• Ewing sarcoma is a rare, small, round, blue-cell tumor of unknown origin arising in bones or soft tissues.
  • Mainly occurs in children and adolescents (median age at diagnosis 15 years), but may occur in adults as well.
  • The most common cause is a genetic translocation that leads to malignant transformation of affected cells.
  • Most patients present with localized, nonmechanical pain and/or swelling, but may also have fever, weight loss, or fatigue.


  • Incidence is reported to be 2.5-3 cases per 1,000,000 people
  • Reported to account for:
    • 2.6% of pediatric cancers
    • 16% of primary bone cancers


  • Gene translocations between Ewing sarcoma breakpoint region 1 (EWSR1) and erythroblast transformation-specific (ETS) family transcription factors, including
    • FLI1 – producing EWSR1-FLI1 t(11;22)(q24;q12) (in 85%)
    • Other ETS members, ERGFEVETV1, and ETV4 (in 5%-10%)
  • Other causes include
    • EWS-free rearrangements with ETS transcription factors (rare)
    • Tumor variants
      • TP53 mutations
      • STAG2 mutations
      • CDKN2A deletions
    • Variation near locus of early growth response 2 (EGR2, 10q21.3), increasing binding efficiency of EWSR1-FLI1 


  • Ewing sarcoma may arise due to expression of oncogenic fusion proteins in:
    • Bone marrow-derived mesenchymal stem cells
    • Neural crest-derived stem cells
    • Bone progenitors
    • Osteochondrogenic progenitors
    • Oncogenic proteins enhance proliferation and malignant transformation through increased molecular target binding, epigenetic deregulation, and alterations in RNA splicing and micro RNA binding

Clinical Presentation

  • Ewing sarcoma may present as
    • Ewing sarcoma of bone
    • Extraskeletal Ewing sarcoma
    • Askin tumor of chest wall (clavicle, scapula, ribs, or sternum)
    • Primitive neuroectodermal tumors of bone and soft tissue (PNET)
  • Most tumors present with localized pain and/or swelling, but may also have fever, weight loss, or fatigue
  • Primary tumor site locations
    • Skeleton – may present in any bone, but commonly
      • Diaphyseal or metadiaphyseal long bones (femur)
      • Pelvis
      • Chest wall
      • Spine
    • Soft tissues


  • Ask about localized swelling and/or pain duration, severity, and timing (for example, night pain)
  • Ask about other symptoms associated with
    • Chest wall tumors (Askin tumor) — fever, cough, dyspnea, and/or chest pain
    • Pelvic tumors — urinary retention, sciatic nerve pain
    • Spinal tumors — back pain, muscle weakness, decreased/altered sensation, imbalance, bowel/bladder issues
  • Pain may be attributed to nonspecific trauma/sports-related injury resulting in delayed diagnosis (from weeks to months)
  • Ask about
    • Recent fracture or injury
    • Previous benign or malignant lesions
    • Radiation therapy
    • Family history of bone cancers


  • Evaluate area associated with pain
  • Swelling may be present only in sarcomas that progressed through the bone cortex and caused periosteal distention

Diagnosis and Staging

Making the diagnosis
  • Suspect Ewing sarcoma in patients with bone pain and/or swelling, or with a lesion seen with poor margins on plain radiograph (x-ray)
  • Perform imaging with x-ray, magnetic resonance imaging (MRI), and/or computed tomography (CT) for staging prior to biopsy  
  • Diagnosis confirmed with open or core needle biopsy
  • Obtain blood tests (may provide prognostic information) include CBC, LDH, ALP, ESR, and CMP
Differential Diagnosis
  • Benign tumors (osteochondroma or osteoid osteoma)
  • Osteomyelitis
  • Malignant bone cancers
    • Osteosarcoma   
    • Chondrosarcoma
    • Chordoma
    • Giant cell bone tumor
  • Other small round-cell neoplasms
    • Neuroblastoma
    • Rhabdomyosarcoma
    • Wilms tumor
    • Desmoplastic small round-cell tumor
    • Non-Hodgkin lymphoma
    • Solitary fibrous tumor
    • Melanoma
    • Extraskeletal mesenchymal chondrosarcoma
    • Poorly differentiated
      • synovial sarcoma
      • neuroendocrine carcinoma
    • Liposarcoma
  • To evaluate for primary site  
    • Plain radiograph; findings may include:
      • Mottled appearance
      • Osteolytic lesions with distinctive onion skin pattern
      • Sharpey fibers with “hair on end” appearance
      • Periosteal elevation (Codman triangle)
    • MRI to define tumor extent
    • CT
      • With MRI for primary site imaging 
  • If uncertain diagnosis, to improve visualization  
  • To evaluate for metastases affecting
    • Skeleton — positron emission tomography/CT, bone scan, or pelvis/spine MRI
  • Lungs — chest CT
  • Bone marrow- bone marrow biopsy
  • Modalities include open (incisional) biopsy or core needle biopsy; no randomized trial exists to guide modality choice, however core needle or open biopsy recommended  
  • Open (incisional) biopsy
    • Reported to be more accurate due to larger tumor sample size
    • Samples may also be used for cytogenetics or immunohistochemistry
  • Percutaneous biopsy
    • Core needle biopsy
      • Diagnostic accuracy reported to be 88% to 96%
      • Reported to have lower risk of tumor seeding
    • Fine-needle aspiration may be controversial; reported to have lower accuracy than core needle biopsy
  • Perform cytogenetic or molecular studies; evaluate with
  • Cytogenetic evaluation
  • RT-PCR if frozen tissue is available
  • FISH if touch preps/formalin-fixed paraffin-embedded tissue available
    • Histology
      • May appear poorly differentiated as small, round, blue cells
  • Positive for
    • Cell surface glycoprotein MIC2 (CD99)
    • Friend leukemia integration 1 (FLI1)
    • Neuron specific enolase (NSE)
    • Periodic-acid Schiff
  • If uncertain histology, confirmation of EWSR1 and ETS translocation required for diagnosis  
Staging System(s)
  • Surgical staging system
    • Stage IA – low grade (G1) and intracompartmental (T1)
    • Stage IB – low grade (G1) and extracompartmental (T2)
    • Stage IIA – high grade (G2) and intracompartmental (T1)
    • Stage IIB – high grade (G2) and extracompartmental (T2)
    • Stage III – any grade with regional or distant metastasis and either intracompartmental or extracompartmental

Management Overview

  • Before treatment
    • Consider enrollment in a clinical trial
    • Provide fertility counseling for patients of child-bearing age
  • May involve multiagent chemotherapy, surgical tumor resection, and/or radiation therapy
    • Treatment duration generally 10 to 12 months
    • Chemotherapy
      • Typically involves 6 drug combinations of vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, and/or dactinomycin
      • Surgical tumor resection is preferred modality for local tumor control
    • Radiation therapy used as definitive or adjuvant therapy
  • Specific treatment
    • Newly diagnosed patients with nonmetastatic disease at presentation, consider
      • Multiagent chemotherapy with vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VAC/IE) for ≥9-12 weeks
      • Growth factor support
    • Patients with stable disease after first-line therapy
      • Local control with surgical tumor resection, definitive radiation therapy, or amputation (in select patients)
      • Adjuvant therapy; in patients having
        • Tumor resection with negative margins — adjuvant chemotherapy
        • Tumor resection with positive margins — continue adjuvant chemotherapy, give adjuvant radiation therapy
        • Limb amputation — continue adjuvant chemotherapy postoperatively, give margin-dependent radiation therapy
    • In patients with metastatic disease
      • At presentation — offer clinical trial, give multiagent chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VAdriaC), VAC/IE, VAI, or VIDE
      • After first-line treatment, consider
        • Radiation therapy and/or surgery for palliation/local control
        • Whole-lung irradiation in patients with lung metastases after completing chemotherapy/surgery
        • Multiagent chemotherapy, best supportive care
    • In patients with recurrent disease
      • Offer clinical trial
      • Give chemotherapy with or without radiation therapy
  • Surveillance
    • Frequent monitoring includes examination, imaging, and blood studies  
    • Life-long surveillance recommended to monitor for late effects of treatments
    • Refer patients for survivorship clinic  
    • After 2 years, may extend surveillance intervals; perform annually after 5 years


  • Metastases affecting bone, bone marrow, or lungs (20%-25% reported to present with metastatic disease) 
  • Treatment-related complications
    • Secondary cancers, such as acute myeloid leukemia 
    • Myelodysplastic syndrome
    • Cardiac dysfunction
    • Infertility in males
    • Premature menopause
    • Growth arrest
    • Bone fracture


  • 5-year prognosis reported to be
    • 60%-85% overall survival in patients with localized disease
    • 27%-40% overall survival in patients with metastatic disease
    • 73% event-free survival
    • <10% survival with surgery or radiotherapy alone
  • Factors at diagnosis associated with disease recurrence include
    • Large tumor size (>8 cm)
    • Presence of metastatic disease
    • Elevated serum lactate dehydrogenase
    • Hypoalbuminemia
    • Older age (>14 years)
    • Axial tumor location

Kendra Church MS, PA-C, is a physician assistant at Dana-Farber Cancer Institute/Brigham & Women’s Hospital, and is also a senior clinical editor for DynaMed, an evidence-based, point-of-care database. 


  1. Jackson TM, Bittman M, Granowetter L. Pediatric malignant bone tumors: a review and update on current challenges, and emerging drug targetsCurr Probl Pediatr Adolesc Health Care. 2016;46(7):213-228. doi:10.1016/j.cppeds.2016.04.00
  2. Biermann JS, Chow W, Adkins DR, et al. Bone cancer. In: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN. August 2017.
  3. European Society for Medical Oncology (ESMO)/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-upAnn Oncol. 2014;25 Suppl 3:iii113-123. doi:10.1093/annonc/mdu25.  Correction: Ann Oncol. 2015;26 Suppl 5:v174.