Soft Tissues: Extraskeletal myxoid chondrosarcoma

2017-03-01   Fei Dong , Vickie Jo 

1.Department of Pathology, Brigham and Womens Hospital, Boston, MA
2.Department of Pathology & Oncology, School of Medicine, University of Occupational & Environmental Health, Japan; vjo@partners.org
3.Department of Pathology, Brigham and Womens Hospital, Boston, MA

Abstract

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

Classification

Atlas Image
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

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.

Pathology

  • 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.

    Cytogenetics

    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
    Atlas Image
    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.

    Cytogenetics morphological

  • 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.

    • Genes Involved and Proteins

    Gene name

    TFG (TRK-fused gene)

    Location

    3q12.2

    Dna rna description

    39.51 kb; 8 exons; 1.9 kb mRNA.

    Protein description

    Putative signal transducer; positive regulator of I-kappaB kinase/NF-kappaB cascade.

    Gene name

    NR4A3 (nuclear receptor subfamily 4, group A, member 3)

    Location

    9q22.33

    Dna rna description

    Transcripts: 2.6 kb and 3.7 kb.

    Protein description

    Steroid-thyroid hormone-retinoid receptor; transcriptional activator.

    Gene name

    TCF12 (transcription factor 12)

    Location

    15q21.3

    Dna rna description

    370 kb; 21 exons; 4 kb mRNA.

    Protein description

    Transcription factor; a basic helix-loop-helix protein.

    Gene name

    TAF15 (TAF15 TAF15 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 68kDa)

    Location

    17q12

    Dna rna description

    16 exons; alternative splicing; 2.2 kb bp mRNA.

    Protein description

    RNA-binding protein; part of theTFIID and RNA polymerase II complex.

    Gene name

    EWSR1 (Ewing sarcoma breakpoint region 1)

    Location

    22q12.2

    Dna rna description

    17 exons; 2.4 kb mRNA.

    Protein description

    RNA-binding protein; transcription repressor.

    Gene name

    FUS (fusion involved in t (12;16) in malignant liposarcoma)

    Location

    16p11.2

    Dna rna description

    15 exons; 1.6 kb mRNA.

    Protein description

    RNA-binding protein.

    Gene name

    >CC: TXT: HSPA8 ID: 40878>

    Location

    11q24.1

    Dna rna description

    9 exons; 1.9 kb mRNA.

    Protein description

    Heat shock protein.

    Gene name

    SMARCB1 (SW1/SNF related, matrix associated, actin dependent regulator of chromatin B1)

    Location

    22q11.23

    Dna rna description

    9 exons; 1.2 kb mRNA.

    Protein description

    Core component of BAF complex.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    247462152014Extraskeletal myxoid chondrosarcoma with non-EWSR1-NR4A3 variant fusions correlate with rhabdoid phenotype and high-grade morphology.Agaram NP et al
    106025201999Identification 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 et al
    245083822014Diagnostic utility of molecular investigation in extraskeletal myxoid chondrosarcoma.Benini S et al
    251309552014Extraskeletal myxoid chondrosarcoma with a t(9;16)(q22;p11.2) resulting in a NR4A3-FUS fusion.Broehm CJ et al
    85702001996Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma.Clark J et al
    39672071985Myxoid chondrosarcoma with a translocation involving chromosomes 9 and 22.Hinrichs SH et al
    151884552004TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma.Hisaoka M et al
    185806822008SMARCB1/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 et al
    86346901995Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation.Labelle Y et al
    111563742000Fusion 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 et al
    283831672017HSPA8 as a novel fusion partner of NR4A3 in extraskeletal myxoid chondrosarcoma.Urbini M et al

    Citation

    Fei Dong ; Vickie Jo

    Soft Tissues: Extraskeletal myxoid chondrosarcoma

    Atlas Genet Cytogenet Oncol Haematol. 2017-03-01

    Online version: http://atlasgeneticsoncology.org/solid-tumor/5025/soft-tissues-extraskeletal-myxoid-chondrosarcoma

    Historical Card

    2004-09-01 Soft Tissues: Extraskeletal myxoid chondrosarcoma by  Masanori Hisaoka,Hiroshi Hashimoto 

    Department of Pathology & Oncology, School of Medicine, University of Occupational & Environmental Health, Japan; vjo@partners.org

    2000-07-01 Soft Tissues: Extraskeletal myxoid chondrosarcoma by  Jérôme Couturier