.
- Pan-TRK IHC demonstrated 58.3% sensitivity and 100% specificity for NTRK1/3 rearrangements in BRAFV600E-negative PTC, with variable staining intensity.
Conclusions:
- NTRK1/3-rearranged PTC exhibits unique morphologic characteristics.
- Pan-TRK IHC is a highly specific but moderately sensitive tool for identifying NTRK1/3 rearrangements in PTC, requiring careful interpretation due to heterogeneity.
- An integrated diagnostic algorithm combining morphology, IHC, and molecular testing is proposed for NTRK1/3 rearrangements in PTC.
