Ewing Sarcoma

Diagnosis

Indications for Testing

  • Childhood tumor at appropriate site (eg, long bones, pelvis)

Histology

  • Densely packed homogeneous small round cells – granular chromatin
    • Biopsy specimen may be difficult to assess because tumor cells resemble other similar sarcomatous or round-cell tumors (eg, lymphoma/leukemia, rhabdomyosarcoma, medulloblastoma, neuroblastoma)
  • Immunohistochemistry
    • CD99 (MIC2, also known as O13) – cell surface glycoprotein expressed in 85-95% of Ewing sarcoma (ES)
      • Also positive in acute lymphoblastic leukemia/lymphoma, synovial sarcoma and desmoplastic small round blue-cell tumor
      • May be helpful in differentiating ES and peripheral primitive neuroectodermal tumors (pPNET) from other small round-cell neoplasms
      • Not an exclusive marker; also found in other sarcomas
    • Friend leukemia integration-1 (Fli-1) protein
    • Must differentiate from other neuroendocrine tumors
      • Consider NSE, PGP 9.5, synaptophysin
  • Molecular studies (PCR, FISH) – may be crucial if tumor is in unusual location
    • EWSR1 rearrangements – supports diagnosis of ES
      • EWSR1/FLI1 fusion [t(11:22)(q24;q12)] – ~85%
      • EWSR1-ERG fusion [t(21;22)(q22;q12)] – ~10%
      • Other chimeric translocations – rare
        • EWSR1-ETV1 [t(7:22)]
        • EWSR1-TVA [t(17;22)]
        • EWSR1-FEV [t(2;22)]

Imaging Studies

  • MRI – standard imaging for ES
    • Both bony and soft tissue components may coexist
    •  “Onion skinning” of reactive periosteum

Prognosis

  • Favorable
    • Normal serum LD
    • Distal site of primary disease
    • Absence of metastatic disease
  • Unfavorable
    • Metastatic disease – most significant adverse factor
      • ~25% present with metastatic disease
      • Lungs, other bones, bone marrow are most common sites
    • Elevated serum LD
    • Primary tumor in pelvic bone
    • Large tumor
    • Age – lower survival rate in adults
  • Other factors affecting prognosis
    • EWS gene fusion/translocation
    • Lower socioeconomic status – poor prognosis
    • Hispanic ethnicity – poor prognosis

Differential Diagnosis

  • Similar-appearing sarcomatous tumors
    • Synovial sarcoma
    • Rhabdomyosarcoma
    • Mesenchymal chondrosarcoma
  • Other childhood tumors
    • Neuroblastoma 
    • Lymphoblastic lymphoma
    • Undifferentiated small round cell tumors

Monitoring

  • Monitor for increased risk of osteosarcoma secondary to radiotherapy
  • Monitor for increased risk (5-8%) of treatment-related leukemias and myelodysplastic syndromes secondary to chemotherapy

Clinical Background

The Ewing sarcoma family of tumors (ESFT) are small round-cell neoplasms and include classic Ewing sarcoma (ES) of the bone, extraskeletal ES, small round-cell tumors of the thoracopulmonary region (Askin tumor), and peripheral primitive neuroectodermal tumors (pPNET).

Epidemiology

  • Incidence – 4/1,000,000
  • Age
    • Second most common neoplasm of the bone in children and adolescents
    • Peak incidence in adolescence
    • 20% diagnosed in patients <10 years and >20 years  
  • Sex – M>F, 1.3:1
  • Ethnicity – in U.S., more common in Caucasians; essentially absent in African Americans

Genetics

  • ES is characterized by fusion of EWS chromosome 22q12 with chromosome in the ETS gene family
    • ETS genes include FLI1, ERG, ETV1, ETV4, FEV
  • EWSR1-FLI1 t(11;22)(q24;q12) found in ~85% of ES
    • May be found in other sarcomas
  • EWSR1-ERG t(21;22)(q22;q12) – more specific for ES and pPNET
  • Numerous other EWS fusions rare

Pathophysiology

  • Classic ES is a poorly differentiated, homogeneous population of small round-cells with high nuclear-to-cytoplasmic ratio
  • Characterized by strong expression of glycoprotein MIC2 (CD99, also known as O13)

Clinical Presentation

  • Symptoms based on location of tumor
  • Primary tumor sites include
    • Pelvis (26%)
    • Femur (20%)
    • Tibia/fibula (18%)
    • Chest wall (16%)
    • Upper extremity (9%)
    • Spine (6%)
    • Other (5%)
  • Pain may be intermittent and variable in intensity
    • Easily mistaken for bone growth or injury in children
  • Palpable mass/swelling at affected site
  • Constitutional – occasionally may present with fever, weight loss, fatigue

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
EWSR1 (22q12) Gene Rearrangement by FISH 2007225
Method: Fluorescence in situ Hybridization
Diagnose members of the Ewing sarcoma family of tumors (ESFT)

Results may be compromised if the recommended fixation procedures have not been followed

Does not identify specific translocation partner

 
EWSR1-FLI1 and EWSR1-ERG Translocations by RT-PCR 0051220
Method: Reverse Transcription Polymerase Chain Reaction

Confirm histological diagnosis of ES by detection of EWSR1-FLI1 and EWSR1-ERG fusions

Limited to detecting the 2 most common translocation partners observed in the Ewing family of tumors

 
Chromosome FISH, Interphase 2002298
Method: Fluorescence in situ Hybridization

Diagnose members of the ESFT; probes must be specified

  • 22q12.2

Fresh tissue or touch-prep

ARUP Oncology FISH Probes menu

   
Ewing Sarcoma (O13) by Immunohistochemistry 2004055
Method: Immunohistochemistry

Aid in histologic diagnosis of ES

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Friend Leukemia Integration-1 (Fli-1) by Immunohistochemistry 2003887
Method: Immunohistochemistry

Aid in histologic diagnosis of ES

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Neuron Specific Enolase, Polyclonal (NSE P) by Immunohistochemistry 2004052
Method: Immunohistochemistry

Differential diagnosis of neuroendocrine tumors in paraffin-embedded tissue

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Protein Gene Product (PGP) 9.5 by Immunohistochemistry 2004091
Method: Immunohistochemistry

Differential diagnosis of neuroendocrine tumors in paraffin-embedded tissue

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Differential diagnosis of neuroendocrine tumors in paraffin-embedded tissue

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Prognostication in Ewing sarcoma