Ewing Sarcoma

• Age and demographics: children and adolescents, typically younger than the osteosarcoma peak, with a marked predominance in patients of European ancestry.
• Genetics: the defining lesion is the t(11;22)(q24;q12) translocation producing the EWSR1–FLI1 fusion oncoprotein — "11 + 22 = 33" is the usual mnemonic.
• Site: the diaphysis of long bones (femur, tibia, humerus) and the pelvis and ribs, in contrast to the metaphyseal osteosarcoma.
• Presentation frequently mimics infection: localised pain and swelling with fever, raised inflammatory markers and leukocytosis, so osteomyelitis is the common misdiagnosis and biopsy is essential.
• Radiographs show a permeative, "moth-eaten" lytic lesion with a lamellated "onion-skin" periosteal reaction and often a large soft-tissue mass.
• Histology: sheets of small round blue cells that are PAS-positive (glycogen) and stain for CD99 (MIC2).
• Treatment: it is chemosensitive and radiosensitive — multi-agent chemotherapy followed by local control with surgery, radiotherapy or both. Prognosis is far worse with metastatic disease at presentation, most often to lung, bone and marrow.

Non-modifiable (the stem always names one of these)

• Age: peak in the second decade, with most cases in patients aged roughly 10–20 years. This is younger than the osteosarcoma peak and much younger than the chondrosarcoma/chordoma age range.
• Ancestry: markedly more common in individuals of European descent and distinctly uncommon in patients of African or East Asian ancestry — one of the few solid tumours with such a strong ancestry gradient. This tracks with inherited polymorphisms in GGAA microsatellite regions, the DNA motif the fusion oncoprotein binds, so the germline background modifies how potently the fusion can act.
• Sex: slight male predominance.
• Somatic, not inherited, genetics: the t(11;22)(q24;q12) EWSR1–FLI1 fusion is acquired in a single progenitor cell. It is not transmitted, and unlike osteosarcoma there is no classic cancer-predisposition syndrome association — do not attribute Ewing sarcoma to hereditary retinoblastoma or Li-Fraumeni syndrome, which are the osteosarcoma associations. A modestly increased incidence of second cancers in families has been reported but is not exam-testable as a syndrome.

Non-causes examiners plant as distractors

• Trauma: an antecedent sports injury is frequently mentioned in the stem because it draws attention to the limb; it is a detection bias, not an etiology.
• Prior radiation: causes secondary osteosarcoma, not Ewing sarcoma.
• Paget disease of bone and bone infarct: substrates for osteosarcoma and malignant fibrous histiocytoma in older adults, irrelevant here.
• Chronic osteomyelitis: the great mimic of Ewing sarcoma clinically, but not a risk factor for it.

The fusion event

• t(11;22)(q24;q12) joins the strong N-terminal transactivation domain of EWSR1 (chromosome 22, a FET-family RNA-binding gene) to the C-terminal ETS DNA-binding domain of FLI1 (chromosome 11). The product is a chimeric transcription factor with a constitutively active activation domain physically tethered to sequence-specific DNA recognition.
• Variant fusions (EWSR1–ERG from t(21;22) and other ETS partners) produce an indistinguishable tumour — this is why molecular testing is done with an EWSR1 break-apart probe rather than a single fusion assay.

Why the fusion transforms the cell

• EWSR1–FLI1 binds GGAA microsatellite repeats and converts them into de novo enhancers, switching on genes that are normally silent in the cell of origin (a mesenchymal/neural-crest-like progenitor) while simultaneously repressing differentiation programmes. The result is a primitive, undifferentiated, uniformly small round blue cell with scant cytoplasm and a high nuclear-to-cytoplasmic ratio.
• Downstream targets include CD99 (MIC2), giving the strong membranous CD99 staining, and NKX2-2, the more specific nuclear marker. The cells accumulate cytoplasmic glycogen, which is why they are PAS-positive and diastase-sensitive.

Why the clinical and radiographic picture follows

• The tumour is highly proliferative and spreads permeatively through Haversian and Volkmann canals of cortical bone rather than destroying it in one block — hence the moth-eaten lytic radiograph with an intact-looking cortex but a large extraosseous mass.
• Successive waves of tumour lifting the periosteum trigger repeated bursts of reactive bone deposition in parallel lamellae — the onion-skin periosteal reaction; a Codman triangle may coexist.
• Tumour and stromal cytokine release (IL-6 and related mediators) plus tumour necrosis produce fever, leukocytosis, anaemia and markedly raised ESR/CRP, so the child looks septic. High cell turnover raises LDH, an adverse prognostic marker.
• Early haematogenous dissemination explains metastasis to lung, bone and bone marrow at presentation.

Local features

• Pain: the earliest symptom — deep, progressive, worse at night, and not relieved by rest. Caused by intramedullary expansion and periosteal stretching. Night pain relieved by NSAIDs points instead to osteoid osteoma, a classic distractor.
• Palpable, warm, tender mass: reflects the large extraosseous soft-tissue component, which is often bigger than the bony lesion and is the reason the mass is clinically obvious.
• Site-specific findings: femoral or tibial diaphyseal disease causes limp and antalgic gait; pelvic disease is insidious and presents late with hip/buttock pain or a bulky mass; rib/chest wall disease (the Askin tumour) presents with chest pain, a mass, or a pleural effusion; vertebral disease presents with back pain and radiculopathy or cord signs.
• Pathologic fracture through the permeatively destroyed cortex may be the presenting event.

Systemic features — why this is mistaken for infection

• Fever, malaise, weight loss, leukocytosis, anaemia and markedly elevated ESR/CRP from tumour-derived cytokines and necrosis. Combined with a painful, warm, swollen limb, the picture is indistinguishable from osteomyelitis on presentation — the single most important clinical point in this disease. Failure to defervesce or improve on antibiotics should prompt imaging and biopsy rather than a second antibiotic course.
• Elevated LDH rather than the elevated alkaline phosphatase seen with osteosarcoma.

Step 1 — plain radiograph of the symptomatic bone (always first)

• Permeative, "moth-eaten" lytic diaphyseal lesion with cortical erosion, a lamellated "onion-skin" periosteal reaction, sometimes a Codman triangle, and a soft-tissue mass disproportionately large for the bone destruction. These are aggressive features (wide zone of transition, no sclerotic rim).

Step 2 — MRI with and without contrast of the entire involved bone

• Defines intramedullary extent, the soft-tissue component, neurovascular involvement and skip lesions, and is required for surgical planning. Imaging must precede biopsy so that biopsy artefact does not obscure extent.

Step 3 — biopsy is mandatory and is the diagnostic step examiners want

• Core needle or open biopsy performed at the sarcoma centre that will resect the tumour, through a tract placed in line with the future resection incision. An unplanned biopsy or excision at a non-specialist centre contaminates compartments and can cost the patient a limb — an NCCN emphasis.
• Histology: sheets of monotonous small round blue cells, scant cytoplasm, PAS-positive glycogen (diastase-sensitive), frequent necrosis.
• Immunohistochemistry: strong membranous CD99 (MIC2), nuclear NKX2-2 and FLI1. CD99 is sensitive but not specific — lymphoblastic lymphoma also stains, so add TdT, CD45, LCA and desmin/myogenin to exclude lymphoma and rhabdomyosarcoma.
• Molecular confirmation (gold standard): EWSR1 break-apart FISH or RT-PCR/next-generation sequencing demonstrating an EWSR1–FLI1 (or variant ETS) fusion.

Step 4 — staging and baseline studies

• CT chest for lung metastases, FDG-PET/CT and/or bone scan for skeletal disease, and bone marrow evaluation per NCCN (PET/CT is increasingly used in place of bilateral marrow biopsy).
• LDH, CBC, ESR/CRP; echocardiogram before anthracyclines; fertility counselling before alkylators.
• There is no eponymous scoring system — staging is functionally localised versus metastatic, with post-chemotherapy percentage tumour necrosis in the resected specimen as the key response measure.

Urgent issues first

• Spinal cord compression from vertebral or paraspinal disease — emergency corticosteroids (dexamethasone) with urgent neurosurgical/radiation oncology input.
• Impending or actual pathologic fracture — immobilisation and orthopaedic oncology consultation, not immediate fixation of an undiagnosed lesion.
• Baseline echocardiogram, tumour lysis precautions with hydration in bulky disease, and fertility preservation counselling before alkylating agents.

First-line therapy — neoadjuvant multi-agent chemotherapy (all patients, even apparently localised disease)

• VDC alternating with IE: vincristine, doxorubicin (anthracycline), cyclophosphamide alternating with ifosfamide, etoposide. Interval-compressed (every-2-week) dosing with growth-factor support improved outcomes in localised disease in Children's Oncology Group trials and is standard in the United States.
• Mesna with cyclophosphamide/ifosfamide to prevent haemorrhagic cystitis; G-CSF to support dose density.
• Ewing sarcoma is exquisitely chemosensitive; chemotherapy shrinks the soft-tissue mass, treats micrometastatic disease (without it, most patients relapse despite perfect local control) and makes limb salvage feasible.

Local control after induction (typically after several cycles)

• Wide surgical resection with limb salvage is preferred when negative margins are achievable, because it avoids the growth arrest and second-malignancy risk of radiation in a growing child.
• Definitive radiotherapy for unresectable sites (spine, central pelvis, skull base) or as adjuvant therapy for positive margins/poor necrosis — the tumour is highly radiosensitive.
• Adjuvant chemotherapy then completes roughly a year of total therapy.

Metastatic and relapsed disease

• Same backbone plus local control of the primary; whole-lung irradiation for pulmonary metastases. Relapse regimens include irinotecan/temozolomide, cyclophosphamide/topotecan, or high-dose ifosfamide. Clinical trial enrolment is explicitly preferred by NCCN.

Disease-related

• Pathologic fracture: permeative cortical destruction; sudden pain and deformity after trivial force.
• Metastasis to lung, bone and bone marrow: haematogenous spread of a highly proliferative tumour; signalled by dyspnoea, new multifocal bone pain, or unexplained cytopenias. Metastatic disease at presentation is the dominant driver of poor survival.
• Spinal cord or cauda equina compression (emergency): vertebral/paraspinal mass; progressive back pain with weakness, sensory level, or bladder/bowel dysfunction — image urgently and give corticosteroids.
• Malignant pleural effusion / respiratory compromise from chest-wall (Askin) tumours.
• Delayed diagnosis from misattribution to osteomyelitis, allowing tumour growth during antibiotic courses.

Treatment-related — chemotherapy

• Febrile neutropenia (emergency): dose-dense myelosuppression; fever in a neutropenic child requires immediate cultures and empiric broad-spectrum antipseudomonal beta-lactam therapy.
• Anthracycline cardiomyopathy: doxorubicin-induced topoisomerase-IIβ/oxidative myocyte injury; cumulative, dose-dependent and often late — falling LVEF on surveillance echocardiography, later heart failure.
• Haemorrhagic cystitis: acrolein metabolite of cyclophosphamide/ifosfamide; gross haematuria — prevented with mesna and hydration.
• Ifosfamide nephrotoxicity (proximal tubular injury causing a Fanconi-like syndrome with phosphate wasting and rickets) and ifosfamide encephalopathy (chloroacetaldehyde metabolite; confusion, hallucinations).
• Vincristine neuropathy: microtubule disruption in long axons — areflexia, foot drop, constipation/ileus.
• Infertility and premature gonadal failure from alkylators.
• Secondary malignancy: therapy-related AML/MDS from alkylators and topoisomerase-II inhibitors (etoposide-associated 11q23/KMT2A rearrangements), typically years later.

Treatment-related — local control

• Radiation-induced secondary sarcoma (classically osteosarcoma in the radiation field), growth-plate arrest with limb-length discrepancy and scoliosis, soft-tissue fibrosis and joint contracture.
• Surgical: infection, endoprosthesis loosening or failure, nonunion of allograft, and functional loss after amputation.

• The buzzword triad: onion-skin lamellated periosteal reaction + diaphysis of a long bone + adolescent = Ewing sarcoma. Osteosarcoma is sunburst + Codman triangle + metaphysis (distal femur/proximal tibia). Codman triangle can occur in Ewing too, so anchor on onion-skin and diaphysis.
• The one association examiners test: t(11;22)(q24;q12) → EWSR1–FLI1 (