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Soft Tissues: Extraskeletal myxoid chondrosarcoma

Written2017-03Fei Dong, Vickie Jo
Department of Pathology, Brigham and Women's Hospital, Boston, MA
This article is an update of :
2004-09Masanori Hisaoka, Hiroshi Hashimoto
Department of Pathology & Oncology, School of Medicine, University of Occupational & Environmental Health, Japan;
2000-07Jérome Couturier
Department of Pathology, Institut Curie, Paris, France

(Note : for Links provided by Atlas : click)


Abstract Review on Extraskeletal myxoid chondrosarcoma, with data on clinics, and the genes involved.


ICD-Topo C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE
ICD-Morpho 9231/3 Extraskeletal myxoid chondrosarcoma ("chordoid" type)
Atlas_Id 5025
Phylum Soft Tissues::Extraskeletal myxoid chondrosarcoma
WHO/OMS Classification Soft Tissues


Note Extraskeletal myxoid chondrosarcoma is characterized by a lobulated architecture (A), with a reticular growth pattern of interconnecting uniform tumor cells having ovoid-to-spindled nuclei and eosinophilic cytoplasm (B).

Clinics and Pathology

Disease Malignant mesenchymal neoplasm of uncertain differentiation.
Epidemiology Extraskeletal myxoid chondrosarcoma is a rare tumor, encompassing 2.3% of soft tissue sarcomas in a Japanese series. Mean ages reported in various series range from 46 to 57 years. Males are affected about twice as often as females.
Clinics Location: deep soft tissues of the lower extremities in about 75% of the cases, especially the thigh, the popliteal fossa, and the buttock, and can also occur in the trunk, abdomen, and head and neck.
  • Macroscopic findings: the tumor presents as lobulated or multinodular mass, generally well circumscribed with pseudocapsule. The size of the tumor at the time of diagnosis may vary from 1 to about 20 cm (median size 7 cm).
  • Histology: Lobulated architecture with uniform round to spindled cells forming interconnecting cords, clusters, or trabeculae in a background of myxoid matrix. The tumor cells have variably eosinophilic or vacuolated cytoplasm that extends to form the reticular growth pattern. A subset of tumors shows hypercellularity, higher grade cytomorphology, and epithelioid or rhabdoid features.
  • A subset of tumors is positive for S100, CD117, synaptophysin, and neuron-specific enolase. INI1 loss is observed in a subset, often with rhabdoid features.
  • Ultrastructurally, at least one third of the tumors demonstrate microtubular aggregates within dilated rough endoplasmic reticulum.
  • Treatment Treatment: surgical excision, with possible adjuvant chemotherapy.
    Prognosis Prognosis: high rates of local and distant recurrence, including pulmonary metastasis, but with associated prolonged survival.


    Note NR4A3 Gene Fusions in Extraskeletal Myxoid Chondrosarcoma
    t(9;22)(q22;q12) EWSR1/NR4A3
    t(3;9)(q12;q22) TFG/NR4A3
    t(9;11)(q22;q24) HSPA8/NR4A3
    t(9;15)(q22;q21) TCF12/NR4A3
    t(9;16)(q22;p11) FUS/NR4A3
    t(9;17)(q22;q11) TAF15/NR4A3
  • Recurrent gene fusions involving NR4A3 on chromosome 9 are observed in the majority of extraskeletal myxoid chondrosarcomas. The most common fusion partner is EWSR1, resulting in t(9;22)(q22;q12) with fusion of the 5' aspect of EWSR1 with NR4A3.
  • Uncommon gene fusion events involving NR4A3 with TAF15, TCF12, TFG, FUS, or HSPA8 have also been reported. These events result in t(9;17)(q22;q11), t(9;15)(q22;q21), t(3;9)(q12;q22), t(9;16)(q22;p11), or t(9;11)(q22;q24), respectively.
  • The breakpoint involving NR4A3 frequently occurs in the 5' untranslated region, with the resultant fusion including the entire NR4A3 protein.
  • In extraskeletal myxoid chondrosarcomas without NR4A3 fusion, tumors may harbor loss of SMARCB1 (INI1) by loss of function mutation or gene deletion.
  • Extraskeletal myxoid chondrosarcomas without EWSR1-NR4A3 fusion may exhibit rhabdoid morphology and high grade pathological features.
  • Left: Karyotype of extraskeletal myxoid chondrosarcoma with t(9;22)(q22;q12). Right: Fluorescence in situ hybridization demonstrating rearrangement of NR4A3 by break apart probe.

    Genes involved and Proteins

    Gene NameTFG (TRK-fused gene)
    Location 3q12.2
    Dna / Rna 39.51 kb; 8 exons; 1.9 kb mRNA.
    Protein Putative signal transducer; positive regulator of I-kappaB kinase/NF-kappaB cascade.

    Gene NameNR4A3 (nuclear receptor subfamily 4, group A, member 3)
    Location 9q22.33
    Dna / Rna Transcripts: 2.6 kb and 3.7 kb.
    Protein Steroid-thyroid hormone-retinoid receptor; transcriptional activator.

    Gene NameTCF12 (transcription factor 12)
    Location 15q21.3
    Dna / Rna 370 kb; 21 exons; 4 kb mRNA.
    Protein Transcription factor; a basic helix-loop-helix protein.

    Gene NameTAF15 (TAF15 TAF15 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 68kDa)
    Location 17q12
    Dna / Rna 16 exons; alternative splicing; 2.2 kb bp mRNA.
    Protein RNA-binding protein; part of theTFIID and RNA polymerase II complex.

    Gene NameEWSR1 (Ewing sarcoma breakpoint region 1)
    Location 22q12.2
    Dna / Rna 17 exons; 2.4 kb mRNA.
    Protein RNA-binding protein; transcription repressor.

    Gene NameFUS (fusion involved in t (12;16) in malignant liposarcoma)
    Location 16p11.2
    Dna / Rna 15 exons; 1.6 kb mRNA.
    Protein RNA-binding protein.

    Gene Name>CC: TXT: HSPA8 ID: 40878>
    Location 11q24.1
    Dna / Rna 9 exons; 1.9 kb mRNA.
    Protein Heat shock protein.

    Gene NameSMARCB1 (SW1/SNF related, matrix associated, actin dependent regulator of chromatin B1)
    Location 22q11.23
    Dna / Rna 9 exons; 1.2 kb mRNA.
    Protein Core component of BAF complex.


    Extraskeletal myxoid chondrosarcoma with non-EWSR1-NR4A3 variant fusions correlate with rhabdoid phenotype and high-grade morphology.
    Agaram NP, Zhang L, Sung YS, Singer S, Antonescu CR.
    Hum Pathol. 2014;45(5):1084-91.
    PMID 24746215
    Identification of a novel fusion gene involving hTAFII68 and CHN from a t(9;17)(q22;q11.2) translocation in an extraskeletal myxoid chondrosarcoma.
    Attwooll C, Tariq M, Harris M, Coyne JD, Telford N, Varley JM
    Oncogene. 1999;18(52):7599-601.
    PMID 10602520
    Diagnostic utility of molecular investigation in extraskeletal myxoid chondrosarcoma.
    Benini S, Cocchi S, Gamberi G, Magagnoli G, Vogel D, Ghinelli C, Righi A, Picci P, Alberghini M, Gambarotti M.
    J Mol Diagn. 2014;16(3):314-23.
    PMID 24508382
    Extraskeletal myxoid chondrosarcoma with a t(9;16)(q22;p11.2) resulting in a NR4A3-FUS fusion.
    Broehm CJ, Wu J, Gullapalli RR, Bocklage T.
    Cancer Genet. 2014;207(6):276-80.
    PMID 25130955
    Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma.
    Clark J, Benjamin H, Gill S, Sidhar S, Goodwin G, Crew J, Gusterson BA, Shipley J, Cooper CS
    Oncogene. 1996 ;12(2):229-35.
    PMID 8570200
    Myxoid chondrosarcoma with a translocation involving chromosomes 9 and 22.
    Hinrichs SH, Jaramillo MA, Gumerlock PH, Gardner MB, Lewis JP, Freeman AE
    Cancer genetics and cytogenetics. 1985;14(3-4):219-26.
    PMID 3967207
    TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma.
    Hisaoka M, Ishida T, Imamura T, Hashimoto H.
    Genes Chromosomes Cancer. 2004;40(4):325-8.
    PMID 15188455
    SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma.
    Kohashi K, Oda Y, Yamamoto H, Tamiya S, Oshiro Y, Izumi T, Taguchi T, Tsuneyoshi M.
    Am J Surg Pathol. 2008;32(8):1168-74.
    PMID 18580682
    Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation.
    Labelle Y, Zucman J, Stenman G, et al.
    Hum Mol Genet. 1995;4(12):2219-26.
    PMID 8634690
    Fusion of the RBP56 and CHN genes in extraskeletal myxoid chondrosarcomas with translocation t(9;17)(q22;q11).
    Panagopoulos I, Mencinger M, Dietrich CU, Bjerkehagen B, Saeter G, Mertens F, Mandahl N, Heim S.
    Oncogene. 1999;18(52):7594-8.
    PMID 10602520
    Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21).
    Sjögren H, Wedell B, Meis-Kindblom JM, Kindblom LG, Stenman G.
    Cancer Res. 2000;60(24):6832-5.
    PMID 11156374
    HSPA8 as a novel fusion partner of NR4A3 in extraskeletal myxoid chondrosarcoma.
    Urbini M, Astolfi A, Pantaleo MA, Serravalle S, Dei Tos AP, Picci P, Indio V, Sbaraglia M, Benini S, Righi A, Gambarotti M, Gronchi A, Colombo C, Dagrada GP, Pilotti S, Maestro R, Polano M, Saponara M, Tarantino G, Pession A, Biasco G, Giovanni Casali P, Stacchiotti S.
    Genes Chromosomes Cancer. 2017 Apr 6. doi: 10.1002/gcc.22462. [Epub ahead of print]
    PMID 28383167


    This paper should be referenced as such :
    Fei Dong, Vickie Jo
    Soft Tissues: Extraskeletal myxoid chondrosarcoma
    Atlas Genet Cytogenet Oncol Haematol. 2018;22(7):313-316.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Couturier, J. Soft tissue tumors: Extraskeletal myxoid chondrosarcoma. Atlas Genet Cytogenet Oncol Haematol. 2000;4(3):145-146.
    Hisaoka, M ; Hashimoto, H. Soft tissue tumors: Extraskeletal myxoid chondrosarcoma. Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):334-335.

    Other genes implicated (Data extracted from papers in the Atlas) [ 7 ]

    Genes EWSR1 PLAGL1 TAF15 TCF12 NR4A3 NR4A3 TFG

    Translocations implicated (Data extracted from papers in the Atlas)

     t(3;9)(q12;q22) TFG/NR4A3
     t(9;15)(q22;q21) TCF12/NR4A3
     t(9;17)(q22;q11) TAF15/NR4A3
     t(9;22)(q22;q12) EWSR1/NR4A3
     t(9;16)(q22;p11) FUS/NR4A3
     t(9;11)(q22;q24) HSPA8/NR4A3

    External links

    Mitelman database t(3;9)(q12;q22) [CaseList]     t(3;9)(q12;q22) [Transloc - MCList]   TFG/NR4A3 Fusion - MCList]
    COSMIC[ TFG ]   [ NR4A3 ]
    Mitelman database t(9;15)(q22;q21) [CaseList]     t(9;15)(q22;q21) [Transloc - MCList]   TCF12/NR4A3 Fusion - MCList]
    COSMIC[ TCF12 ]   [ NR4A3 ]
    Mitelman database t(9;17)(q22;q11) [CaseList]     t(9;17)(q22;q11) [Transloc - MCList]   TAF15/NR4A3 Fusion - MCList]
    COSMIC[ TAF15 ]   [ NR4A3 ]
    Mitelman database t(9;22)(q22;q12) [CaseList]     t(9;22)(q22;q12) [Transloc - MCList]   EWSR1/NR4A3 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ NR4A3 ]
    Mitelman database t(9;16)(q22;p11) [CaseList]     t(9;16)(q22;p11) [Transloc - MCList]   FUS/NR4A3 Fusion - MCList]
    COSMIC[ FUS ]   [ NR4A3 ]
    Mitelman database t(9;11)(q22;q24) [CaseList]     t(9;11)(q22;q24) [Transloc - MCList]   HSPA8/NR4A3 Fusion - MCList]
    COSMIC[ HSPA8 ]   [ NR4A3 ]
    arrayMap Topo ( C47,C49) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
    Mitelman databaseEWSR1/NR4A3[MCList]    EWSR1 (22q12.2) NR4A3 (9q22.33)   t(9;22)(q31;q12)
    TICdbEWSR1/NR4A3    EWSR1 (22q12.2) NR4A3 (9q22.33)
    COSMIC_fusionTAF15 (17q12) NR4A3 (9q22.33)    [fusion589] [fusion657] [fusion658] [fusion957] [fusion958] [fusion959]
    TICdbTAF15/NR4A3    TAF15 (17q12) NR4A3 (9q22.33)
    COSMIC_fusionTCF12 (15q21.3) NR4A3 (9q22.33)    [fusion754] [fusion755]
    Mitelman databaseTCF12/NR4A3[MCList]    TCF12 (15q21.3) NR4A3 (9q22.33)   t(9;15)(q31;q21)
    COSMIC_fusionTFG (3q12.2) NR4A3 (9q22.33)    [fusion1187] [fusion610]
    Mitelman databaseTFG/NR4A3[MCList]    TFG (3q12.2) NR4A3 (9q22.33)   t(3;9)(q12;q31)
    TICdbTFG/NR4A3    TFG (3q12.2) NR4A3 (9q22.33)
    Disease databaseSoft Tissues: Extraskeletal myxoid chondrosarcoma
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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