Ewing Sarcoma

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Ewing Sarcoma

Overview

Ewing sarcoma is a malignant tumor of bone (and occasionally soft tissue) composed of small round blue cells, defined molecularly by translocations involving the EWSR1 gene on chromosome 22. It is the second most common primary bone sarcoma in children and adolescents (after osteosarcoma), and the most common primary bone malignancy in children under 10 years of age. The incidence is less than 1 per million per year, with roughly 200 new cases diagnosed annually in the United States.

Epidemiology

Age: Most cases occur between ages 5-25 years; 80% of patients are under 20
Sex: Slight male predominance
Race: Exceedingly rare in individuals of African descent; predominantly affects Whites of European origin
No known predisposing factors

Molecular Pathogenesis

The hallmark of Ewing sarcoma is a chromosomal translocation generating a chimeric fusion protein:

Translocation	Genes Involved	Frequency
t(11;22)(q24;q12)	EWSR1 - FLI1	~85-90% of cases
t(21;22)(q22;q12)	EWSR1 - ERG	Less common
t(7;22)(p22;q12)	EWSR1 - ETV1	Rare

The resulting EWS/FLI1 chimeric protein binds to chromatin and dysregulates transcription, driving uncontrolled growth and abnormal differentiation. The cell of origin is uncertain but most likely mesenchymal stem cells or primitive neuroectodermal cells.

Location

Long bones: Most common - metaphyses with frequent extension into the diaphysis; the classic description is "diaphyseal" but metaphyseal origin is more frequent
Flat bones: Pelvis, ribs, shoulder girdle
Spine: Primarily the sacrum (up to 50% of spinal cases), with posterior elements of the mobile spine commonly affected
Extraskeletal (extraosseous): ~20% of cases arise in soft tissue

Clinical Presentation

Pain - nearly universal; onset is insidious, often mild and intermittent initially
Average diagnostic delay: ~34 weeks from symptom onset (15 weeks patient delay + 19 weeks physician delay)
Soft tissue swelling over the affected site, often warm and tender
Systemic symptoms mimicking osteomyelitis or infection: fever, erythema, leukocytosis, elevated ESR, elevated CRP
Lab findings may include anemia and elevated inflammatory markers - leading to frequent initial misdiagnosis as osteomyelitis

Radiology

Plain Radiograph:

Destructive lytic lesion with permeative ("moth-eaten") margins
Classic "onion-skin" periosteal reaction - layers of reactive bone from tumor advancing through periosteum
Large soft-tissue mass common

MRI (study of choice for local staging):

Isointense to hyperintense on T2; isointense on T1
Intense gadolinium enhancement due to hypercellularity
"Curtain sign" - invasion of the spinal canal
Paraspinal soft-tissue component often larger than the intraosseous lesion
Should image the entire bone (not just the lesion) as large portions or even the whole bone may be involved

CT: Greater sensitivity than plain films for permeative appearance; chest CT mandatory to evaluate for pulmonary metastases (lung = most common metastatic site)

Bone Scan: Evaluates for bone metastases (2nd most common site)

FDG-PET/CT: Now the standard for initial staging and detection of recurrence; the initial SUV of the primary tumor correlates with tumor aggressiveness

Here is the MRI appearance of Ewing sarcoma of the L2 vertebral body, showing replacement of normal fatty marrow signal and paraspinal extension:

Ewing Sarcoma spine MRI - T1/T2 images showing L2 vertebral body involvement with 'curtain sign'

Pathology / Histology

Gross: Soft, tan-white tumor with areas of hemorrhage and necrosis. Arises in medullary cavity and invades cortex, periosteum, and soft tissue.

Microscopy:

Ewing sarcoma - sheets of small round blue cells with minimal clear cytoplasm (Robbins Pathology)

Fig. 19.23 - Ewing sarcoma composed of sheets of small round cells with minimal clear cytoplasm. (Robbins & Kumar Basic Pathology)

Small round blue cells - sheets of uniform cells, slightly larger and more cohesive than lymphocytes
Scant cytoplasm - appears clear due to intracellular glycogen
Homer-Wright rosettes (circular groupings with central fibrillary core) - may be present
Tumor cells do NOT produce bone or cartilage (distinguishes from osteosarcoma)
PAS positive (glycogen), reticulin negative
MIC-2 (CD99) positive by immunohistochemistry - relatively specific for Ewing sarcoma

Differential Diagnosis (Small Round Blue Cell Tumors of Childhood)

Tumor	Distinguishing Feature
Ewing sarcoma	CD99+, PAS+, reticulin-, t(11;22)
Lymphoma	PAS-, reticulin+, LCA+, T/B cell markers+
Embryonal rhabdomyosarcoma	Desmin+, myoglobin+, muscle-specific actins+
Metastatic small cell carcinoma	Cytokeratin+
Melanoma	Cytokeratin+, S100+
Hemangiopericytoma	Factor VIII+
Neuroblastoma	NSE+, catecholamines elevated

Staging Workup

Plain radiograph of primary lesion
MRI of entire involved bone
CT chest (lung metastases)
Bone scan (skeletal metastases)
FDG-PET/CT (preferred for full staging)
Bone marrow aspirate (at some centers) to rule out diffuse systemic disease

Treatment

Treatment requires a multimodal approach. Before multiagent chemotherapy, long-term survival was <10%. Today, most centers report 60-75% long-term survival.

Chemotherapy (Neoadjuvant + Adjuvant)

The standard regimen is:

VDC/IE alternating cycles:
- Vincristine + Doxorubicin + Cyclophosphamide (VDC)
- alternating with Ifosfamide + Etoposide (IE)
Dose intensification has been shown to improve outcomes
5-year event-free survival with multiagent chemotherapy: ~70%

Local Control (Surgery vs. Radiation)

Ewing sarcoma is radiosensitive, but surgery is preferred when feasible:

Wide surgical resection - associated with local recurrence rates <10% and improved overall survival; preferred for accessible lesions in expendable bones
Radiation therapy - reserved for large, central, or unresectable tumors (e.g., pelvis, spine); also used when surgical margins are inadequate
Decision is individualized; repeat staging after neoadjuvant chemotherapy guides surgical planning
In growing children, wide resection avoids radiation-related complications (growth disturbance, secondary malignancies)

Metastatic / Relapsed Disease

Prognosis is poor for patients with clinically detectable metastases at diagnosis
Salvage regimens include:
- Cyclophosphamide + Topotecan
- Irinotecan + Temozolomide
- Gemcitabine + Docetaxel

Prognosis

Disease Status	Outcome
Localized disease (neoadjuvant chemo + surgery ± radiation)	75% 5-year survival; ~50% long-term cure
All patients with multiagent chemotherapy	~70% 5-year event-free survival
Clinically detectable metastatic disease	Poor

Favorable prognostic factors: Small tumor volume, distal extremity location, localized disease, good histologic response to neoadjuvant chemotherapy (>90% necrosis)

Unfavorable factors: Pelvic/axial location, large tumor volume, metastatic disease at presentation, older age, poor response to chemotherapy

Key High-Yield Points

Translocation: t(11;22) - EWSR1-FLI1 fusion (>90% of cases)
Histology: Small round blue cell tumor; PAS+, CD99+, reticulin-
Radiograph: Lytic, permeative lesion + "onion-skin" periosteal reaction
Most common site of metastasis: Lungs (then bone)
Treatment backbone: VDC/IE chemotherapy + surgery ± radiation
Mimics osteomyelitis: Fever, leukocytosis, elevated ESR/CRP
Rare in African descendants; predominantly European-descent population

Sources: Robbins & Kumar Basic Pathology, p. 786 | Goldman-Cecil Medicine, p. 2115 | Campbell's Operative Orthopaedics 15th Ed 2026, p. 1221-1222 | Grainger & Allison's Diagnostic Radiology, p. 1285 | Miller's Review of Orthopaedics 9th Ed

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