STBT5:NTRK-rearranged spindle cell neoplasm (emerging)

Soft Tissue and Bone Tumours (Who Classification, 5th ed.)

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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).

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 TPR::NTRK1 LMNA::NTRK1 Many other fusion partners also possible	In-frame fusions that include the tyrosine kinase domain result in constitutive activation of the neurotrophic tyrosine receptor kinase and downstream pathways including the MAP-kinase and PI3-kinase pathways.	t(1;1)(q21.3;q23.1) t(1;1)(q31.1;q23.1) t(1;1)(q22;q23.1)	Common	D, T	Yes (WHO, NCCN)	Larotrectinib, entrectinib, and repotrectinib are FDA approved for the treatment of solid tumors harboring an NTRK fusion.

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
9	Loss	chr9p21	CDKN2A		No

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).