Adult Sarcomas with NTRK Fusions: Clinicopathologic and Genomic Heterogeneity

Background: NTRK gene fusions are established oncogenic drivers in a diverse spectrum of mesenchymal neoplasms. Although classically described in pediatric entities, NTRK-rearranged sarcomas also occur in adults, where their clinicopathologic features, genomic context, and response to TRK inhibition are less well characterized. Methods: We retrospectively queried a national referral genomics database to identify sarcomas in patients >18 years harboring pathogenic NTRK1, NTRK2, or NTRK3 fusions. Gastrointestinal stromal tumors, duplicate specimens, and cases lacking digitized hematoxylin and eosin slides were excluded. Fusions were identified by whole-transcriptome sequencing, co-occurring genomic alterations by exome-based sequencing, and real-world survival and time on TRK inhibitor therapy were derived from linked insurance claims data; fusion-negative sarcomas and NTRK-rearranged non-sarcoma tumors from the same database served as comparison cohorts. Results: Among 13,040 profiled sarcomas, 19 adult tumors with pathogenic NTRK fusions were identified (median age, 43 years; range, 21–77), most of which were high grade (68%) and advanced stage (63% stage IV). Histology was heterogeneous, including spindle cell sarcoma (53%), pleomorphic sarcoma (21%), and tumors corresponding to defined entities such as NF1-associated malignant peripheral nerve sheath tumor and MDM2-amplified dedifferentiated liposarcoma (11% each). NTRK1 and NTRK3 fusions were equally frequent (9 cases each); fusion partners were diverse, with TPM3 (n = 5), EML4 (n = 2), and TFG (n = 2) recurrent and other partners non-recurrent. Additional genomic alterations were common and heterogeneous (72%), including high genome-wide loss of heterozygosity and infrequent but recurrent alterations involving the TERT promoter, NF1, and RB1. All evaluable tumors showed transcriptional activation of the NTRK fusion and increased MAPK pathway activity compared with fusion-negative sarcomas. Nine patients received TRK inhibitors; median time on larotrectinib was 12.5 months, similar to that observed in NTRK-rearranged non-sarcoma tumors, but treatment duration was variable. Conclusions: Adult sarcomas harboring NTRK fusions are rare, morphologically heterogeneous, and biologically diverse. NTRK fusion status alone may not fully capture oncogenic dependence and should be interpreted within the broader clinicopathologic and genomic context.