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Context.— Food and Drug Administration–approved TRK inhibitors with impressive overall response rates are now available for patients with multiple cancer types that harbor NTRK rearrangements, yet the identification of NTRK fusions remains a difficult challenge. These alterations are highly recurrent in extremely rare malignancies or can be detected in exceedingly small subsets of common tumor types. A 2-step approach has been proposed, involving a screening by immunohistochemistry (IHC) followed by a confirmatory method (fluorescence in situ hybridization, reverse transcriptase–polymerase chain reaction, or next-generation sequencing) in cases expressing the protein. However, there is no interpretation guide for any of the available IHC clones. Objective.— To provide a pragmatic update on the use of pan-TRK IHC. Selected examples of the different IHC staining patterns across multiple histologies are shown. Data Sources.— Primary literature review with PubMed, combined with personal diagnostic and research experience. Conclusions.— In-depth knowledge of pan-TRK IHC will help pathologists implement a rational approach to the detection of NTRK fusions in human malignancies.

Pan-TRK Immunohistochemistry: An Example-Based Practical Approach to Efficiently Identify Patients With NTRK Fusion Cancer