Surgical Resection and Targeted Therapy in a Pediatric NTRK-Rearranged Low- Grade Spindle Cell Sarcoma: A Case Report

Surgical Resection and Targeted Therapy in a Pediatric NTRK-Rearranged Low- Grade Spindle Cell Sarcoma: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Surgical Resection and Targeted Therapy in a Pediatric NTRK-Rearranged Low- Grade Spindle Cell Sarcoma: A Case Report Chien-Kai Wang, Shu-Mei Chen, Yen-Lin Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7167572/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Dec, 2025 Read the published version in Child's Nervous System → Version 1 posted 9 You are reading this latest preprint version Abstract Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions have emerged as important oncogenic drivers across a wide range of malignancies, including soft tissue sarcomas. Early detection of these fusions facilitates precision treatment with TRK inhibitors, significantly improving clinical outcomes. However, diagnosing NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) remains challenging due to their histological heterogeneity and overlap with other soft tissue tumors. Case Presentation We report the case of an 8-year-old boy with a history of infantile fibromatosis, who developed progressive right ankle dorsiflexion weakness and right foot drop. Magnetic resonance imaging revealed a large, homogeneously enhancing soft tissue mass with extensive perineural involvement and spinal cord compression spread from T8 to L3 levels. The patient underwent T10–L1 laminectomy and partial tumor resection under intraoperative neurophysiological monitoring. Diagnosis, Treatment and Outcome Histopathological analysis identified a low-grade spindle cell neoplasm with focal positivity for S100 and CD34, and patchy pan-tropomyosin receptor kinase (TRK) expression. Molecular studies using fluorescence in situ hybridization and RNA-based next-generation sequencing confirmed a TPM3-NTRK1 fusion, establishing the diagnosis of NTRK-rearranged low-grade spindle cell sarcoma. Postoperatively, targeted therapy with a TRK inhibitor-Larotrectinib (100 mg/m²/dose twice daily) was initiated. Over a two-year follow-up period, the patient demonstrated significant neurological improvement and stable disease without evidence of progression on serial imaging studies. Conclusion This case underscores the importance of integrating molecular diagnostics into the evaluation of atypical spindle cell tumors, particularly those presenting with aggressive clinical features despite low-grade histology. Early identification of NTRK fusions enables timely initiation of TRK inhibitor therapy, offering durable disease control and functional recovery. Broader awareness and implementation of molecular testing can greatly enhance the management of rare pediatric sarcomas. pediatric sarcoma NTRK fusion targeted therapy Larotrectinib spinal tumor Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions have emerged as critical oncogenic drivers across various malignancies, including sarcomas【1】. These fusions involve the NTRK1, NTRK2, and NTRK3 genes, leading to the constitutive activation of the tropomyosin receptor kinase (TRK) family of proteins, which play pivotal roles in cellular proliferation, differentiation, and survival【2】. While NTRK fusions are frequently observed in rare tumors such as infantile fibrosarcoma, their presence in a broader spectrum of sarcomas has been increasingly reported【3】. Given their role as tumor-agnostic alterations, these fusions represent an actionable target for TRK inhibitors, such as Larotrectinib and Entrectinib, which have demonstrated remarkable efficacy in NTRK fusion-positive malignancies【4】. Despite the therapeutic potential of targeting NTRK fusions, several challenges remain in their identification and clinical management. Diagnosing NTRK fusion-positive sarcomas is particularly complex due to their histological diversity and the absence of pathognomonic morphological characteristics【5】. Current diagnostic approaches rely on immunohistochemistry (IHC) for pan-TRK expression, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS)【6】. However, limitations in sensitivity and specificity necessitate the development of standardized diagnostic guidelines to optimize patient selection for TRK-targeted therapies【7】. In this case report, we presented our experience of an 8-year-old boy diagnosed with NTRK-rearranged low-grade spindle cell sarcoma. Despite undergoing multiple surgical resections since infancy, the patient experienced recurrent disease with progressive neurological symptoms due to extensive paraspinal and spinal involvement. The refractory nature of the tumor and its tendency to invade critical anatomical structures made complete surgical eradication difficult and highlighted the importance of molecular diagnostics. Postoperatively, the patient initiated targeted therapy with Larotrectinib, a selective TRK inhibitor, which led to gradual improvement in lower limb motor function and sustained radiographic disease stability over a two-year follow-up period. Case description An 8-year-old boy presented to the outpatient department with a one-year history of progressive lower limb weakness, predominantly affecting right ankle dorsiflexion, accompanied by increasing stiffness in the right foot. His medical history was notable for infantile fibromatosis, which had been confirmed through fine-needle biopsy in 2015. At 3 months of age, his parents noticed an abnormal protrusion in his lower back. A computed tomography (CT) scan revealed a retroperitoneal mass invading the paraspinal muscles and vertebral bodies. He underwent surgical decompression and partial tumor removal at 10 months old, and another surgery at 3 years and 10 months old due to progression of bilateral lower leg weakness resulted from cord compression by tumor. Pathological findings indicated an atypical spindle cell tumor, with immunohistochemistry showing multifocal positive for S100 and CD34, preserved H3K27me3 expression, negative for SMA, EMA, SOX10, desmin, myogenin, STATG and generally low Ki-67 staining (3–5%), suggestive of a lipofibromatosis-like neural tumor. Approximately one year prior to his current presentation at our outpatient department, the patient began experiencing weakness in right ankle dorsiflexion, a symptom that gradually worsened over time. More recently, he developed a right foot drop, which significantly affected his ability to walk. Despite an otherwise unremarkable neurological examination, muscle strength testing revealed severe weakness in right ankle dorsiflexion (grade 1/5) and moderate weakness in right great toe extension (grade 2/5) on the Medical Research Council (MRC) scale. A Gadolinium-enhanced thoraco-lumbar spine magnetic resonance imaging (MRI) revealed a large, homogeneously enhancing soft tissue mass extending from the right paraspinal soft tissue to the posterior pararenal region. The tumor exhibited perineural involvement from the right T8-9 to L3-4 neural foramina, extending into the T9 to T12 epidural space. Furthermore, contralateral tumor extension was observed in the left T9 to T12 paraspinal soft tissue, with associated external bony erosion from T9 to L4 vertebrae. This extensive involvement affected the vertebral bodies, pedicles, transverse processes, and facets. Additionally, the lesion caused significant compression and infiltration of the spinal cord from T10 to the conus medullaris. Given these findings, the patient underwent a T10-L1 laminectomy with spinal tumor resection under intraoperative neurophysiological monitoring (IONM). Immediate post-decompression, electromyography (EMG) monitoring indicated improved motor response. Histopathological analysis of the resected specimen confirmed the diagnosis of a low-grade spindle cell sarcoma. Immunohistochemical staining revealed focal positivity for S100 and CD34, while pan-TRK immunostaining demonstrated patchy positivity. EMA staining was negative, and Ki-67 staining showed a low proliferative index (< 5%). Further molecular studies, including fluorescence in situ hybridization (FISH) and RNA-based next-generation sequencing (NGS), confirmed an NTRK1 fusion with a TPM3( 8 )-NTRK1( 10 ) rearrangement, leading to the definitive diagnosis of an NTRK-rearranged low-grade spindle cell sarcoma. Based on these findings, the patient was initiated on targeted therapy with the tropomyosin receptor kinase (TRK) inhibitor Larotrectinib (100 mg/m²/dose BID) following surgery to achieve further disease control. At the three-month follow-up, the patient demonstrated improvement in ankle strength. Subsequent MRI scans showed no significant interval changes compared to previous imaging. Over the course of two years, follow-up MRIs continued to indicate stable disease without evidence of progression, suggesting effective disease control. Discussion NTRK-rearranged spindle cell sarcomas (NTRK-RSCNs) are a recently recognized subset of soft tissue tumors characterized by fusions of the neurotrophic tyrosine receptor kinase (NTRK) genes, most notably NTRK1【1,3】. These fusions drive oncogenesis via constitutive activation of TRK signaling, independent of the tumor's site or histologic classification【2】. While originally described in infantile fibrosarcoma, NTRK fusions have since been identified in a wide spectrum of spindle cell neoplasms, often with low-grade morphology but variable clinical behavior【3】. Despite the advent of effective targeted therapies, diagnosing NTRK fusion-positive tumors remains a major challenge due to their histological heterogeneity, lack of pathognomonic features, and overlapping immunohistochemical profiles with other entities【5】. In our case, the diagnostic process was particularly complex. The patient had a long-standing diagnosis of infantile fibromatosis with multiple local recurrences and progressive neurologic deterioration, but histopathological analyses from serial resections consistently revealed a low-grade spindle cell tumor with S100 and CD34 positivity, preserved H3K27me3, and low mitotic activity—findings insufficient for a definitive diagnosis. These features are shared by several soft tissue neoplasms, including lipofibromatosis-like neural tumors, low-grade malignant peripheral nerve sheath tumors, and myofibroblastic proliferations. Additionally, the clinical course was discordant with the indolent nature expected of infantile fibromatosis, raising suspicion for an underlying oncogenic driver. This diagnostic ambiguity underscores what several studies have reported—that NTRK-RSCNs frequently evade detection via conventional histology and immunohistochemistry alone, necessitating molecular diagnostics, such as RNA-based next-generation sequencing (NGS), for confirmation【6,7】. This diagnostic ambiguity reflects a growing consensus that a subset of morphologically bland spindle cell tumors harbor actionable oncogenic fusions that are not discernible through routine histopathology alone. Recent studies have emphasized the utility of RNA-based NGS in such cases, particularly when pan-TRK immunohistochemistry is equivocal or lacks specificity【6】. Our patient’s diagnosis was ultimately confirmed by identifying a TPM3-NTRK1 fusion, a recurrent rearrangement reported in NTRK-RSCNs and associated with both pediatric and adult-onset cases【8】. This fusion, combined with the tumor’s infiltrative pattern, perineural extension, and significant spinal cord compression, shows that NTRK-RSCNs often exhibit deep soft tissue involvement and aggressive local behavior despite low-grade histology【7】. Moreover, radiologic appearance in our case—demonstrating a highly vascular, homogeneously enhancing mass with extensive neural foraminal involvement and bony erosion—are consistent with published radiologic profiles of NTRK-RSCNs, which frequently show infiltrative margins and rich vascularity, mimicking other soft tissue sarcomas such as solitary fibrous tumors and alveolar soft part sarcoma (ASPS)【7】. Following tumor resection and decompression, targeted therapy with a highly selective TRK inhibitor—Larotrectinib—was initiated. Remarkably, within three months, he showed improved muscle strength, and over a two-year follow-up period, maintained stable disease without radiographic progression or neurological deterioration. This favorable response is in line with clinical trial data and case reports that demonstrate robust efficacy of Larotrectinib in both pediatric and adult populations with NTRK fusion-positive tumors【4,10】. In addition to symptomatic relief and tumor control, TRK inhibitors are particularly advantageous in functionally sensitive anatomical sites such as the spine, where complete resection is often not feasible without significant morbidity【11】. Although acquired resistance to TRK inhibitors has been described—primarily due to secondary mutations in the kinase domain, including the G595R gatekeeper mutation or solvent front alterations—our patient has not exhibited radiographic or clinical evidence of disease progression to date【9】. This underscores the potential for long-term disease control in fusion-positive, low-grade sarcomas when molecularly matched targeted therapy is implemented early【4】. Conclusion This case report underscores the clinical and diagnostic challenges of NTRK-rearranged spindle cell sarcomas in the pediatric population. The absence of distinct histological features delayed definitive diagnosis until advanced molecular testing confirmed a TPM3-NTRK1 fusion. Despite its low-grade histology, the tumor exhibited locally aggressive behavior, including spinal cord compression and neurologic deficits. Targeted therapy with Larotrectinib, initiated after surgical decompression, led to improved motor function and sustained radiologic stability over two years. This case highlights the value of integrating molecular diagnostics into the routine evaluation of spindle cell tumors, particularly those with atypical presentations. Early identification of NTRK fusions can facilitate precision treatment, improve clinical outcomes, and avoid overtreatment or misdiagnosis. As awareness and accessibility of NTRK testing increase, more patients may benefit from the paradigm shift that TRK inhibitors represent in sarcoma care. Declarations Author Contributions Chien-Kai Wang contributed to the acquisition of clinical data, patient evaluation, literature review and manuscript drafting. Yen-Lin Liu contributed to data interpretation, targeted therapy of the patient, and literature review. Shu-Mei Chen contributed to the conception and design of the study, surgical management of the patient, and critical revision of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Conflict of Interest and Funding Declaration The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest and with no funding support. Ethics Statement Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. Ethical approval was not required for this study in accordance with local legislation and institutional requirements. References Vaishnavi A, Le AT, Doebele RC (2015) TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 5(1):25–34. 10.1158/2159-8290.CD-14-0765 Epub 2014 Dec 19 Siozopoulou V, Smits E, De Winne K, Marcq E, Pauwels P (2021) NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects. Diagnostics (Basel) 11(3):478. 10.3390/diagnostics11030478 Cocco E, Scaltriti M, Drilon A (2018) NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 15(12):731–747. 10.1038/s41571-018-0113-0 Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, Doebele RC, Farago AF, Pappo AS, Turpin B, Dowlati A, Brose MS, Mascarenhas L, Federman N, Berlin J, El-Deiry WS, Baik C, Deeken J, Boni V, Nagasubramanian R, Taylor M, Rudzinski ER, Meric-Bernstam F, Sohal DPS, Ma PC, Raez LE, Hechtman JF, Benayed R, Ladanyi M, Tuch BB, Ebata K, Cruickshank S, Ku NC, Cox MC, Hawkins DS, Hong DS, Hyman DM (2018) Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378(8):731–739. 10.1056/NEJMoa1714448 Solomon JP, Linkov I, Rosado A, Mullaney K, Rosen EY, Frosina D, Jungbluth AA, Zehir A, Benayed R, Drilon A, Hyman DM, Ladanyi M, Sireci AN, Hechtman JF (2020) NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol 33(1):38–46. 10.1038/s41379-019-0324-7 Epub 2019 Aug 2 Brčić I, Godschachner TM, Bergovec M, Igrec J, Till H, Lackner H, Scheipl S, Kashofer K, Brodowicz T, Leithner A, Szkandera J, Liegl-Atzwanger B (2021) Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions. Mod Pathol 34(2):396–407. 10.1038/s41379-020-00657-x Epub 2020 Aug 28 Kobayashi H, Teramura Y, Yamashita K, Makise N, Ae K, Tanaka S (2023) Imaging findings of NTRK–rearranged spindle cell neoplasms: A case series. Mol Clin Oncol 18(3):14. 10.3892/mco.2023.2610 Cao Q, Huang Z, Liang H, Hu X, Wang L, Yang Y, Lian B, Huang J, Guo J (2024) Case report: Adult NTRK-rearranged spindle cell neoplasms with TPM3-NTRK1 fusion in the pelvic. Front Oncol 14:1308916. 10.3389/fonc.2024.1308916 Amatu A, Sartore-Bianchi A, Siena S (2016) NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 1(2):e000023. 10.1136/esmoopen-2015-000023 Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, Nagasubramanian R, Davis JL, Rudzinski E, Feraco AM, Tuch BB, Ebata KT, Reynolds M, Smith S, Cruickshank S, Cox MC, Pappo AS, Hawkins DS (2018) Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. ;19(5):705–714. doi: 10.1016/S1470-2045(18)30119-0. Epub 2018 Mar 29. Erratum in: Lancet Oncol. 2018;19(5):e229. 10.1016/S1470-2045(18)30286-9 Farago AF, Le LP, Zheng Z, Muzikansky A, Drilon A, Patel M, Bauer TM, Liu SV, Ou SH, Jackman D, Costa DB, Multani PS, Li GG, Hornby Z, Chow-Maneval E, Luo D, Lim JE, Iafrate AJ, Shaw AT (2015) Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol 10(12):1670–1674. 10.1097/01.JTO.0000473485.38553.f0 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 05 Dec, 2025 Read the published version in Child's Nervous System → Version 1 posted Editorial decision: Revision requested 12 Oct, 2025 Reviews received at journal 28 Sep, 2025 Reviews received at journal 23 Sep, 2025 Reviewers agreed at journal 16 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers invited by journal 15 Sep, 2025 Editor assigned by journal 25 Jul, 2025 Submission checks completed at journal 25 Jul, 2025 First submitted to journal 20 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7167572","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":516014624,"identity":"e1f64e3c-a0d5-4ea5-8378-70810648b928","order_by":0,"name":"Chien-Kai Wang","email":"","orcid":"","institution":"Taipei Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chien-Kai","middleName":"","lastName":"Wang","suffix":""},{"id":516014625,"identity":"9bfea21a-6813-4842-8134-71f301fd4629","order_by":1,"name":"Shu-Mei 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1","display":"","copyAsset":false,"role":"figure","size":691920,"visible":true,"origin":"","legend":"\u003cp\u003eSerial spinal MRI demonstrating tumor progression and post-treatment response.\u003c/p\u003e\n\u003cp\u003e(A-B) Sagittal T2-weighted MRI in 2015 showed a retroperitoneal soft tissue mass with extension into the paraspinal region and vertebral involvement.\u003c/p\u003e\n\u003cp\u003e(C-D, E-F) In 2021, Sagittal T2-weighted MRI and contrast-enhanced T1-weighted MRI revealed tumor progression with epidural extension, spinal cord compression, and perineural spread from T8 to L3 levels.\u003c/p\u003e\n\u003cp\u003e(G-H, I-J) Follow-up MRIs obtained after Larotrectinib treatment in 2023 showed stable tumor size and no further progression, with reduced spinal cord compression.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7167572/v1/414994891fba52a0b4cc39a0.png"},{"id":91977424,"identity":"deaf56a9-38bb-4d26-bbf0-dc97d6dc2744","added_by":"auto","created_at":"2025-09-23 10:20:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":761712,"visible":true,"origin":"","legend":"\u003cp\u003ePre- and post-treatment evaluation of right foot deformity and ankle supination.\u003c/p\u003e\n\u003cp\u003e(A) Preoperative anteroposterior radiograph of both feet showing no osseous abnormality, but subtle forefoot inversion and elevated medial arch of the right foot, suggestive of supination deformity.\u003c/p\u003e\n\u003cp\u003e(B) Preoperative clinical photograph demonstrating right foot drop with ankle dorsiflexion weakness and prominent supination posture.\u003c/p\u003e\n\u003cp\u003e(C) Postoperative photograph one month after partial tumor resection showing improved right foot alignment, with neutral positioning and restored weight-bearing capacity.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7167572/v1/e68ff64828a29ef237783a6e.png"},{"id":91977412,"identity":"8b8b6d37-1f96-4c13-91a5-cce3b48f96a0","added_by":"auto","created_at":"2025-09-23 10:20:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2197403,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological evolution from infantile fibromatosis to low-grade spindle cell sarcoma. Representative H\u0026amp;E-stained sections from surgical specimens across institutions and timepoints.\u003c/p\u003e\n\u003cp\u003e(Upper left) 2015 specimen from MKMH diagnosed as infantile fibromatosis.\u003c/p\u003e\n\u003cp\u003e(Upper right) 2018 NTUH specimen showing lipofibromatosis-like features.\u003c/p\u003e\n\u003cp\u003e(Lower panels) 2022 TMUH specimen demonstrating increased cellularity and spindle cell proliferation with mild nuclear atypia, consistent with low-grade spindle cell sarcoma.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7167572/v1/0dc32ee1311b399789d14001.png"},{"id":91978640,"identity":"7965482d-1ef8-4ef8-8856-931fee83203b","added_by":"auto","created_at":"2025-09-23 10:28:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2091296,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical findings confirming NTRK-rearranged spindle cell sarcoma.\u003c/p\u003e\n\u003cp\u003eIHC stains from the 2022 resected tumor:\u003c/p\u003e\n\u003cp\u003eS-100: focal cytoplasmic positivity.\u003c/p\u003e\n\u003cp\u003eCD34: diffuse membranous positivity.\u003c/p\u003e\n\u003cp\u003eKi-67: low proliferative index (\u0026lt;5%).\u003c/p\u003e\n\u003cp\u003ePan-TRK: patchy cytoplasmic staining, supporting the presence of NTRK fusion.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7167572/v1/52486d8829e4a927f1b793f0.png"},{"id":97723829,"identity":"06cb202d-4662-42e1-9ef4-ca15cb386a77","added_by":"auto","created_at":"2025-12-08 16:08:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7121992,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7167572/v1/f1aea792-57f1-40e3-91ba-520ccb119899.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Surgical Resection and Targeted Therapy in a Pediatric NTRK-Rearranged Low- Grade Spindle Cell Sarcoma: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeurotrophic tropomyosin receptor kinase (NTRK) gene fusions have emerged as critical oncogenic drivers across various malignancies, including sarcomas【1】. These fusions involve the NTRK1, NTRK2, and NTRK3 genes, leading to the constitutive activation of the tropomyosin receptor kinase (TRK) family of proteins, which play pivotal roles in cellular proliferation, differentiation, and survival【2】. While NTRK fusions are frequently observed in rare tumors such as infantile fibrosarcoma, their presence in a broader spectrum of sarcomas has been increasingly reported【3】. Given their role as tumor-agnostic alterations, these fusions represent an actionable target for TRK inhibitors, such as Larotrectinib and Entrectinib, which have demonstrated remarkable efficacy in NTRK fusion-positive malignancies【4】.\u003c/p\u003e\u003cp\u003eDespite the therapeutic potential of targeting NTRK fusions, several challenges remain in their identification and clinical management. Diagnosing NTRK fusion-positive sarcomas is particularly complex due to their histological diversity and the absence of pathognomonic morphological characteristics【5】. Current diagnostic approaches rely on immunohistochemistry (IHC) for pan-TRK expression, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS)【6】. However, limitations in sensitivity and specificity necessitate the development of standardized diagnostic guidelines to optimize patient selection for TRK-targeted therapies【7】.\u003c/p\u003e\u003cp\u003eIn this case report, we presented our experience of an 8-year-old boy diagnosed with NTRK-rearranged low-grade spindle cell sarcoma. Despite undergoing multiple surgical resections since infancy, the patient experienced recurrent disease with progressive neurological symptoms due to extensive paraspinal and spinal involvement. The refractory nature of the tumor and its tendency to invade critical anatomical structures made complete surgical eradication difficult and highlighted the importance of molecular diagnostics. Postoperatively, the patient initiated targeted therapy with Larotrectinib, a selective TRK inhibitor, which led to gradual improvement in lower limb motor function and sustained radiographic disease stability over a two-year follow-up period.\u003c/p\u003e"},{"header":"Case description","content":"\u003cp\u003eAn 8-year-old boy presented to the outpatient department with a one-year history of progressive lower limb weakness, predominantly affecting right ankle dorsiflexion, accompanied by increasing stiffness in the right foot. His medical history was notable for infantile fibromatosis, which had been confirmed through fine-needle biopsy in 2015.\u003c/p\u003e\u003cp\u003eAt 3 months of age, his parents noticed an abnormal protrusion in his lower back. A computed tomography (CT) scan revealed a retroperitoneal mass invading the paraspinal muscles and vertebral bodies. He underwent surgical decompression and partial tumor removal at 10 months old, and another surgery at 3 years and 10 months old due to progression of bilateral lower leg weakness resulted from cord compression by tumor. Pathological findings indicated an atypical spindle cell tumor, with immunohistochemistry showing multifocal positive for S100 and CD34, preserved H3K27me3 expression, negative for SMA, EMA, SOX10, desmin, myogenin, STATG and generally low Ki-67 staining (3–5%), suggestive of a lipofibromatosis-like neural tumor.\u003c/p\u003e\u003cp\u003eApproximately one year prior to his current presentation at our outpatient department, the patient began experiencing weakness in right ankle dorsiflexion, a symptom that gradually worsened over time. More recently, he developed a right foot drop, which significantly affected his ability to walk. Despite an otherwise unremarkable neurological examination, muscle strength testing revealed severe weakness in right ankle dorsiflexion (grade 1/5) and moderate weakness in right great toe extension (grade 2/5) on the Medical Research Council (MRC) scale.\u003c/p\u003e\u003cp\u003eA Gadolinium-enhanced thoraco-lumbar spine magnetic resonance imaging (MRI) revealed a large, homogeneously enhancing soft tissue mass extending from the right paraspinal soft tissue to the posterior pararenal region. The tumor exhibited perineural involvement from the right T8-9 to L3-4 neural foramina, extending into the T9 to T12 epidural space. Furthermore, contralateral tumor extension was observed in the left T9 to T12 paraspinal soft tissue, with associated external bony erosion from T9 to L4 vertebrae. This extensive involvement affected the vertebral bodies, pedicles, transverse processes, and facets. Additionally, the lesion caused significant compression and infiltration of the spinal cord from T10 to the conus medullaris.\u003c/p\u003e\u003cp\u003eGiven these findings, the patient underwent a T10-L1 laminectomy with spinal tumor resection under intraoperative neurophysiological monitoring (IONM). Immediate post-decompression, electromyography (EMG) monitoring indicated improved motor response. Histopathological analysis of the resected specimen confirmed the diagnosis of a low-grade spindle cell sarcoma. Immunohistochemical staining revealed focal positivity for S100 and CD34, while pan-TRK immunostaining demonstrated patchy positivity. EMA staining was negative, and Ki-67 staining showed a low proliferative index (\u0026lt; 5%). Further molecular studies, including fluorescence in situ hybridization (FISH) and RNA-based next-generation sequencing (NGS), confirmed an NTRK1 fusion with a TPM3(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)-NTRK1(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) rearrangement, leading to the definitive diagnosis of an NTRK-rearranged low-grade spindle cell sarcoma.\u003c/p\u003e\u003cp\u003eBased on these findings, the patient was initiated on targeted therapy with the tropomyosin receptor kinase (TRK) inhibitor Larotrectinib (100 mg/m²/dose BID) following surgery to achieve further disease control. At the three-month follow-up, the patient demonstrated improvement in ankle strength. Subsequent MRI scans showed no significant interval changes compared to previous imaging. Over the course of two years, follow-up MRIs continued to indicate stable disease without evidence of progression, suggesting effective disease control.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNTRK-rearranged spindle cell sarcomas (NTRK-RSCNs) are a recently recognized subset of soft tissue tumors characterized by fusions of the neurotrophic tyrosine receptor kinase (NTRK) genes, most notably NTRK1【1,3】. These fusions drive oncogenesis via constitutive activation of TRK signaling, independent of the tumor's site or histologic classification【2】. While originally described in infantile fibrosarcoma, NTRK fusions have since been identified in a wide spectrum of spindle cell neoplasms, often with low-grade morphology but variable clinical behavior【3】. Despite the advent of effective targeted therapies, diagnosing NTRK fusion-positive tumors remains a major challenge due to their histological heterogeneity, lack of pathognomonic features, and overlapping immunohistochemical profiles with other entities【5】.\u003c/p\u003e\u003cp\u003eIn our case, the diagnostic process was particularly complex. The patient had a long-standing diagnosis of infantile fibromatosis with multiple local recurrences and progressive neurologic deterioration, but histopathological analyses from serial resections consistently revealed a low-grade spindle cell tumor with S100 and CD34 positivity, preserved H3K27me3, and low mitotic activity\u0026mdash;findings insufficient for a definitive diagnosis. These features are shared by several soft tissue neoplasms, including lipofibromatosis-like neural tumors, low-grade malignant peripheral nerve sheath tumors, and myofibroblastic proliferations. Additionally, the clinical course was discordant with the indolent nature expected of infantile fibromatosis, raising suspicion for an underlying oncogenic driver. This diagnostic ambiguity underscores what several studies have reported\u0026mdash;that NTRK-RSCNs frequently evade detection via conventional histology and immunohistochemistry alone, necessitating molecular diagnostics, such as RNA-based next-generation sequencing (NGS), for confirmation【6,7】.\u003c/p\u003e\u003cp\u003eThis diagnostic ambiguity reflects a growing consensus that a subset of morphologically bland spindle cell tumors harbor actionable oncogenic fusions that are not discernible through routine histopathology alone. Recent studies have emphasized the utility of RNA-based NGS in such cases, particularly when pan-TRK immunohistochemistry is equivocal or lacks specificity【6】. Our patient\u0026rsquo;s diagnosis was ultimately confirmed by identifying a TPM3-NTRK1 fusion, a recurrent rearrangement reported in NTRK-RSCNs and associated with both pediatric and adult-onset cases【8】. This fusion, combined with the tumor\u0026rsquo;s infiltrative pattern, perineural extension, and significant spinal cord compression, shows that NTRK-RSCNs often exhibit deep soft tissue involvement and aggressive local behavior despite low-grade histology【7】. Moreover, radiologic appearance in our case\u0026mdash;demonstrating a highly vascular, homogeneously enhancing mass with extensive neural foraminal involvement and bony erosion\u0026mdash;are consistent with published radiologic profiles of NTRK-RSCNs, which frequently show infiltrative margins and rich vascularity, mimicking other soft tissue sarcomas such as solitary fibrous tumors and alveolar soft part sarcoma (ASPS)【7】.\u003c/p\u003e\u003cp\u003eFollowing tumor resection and decompression, targeted therapy with a highly selective TRK inhibitor\u0026mdash;Larotrectinib\u0026mdash;was initiated. Remarkably, within three months, he showed improved muscle strength, and over a two-year follow-up period, maintained stable disease without radiographic progression or neurological deterioration. This favorable response is in line with clinical trial data and case reports that demonstrate robust efficacy of Larotrectinib in both pediatric and adult populations with NTRK fusion-positive tumors【4,10】. In addition to symptomatic relief and tumor control, TRK inhibitors are particularly advantageous in functionally sensitive anatomical sites such as the spine, where complete resection is often not feasible without significant morbidity【11】.\u003c/p\u003e\u003cp\u003eAlthough acquired resistance to TRK inhibitors has been described\u0026mdash;primarily due to secondary mutations in the kinase domain, including the G595R gatekeeper mutation or solvent front alterations\u0026mdash;our patient has not exhibited radiographic or clinical evidence of disease progression to date【9】. This underscores the potential for long-term disease control in fusion-positive, low-grade sarcomas when molecularly matched targeted therapy is implemented early【4】.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case report underscores the clinical and diagnostic challenges of NTRK-rearranged spindle cell sarcomas in the pediatric population. The absence of distinct histological features delayed definitive diagnosis until advanced molecular testing confirmed a TPM3-NTRK1 fusion. Despite its low-grade histology, the tumor exhibited locally aggressive behavior, including spinal cord compression and neurologic deficits. Targeted therapy with Larotrectinib, initiated after surgical decompression, led to improved motor function and sustained radiologic stability over two years. This case highlights the value of integrating molecular diagnostics into the routine evaluation of spindle cell tumors, particularly those with atypical presentations. Early identification of NTRK fusions can facilitate precision treatment, improve clinical outcomes, and avoid overtreatment or misdiagnosis. As awareness and accessibility of NTRK testing increase, more patients may benefit from the paradigm shift that TRK inhibitors represent in sarcoma care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChien-Kai Wang contributed to the acquisition of clinical data, patient evaluation, literature review and manuscript drafting. Yen-Lin Liu contributed to data interpretation, targeted therapy of the patient, and literature review. Shu-Mei Chen contributed to the conception and design of the study, surgical management of the patient, and critical revision of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest and Funding Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest and with no funding support.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. Ethical approval was not required for this study in accordance with local legislation and institutional requirements.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVaishnavi A, Le AT, Doebele RC (2015) TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 5(1):25\u0026ndash;34. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/2159-8290.CD-14-0765\u003c/span\u003e\u003cspan address=\"10.1158/2159-8290.CD-14-0765\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2014 Dec 19\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSiozopoulou V, Smits E, De Winne K, Marcq E, Pauwels P (2021) NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects. 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Erratum in: Lancet Oncol. 2018;19(5):e229. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1470-2045(18)30286-9\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(18)30286-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFarago AF, Le LP, Zheng Z, Muzikansky A, Drilon A, Patel M, Bauer TM, Liu SV, Ou SH, Jackman D, Costa DB, Multani PS, Li GG, Hornby Z, Chow-Maneval E, Luo D, Lim JE, Iafrate AJ, Shaw AT (2015) Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol 10(12):1670\u0026ndash;1674. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/01.JTO.0000473485.38553.f0\u003c/span\u003e\u003cspan address=\"10.1097/01.JTO.0000473485.38553.f0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"pediatric sarcoma, NTRK fusion, targeted therapy, Larotrectinib, spinal tumor","lastPublishedDoi":"10.21203/rs.3.rs-7167572/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7167572/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eNeurotrophic tropomyosin receptor kinase (NTRK) gene fusions have emerged as important oncogenic drivers across a wide range of malignancies, including soft tissue sarcomas. Early detection of these fusions facilitates precision treatment with TRK inhibitors, significantly improving clinical outcomes. However, diagnosing NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) remains challenging due to their histological heterogeneity and overlap with other soft tissue tumors.\u003c/p\u003e\n\u003cp\u003eCase Presentation\u003c/p\u003e\n\u003cp\u003eWe report the case of an 8-year-old boy with a history of infantile fibromatosis, who developed progressive right ankle dorsiflexion weakness and right foot drop. Magnetic resonance imaging revealed a large, homogeneously enhancing soft tissue mass with extensive perineural involvement and spinal cord compression spread from T8 to L3 levels. The patient underwent T10–L1 laminectomy and partial tumor resection under intraoperative neurophysiological monitoring.\u003c/p\u003e\n\u003cp\u003eDiagnosis, Treatment and Outcome\u003c/p\u003e\n\u003cp\u003eHistopathological analysis identified a low-grade spindle cell neoplasm with focal positivity for S100 and CD34, and patchy pan-tropomyosin receptor kinase (TRK) expression. Molecular studies using fluorescence in situ hybridization and RNA-based next-generation sequencing confirmed a TPM3-NTRK1 fusion, establishing the diagnosis of NTRK-rearranged low-grade spindle cell sarcoma. Postoperatively, targeted therapy with a TRK inhibitor-Larotrectinib (100 mg/m²/dose twice daily) was initiated. Over a two-year follow-up period, the patient demonstrated significant neurological improvement and stable disease without evidence of progression on serial imaging studies.\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eThis case underscores the importance of integrating molecular diagnostics into the evaluation of atypical spindle cell tumors, particularly those presenting with aggressive clinical features despite low-grade histology. Early identification of NTRK fusions enables timely initiation of TRK inhibitor therapy, offering durable disease control and functional recovery. Broader awareness and implementation of molecular testing can greatly enhance the management of rare pediatric sarcomas.\u003c/p\u003e","manuscriptTitle":"Surgical Resection and Targeted Therapy in a Pediatric NTRK-Rearranged Low- Grade Spindle Cell Sarcoma: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 10:20:46","doi":"10.21203/rs.3.rs-7167572/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-13T01:45:38+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-29T03:47:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-23T20:15:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"203936937375771176552743402934814088999","date":"2025-09-16T14:35:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14536652932951251728482746281396205627","date":"2025-09-15T10:36:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-15T07:24:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-25T11:26:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-25T11:24:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Child's Nervous System","date":"2025-07-20T04:47:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"da762318-d4b8-4e51-b78c-377533e54656","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:01:17+00:00","versionOfRecord":{"articleIdentity":"rs-7167572","link":"https://doi.org/10.1007/s00381-025-07062-2","journal":{"identity":"childs-nervous-system","isVorOnly":false,"title":"Child's Nervous System"},"publishedOn":"2025-12-05 15:57:35","publishedOnDateReadable":"December 5th, 2025"},"versionCreatedAt":"2025-09-23 10:20:46","video":"","vorDoi":"10.1007/s00381-025-07062-2","vorDoiUrl":"https://doi.org/10.1007/s00381-025-07062-2","workflowStages":[]},"version":"v1","identity":"rs-7167572","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7167572","identity":"rs-7167572","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}