Summary
NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) represent an emerging group of rare tumours defined using molecular means.
To the best of our knowledge, there have been no large series of reports about this
tumour in the Chinese population in English full-text articles. Herein, we present
13 NTRK-RSCNs with peculiar characteristics. Ten of the 13 (77%) patients were children without
sex differences. The tumour locations included six trunks, four extremities, two recta,
and one small bowel. The histological morphology included four lipofibromatosis-like
neural tumour (LPF-NT)-like, eight malignant peripheral nerve sheath tumours (MPNST)/fibrosarcoma-like,
and one extremely rare myxofibrosarcoma-like pattern. Immunohistochemically, all cases
were CD34, pan-TRK and TRK-A positive, SOX-10 negative, and H3K27me3 intact. S-100
protein expression was identified in 11 of 13 (85%) cases. Genetically, NTRK1 rearrangements were considered positive (7/13, 54%) or suspicious for positivity
(6/13, 46%) by fluorescence in situ hybridisation. Next-generation sequencing and Sanger sequencing confirmed NTRK1 fusions with a variety of partner genes, including five LMNA, three TPM3, one SQSTM1, three novel CPSF6, IGR (downstream PMVK), and GAS2L1 genes. Interestingly, the last tumour concurrently harboured a second EWSR1-PBX1 fusion, which has never been reported. Four patients developed local recurrence and
two of them suffered metastasis. In our study, NTRK-RSCNs had peculiar fusions that displayed unusual or complicated clinicopathological
features. Histological clues and IHC helped streamline a small subset of potential
candidates. Although FISH is a powerful technology for identifying NTRK rearrangements, RNA-/DNA-based NGS is recommended for highly suspected cases in which
FISH signal patterns are not discernible as classic positive patterns, particularly
if targeted therapy is considered.
Key words
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References
- Trk receptor tyrosine kinases: a bridge between cancer and neural development.Cancer Lett. 2001; 169: 107-114
- NTRK gene fusions as novel targets of cancer therapy across multiple tumour types.ESMO Open. 2016; 1e000023
- A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences.Nature. 1986; 319: 743-748
- Molecular characterization of cancers with NTRK gene fusions.Mod Pathol. 2019; 32: 147-153
- Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population.NPJ Precis Oncol. 2021; 5: 69
- Pan-TRK immunohistochemistry.Arch Pathol Lab Med. 2020; 145: 1031-1040
- NTRK fusions and Trk proteins: what are they and how to test for them.Hum Pathol. 2021; 112: 59-69
- Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.Lancet Oncol. 2020; 21: 271-282
- Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.Lancet Oncol. 2020; 21: 531-540
- TRK inhibition in soft tissue sarcomas: a comprehensive review.Semin Oncol. 2020; 47: 73-84
- US phase I first-in-human study of taletrectinib (DS-6051b/AB-106), a ROS1/TRK inhibitor, in patients with advanced solid tumors.Clin Cancer Res. 2020; 26: 4785-4794
- Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent- front mutations.Cancer Discov. 2018; 8: 1227-1236
- TRK inhibitors in TRK fusion-positive cancers.Ann Oncol. 2019; 30 (viii23–30)
- A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma.Nat Genet. 1998; 18: 184-187
- NTRK insights: best practices for pathologists.Mod Pathol. 2021; 35: 298-305
- Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions.Mod Pathol. 2021; 34: 396-407
- Identification of NTRK fusions in pediatric mesenchymal tumors.Pediatr Blood Cancer. 2017; 64https://doi.org/10.1002/pbc.26433
- Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern.J Pathol. 2016; 238: 700-710
- 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: 611-621
- The histologic spectrum of soft tissue spindle cell tumors with NTRK3 gene rearrangements.Genes Chromosomes Cancer. 2019; 58: 739-746
- Soft tissue tumors characterized by a wide spectrum of kinase fusions share a lipofibromatosis-like neural tumor pattern.Genes Chromosomes Cancer. 2020; 59: 575-583
- Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis-like neural tumors.Am J Surg Pathol. 2016; 40: 1407-1416
- Lipofibromatosis-like neural tumour: a clinicopathological study of ten additional cases of an emerging novel entity.Pathology. 2018; 50: 519-523
- Expanding the spectrum of pediatric NTRK-rearranged mesenchymal tumors.Am J Surg Pathol. 2019; 43: 435-445
- Infantile NTRK-associated mesenchymal tumors.Pediatr Dev Pathol. 2018; 21: 68-78
- Pan-Trk immunohistochemistry identifies NTRK rearrangements in pediatric mesenchymal tumors.Am J Surg Pathol. 2018; 42: 927-935
- NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma.Am J Surg Pathol. 2018; 42: 791-798
- NTRK fusion cervical sarcoma: a report of three cases, emphasising morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.Histopathology. 2020; 77: 100-111
- Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.Mod Pathol. 2019; 32: 1008-1022
- Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements: a clinicopathological, immunophenotypic, and molecular study of eight cases, emphasizing their distinction from gastrointestinal stromal tumor (GIST).Mod Pathol. 2020; 34: 95-103
- Adult NTRK-rearranged spindle cell neoplasms of the viscera: with an emphasis on rare locations and heterologous elements.Mod Pathol. 2022; 35: 911-921
- Chromosomal imbalances detected in NTRK-rearranged sarcomas by comparative genomic hybridization.Histopathology. 2020; 78: 932-942
- NTRK-rearranged mesenchymal tumours: diagnostic challenges, morphological patterns and proposed testing algorithm.Pathology. 2020; 52: 401-409
- WHO Classification of Tumours: Soft Tissue and Bone Tumours.5th ed. IARC, Lyon2020
- Primary pleuropulmonary and mediastinal synovial sarcoma: a clinicopathologic and molecular study of 26 genetically confirmed cases in the largest institution of southwest China.Cell Death Dis. 2016; 11: 62
- An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101.Cancer Discov. 2015; 5: 1049-1057
- NTRK fusion in soft tissue sarcomas harboring MDM2/CDK4 amplification: three case reports.Ann Oncol. 2021; 32: 813-814
- Larotrectinib in a NTRK-rearranged soft tissue sarcoma in the neoadjuvant setting: a case report.Clin Case Rep. 2021; 9: 1694-1698
- Unclassified mesenchymal sarcoma with NTRK1-KHDRBS1 gene fusion: a case report of long-term tumor-free survival with crizotinib treatment.World J Surg Oncol. 2021; 19: 136
- NTRK-rearranged cervical sarcoma: expanding the clinicopathologic spectrum.Int J Gynecol Pathol. 2021; 40: 73-77
- A case of Inv(1)(q23q31) TPR-NTRK1 fusion-positive spindle cell neoplasm in an infant-uncovered by next-generation sequencing: diagnostic challenge, review, and therapeutic implications.Int J Surg Pathol. 2021; 29: 102-108
- LMNA-NTRK1 rearranged mesenchymal tumor (lipofibromatosis-like neural tumor) mimicking pigmented dermatofibrosarcoma protuberans.J Cutan Pathol. 2021; 48: 290-294
- Clinicopathological findings of pediatric NTRK fusion mesenchymal tumors.Diagn Pathol. 2020; 15: 114
- Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1.JCO Precis Oncol. 2020; 4: 79-90
- Larotrectinib followed by selitrectinib in a novel DCTN1-NTRK1 fusion undifferentiated pleomorphic sarcoma.J Oncol Pharm Pract. 2021; 27: 485-489
- Successful treatment of lipofibromatosis-like neural tumor of the lumbar spine with an NTRK-fusion inhibitor.Clin Sarcoma Res. 2020; 10: 14
- Myxoid spindle cell sarcoma with LMNA-NTRK fusion: expanding the morphologic spectrum of NTRK-rearranged tumors.Int J Surg Pathol. 2020; 28: 574-578
- An addition to the evolving spectrum of lipofibromatosis and lipofibromatosis-like neural tumor: molecular findings in an unusual phenotype aid in accurate classification.Pathol Res Pract. 2020; 216152942
- Novel NTRK3 fusions in fibrosarcomas of adults.Am J Surg Pathol. 2019; 43: 523-530
- NTRK-1 fusion in endocervical fibroblastic malignant peripheral nerve sheath tumor marking eligibility for larotrectinib therapy: a case report.Gynecol Oncol Rep. 2019; 28: 141-144
- NTRK-rearranged mesenchymal tumour in a 3-year-old female: a diagnostic quandary.Histopathology. 2019; 75: 772-775
- Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.Mod Pathol. 2019; 32: 1008-1022
- Expanding the molecular characterization of thoracic inflammatory myofibroblastic tumors beyond ALK gene rearrangements.J Thorac Oncol. 2019; 14: 825-834
- Refractory and metastatic infantile fibrosarcoma harboring LMNA-NTRK1 fusion shows complete and durable response to crizotinib.Cold Spring Harb Mol Case Stud. 2019; 5: a003376
- A primary undifferentiated pleomorphic sarcoma of the lumbosacral region harboring a LMNA-NTRK1 gene fusion with durable clinical response to crizotinib: a case report.BMC Cancer. 2018; 18: 842
- A novel case of an aggressive superficial spindle cell sarcoma in an adult resembling fibrosarcomatous dermatofibrosarcoma protuberans and harboring an EML4-NTRK3 fusion.J Cutan Pathol. 2018; 45: 933-939
- Pediatric soft tissue tumor of the upper arm with LMNA-NTRK1 fusion.Hum Pathol. 2018; 72: 167-173
- Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics.Histopathology. 2018; 73: 634-644
- The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas.Cancer. 2018; 124: 4241-4247
- Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy.Mod Pathol. 2018; 31: 463-473
- Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma.Cold Spring Harb Mol Case Stud. 2015; 1: a000471
- Lipofibromatosis-like neural tumor: case report of a unique infantile presentation.JAAD Case Rep. 2018; 4: 185-188
- ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours.Histopathology. 2016; 69: 72-83
- Evaluation of a congenital infantile fibrosarcoma by comprehensive genomic profiling reveals an LMNA-NTRK1 gene fusion responsive to crizotinib.J Natl Cancer Inst. 2016; 108: djv307
- FGFR1 and NTRK3 actionable alterations in "wild-type" gastrointestinal stromal tumors.J Transl Med. 2016; 14: 339
- Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST.J Pathol. 2016; 238: 543-549
- ETV6-NTRK3 is expressed in a subset of ALK-negative inflammatory myofibroblastic tumors.Am J Surg Pathol. 2016; 40: 1051-1061
- Novel fusion sarcomas including targetable NTRK and ALK.Ann Diagn Pathol. 2021; 54151800
- NTRK-rearranged mesenchymal tumour with epithelioid features: expanding the morphological spectrum of NTRK-fused neoplasms.Histopathology. 2022; 80: 736-739
- Expanding the spectrum of adult NTRK3-rearranged spindle cell neoplasms.Am J Clin Pathol. 2022; 157: 485-493
- Case report: adult NTRK-rearranged spindle cell neoplasm: early tumor shrinkage in a case with bone and visceral metastases treated with targeted therapy.Front Oncol. 2021; 11740676
- NTRK fusions in a sarcomas series: pathology, molecular and clinical aspects.Pathol Oncol Res. 2022; 281610423
- A novel TMTC2-NTRK3 fusion in undifferentiated high-grade pleomorphic sarcoma.J Cancer Res Clin Oncol. 2022; 148: 2933-2937
- Primary NTRK-rearranged spindle cell neoplasm of the lung: a clinicopathologic and molecular analysis of 3 cases.Am J Surg Pathol. 2022; 46: 1007-1013
- Emerging soft tissue tumors with kinase fusions: an overview of the recent literature with an emphasis on diagnostic criteria.Genes Chromosomes Cancer. 2020; 59: 437-444
- NTRK fusions in sarcomas: diagnostic challenges and clinical aspects.Diagnostics (Basel). 2021; 11: 478
- NTRK and other recently described kinase fusion positive uterine sarcomas: a review of a group of rare neoplasms.Genes Chromosomes Cancer. 2021; 60: 147-159
- Diagnostic utility of SOX10 to distinguish malignant peripheral nerve sheath tumor from synovial sarcoma, including intraneural synovial sarcoma.Mod Pathol. 2014; 27: 55-61
- Significance of H3K27me3 loss in the diagnosis of malignant peripheral nerve sheath tumors.Mod Pathol. 2017; 30: 1710-1719
- Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions.Am J Surg Pathol. 2017; 41: 1547-1551
- NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls.Mod Pathol. 2020; 33: 38-46
- ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research.Ann Oncol. 2019; 30: 1417-1427
- Comparison of molecular testing modalities for detection of ROS1 rearrangements in a cohort of positive patient samples.J Thorac Oncol. 2018; 13: 1474-1482
- Testing algorithm for identification of patients with TRK fusion cancer.J Clin Pathol. 2019; 72: 460-467
- NTRK fusion genes in thyroid carcinomas: clinicopathological characteristics and their impacts on prognosis.Cancers (Basel). 2021; 13: 1932
- Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer.J Thorac Oncol. 2015; 10: 1670-1674
- CPSF6 is a clinically relevant breast cancer vulnerability target: role of CPSF6 in breast cancer.EBioMedicine. 2017; 21: 65-78
- RNA-binding proteins in acute leukemias.Int J Mol Sci. 2020; 21: 3409
- CPSF6 links alternative polyadenylation to metabolism adaption in hepatocellular carcinoma progression.J Exp Clin Cancer Res. 2021; 40: 85
- Integrative analysis regarding the correlation between GAS2 family genes and human glioma prognosis.Cancer Med. 2021; 10: 2826-2839
- GAS2L1 is a potential biomarker of circulating tumor cells in pancreatic cancer.Cancers (Basel). 2020; 12: 3774
- Linear and disseminated porokeratosis in one family showing identical and independent second hits in MVD among skin lesions, respectively: a proof of concept study.Br J Dermatol. 2021; 184: 1209-1212
- Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1-PBX1 fusion gene in a myoepithelioma.Genes Chromosomes Cancer. 2008; 47: 558-564
- Thoracic myoepithelial tumors: a pathologic and molecular study of 8 cases with review of the literature.Am J Surg Pathol. 2016; 40: 212-223
- A “double-hit” translocation sarcoma—first report of the co-occurrence of EWSR1-FLI1 and MTMR2-NTRK2 fusion in a small round blue cell sarcoma.AJSP Rev Rep. 2020; 25: 97-100
- Co-occurrence of NTRK fusions with other genomic biomarkers in cancer patients.Ann Oncol. 2019; 30: v29-v30
- TRK fusion cancer: patient characteristics and survival analysis in the real-world setting.Target Oncol. 2021; 16: 389-399
- A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors.Cancer Discov. 2017; 7: 963
Article info
Publication history
Published online: January 12, 2023
Accepted:
October 9,
2022
Received in revised form:
August 20,
2022
Received:
April 14,
2022
Identification
Copyright
© 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.
