NTRK-rearranged spindle cell neoplasm (emerging)
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[1][2]. 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[3]. 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[4][5].
| 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 | Unknown | No |
Characteristic Chromosomal or Other Global Mutational Patterns
None
| 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 |
|---|---|---|---|---|---|
| N/A | N/A | N/A | N/A | N/A | N/A |
Gene Mutations (SNV/INDEL)
None
| 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 |
|---|---|---|---|---|---|---|
| N/A | N/A | N/A | N/A | N/A | N/A | N/A |
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
None
Genes and Main Pathways Involved
| 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[5][6][7][8]. 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
- 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[9].
- 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[10].
Familial Forms
None
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[11].
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[12]. 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[12][13]. Case reports have demonstrated the efficacy of these treatments for NTRK-rearranged spindle cell neoplasms[14].
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[5], especially the uterine cervix[15].
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[16]. 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[1]. 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[1][12], while others have a nonspecific immunophenotype.
Links
None
References
- ↑ 1.0 1.1 1.2 Suurmeijer, Albert J. H.; Dickson, Brendan C.; Swanson, David; Zhang, Lei; Sung, Yun-Shao; Cotzia, Paolo; Fletcher, Christopher D. M.; Antonescu, Cristina R. (2018-12). "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. 57 (12): 611–621. doi:10.1002/gcc.22671. ISSN 1098-2264. PMC 6746236. PMID 30276917.
{{cite journal}}: Check date values in:|date=(help) - ↑ Yamazaki, Fumito; Nakatani, Fumihiko; Asano, Naofumi; Wakai, Susumu; Sekimizu, Masaya; Mitani, Sachiyo; Kubo, Takashi; Kawai, Akira; Ichikawa, Hitoshi (2019-04). "Novel NTRK3 Fusions in Fibrosarcomas of Adults". The American Journal of Surgical Pathology. 43 (4): 523–530. doi:10.1097/PAS.0000000000001194. ISSN 1532-0979. PMID 30520818.
{{cite journal}}: Check date values in:|date=(help) - ↑ Hsiao, Susan J.; Zehir, Ahmet; Sireci, Anthony N.; Aisner, Dara L. (2019-07). "Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy". The Journal of molecular diagnostics: JMD. 21 (4): 553–571. doi:10.1016/j.jmoldx.2019.03.008. ISSN 1943-7811. PMC 7456740. PMID 31075511.
{{cite journal}}: Check date values in:|date=(help) - ↑ Croce, Sabrina; Hostein, Isabelle; Longacre, Teri A.; Mills, Anne M.; Pérot, Gaëlle; Devouassoux-Shisheboran, Mojgan; Velasco, Valérie; Floquet, Anne; Guyon, Frédéric (2019-07). "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". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 32 (7): 1008–1022. doi:10.1038/s41379-018-0184-6. ISSN 1530-0285. PMID 30877273.
{{cite journal}}: Check date values in:|date=(help) - ↑ 5.0 5.1 5.2 Tsai, Jen-Wei; Lee, Jen-Chieh; Hsieh, Tsung-Han; Huang, Shih-Chiang; Lee, Pei-Hang; Liu, Ting-Ting; Kao, Yu-Chien; Chang, Ching-Di; Weng, Te-Fu (2022-07). "Adult NTRK-rearranged spindle cell neoplasms of the viscera: with an emphasis on rare locations and heterologous elements". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 35 (7): 911–921. doi:10.1038/s41379-021-01005-3. ISSN 1530-0285. PMID 35149769.
{{cite journal}}: Check date values in:|date=(help) - ↑ Solomon, James P.; Linkov, Irina; Rosado, Andrea; Mullaney, Kerry; Rosen, Ezra Y.; Frosina, Denise; Jungbluth, Achim A.; Zehir, Ahmet; Benayed, Ryma (2020-01). "NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 33 (1): 38–46. doi:10.1038/s41379-019-0324-7. ISSN 1530-0285. PMC 7437403. PMID 31375766.
{{cite journal}}: Check date values in:|date=(help) - ↑ Hung, Yin P.; Fletcher, Christopher D. M.; Hornick, Jason L. (2018-10). "Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics". Histopathology. 73 (4): 634–644. doi:10.1111/his.13666. ISSN 1365-2559. PMID 29863809.
{{cite journal}}: Check date values in:|date=(help) - ↑ Kao, Yu-Chien; Sung, Yun-Shao; Argani, Pedram; Swanson, David; Alaggio, Rita; Tap, William; Wexler, Leonard; Dickson, Brendan C.; Antonescu, Cristina R. (2020-07). "NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 33 (7): 1341–1349. doi:10.1038/s41379-020-0495-2. ISSN 1530-0285. PMC 7329614. PMID 32034283.
{{cite journal}}: Check date values in:|date=(help) - ↑ Amatu, A.; Sartore-Bianchi, A.; Bencardino, K.; Pizzutilo, E. G.; Tosi, F.; Siena, S. (2019-11-01). "Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer". Annals of Oncology: Official Journal of the European Society for Medical Oncology. 30 (Suppl_8): viii5–viii15. doi:10.1093/annonc/mdz383. ISSN 1569-8041. PMC 6859819. PMID 31738427.
- ↑ Saliba, Jason; Church, Alanna J.; Rao, Shruti; Danos, Arpad; Furtado, Larissa V.; Laetsch, Theodore; Zhang, Liying; Nardi, Valentina; Lin, Wan-Hsin (2022-06). "Standardized evidence-based approach for assessment of oncogenic and clinical significance of NTRK fusions". Cancer Genetics. 264–265: 50–59. doi:10.1016/j.cancergen.2022.03.001. ISSN 2210-7762. PMC 9252326. PMID 35366592.
{{cite journal}}: Check date values in:|date=(help) - ↑ Sbaraglia, Marta; Bellan, Elena; Dei Tos, Angelo P. (2021-04). "The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives". Pathologica. 113 (2): 70–84. doi:10.32074/1591-951X-213. ISSN 1591-951X. PMC 8167394. PMID 33179614.
{{cite journal}}: Check date values in:|date=(help) - ↑ 12.0 12.1 12.2 Demetri, G. D.; Antonescu, C. R.; Bjerkehagen, B.; Bovée, J. V. M. G.; Boye, K.; Chacón, M.; Dei Tos, A. P.; Desai, J.; Fletcher, J. A. (2020-11). "Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network". Annals of Oncology: Official Journal of the European Society for Medical Oncology. 31 (11): 1506–1517. doi:10.1016/j.annonc.2020.08.2232. ISSN 1569-8041. PMC 7985805. PMID 32891793.
{{cite journal}}: Check date values in:|date=(help) - ↑ Drilon, Alexander; Laetsch, Theodore W.; Kummar, Shivaani; DuBois, Steven G.; Lassen, Ulrik N.; Demetri, George D.; Nathenson, Michael; Doebele, Robert C.; Farago, Anna F. (2018-02-22). "Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children". The New England Journal of Medicine. 378 (8): 731–739. doi:10.1056/NEJMoa1714448. ISSN 1533-4406. PMC 5857389. PMID 29466156.
- ↑ Recine, Federica; De Vita, Alessandro; Fausti, Valentina; Pieri, Federica; Bongiovanni, Alberto; Franchini, Eugenia; Casadei, Roberto; Falasconi, Maria Cristina; Oboldi, Devil (2021). "Case Report: Adult NTRK-Rearranged Spindle Cell Neoplasm: Early Tumor Shrinkage in a Case With Bone and Visceral Metastases Treated With Targeted Therapy". Frontiers in Oncology. 11: 740676. doi:10.3389/fonc.2021.740676. ISSN 2234-943X. PMC 8776642. PMID 35070960.
{{cite journal}}: CS1 maint: article number as page number (link) CS1 maint: unflagged free DOI (link) - ↑ Chiang, Sarah; Cotzia, Paolo; Hyman, David M.; Drilon, Alexander; Tap, William D.; Zhang, Lei; Hechtman, Jaclyn F.; Frosina, Denise; Jungbluth, Achim A. (2018-06). "NTRK Fusions Define a Novel Uterine Sarcoma Subtype With Features of Fibrosarcoma". The American Journal of Surgical Pathology. 42 (6): 791–798. doi:10.1097/PAS.0000000000001055. ISSN 1532-0979. PMC 6764747. PMID 29553955.
{{cite journal}}: Check date values in:|date=(help) - ↑ Agaram, Narasimhan P.; Zhang, Lei; Sung, Yun-Shao; Chen, Chun-Liang; Chung, Catherine T.; Antonescu, Cristina R.; Fletcher, Christopher Dm (2016-10). "Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors". The American Journal of Surgical Pathology. 40 (10): 1407–1416. doi:10.1097/PAS.0000000000000675. ISSN 1532-0979. PMC 5023452. PMID 27259011.
{{cite journal}}: Check date values in:|date=(help)
Notes
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Prior Author(s): *Citation of this Page: “NTRK-rearranged spindle cell neoplasm (emerging)”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/26/2026, https://ccga.io/index.php/STBT5:NTRK-rearranged spindle cell neoplasm (emerging).