Clinicopathological findings of pediatric NTRK fusion mesenchymal tumors

Jeongwan Kang,Jung Yoon Choi,Hyoung Jin Kang,Jae-Kyung Won,Hongseok Yun,Woo Sun Kim,Jeong Mo Bae,Jaemoon Koh,Seung-Ki Kim,Sung-Hye Park,Jeemin Yim,Jin Woo Park,Joo Heon Shin

doi:10.1186/s13000-020-01031-w

Abstract

BackgroundWhile ETV6- NTRK3 fusion is common in infantile fibrosarcoma, NTRK1/3 fusion in pediatric tumors is scarce and, consequently, not well known. Herein, we evaluated for the presence of NTRK1/3 fusion in pediatric mesenchymal tumors, clinicopathologically and immunophenotypically.MethodsWe reviewed nine NTRK fusion-positive pediatric sarcomas confirmed by fluorescence in situ hybridization and/or next-generation sequencing from Seoul National University Hospital between 2002 and 2020.ResultsOne case of TPR-NTRK1 fusion-positive intracranial, extra-axial, high-grade undifferentiated sarcoma (12-year-old boy), one case of LMNA-NTRK1 fusion-positive low-grade infantile fibrosarcoma of the forehead (3-year-old boy), one case of ETV6-NTRK3 fusion-positive inflammatory myofibroblastic tumor (IMT) (3-months-old girl), and six cases of ETV6-NTRK3 fusion-positive infantile fibrosarcoma (median age: 2.6 months, range: 1.6–5.6 months, M: F = 5:1) were reviewed. The Trk immunopositivity patterns were distinct, depending on what fusion genes were present. We observed nuclear positivity in TPR-NTRK1 fusion-positive sarcoma, nuclear membrane positivity in LMNA-NTRK1 fusion-positive sarcoma, and both cytoplasmic and nuclear positivity in ETV6-NTRK3 fusion-positive IMT and infantile fibrosarcomas. Also, the TPR-NTRK1 fusion-positive sarcoma showed robust positivity for CD34/nestin, and also showed high mitotic rate. The LMNA-NTRK1 fusion-positive sarcoma revealed CD34/S100 protein/nestin/CD10 coexpression, and a low mitotic rate. The IMT with ETV6-NTRK3 fusion expressed SMA. Six infantile fibrosarcomas with ETV6-NTRK3 fusion showed variable coexpression of nestin (6/6)/CD10 (4/5)/ S100 protein (3/6).ConclusionsAll cases of NTRK1 and NTRK3 fusion-positive pediatric tumors robustly expressed the Trk protein. A Trk immunopositive pattern and CD34/S100/nestin/CD10/SMA immunohistochemical expression may suggest the presence of NTRK fusion partner genes. LMNA-NTRK1 fusion sarcoma might be a low-grade subtype of infantile fibrosarcoma. Interestingly, more than half of the infantile fibrosarcoma cases were positive for S100 protein and CD10. The follow-up period of TPR-NTRK1 and LMNA-NTRK1 fusion-positive tumors are not enough to predict prognosis. However, ETV6-NTRK3 fusion-positive infantile fibrosarcomas showed an excellent prognosis with no evidence of disease for an average of 11.7 years, after gross total resection of the tumor.

Highlights

While Ets variant 6 (ETV6)- NTRK3 fusion is common in infantile fibrosarcoma, NTRK1/3 fusion in pediatric tumors is scarce and, not well known
The erythroblast transformationspecific (ETS) variant 6 (ETV6)-neurotrophic receptor kinase (NTRK3) fusion has been identified in glioblastoma, mammary secretory carcinoma, salivary gland mammary carcinoma, adult lung cancer, papillary thyroid cancer, and mesenchymal tumors including infantile fibrosarcoma, mesoblastic nephroma, inflammatory myofibroblastic tumor (IMT), and gastrointestinal stromal tumors [1, 2, 4,5,6,7,8]
Echinoderm Microtubule Associated Protein like-4 (EML4)-NTRK3 fusion has been identified in infantile fibrosarcomas and congenital mesoblastic nephroma, in addition to ETV6-NTRK3 fusion [9]

Summary

Introduction

While ETV6- NTRK3 fusion is common in infantile fibrosarcoma, NTRK1/3 fusion in pediatric tumors is scarce and, not well known. Until now, the clinicopathological characteristics of all these gene fusion tumors have not been clarified Among these recent discoveries are neurotrophic receptor kinase (NTRK) gene fusions. NTRK1, NTRK2, and NTRK3 encode the neurotrophic tyrosine kinase receptor family TrkA, TrkB, and TrkC transmembrane proteins [2] These genes play an essential role in nervous system development and function through activation by neurotrophins [3]. The erythroblast transformationspecific (ETS) variant 6 (ETV6)-neurotrophic receptor kinase (NTRK3) fusion has been identified in glioblastoma, mammary secretory carcinoma, salivary gland mammary carcinoma, adult lung cancer, papillary thyroid cancer, and mesenchymal tumors including infantile fibrosarcoma, mesoblastic nephroma, IMT, and gastrointestinal stromal tumors [1, 2, 4,5,6,7,8]. Additional fusion partners of NTRK1 include RAB GTPase activating protein 1-like (RABGAP1L), chromatin target of Protein Arginine Methyltransferase 1 (PRMT1) (CHTOP), Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), neurofascin (NFASC), and brevican (BCAN) [11]

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