Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Clinical presentation, staging, and prognostic factors of the Ewing sarcoma family of tumors

Thomas F DeLaney, MD
Francis J Hornicek, MD, PhD
Henry J Mankin, MD
Section Editors
Alberto S Pappo, MD
Robert Maki, MD, PhD
Deputy Editor
Diane MF Savarese, MD


Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumor (PNET, previously called peripheral neuroepithelioma) were originally described in the early 1900s as distinct clinicopathologic entities. It became evident that these entities are actually part of a spectrum of neoplastic diseases known as the ES family of tumors (EFT), which also includes extraosseous ES (EES), PNET, malignant small-cell tumor of the thoracopulmonary region (Askin's tumor), and atypical ES. Because of their similar histologic and immunohistochemical characteristics, and shared nonrandom chromosomal translocations, these tumors are considered to be derived from a common cell of origin. Although the histogenetic origin has been debated over the years, increasing evidence from immunohistochemical, cytogenetic, and molecular genetic studies supports a mesenchymal progenitor cell origin for all EFT [1]. (See "Epidemiology, pathology, and molecular genetics of the Ewing sarcoma family of tumors" and "Diseases of the chest wall", section on 'Malignant neoplasms'.)

The EFT can develop in almost any bone or soft tissue but is most common in the pelvis, axial skeleton, and femur; patients typically present with localized pain and swelling. Although overt metastatic disease is found in fewer than 25 percent at the time of diagnosis, subclinical metastatic disease is presumed to be present in nearly all patients because of the 80 to 90 percent relapse rate in patients undergoing local therapy alone. As a result, systemic chemotherapy has evolved as an important component of treatment [2].

Advances in multidisciplinary management of EFT over the past 30 years have resulted in a marked improvement in survival and a greater likelihood of limb-sparing surgery rather than amputation [3-6] (see "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management"). In data derived from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, five-year survival rates for patients with ES rose from 36 to 56 percent during the periods 1975 to 1984 and 1985 to 1994 [3]. With modern multidisciplinary treatment, long-term survival can be achieved in 70 to 80 percent of patients presenting with nonmetastatic disease [4,5,7].

Here we will discuss the clinical presentation, diagnosis, and staging of EFT. The epidemiology, pathology, molecular genetics, and treatment of these tumors, principles underlying the performance of a diagnostic bone biopsy, and central (supratentorial) PNET are discussed elsewhere. (See "Epidemiology, pathology, and molecular genetics of the Ewing sarcoma family of tumors" and "Bone tumors: Diagnosis and biopsy techniques" and "Treatment of the Ewing sarcoma family of tumors" and "Radiation therapy for Ewing sarcoma family of tumors" and "Uncommon brain tumors", section on 'Supratentorial primitive neuroectodermal tumors'.)


Primary sites — The Ewing sarcoma family of tumors (EFT) most often arise in the long bones of the extremities (predominantly the femur but also the tibia, fibula, and humerus) and the bones of the pelvis. The spine, hands, and feet are affected considerably less often [8,9]. In a compilation of data from 975 patients from the European Intergroup Cooperative Ewing Sarcoma Studies (EI-CESS) trials, the distribution of primary sites was as follows [9]:


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Oct 17, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Jedlicka P. Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions. Int J Clin Exp Pathol 2010; 3:338.
  2. Nesbit ME Jr, Gehan EA, Burgert EO Jr, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study. J Clin Oncol 1990; 8:1664.
  3. Smith MAS, Gurney JG, Ries LA. Cancer in adolescents 15 to 19 years old. In: Cancer incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, Pub #99-4649, Smith MAS, Gurney JG, Ries LA, et al (Eds), National Cancer Institute, Bethesda, MD 1999.
  4. Jürgens H, Exner U, Gadner H, et al. Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer 1988; 61:23.
  5. Grier H, Krailo M, Link M, et al. Improved outcome in non-metastatic Ewing's sarcoma (EWS) and PNET of bone with the addition of ifosfamide (I) and etoposide (E) to vincristine (V), Adriamycin (Ad), cyclophosphamide (C) and actinomycin (A): A Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) report (abstract). Proc Am Soc Clin Oncol 1994; 13:421.
  6. Gatta G, Capocaccia R, Stiller C, et al. Childhood cancer survival trends in Europe: a EUROCARE Working Group study. J Clin Oncol 2005; 23:3742.
  7. Granowetter L, Womer R, Devidas M, et al. Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 2009; 27:2536.
  8. Ginsberg JP, Woo SY, Hicks MJ, Horowitz ME. Ewing's sarcoma family of tumors: Ewing's sarcoma of bone and soft tissue and the peripheral primitive neuroectodermal tumors. In: Priniciples and Practice of Pediatric Oncology, 4th, Pizzo PA, Poplack DG (Eds), Lippincott, Williams and Wilkins, Philadelphia 2002.
  9. Cotterill SJ, 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 Clin Oncol 2000; 18:3108.
  10. Raney RB, Asmar L, Newton WA Jr, et al. Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991. J Clin Oncol 1997; 15:574.
  11. Applebaum MA, Worch J, Matthay KK, et al. Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. Cancer 2011; 117:3027.
  12. Pradhan A, Grimer RJ, Spooner D, et al. Oncological outcomes of patients with Ewing's sarcoma: is there a difference between skeletal and extra-skeletal Ewing's sarcoma? J Bone Joint Surg Br 2011; 93:531.
  13. Rud NP, Reiman HM, Pritchard DJ, et al. Extraosseous Ewing's sarcoma. A study of 42 cases. Cancer 1989; 64:1548.
  14. Parasuraman S, Langston J, Rao BN, et al. Brain metastases in pediatric Ewing sarcoma and rhabdomyosarcoma: the St. Jude Children's Research Hospital experience. J Pediatr Hematol Oncol 1999; 21:370.
  15. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am 2000; 82:667.
  16. Mendenhall CM, Marcus RB Jr, Enneking WF, et al. The prognostic significance of soft tissue extension in Ewing's sarcoma. Cancer 1983; 51:913.
  17. Mankin HJ. Ewing sarcoma. Curr Opinion Ortho 2000; 11:479.
  18. Askin FB, Rosai J, Sibley RK, et al. Malignant small cell tumor of the thoracopulmonary region in childhood: a distinctive clinicopathologic entity of uncertain histogenesis. Cancer 1979; 43:2438.
  19. Sneppen O, Hansen LM. Presenting symptoms and treatment delay in osteosarcoma and Ewing's sarcoma. Acta Radiol Oncol 1984; 23:159.
  20. Ferrari S, Bertoni F, Mercuri M, et al. Ewing's sarcoma of bone: relation between clinical characteristics and staging. Oncol Rep 2001; 8:553.
  21. Wilkins RM, Pritchard DJ, Burgert EO Jr, Unni KK. Ewing's sarcoma of bone. Experience with 140 patients. Cancer 1986; 58:2551.
  22. Miser JS, Krailo MD, Tarbell NJ, et al. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 2004; 22:2873.
  23. Cangir A, Vietti TJ, Gehan EA, et al. Ewing's sarcoma metastatic at diagnosis. Results and comparisons of two intergroup Ewing's sarcoma studies. Cancer 1990; 66:887.
  24. Panicek DM, Gatsonis C, Rosenthal DI, et al. CT and MR imaging in the local staging of primary malignant musculoskeletal neoplasms: Report of the Radiology Diagnostic Oncology Group. Radiology 1997; 202:237.
  25. Campanacci M. Bone and Soft Tissue Tumors, 2nd, Springer Verlag, New York 1999. p.653.
  26. Meyer JS, Nadel HR, Marina N, et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 2008; 51:163.
  27. Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 2006; 47:22.
  28. Protocol information available online at http://clinicaltrials.gov/ct2/show/NCT00020566?term=EURO+Ewing+99&rank=1 (Accessed on June 30, 2011).
  29. Hawkins DS, Rajendran JG, Conrad EU 3rd, et al. Evaluation of chemotherapy response in pediatric bone sarcomas by [F-18]-fluorodeoxy-D-glucose positron emission tomography. Cancer 2002; 94:3277.
  30. Franzius C, Sciuk J, Brinkschmidt C, et al. Evaluation of chemotherapy response in primary bone tumors with F-18 FDG positron emission tomography compared with histologically assessed tumor necrosis. Clin Nucl Med 2000; 25:874.
  31. McCarville MB, Christie R, Daw NC, et al. PET/CT in the evaluation of childhood sarcomas. AJR Am J Roentgenol 2005; 184:1293.
  32. Völker T, Denecke T, Steffen I, et al. Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 2007; 25:5435.
  33. Franzius C, Daldrup-Link HE, Sciuk J, et al. FDG-PET for detection of pulmonary metastases from malignant primary bone tumors: comparison with spiral CT. Ann Oncol 2001; 12:479.
  34. Györke T, Zajic T, Lange A, et al. Impact of FDG PET for staging of Ewing sarcomas and primitive neuroectodermal tumours. Nucl Med Commun 2006; 27:17.
  35. Franzius C, Sciuk J, Daldrup-Link HE, et al. FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy. Eur J Nucl Med 2000; 27:1305.
  36. Kleis M, Daldrup-Link H, Matthay K, et al. Diagnostic value of PET/CT for the staging and restaging of pediatric tumors. Eur J Nucl Med Mol Imaging 2009; 36:23.
  37. Ulaner GA, Magnan H, Healey JH, et al. Is methylene diphosphonate bone scan necessary for initial staging of Ewing sarcoma if 18F-FDG PET/CT is performed? AJR Am J Roentgenol 2014; 202:859.
  38. Hawkins DS, Schuetze SM, Butrynski JE, et al. [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol 2005; 23:8828.
  39. Koshkin VS, Bolejack V, Schwartz LH, et al. Assessment of Imaging Modalities and Response Metrics in Ewing Sarcoma: Correlation With Survival. J Clin Oncol 2016.
  40. National Comprehensive Cancer NEtwork (NCCN) guidelines available online at www.nccn.org (Accessed on June 30, 2011).
  41. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.281.
  42. Enneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res 1986; :9.
  43. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.291.
  44. Glaubiger DL, Makuch R, Schwarz J, et al. Determination of prognostic factors and their influence on therapeutic results in patients with Ewing's sarcoma. Cancer 1980; 45:2213.
  45. Bacci G, Capanna R, Orlandi M, et al. Prognostic significance of serum lactic acid dehydrogenase in Ewing's tumor of bone. Ric Clin Lab 1985; 15:89.
  46. Oberlin O, Bayle C, Hartmann O, et al. Incidence of bone marrow involvement in Ewing's sarcoma: value of extensive investigation of the bone marrow. Med Pediatr Oncol 1995; 24:343.
  47. Terrier P, Llombart-Bosch A, Contesso G. Small round blue cell tumors in bone: prognostic factors correlated to Ewing's sarcoma and neuroectodermal tumors. Semin Diagn Pathol 1996; 13:250.
  48. Rodríguez-Galindo C, Liu T, Krasin MJ, 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.
  49. Barbieri E, Emiliani E, Zini G, et al. Combined therapy of localized Ewing's sarcoma of bone: analysis of results in 100 patients. Int J Radiat Oncol Biol Phys 1990; 19:1165.
  50. Perotti D, Corletto V, Giardini R, et al. Retrospective analysis of ploidy in primary osseous and extraosseous Ewing family tumors in children. Tumori 1998; 84:493.
  51. Orr WS, Denbo JW, Billups CA, et al. Analysis of prognostic factors in extraosseous Ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital experience. Ann Surg Oncol 2012; 19:3816.
  52. Chow E, Merchant TE, Pappo A, et al. Cutaneous and subcutaneous Ewing's sarcoma: an indolent disease. Int J Radiat Oncol Biol Phys 2000; 46:433.
  53. Lee CS, Southey MC, Slater H, et al. Primary cutaneous Ewing's sarcoma/peripheral primitive neuroectodermal tumors in childhood. A molecular, cytogenetic, and immunohistochemical study. Diagn Mol Pathol 1995; 4:174.
  54. Paulussen M, Ahrens S, Dunst J, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol 2001; 19:1818.
  55. Rosito P, Mancini AF, Rondelli R, et al. Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 1999; 86:421.
  56. Wunder JS, Paulian G, Huvos AG, et al. 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.
  57. Oberlin O, Deley MC, Bui BN, et al. Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 2001; 85:1646.
  58. Albergo JI, Gaston CL, Laitinen M, et al. Ewing's sarcoma: only patients with 100% of necrosis after chemotherapy should be classified as having a good response. Bone Joint J 2016; 98-B:1138.
  59. Jürgens H, Bier V, Harms D, et al. Malignant peripheral neuroectodermal tumors. A retrospective analysis of 42 patients. Cancer 1988; 61:349.
  60. Bacci G, Ferrari S, Bertoni F, et al. Neoadjuvant chemotherapy for peripheral malignant neuroectodermal tumor of bone: recent experience at the istituto rizzoli. J Clin Oncol 2000; 18:885.
  61. Parham DM, Hijazi Y, Steinberg SM, et al. Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 1999; 30:911.
  62. Baldini EH, Demetri GD, Fletcher CD, et al. Adults with Ewing's sarcoma/primitive neuroectodermal tumor: adverse effect of older age and primary extraosseous disease on outcome. Ann Surg 1999; 230:79.
  63. Craft A, Cotterill S, Malcolm A, et al. Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol 1998; 16:3628.
  64. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003; 348:694.
  65. Bacci G, Ferrari S, Comandone A, et al. Neoadjuvant chemotherapy for Ewing's sarcoma of bone in patients older than thirty-nine years. Acta Oncol 2000; 39:111.
  66. Fizazi K, Dohollou N, Blay JY, et al. Ewing's family of tumors in adults: multivariate analysis of survival and long-term results of multimodality therapy in 182 patients. J Clin Oncol 1998; 16:3736.
  67. Marina N, Granowetter L, Grier HE, et al. Age, Tumor Characteristics, and Treatment Regimen as Event Predictors in Ewing: A Children's Oncology Group Report. Sarcoma 2015; 2015:927123.
  68. Gupta AA, Pappo A, Saunders N, et al. Clinical outcome of children and adults with localized Ewing sarcoma: impact of chemotherapy dose and timing of local therapy. Cancer 2010; 116:3189.
  69. Verrill MW, Judson IR, Wiltshaw E, et al. The use of paediatric chemotherapy protocols at full dose is both a rational and feasible treatment strategy in adults with Ewing's family tumours. Ann Oncol 1997; 8:1099.
  70. Hattinger CM, Rumpler S, Strehl S, et al. Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer 1999; 24:243.
  71. Zoubek A, Dockhorn-Dworniczak B, Delattre O, et al. Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol 1996; 14:1245.
  72. de Alava E, Kawai A, Healey JH, et al. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol 1998; 16:1248.
  73. Lin PP, Brody RI, Hamelin AC, et al. Differential transactivation by alternative EWS-FLI1 fusion proteins correlates with clinical heterogeneity in Ewing's sarcoma. Cancer Res 1999; 59:1428.
  74. van Doorninck JA, Ji L, Schaub B, et al. Current treatment protocols have eliminated the prognostic advantage of type 1 fusions in Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 2010; 28:1989.
  75. de Alava E, Antonescu CR, Panizo A, et al. Prognostic impact of P53 status in Ewing sarcoma. Cancer 2000; 89:783.
  76. Huang HY, Illei PB, Zhao Z, 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.
  77. Karski EE, McIlvaine E, Segal MR, et al. Identification of Discrete Prognostic Groups in Ewing Sarcoma. Pediatr Blood Cancer 2016; 63:47.
  78. Goldstein G, Shemesh E, Frenkel T, et al. Abnormal body mass index at diagnosis in patients with Ewing sarcoma is associated with inferior tumor necrosis. Pediatr Blood Cancer 2015; 62:1892.