Simple Summary
Adult sarcomas harboring NTRK fusions are rare and represent a biologically heterogeneous group with diverse morphologic, genomic, and clinical features. In this retrospective cohort of 19 adult sarcomas with NTRK fusions, we found substantial variation in fusion partners, secondary genomic alterations, and histologic appearance, including tumors arising within established entities such as NF1-associated malignant peripheral nerve sheath tumor and MDM2-amplified dedifferentiated liposarcoma. Although all evaluable tumors showed transcriptional activation of the fusion and increased MAPK pathway activity, clinical benefit from TRK inhibition was variable. These findings suggest that NTRK fusions may function in different biological contexts across adult sarcomas and that fusion status alone may not fully capture oncogenic dependence or therapeutic susceptibility to TRK inhibitors. Thus, adult sarcomas harboring NTRK fusions should be interpreted in the broader clinicopathologic and genomic context.