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      Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions

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          Abstract

          Background

          Activating neurotrophic tyrosine receptor kinase ( NTRK) fusions, typically detected via nucleic acid based assays, are highly targetable and define certain tumors. Here, we explore the utility of pan-TRK immunohistochemistry (IHC) to detect NTRK fusions.

          Design

          NTRK rearrangements were detected prospectively using MSK-IMPACT, a DNA-based next generation sequencing assay. Transcription of novel NTRK rearrangements into potentially functional fusion transcripts was assessed via Archer Dx fusion assay. Pan-Trk IHC testing with mAb EPR17341 was performed on all NTRK rearranged cases and 20 cases negative for NTRK fusions on Archer.

          Results

          Of 23 cases with NTRK rearrangements, 15 had known activating fusions. Archer detected fusion transcripts in 6 of 8 novel NTRK rearrangements of uncertain functional significance. Pan-Trk IHC was positive in 20 of 21 cases with NTRK fusion transcripts confirmed by Archer. The discordant negative case was a mismatch repair-deficient colorectal carcinoma with an ETV6- NTRK3 fusion. All 20 additional Archer-negative cases had concordant pan-TRK IHC results. Pan-Trk IHC sensitivity and specificity for transcribed NTRK fusions was 95.2% and 100%, respectively. All positive IHC cases had cytoplasmic staining while the following fusion partner-specific patterns were discovered: all 5 LMNA-NTRK1 fusions displayed nuclear membrane accentuation, all 4 TPM3/4 fusions displayed cellular membrane accentuation, and half (3/6) of ETV6- NTRK3 fusions displayed nuclear staining.

          Conclusion

          Pan-Trk IHC is a time- and tissue-efficient screen for NTRK fusions, particularly in driver-negative advanced malignancies and potential cases of secretory carcinoma and congenital fibrosarcoma. Pan-Trk IHC can help determine whether translation occurs for novel NTRK rearrangements.

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          Author and article information

          Journal
          7707904
          470
          Am J Surg Pathol
          Am. J. Surg. Pathol.
          The American journal of surgical pathology
          0147-5185
          1532-0979
          24 June 2017
          November 2017
          01 November 2018
          : 41
          : 11
          : 1547-1551
          Affiliations
          [1 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065
          [2 ]Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065
          Author notes
          [* ]Corresponding author: Hechtmaj@ 123456mskcc.org
          Article
          PMC5636652 PMC5636652 5636652 nihpa883557
          10.1097/PAS.0000000000000911
          5636652
          28719467
          bdbd9322-8624-4ec1-bd50-a545a7ae0ac1
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