Ewing Sarcoma - Primitive Neuroectodermal Tumor

Diagnosis

Indications for Testing

  • Tumor with initial histology at appropriate site (eg, bony tumor in childhood)

Histology

  • Densely packed homogeneous small round blue cells
    • Biopsy specimen may be difficult to assess because tumor cells resemble other similar sarcomatous or round-cell tumors (eg, lymphoma/leukemia, rhabdomyosarcoma, medulloblastoma, neuroblastoma, desmoplastic small round cell tumor [DSRCT], poorly differentiated carcinoma, poorly differentiated synovial sarcoma, melanoma)
  • Immunohistochemistry
    • CD99 (MIC2, also known as O13) – cell surface glycoprotein
      • Highly sensitive
      • Found in 85-95% of Ewing sarcoma (ES)
      • Not specific – expressed in acute lymphoblastic leukemia/lymphoma; synovial sarcoma and DSRCT; and other sarcomas
      • May be helpful in differentiating ES and peripheral primitive neuroectodermal tumors (pPNET) from other small round-cell neoplasms
    • Friend leukemia integration-1 (Fli-1) protein
      • Nuclear staining found in ~70% of ES
      • Not specific – found in acute lymphoblastic lymphomas, DSRCT, Merkel cell carcinoma, and synovial sarcoma
  • Molecular studies (PCR, FISH) – may be crucial if tumor is in unusual location; studies together may provide complementary information
    • EWSR1 rearrangements – supports diagnosis of ES
      • EWSR1-FLI1 fusion [t(11:22)(q24;q12)] – 85-90%
      • EWSR1-ERG fusion [t(21;22)(q22;q12)] – 5-10%
      • Other chimeric translocations are rare (most common listed below); for other fusions, see Sarcoma topic
        • EWSR1-ETV1 [t(7:22) (p22;q12)]
        • EWSR1-TVA [t(17;22) (q21;q12)]
        • EWSR1-FEV [t(2;22) (q35;q12)]

Imaging Studies

  • Plain radiographs – may show a lytic lesion of bone
  • MRI
    • Both bony and soft tissue components may coexist
    • “Onion skinning” of reactive periosteum
    • Saucerization – concave cortical defect in bone due to erosion of outer cortex
    • “Hair on end” – vertical form of periosteal reaction in bone
  • Bone scan or FDG-PET may be used for staging

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

Differential Diagnosis

  • Similar-appearing sarcomatous tumors
    • DSRCT
    • Poorly differentiated synovial sarcoma
    • Alveolar rhabdomyosarcoma
    • Mesenchymal chondrosarcoma
    • Undifferentiated small round cell sarcomas with CIC-DUX4 or BCOR-CCNB3 fusions
    • Small cell osteosarcoma
    • Undifferentiated small round cell sarcoma/Ewing-like sarcoma
  • Other tumors
    • Neuroblastoma 
    • Lymphoblastic lymphoma
    • Small cell carcinoma
    • Merkel cell carcinomas
    • Melanoma, small cell malignant variant

Monitoring

  • Tumor recurrence and/or distant spread
  • Increased risk of osteosarcoma secondary to radiotherapy
  • 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 blue 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-type primitive neuroectodermal tumors (pPNET).

Epidemiology

  • Incidence – 4/1,000,000 (SEER)
  • Age
    • Second most common neoplasm of the bone in children and adolescents
    • Peak incidence in second decade
    • Small percent in patients <10 years and >20 years; rare in >30 years 
  • Sex – M>F, 1.5:1
  • Ethnicity – in U.S., more common in Caucasians; infrequent 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 85-90% of ES
  • EWSR1-ERG t(21;22)(q22;q12)
  • EWSR1 gene is also rearranged in a variety of other tumors with a variety of other partners

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 CD99 (also known as O13)
  • Majority arise in bone; remainder in soft tissue
    • In bone – most frequent in diaphysis or metaphyseal region

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
Use in conjunction with histologic and clinical information for the diagnosis of members of the Ewing sarcoma family of tumors (ESFT)

Results may be compromised if the recommended fixation procedures have not been followed (avoid decalcification)

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

Results may be compromised if the recommended fixation procedures have not been followed (avoid decalcification)

 
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

Insufficient for diagnosis as a stand-alone test

 
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

Insufficient for diagnosis as a stand-alone test

 
Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Prognostication in Ewing sarcoma