This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, staging, and treatment of the Ewing’s family of tumors (EFTs). EFTs include Ewing’s tumor of bone (ETB or Ewing’s sarcoma of bone), extraosseus Ewing’s (EOE), primitive neuroectodermal tumors (PNET or peripheral primitive neuroepithelioma), and Askin’s tumor (PNET of the chest wall). Studies using immunohistochemical markers,[1] cytogenetics,[2,3] molecular genetics, and tissue culture [4] indicate that these tumors are all derived from the same primordial stem cell.[3]

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[5] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ Late Effects of Childhood Cancer Therapies for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

EFTs occur most frequently in the second decade of life and account for 4% of childhood and adolescent malignancies. The incidence in boys is slightly higher than in girls (ratio of 1.1:1). ETB is estimated to be 60% of the EFTs. The sites of origin for ETB are: distal (27%) and proximal extremities (25%), pelvis (20%), chest (20%), and spine and skull (9%).[6,7] For the EOE, the most common sites are: trunk (32%), extremity (26%), head and neck (18%), retroperitoneum (16%), and all other sites (8%).[8] Common sites for PNET are the chest (44%), abdomen/pelvis (26%), extremities (20%), head and neck (6%), and all other sites (4%).[8] Except for the head and neck, the sites of origin of EOE and PNET are similar.

Major prognostic factors include site, tumor volume, and the presence of metastases. Clinical and biological factors for ETB and, to some extent EOE, are discussed below.

• Site, size, age, and sex: In ETB the most favorable sites are distal extremities. Central location (e.g., skull, clavicle, vertebrae, and ribs), proximal extremities and the pelvis are associated with a much less favorable prognosis.[7,9] Size is also significant,[10,11] but larger lesions tend to occur in the more unfavorable sites.[7] Younger children have better event-free survival than older adolescents and young adults.[9,12-14] Girls with ETB have a better prognosis than boys.[13]



• Clinical findings: The presence of fever, anemia, or an elevated lactic dehydrogenase (LDH) are poor prognostic signs for patients with ETB.[9,15] Increased serum LDH levels prior to treatment correlate with metastatic disease and shorter disease-free survival.[15]



• Surgical resectability: Surgical resection for ETB, EOE, and for PNET is an important variable. This applies to both complete resection or incomplete resection with only microscopic residual disease.[7,16,17]



• Chemotherapy: Approximately 20% to 30% of the patients with ETB have overt metastases at the time of diagnosis. For EOE, 13% have overt metastases at diagnosis.[16] Less than 20% of children with localized ETB survive their disease with only local therapy, i.e., a complete surgical excision and/or intensive radiation therapy. The overall survival markedly improved when multiagent intensive chemotherapy was added to radiation therapy,[18] and the 5-year survival is up to 70% in many large studies, and 10-year event-free survival is approximately 50%.[9,10,13,14,19]



• Metastases: Although the prognosis is thought to be poor, it has been observed that with intensive therapy, survival in patients with ETB who have only pulmonary metastases is slightly higher than for patients with bone or bone marrow metastases.[9]



• Routine histopathology: Traditionally, a major distinction has been made between classical Ewing’s sarcoma (which shows minimal evidence of differentiation) and PNET (which shows evidence of neural differentiation), however, the degree of neural differentiation does not influence outcome.[20,21]



• Biological features: Reverse transcription polymerase chain reaction (RT-PCR) of the fusion transcripts from 112 patients with ETB and EOE revealed that the type I EWS-FL1 transcript was an important favorable prognostic feature in patients with localized primary tumors.[22] In a study of a relatively small number of patients, overexpression of the p53 protein was a highly unfavorable prognostic feature.[23] The presence of additional cytogenetic abnormalities, in particular loss of 16q, may be unfavorable.[24] RT-PCR can be used to examine bone marrow for the presence of detectable translocation transcripts. In a single retrospective study among patients who did not have clinically detectable metastatic disease, positive RT-PCR for fusion transcripts was associated with a greater risk of recurrence after treatment.[25] Telomerase activity (TA) as determined by RT-PCR in peripheral blood during therapy and follow-up was found to correlate significantly with prognosis; high TA with poor prognosis, low TA with good prognosis.[26]



• Response to preoperative therapy: Multiple studies have shown that patients with minimal or no residual tumor after presurgical chemotherapy have a significantly better event-free survival compared to patients with larger amounts of viable tumor.[9,10,12,27,28] Massive tumor necrosis after induction chemotherapy is a very favorable sign.[9,27,29]

References

1. Ambros IM, Ambros PF, Strehl S, et al.: MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing's sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 67 (7): 1886-93, 1991.  [PUBMED Abstract]
   
   
2. Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994.  [PUBMED Abstract]
   
   
3. Denny CT: Gene rearrangements in Ewing's sarcoma. Cancer Invest 14 (1): 83-8, 1996.  [PUBMED Abstract]
   
   
4. Llombart-Bosch A, Carda C, Peydro-Olaya A, et al.: Soft tissue Ewing's sarcoma. Characterization in established cultures and xenografts with evidence of a neuroectodermic phenotype. Cancer 66 (12): 2589-601, 1990.  [PUBMED Abstract]
   
   
5. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  [PUBMED Abstract]
   
   
6. 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 16 (11): 3628-33, 1998.  [PUBMED Abstract]
   
   
7. Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998.  [PUBMED Abstract]
   
   
8. Coffin CM, Dehner LP: Neurogenic tumors of soft tissue. In: Coffin CM, Dehner LP, O'Shea PA: Pediatric Soft Tissue Tumors: A Clinical, Pathological, and Therapeutic Approach. Baltimore, Md: Williams and Wilkins, 1997, pp 80-132. 
   
   
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 18 (17): 3108-14, 2000.  [PUBMED Abstract]
   
   
10. 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 19 (6): 1818-29, 2001.  [PUBMED Abstract]
    
    
11. Bacci G, Picci P, Mercuri M, et al.: Predictive factors of histological response to primary chemotherapy in Ewing's sarcoma. Acta Oncol 37 (7-8): 671-6, 1998.  [PUBMED Abstract]
    
    
12. 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 86 (3): 421-8, 1999.  [PUBMED Abstract]
    
    
13. Shankar AG, Pinkerton CR, Atra A, et al.: Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG). Eur J Cancer 35 (12): 1698-704, 1999.  [PUBMED Abstract]
    
    
14. 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 348 (8): 694-701, 2003.  [PUBMED Abstract]
    
    
15. Bacci G, Ferrari S, Longhi A, et al.: Prognostic significance of serum LDH in Ewing's sarcoma of bone. Oncol Rep 6 (4): 807-11, 1999 Jul-Aug.  [PUBMED Abstract]
    
    
16. 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 15 (2): 574-82, 1997.  [PUBMED Abstract]
    
    
17. Ahmad R, Mayol BR, Davis M, et al.: Extraskeletal Ewing's sarcoma. Cancer 85 (3): 725-31, 1999.  [PUBMED Abstract]
    
    
18. 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 8 (10): 1664-74, 1990.  [PUBMED Abstract]
    
    
19. Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995.  [PUBMED Abstract]
    
    
20. Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999.  [PUBMED Abstract]
    
    
21. Luksch R, Sampietro G, Collini P, et al.: Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing's sarcoma family of tumors in children. Tumori 85 (2): 101-7, 1999 Mar-Apr.  [PUBMED Abstract]
    
    
22. 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 16 (4): 1248-55, 1998.  [PUBMED Abstract]
    
    
23. Abudu A, Mangham DC, Reynolds GM, et al.: Overexpression of p53 protein in primary Ewing's sarcoma of bone: relationship to tumour stage, response and prognosis. Br J Cancer 79 (7-8): 1185-9, 1999.  [PUBMED Abstract]
    
    
24. Ozaki T, Paulussen M, Poremba C, et al.: Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. Genes Chromosomes Cancer 32 (2): 164-71, 2001.  [PUBMED Abstract]
    
    
25. Schleiermacher G, Peter M, Oberlin O, et al.: Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol 21 (1): 85-91, 2003.  [PUBMED Abstract]
    
    
26. Ohali A, Avigad S, Cohen IJ, et al.: Association between telomerase activity and outcome in patients with nonmetastatic Ewing family of tumors. J Clin Oncol 21 (20): 3836-43, 2003.  [PUBMED Abstract]
    
    
27. 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 80 (7): 1020-33, 1998.  [PUBMED Abstract]
    
    
28. 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 85 (11): 1646-54, 2001.  [PUBMED Abstract]
    
    
29. Dyke JP, Panicek DM, Healey JH, et al.: Osteogenic and Ewing sarcomas: estimation of necrotic fraction during induction chemotherapy with dynamic contrast-enhanced MR imaging. Radiology 228 (1): 271-8, 2003.  [PUBMED Abstract]
    
    

Back to Top

Next Section >