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RISK FACTORS	Age 10 to 20 years; male sex; White/European descent (rare in Black and Asian populations); no known hereditary predisposition
ETIOLOGY	Chromosomal translocation t(11;22)(q24;q12) producing the EWS-FLI1 fusion oncoprotein in over 85% of cases
PATIENT PRESENTATION	Progressive, localized bone pain and swelling over weeks to months; constitutional symptoms (fever, fatigue, weight loss) in disseminated disease
CLASSIC PHYSICAL EXAM	Tender, firm, fixed mass over the affected bone; warmth and erythema overlying the lesion; possible restricted range of motion of the adjacent joint
KEY DIAGNOSTIC RESULTS	X-ray: permeative ("moth-eaten") lytic lesion with lamellated ("onion-skin") periosteal reaction; MRI for local extent; biopsy: sheets of small round blue cells; molecular confirmation of EWS-FLI1 fusion transcript
MANAGEMENT	Neoadjuvant multi-agent chemotherapy (VDC/IE protocol) followed by local control (surgical resection preferred, radiation if unresectable) followed by adjuvant chemotherapy; total treatment duration approximately 30 to 49 weeks
KEYWORDS	"Onion-skin" periosteal reaction; small round blue cell tumor; t(11;22); diaphysis of long bone in a teenager; EWS-FLI1; lytic permeative lesion; fever mimicking osteomyelitis

1. Pathophysiology

Ewing sarcoma arises from a neuroectodermal progenitor cell and is driven by a characteristic balanced chromosomal translocation. In approximately 85 to 90 percent of cases, the translocation is t(11;22)(q24;q12), which fuses the EWSR1 gene on chromosome 22 to the FLI1 gene on chromosome 11. The resulting EWS-FLI1 fusion protein acts as an aberrant transcription factor that drives uncontrolled cell proliferation, blocks differentiation, and promotes survival of the tumor cells. A smaller subset (10 to 15 percent) harbors variant translocations such as t(21;22) producing EWS-ERG, but the underlying oncogenic mechanism is the same: deregulated transcriptional activity from a chimeric EWS protein.

The tumor preferentially involves the diaphysis and metadiaphysis of long bones, which distinguishes it from osteosarcoma that favors the metaphysis. The femur is the single most common site, followed by the pelvis, tibia, and fibula. Flat bones (pelvis, scapula, ribs) are involved more frequently than in osteosarcoma, and pelvic tumors tend to present later with larger tumor burden, conferring a worse prognosis.

Pain occurs because the rapidly proliferating tumor infiltrates through the medullary cavity, destroys cortical bone in a permeative pattern, and elevates the periosteum. As the periosteum is lifted and re-deposited in successive layers, the classic "onion-skin" (lamellated) periosteal reaction forms on imaging. A soft tissue mass frequently accompanies the bony lesion because the tumor breaks through the cortex and extends into surrounding soft tissues. Constitutional symptoms such as fever, elevated inflammatory markers, and leukocytosis arise because the tumor can elaborate cytokines, creating a clinical picture that closely mimics osteomyelitis, a classic exam distractor.

The tumor is classified histologically as a small round blue cell tumor, a group that also includes lymphoma, rhabdomyosarcoma, and neuroblastoma. All of these appear as sheets of monotonous, small cells with high nuclear-to-cytoplasmic ratios and scant cytoplasm. Therefore, immunohistochemistry and molecular studies are essential to differentiate Ewing sarcoma from its histologic look-alikes. Ewing sarcoma cells characteristically express CD99 (MIC2) on the cell surface, although CD99 is not entirely unique to Ewing sarcoma and must be paired with molecular confirmation of the fusion transcript.

2. Classification and Clinical Manifestation

Ewing sarcoma is part of the Ewing sarcoma family of tumors (ESFT), which share the same translocation-driven biology but differ by site of origin.

SUBTYPE	SITE OF ORIGIN	DISTINGUISHING FEATURES
Classic Ewing sarcoma of bone	Diaphysis/metadiaphysis of long bones; flat bones (pelvis, ribs, scapula)	Most common subtype; lytic permeative bone lesion with onion-skin periosteal reaction
Extraosseous (extraskeletal) Ewing sarcoma	Soft tissues of trunk, extremities, retroperitoneum	No primary bone involvement; presents as a deep soft tissue mass; same translocation and histology
Peripheral primitive neuroectodermal tumor (pPNET)	Bone or soft tissue, particularly chest wall (Askin tumor)	Greater degree of neural differentiation (rosette formation); same EWS-FLI1 translocation; Askin tumor involves the chest wall in young patients

Clinical manifestations can be further organized by disease extent:

FEATURE	LOCALIZED DISEASE	METASTATIC DISEASE
Frequency at diagnosis	Approximately 75%	Approximately 25%
Common sites	Single bone with or without adjacent soft tissue extension	Lung (most common metastatic site), bone/bone marrow, rarely liver or lymph nodes
Symptoms	Localized pain, palpable mass, mild swelling	All localized symptoms plus fever, weight loss, fatigue, cytopenias if marrow is involved
Prognosis (5-year survival)	65 to 75% with current regimens	20 to 30%

3. Diagnostic Workup

TEST	ROLE	KEY FINDINGS
Plain radiograph (X-ray)	Best initial test	Permeative ("moth-eaten") lytic lesion in the diaphysis; lamellated ("onion-skin") periosteal reaction; possible soft tissue mass shadow
MRI of the affected bone (entire bone including joints above and below)	Best test for local staging	Full extent of intramedullary involvement, soft tissue component, neurovascular proximity; skip lesions
CT chest	Metastatic workup	Pulmonary metastases (lung is the most common distant site)
Bone scan (technetium-99m) or PET-CT	Metastatic workup	Other skeletal metastases; PET-CT increasingly preferred for combined metabolic and anatomic staging
Bone marrow biopsy (bilateral iliac crest)	Metastatic workup	Marrow involvement by small round blue cells
Core needle or open biopsy of the lesion	Confirmatory / gold standard step	Sheets of small round blue cells with high nuclear-to-cytoplasmic ratio; strong membranous CD99 (MIC2) positivity
Molecular studies (FISH or RT-PCR)	Most accurate / definitive confirmation	Detection of t(11;22) or variant translocation; EWS-FLI1 (or EWS-ERG) fusion transcript
Serum LDH	Prognostic marker	Elevated LDH correlates with higher tumor burden and worse prognosis
ESR and CRP	Supportive	Often elevated; contributes to the clinical confusion with osteomyelitis
CBC	Baseline and staging	Leukocytosis may be present; cytopenias suggest marrow involvement

Workup logic. When a teenager presents with progressive bone pain, the first step is always a plain radiograph. The combination of a permeative lytic lesion in the diaphysis with an onion-skin periosteal reaction should immediately raise suspicion for Ewing sarcoma. The next step is MRI of the entire involved bone to define the full extent of the tumor within the marrow cavity and any soft tissue extension, which is essential for surgical planning.

Once the imaging is suspicious, a tissue biopsy is required before any treatment. The biopsy must be performed by, or in coordination with, the surgeon who will perform the definitive resection, because a poorly placed biopsy tract can compromise future limb-salvage surgery. Histologically, the pathologist sees uniform small round blue cells. CD99 positivity on immunohistochemistry supports the diagnosis but is not sufficient alone because CD99 can be expressed by lymphoblastic lymphoma and other small round blue cell tumors. Therefore, molecular confirmation with FISH or RT-PCR demonstrating the EWS-FLI1 fusion transcript is the gold standard for definitive diagnosis.

Simultaneously, metastatic staging is completed with CT of the chest (for lung metastases), whole-body bone scan or PET-CT (for skeletal metastases), and bilateral bone marrow biopsies (for marrow involvement). Serum LDH is obtained as a prognostic biomarker: a markedly elevated LDH at diagnosis indicates a larger disease burden and is associated with inferior outcomes.

4. Management and Treatment

PHASE	INTERVENTION	DETAILS
Neoadjuvant chemotherapy	VDC/IE regimen	Vincristine 2 mg/m$^2$ IV (max 2 mg) + Doxorubicin 75 mg/m$^2$ IV + Cyclophosphamide 1200 mg/m$^2$ IV alternating with Ifosfamide 1800 mg/m$^2$/day IV x 5 days + Etoposide 100 mg/m$^2$/day IV x 5 days; cycles every 2 weeks for approximately 12 weeks (typically 6 cycles)
Local control	Surgery (preferred) or radiation therapy	Wide surgical resection with limb salvage when feasible; radiation (45 to 55.8 Gy) reserved for unresectable tumors (e.g., axial/pelvic) or positive margins
Adjuvant chemotherapy	VDC/IE continued	Same regimen continued post-local control to complete a total of approximately 14 cycles (total treatment duration 30 to 49 weeks)
Metastatic disease	Intensified chemotherapy, consider high-dose chemotherapy with autologous stem cell transplant	Whole-lung irradiation (15 to 18 Gy) for patients with lung-only metastases who achieve complete remission with chemotherapy

Treatment logic. Ewing sarcoma is a chemosensitive tumor, and multi-agent systemic chemotherapy is the backbone of therapy. Treatment begins with neoadjuvant (induction) chemotherapy using the VDC/IE protocol, which is the current standard of care. This regimen alternates cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) with cycles of ifosfamide and etoposide (IE), administered every 2 weeks with growth factor support (G-CSF).

The purpose of neoadjuvant chemotherapy is twofold: it treats potential micrometastatic disease early, and it reduces the primary tumor size to facilitate local control. After approximately 12 weeks, the degree of tumor necrosis at the time of surgical resection is assessed. Greater than 90 percent necrosis correlates with improved prognosis.

Local control follows neoadjuvant chemotherapy. Surgical resection with wide margins is preferred whenever it is technically feasible and functional outcomes are acceptable. For tumors in locations where complete resection would cause unacceptable morbidity (such as the pelvis or spine), definitive radiation therapy is used instead. Radiation may also be added post-operatively if surgical margins are positive or close.

After local control, adjuvant chemotherapy using the same VDC/IE regimen is continued to eliminate residual microscopic disease. The total duration of chemotherapy spans approximately 30 to 49 weeks.

Contraindications and precautions to be aware of:

Doxorubicin carries a risk of dose-dependent cardiotoxicity. Cumulative lifetime dose must be monitored (generally not to exceed 375 to 450 mg/m$^2$ in pediatric protocols). Serial echocardiography is required during treatment.
Ifosfamide can cause hemorrhagic cystitis, which is prevented by co-administration of mesna (a uroprotective agent). It is also nephrotoxic and may cause Fanconi syndrome.
Cyclophosphamide also requires mesna and adequate hydration for bladder protection.
Vincristine causes dose-limiting peripheral neuropathy; dose capping at 2 mg per dose is standard.

For patients who present with metastatic disease, the same chemotherapy backbone is used with intensification strategies. Patients with isolated pulmonary metastases who achieve complete remission may benefit from bilateral whole-lung irradiation (15 to 18 Gy) as consolidation. The role of high-dose chemotherapy with autologous stem cell rescue remains investigational and is generally reserved for very high-risk presentations.

5. Differential Diagnosis and Distractors

DIFFERENTIAL	WHY IT IS SIMILAR	KEY DISCRIMINATOR
Osteomyelitis	Bone pain, swelling, fever, elevated ESR and WBC; can look permeative on X-ray	Osteomyelitis typically involves the metaphysis in children, not the diaphysis; usually acute onset with high fever; blood cultures may be positive; no soft tissue mass with onion-skin reaction; clinical improvement with antibiotics
Osteosarcoma	Most common primary malignant bone tumor in adolescents; also causes pain and swelling near a joint	Osteosarcoma favors the metaphysis (distal femur, proximal tibia); X-ray shows a mixed lytic-blastic lesion with sunburst periosteal reaction and Codman triangle; histology shows malignant osteoid production, not small round blue cells
Lymphoma of bone (primary)	Can produce a permeative lytic bone lesion in a young patient; also a small round blue cell tumor	Lymphoma cells are CD45 (LCA) positive and CD99 negative; lack the EWS-FLI1 translocation; may show lymphadenopathy and B-symptoms more prominently
Neuroblastoma (metastatic to bone)	Small round blue cell tumor in a child; bone pain and systemic symptoms	Neuroblastoma occurs in younger children (under 5 years); arises from the adrenal medulla or sympathetic chain; urine catecholamines (VMA, HVA) are elevated; Homer-Wright rosettes on histology
Rhabdomyosarcoma	Another small round blue cell tumor in children/adolescents	Arises from skeletal muscle, not bone; most common in the head/neck or genitourinary tract; desmin and myogenin positive on immunohistochemistry; no EWS translocation
Langerhans cell histiocytosis (eosinophilic granuloma)	Lytic bone lesion in a child or young adult; can cause pain and swelling	Lesion is typically well-circumscribed and punched-out, not permeative; histology shows Birbeck granules on electron microscopy and CD1a / S-100 positivity, not small round blue cells

6. Traps and High-Yield Pearls

The single most common way students lose points on Ewing sarcoma questions is by confusing it with osteomyelitis. The vignette will describe a teenager with bone pain, fever, elevated ESR, and an aggressive-looking bone lesion. Students who anchor on the fever and elevated inflammatory markers reflexively choose osteomyelitis without carefully examining the imaging description. The critical discriminator is the location and imaging pattern: Ewing sarcoma involves the diaphysis with an onion-skin periosteal reaction, while osteomyelitis in children targets the metaphysis and typically lacks a large associated soft tissue mass.

The second common trap is confusing Ewing sarcoma with osteosarcoma. Both occur in teenagers and involve long bones, but the exam will almost always provide enough information to distinguish them. Osteosarcoma sits in the metaphysis, produces a sunburst pattern and Codman triangle on X-ray, and shows malignant osteoid on biopsy. Ewing sarcoma sits in the diaphysis, produces onion-skin layering, and shows small round blue cells on biopsy.

Another high-yield testing point is the histologic category. When a vignette describes a biopsy showing "sheets of small round blue cells" in a bone lesion of a teenager, the answer is almost always Ewing sarcoma. However, the examiner may test whether you know how to confirm it. CD99 positivity supports but does not confirm the diagnosis. The definitive confirmatory test is molecular detection of the EWS-FLI1 fusion via FISH or RT-PCR.

Finally, remember the racial epidemiology. Ewing sarcoma is overwhelmingly a disease of White/European-descent populations and is exceedingly rare in Black and Asian patients. If the vignette describes a primary bone tumor in a Black adolescent, the answer is far more likely to be osteosarcoma than Ewing sarcoma. This demographic detail is a reliable discriminating clue on exam questions.

The core competency being tested is the ability to integrate patient demographics (age, race), lesion location (diaphysis vs. metaphysis), imaging pattern (onion-skin vs. sunburst), histologic appearance (small round blue cells vs. malignant osteoid), and molecular confirmation into a single diagnostic framework, and to resist the distraction of systemic inflammatory signs that mimic infection.

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