Review articles

Advances in molecular pathology of Ewing sarcoma

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  • Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Received date: 2023-05-20

  Online published: 2024-03-18

Abstract

Ewing sarcoma is a rare malignant small round cell mesenchymal neoplasm with a characteristic FET family-ETS family fusion gene, and is classified as undifferentiated small round cell sarcoma in the fifth revision of the WHO Classification of Tumors of Soft Tissue and Bone (2020). Microscopically, Ewing sarcoma is composed of a monomorphic round cell population, accompanied by different degrees of neuroectodermal differentiation. Although surgery combined with chemotherapy has increased the 5-year survival rate of Ewing sarcoma to about 70%, the 5-year survival rate of patients with metastases at diagnosis is still less than 30%. With the rapid development of molecular pathology, the molecular mechanism of Ewing sarcoma has also become a focus of research. This article reviews the latest research progress on the unique pathological features, molecular mechanisms and genetic diagnostic criteria of Ewing sarcoma, in order to provide a new direction for the clinical diagnosis, treatment and prognosis of Ewing sarcoma.

Cite this article

LIU Hengan, WANG Chaofu . Advances in molecular pathology of Ewing sarcoma[J]. Journal of Diagnostics Concepts & Practice, 2023 , 22(06) : 587 -592 . DOI: 10.16150/j.1671-2870.2023.06.012

References

[1] GEREIGE R, KUMAR M. Bone lesions: benign and malignant[J]. Pediatr Rev, 2010, 31(9):355-362.
[2] RIGGI N, SUVà M L, STAMENKOVIC I. Ewing's Sarcoma[J]. N Engl J Med, 2021, 384(2):154-164.
[3] BOARD W C O T E. World Health Organization classification of soft tissue and bone tumours, 5th ed[M]. Lyon (France):International Agency for Research on Cancer. Lyon (France): International Agency for Research on Cancer, 2020.
[4] 魏雪静, 程鸣. 尤文肉瘤及尤文样肉瘤临床病理学研究进展[J]. 中国肿瘤临床, 2020, 47(15):803-808.
  WEI X J, CHENG M. Progress in clinicopathological features of Ewing's sarcoma and Ewing-like sarcoma[J]. Chin J Clin Oncol, 2020, 47(15):803-808.
[5] EWING J. Classics in oncology. Diffuse endothelioma of bone. James Ewing. Proceedings of the New York Pathological Society, 1921[J]. CA Cancer J Clin, 1972, 22(2):95-98.
[6] AURIAS A, RIMBAUT C, BUFFE D, et al. Translocation involving chromosome 22 in Ewing's sarcoma. A cytogenetic study of four fresh tumors[J]. Cancer Genet Cytogenet, 1984, 12(1):21-25.
[7] TURC-CAREL C, PHILIP I, BERGER M P, et al. Chromosome study of Ewing's sarcoma (ES) cell lines. Consistency of a reciprocal translocation t(11;22)(q24;q12)[J]. Cancer Genet Cytogenet, 1984, 12(1):1-19.
[8] COTTERILL S J, AHRENS S, PAULUSSEN M, et al. Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group[J]. J Clin Oncol, 2000, 18(17):3108-3114.
[9] CARUSO J, SHULMAN D S, DUBOIS S G. Second malignancies in patients treated for Ewing sarcoma: A systematic review[J]. Pediatr Blood Cancer, 2019, 66(11):e27938.
[10] MARINA N M, LIU Q, DONALDSON S S, et al. Longitudinal follow-up of adult survivors of Ewing sarcoma: A report from the Childhood Cancer Survivor Study[J]. Cancer, 2017, 123(13):2551-2560.
[11] SHULMAN D S, WHITTLE S B, SURDEZ D, et al. An international working group consensus report for the prio-ritization of molecular biomarkers for Ewing sarcoma[J]. NPJ Precis Oncol, 2022, 6(1):65.
[12] OGURA K, ELKRIEF A, BOWMAN A S, et al. Prospective Clinical Genomic Profiling of Ewing Sarcoma: ERF and FGFR1 Mutations as Recurrent Secondary Alterations of Potential Biologic and Therapeutic Relevance[J]. JCO Precis Oncol, 2022, 6:e2200048.
[13] LLOMBART-BOSCH A, MACHADO I, NAVARRO S, et al. Histological heterogeneity of Ewing's sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support[J]. Virchows Arch, 2009, 455(5):397-411.
[14] SBARAGLIA M, RIGHI A, GAMBAROTTI M, et al. Ewi-ng sarcoma and Ewing-like tumors[J]. Virchows Arch, 2020, 476(1):109-119.
[15] LUM C A, MOTAMED N A, HWANG C D, et al. Pleomorphic atypical extraosseous ewing sarcoma in a 25-year-old woman: a cytogenetic diagnosis[J]. Appl Immunohistochem Mol Morphol, 2005, 13(2):201-204.
[16] YOSHIDA A, SEKINE S, TSUTA K, et al. NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma[J]. Am J Surg Pathol, 2012, 36(7):993-999.
[17] SHIBUYA R, MATSUYAMA A, NAKAMOTO M, et al. The combination of CD99 and NKX2.2, a transcriptional target of EWSR1-FLI1, is highly specific for the diagnosis of Ewing sarcoma[J]. Virchows Arch, 2014, 465(5):599-605.
[18] WANG W L, PATEL N R, CARAGEA M, et al. Expression of ERG, an Ets family transcription factor, identifies ERG-rearranged Ewing sarcoma[J]. Mod Pathol, 2012, 25(10):1378-1383.
[19] SANNINO G, MARCHETTO A, RANFT A, et al. Gene expression and immunohistochemical analyses identify SOX2 as major risk factor for overall survival and relapse in Ewing sarcoma patients[J]. EBioMedicine, 2019,47:156-162.
[20] MACHADO I, LóPEZ-GUERRERO J A, SCOTLANDI K, et al. Immunohistochemical analysis and prognostic significance of PD-L1, PD-1, and CD8+ tumor-infiltrating lymphocytes in Ewing's sarcoma family of tumors (ESFT)[J]. Virchows Arch, 2018, 472(5):815-824.
[21] TIRODE F, SURDEZ D, MA X, et al. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations[J]. Cancer Discov, 2014, 4(11):1342-1353.
[22] SORENSEN P H, LESSNICK S L, LOPEZ-TERRADA D, et al. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG[J]. Nat Genet, 1994, 6(2):146-151.
[23] SHING D C, MCMULLAN D J, ROBERTS P, et al. FUS/ERG gene fusions in Ewing's tumors[J]. Cancer Res, 2003, 63(15):4568-4576.
[24] LE DELEY M C, DELATTRE O, SCHAEFER K L, et al. Impact of EWS-ETS fusion type on disease progression in Ewing's sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial[J]. J Clin Oncol, 2010, 28(12):1982-1988.
[25] HARRISON A F, SHORTER J. RNA-binding proteins with prion-like domains in health and disease[J]. Biochem J, 2017, 474(8):1417-1438.
[26] LI K K, LEE K A. Transcriptional activation by the Ewi-ng's sarcoma (EWS) oncogene can be cis-repressed by the EWS RNA-binding domain[J]. J Biol Chem, 2000, 275(30):23053-23058.
[27] TOMLINS S A, RHODES D R, PERNER S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer[J]. Science, 2005, 310(5748):644-648.
[28] FINDLAY V J, LARUE A C, TURNER D P, et al. Understanding the role of ETS-mediated gene regulation in complex biological processes[J]. Adv Cancer Res, 2013,119:1-61.
[29] PICARD C, MACAGNO N, CORRADINI N, et al. Identification of a novel translocation producing an in-frame fusion of TAF15 and ETV4 in a case of extraosseous Ewing sarcoma revealed in the prenatal period[J]. Virchows Arch, 2022, 481(4):665-669.
[30] GUILLON N, TIRODE F, BOEVA V, et al. The oncogenic EWS-FLI1 protein binds in vivo GGAA microsatellite sequences with potential transcriptional activation function[J]. PLoS One, 2009, 4(3):e4932.
[31] RIGGI N, KNOECHEL B, GILLESPIE S M, et al. EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma[J]. Cancer Cell, 2014, 26(5):668-681.
[32] GORTHI A, ROMERO J C, LORANC E, et al. EWS-FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma[J]. Nature, 2018, 555(7696):387-391.
[33] ABBOTT D, O'BRIEN S, FARNHAM J M, et al. Increased risk for other cancers in individuals with Ewing sarcoma and their relatives[J]. Cancer Med, 2019, 8(18):7924-7930.
[34] CROMPTON B D, STEWART C, TAYLOR-WEINER A, et al. The genomic landscape of pediatric Ewing sarcoma[J]. Cancer Discov, 2014, 4(11):1326-1341.
[35] SOLOMON D A, KIM T, DIAZ-MARTINEZ L A, et al. Mutational inactivation of STAG2 causes aneuploidy in human cancer[J]. Science, 2011, 333(6045):1039-1043.
[36] PATEL M, GOMEZ N C, MCFADDEN A W, et al. PTEN deficiency mediates a reciprocal response to IGFI and mTOR inhibition[J]. Mol Cancer Res, 2014, 12(11):1610-1620.
[37] NIEMEYER B F, PARRISH J K, SPOELSTRA N S, et al. Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes[J]. PLoS One, 2015, 10(1):e0116895.
[38] DE VITO C, RIGGI N, CORNAZ S, et al. A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic rea-gents in Ewing sarcoma[J]. Cancer Cell, 2012, 21(6):807-821.
[39] 中国抗癌协会肉瘤专业委员会. 骨与软组织肿瘤二代测序中国专家共识(2021年版)[J]. 中国肿瘤临床, 2021, 48(20):1027-1035.
  China Anti-Cancer Association Committee of Sarcoma. Chinese expert consensus on the application of next-gene-ration sequencing for bone and soft tissue tumors (2021 version)[J]. Chin J Clin Oncol, 2021, 48(20):1027-1035.
[40] GUSHO C A, WEISS M C, LEE L, et al. The clinical uti-lity of next-generation sequencing for bone and soft tissue sarcoma[J]. Acta Oncol, 2022, 61(1):38-44.
[41] 唐天喜, 杨溯, 韩鹏飞, 等. 尤文肉瘤分子病理学诊断与治疗的研究新进展[J]. 基层医学论坛, 2022, 26(7):124-126.
  TANG T X, YANG S, HAN P F, et al. New progress in molecular pathology diagnosis and treatment of Ewing's sarcoma[J]. Med Forum, 2022, 26(7):124-126.
[42] ERKIZAN H V, KONG Y, MERCHANT M, et al. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma[J]. Nat Med, 2009, 15(7):750-756.
[43] BRENNER J C, FENG F Y, HAN S, et al. PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma[J]. Cancer Res, 2012, 72(7):1608-1613.
[44] CORNAZ-BUROS S, RIGGI N, DEVITO C, et al. Targe-ting cancer stem-like cells as an approach to defeating cellular heterogeneity in Ewing sarcoma[J]. Cancer Res, 2014, 74(22):6610-6622.
[45] LAMHAMEDI-CHERRADI S E, MENEGAZ B A, RAMAMOORTHY V, et al. An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma[J]. Mol Cancer Ther, 2015, 14(7):1591-1604.
[46] LUDWIG J A, FEDERMAN N C, ANDERSON P M, et al. TK 216 for relapsed/refractory Ewing sarcoma: Interim phase 1/2 results[J]. Journal of Clinical Oncology, 2021, 39(15_suppl):11500.
[47] BENNANI-BAITI I M, MACHADO I, LLOMBART-BOSCH A, et al. Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma[J]. Hum Pathol, 2012, 43(8):1300-1307.
[48] PISHAS K I, DRENBERG C D, TASLIM C, et al. Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response[J]. Mol Cancer Ther, 2018, 17(9):1902-1916.
[49] GAO Y, HE X Y, WU X S, et al. ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation[J]. Nat Cell Biol, 2023, 25(2):298-308.
[50] THOMSON D W, DINGER M E. Endogenous microRNA sponges: evidence and controversy[J]. Nat Rev Genet, 2016, 17(5):272-283.
[51] ROBERTO G M, VIEIRA G M, DELSIN L E A, et al. MiR-708-5p is inversely associated with EWS/FLI1 Ewi-ng sarcoma but does not represent a prognostic predictor[J]. Cancer Genet, 2019,230:21-27.
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