Ewing sarcoma

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Ewing Sarcoma

Overview

Ewing sarcoma is the third most common nonhematologic primary bone malignancy overall, but the second most common bone sarcoma in patients under 30 (after osteosarcoma) and the most common in patients under 10 years of age. It accounts for approximately 10-15% of all primary malignant bone tumors. Around 200 cases are diagnosed in the United States per year - incidence is less than 1 per million per year. There is a slight male predominance. Ewing sarcoma is exceedingly rare in individuals of African descent and occurs primarily in whites of European origin.

Campbell's Operative Orthopaedics 15th Ed 2026, p. 1221
Robbins & Kumar Basic Pathology, p. 786
Goldman-Cecil Medicine, p. 1432

Molecular Pathogenesis

The defining feature of Ewing sarcoma is a balanced chromosomal translocation involving the EWSR1 gene on chromosome 22:

Translocation	Genes fused	Frequency
t(11;22)(q24;q12)	EWSR1 - FLI1	~85%
t(21;22)(q22;q12)	EWSR1 - ERG	~10%
t(7;22)(p22;q12)	EWSR1 - ETV1	Rare

90% of cases carry one of these EWS-ETS family fusions
The chimeric EWS/FLI1 protein binds chromatin and dysregulates transcription, leading to uncontrolled growth and abnormal differentiation
The cell of origin is uncertain - mesenchymal stem cells and primitive neuroectodermal cells are the leading candidates

The specific translocation type (t(11;22) vs. t(21;22)) does not seem to affect the clinical course, though secondary genetic alterations such as aberrant TP53 expression may carry prognostic significance.

Robbins & Kumar Basic Pathology, p. 786
Miller's Review of Orthopaedics 9th Ed
Campbell's Operative Orthopaedics 15th Ed 2026, p. 1222

Epidemiology & Location

Age: Most cases ages 5-25 years; peak in the second decade. About 20% occur in older patients.
Sex: Slight male predominance
Sites: Metaphyses of long bones (with frequent extension into the diaphysis), flat bones of the shoulder and pelvic girdles. Classic teaching is "diaphyseal" but metaphyseal origin is actually more common, with diaphyseal extension.
Also: pelvis, ribs, sacrum (vertebral Ewing sarcoma accounts for 3.3-15% of cases, with sacral involvement in up to 50%)
Extraskeletal: ~20% of Ewing sarcomas are extraskeletal ("extraosseous Ewing sarcoma")
Rare: spine, small bones of the hands/feet

Clinical Presentation

Pain is almost universal. Key features:

Insidious onset with long duration before diagnosis (average delay = 34 weeks)
- Patient delay: ~15 weeks to first appointment
- Physician delay: ~19 weeks from first visit to diagnosis
Pain may initially be mild/intermittent and respond to conservative treatment
Fever, erythema, and swelling - can mimic osteomyelitis (a notorious diagnostic pitfall)
Lab abnormalities: elevated WBC, elevated ESR, elevated CRP, elevated LDH (a prognostic marker)
A needle aspirate may grossly resemble pus - always send specimen for both culture and pathology

Imaging

Plain Radiograph

Classically: destructive diaphyseal lesion with "onion skin" periosteal reaction (layers of reactive bone)
Also: permeative / "moth-eaten" appearance
A large portion of the bone or even the entire bone may be involved
Flat bones show a nonspecific destructive appearance
Associated soft-tissue mass is often very large

MRI (modality of choice for staging)

Order for the entire bone - extent typically exceeds what is apparent on plain films
Evaluates the soft-tissue component
Vertebral Ewing: usually isointense to hyperintense on T2; isointense on T1; intense gadolinium enhancement ("curtain sign" on axial images for spinal canal invasion)

Staging workup

Study	Purpose
Chest X-ray + CT	Lung - most common metastatic site
Bone scan	Bone - second most common metastatic site
FDG-PET/CT	High sensitivity for staging, detecting recurrence; new standard; initial SUV correlates with prognosis
Bone marrow aspirate	Rule out diffuse systemic disease
Whole-body MRI	Alternative to bone scan/PET

Ewing sarcoma of the fibula - X-rays, MRI, histology, and post-treatment imaging

Fig: (A,B) AP and lateral radiographs of left fibula of a 7-year-old girl with Ewing sarcoma. (C) MRI shows large soft-tissue mass. (D) Typical microscopic appearance. (E,F) After neoadjuvant chemotherapy - increased ossification. (G) Post-chemo MRI showing marked reduction in soft-tissue mass. (H,I) After wide resection. - Campbell's Operative Orthopaedics 15th Ed 2026

Histopathology

Ewing sarcoma belongs to the small round blue cell tumors of childhood. Key histological features:

Sheets of uniform, small round cells slightly larger than lymphocytes
Minimal intercellular matrix - no bone or cartilage production (distinguishes from osteosarcoma)
Scant cytoplasm, may appear clear due to glycogen content
Usually arises in the medullary cavity, invades cortex, periosteum, and soft tissue
Homer-Wright rosettes (circular cell groupings with a central fibrillary core) may be present

Special stains and IHC

Marker	Ewing sarcoma	Lymphoma
PAS stain	Positive (glycogen)	Negative
Reticulin	Negative	Positive
MIC-2 (CD99)	Positive - specific for Ewing	Negative
Leukocyte common antigen (CD45)	Negative	Positive

Cytogenetic or IHC studies are usually required to distinguish Ewing sarcoma from other small blue cell tumors (lymphoma, rhabdomyosarcoma, neuroblastoma, small cell carcinoma).

Ewing sarcoma histology - sheets of small round cells with minimal clear cytoplasm

Fig: Ewing sarcoma composed of sheets of small round cells with minimal clear cytoplasm. H&E stain. - Robbins & Kumar Basic Pathology

Treatment

Treatment is multimodal and must always include systemic chemotherapy because micrometastatic disease is presumed present at diagnosis.

Chemotherapy

Neoadjuvant + adjuvant chemotherapy is the cornerstone
Standard regimen: VDC/IE - vincristine, doxorubicin, cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE), administered under expert guidance with dose intensification
Salvage regimens for relapse: cyclophosphamide/topotecan, irinotecan/temozolomide, gemcitabine/docetaxel

Local Control (Surgery vs. Radiation)

The choice is individualized:

Option	Considerations
Wide surgical resection	Preferred when achievable with acceptable functional deficit; local recurrence rate <10%; avoids radiation-related growth disturbances in children
Radiation therapy	Ewing sarcoma is radiosensitive; used for large, central, unresectable tumors (e.g., pelvis); adjuvant after marginal or contaminated resection
Combination	Radiation as adjuvant after surgery if margins are inadequate

Repeat staging (radiographs + MRI) is obtained after neoadjuvant chemotherapy before deciding on local treatment. Response is often dramatic - increased ossification on X-ray and marked reduction of soft-tissue mass on MRI.

Prognosis

Overall Survival

With modern multiagent chemotherapy: 5-year event-free survival ~70% (localized disease)
Before multiagent chemotherapy: <10% long-term survival
Current centers report 60-75% long-term survival for localized disease

Poor Prognostic Factors

Factor	Comment
Distant metastases at presentation	Most important; 20-30% long-term survival despite aggressive treatment
Large primary tumor size	Consistently significant
Proximal/axial location	Often reflects larger tumor size
Elevated LDH, WBC, ESR	Indicates more extensive disease
Fever and anemia	More extensive disease
Older age (>12-15 years)	Worse prognosis
Male gender	Slight disadvantage
Aberrant TP53 expression	Secondary genetic alteration with adverse impact
Poor histologic response to neoadjuvant chemo	<90% necrosis = poor response

Good Prognostic Factor

>90% necrosis after neoadjuvant chemotherapy = good histologic response and favorable prognosis

Recurrence

Local recurrence: ~20% 5-year survival
Distant relapse: ~10% 5-year survival
Relapse within the first year carries a worse prognosis than late relapse

Differential Diagnosis (Small Round Blue Cell Tumors in Children)

Lymphoma - PAS negative, reticulin positive, LCA positive
Rhabdomyosarcoma - desmin, myoglobin, muscle-specific actin positive
Neuroblastoma - paraspinal, adrenal; urinary catecholamines elevated
Small cell carcinoma - cytokeratin positive
Osteomyelitis - can be clinically indistinguishable (both cause pain, fever, elevated inflammatory markers, pus-like aspirate)

Key sources: Campbell's Operative Orthopaedics 15th Ed 2026, pp. 1221-1223; Robbins & Kumar Basic Pathology, pp. 786-787; Goldman-Cecil Medicine, pp. 1432-1443; Grainger & Allison's Diagnostic Radiology, p. 1285

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