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

doi:10.21203/rs.3.rs-5283368/v1

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Case Report

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

https://doi.org/10.21203/rs.3.rs-5283368/v1

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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

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.

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)
MTRK3	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.

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.

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.

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

No competing interests reported.

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

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Case Report

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Data Statement

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References

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