Infantile fibrosarcoma
Soft Tissue and Bone Tumours (Who Classification, 5th ed.)
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Primary Author(s)*
Kathleen Schieffer, PhD, FACMG
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Soft Tissue and Bone Tumours (5th ed.) |
| Category | Soft tissue tumours |
| Family | Fibroblastic and myofibroblastic tumours |
| Type | Infantile fibrosarcoma |
| Subtype(s) | N/A |
Related Terminology
| Acceptable | Congenital fibrosarcoma; infantile fibrosarcoma-like tumour; cellular congenital mesoblastic nephroma |
| Not Recommended | N/A |
Gene Rearrangements
Put your text here and fill in the table (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 |
|---|---|---|---|---|---|---|---|
| NTRK3 | ETV6 | In-frame fusion that results in constitutive activation of the NTRK3 tyrosine kinase domain through heterodimerization and transphosphorylation of the helix-loop-helix domain of ETV6.[1] Breakpoints typically involve exon 5 of ETV6 (NM_001987.4) and exons 14 or 15 of NTRK3 (NM_001243101.1).[2] | t(12;15)(p13;q25) | Common | D, T | Yes (WHO, NCCN) | The ETV6::NTRK3 fusion [t(12;15)] is diagnostic of infantile fibrosarcoma in the appropriate morphology and clinical context.[2][3][4][5] This fusion is found in the majority of infantile fibrosarcoma cases. Studies have demonstrated that this fusion is sensitive to TRK inhibitors.[6][7][8][9][10] |
| NTRK3 | EML4 | In-frame fusion that is predicted to result in constitutive activation of the NTRK3 tyrosine kinase domain through autodimerization of EML4.[1] Breakpoints typically involve exon 2 of EML4 (NM_0019063.4) and exons 14 of NTRK3 (NM_001243101.1).[2] | None | Recurrent | D, T | Yes (WHO) | The EML4::NTRK3 fusion is diagnostic of infantile fibrosarcoma in the appropriate morphology and clinical context.[2][4][11][12] Studies have demonstrated that this fusion is sensitive to TRK inhibitors.[7][9][10] |
| NTRK1 | LMNA, TPM3, SQSTM1, MIR584F1 | In-frame fusion that is predicted to result in constitutive activation of the NTRK1 tyrosine kinase domain likely through dimerization of the 5' fusion partner.[1] | None | Recurrent | D, T | Yes (WHO) | NTRK1 fusions may be diagnostic of infantile fibrosarcoma in the appropriate morphology and clinical context.[11][12][13] Studies have demonstrated that NTRK1 fusions are sensitive to TRK inhibitors.[7][8][9][10] |
| NTRK3 | SPECC1L | In-frame fusion that results in constitutive activation of the NTRK3 tyrosine kinase through heterodimerization and transphosphorylation of the SMC (structural maintenance of chromosomes) domain of SPECC1L. In this case, the breakpoint was in exon 9 of SPECC1L (NM_015330) and exon 13 of NTRK3 (NM_002530) and encompassed the entire tyrosine kinase domain of NTRK3.[14] | None | Rare | D, T | No | A SPECC1L::NTRK3 fusion was reported in a single individual with a large infantile fibrosarcoma of the chest wall. The patient was treated with a TRK inhibitor with excellent clinical response.[14] |
| BRAF | PT7, CUX1 | None | Rare | No | |||
| BRAF | Deletion of CR1 domain and tandem duplication within exon 2 | Intragenic gene rearrangement that is predicted to result in a constitutively active form of BRAF due to loss of the negative regulatory Ras-binding domain.[4] | None | Rare | No | ||
| RET | CLIP2, MYH10 | None | Rare | No | |||
| MET | TFG | In-frame fusion that is predicted to result in constitutive action of the MET tyrosine kinase domain through dimerization of the TFG dimerization domains. In this case, the breakpoint was in exon 7 of TFG and exon 15 of MET and encompassed the entire tyrosine kinase domain of MET.[15] | None | Rare | D | Yes (WHO) | A TFG::MET fusion was reported in a single individual with an unusual infantile spindle cell sarcoma that morphologically resembled infantile fibrosarcoma. MET IHC showed diffuse expression with moderate intensity and RNA expression analysis indicated an intermediate overexpression of MET.[15] |
Individual Region Genomic Gain/Loss/LOH
Whole chromosome gain of 8, 11, 17, and 20 (in various combinations) are commonly observed in infantile fibrosarcoma.
| 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 |
|---|---|---|---|---|---|---|
| 8 | Gain | Whole chromosome 8 | Unknown | D | No | Whole chromosome gain of 8 is commonly observed in infantile fibrosarcoma.[2][5][11][16] |
| 11 | Gain | Whole chromosome 11 | Unknown | D | No | Whole chromosome gain of 11 is commonly observed in infantile fibrosarcoma.[2][5][11][16] |
| 17 | Gain | Whole chromosome 17 | Unknown | D | No | Whole chromosome gain of 17 is commonly observed in infantile fibrosarcoma.[2][5][11][16] |
| 20 | Gain | Whole chromosome 20 | Unknown | D | No | Whole chromosome gain of 20 is commonly observed in infantile fibrosarcoma.[2][5][11][16] |
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 |
|---|---|---|---|---|---|
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 |
|---|---|---|---|---|---|---|
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
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; Activating fusion | RAS/MAPK signaling | Increased cell growth and proliferation |
Genetic Diagnostic Testing Methods
- Fusion testing
- Targeted sequencing (such as RT-PCR or targeted next-generation sequencing (NGS) panels)
- For targeted NGS panels, consider if the assay requires both gene partners to be included on the panel or if it is able to identify novel fusions as long as one of the partners is included on the panel
- Whole transcriptome RNA-sequencing
- Provides an unbiased approach to fusion calling
- Targeted sequencing (such as RT-PCR or targeted next-generation sequencing (NGS) panels)
- Fluorescence in situ hybridization (FISH)
- Break apart probes for ETV6 and/or NTRK3 will identify a rearrangement (ETV6::NTRK3) present in the majority of infantile fibrosarcoma. Consider other fusion partners is ETV6 FISH is negative.
- Karyotyping
- Can identify the t(12;15) rearrangement as well as other commonly reported aneusomies (i.e. whole chromosome gains of 8, 11, 17, 20)
- DNA sequencing
- Can identify the commonly reported aneusomies if copy number variant calling is performed
- Currently, there are no recurrently described somatic SNV/indels for infantile fibrosarcoma
Familial Forms
None
Additional Information
None
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: “Infantile fibrosarcoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/5/2025, https://ccga.io/index.php/STBT5:Infantile fibrosarcoma.
- ↑ 1.0 1.1 1.2 Aepala, Megha R.; et al. (2022-12). "Nefarious NTRK oncogenic fusions in pediatric sarcomas: Too many to Trk". Cytokine & Growth Factor Reviews. 68: 93–106. doi:10.1016/j.cytogfr.2022.08.003. ISSN 1879-0305. PMID 36153202 Check
|pmid=value (help). Check date values in:|date=(help) - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Church, Alanna J.; et al. (2018-03). "Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 31 (3): 463–473. doi:10.1038/modpathol.2017.127. ISSN 1530-0285. PMID 29099503. Check date values in:
|date=(help) - ↑ Caldwell, Kenneth J.; et al. (2020-09). "A newborn with a large NTRK fusion positive infantile fibrosarcoma successfully treated with larotrectinib". Pediatric Blood & Cancer. 67 (9): e28330. doi:10.1002/pbc.28330. ISSN 1545-5017. PMID 32452122 Check
|pmid=value (help). Check date values in:|date=(help) - ↑ 4.0 4.1 4.2 Wegert, Jenny; et al. (2018-06-18). "Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants". Nature Communications. 9 (1): 2378. doi:10.1038/s41467-018-04650-6. ISSN 2041-1723. PMC 6006309. PMID 29915264.
- ↑ 5.0 5.1 5.2 5.3 5.4 Rubin, B. P.; et al. (1998-11). "Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma". The American Journal of Pathology. 153 (5): 1451–1458. doi:10.1016/S0002-9440(10)65732-X. ISSN 0002-9440. PMC 1853403. PMID 9811336. Check date values in:
|date=(help) - ↑ Cardesa-Salzmann, Teresa M.; et al. (2025-05). "On TRacK With Larotrectinib in a Neonate With a Giant Congenital ETV6::NTRK3 Fusion-Positive Infantile Fibrosarcoma of the Head and Neck". Head & Neck. 47 (5): E50–E57. doi:10.1002/hed.28058. ISSN 1097-0347. PMC 12038221 Check
|pmc=value (help). PMID 39737858 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 7.0 7.1 7.2 Hong, D. S.; et al. (2025-06). "Efficacy and safety of larotrectinib as first-line treatment for patients with TRK fusion cancer". ESMO open. 10 (6): 105110. doi:10.1016/j.esmoop.2025.105110. ISSN 2059-7029. PMC 12151180 Check
|pmc=value (help). PMID 40408921 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 8.0 8.1 Drilon, Alexander; et al. (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.
- ↑ 9.0 9.1 9.2 Hong, David S.; et al. (2020-04). "Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials". The Lancet. Oncology. 21 (4): 531–540. doi:10.1016/S1470-2045(19)30856-3. ISSN 1474-5488. PMC 7497841 Check
|pmc=value (help). PMID 32105622 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 10.0 10.1 10.2 Laetsch, Theodore W.; et al. (2025-04). "Larotrectinib for Newly Diagnosed Infantile Fibrosarcoma and Other Pediatric NTRK Fusion-Positive Solid Tumors (Children's Oncology Group ADVL1823)". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 43 (10): 1188–1197. doi:10.1200/JCO-24-01854. ISSN 1527-7755. PMC 11954674 Check
|pmc=value (help). PMID 39652801 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 11.0 11.1 11.2 11.3 11.4 11.5 Davis, Jessica L.; et al. (2018). "Infantile NTRK-associated Mesenchymal Tumors". Pediatric and Developmental Pathology: The Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 21 (1): 68–78. doi:10.1177/1093526617712639. ISSN 1093-5266. PMID 28683589.
- ↑ 12.0 12.1 Kao, Yu-Chien; et al. (2018-01). "Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas: Expanding the Genetic Spectrum of Tumors With Overlapping Features With Infantile Fibrosarcoma". The American Journal of Surgical Pathology. 42 (1): 28–38. doi:10.1097/PAS.0000000000000938. ISSN 1532-0979. PMC 5730460. PMID 28877062. Check date values in:
|date=(help) - ↑ Pavlick, Dean; et al. (2017-08). "Identification of NTRK fusions in pediatric mesenchymal tumors". Pediatric Blood & Cancer. 64 (8). doi:10.1002/pbc.26433. ISSN 1545-5017. PMID 28097808. Check date values in:
|date=(help) - ↑ 14.0 14.1 Khuong-Quang, Dong-Anh; et al. (2020-12). "Recurrent SPECC1L-NTRK fusions in pediatric sarcoma and brain tumors". Cold Spring Harbor Molecular Case Studies. 6 (6): a005710. doi:10.1101/mcs.a005710. ISSN 2373-2873. PMC 7784491 Check
|pmc=value (help). PMID 33144287 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 15.0 15.1 Flucke, Uta; et al. (2017-09). "TFG-MET fusion in an infantile spindle cell sarcoma with neural features". Genes, Chromosomes & Cancer. 56 (9): 663–667. doi:10.1002/gcc.22470. ISSN 1098-2264. PMC 5507719. PMID 28510278. Check date values in:
|date=(help) - ↑ 16.0 16.1 16.2 16.3 Sandberg, Avery A.; et al. (2002-01-01). "Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: congenital (infantile) fibrosarcoma and mesoblastic nephroma". Cancer Genetics and Cytogenetics. 132 (1): 1–13. doi:10.1016/s0165-4608(01)00528-3. ISSN 0165-4608. PMID 11801301.