Ewing Sarcoma

Ewing sarcoma is a highly malignant, undifferentiated small round blue cell tumour of bone (and occasionally soft tissue) that strikes children and adolescents. It is the prototype of the Ewing family of tumours (EFT), unified by the pathognomonic t(11;22) EWS-FLI1 translocation and membranous CD99 (MIC2) positivity. For NEET PG it is a perennial favourite for histology, cytogenetics, radiology, and the "diaphysis vs metaphysis" distinction from osteosarcoma.

Definition & place among bone tumours

Ewing sarcoma is the second most common primary malignant bone tumour in children and adolescents (osteosarcoma is first). It arises most often in the diaphysis (shaft) of long bones and in flat bones (pelvis, ribs, scapula). It was first described by James Ewing in 1921 as a "diffuse endothelioma of bone".

The Ewing family of tumours is a spectrum unified by the same molecular signature:

Tumour	Site	Differentiation
Classic Ewing sarcoma	Bone	Undifferentiated
Extraskeletal (extraosseous) Ewing	Soft tissue	Undifferentiated
PNET (peripheral primitive neuroectodermal tumour)	Bone/soft tissue	Neural (Homer-Wright rosettes)
Askin tumour	Chest wall / thoracopulmonary	Neuroectodermal

High-yield: Ewing sarcoma, PNET and Askin tumour are the same disease at different points of neural differentiation, all carrying the EWS-FLI1 fusion. Askin tumour = Ewing/PNET of the chest wall.

Epidemiology

• Age: peak 5–20 years (most common 10–15 years); rare after 30.
• Sex: slight male predominance (~1.3:1).
• Race: markedly more common in Caucasians; distinctly rare in those of African and East-Asian descent — an exam point reflecting the underlying genetic susceptibility.
• It is the most common bone tumour of the rib and a leading cause of malignant bone tumour in the pelvis of young patients.

Cytogenetics & pathophysiology

Ewing sarcoma is driven by a balanced reciprocal translocation that fuses the EWSR1 gene on chromosome 22 to an ETS-family transcription factor, most commonly FLI1 on chromosome 11.

• t(11;22)(q24;q12) → EWS-FLI1 fusion — present in ~85–90% of cases. This is the single most-tested fact.
• t(21;22)(q22;q12) → EWS-ERG fusion — the second most common (~10%).
• Rarer variants: EWS-ETV1, EWS-E1AF, EWS-FEV.

The chimeric EWS-FLI1 protein acts as an aberrant transcription factor, dysregulating genes that control proliferation, differentiation and apoptosis. The cell of origin is debated but is thought to be a mesenchymal stem cell or neural crest–derived primitive cell.

High-yield: EWS (22) + FLI1 (11) → remember "22 + 11 = Ewing". The fusion can be confirmed by FISH (break-apart EWSR1 probe) or RT-PCR — the molecular gold standard for diagnosis.

Histopathology

The classic appearance is a small round blue cell tumour (SRBCT):

• Sheets of uniform, small round cells with scant cytoplasm and round nuclei with finely dispersed ("salt-and-pepper") chromatin.
• High nuclear-to-cytoplasmic ratio; few mitoses but high cellularity.
• Cytoplasm is rich in glycogen → PAS-positive, diastase-sensitive (glycogen is digested by diastase).
• Homer-Wright rosettes (cells around a central fibrillary core, no lumen) are seen when there is neural/PNET differentiation.

Immunohistochemistry

Marker	Result	Note
CD99 (MIC2 / O13)	Strong membranous positivity	Sensitive but not specific
FLI1	Nuclear positive	Confirms ETS fusion
NSE / S100 / synaptophysin	Positive in PNET variants	Neural differentiation
Vimentin	Often positive	Mesenchymal
Leukocyte common antigen (LCA/CD45)	Negative	Excludes lymphoma
Desmin / myogenin	Negative	Excludes rhabdomyosarcoma

High-yield: CD99 membranous positivity + PAS-positive (diastase-labile) glycogen + t(11;22) is the classic triad. CD99 alone is not specific (also positive in lymphoblastic lymphoma, synovial sarcoma) — confirm with molecular testing.

Differentiating the small round blue cell tumours (SRBCTs)

This is a favourite single-best-answer trap. The differentials and their distinguishing markers:

Tumour	Key marker / clue
Ewing sarcoma / PNET	CD99 (membranous), FLI1, t(11;22), glycogen+
Neuroblastoma	NSE, synaptophysin, ↑urinary VMA/HVA, N-myc, Homer-Wright rosettes, age <5 yr
Rhabdomyosarcoma	Desmin, myogenin, MyoD1; t(2;13) in alveolar type
Lymphoma / leukaemia	LCA (CD45), TdT, CD20/CD3
Small cell osteosarcoma	Produces osteoid
Wilms (blastemal)	WT1, kidney mass

Clinical features

• Localised pain and swelling over weeks to months, classically intermittent and worse at night, progressively becoming constant.
• A palpable, warm, tender mass is common because the tumour often breaks through cortex into surrounding soft tissue.
• Systemic / constitutional symptoms are characteristic and can mimic infection: fever, malaise, weight loss, raised ESR, leucocytosis, anaemia.

High-yield: Ewing sarcoma may mimic osteomyelitis clinically (fever, raised ESR/WBC, bone pain). Always biopsy a "non-resolving osteomyelitis" in a child to exclude Ewing.

• Pathological fracture can be a presenting feature.
• Pelvic and vertebral lesions present late and may cause neurological deficits.

Common sites

The classic teaching: Ewing favours the DIAPHYSIS; osteosarcoma favours the METAPHYSIS.

Most common sites overall → diaphysis/metadiaphysis of femur, followed by pelvis (ilium), tibia, fibula, humerus, and ribs. In young children, flat bones are relatively more often involved.

Radiological features

Plain radiograph is the first investigation; findings reflect aggressive permeative growth:

• "Onion-peel" / "onion-skin" lamellated periosteal reaction — the hallmark, due to successive layers of reactive periosteal new bone. (Note: not pathognomonic — also seen in osteomyelitis and eosinophilic granuloma.)
• Permeative / "moth-eaten" lytic destruction of the diaphysis with ill-defined margins.
• Codman triangle — periosteum elevated at the tumour margin (also seen in osteosarcoma).
• "Sunburst" / spiculated reaction may occasionally be seen.
• A large soft-tissue mass out of proportion to bony destruction is typical and best shown on MRI.

Feature	Ewing sarcoma	Osteosarcoma
Typical age	5–20 yr	10–20 yr (& elderly, Paget)
Bone region	Diaphysis	Metaphysis (around knee)
Matrix	Lytic/permeative	Osteoblastic (osteoid)
Periosteal reaction	Onion-peel	Sunburst + Codman
Genetics	t(11;22) EWS-FLI1	RB1, TP53 mutations
Systemic symptoms	Common (fever, ↑ESR)	Uncommon
Radiosensitive	Yes (very)	No

High-yield: Onion-peel periosteal reaction = Ewing; Sunburst + Codman triangle = osteosarcoma (Codman is shared). Diaphyseal location strongly favours Ewing.

Diagnostic approach (stepwise)

Clinical suspicion → Plain radiograph → MRI of whole bone (local staging, marrow & soft-tissue extent) → Biopsy (core/open) for histology + IHC + molecular FISH/RT-PCR → Staging: CT chest, whole-body PET-CT/bone scan, bilateral bone marrow aspiration & biopsy → Treatment planning by multidisciplinary tumour board.

• Investigation of choice for local extent: MRI (defines marrow involvement, skip lesions, soft-tissue mass — guides surgical margins).
• Definitive / confirmatory diagnosis: Biopsy with IHC (CD99) and molecular confirmation of EWS-FLI1 (FISH or RT-PCR).
• Staging: CT chest (lung is the commonest site of metastasis), PET-CT and/or bone scan, and bone marrow biopsy (marrow is a frequent metastatic site).
• Bloods: raised ESR, LDH (LDH is a prognostic marker — high LDH = worse prognosis), leucocytosis, anaemia.

High-yield: Biopsy must be planned by the treating surgeon so the tract can be excised en bloc later — a poorly placed biopsy contaminates compartments and worsens outcome. Always biopsy before definitive surgery.

Metastasis & staging

• Sites: lungs (most common), bone, and bone marrow. Lymph node spread is uncommon.
• ~25% have detectable metastases at diagnosis, and many more harbour micrometastases — hence systemic chemotherapy is essential in all patients.
• Ewing is staged broadly as localised vs metastatic, the single strongest prognostic divider.

Management — multimodal

Treatment is always multimodal because Ewing is a systemic disease. Sequence:

Neoadjuvant chemotherapy (induction) → Local control (surgery and/or radiotherapy) → Adjuvant (consolidation) chemotherapy.

Chemotherapy (the backbone)

• Given before and after local control; Ewing is highly chemosensitive.
• Standard regimen: VDC/IE — alternating Vincristine + Doxorubicin + Cyclophosphamide with Ifosfamide + Etoposide, given in interval-compressed (every 2 weeks) cycles, which improves outcomes.
• Doxorubicin, cyclophosphamide and ifosfamide are the most active agents.

Local control

• Surgery (wide local excision / limb salvage) is preferred when the tumour is resectable with adequate margins, giving the best local control and avoiding radiation late effects.
• Radiotherapy is reserved for unresectable sites (e.g. pelvis, spine), as adjuvant for positive margins/poor histological response, or where surgery would cause unacceptable morbidity.

High-yield: Ewing sarcoma is one of the most RADIOSENSITIVE bone tumours — radiotherapy is a genuine local-control option. Osteosarcoma, by contrast, is radioresistant. This single fact is a classic distinguishing MCQ.

Metastatic / relapsed disease

• Metastatic disease still receives intensive chemotherapy + local control; lung metastases may be treated with whole-lung irradiation.
• High-dose chemotherapy with autologous stem-cell rescue is used in selected high-risk/relapsed cases.

Prognosis

• Overall, localised disease has a 5-year survival of ~65–75% with modern multimodal therapy; metastatic disease falls to ~20–30%.

Favourable factors: localised disease, distal extremity tumour, small tumour volume, good histological response to neoadjuvant chemo (>90–95% necrosis), normal LDH, younger age.

Adverse factors: metastases at diagnosis (especially bone/marrow worse than lung-only), axial/pelvic primary, large volume, high LDH, poor chemo response.

High-yield: Histological response to neoadjuvant chemotherapy (% tumour necrosis) is the most important treatment-related prognostic factor — mirrors the Huvos grading used in osteosarcoma.

Complications

• Pathological fracture through weakened bone.
• Metastatic spread (lung, bone, marrow).
• Treatment-related: anthracycline (doxorubicin) cardiotoxicity; cyclophosphamide/ifosfamide haemorrhagic cystitis (prevent with mesna + hydration); secondary malignancies — therapy-related AML/MDS (alkylators, etoposide) and radiation-induced sarcoma; growth disturbance/limb-length discrepancy after radiation in children; infertility.

Key differentials (quick recall)

• Osteomyelitis — fever, raised ESR, onion-peel reaction; the great clinical mimic → biopsy resolves it.
• Osteosarcoma — metaphyseal, osteoid-forming, sunburst, radioresistant.
• Eosinophilic granuloma (Langerhans cell histiocytosis) — "great mimicker", can also give onion-peel/lytic lesions in children.
• Metastatic neuroblastoma — in children <5 yr, raised VMA/HVA.
• Lymphoma of bone, acute leukaemia — small round cell, LCA/TdT positive.
• Acute osteomyelitis vs Ewing is the classic "do not miss" pairing.

Mnemonics

• "CD99 + onion + 11:22 = Ewing" — links the three signature facts.
• SRBCTs — "LEARN": Lymphoma/Leukaemia, Ewing/PNET, A (rhAbdomyosarcoma), Retinoblastoma, Neuroblastoma/Nephroblastoma (Wilms) — the differential list of small round blue cell tumours.
• "Ewing Eats the shaft" — diaphyseal location; osteosarcoma sits at the metaphysis.

Recently asked / exam angle

• Cytogenetics: "Translocation in Ewing sarcoma?" → t(11;22)(q24;q12), EWS-FLI1 — asked almost every year. Also know EWS-ERG = t(21;22).
• IHC: "Most useful immunohistochemical marker?" → CD99 (MIC2), membranous. Trap: CD99 is also positive in lymphoblastic lymphoma → confirm with FISH.
• Radiology image-based: "Onion-peel periosteal reaction" diaphyseal lesion in a child → Ewing. Contrast with sunburst/Codman = osteosarcoma.
• Histology: PAS-positive, diastase-sensitive cytoplasmic glycogen; Homer-Wright rosettes indicate PNET differentiation (vs Flexner-Wintersteiner rosettes in retinoblastoma — a common distractor).
• Clinical: child with bone pain, fever, raised ESR mimicking osteomyelitis → think Ewing.
• Treatment: "Most radiosensitive bone tumour" → Ewing sarcoma. "Drug regimen" → VDC/IE.
• Eponyms: Askin tumour = chest-wall Ewing/PNET; James Ewing first description.
• Prognosis: raised LDH = poor prognosis; metastasis at presentation = strongest adverse factor.

Rapid revision

1. Ewing sarcoma = 2nd most common malignant bone tumour in children (after osteosarcoma).
2. Diaphysis of long bones and flat bones (pelvis, ribs); femur most common bone overall.
3. Genetics: t(11;22)(q24;q12) → EWS-FLI1 (~85–90%); second = t(21;22) EWS-ERG.
4. Histology: small round blue cell tumour; PAS-positive, diastase-sensitive glycogen.
5. IHC: CD99 (MIC2) membranous + FLI1 positive; LCA/desmin negative.
6. Radiology: onion-peel lamellated periosteal reaction, permeative lytic lesion, large soft-tissue mass; Codman triangle may occur.
7. Clinically mimics osteomyelitis — fever, raised ESR/WBC, bone pain.
8. MRI = best for local extent; biopsy + molecular FISH/RT-PCR = definitive diagnosis.
9. Metastasis to lung (commonest), bone, marrow; ~25% metastatic at diagnosis.
10. Most radiosensitive bone tumour — radiotherapy is a real local-control option.
11. Treatment is multimodal: neoadjuvant chemo (VDC/IE) → surgery ± RT → adjuvant chemo.
12. Prognosis: localised ~65–75% 5-yr survival; raised LDH and metastasis = poor; % necrosis post-chemo = key prognostic marker.