NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome

Abstract

Purpose: Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as oncogenic drivers in a variety of tumors. However, little is known about the overall frequency of NTRK fusion in unselected pediatric tumors. Here, we assessed the frequency, fusion partners, and clinical course in pediatric patients with NTRK fusion-positive tumors.

Patients and methods: We studied 1,347 consecutive pediatric tumors from 1,217 patients who underwent tumor genomic profiling using custom-designed DNA and RNA next-generation sequencing panels. NTRK fusions identified were orthogonally confirmed.

Results and discussion: NTRK fusions were identified in 29 tumors from 27 patients with a positive yield of 2.22% for all patients and 3.08% for solid tumors. Although NTRK2 fusions were found exclusively in CNS tumors and NTRK1 fusions were highly enriched in papillary thyroid carcinomas, NTRK3 fusions were identified in all tumor categories. The most canonical fusion was ETV6-NTRK3 observed in 10 patients with diverse types of tumors. Several novel NTRK fusions were observed in rare tumor types, including KCTD16-NTRK1 in ganglioglioma and IRF2BP2-NTRK3 in papillary thyroid carcinomas. The detection of an NTRK fusion confirmed the morphologic diagnosis including five cases where the final tumor diagnosis was largely based on the discovery of an NTRK fusion. In one patient, the diagnosis was changed because of the identification of an ETV6-NTRK3 fusion. One patient with infantile fibrosarcoma was treated with larotrectinib and achieved complete pathologic remission.

Conclusion: NTRK fusions are more frequently seen in pediatric tumors than in adult tumors and involve a broader panel of fusion partners and a wider range of tumors than previously recognized. These results highlight the importance of screening for NTRK fusions as part of the tumor genomic profiling for patients with pediatric cancer.

FIG 1.

Summary of molecular findings of NTRK fusion–positive patients identified in the cohort at CHOP.

FIG 2.

Representative examples of soft-tissue tumors (A-C) and papillary thyroid carcinoma (D-F). Case 12 with RBPMS-NTRK3 tumor of the liver hilum showing nuclear palisading (A, H&E, 200×). Case 13 demonstrates an IF with canonical ETV6-NTRK3 showing tissue culture–like growth with interspersed inflammatory cells (B, H&E 200×). Case 17 demonstrates a low-grade tumor with STRN3-NTRK3 showing moderately cellular spindle to round cell proliferation with prominent vascular proliferation (C, H&E, 200×). Case 21 shows widely invasive follicular variant of papillary thyroid carcinoma with ETV6-NTRK3 demonstrating extrathyroidal extension and angioinvasion (D, H&E, 50×) and nuclear features of papillary thyroid carcinoma (inset, 400×). Two cases demonstrate the diffuse sclerosing variant of papillary thyroid carcinoma showing solid and papillary groups infiltrating the thyroid parenchyma with numerous psammomatous calcifications (E, H&E, 100×). Case 19 on high power shows solid tumor cell groups (squamoid morphology) with psammomatous calcifications (F, H&E, 400×). H&E, hematoxylin and eosin staining.

FIG 3.

Case 15 with infantile fibrosarcoma with SPECC1L-NTRK3 fusion. Magnetic resonance imaging at diagnosis (A), 1 month post-targeted therapy (B), and 5 months post-therapy (C) showing marked tumor shrinkage. At diagnosis, the tumor contained densely cellular areas with spindled to round cells and increased mitosis (D, H&E 400×) with cytoplasmic and membranous pan-TRK immunohistochemistry (inset). Other areas at diagnosis were less cellular with lower mitotic rate and demonstrate fat and skeletal muscle infiltration (E, H&E 200×). Resection following targeted therapy showed fibrosis and foamy histiocytes; no residual tumor was identified (F, H&E 200×). Schematic diagram demonstrates protein domains of SPECC1L-NTRK3 fusion, detailed fusion sequences, and Sanger confirmation (G). CCD, coiled-coil domain; CHD, calponin homology domain; ECD-LB, extracellular ligand binding domain; H&E, hematoxylin and eosin staining; PKT, protein Tyr kinase; TM, transmembrane domain; SS, signal sequence.