A high-grade sarcoma with TRIM25::NTRK2 rearrangements in the head and neck: case report

A high-grade sarcoma with TRIM25::NTRK2 rearrangements in the head and neck: 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 A high-grade sarcoma with TRIM25::NTRK2 rearrangements in the head and neck: case report Wangwang Liu, Wen Tang, Yufan Xu, Xiaoqing Cheng, Jiling Zeng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8038082/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract NTRK-rearranged spindle cell tumor is a newly identified pathohistological entity defined by molecular features in the 5th edition of the WHO classification of soft tissue and bone tumors. This tumor type most commonly arises in the superficial or deep soft tissues of the extremities, with approximately half of reported cases occurring in children and adolescents. Histologically, it exhibits two main morphological patterns: one resembling low-grade malignant peripheral nerve sheath tumors (neurinomatous type) and the other resembling lipofibromatosis-like neural tumors. Immunohistochemically, it is characterized by co-expression of S-100 and CD34, along with diffuse pan-TRK positivity. Genetically, most cases involve rearrangements of the NTRK1 or NTRK3 genes, often with fusion partners such as LMNA, TPM3, and TPR. Rearrangements involving NTRK2 are considerably rarer. Herein, we report a rare case of high-grade spindle cell sarcoma with a TRIM25::NTRK2 fusion located in the head and neck region, supported by clinicopathologic and molecular genetic analyses. The patient was an 84-year-old male who presented with facial radiculoneuralgia and subsequently underwent partial resection of a right submandibular mass. Microscopic examination at low magnification revealed ill-defined borders, infiltrative growth patterns, and extensive necrosis. At higher magnification, the tumor cells exhibited short spindle-shaped or ovoid morphology, with abundant cytoplasm, nuclear pleomorphism, prominent nucleoli, and frequent mitotic figures. Some tumor cells contained paranuclear vacuoles resembling univacuolated lipoblasts. The stroma showed collagen deposition, with focal lymphocytic infiltration and hemorrhage. Immunohistochemical analysis demonstrated diffuse positivity for pan-TRK and S-100, partial expression of CD34, and negative staining for CK-pan, SOX10, Desmin, SMA, ALK, P16, MDM2, CDK4, NUT, and other markers. INI-1 and BRG1 expression was preserved. Next-generation sequencing confirmed the presence of the TRIM25::NTRK2 gene fusion. Spindle cell tumors with NTRK2 gene rearrangements are rare. This case expands the morphological and genetic spectrum of NTRK-rearranged spindle cell tumors. Combined with its characteristic immunohistochemical and molecular pathological findings, this case provides insights into potential clinical therapeutic targets. Figures Figure 1 Figure 2 Figure 3 Case Presentation The patient first presented with a right submandibular mass detected by ultrasound at an external hospital three months prior, following self-reported facial radiculoneuralgia. Over the subsequent three months, the mass gradually increased in size, accompanied by persistent vague pain and dysphagia. Physical examination revealed a well-defined, firm, egg-sized swelling on the right side of the neck, with clear margins, mobility, normal overlying skin, no tenderness, and smooth oral mucosa. Imaging studies showed a lobulated, right submandibular mass measuring approximately 63mm × 56 mm on contrast-enhanced CT (Fig. 1). The lesion exhibited heterogeneous enhancement with more pronounced peripheral enhancement, central necrotic areas without enhancement, ill-defined borders, and surrounding tissue compression, including indistinct separation from the right submandibular gland. The tumor extended upward along the cervical sheath to the skull base. Surgical excision was performed, revealing a hard, poorly defined mass adhered to the surrounding tissues. Careful dissection was carried out to preserve critical structures, including the lingual and hypoglossal nerves, followed by partial resection of the tumor. Histopathological Findings: Gross examination revealed a dark red tissue specimen measuring 35 mm × 22 mm × 12 mm, containing grayish-white and grayish-red nodules (23 mm × 18 mm × 12 mm) of moderate consistency and poorly defined margins. Microscopically, the tumor margin was indistinct with an infiltrative growth pattern (Fig. 2). At high magnification, the tumor cells were predominantly short, spindle-shaped, or ovoid. Some tumor cells displayed abundant slightly basophilic cytoplasm and contained paranuclear vacuoles resembling single vesicular lipoblasts. The nuclei were eccentrically located with prominent nucleoli and frequent nuclear atypia. The stroma showed sparse lymphocytic infiltration, hemorrhage, and extensive areas of necrosis. Immunohistochemically, the tumor cells showed diffuse expression of pan-TRK and S-100, with focal expression of CD34. No expression was detected for CK-pan, SOX10, Desmin, SMA, ALK, P16, MDM2, CDK4, NUT, and other related markers. INI-1 and BRG1 expression was retained. Subsequent molecular analysis by next-generation sequencing confirmed the presence of a TRIM25::NTRK2 gene fusion (Fig. 3). Pathologic diagnosis: (Right submandibular region) Spindle cell tumor with TRIM25::NTRK2 gene fusion. Follow-up: The patient underwent a partial resection of the mass without complete resection of the lesion; he was admitted to the ICU after surgery with significant symptoms of tumor compression and unstable vital signs. 6 months later, the patient died of multiple organ failure. DISCUSSION NTRK-rearranged spindle cell tumors represent a newly defined pathohistological entity based on molecular characteristics in the 5th edition of the WHO classification of soft tissue and bone tumors. These tumors can arise in superficial or deep soft tissues of the extremities; approximately half of reported cases occur in children and adolescents, with no significant gender predilection. Clinically, patients often lack specific symptoms and typically present with signs related to tumor compression. The tumors exhibit a broad morphological and histological spectrum. At one end of the spectrum are low-grade lesions resembling lipofibromatosis-like nerve tumors, composed predominantly of monomorphic spindle cells arranged in fascicles, interwoven patterns, or sheets, with mild cellular atypia, rare mitotic figures, and a tendency for infiltrative growth. At the other end are high-grade tumors morphologically similar to malignant peripheral nerve sheath tumors, demonstrating significant cellularity, marked nuclear pleomorphism, and frequent mitotic activity. The microscopic features of the current case are consistent with the high-grade variant. Immunophenotypically, NTRK-rearranged spindle cell tumors frequently co-express CD34 and S-100 proteins, necessitating differentiation from myofibroblastic tumors and other peripheral neurogenic neoplasms. Studies indicate that tumors with CD34 and S-100 co-expression may harbor genetic alterations in RET, BRAF, RAF, ALK, and other genes in addition to NTRK rearrangements( 1 – 4 ). Pan-TRK immunohistochemistry can be a useful diagnostic aid, typically showing cytoplasmic or nuclear staining. However, due to the limited specificity of TRK protein expression( 5 ), molecular testing remains essential for definitive diagnosis. In 2025, Professor Jian Wang and colleagues from the Affiliated Cancer Hospital of Fudan University published a study entitled "Cost-effectiveness of NTRK testing strategies for detecting NTRK fusions in solid tumors in China" on the website of the American Society of Clinical Oncology (ASCO). They recommended a two-step strategy - “initial pan-TRK IHC testing followed by next-generation sequencing (NGS) confirmation for positive results” - as the optimal approach for detecting NTRK fusions. Structurally, receptor tyrosine kinases (RTKs) are highly conserved, comprising an extracellular ligand-binding domain, transmembrane domains, and an intracellular tyrosine kinase domain (TKD). Under physiological conditions, extracellular ligands bind to the extracellular ligand-binding domain of RTKs, inducing RTK dimerization and subsequent TKD autophosphorylation. This activates multiple downstream signaling pathways (e.g., MAPK, PI3K-AKT, and PLCγ), which ultimately participate in biological processes such as cell proliferation, differentiation, and survival. Pathologically, RTK dysregulation may result from gain-of-function mutations, amplification, chromosomal rearrangements, TKD duplications, or autocrine/paracrine activation. Such dysregulation leads to abnormal RTK activation, manifesting as enhanced proliferation, differentiation, and angiogenesis, alongside disrupted cell cycle and metabolism( 1 ). In gene fusions, the 3' end of the RTK gene, encoding the kinase domain, fuses with the 5' end of a partner gene. These partner genes often contribute oligomerization domains (e.g., coiled-coil, zinc finger, or WD repeat domains), which are critical for conferring constitutive activation to the downstream kinase( 6 ). NTRK (neurotrophin receptor kinase) is a family of neurotrophin receptor tyrosine kinases, comprising NTRK1, NTRK2, and NTRK3, which encode the neurotrophin receptors TrkA, TrkB, and TrkC, respectively. NTRK gene rearrangements occur mainly in adolescents and children. NTRK3 and NTRK1 are the most frequently involved genes, while NTRK2 rearrangements are the least common. Among the three, NTRK2 is the most structurally complex and has been implicated in a variety of tumorigenesis, such as glioma, atypical Spitz nevus, lung cancer, and gastrointestinal mesenchymal tumors( 6 – 9 ), often associated with a poorer prognosis. So far, about 42 partner genes have been implicated in NTRK2 rearrangement. Still, only STRN, RBPMS, WWOX, and GNAQ have been previously documented as fusion partners with NTRK2 in adult soft tissue tumors( 6 , 10 – 12 ). This report of a TRIM25::NTRK2 fusion further expands the genomic landscape of this tumor type. The tripartite-motif protein (Trim) family is a family of proteins possessing a RING finger structural domain and functioning as E3 ligases( 13 ), which are involved in a series of pathophysiological processes in the organism, and some of the members of the family are involved in tumorigenesis and progression, including transcriptional regulation, cell proliferation, and apoptosis etc.( 14 – 16 ). TRIM25 (tripartite motif 25) is an E3 ubiquitin ligase consisting of 630 amino acids with a molecular weight of 71 kDa, and its structure contains the N-terminal RING domain, the B-box domain, the coiled-coil (CC) domain, and the C-terminal variable SPRY domain, which can bind RNA( 13 , 17 ). TRIM25 is widely expressed in various human cell types. It is important in suppressing viral replication as an interferon-induced E3 ligase, which participates in human antiviral innate immunity through ubiquitination modifications that modulate key signaling pathways( 15 , 18 , 19 ). Studies have shown that the TRIM25 gene can promote tumor survival, and its expression is significantly upregulated in a variety of malignant tumors (such as breast cancer, lung cancer, etc.), which is significantly associated with poor prognosis( 20 , 21 ). TRIM25 regulates a variety of cell death pathways through ubiquitination modifications (e.g., inhibition of apoptosis, inhibition of ferroptosis, promotion of autophagy, inhibition of focalization, and inhibition of cell death). Autophagy, Pyroptosis and Necroptosis, etc.), thus contributing to tumorigenesis, progression, and chemoresistance( 22 ); in addition, TRIM25 constructs an immunosuppressive microenvironment through activation of the NF-κB-PD-L1 axis( 23 ). The aberrant expression of TRIM25 in a variety of tumors makes it a potential biomarker for targeting TRIM25. Aberrant expression of TRIM25 in various tumors makes it a potential biomarker, and therapeutic strategies targeting TRIM25 can restore the sensitivity of tumor cells to drugs and overcome chemoresistance; in combination with immune checkpoint inhibitors, it can enhance anti-tumor immunity and relieve immune escape( 24 ). In the future, the combination of specific inhibitors targeting TRIM25 (e.g., PROTAC, siRNA) with chemotherapy/immunotherapy may become a key breakthrough direction to overcome tumor drug resistance( 22 ). In terms of treatment and prognosis, the prognosis of NTRK-rearranged spindle cell tumors is related to histological grade, with low-grade forms (e.g., lipofibromatoid neural tumors) tending to recur locally( 25 , 26 ); tumors with high-grade morphologic features can exhibit aggressive biological behavior and metastasize to the lungs and other organs( 27 ). Surgical resection is the mainstay of treatment; however, with the development of molecularly targeted therapies, the proto-oncogene receptor tyrosine kinase (TRK) inhibitors larotrectinib and entrectinib have demonstrated better efficacy in patients with NTRK-rearranged spindle cell tumors( 6 , 28 , 29 ). They are therefore recommended as first-line therapeutic choices in patients with NTRK-rearranged spindle cell tumors in the NCCN guidelines. In summary, we describe a rare case of a TRIM25::NTRK2 fusion-positive spindle cell tumor in the head and neck region, characterized by a predominantly short spindle or ovoid morphology mimicking myoepithelial cells. This case broadens the morphological and molecular spectrum of NTRK-rearranged spindle cell tumors. The accompanying TRIM25 gene alterations are primarily associated with poor patient prognosis, immunosuppression, or chemoresistance; however, they also represent potential therapeutic targets that could be crucial for overcoming tumor drug resistance. Declarations Ethical approval : For this type of study, formal consent is not required. Consent to Participate : This study has obtained IRB approval from Sir Run Run Shaw Hospital, and the need for informed consent was waived. Consent for publication : Consent for publication was obtained for every individual person’s data included in the study. Funding: This study was not supported by any funding. Author Contribution Wangwang Liu wrote the main manuscript text; Wen Tang and Yufan Xu collected clinical and pathological data; Jiling Zeng performed immunohistochemical analysis; Xiaoqing Cheng conducted molecular testing and data interpretation; Jin Wang designed the study and revised the manuscript. All authors reviewed the manuscript. Code Availability: No software application or custom code has been used in the preparation. References Tomuleasa C, Tigu A-B, Munteanu R, Moldovan C-S, Kegyes D, Onaciu A, Gulei D, Ghiaur G, Einsele H, Croce CM. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduct Target Ther. 2024;9:201. 10.1038/s41392-024-01899-w . Suurmeijer AJH, Dickson BC, Swanson D, Zhang L, Sung Y-S, Cotzia P, Fletcher CDM, Antonescu CR. A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Genes. Chromosomes Cancer. 2018;57:611–21. 10.1002/gcc.22671 . Antonescu CR, Dickson BC, Swanson D, Zhang L, Sung Y-S, Kao Y-C, Chang W-C, Ran L, Pappo A, Bahrami A, et al. Spindle cell tumors with RET gene fusions exhibit a morphologic spectrum akin to tumors with NTRK gene fusions. Am J Surg Pathol. 2019;43:1384–91. 10.1097/PAS.0000000000001297 . 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Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378:731–9. 10.1056/NEJMoa1714448 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. 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00:48:27","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":77474,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8038082/v1/84b0121836bee53524827d88.html"},{"id":96365449,"identity":"fab0d654-dfbc-430a-b106-a7df71f420c3","added_by":"auto","created_at":"2025-11-20 10:10:22","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":57852,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8038082/v1/0b5206b5a7f82530435c54b5.jpeg"},{"id":96330294,"identity":"88aefd1e-9651-4b90-8cff-d3672318f10d","added_by":"auto","created_at":"2025-11-20 00:48:26","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":290217,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8038082/v1/763ab8d761f161c3520a9c9e.jpeg"},{"id":96366254,"identity":"faf111f6-11b1-49d2-94ac-e470fae78e75","added_by":"auto","created_at":"2025-11-20 10:11:19","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":223974,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8038082/v1/86a38f5e5eda524ceb5141f8.jpeg"},{"id":96709092,"identity":"fa584c29-244a-4777-b533-ac3d7fbf859b","added_by":"auto","created_at":"2025-11-25 10:07:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":928333,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8038082/v1/d9514f14-90b1-4be2-93f4-b9178a83211d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A high-grade sarcoma with TRIM25::NTRK2 rearrangements in the head and neck: case report","fulltext":[{"header":"Case Presentation","content":"\u003cp\u003eThe patient first presented with a right submandibular mass detected by ultrasound at an external hospital three months prior, following self-reported facial radiculoneuralgia. Over the subsequent three months, the mass gradually increased in size, accompanied by persistent vague pain and dysphagia. Physical examination revealed a well-defined, firm, egg-sized swelling on the right side of the neck, with clear margins, mobility, normal overlying skin, no tenderness, and smooth oral mucosa. Imaging studies showed a lobulated, right submandibular mass measuring approximately 63mm \u0026times; 56 mm on contrast-enhanced CT (Fig.\u0026nbsp;1). The lesion exhibited heterogeneous enhancement with more pronounced peripheral enhancement, central necrotic areas without enhancement, ill-defined borders, and surrounding tissue compression, including indistinct separation from the right submandibular gland. The tumor extended upward along the cervical sheath to the skull base. Surgical excision was performed, revealing a hard, poorly defined mass adhered to the surrounding tissues. Careful dissection was carried out to preserve critical structures, including the lingual and hypoglossal nerves, followed by partial resection of the tumor.\u003c/p\u003e\n\u003ch3\u003eHistopathological Findings:\u003c/h3\u003e\n\u003cp\u003eGross examination revealed a dark red tissue specimen measuring 35 mm \u0026times; 22 mm \u0026times; 12 mm, containing grayish-white and grayish-red nodules (23 mm \u0026times; 18 mm \u0026times; 12 mm) of moderate consistency and poorly defined margins. Microscopically, the tumor margin was indistinct with an infiltrative growth pattern (Fig.\u0026nbsp;2). At high magnification, the tumor cells were predominantly short, spindle-shaped, or ovoid. Some tumor cells displayed abundant slightly basophilic cytoplasm and contained paranuclear vacuoles resembling single vesicular lipoblasts. The nuclei were eccentrically located with prominent nucleoli and frequent nuclear atypia. The stroma showed sparse lymphocytic infiltration, hemorrhage, and extensive areas of necrosis.\u003c/p\u003e\u003cp\u003eImmunohistochemically, the tumor cells showed diffuse expression of pan-TRK and S-100, with focal expression of CD34. No expression was detected for CK-pan, SOX10, Desmin, SMA, ALK, P16, MDM2, CDK4, NUT, and other related markers. INI-1 and BRG1 expression was retained. Subsequent molecular analysis by next-generation sequencing confirmed the presence of a TRIM25::NTRK2 gene fusion (Fig.\u0026nbsp;3).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePathologic diagnosis:\u003c/h2\u003e\u003cp\u003e(Right submandibular region) Spindle cell tumor with TRIM25::NTRK2 gene fusion.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eFollow-up:\u003c/h3\u003e\n\u003cp\u003eThe patient underwent a partial resection of the mass without complete resection of the lesion; he was admitted to the ICU after surgery with significant symptoms of tumor compression and unstable vital signs. 6 months later, the patient died of multiple organ failure.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eNTRK-rearranged spindle cell tumors represent a newly defined pathohistological entity based on molecular characteristics in the 5th edition of the WHO classification of soft tissue and bone tumors. These tumors can arise in superficial or deep soft tissues of the extremities; approximately half of reported cases occur in children and adolescents, with no significant gender predilection. Clinically, patients often lack specific symptoms and typically present with signs related to tumor compression.\u003c/p\u003e\u003cp\u003eThe tumors exhibit a broad morphological and histological spectrum. At one end of the spectrum are low-grade lesions resembling lipofibromatosis-like nerve tumors, composed predominantly of monomorphic spindle cells arranged in fascicles, interwoven patterns, or sheets, with mild cellular atypia, rare mitotic figures, and a tendency for infiltrative growth. At the other end are high-grade tumors morphologically similar to malignant peripheral nerve sheath tumors, demonstrating significant cellularity, marked nuclear pleomorphism, and frequent mitotic activity. The microscopic features of the current case are consistent with the high-grade variant.\u003c/p\u003e\u003cp\u003eImmunophenotypically, NTRK-rearranged spindle cell tumors frequently co-express CD34 and S-100 proteins, necessitating differentiation from myofibroblastic tumors and other peripheral neurogenic neoplasms. Studies indicate that tumors with CD34 and S-100 co-expression may harbor genetic alterations in RET, BRAF, RAF, ALK, and other genes in addition to NTRK rearrangements(\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Pan-TRK immunohistochemistry can be a useful diagnostic aid, typically showing cytoplasmic or nuclear staining. However, due to the limited specificity of TRK protein expression(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), molecular testing remains essential for definitive diagnosis. In 2025, Professor Jian Wang and colleagues from the Affiliated Cancer Hospital of Fudan University published a study entitled \"Cost-effectiveness of NTRK testing strategies for detecting NTRK fusions in solid tumors in China\" on the website of the American Society of Clinical Oncology (ASCO). They recommended a two-step strategy - \u0026ldquo;initial pan-TRK IHC testing followed by next-generation sequencing (NGS) confirmation for positive results\u0026rdquo; - as the optimal approach for detecting NTRK fusions.\u003c/p\u003e\u003cp\u003eStructurally, receptor tyrosine kinases (RTKs) are highly conserved, comprising an extracellular ligand-binding domain, transmembrane domains, and an intracellular tyrosine kinase domain (TKD). Under physiological conditions, extracellular ligands bind to the extracellular ligand-binding domain of RTKs, inducing RTK dimerization and subsequent TKD autophosphorylation. This activates multiple downstream signaling pathways (e.g., MAPK, PI3K-AKT, and PLCγ), which ultimately participate in biological processes such as cell proliferation, differentiation, and survival. Pathologically, RTK dysregulation may result from gain-of-function mutations, amplification, chromosomal rearrangements, TKD duplications, or autocrine/paracrine activation. Such dysregulation leads to abnormal RTK activation, manifesting as enhanced proliferation, differentiation, and angiogenesis, alongside disrupted cell cycle and metabolism(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In gene fusions, the 3' end of the RTK gene, encoding the kinase domain, fuses with the 5' end of a partner gene. These partner genes often contribute oligomerization domains (e.g., coiled-coil, zinc finger, or WD repeat domains), which are critical for conferring constitutive activation to the downstream kinase(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eNTRK (neurotrophin receptor kinase) is a family of neurotrophin receptor tyrosine kinases, comprising NTRK1, NTRK2, and NTRK3, which encode the neurotrophin receptors TrkA, TrkB, and TrkC, respectively. NTRK gene rearrangements occur mainly in adolescents and children. NTRK3 and NTRK1 are the most frequently involved genes, while NTRK2 rearrangements are the least common. Among the three, NTRK2 is the most structurally complex and has been implicated in a variety of tumorigenesis, such as glioma, atypical Spitz nevus, lung cancer, and gastrointestinal mesenchymal tumors(\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), often associated with a poorer prognosis. So far, about 42 partner genes have been implicated in NTRK2 rearrangement. Still, only STRN, RBPMS, WWOX, and GNAQ have been previously documented as fusion partners with NTRK2 in adult soft tissue tumors(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This report of a TRIM25::NTRK2 fusion further expands the genomic landscape of this tumor type.\u003c/p\u003e\u003cp\u003eThe tripartite-motif protein (Trim) family is a family of proteins possessing a RING finger structural domain and functioning as E3 ligases(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), which are involved in a series of pathophysiological processes in the organism, and some of the members of the family are involved in tumorigenesis and progression, including transcriptional regulation, cell proliferation, and apoptosis etc.(\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). TRIM25 (tripartite motif 25) is an E3 ubiquitin ligase consisting of 630 amino acids with a molecular weight of 71 kDa, and its structure contains the N-terminal RING domain, the B-box domain, the coiled-coil (CC) domain, and the C-terminal variable SPRY domain, which can bind RNA(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). TRIM25 is widely expressed in various human cell types. It is important in suppressing viral replication as an interferon-induced E3 ligase, which participates in human antiviral innate immunity through ubiquitination modifications that modulate key signaling pathways(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Studies have shown that the TRIM25 gene can promote tumor survival, and its expression is significantly upregulated in a variety of malignant tumors (such as breast cancer, lung cancer, etc.), which is significantly associated with poor prognosis(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). TRIM25 regulates a variety of cell death pathways through ubiquitination modifications (e.g., inhibition of apoptosis, inhibition of ferroptosis, promotion of autophagy, inhibition of focalization, and inhibition of cell death). Autophagy, Pyroptosis and Necroptosis, etc.), thus contributing to tumorigenesis, progression, and chemoresistance(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e); in addition, TRIM25 constructs an immunosuppressive microenvironment through activation of the NF-κB-PD-L1 axis(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The aberrant expression of TRIM25 in a variety of tumors makes it a potential biomarker for targeting TRIM25. Aberrant expression of TRIM25 in various tumors makes it a potential biomarker, and therapeutic strategies targeting TRIM25 can restore the sensitivity of tumor cells to drugs and overcome chemoresistance; in combination with immune checkpoint inhibitors, it can enhance anti-tumor immunity and relieve immune escape(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). In the future, the combination of specific inhibitors targeting TRIM25 (e.g., PROTAC, siRNA) with chemotherapy/immunotherapy may become a key breakthrough direction to overcome tumor drug resistance(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn terms of treatment and prognosis, the prognosis of NTRK-rearranged spindle cell tumors is related to histological grade, with low-grade forms (e.g., lipofibromatoid neural tumors) tending to recur locally(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e); tumors with high-grade morphologic features can exhibit aggressive biological behavior and metastasize to the lungs and other organs(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Surgical resection is the mainstay of treatment; however, with the development of molecularly targeted therapies, the proto-oncogene receptor tyrosine kinase (TRK) inhibitors larotrectinib and entrectinib have demonstrated better efficacy in patients with NTRK-rearranged spindle cell tumors(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). They are therefore recommended as first-line therapeutic choices in patients with NTRK-rearranged spindle cell tumors in the NCCN guidelines.\u003c/p\u003e\u003cp\u003eIn summary, we describe a rare case of a TRIM25::NTRK2 fusion-positive spindle cell tumor in the head and neck region, characterized by a predominantly short spindle or ovoid morphology mimicking myoepithelial cells. This case broadens the morphological and molecular spectrum of NTRK-rearranged spindle cell tumors. The accompanying TRIM25 gene alterations are primarily associated with poor patient prognosis, immunosuppression, or chemoresistance; however, they also represent potential therapeutic targets that could be crucial for overcoming tumor drug resistance.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003e\u003cb\u003eEthical approval\u003c/b\u003e:\u003c/h2\u003e\u003cp\u003eFor this type of study, formal consent is not required.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cb\u003eConsent to Participate\u003c/b\u003e:\u003c/strong\u003e\u003cp\u003eThis study has obtained IRB approval from Sir Run Run Shaw Hospital, and the need for informed consent was waived.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cb\u003eConsent for publication\u003c/b\u003e:\u003c/strong\u003e\u003cp\u003eConsent for publication was obtained for every individual person\u0026rsquo;s data included in the study.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis study was not supported by any funding.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eWangwang Liu wrote the main manuscript text; Wen Tang and Yufan Xu collected clinical and pathological data; Jiling Zeng performed immunohistochemical analysis; Xiaoqing Cheng conducted molecular testing and data interpretation; Jin Wang designed the study and revised the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eCode Availability:\u003c/h2\u003e\u003cp\u003eNo software application or custom code has been used in the preparation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTomuleasa C, Tigu A-B, Munteanu R, Moldovan C-S, Kegyes D, Onaciu A, Gulei D, Ghiaur G, Einsele H, Croce CM. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduct Target Ther. 2024;9:201. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41392-024-01899-w\u003c/span\u003e\u003cspan address=\"10.1038/s41392-024-01899-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSuurmeijer AJH, Dickson BC, Swanson D, Zhang L, Sung Y-S, Cotzia P, Fletcher CDM, Antonescu CR. 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N Engl J Med. 2018;378:731\u0026ndash;9. \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\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8038082/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8038082/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNTRK-rearranged spindle cell tumor is a newly identified pathohistological entity defined by molecular features in the 5th edition of the WHO classification of soft tissue and bone tumors. This tumor type most commonly arises in the superficial or deep soft tissues of the extremities, with approximately half of reported cases occurring in children and adolescents. Histologically, it exhibits two main morphological patterns: one resembling low-grade malignant peripheral nerve sheath tumors (neurinomatous type) and the other resembling lipofibromatosis-like neural tumors. Immunohistochemically, it is characterized by co-expression of S-100 and CD34, along with diffuse pan-TRK positivity. Genetically, most cases involve rearrangements of the NTRK1 or NTRK3 genes, often with fusion partners such as LMNA, TPM3, and TPR. Rearrangements involving NTRK2 are considerably rarer. Herein, we report a rare case of high-grade spindle cell sarcoma with a TRIM25::NTRK2 fusion located in the head and neck region, supported by clinicopathologic and molecular genetic analyses. The patient was an 84-year-old male who presented with facial radiculoneuralgia and subsequently underwent partial resection of a right submandibular mass. Microscopic examination at low magnification revealed ill-defined borders, infiltrative growth patterns, and extensive necrosis. At higher magnification, the tumor cells exhibited short spindle-shaped or ovoid morphology, with abundant cytoplasm, nuclear pleomorphism, prominent nucleoli, and frequent mitotic figures. Some tumor cells contained paranuclear vacuoles resembling univacuolated lipoblasts. The stroma showed collagen deposition, with focal lymphocytic infiltration and hemorrhage. Immunohistochemical analysis demonstrated diffuse positivity for pan-TRK and S-100, partial expression of CD34, and negative staining for CK-pan, SOX10, Desmin, SMA, ALK, P16, MDM2, CDK4, NUT, and other markers. INI-1 and BRG1 expression was preserved. Next-generation sequencing confirmed the presence of the TRIM25::NTRK2 gene fusion. Spindle cell tumors with NTRK2 gene rearrangements are rare. This case expands the morphological and genetic spectrum of NTRK-rearranged spindle cell tumors. Combined with its characteristic immunohistochemical and molecular pathological findings, this case provides insights into potential clinical therapeutic targets.\u003c/p\u003e","manuscriptTitle":"A high-grade sarcoma with TRIM25::NTRK2 rearrangements in the head and neck: case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-20 00:48:22","doi":"10.21203/rs.3.rs-8038082/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3f8573e2-43cb-4205-b9e0-df474f82b040","owner":[],"postedDate":"November 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T06:23:56+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-20 00:48:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8038082","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8038082","identity":"rs-8038082","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}