Soft Tissues: Ewing's tumors/Primitive neurectodermal tumors (PNET)

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Written1998-06Jérôme Couturier
Department of Pathology, Institut Curie, Paris, France

(Note : for Links provided by Atlas : click)

1. Identity

ICD-Topo C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE
ICD-Morpho 9364/3 9260/3 Peripheral neuroectodermal tumor
Atlas_Id 5010
Phylum Soft Tissues::Ewing sarcoma / Primitive neurectodermal tumor (PNET)
WHO/OMS Classification Soft Tissues
Note Ewing tumours form a histologically heterogeneous family belonging to the group of small round-cell tumours and derived from neural crests cells.

2. Classification

    Ewing's tumors cover several distinct histological types:
  • peripheral neuroepithelioma
  • esthesioneuroblastoma
  • Askin's tumour
  • Ewing's sarcoma of bones and soft tissues
  • 3. Clinics and Pathology

    Epidemiology peripheral neuroepithelioma is a very rare tumour (1% of all sarcomas); Ewing's sarcoma represents 5 to 15% of malignant bone and soft tissue tumours; two thirds of cases of Ewing's tumours occur before age 35 years, with a median age of 20 years.
  • peripheral neuroepithelioma typically occurs in the extremities (buttock and upper thigh, shoulder and upper arm);
  • esthesioneuroblastoma probably develops from the olfactive placode, in the nasal vault
  • Ewing's sarcoma of bones affects preferentially long bones (especially the femur), the pelvis, and the ribs; extraskeletal Ewing's sarcoma occur in the paravertebral region and chest wall, often in association with vertebrae and ribs, and in lower extremities
  • Askin's tumour is a paediatric tumour affecting mostly the chest wall and ribs
    Ewing's tumor : the tumor is composed of blastematous tissue with some differentiated glomerular structures associated with mesenchymal tissue and tubules. Courtesy Pierre Bedossa.
  • peripheral neuroepithelioma show sheets or lobules of small round-cells with a scarce cytoplasm; cells are often arranged in rosettes with a neurofibrillar center (Homer-Wright rosettes)
  • esthesioneuroblastoma is histologically very similar to neuroblastoma; rosettes may be present
  • Askin's tumour seems to be more related to neuroepithelioma than to Ewing's sarcoma
  • Ewing's sarcoma forms sheets of uniform small round-cells, sometimes arranged in a lobular pattern; the cytoplasm is scanty, pale stained and often vacuolated (glycogen); Ewing's sarcoma is considered as the less differentiated form of the Ewing's tumours family
  • Treatment the treatment of Ewing's tumours is generally based on combined therapy with adjuvant chemotherapy, surgical resection and radiotherapy.
    Prognosis combined therapies have largely improved the prognosis of Ewing's tumours in the recent years; the prognosis is mainly determined by the presence of metastases at the time of diagnosis (15 to 35% of the cases); the 5-year survival rate is 10-35% in patients with mestastases, and 54-74% for patients with a localised disease at presentation.

    4. Cytogenetics

    about 90% of Ewing's tumours, whatever their type, show a t(11;22)(q24;q12); the translocation results in the fusion of the EWS gene with the transcription factor gene FLI1, leading to a hybrid transcript and an oncogenic chimeric protein; in about 5% of the cases, the EWS gene is involved in variant translocations: t(21;22)(q12;q12) and t(7;22)(p22;q12), leading to fusions EWS-ERG and EWS-ETV1, respectively.
    t(11;22)(q24;q12) in Ewing sarcoma, G- banding - top: courtesy Jean Luc Lai (with trisomy 8 on the right); - bottom: courtesy G. Reza Hafez, Eric B.Johnson, and Sara Morrison-Delap, UW Cytogenetic Services
    Cytogenetics Molecular additional anomalies in Ewing's tumours mainly consist in chromosome gains: +8 (45% of the cases) and, with a much lower frequency, trisomies 2, 5, 7, 9, 12 (between 10 and 15% of the cases); trisomy 1q, through unbalanced t(1q;16q), is observed in about 25% of the cases

    5. Genes involved and Proteins

    Gene NameEWSR1 (Ewing sarcoma breakpoint region 1)
    Location 22q12.2
    Protein RNA binding

    Gene NameFLI1 (Friend leukemia virus integration 1)
    Location 11q24.3

    Gene NameERG (v-ets erythroblastosis virus E26 oncogene like (avian))
    Location 21q22.2

    Gene NameETV1 (ets variant 1)
    Location 7p21.2

    6. Result of the chromosomal anomaly

    Hybrid Gene
    Description the 5' EWSR1 is fused to parts of either FLI1, ERG, or ETV1
    Fusion Protein
    Description N terminal domain of EWS protein with DNA binding domain of FLI1, ERG (ETS family genes)
    Oncogenesis through transcription dysregulation

    7. Bibliography

    The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts.
    Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, Ambros PF, Sheer D, Turc-Carel C, Triche TJ
    The New England journal of medicine. 1994 ; 331 (5) : 294-299.
    PMID 8022439
    Soft tissue tumors.
    Enzinger FM, Weiss SW
    Soft tissue tumors..
    Forest M, Tomeno B, Vanel D
    Orthopedic surgical pathology, pp. 1944.
    A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1.
    Jeon IS, Davis JN, Braun BS, Sublett JE, Roussel MF, Denny CT, Shapiro DN
    Oncogene. 1995 ; 10 (6) : 1229-1234.
    PMID 7700648
    Chromosomes in Ewing's sarcoma. II. Nonrandom additional changes, trisomy 8 and der(16)t(1;16).
    Mugneret F, Lizard S, Aurias A, Turc-Carel C
    Cancer genetics and cytogenetics. 1988 ; 32 (2) : 239-245.
    PMID 3163262
    Cytogenetic and pathologic aspects of Ewing's sarcoma and neuroectodermal tumors.
    Stephenson CF, Bridge JA, Sandberg AA
    Human pathology. 1992 ; 23 (11) : 1270-1277.
    PMID 1330877
    Chromosomes in Ewing's sarcoma. I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12).
    Turc-Carel C, Aurias A, Mugneret F, Lizard S, Sidaner I, Volk C, Thiery JP, Olschwang S, Philip I, Berger MP
    Cancer genetics and cytogenetics. 1988 ; 32 (2) : 229-238.
    PMID 3163261

    8. Citation

    This paper should be referenced as such :
    Couturier, J
    Soft tissue tumors: Ewing's tumors
    Atlas Genet Cytogenet Oncol Haematol. 1998;2(4):148-151.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    9. Translocations implicated (Data extracted from papers in the Atlas)

     inv(22)(q12q12) EWSR1/PATZ1
     t(11;22)(q24;q12) EWSR1/FLI1
     t(16;21)(p11;q22) FUS/ERG
     t(17;22)(q21;q12) EWSR1/ETV4
     t(2;16)(q35;p11) FUS/FEV
     t(2;22)(q36;q12) EWSR1/FEV
     t(20;22)(q13;q12) EWSR1/NFATC2
     t(21;22)(q21;q12) EWSR1/ERG
     t(7;22)(p22;q12) EWSR1/ETV1

    10. External links

    Mitelman database inv(22)(q12q12) [CaseList]     inv(22)(q12q12) [Transloc - MCList]   EWSR1/PATZ1 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ PATZ1 ]
    Mitelman database t(11;22)(q24;q12) [CaseList]     t(11;22)(q24;q12) [Transloc - MCList]   EWSR1/FLI1 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ FLI1 ]
    Mitelman database t(16;21)(p11;q22) [CaseList]     t(16;21)(p11;q22) [Transloc - MCList]   FUS/ERG Fusion - MCList]
    COSMIC[ FUS ]   [ ERG ]
    Mitelman database t(17;22)(q21;q12) [CaseList]     t(17;22)(q21;q12) [Transloc - MCList]   EWSR1/ETV4 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ ETV4 ]
    Mitelman database t(2;16)(q35;p11) [CaseList]     t(2;16)(q35;p11) [Transloc - MCList]   FUS/FEV Fusion - MCList]
    COSMIC[ FUS ]   [ FEV ]
    Mitelman database t(2;22)(q36;q12) [CaseList]     t(2;22)(q36;q12) [Transloc - MCList]   EWSR1/FEV Fusion - MCList]
    COSMIC[ EWSR1 ]   [ FEV ]
    Mitelman database t(20;22)(q13;q12) [CaseList]     t(20;22)(q13;q12) [Transloc - MCList]   EWSR1/NFATC2 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ NFATC2 ]
    Mitelman database t(21;22)(q21;q12) [CaseList]     t(21;22)(q21;q12) [Transloc - MCList]   EWSR1/ERG Fusion - MCList]
    COSMIC[ EWSR1 ]   [ ERG ]
    Mitelman database t(7;22)(p22;q12) [CaseList]     t(7;22)(p22;q12) [Transloc - MCList]   EWSR1/ETV1 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ ETV1 ]
    arrayMap Topo ( C47,C49) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
    Mitelman databaseEWSR1/ERG[MCList]    EWSR1 (22q12.2) ERG (21q22.2)   ins(21;22)(q22;q12q12)
    TICdbEWSR1/ERG    EWSR1 (22q12.2) ERG (21q22.2)
    Mitelman databaseEWSR1/ETV1[MCList]    EWSR1 (22q12.2) ETV1 (7p21.2)   t(7;22)(p21;q12)
    TICdbEWSR1/ETV1    EWSR1 (22q12.2) ETV1 (7p21.2)
    Mitelman databaseEWSR1/ETV4[MCList]    EWSR1 (22q12.2) ETV4 (17q21.31)   t(17;22)(q21;q12)
    TICdbEWSR1/ETV4    EWSR1 (22q12.2) ETV4 (17q21.31)
    Mitelman databaseEWSR1/FEV[MCList]    EWSR1 (22q12.2) FEV (2q35)   t(2;22)(q35;q12)
    TICdbEWSR1/FEV    EWSR1 (22q12.2) FEV (2q35)
    COSMIC_fusionEWSR1 (22q12.2) FLI1 (11q24.3)    [fusion1302] [fusion1303] [fusion165] [fusion166] [fusion167] [fusion168] [fusion169] [fusion170] [fusion171] [fusion172] [fusion173] [fusion174] [fusion175] [fusion176] [fusion177] [fusion178] [fusion179] [fusion180] [fusion181] [fusion182] [fusion183] [fusion184] [fusion185] [fusion204] [fusion205] [fusion227] [fusion228]
    Mitelman databaseEWSR1/FLI1[MCList]    EWSR1 (22q12.2) FLI1 (11q24.3)   ins(11;22)(q24;q12q12)
    TICdbEWSR1/FLI1    EWSR1 (22q12.2) FLI1 (11q24.3)
    Mitelman databaseEWSR1/NFATC2[MCList]    EWSR1 (22q12.2) NFATC2 (20q13.2)   t(20;22)(q13;q12)
    TICdbEWSR1/NFATC2    EWSR1 (22q12.2) NFATC2 (20q13.2)
    COSMIC_fusionEWSR1 (22q12.2) PATZ1 (22q12.2)    [fusion283] [fusion308]
    Mitelman databaseEWSR1/PATZ1[MCList]    EWSR1 (22q12.2) PATZ1 (22q12.2)   inv(22)(q12q12)
    TICdbEWSR1/PATZ1    EWSR1 (22q12.2) PATZ1 (22q12.2)
    Mitelman databaseFUS/ERG[MCList]    FUS (16p11.2) ERG (21q22.2)   t(16;21)(p11;q22)
    TICdbFUS/ERG    FUS (16p11.2) ERG (21q22.2)
    COSMIC_fusionFUS (16p11.2) FEV (2q35)    [fusion295] [fusion326]
    Mitelman databaseFUS/FEV[MCList]    FUS (16p11.2) FEV (2q35)   t(2;16)(q35;p11)
    TICdbFUS/FEV    FUS (16p11.2) FEV (2q35)
    Disease databaseSoft Tissues: Ewing's tumors/Primitive neurectodermal tumors (PNET)
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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