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Pathology of Ewing’s sarcoma/PNET: Current opinion and emerging concepts

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Abstract

Ewing’s sarcoma/PNET are small round cell tumors showing a varying degree of neuroectodermal differentiation. They are one of the commonest tumors of childhood and occur in bone and within soft tissues. Traditionally, light microscopy with the aid of immunohistochemical stains was suitable fordiagnosis. But now translocation analyses are being used not only for the diagnosis and classification of small round cell tumors, but to ascertain their prognostic significance, detect micrometastasis, and monitor minimal residual disease, with potential for targeted therapy. This article analyzes the pathology, biology, and molecular aspects of Ewing’s sarcoma/PNET and discusses their clinical and therapeutic implications.

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References

  1. Stout AP. A tumor of the ulnar nerve. Proc NY Pathol Soc 1918;12:2–12.

    Google Scholar 

  2. Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc 1921;21:17–24.

    Google Scholar 

  3. Angervall L, Enzinger FM. Extraskeletal neoplasm resembling Ewing’s sarcoma. Cancer 1975;36:240–51.

    Article  CAS  PubMed  Google Scholar 

  4. Jaffe R, Santamaria M, Yunis EJ, Tannery NH, Agostini RM Jr, Medina J, et al. The neuroectodermal tumor of bone. Am J Surg Pathol 1984;8:885–98.

    Article  CAS  PubMed  Google Scholar 

  5. Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. In: Ries LA, et al, editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, MD: National Cancer Institute. SEER Program. NIH Pub. No. 99-4649; 1999. p. 99–110.

    Google Scholar 

  6. Fletcher CDM, Unni KK, Mertens F. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon: IARC Press; 2002.

    Google Scholar 

  7. Zamora P, García de Paredes ML, Gonzalez Baron M, Diaz MA, Escobar Y, Ordóñez A, et al. Ewing’s tumor in brothers. An unusual observation. Am J Clin Oncol 1986;9:358–60.

    Article  CAS  PubMed  Google Scholar 

  8. Nascimento AG, Unii KK, Pritchard DJ, Cooper KL, Dahlin DC. A clinicopathologic study of 20 cases of large-cell (atypical) Ewing’s sarcoma of bone. Am J Surg Pathol 1980;4:29–36.

    Article  CAS  PubMed  Google Scholar 

  9. Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol 2005;12:212–20.

    Article  PubMed  Google Scholar 

  10. Nilsson G, Wang M, Wejde J, Kreicbergs A, Larsson O. Detection of EWS/FLI-1 by immunostaining. An adjunctive tool in diagnosis of Ewing’s sarcoma and primitive neuroectodermal tumour on cytological samples and paraffin-embedded archival material. Sarcoma 1999;3:25–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Folpe AL, Hill CE, Parham DM, O’Shea PA, Weiss SW. Immunohistochemical detection of FLI-1 protein expression: A study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing’s sarcoma. Primitive Neuroectodermal Tumor 2000;24:1657–62.

    CAS  Google Scholar 

  12. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 1992;359:162–5.

    Article  CAS  PubMed  Google Scholar 

  13. Sorensen PH, Triche TJ. Gene fusions encoding chimaeric transcription factors in solid tumours. Semin Cancer Biol 1996;7:3–14.

    Article  CAS  PubMed  Google Scholar 

  14. Urano F, Umezawa A, Hong W, Kikuchi H, Hata J. Anovel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing’s sarcoma. Biochem Biophys Res Commun 1996;219:608–12.

    Article  CAS  PubMed  Google Scholar 

  15. Peter M, Couturier J, Pacquement H, Michon J, Thomas G, Magdelenat H, et al. A new member of the ETS family fused to EWS in Ewing tumors. Oncogene 1997;14:1159–64.

    Article  CAS  PubMed  Google Scholar 

  16. Ohno T, Ouchida M, Lee L, Gatalica Z, Rao VN, Reddy ES. The EWS gene, involved in Ewing family of tumours, malignant melanoma of soft parts and desmoplastic small round cell tumours, codes for an RNA binding protein with novel regulatory domains. Oncolgne 1994;9:3087–97.

    CAS  Google Scholar 

  17. Yang L, Chansky HA, Hickstein DD. EWS-FLI1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine-arginine protein-mediated RNA splicing. J Biol Chem 2000;275:37612–8.

    Article  CAS  PubMed  Google Scholar 

  18. Ben-David Y, Giddens EB, Letwin K, Bernstein A. Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, FLI-1, closely linked to c-ets-1. Genes Dev 1991;5:908–18.

    Article  CAS  PubMed  Google Scholar 

  19. Mélet F, Motro B, Rossi DJ, Zhang L, Bernstein A. Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia. Mol Cell Biol 1996;16:2708–18.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Pereira R, Quang CT, Lesault I, Dolznig H, Beug H, Ghysdael J. FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts. Oncogene 1999;18:1597–608.

    Article  CAS  PubMed  Google Scholar 

  21. Tamir A, Howard J, Higgins RR, Li YJ, Berger L, Zacksenhaus E, et al. Fli-1, an Ets-related transcription factor, regulates erythropoietin-induced erythroid proliferation and differentiation: evidence for direct transcriptional repression of the Rb gene during differentiation. Mol Cell Biol 1999; 19:4452–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thompson AD, Teitell MA, Arvand A, Denny CT. Divergent Ewing’s sarcoma EWS/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells. Oncogene 1999;18:5506–13.

    Article  CAS  PubMed  Google Scholar 

  23. Eliazer S, Spencer J, Ye D, Olson E, Ilaria RL Jr. Alteration of mesodermal cell differentiation by EWS/FLI-1, the oncogene implicated in Ewing’s sarcoma. Mol Cell Biol 2003;23:482–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rorie CJ, Thomas VD, Chen P, Pierce HH, O’Bryan JP, Weissman BE. The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors. Cancer Res 2004; 64:1266–77.

    Article  CAS  PubMed  Google Scholar 

  25. Kovar H, Aryee DN, Jug G, Henöckl C, Schemper M, Delattre O, et al. EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. Cell Growth Differ 1996;7:429–37.

    CAS  PubMed  Google Scholar 

  26. Tanaka K, Iwakuma T, Harimaya K, Sato H, Iwamoto Y. EWS-Flil antisense oligodeoxynucleotide inhibits proliferation of human Ewing’s sarcoma and primitive neuroectodermal tumor cells. J Clin Invest 1997;99:239–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zwerner JP, May WA. PDGF-C is an EWS-FLI induced transforming growth factor in Ewing family tumors. Oncogene 2001;20:626–33.

    Article  CAS  PubMed  Google Scholar 

  28. Toretsky JA, Steinberg SM, Thakar M, Counts D, Pironis B, Parente C, et al. Insulin-like growth factor type 1 (IGF-1) and IGF binding protein-3 in patients with Ewing sarcoma family of tumors. Cancer 2001;92:2941–7.

    Article  CAS  PubMed  Google Scholar 

  29. Bailly RA, Bosselut R, Zucman J, Cormier F, Delattre O, Roussel M, etal. DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t (11;22) translocation in Ewing sarcoma. Mol Cell Biol 1994;14:3230–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wai DH, Schaefer KL, Schramm A, Korsching E, Van Valen F, Ozaki T, et al. Expression analysis of pediatric solid tumor cell lines using oligonucleotide microarrays. Int J Oncol 2002;20:441–51.

    CAS  PubMed  Google Scholar 

  31. Smith R, Owen LA, Trem DJ, Wong JS, Whangbo JS, Golub TR, et al. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell 2006;9:405–16.

    Article  CAS  PubMed  Google Scholar 

  32. Nakatani F, Tanaka K, Sakimura R, Matsumoto Y, Matsunobu T, Li X, et al. Identification of p21WAFl/CIPl as a direct target of EWS-Flil oncogenic fusion protein. J Biol Chem 2003;278:15105–15.

    Article  CAS  PubMed  Google Scholar 

  33. Dauphinot L, De Oliveira C, Melot T, Sevenet N, Thomas V, Weissman BE, et al. Analysis of the expression of cell cycle regulators in Ewingcell lines: EWS-FLI-1 modulates p57KIP2and c-Myc expression. Oncogene 2001;20:3258–65.

    Article  CAS  PubMed  Google Scholar 

  34. Hahm KB. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. Nat Genet 1999;23:481.

    Article  PubMed  CAS  Google Scholar 

  35. Prieur A, Tirode F, Cohen P, Delattre O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol 2004;24:7275–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lessnick SL, Dacwag CS, Golub TR. The Ewing’s sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts. Cancer Cell 2002;1:393–401.

    Article  CAS  PubMed  Google Scholar 

  37. Riggi N, Cironi L, Provero P, Suva ML, Kaloulis K, Garcia-Echeverria C, et al. Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res 2005;65:11459–68.

    Article  CAS  PubMed  Google Scholar 

  38. Yee D, Favoni RE, Lebovic GS, Lombana F, Powell DR, Reynolds CP, et al. Insulin-like growth factor I expression by tumors of neuroectodermal origin with the t(11;22) chromosomal translocation. A potential autocrine growth factor. J Clin Invest 1990;86:1806–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Qian X, Jin L, Shearer BM, Ketterling RP, Jalal SM, Lloyd RV. Molecular diagnosis of Ewing’s sarcoma/primitive neuroectodermal tumor in formalin-fixed paraffin-embedded tissues by RT-PCR and fluorescence in situ hybridization. Diagn Mol Pathol 2005;14:23–11.

    Article  CAS  PubMed  Google Scholar 

  40. Lin PP, Jaffe N, Herzog CE, Costelloe CM, Deavers MT, Kelly JS, et al. Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma. Cancer 2007;109:603–11.

    Article  PubMed  Google Scholar 

  41. Ferrari S, Bertoni F, Palmerini E, Errani C, Bacchini P, Pignotti E, et al. Predictive Factors of Histologic Response to Primary Chemotherapy in Patients With Ewing Sarcoma. J Pediatr Hematol Oncol 2007;29:364–8.

    Article  CAS  PubMed  Google Scholar 

  42. Wunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH. The Histological Response to Chemotherapy as a Predictor of the Oncological Outcome of Operative Treatment of Ewing Sarcoma. J Bone Joint Surg Am 1998;80:1020–33.

    Article  CAS  PubMed  Google Scholar 

  43. Cotterill SJ, Ahrens S, Paulussen M, Jurgens HF, Voute PA, Gadner H, 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 Clin Oncol 2000;18:3108–14.

    Article  CAS  PubMed  Google Scholar 

  44. Rodríguez-Galindo C, Liu T, Krasin MJ, Wu J, Billups CA, Daw NC, et al. Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children’s Research Hospital studies. Cancer 2007;110:375–84.

    Article  PubMed  Google Scholar 

  45. Paulino AC, Nguyen TX, Mai WY. An analysis of primary site control and late effects according to local control modality in non-metastatic Ewing sarcoma. Peditr Blood Cancer 2007;48:423–9.

    Article  Google Scholar 

  46. Avigad S, Cohen IJ, Zilberstein J, Liberzon E, Goshen Y, Ash S, et al. The predictive potential of molecular detection in the nonmetastatic Ewing family of tumors. Cancer 2004; 100:1053–8.

    Article  PubMed  Google Scholar 

  47. Schleiermacher G, Peter M, Oberlin O, Philip T, Rubie H, Mechinaud F, et al. Société Française d’Oncologie Pédiatrique. Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol 2003;21:85–91.

    Article  PubMed  Google Scholar 

  48. Zoubek A, Ladenstein R, Windhager R, Amann G, Fischmeister G, Kager L, et al. Predictive potential of testing for bone marrow involvement in Ewing tumor patients by RT-PCR: a preliminary evaluation. Int J Cancer 1998;79:6–60.

    Article  Google Scholar 

  49. de Alava E, Panizo A, Antonescu CR, Huvos AG, Pardo-Mindán FJ, Barr FG, et al. Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing’s sarcoma. Am J Pathol 2000;156:849–55.

    Article  PubMed  PubMed Central  Google Scholar 

  50. de Alava E, Antonescu CR, Panizo A, Leung D, Meyers PA, Huvos AG, et al. Prognostic impact of P53 status in Ewing sarcoma. Cancer 2000;89:783–92.

    Article  PubMed  Google Scholar 

  51. Huang HY, Illei PB, Zhao Z, Mazumdar M, Huvos AG, Healey JH, et al. Ewing Sarcomas With p53 Mutation or p16/p14ARF Homozygous Deletion: A Highly Lethal Subset Associated With Poor Chemoresponse. J Clin Oncol 2005;23:548–58.

    Article  CAS  PubMed  Google Scholar 

  52. Maitra A, Roberts H, Weinberg AG, Geradts J. Aberrant expression of tumor suppressor proteins in the Ewing family of tumors. Arch Pathol Lab Med 2001;125:1207–12.

    CAS  PubMed  Google Scholar 

  53. Wei G, Antonescu CR, de Alava E, Leung D, Huvos AG, Meyers PA, et al. Prognostic impact of INK4A deletion in Ewing sarcoma. Cancer 2000;89:793–9.

    Article  CAS  PubMed  Google Scholar 

  54. Uren A, Toretsky JA. Ewing’s sarcoma oncoprotein EWS-FLI1: the perfect target without a therapeutic agent. Future Oncol 2005;1:521–8.

    Article  CAS  PubMed  Google Scholar 

  55. Ludwig JA. Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol 2008;20:412–8.

    Article  PubMed  Google Scholar 

  56. Nozawa S, Ohno T, Banno Y, Dohjima T, Wakahara K, Fan DG, et al. Inhibition of platelet-derived growth factor-induced cell growth signaling by a short interfering RNA for EWS-Flil via down-regulation of phospholipase D2 in Ewing sarcoma cells. J Biol Chem 2005;280:27544–51.

    Article  CAS  PubMed  Google Scholar 

  57. Abaan OD, Levenson A, Khan O, Furth PA, Uren A, Toretsky JA. PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing’s Sarcoma tumorigenesis. Oncogene 2005;24:2715–22.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Nirmala A. Jambhekar.

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Desai, S.S., Jambhekar, N.A. Pathology of Ewing’s sarcoma/PNET: Current opinion and emerging concepts. IJOO 44, 363–368 (2010). https://doi.org/10.4103/0019-5413.69304

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