NTRK-rearranged mesenchymal tumours: diagnostic challenges, morphological patterns and proposed testing algorithm

Oncogenic fusions involving neurotrophic receptor tyrosine kinase (NTRK) genes are being increasingly identified in a range of mesenchymal tumours unrelated to infantile fibrosarcoma or cellular congenital mesoblastic nephroma, where the canonical ETV6-NTRK3 fusion was first described more than two decades ago. Recognition of these NTRK-rearranged tumours poses a diagnostic challenge to surgical pathologists due to their non-specific clinical and pathological features. However, their recognition is of heightened importance, particularly in locally advanced and metastatic sarcomas, due to the recent availability of selective and highly effective targeted therapy. Herein, we present an Australian multi-institutional series of six of these rare NTRK-rearranged mesenchymal neoplasms to share the local experience and diagnostic challenges as well as to highlight key morphological patterns and immunoprofiles that provide the most helpful clues in routine practice. We also propose a diagnostic algorithm for the detection of these fusions, drawing attention to the limitations of ancillary studies including immunohistochemistry against tropomyosin receptor kinase (TRK) protein, fluorescence in situ hybridisation (FISH) and next generation sequencing.