NTRK-Rearranged Spindle Cell Tumor with SPECC1L-NTRK3 Fusion in the Thoracic Spine: A Case Report

NTRK-Rearranged Spindle Cell Tumor with SPECC1L-NTRK3 Fusion in the Thoracic Spine: 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 NTRK-Rearranged Spindle Cell Tumor with SPECC1L-NTRK3 Fusion in the Thoracic Spine: A Case Report Mi Zhou, Huaiyuan Xu, Jianxiong Niu, Qibing Yang, Anqi Wang, Hao WU, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5283368/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Dec, 2024 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted 7 You are reading this latest preprint version Abstract Neurotrophic Tyrosine Receptor Kinase (NTRK)-rearranged spindle cell tumors are a category of soft tissue tumors characterized by rearrangements of the NTRK gene that exhibit unique molecular genetics, morphological, and immunophenotypic features. The core feature of NTRK-rearranged tumors is rearrangement of the NTRK gene family (NTRK1, NTRK2, and NTRK3), often involving fusion with other genes, leading to abnormal tropomyosin receptor kinase (TRK) protein expression and activation. Herein, we report the first case of an NTRK spindle cell tumor with SPECC1L-NTRK3 fusion. This case highlights the significance of next-generation sequencing (NGS) for tumor diagnosis and targeted drug selection. After one month ofentrectinib therapy, the patient had considerable tumor shrinkage and symptom relief. For bone-derived NTRK-rearranged spindle cell sarcomas, entrectinib has demonstrated favorable therapeutic effects and can be considered priority treatment option. NTRK-rearranged spindle cell tumor molecular characteristics NTRK3 pathological report SPECC1L Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction In the 5th edition of the World Health Organization classification of soft tissue and bone tumors in 2020, neurotrophic receptor kinase (NTRK)-rearranged spindle cell tumors were defined as a new subtype [ 1 ]. NTRK is an important gene encoding members of the tropomyosin receptor kinase (TRK) family, including NTRK1, NTRK2, and NTRK3, which correspond to the three proteins TRKA, TRKB, and TRKC. The NTRK rearrangement, also known as NTRK gene fusion, is a genetic rearrangement phenomenon. It refers to the abnormal fusion of the NTRK gene family (including NTRK1, NTRK2, and NTRK3) with other genes, resulting in the abnormal activation of NTRK gene expression, abnormal cell proliferation and carcinogenesis, leading to neuronal differentiation and malignant mitosis. Common NTRK fusion types include ETV6-NTRK3, TPM3-NTRK1, and LMNA-NTRK1[ 2 – 4 ]. The sperm antigen with calmodulin homology and coiled-coil domain 1-like (SPECC1L) functions as a cytoskeletal scaffolding protein and is associated with microtubules, filamentous actin, and non-muscle myosin II (NMII), as well as membrane-associated components of adherens junctions[ 5 ]. In sarcoma pathogenesis, NTRK fusions are more common in pediatric tumors than in adult tumors. In a fusion gene study of tumors from 1217 pediatric patients, NTRK fusions were identified in 29 tumors from 27 patients, with a positive rate of 2.22% for all tumors and 3.08% for solid tumors.[ 6 ]The first-generation TRK inhibitors mainly include larotrectinib and entrectinib, which have been widely used in various types of tumors and achieve good therapeutic effects.[ 7 ] In this study we present the first case of SPECC1L-NTRK3 gene fusion spindle cell sarcoma occurring in the thoracic spine. The treatment experience presented in this case report can serve as a valuable reference for future clinical encounters with similar bone and soft tissue tumors, potentially saving diagnostic time, enabling early targeted treatment, and improving therapeutic outcomes. Case Report A 25-year-old woman complained of persistent low back pain over the previous three months, she experienced weakness in both lower extremities for three days. Physical examination showed grade 0/5 muscle strength in both lower extremities. Magnetic resonance imaging (MRI) and computed tomography (CT) scan revealed a large lytic lesion with a huge extraspinal component involving the T11and T12 spinal segment. The mass was approximately 11.26 cm x 7.29 cm, compressing and involving the spinal cord at the T11 level, with invasion of the left erector spinae (Fig. 1 ). The pathological review of the percutaneous needle biopsy demonstrated a diagnosis of spindle cell sarcoma. Microscopically, atypical cells were observed in a fascicular or woven pattern, with relatively uniform cell morphology and distribution around the blood vessels. The nuclei were round or short spindle-shaped with visible small nucleoli, and focal involvement of the striated muscle was noted. Immunohistochemical analysis revealed positive staining for NTrk, partial positivity for S-100, positivity for CD99, GFAP (weak positivity in a small amount), H3K27Me3, and INI-1, and partial positivity for S100(Duo). The results were negative for Demin and SOX-10, and Ki-67 staining showed a labeling index of 40%. Given these findings, second-generation sequencing is recommended for further molecular analysis. To further investigate the true nature of the tumor, assess its mutational profile, and identify potential therapeutic targets, we conducted extensive high-throughput sarcoma testing. The testing encompassed DNA sequencing of all exons in 706 genes, partial introns in 67 genes, RNA sequencing of all exons in 649 genes, calculation of tumor mutational burden (TMB), microsatellite instability (MSI) assessment, HLA-I genotyping, HED SCORE calculation, germline pathogenic variant screening covering all exons of 65 genes, analysis of gene variant interactions and their therapeutic relevance, and variants of unknown significance (VUS) in both DNA and RNA sequencing. The results revealed 20 potentially clinically significant variants and 10 VUS variants in DNA sequencing, while RNA sequencing identified one clinically significant rearrangement and no VUS rearrangements. Harmful germline variants were not detected. Human leukocyte antigen (HLA)-I genotyping revealed a heterozygous profile. Based on the gene variant detection results recommended by clinical guidelines for the adjunctive diagnosis of soft tissue sarcomas, a gene rearrangement in NTRK3 was identified, specifically, a SPECC1L exon6-NTRK3 exon14 fusion. The abundance of gene mutations was 52%. FISH also detected a break in the NTRK gene (Fig. 2 ). This suggested that the tumor was classified as an NTRK rearrangement spindle cell tumor. Given these findings, the patient may benefit from targeted therapies such as entrectinib and larotrectinib.(Table.1) Table 1 DNA Clear sequencing/potential clinical significance variation Gene Mutation Gene Abundance /Copy number Potentially sensitive/resistant drugs and evidence levels MTRK3 exon14_exon20amp CNV 15q25.3 6.9copy Entrectinib (Sensitive-A) SPECCIlexon6-NTRK3 exon14 Fusion - 52% Larotrectinib (Sensitive-A) CRKL gene amplification CNV 22q11.21 8.7copy Dasatinib (Sensitive-D) CCNEI gene amplification CNV 19q12 5.4copy - KRAS gene amplification CNV 12pl2.1 4.4copy - MAP2K2(MEKI) gene amplification CNV 15q22.31 7.2copy - MDM2 gene amplification CNV 12q15 5.3copy - BCR gene amplification CNV 22q11.23 6.5copy - CSK gene amplification CNV 15q24.1 6.9copy - DGCR8 gene amplification CNV 22q11.21 6.9copy - FBXO22 gene amplification CNV 15q24.2 6.9copy - FGF7 gene amplification CNV 15q21.2 7.2copy - FRS2 gene amplification CNV 12q15 5.3copy - KDM5A gene amplification CNV 12p13.33 5.8copy - MAPKI gene amplification CNV 22q11.21- 22q11.22 6.5copy - PTPNI1 gene amplification CNV 12q24.13 5.3copy - RECQL gene amplification CNV 12pl2.1 4.4copy - SMAD3 gene amplification CNV 15q22.33 7.2copy - SRGAP1 gene amplification CNV 12q14.2 5.2copy - W/NK1 gene amplification CNV 12p13.33 4.9copy - The results of high-throughput sequencing for sarcoma indicated that the patient had a SPECC1L exon6-NTRK3 exon14 gene fusion, and the patient may benefit from targeted drugs, such as Entrectinib and Larotrectinib. The patient received two cycles of doxorubicin/ifosfamide combination chemotherapy while awaiting NGS testing. MRI scan after chemotherapy showing no significant changes compared to previous scans. Indicating that the tumor did not respond well to chemotherapy. After discussion in the multidisciplinary team meetings, the patient was advised to undergo targeted therapy with entrectinib 600 mg QD PO. After one month of entrectinib treatment, the patient experienced sensory recovery in both lower extremities, with gradual improvement in muscle strength. Overall, muscle strength in the lower extremities was approximately 2–3 out of 5 grades. MRI and Computed Tomography(CT) scans revealed considerable tumor shrinkage and en bloc resection was feasible (Fig. 1 ). On May 15, 2024, on the basis of electrophysiological monitoring, the patient completely removed the three vertebral bodies invaded by the tumor and the surrounding soft tissues and ribs through posterior approach, and reconstructed the spine through 3D printed metal vertebral bodies. The operation lasted about 9 hours and 3 minutes, and the intraoperative blood loss was 2500ml.The patient was discharged uneventfully one month after the operation. Prior to discharge, the patient was able to sit upright independently without requiring any external assistance. Regarding muscle strength, the lower extremities exhibited an overall strength of approximately 2–3 grades. The postoperative pathological results were consistent with those before operation, the tumor necrosis rate was about 70%, the postoperative pathological margin was negative, and the invasion of striated muscle and adipose tissue was seen under the microscope(Fig. 3 ). Immunohistochemical analysis revealed variable positivity for NTrk, partial positivity for S-100, and approximately 10% positivity for Ki-67. Figure 4 . After operation, the patient continued to be treated with entrectinib orally. At the last follow-up visit, the patient's wound healed well, and the muscle strength of both lower limbs improved compared with before. However, he still couldn't stand alone, and needed family members and walkers to assist him in standing. mr and ct showed that the tumor had no obvious metastasis and recurrence. Discussion This case report presents the first instance of a bone-derived spindle cell tumor harboring a SPECC1L-NTRK3 fusion rearrangement, thus providing valuable clinical experience in the diagnosis and treatment of similar cases. The patient achieved significant therapeutic benefits and symptom relief following entrectinib treatment. NGS technology, with its high-throughput and efficient characteristics, has demonstrated immense potential for detecting gene fusions. Through massive parallel sequencing, NGS can comprehensively examine mutations, fusions, and aberrant expression in the genome, providing a rich set of molecular markers for tumor diagnosis. Specifically, in the detection of fusion genes, NGS not only identifies known fusion types but also discovers new, unknown fusions, offering robust support for precise tumor diagnosis. In this case, detection of the SPECC1L-NTRK3 fusion was critical for determining the appropriate treatment strategy. Entrectinib, a tyrosine kinase inhibitor that specifically targets NTRK fusion proteins, was administered based on the genetic profile of the tumor. This successful outcome highlights the importance of precision medicine in cancer therapy, where personalized treatment plans are tailored to the molecular characteristics of the individual tumor. Furthermore, the clinical course of this case demonstrated the potential value of continuous monitoring and adaptive treatment strategies. The patient’s response to entrectinib was carefully monitored and the treatment plan was adjusted accordingly to ensure optimal therapeutic outcomes. This approach is essential for managing complex cases, such as those involving NTRK fusion-positive tumors, where treatment resistance and disease progression can occur. In summary, this case report provides valuable insights into the management of NTRK fusion-positive tumors and the role of NGS technology in precise tumor diagnosis. This emphasizes the importance of genetic profiling for guiding personalized treatment plans and continuous monitoring to ensure therapeutic success. Previous reports of SPECC1L-NTRK3 fusion tumors are rare, and only very rare uterine sarcomas have been reported. In the case report of uterine sarcoma, the tumor exhibits alternating high-and low-cell regions of epithelioid and spindle cell proliferation. The hypercellular zone consists predominantly of epithelioid cells with moderate nuclear atypia, coarse chromatin, small nucleoli, and moderate number of eosinophilic cytoplasm. The hypocellular zone consists predominantly of spindle-shaped cells arranged in bundles and cords with a mucoid background. Immunostaining positive for S100 and CD34.[ 8 ]In our department’s case report, the pathological features revealed. Immunohistochemical analysis showed positivity for NTrk, partial positivity for S-100, positivity for CD99, weak positivity for GFAP (in a small quantity), positivity for H3K27Me3, INI-1, partial positivity for S100 (Duo), negativity for Demin, negativity for SOX-10, and Ki-67 expression of 40%. Currently, the main therapeutic options for NTRK gene fusions are entrectinib and larotrectinib. Larotrectinib demonstrated a response rate of 75% in a study of 55 patients. During a one-year follow-up, 71% of the patients showed a durable response, and 55% achieved disease progression-free status. No patients discontinued treatment due to drug-related adverse events, indicating that larotrectinib has significant and durable antitumor activity in NTRK fusion-positive cancer patients, regardless of age or tumor type[ 9 ]. In a key comprehensive analysis of three trials (Phase 1 adult, Phase 2 adult and adolescent, and Phase 1–2 pediatric) of larotrectinib, the proportion of patients achieving objective response was higher than the response rate in the entrectinib comprehensive analysis.[ 10 ] This case reports an extremely rare spindle cell sarcoma of spinal origin with SPECC1L-NTRK3 gene fusion. The treatment experience of this case provides valuable diagnostic experience and results for future patients with malignant tumors with NTRK gene fusion. Second-generation gene sequencing plays a very important role in diagnosis, which can provide patients with good targeted drug selection, emphasizing the importance of early detection and timely treatment. Declarations Data Statement These studies involving humans received approval from the Ethics Committee of Sun Yat-sen University Cancer Center. This research was conducted in accordance with local legislation and institutional requirements. The surgical specimens used in this study were obtained via surgical excision at our institution. Based on the national legislation and institutional guidelines, participants or their legal guardians/next of kin were not required to provide written informed consent. Written informed consent was obtained from all individuals for the publication of any potentially identifiable images or data included in this document. Author Contribution Mi Zhou: Data management, formal analysis, writing, and the original draft. Huaiyuan Xu: Review and editing. Jianxiong Niu: prepared figures 1. Qinglian Tang: Data management, formal analysis, writing, reviewing, and editing. Qingbing Yang:prepared figures 2. Hao Wu: prepared figures 3. Angqi Wang: prepared figures 4. Xiangqin Wang: prepared table 1.Jinxin Hu：Article modification. Jin Wang: Conceptualization, project administration, writing, reviewing, and editing. References Choi JH, Ro JY (2021) The 2020 WHO Classification of Tumors of Soft Tissue: Selected Changes and New Entities. Adv Anat Pathol 28:44–58. 10.1097/pap.0000000000000284 Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH (1998) A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18:184–187. 10.1038/ng0298-184 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 Nakata E, Osone T, Ogawa T, Taguchi T, Hattori K, Kohsaka S (2024) Prevalence of neurotrophic tropomyosin receptor kinase (NTRK) fusion gene positivity in patients with solid tumors in Japan. Cancer Med 13:e7351. 10.1002/cam4.7351 Saadi I, Goering JP, Hufft-Martinez BM, Tran PV (2023) SPECC1L: a cytoskeletal protein that regulates embryonic tissue dynamics. Biochem Soc Trans 51:949–958. 10.1042/bst20220461 Zhao X, Kotch C, Fox E, Surrey LF, Wertheim GB, Baloch ZW, Lin F, Pillai V, Luo M, Kreiger PA, Pogoriler JE, Linn RL, Russo PA, Santi M, Resnick AC, Storm PB, Hunger SP, Bauer AJ, Li MM (2021) NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome. JCO Precis Oncol 1. 10.1200/po.20.00250 Siozopoulou V, Smits E, De Winne K, Marcq E, Pauwels P (2021) NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects. Diagnostics (Basel) 11. 10.3390/diagnostics11030478 Nilforoushan N, Wethington SL, Nonogaki H, Gross J, Vang R, Xing D (2022) NTRK-Fusion Sarcoma of the Uterine Cervix: Report of 2 Cases With Comparative Clinicopathologic Features. Int J Gynecol Pathol 41:642–648. 10.1097/pgp.0000000000000834 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 378:731–739. 10.1056/NEJMoa1714448 Sidaway P (2018) Targeted therapy: Larotrectinib effective against TRK-fusion-positive cancers. Nat Rev Clin Oncol 15:264. doi: 10.1038/nrclinonc.2018.40 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 11 Dec, 2024 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted Editorial decision: Revision requested 28 Oct, 2024 Reviews received at journal 27 Oct, 2024 Reviewers agreed at journal 20 Oct, 2024 Reviewers invited by journal 20 Oct, 2024 Editor assigned by journal 19 Oct, 2024 Submission checks completed at journal 19 Oct, 2024 First submitted to journal 17 Oct, 2024 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5283368","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":371326065,"identity":"8069b8e7-616f-43c9-b95a-88b389e599d3","order_by":0,"name":"Mi Zhou","email":"","orcid":"","institution":"Sun Yat-Sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Mi","middleName":"","lastName":"Zhou","suffix":""},{"id":371326066,"identity":"f81b3485-75d5-4dff-a785-bdc6b709d7b2","order_by":1,"name":"Huaiyuan Xu","email":"","orcid":"","institution":"Sun Yat-Sen University Cancer 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13:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5283368/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5283368/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00432-024-06042-4","type":"published","date":"2024-12-11T15:57:55+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":68004373,"identity":"f9852df2-a21e-4bec-85dd-1d4a810522a7","added_by":"auto","created_at":"2024-11-01 08:31:55","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":598539,"visible":true,"origin":"","legend":"\u003cp\u003eMRI Results:\u003c/p\u003e\n\u003cp\u003e(A)MRI shows thoracic spine tumor before chemotherapy treatment，The red arrow indicates that the spinal cord is compressed by the tumor.(B) Follow up MRI examination after two rounds of chemotherapy showed that the tumor had little change compared to before。Red arrows indicate that the spinal cord is still severely squeezed;\u003c/p\u003e\n\u003cp\u003e(C)Follow up MRI examination after one month of treatment with Enqutinib showed a tumor in the 11th thoracic vertebra, with the spinal cord being compressed and the tumor significantly shrinking compared to before. The red arrow indicates that the spinal cord compression is reduced and the spinal cord gradually returns to its normal position\u003c/p\u003e\n\u003cp\u003e(D) Follow up MRI examination after 2 months of continuous treatment with Enqutinib showed a tumor in the 11th thoracic vertebra, with the spinal cord being compressed and the tumor further shrinking compared to before. The red arrow indicates that the spinal cord compression is further reduced, and the transparent cerebrospinal fluid is visible.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5283368/v1/9848e7dbad8db7f6bd105742.jpeg"},{"id":68004375,"identity":"33ab597a-600c-4d64-a6ac-51bee3759f21","added_by":"auto","created_at":"2024-11-01 08:31:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":419839,"visible":true,"origin":"","legend":"\u003cp\u003eGene molecular diagnostic report\u003c/p\u003e\n\u003cp\u003e(A) The test sample showed that 100 tumor cells were counted, and more than 15% of them showed isolated signals and interpreted as positive. NTRK gene break tested positive.(B) Positive control experiment\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5283368/v1/22ec9562cce1d6b6335590f0.png"},{"id":68005608,"identity":"c18d52e1-32b8-4670-a6e9-957826956fd7","added_by":"auto","created_at":"2024-11-01 08:39:55","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":825695,"visible":true,"origin":"","legend":"\u003cp\u003ePictures of tumor specimens removed during operation and pictures of X-ray fluoroscopic images during operation\u003c/p\u003e\n\u003cp\u003e(A) Front view of specimen. (B) Rear view of specimen. (C) Intraoperative fluoroscopy of specimens, upper and lower fluoroscopy. (D) Intraoperative fluoroscopy of specimens, anteroposterior fluoroscopy.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5283368/v1/1ed1e1413e6d8188b16562a2.jpeg"},{"id":68005609,"identity":"ad895384-5951-40da-8748-c545bfc2eaf3","added_by":"auto","created_at":"2024-11-01 08:39:55","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":260633,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological Features:(A) Specimen after block resection of the thoracic tumor. Yellow arrows indicate staining boundaries.\u003cbr\u003e\n(B) Tumor cells invade adipose tissue and striated muscle tissue under low magnification microscope. (C) Tumor cells invade adipose tissue and striated muscle tissue under medium magnification microscope. (D) Tumor cells invade adipose tissue and striated muscle tissue under high magnification microscope.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5283368/v1/83afe16f789b301d390e995a.jpeg"},{"id":71552494,"identity":"71a3cbc1-15b5-4673-9379-942cdf64594c","added_by":"auto","created_at":"2024-12-16 16:06:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2427431,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5283368/v1/5f09df22-6417-4915-b70f-84fc430099f9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"NTRK-Rearranged Spindle Cell Tumor with SPECC1L-NTRK3 Fusion in the Thoracic Spine: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn the 5th edition of the World Health Organization classification of soft tissue and bone tumors in 2020, neurotrophic receptor kinase (NTRK)-rearranged spindle cell tumors were defined as a new subtype [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. NTRK is an important gene encoding members of the tropomyosin receptor kinase (TRK) family, including NTRK1, NTRK2, and NTRK3, which correspond to the three proteins TRKA, TRKB, and TRKC. The NTRK rearrangement, also known as NTRK gene fusion, is a genetic rearrangement phenomenon. It refers to the abnormal fusion of the NTRK gene family (including NTRK1, NTRK2, and NTRK3) with other genes, resulting in the abnormal activation of NTRK gene expression, abnormal cell proliferation and carcinogenesis, leading to neuronal differentiation and malignant mitosis. Common NTRK fusion types include ETV6-NTRK3, TPM3-NTRK1, and LMNA-NTRK1[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The sperm antigen with calmodulin homology and coiled-coil domain 1-like (SPECC1L) functions as a cytoskeletal scaffolding protein and is associated with microtubules, filamentous actin, and non-muscle myosin II (NMII), as well as membrane-associated components of adherens junctions[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In sarcoma pathogenesis, NTRK fusions are more common in pediatric tumors than in adult tumors. In a fusion gene study of tumors from 1217 pediatric patients, NTRK fusions were identified in 29 tumors from 27 patients, with a positive rate of 2.22% for all tumors and 3.08% for solid tumors.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]The first-generation TRK inhibitors mainly include larotrectinib and entrectinib, which have been widely used in various types of tumors and achieve good therapeutic effects.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn this study we present the first case of SPECC1L-NTRK3 gene fusion spindle cell sarcoma occurring in the thoracic spine.\u003c/p\u003e \u003cp\u003eThe treatment experience presented in this case report can serve as a valuable reference for future clinical encounters with similar bone and soft tissue tumors, potentially saving diagnostic time, enabling early targeted treatment, and improving therapeutic outcomes.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 25-year-old woman complained of persistent low back pain over the previous three months, she experienced weakness in both lower extremities for three days. Physical examination showed grade 0/5 muscle strength in both lower extremities. Magnetic resonance imaging (MRI) and computed tomography (CT) scan revealed a large lytic lesion with a huge extraspinal component involving the T11and T12 spinal segment. The mass was approximately 11.26 cm x 7.29 cm, compressing and involving the spinal cord at the T11 level, with invasion of the left erector spinae (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe pathological review of the percutaneous needle biopsy demonstrated a diagnosis of spindle cell sarcoma. Microscopically, atypical cells were observed in a fascicular or woven pattern, with relatively uniform cell morphology and distribution around the blood vessels. The nuclei were round or short spindle-shaped with visible small nucleoli, and focal involvement of the striated muscle was noted.\u003c/p\u003e \u003cp\u003eImmunohistochemical analysis revealed positive staining for NTrk, partial positivity for S-100, positivity for CD99, GFAP (weak positivity in a small amount), H3K27Me3, and INI-1, and partial positivity for S100(Duo). The results were negative for Demin and SOX-10, and Ki-67 staining showed a labeling index of 40%. Given these findings, second-generation sequencing is recommended for further molecular analysis.\u003c/p\u003e \u003cp\u003eTo further investigate the true nature of the tumor, assess its mutational profile, and identify potential therapeutic targets, we conducted extensive high-throughput sarcoma testing. The testing encompassed DNA sequencing of all exons in 706 genes, partial introns in 67 genes, RNA sequencing of all exons in 649 genes, calculation of tumor mutational burden (TMB), microsatellite instability (MSI) assessment, HLA-I genotyping, HED SCORE calculation, germline pathogenic variant screening covering all exons of 65 genes, analysis of gene variant interactions and their therapeutic relevance, and variants of unknown significance (VUS) in both DNA and RNA sequencing.\u003c/p\u003e \u003cp\u003eThe results revealed 20 potentially clinically significant variants and 10 VUS variants in DNA sequencing, while RNA sequencing identified one clinically significant rearrangement and no VUS rearrangements. Harmful germline variants were not detected. Human leukocyte antigen (HLA)-I genotyping revealed a heterozygous profile.\u003c/p\u003e \u003cp\u003eBased on the gene variant detection results recommended by clinical guidelines for the adjunctive diagnosis of soft tissue sarcomas, a gene rearrangement in NTRK3 was identified, specifically, a SPECC1L exon6-NTRK3 exon14 fusion. The abundance of gene mutations was 52%. FISH also detected a break in the NTRK gene (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This suggested that the tumor was classified as an NTRK rearrangement spindle cell tumor. Given these findings, the patient may benefit from targeted therapies such as entrectinib and larotrectinib.(Table.1)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDNA Clear sequencing/potential clinical significance variation\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eMutation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAbundance /Copy number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePotentially sensitive/resistant drugs and evidence levels\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMTRK3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eexon14_exon20amp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15q25.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.9copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEntrectinib (Sensitive-A)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSPECCIlexon6-NTRK3 exon14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLarotrectinib (Sensitive-A)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRKL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22q11.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.7copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDasatinib (Sensitive-D)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCNEI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e 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colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15q22.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.2copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMDM2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12q15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.3copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22q11.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e 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\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15q24.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.9copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGF7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15q21.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.2copy\u003c/p\u003e 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\u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12p13.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.8copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAPKI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22q11.21-\u003c/p\u003e \u003cp\u003e22q11.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.5copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTPNI1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12q24.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.3copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRECQL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12pl2.1\u003c/p\u003e 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amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12q14.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.2copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eW/NK1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egene amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCNV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12p13.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.9copy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe results of high-throughput sequencing for sarcoma indicated that the patient had a SPECC1L exon6-NTRK3 exon14 gene fusion, and the patient may benefit from targeted drugs, such as Entrectinib and Larotrectinib.\u003c/p\u003e \u003cp\u003eThe patient received two cycles of doxorubicin/ifosfamide combination chemotherapy while awaiting NGS testing. MRI scan after chemotherapy showing no significant changes compared to previous scans. Indicating that the tumor did not respond well to chemotherapy. After discussion in the multidisciplinary team meetings, the patient was advised to undergo targeted therapy with entrectinib 600 mg QD PO.\u003c/p\u003e\u003cp\u003eAfter one month of entrectinib treatment, the patient experienced sensory recovery in both lower extremities, with gradual improvement in muscle strength. Overall, muscle strength in the lower extremities was approximately 2\u0026ndash;3 out of 5 grades. MRI and Computed Tomography(CT) scans revealed considerable tumor shrinkage and en bloc resection was feasible (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn May 15, 2024, on the basis of electrophysiological monitoring, the patient completely removed the three vertebral bodies invaded by the tumor and the surrounding soft tissues and ribs through posterior approach, and reconstructed the spine through 3D printed metal vertebral bodies. The operation lasted about 9 hours and 3 minutes, and the intraoperative blood loss was 2500ml.The patient was discharged uneventfully one month after the operation. Prior to discharge, the patient was able to sit upright independently without requiring any external assistance. Regarding muscle strength, the lower extremities exhibited an overall strength of approximately 2\u0026ndash;3 grades.\u003c/p\u003e \u003cp\u003eThe postoperative pathological results were consistent with those before operation, the tumor necrosis rate was about 70%, the postoperative pathological margin was negative, and the invasion of striated muscle and adipose tissue was seen under the microscope(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eImmunohistochemical analysis revealed variable positivity for NTrk, partial positivity for S-100, and approximately 10% positivity for Ki-67. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eAfter operation, the patient continued to be treated with entrectinib orally. At the last follow-up visit, the patient's wound healed well, and the muscle strength of both lower limbs improved compared with before. However, he still couldn't stand alone, and needed family members and walkers to assist him in standing. mr and ct showed that the tumor had no obvious metastasis and recurrence.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case report presents the first instance of a bone-derived spindle cell tumor harboring a SPECC1L-NTRK3 fusion rearrangement, thus providing valuable clinical experience in the diagnosis and treatment of similar cases. The patient achieved significant therapeutic benefits and symptom relief following entrectinib treatment.\u003c/p\u003e \u003cp\u003eNGS technology, with its high-throughput and efficient characteristics, has demonstrated immense potential for detecting gene fusions. Through massive parallel sequencing, NGS can comprehensively examine mutations, fusions, and aberrant expression in the genome, providing a rich set of molecular markers for tumor diagnosis. Specifically, in the detection of fusion genes, NGS not only identifies known fusion types but also discovers new, unknown fusions, offering robust support for precise tumor diagnosis.\u003c/p\u003e \u003cp\u003eIn this case, detection of the SPECC1L-NTRK3 fusion was critical for determining the appropriate treatment strategy. Entrectinib, a tyrosine kinase inhibitor that specifically targets NTRK fusion proteins, was administered based on the genetic profile of the tumor. This successful outcome highlights the importance of precision medicine in cancer therapy, where personalized treatment plans are tailored to the molecular characteristics of the individual tumor.\u003c/p\u003e \u003cp\u003eFurthermore, the clinical course of this case demonstrated the potential value of continuous monitoring and adaptive treatment strategies. The patient\u0026rsquo;s response to entrectinib was carefully monitored and the treatment plan was adjusted accordingly to ensure optimal therapeutic outcomes. This approach is essential for managing complex cases, such as those involving NTRK fusion-positive tumors, where treatment resistance and disease progression can occur.\u003c/p\u003e \u003cp\u003eIn summary, this case report provides valuable insights into the management of NTRK fusion-positive tumors and the role of NGS technology in precise tumor diagnosis. This emphasizes the importance of genetic profiling for guiding personalized treatment plans and continuous monitoring to ensure therapeutic success.\u003c/p\u003e \u003cp\u003ePrevious reports of SPECC1L-NTRK3 fusion tumors are rare, and only very rare uterine sarcomas have been reported. In the case report of uterine sarcoma, the tumor exhibits alternating high-and low-cell regions of epithelioid and spindle cell proliferation. The hypercellular zone consists predominantly of epithelioid cells with moderate nuclear atypia, coarse chromatin, small nucleoli, and moderate number of eosinophilic cytoplasm. The hypocellular zone consists predominantly of spindle-shaped cells arranged in bundles and cords with a mucoid background. Immunostaining positive for S100 and CD34.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]In our department\u0026rsquo;s case report, the pathological features revealed. Immunohistochemical analysis showed positivity for NTrk, partial positivity for S-100, positivity for CD99, weak positivity for GFAP (in a small quantity), positivity for H3K27Me3, INI-1, partial positivity for S100 (Duo), negativity for Demin, negativity for SOX-10, and Ki-67 expression of 40%.\u003c/p\u003e \u003cp\u003eCurrently, the main therapeutic options for NTRK gene fusions are entrectinib and larotrectinib. Larotrectinib demonstrated a response rate of 75% in a study of 55 patients. During a one-year follow-up, 71% of the patients showed a durable response, and 55% achieved disease progression-free status. No patients discontinued treatment due to drug-related adverse events, indicating that larotrectinib has significant and durable antitumor activity in NTRK fusion-positive cancer patients, regardless of age or tumor type[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In a key comprehensive analysis of three trials (Phase 1 adult, Phase 2 adult and adolescent, and Phase 1\u0026ndash;2 pediatric) of larotrectinib, the proportion of patients achieving objective response was higher than the response rate in the entrectinib comprehensive analysis.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThis case reports an extremely rare spindle cell sarcoma of spinal origin with SPECC1L-NTRK3 gene fusion. The treatment experience of this case provides valuable diagnostic experience and results for future patients with malignant tumors with NTRK gene fusion. Second-generation gene sequencing plays a very important role in diagnosis, which can provide patients with good targeted drug selection, emphasizing the importance of early detection and timely treatment.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eData Statement\u003c/h2\u003e \u003cp\u003eThese studies involving humans received approval from the Ethics Committee of Sun Yat-sen University Cancer Center. This research was conducted in accordance with local legislation and institutional requirements. The surgical specimens used in this study were obtained via surgical excision at our institution. Based on the national legislation and institutional guidelines, participants or their legal guardians/next of kin were not required to provide written informed consent. Written informed consent was obtained from all individuals for the publication of any potentially identifiable images or data included in this document.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMi Zhou: Data management, formal analysis, writing, and the original draft. Huaiyuan Xu: Review and editing. Jianxiong Niu: prepared figures 1. Qinglian Tang: Data management, formal analysis, writing, reviewing, and editing. Qingbing Yang:prepared figures 2. Hao Wu: prepared figures 3. Angqi Wang: prepared figures 4. Xiangqin Wang: prepared table 1.Jinxin Hu：Article modification. Jin Wang: Conceptualization, project administration, writing, reviewing, and editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChoi JH, Ro JY (2021) The 2020 WHO Classification of Tumors of Soft Tissue: Selected Changes and New Entities. 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N Engl J Med 378:731\u0026ndash;739. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1714448\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1714448\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSidaway P (2018) Targeted therapy: Larotrectinib effective against TRK-fusion-positive cancers. Nat Rev Clin Oncol 15:264. doi: 10.1038/nrclinonc.2018.40\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":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"NTRK-rearranged spindle cell tumor, molecular characteristics, NTRK3, pathological report, SPECC1L","lastPublishedDoi":"10.21203/rs.3.rs-5283368/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5283368/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNeurotrophic Tyrosine Receptor Kinase (NTRK)-rearranged spindle cell tumors are a category of soft tissue tumors characterized by rearrangements of the NTRK gene that exhibit unique molecular genetics, morphological, and immunophenotypic features. The core feature of NTRK-rearranged tumors is rearrangement of the NTRK gene family (NTRK1, NTRK2, and NTRK3), often involving fusion with other genes, leading to abnormal tropomyosin receptor kinase (TRK) protein expression and activation. Herein, we report the first case of an NTRK spindle cell tumor with SPECC1L-NTRK3 fusion. This case highlights the significance of next-generation sequencing (NGS) for tumor diagnosis and targeted drug selection. After one month ofentrectinib therapy, the patient had considerable tumor shrinkage and symptom relief. For bone-derived NTRK-rearranged spindle cell sarcomas, entrectinib has demonstrated favorable therapeutic effects and can be considered priority treatment option.\u003c/p\u003e","manuscriptTitle":"NTRK-Rearranged Spindle Cell Tumor with SPECC1L-NTRK3 Fusion in the Thoracic Spine: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-01 08:31:50","doi":"10.21203/rs.3.rs-5283368/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-28T15:03:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-28T01:44:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246633319909551454785737177599440561027","date":"2024-10-20T16:36:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-20T13:50:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-19T13:29:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-19T13:29:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cancer Research and Clinical Oncology","date":"2024-10-17T13:48:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"49a2a9bb-3f17-4ea7-bb48-806d758ccbc6","owner":[],"postedDate":"November 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-16T16:03:10+00:00","versionOfRecord":{"articleIdentity":"rs-5283368","link":"https://doi.org/10.1007/s00432-024-06042-4","journal":{"identity":"journal-of-cancer-research-and-clinical-oncology","isVorOnly":false,"title":"Journal of Cancer Research and Clinical Oncology"},"publishedOn":"2024-12-11 15:57:55","publishedOnDateReadable":"December 11th, 2024"},"versionCreatedAt":"2024-11-01 08:31:50","video":"","vorDoi":"10.1007/s00432-024-06042-4","vorDoiUrl":"https://doi.org/10.1007/s00432-024-06042-4","workflowStages":[]},"version":"v1","identity":"rs-5283368","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5283368","identity":"rs-5283368","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}