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 – ~225 new cases annually in U.S.
• 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
  • Poorer prognosis in Hispanics

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
• EWS-FLI1 t(11;22)(q24;q12) found in ~85% of ES
  • May be found in other sarcomas
• EWS-ERG t(21;22)(q22;q12) – more specific for ES and pPNET
• 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 and signs are based on location of tumor
• Primary tumor sites include the following
  • Pelvis (26%)
  • Femur (20%)
  • Tibia/fibula (18%)
  • Chest wall (16%)
  • Upper extremity (9%)
  • Spine (6%)
  • Other (5%) – tumor can involve any bone or may be extraskeletal
• Pain may be intermittent and variable in intensity
  • May be 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 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 ES
    • Also positive in acute lymphoblastic leukemia/lymphoma, synovial sarcoma and desmoplastic small round blue-cell tumor
    • May be helpful in differentiating ES and pPNET from other small round-cell neoplasms
    • Not an exclusive marker; may also be 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
  • t(11;22)(q24;12) translocation (EWS-FLI1) – found in ~85% of Ewing sarcomas
    • Not as sensitive as other EWSR1 transcriptions seen in ES and in some other sarcomas, including desmoplastic small round-cell tumors, clear-cell sarcomas, and extraskeletal myxoid liposarcomas

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
  • Hispanic ethnicity

Differential Diagnosis

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

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

Tests generally appear in the order most useful for common clinical situations

Guidelines

• College of American Pathologists (CAP). Protocol for the Examination of Specimens from Patients with Primitive Neuroectodermal Tumor (PNET)/ Ewing Sarcoma (ES). Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: October 2009. [Accessed: 29 Jun 2010] 
• NCCN Clinical Practice Guidelines in Oncology, Bone Cancer. National Comprehensive Cancer Network. Fort Washington: Pennsylvania [Accessed: 19 Apr 2011] 
• NCCN Clinical Practice Guidelines in Oncology, Soft Tissue Sarcomas. National Comprehensive Cancer Network. Fort Washington: Pennsylvania [Accessed: 10 May 2011] 

General

• Balamuth NJ, Womer RB. Ewing's sarcoma. Lancet Oncol. 2010; 11 (2) :184-192.PubMed
• Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, Teot LA, Juergens H. Ewing's sarcoma family of tumors: current management. Oncologist. 2006; 11 (5) :503-519.PubMed
• Bovee JV, Hogendoorn PC. Molecular pathology of sarcomas: concepts and clinical implications. Virchows Arch. 2010; 456 (2) :193-199.PubMed
• Gulley ML, Kaiser-Rogers KA. A rational approach to genetic testing for sarcoma. Diagn Mol Pathol. 2009; 18 (1) :1-10.PubMed
• Iwamoto Y. Diagnosis and treatment of Ewing's sarcoma. Jpn J Clin Oncol. 2007; 37 (2) :79-89.PubMed
• Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005; 12 (4) :212-220.PubMed
• Ludwig JA. Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol. 2008; 20 (4) :412-418.PubMed
• Osuna D, de Alava E. Molecular pathology of sarcomas. Rev Recent Clin Trials. 2009; 4 (1) :12-26.PubMed
• Slater O, Shipley J. Clinical relevance of molecular genetics to paediatric sarcomas. J Clin Pathol. 2007; 60 (11) :1187-1194.PubMed
• Toomey EC, Schiffman JD, Lessnick SL. Recent advances in the molecular pathogenesis of Ewing's sarcoma. Oncogene. 2010; 29 (32) :4504-4516.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Lewis TB, Coffin CM, Bernard PS. Differentiating Ewing's sarcoma from other round blue cell tumors using a RT-PCR translocation panel on formalin-fixed paraffin-embedded tissues. Mod Pathol. 2007; 20 (3) :397-404.PubMed

Acute Lymphoblastic Leukemia
Lymphoma Phenotyping
Mold-Associated Infections
Neuroblastoma
Sarcoma
Tumor Markers