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.

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Author notes

This study was mainly funded by Roche Spain. We also thank Instituto de Salud Carlos III (ISCIII) (Fondos FEDER and Plan Estatal I+D+I 2008–2011 [PI11/02866] and 2013–2016 [PI14-01176 y PI17-01001]) and the iLUNG Program (B2017/BMD-3884) from the Comunidad de Madrid. Thermo Fisher Scientific provided an unrestricted grant for the optimization of the next-generation sequencing.

Dr Conde receives honoraria from Roche and Pfizer; travel expenses were covered by Roche, Pfizer, and Merck Sharp & Dohme. Dr Lopez-Rios received honoraria from Lilly, Roche, Thermo Fischer Scientific, Pfizer, Bristol-Myers Squibb, Bayer, AstraZeneca, Merck Sharp & Dohme; research funding was received from Lilly, Roche, and Thermo Fischer Scientific. The other authors have no relevant financial interest in the products or companies described in this article.