NTRK-rearranged spindle cell neoplasm (emerging)
Soft Tissue and Bone Tumours (Who Classification, 5th ed.)
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(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
Primary Author(s)*
James P. Solomon, M.D., Ph.D.
Weill Cornell Medicine
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Soft Tissue and Bone Tumours (5th ed.) |
| Category | Soft tissue tumours |
| Family | Tumours of uncertain differentiation |
| Type | NTRK-rearranged spindle cell neoplasm (emerging) |
| Subtype(s) | N/A |
Related Terminology
| Acceptable | Lipofibromatosis-like neural tumour; NTRK-positive tumour resembling peripheral nerve sheath tumour |
| Not Recommended | N/A |
Gene Rearrangements
Fusions involving NTRK1 are the most common oncogenic driver in NTRK-rearranged spindle cell neoplasm, but NTRK2 or NTRK3 fusions are also occasionally seen (PMID: 30276917, 30520818). In-frame fusions that include the kinase domain of any of NTRK1, NTRK2, or NTRK3 could represent the oncogenic driver, and there are over 80 partners that have been reported for NTRK fusions (PMID: 31075511). As this is an emerging entity, prevalence of specific pairings is unknown. RNA sequencing-based fusion detection methods provide the most information about the identity of both gene partners (see Genetic Testing Diagnostic Methods section below). (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
| NTRK1 | TPM3::NTRK1 | EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. | EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: Common (CML) | EXAMPLE: D, P, T | EXAMPLE: Yes (WHO, NCCN) | EXAMPLE:
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference). |
| NTRK1 | EXAMPLE: TPR::NTRK1 | EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. | EXAMPLE: t(4;19)(q25;q13) | EXAMPLE: Common (CIC-rearranged sarcoma) | EXAMPLE: D | EXAMPLE:
DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references). | |
| NTRK1 | EXAMPLE: TPM3::ALK
|
EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. | EXAMPLE: N/A | EXAMPLE: Rare (Lung adenocarcinoma) | EXAMPLE: T | EXAMPLE:
Both balanced and unbalanced forms are observed by FISH (add references). |
Individual Region Genomic Gain/Loss/LOH
CDKN2A homozygous deletion is recurrently reported in NTRK-rearranged spindle cell neoplasms (PMID: 30877273, 35149769).
(Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE: No | EXAMPLE:
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add references). | |
| EXAMPLE:
17 |
EXAMPLE: Amp | EXAMPLE:
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb] |
EXAMPLE:
ERBB2 |
EXAMPLE: D, P, T | EXAMPLE:
Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined. | |
Characteristic Chromosomal or Other Global Mutational Patterns
Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). | EXAMPLE: Common (Oligodendroglioma) | EXAMPLE: D, P | ||
| EXAMPLE:
Microsatellite instability - hypermutated |
EXAMPLE: Common (Endometrial carcinoma) | EXAMPLE: P, T | |||
Gene Mutations (SNV/INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:EGFR
|
EXAMPLE: Exon 18-21 activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (lung cancer) | EXAMPLE: T | EXAMPLE: Yes (NCCN) | EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references). |
| EXAMPLE: TP53; Variable LOF mutations
|
EXAMPLE: Variable LOF mutations | EXAMPLE: Tumor Supressor Gene | EXAMPLE: Common (breast cancer) | EXAMPLE: P | EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer. | |
| EXAMPLE: BRAF; Activating mutations | EXAMPLE: Activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (melanoma) | EXAMPLE: T | ||
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
N/A
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| NTRK1/2/3 fusion | NTRK signaling | Increased cell growth and proliferation |
Genetic Diagnostic Testing Methods
Immunohistochemistry: Antibodies have been developed for detection of NTRK fusions and are being used in clinical laboratories. Immunohistochemistry has a fast turnaround time, but sensitivity and specificity for detection of NTRK fusions are lower than other methods listed here. In sarcomas in particular, false positives can be seen in neural-derived tumors and in tumors harboring BCOR alterations (PMID: 31375766, 29863809, 32034283, 35149769). Confirmatory testing with other molecular-based methods is recommended.
Fluorescent in situ hybridization (FISH): Breakapart probes for NTRK1, NTRK2, and NTRK3 can identify breaks in these genes, although the probes not widely available in clinical laboratories. Benefits of this approach include high sensitivity, particularly in samples with low tumor content, fast turnaround time, and only require a few unstained slides. This approach does not allow for identification of the fusion partner nor for a detailed evaluation of oncogenicity.
Reverse transcriptase polymerase chain reaction (RT-PCR) can only identify specific fusion pairs (e.g. ETV6::NTRK3), such that alternate pairings will be missed. With the availability of RNA-based sequencing, this technique is now rarely used clinically.
RNA-based sequencing is becoming widely used for comprehensive fusion detection. It is often performed as a comprehensive panel, so NTRK fusions can be assessed at the same time as many other sarcoma-associated fusions. A platform that supports fusion detection in a partner agnostic manner such as anchored multiplex PCR or hybridization capture methods is preferred (PMID: 31738428). A systematic approach should be used to assess oncogenicity of NTRK fusions including stranding and directionality, inclusion of the kinase domain, and review of the literature (PMID: 35366592).
Familial Forms
N/A (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)
Additional Information
Definition/Description of Disease
This “emerging entity” is defined by the molecular identification of an oncogenic fusion involving NTRK1, NTRK2, or NTRK3. This provisional category excludes tumors with distinct classifications like infantile fibrosarcoma, congenital mesoblastic nephroma and inflammatory myofibroblastic tumor. Because of the availability and efficacy of the FDA-approved NTRK inhibitors, the identification of NTRK fusions and accurate characterization of these tumors is paramount (PMID: 33179614).
Epidemiology/Prevalence
According to current evidence, these tumors are very rare. As an emerging entity, more data is needed to accurately determine the true prevalence. With increasing awareness of this entity, use of immunohistochemical and molecular techniques to screen for NTRK fusions, this diagnosis may become more frequent.
Clinical Features
The clinical presentation and behavior of these entities is variable (PMID: 32891793). While most often seen in the pediatric and young adult population, it can also present in adulthood. Clinical course is variable, with aggressiveness and propensity to metastasize correlated with clinical and morphological features. All tumors with NTRK fusions are eligible for NTRK-targeted therapies (PMID: 29466156, 32891793). Case reports have demonstrated the efficacy of these treatments for NTRK-rearranged spindle cell neoplasms (PMID: 35070960).
Sites of Involvement
Most often reported in the superficial or deep soft tissue of the extremities and trunk, also reported in other sites, including in the viscera (PMID: 35149769), especially the uterine cervix (PMID: 29553955).
Morphologic Features
NTRK-rearranged spindle cell neoplasms exhibit a histologic spectrum from a lipofibromatosis-like neural tumor to a peripheral nerve sheath tumor-like morphology. The lipofibromatosis-like tumor has an infiltrative growth pattern, with monomorphic spindle cells with cytologic atypia infiltrating into subcutaneous fat. Mitotic count is low and there is a lack of necrosis (PMID: 27259011). Peripheral nerve sheath tumor-like morphology is more cellular with streaming monomorphic spindle cells and a background of prominent stromal bands and keloid-like collagen (PMID: 30276917). Some tumors exhibit a mixture of features or may be spatially heterogeneous with areas closer to one end of the spectrum. Some reports have also identified tumors with other morphologic features, including abundant myxoid stroma (PMID: 32050835).
Immunophenotype
Many NTRK-rearranged spindle cell neoplasms exhibit co-expression of S100 and CD34 (PMID: 30276917, 32891793), while others have a nonspecific immunophenotype.
Links
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References
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Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s): *Citation of this Page: “NTRK-rearranged spindle cell neoplasm (emerging)”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/22/2025, https://ccga.io/index.php/STBT5:NTRK-rearranged spindle cell neoplasm (emerging).