Differentiating Osteosarcoma from Ewing Sarcoma
Osteosarcoma and Ewing sarcoma can be reliably differentiated through a combination of clinical demographics, molecular testing, and imaging characteristics, with molecular analysis being the definitive diagnostic tool. 1
Clinical and Demographic Features
Age Distribution
- Osteosarcoma shows a bimodal age distribution with the first peak in teenagers/young adults and a second peak in the seventh and eighth decades 1
- Ewing sarcoma occurs predominantly in childhood and adolescence with a median age of 14 years, and 90% of patients are under 20 years 1
Racial Predilection
- Osteosarcoma is slightly more common in Black patients 1
- Ewing sarcoma is distinctly less common in people of Chinese or Black African origin 1
Anatomic Location
- Osteosarcoma typically arises in the metaphysis of extremity long bones, most commonly around the knee, with some tumors (predominantly in adults) arising in the axial skeleton, pelvis, or craniofacial bones 1
- Ewing sarcoma affects 50% extremity and 20% pelvic locations, and is often associated with a large soft tissue component 1
Molecular and Genetic Differentiation (Definitive)
Osteosarcoma Molecular Profile
- Complex genome rearrangements via chromoplexy and chromothripsis 1
- TP53 loss-of-function mutations (or mutant gain-of-function) 1
- MYC amplification, RB1 deletion and mutation in specific cases 1
- No EWSR1 gene rearrangements (with rare exceptions in small cell osteosarcoma variant) 2
Ewing Sarcoma Molecular Profile
- FET::ETS gene fusions (most commonly EWSR1::FLI1) present in >90% of cases 1
- Detection by cytogenetics or PCR of translocations t(11;22)(q24;q12) or t(21;22)(q22;q12) is diagnostic 1
- MIC2 gene expression distinguishes Ewing sarcoma immunohistochemically from other pediatric "blue tumors" 1, 3
- Additional STAG2 and TP53 cooperative mutations associated with poorer survival 1
Imaging Characteristics
MRI/DWI Differentiation
- Ewing sarcoma demonstrates significantly lower ADC values (mean ADCmin 0.551-0.566 × 10⁻³ mm²/s) reflecting higher cellularity 4
- Osteosarcoma shows higher ADC values (mean ADCmin 1.182-1.193 × 10⁻³ mm²/s) 4
- This difference is statistically significant (P < 0.001) and can aid in borderline cases 4
Radiological Features
- Ewing sarcoma frequently presents with a large soft tissue component 1
- Osteosarcoma typically shows osteoid matrix formation on imaging 1
Diagnostic Algorithm
Step 1: Clinical Assessment
├─ Age <20 years + non-Black ethnicity → Consider Ewing sarcoma [1]
├─ Bimodal age (teen or >60 years) → Consider osteosarcoma [1]
└─ Large soft tissue mass → Favor Ewing sarcoma [1]
Step 2: Imaging
├─ MRI with DWI: ADC <0.6 × 10⁻³ mm²/s → Ewing sarcoma [4]
└─ MRI with DWI: ADC >1.1 × 10⁻³ mm²/s → Osteosarcoma [4]
Step 3: Molecular Testing (DEFINITIVE)
├─ EWSR1::FLI1 or other FET::ETS fusion positive → Ewing sarcoma [1]
├─ MIC2 gene expression positive → Ewing sarcoma [1]
├─ Complex chromosomal rearrangements + TP53 mutation → Osteosarcoma [1]
└─ No EWSR1 rearrangement → Osteosarcoma (usual) [2]Critical Diagnostic Pitfalls
- Small cell osteosarcoma can rarely harbor EWSR1 gene rearrangements, making molecular testing alone insufficient for definitive diagnosis 2
- Do not rely solely on molecular studies when distinguishing small cell osteosarcoma from Ewing sarcoma; integrate morphology, immunohistochemistry, and clinical context 2
- Refer patients to specialized bone sarcoma centers before biopsy to avoid tissue contamination that compromises subsequent management 1, 3
- Complete radiological assessment of the entire affected bone must be performed before any biopsy 1, 3
Treatment Implications of Correct Diagnosis
- Osteosarcoma requires cisplatin, doxorubicin, and high-dose methotrexate as standard chemotherapy 5
- Ewing sarcoma requires doxorubicin, vincristine, etoposide, and cyclophosphamide/ifosfamide with dose-intensified regimens 1, 5
- Misdiagnosis leads to inappropriate chemotherapy selection and compromised survival outcomes 5