Myxoinflammatory fibroblastic sarcoma

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

Primary Author(s)*

Mokhtar H. Abdelhammed, MD; Kathleen Schieffer, PhD

WHO Classification of Disease

Structure Disease
Book Soft Tissue and Bone Tumours (5th ed.)
Category Soft tissue tumours
Family Fibroblastic and myofibroblastic tumours
Type Myxoinflammatory fibroblastic sarcoma
Subtype(s) N/A

Related Terminology

Acceptable N/A
Not Recommended Inflammatory myxohyaline tumour of the distal extremities with virocyte-like or Reed–Sternberg–like cells; acral myxoinflammatory fibroblastic sarcoma; inflammatory myxoid tumour of the soft parts with bizarre giant cells

Gene Rearrangements

BRAF gene fusions are identified in approximately 33% of myxoinflammatory fibroblastic sarcoma (MIFS) cases.[1][2][3][4][5][6] Multiple fusion partners have been described, including TOM1L2, SND1, ZNF335, TRIM24, and ROBO1. In addition, TGFBR3-OGA (MGEA5) rearrangements, resulting from the t(1;10)(p22;q24) translocation, are detected in approximately 32% of cases.[1][6][7][8][9][10][11][12][13][14] YAP1::MAML2 fusions are characteristic of the “nodular necrotizing” variant of MIFS and can co-exist with BRAF fusions.[1][15] More recently, several novel fusions have been described, including RRAGB::CCNB3, FGFR1::ZBTB47, SEC23IP::VGLL3, and TEAD1::MRTFB.[1][3]

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
BRAF [1][2][3][4][5][6] TOM1L2::BRAF [2]; SND1::BRAF[3]; ZNF335::BRAF[4]; TRIM24::BRAF[5]; ROBO1::BRAF[6] Fusion leads to constitutive activation of the MAPK (MEK/ERK) pathway Variable; partner dependent Recurrent (33%) [1][2][3][4][5][6] D, T[3] Yes (WHO)  Potential sensitivity to MEK inhibitors[3]
TGFBR3[1][6][7][8][9][10][11][12][13][14]  TGFBR3-OGA (MGEA5)  Translocation t(1;10) does not result in a fusion transcript [6][8] but results in transcriptional dysregulation related to breakpoint rearrangement; altered TGF-β signaling modulation and transcriptionally activated of nearby genes to OGA including FGF8, NPM3 as a consequence of the rearrangement  Balanced or unbalanced t(1;10)(p22;q24); hybrid MIFS/ Haemosiderotic fibrohistiocytic lipomatous lesion (HFLT) with der(10)t(1;10) 32% of pure MIFS[1]  D  Yes (WHO)  Recurrent in HFLT, PHAT, and subsets of MIFS; supports neoplastic nature[10][11][12] Frequently identified in hybrid HFLT/MIFS lesions[13][14]
YAP1[1][5][15] YAP1::MAML2 Activates transcriptional programs related to proliferation and survival (Hippo pathway dysregulation) Variable

YAP1 locus in 11q22.1 and MAML2 in 11q21[15]


Involving exon 6 of YAP1 and exon 2 of MAML2[5]

Recurrent in 7 cases   D No Characteristic of nodular necrotizing MIFS[5]
RRAGB[1] RRAGB::CCNB3 Likely dysregulation of cell cycle signaling Intra-chromosomal X, includes exons 1–6 of RRAGB and the entire coding sequencing of CCNB3 Rare, 1 case D No Newly described
FGFR1[1] FGFR1::ZBTB47 Possible activation of FGFR signaling t(3;8)(p22.1; p11.23). The fusion transcript is composed of the FGFR1 exons1–17 and ZBTB47 exons 2–6 Rare, 1 case D, T No Possible therapeutic relevance
VGLL3[3] SEC23IP::VGLL3 Upregulation of TEAD-mediated transcription (Hippo pathway) Involving exon 2 of SEC23IP and exon 2 of VGLL3 Rare, 2 cases D No Alternative mechanism of VGLL3 activation
TEAD1[3] TEAD1::MRTFB TEAD pathway activation Involving exon 9 of TEAD1 and exon 13 of MRTFB Rare, 1 case D No Supports Hippo pathway involvement

Individual Region Genomic Gain/Loss/LOH

Chromosome 3 amplification involving VGLL3 and CHMP2B is the most common genetic alteration in MIFS.[1][2][6][8][10]

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
3[1][2][6][8][10] Amplification 3p11–12 VGLL3, CHMP2B D, P Yes (WHO) Present in majority of MIFS; associated with increased recurrence and metastasis risk[1]
9[6] Homozygous deletion 9p21 CDKN2A/B - No -
13[6] Loss 13q14 RB1 - No -

Characteristic Chromosomal or Other Global Mutational Patterns

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
Complex copy number alterations[1][6][8] Multiple amplifications and deletions Common   D No -

Gene Mutations (SNV/INDEL)

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
NA NA NA NA NA NA NA

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

No specific recurrent epigenetic modification pattern has been defined in MIFS.

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
VGLL3 amplification Hippo–TEAD signaling TEAD-driven tumor initiation and progression
BRAF; fusions MAPK (MEK/ERK) Increased proliferation via ERK activation  
TGFBR3::OGA (MGEA5) with FGF8 upregulation FGF signaling Growth factor–mediated proliferation  
YAP1::MAML2 Hippo pathway Enhanced transcription of pro-proliferative genes  

Genetic Diagnostic Testing Methods

  • Fluorescence In Situ Hybridization (FISH)
    • TGFBR3 and OGA (MGEA5) rearrangement analysis using FISH using break-apart probes is the primary diagnostic tool for detecting the t(1;10)(p22;q24).  
    • VGLL3 amplification can also be detected by FISH on chromosome 3p12.1.  
  • Karyotyping  
    • Can identify:
      • t(1;10)(p22;q24)
      • Unbalanced der(10)t(1;10) chromosomes in hybrid MIFS/HFLT
      • Chromosome 3 with 3p11–12 amplification
  • RNA Sequencing  
    • BRAF gene fusions with associated partners TOM1L2, SND1, ZNF335, TRIM24, and ROBO1
    • YAP1::MAML2
    • Other rare fusions RRAGB::CCNB3, FGFR1::ZBTB47, SEC23IP::VGLL3, and TEAD1::MRTFB
    • Identify fusion transcripts associated with the t(1;10) rearrangement. However: The t(1;10) translocation may not always generate functional fusion transcripts.  
  • Real-Time Quantitative PCR (RT-qPCR)  
    • Expression of VGLL3 and CHMP2B associated with 3p amplification  

Familial Forms

No hereditary or germline predisposition syndrome has been associated with MIFS.  

Additional Information

NA

Links

NA

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 Hirose, Takeshi; Chang, Hsin‐Yi; Saoud, Carla; Lefkowitz, Robert A.; Athanasian, Edward; Antonescu, Cristina R. (2025-01). "A Clinicopathologic and Molecular Reappraisal of Myxoinflammatory Fibroblastic Sarcoma—A Controversial and Pathologically Challenging Low‐Grade Sarcoma". Genes, Chromosomes and Cancer. 64 (1). doi:10.1002/gcc.70018. ISSN 1045-2257. {{cite journal}}: Check date values in: |date= (help)
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Kao, Yu-Chien; Ranucci, Valentina; Zhang, Lei; Sung, Yun-Shao; Athanasian, Edward A.; Swanson, David; Dickson, Brendan C.; Antonescu, Cristina R. (2017-11). "Recurrent BRAF Gene Rearrangements in Myxoinflammatory Fibroblastic Sarcomas, but Not Hemosiderotic Fibrolipomatous Tumors". American Journal of Surgical Pathology. 41 (11): 1456–1465. doi:10.1097/PAS.0000000000000899. ISSN 0147-5185. {{cite journal}}: Check date values in: |date= (help)
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Klubíčková, Natálie; Agaimy, Abbas; Hájková, Veronika; Ptáková, Nikola; Grossmann, Petr; Šteiner, Petr; Michal, Michal; Michal, Michael (2022-10). "RNA-sequencing of myxoinflammatory fibroblastic sarcomas reveals a novel SND1::BRAF fusion and 3 different molecular aberrations with the potential to upregulate the TEAD1 gene including SEC23IP::VGLL3 and TEAD1::MRTFB gene fusions". Virchows Archiv. 481 (4): 613–620. doi:10.1007/s00428-022-03368-7. ISSN 0945-6317. {{cite journal}}: Check date values in: |date= (help)
  4. ↑ 4.0 4.1 4.2 4.3 Suster, David; Michal, Michael; Huang, Huiya; Ronen, Shira; Springborn, Stephanie; Debiec-Rychter, Maria; Billings, Steven D.; Goldblum, John R.; Rubin, Brian P. (2020-12). "Myxoinflammatory fibroblastic sarcoma: an immunohistochemical and molecular genetic study of 73 cases". Modern Pathology. 33 (12): 2520–2533. doi:10.1038/s41379-020-0580-6. {{cite journal}}: Check date values in: |date= (help)
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Harnisch, Kim; Bode, Beata; Chijioke, Obinna; Hench, Ivana Bratic; Kazakov, Dmitry V. (2025-12). "Myxoinflammatory Fibroblastic Sarcoma, Nodular-Necrotizing Variant With Two YAP1::MAML2 Fusions and TRIM24::BRAF Fusion". The American Journal of Dermatopathology. 47 (12): 976–978. doi:10.1097/DAD.0000000000003107. ISSN 0193-1091. {{cite journal}}: Check date values in: |date= (help)
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 Arbajian, Elsa; Hofvander, Jakob; Magnusson, Linda; Mertens, Fredrik (2020-05). "Deep sequencing of myxoinflammatory fibroblastic sarcoma". Genes, Chromosomes and Cancer. 59 (5): 309–317. doi:10.1002/gcc.22832. ISSN 1045-2257. {{cite journal}}: Check date values in: |date= (help)
  7. ↑ 7.0 7.1 Lambert, Isabelle; Debiec-Rychter, Maria; Guelinckx, Paul; Hagemeijer, Anne; Sciot, Raf (2001-05). "Acral myxoinflammatory fibroblastic sarcoma with unique clonal chromosomal changes". Virchows Archiv. 438 (5): 509–512. doi:10.1007/s004280000376. ISSN 0945-6317. {{cite journal}}: Check date values in: |date= (help)
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Hallor, Karolin H; Sciot, Raf; Staaf, Johan; Heidenblad, Markus; Rydholm, Anders; Bauer, Henrik CF; Åström, Kristina; Domanski, Henryk A; Meis, Jeanne M (2009-04). "Two genetic pathways, t(1;10) and amplification of 3p11–12, in myxoinflammatory fibroblastic sarcoma, haemosiderotic fibrolipomatous tumour, and morphologically similar lesions". The Journal of Pathology. 217 (5): 716–727. doi:10.1002/path.2513. ISSN 0022-3417. {{cite journal}}: Check date values in: |date= (help)
  9. ↑ 9.0 9.1 Liu, Huifei; Sukov, William R.; Ro, Jae Y. (2019-02-01). "The t(1;10)(p22;q24) TGFBR3/MGEA5 Translocation in Pleomorphic Hyalinizing Angiectatic Tumor, Myxoinflammatory Fibroblastic Sarcoma, and Hemosiderotic Fibrolipomatous Tumor". Archives of Pathology & Laboratory Medicine. 143 (2): 212–221. doi:10.5858/arpa.2017-0412-RA. ISSN 0003-9985.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 Antonescu, Cristina R.; Zhang, Lei; Nielsen, G.Petur; Rosenberg, Andrew E.; Cin, Paola Dal; Fletcher, Christopher D. M. (2011-10). "Consistent t(1;10) with rearrangements of TGFBR3 and MGEA5 in both myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor". Genes, Chromosomes and Cancer. 50 (10): 757–764. doi:10.1002/gcc.20897. ISSN 1045-2257. {{cite journal}}: Check date values in: |date= (help)
  11. ↑ 11.0 11.1 11.2 Boland, Jennifer M.; Folpe, Andrew L. (2017-09). "Hemosiderotic Fibrolipomatous Tumor, Pleomorphic Hyalinizing Angiectatic Tumor, and Myxoinflammatory Fibroblastic Sarcoma: Related or Not?". Advances in Anatomic Pathology. 24 (5): 268–277. doi:10.1097/PAP.0000000000000151. ISSN 1072-4109. {{cite journal}}: Check date values in: |date= (help)
  12. ↑ 12.0 12.1 12.2 Elco, Christopher P.; Mariño-Enríquez, Adrián; Abraham, John A.; Cin, Paola Dal; Hornick, Jason L. (2010-11). "Hybrid Myxoinflammatory Fibroblastic Sarcoma/Hemosiderotic Fibrolipomatous Tumor: Report of a Case Providing Further Evidence for a Pathogenetic Link". American Journal of Surgical Pathology. 34 (11): 1723–1727. doi:10.1097/PAS.0b013e3181f17d51. ISSN 0147-5185. {{cite journal}}: Check date values in: |date= (help)
  13. ↑ 13.0 13.1 13.2 Zreik, Riyam T.; Carter, Jodi M.; Sukov, William R.; Ahrens, William A.; Fritchie, Karen J.; Montgomery, Elizabeth A.; Weiss, Sharon W.; Folpe, Andrew L. (2016-07). "TGFBR3 and MGEA5 rearrangements are much more common in "hybrid" hemosiderotic fibrolipomatous tumor-myxoinflammatory fibroblastic sarcomas than in classical myxoinflammatory fibroblastic sarcomas: a morphological and fluorescence in situ hybridization study". Human Pathology. 53: 14–24. doi:10.1016/j.humpath.2016.02.005. {{cite journal}}: Check date values in: |date= (help)
  14. ↑ 14.0 14.1 14.2 Carter, Jodi M.; Sukov, William R.; Montgomery, Elizabeth; Goldblum, John R.; Billings, Steven D.; Fritchie, Karen J.; Folpe, Andrew L. (2014-09). "TGFBR3 and MGEA5 Rearrangements in Pleomorphic Hyalinizing Angiectatic Tumors and the Spectrum of Related Neoplasms". American Journal of Surgical Pathology. 38 (9): 1182–1992. doi:10.1097/PAS.0000000000000212. ISSN 0147-5185. {{cite journal}}: Check date values in: |date= (help)
  15. ↑ 15.0 15.1 15.2 Perret, Raul; Tallegas, Matthias; Velasco, Valérie; Soubeyran, Isabelle; Coindre, Jean-Michel; Azmani, Rihab; Baud, Jessica; Bacle, Guillaume; De Pinieux, Gonzague (2022-10). "Recurrent YAP1::MAML2 fusions in "nodular necrotizing" variants of myxoinflammatory fibroblastic sarcoma: a comprehensive study of 7 cases". Modern Pathology. 35 (10): 1398–1404. doi:10.1038/s41379-022-01096-6. {{cite journal}}: Check date values in: |date= (help)

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: “Myxoinflammatory fibroblastic sarcoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/8/2026, https://ccga.io/index.php/STBT5:Myxoinflammatory fibroblastic sarcoma.

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