Ewing Sarcoma

Ewing sarcoma is the second most common primary bone malignancy in children and adolescents, after osteosarcoma, and accounts for 10-15% of all primary bone tumours. Before chemotherapy arrived in the 1970s five-year survival was under 10%; multimodal treatment has taken it to 70% for localised disease. It is a highly aggressive small round cell tumour and it is treated urgently.

Who. Three quarters of patients are aged 10-20, a further 15% are 20-30, and only 10% are over 30. Males outnumber females 1.5:1. About 85% of patients are white, and the tumour is rare in African and Asian populations.

Where. The femur and the pelvis are the commonest sites:

• Femur - 25%, the commonest single site
• Pelvis - 20%, the worst prognosis of any site because of the size these tumours reach
• Tibia and fibula - 15%
• Humerus - 10%
• Ribs - 10%
• Axial skeleton - 20% (vertebrae, scapula)

The diaphysis. In 90% of extremity cases the tumour sits in the diaphysis of a long bone, which distinguishes Ewing from osteosarcoma, a metaphyseal tumour; lymphoma of bone may occupy either the metaphysis or the diaphysis. A pelvic tumour lies deep and its symptoms are delayed, so it is often large by the time anyone finds it; axial disease can present late, with neurological or visceral symptoms.

It is not only a bone tumour. True Ewing sarcoma is one member of the Ewing sarcoma family of tumours (ESFT), a group unified by the same EWSR1-ETS fusion, and the same CD99/NKX2-2 phenotype, regardless of where it arises. The members are skeletal Ewing sarcoma, extraskeletal (extraosseous) Ewing sarcoma arising primarily in soft tissue with no bone of origin, the Askin tumour (Ewing of the chest wall and thoracopulmonary region), and peripheral primitive neuroectodermal tumour (pPNET), the more neurally differentiated end of the same spectrum.

Extraskeletal Ewing tends to occur in slightly older patients and in axial, paraspinal or chest-wall sites. It is treated on the same multi-agent chemotherapy backbone as bone Ewing, but local control follows soft-tissue sarcoma surgical principles: wide excision of the soft-tissue mass, with radiotherapy where margins are constrained. The unifying concept for a viva is that the Ewing family is defined by its molecular fusion, not by whether it started in bone.

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The fusion. The t(11;22)(q24;q12) translocation joins EWS to FLI1 and creates the EWS-FLI1 fusion oncogene in 85% of cases; the remaining 15% carry variant translocations such as EWS-ERG. The fusion product behaves as an aberrant transcription factor, driving uncontrolled proliferation of primitive neuroectodermal cells. FISH or RT-PCR for an EWS rearrangement is mandatory for diagnosis: it confirms Ewing sarcoma and separates it from the other small round cell tumours.

The cells. Sheets of small, round, blue cells with a high nuclear-to-cytoplasmic ratio, arising from primitive neuroectodermal cells (mesenchymal stem cells). The cytoplasm holds PAS-positive glycogen, and the cells express CD99 (MIC2) strongly, in a diffuse membrane pattern, with nuclear NKX2-2 and FLI1 supporting the diagnosis. None of the three is specific on its own.

How it grows. Permeative growth through the marrow spaces, lytic destruction of the cortex, periosteal reaction in an onion-skin or sunburst pattern, and extensive soft-tissue extension are all characteristic. Spread is early and haematogenous, to lung, bone and bone marrow.

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Ewing sarcoma is always high-grade, so of the Enneking stages only IB, IIB and III are ever used, and most tumours are IIB at presentation: high-grade, extracompartmental, no metastases. The system asks three questions — grade, compartment, metastases — and the compartment is the one worth getting right. Intracompartmental means the tumour is confined within the bone cortex or within a single anatomic compartment such as the anterior thigh; extracompartmental means it has broken through the cortex into soft tissue, or has crossed an anatomic barrier such as a joint or a neurovascular bundle.

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The history. Localised bone pain in 90%, progressive and worse at night, with a palpable soft-tissue mass in 60%. Systemic features are common: fever in 30%, weight loss, malaise. Symptoms have usually run for 2-6 months before the diagnosis is made, an average of 3, and 30% report an injury beforehand, which is coincidental rather than causative.

The examination. Visible swelling, skin erythema and venous distension over a warm, tender mass, with soft-tissue extension common. A lower limb tumour produces a limp and a restricted range of movement. The neurovascular structures are usually intact, because invasion is rare, and regional nodes are rarely involved, unlike soft tissue Ewing.

The trap. Around 30% of patients arrive with fever, a raised white cell count and a raised ESR, and are treated for osteomyelitis. The features that separate them are the duration, months rather than weeks, the diaphyseal location, and the large soft-tissue mass.

Radiographs first. AP and lateral views of the affected bone plus the joint above and below. The classic picture is a permeative lytic lesion in the diaphysis with moth-eaten bone destruction, a wide zone of transition, onion-skin (lamellated) periosteal reaction, a Codman triangle of elevated periosteum, and a large soft-tissue mass. A sunburst pattern occurs but is less common than in osteosarcoma. The periosteal reaction is suggestive rather than pathognomonic: infection and other aggressive tumours stay in the differential until the biopsy returns.

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MRI with contrast is the gold standard for local extent. It defines intramedullary involvement, soft-tissue extension, the neurovascular relationship and skip lesions, and it is what the surgical plan is built on. Marrow signal is low on T1 and high on T2 along with the surrounding oedema, and viable tumour enhances heterogeneously. Map the entire involved bone, including marrow length, cortical breach, the soft-tissue component and the joint: the soft-tissue mass may be disproportionately large compared with the radiographic osseous change.

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CT answers a different question. It shows cortical destruction and any mineralisation, while MRI shows the marrow and the soft tissues. Stage the whole compartment on both, and never choose a biopsy trajectory before the MRI has been reviewed.

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Staging is whole-body, and it is completed before treatment starts.

• High-resolution CT chest for pulmonary metastases: present in 15% at diagnosis, and the nodules may be under 5mm. Repeat every 3 months during treatment
• PET-CT or bone scan for skeletal metastases: 10% at diagnosis. PET-CT also tracks chemotherapy response, a falling SUV indicating a good response
• Bilateral iliac crest marrow aspirate and biopsy for marrow disease: 5% at diagnosis, and it carries a prognosis similar to metastatic disease

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The bloods support a suspicion rather than settle it. Anaemia in 30% and leucocytosis in 25%; ESR and CRP raised in 50%, non-specifically; LDH raised in 60%, where it carries prognostic weight. Alkaline phosphatase is normal or mildly raised. Renal and hepatic function are the baselines chemotherapy will be judged against.

Histology decides. Sheets of uniform small round blue cells; PAS-positive glycogen, diastase-sensitive; CD99 (MIC2) strong and diffuse on the membrane in 95%; and the EWS-FLI1 fusion on FISH or RT-PCR in 85%. The negative stains earn their place too: LCA negative argues against lymphoma, desmin negative against rhabdomyosarcoma.

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Chemotherapy comes before surgery, always. Ewing sarcoma is a systemic disease from the day it is found, and local control waits 10-14 weeks while induction chemotherapy runs. Treating first does three things an operation cannot: it treats micrometastases early, it shrinks the tumour so that resection is easier and a borderline case may convert to limb salvage, and it measures chemosensitivity in a resected specimen, where over 90% necrosis marks the good responder.

Algorithm

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Choosing local control. Surgery is preferred wherever it is feasible. Local recurrence runs 5-10% after surgery against 10-20% after radiotherapy, surgery avoids radiation-induced growth arrest in a skeletally immature patient and the 1-2% at 10 years risk of radiation-induced sarcoma, and only a resected specimen yields a necrosis figure. Ewing is radiosensitive, though, and definitive radiotherapy achieves excellent local control at the sites — pelvis, spine, skull base — where resection would carry unacceptable morbidity.

Necrosis is the factor treatment can change. Over 90% tumour necrosis after neoadjuvant chemotherapy carries 75% five-year survival against 50% below that threshold, and it sets the intensity of what follows: good responders continue the standard protocol, poor responders are considered for an intensified regimen or a trial. For local control, though, surgical margins matter more than necrosis.

Size and margins. A tumour over 8cm does worse than one under 8cm, and it is positive or marginal margins, not the necrosis figure, that drive local recurrence.

Age. Younger patients do better than older ones. The quantified comparison below draws the line at 15 years, and the adverse group has also been defined as those over 18.

The goal. An en bloc resection through normal tissue with the pseudocapsule intact, reconstructed so that the limb works and so that adjuvant chemotherapy can restart on time. Wound healing is part of the oncological plan, because the adjuvant chemotherapy waits for it.

Enneking's margins name what was actually achieved, and the words matter in a viva:

• Intralesional - through tumour, inadequate
• Marginal - through the reactive zone, high recurrence
• Wide - through normal tissue, the goal for cure
• Radical - the entire compartment, rarely needed

Timing. Surgery follows 10-14 weeks of chemotherapy, once the patient has recovered from its toxicity and the counts allow — platelets over 100 and white cells over 3 — which is usually 2-3 weeks after the last cycle. Coordinate the date with the oncology team rather than announcing it.

The biopsy tract goes with the specimen. Whether the diagnosis came from an incisional or a needle biopsy, the tract is contaminated tissue and is excised en bloc; nothing contaminated may be left behind.

Margins. Aim for 2-3cm of soft tissue where the anatomy allows, 2cm being the usual working figure, with a cuff of normal muscle around the tumour. Structures that have been contaminated are sacrificed with the specimen, and frozen section of the margins intraoperatively confirms what has been achieved. The specimen itself goes to pathology fresh, for assessment of necrosis. Neurovascular structures are preserved if they are not encased, which is usually the case.

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Neurovascular judgement is made on the imaging, before the incision. MRI shows the relationship, angiography is added if encasement is suspected, and a vascular surgeon is involved early if a bypass is likely.

• A vessel displaced but not encased is preserved
• An encased vessel is sacrificed and reconstructed
• A critical nerve is sacrificed only if it is encased

Soft-tissue cover is planned with the resection. Anticipate the defect, and choose between local muscle flaps — gastrocnemius, soleus, latissimus — and a free flap for a large defect, with plastic surgical input where needed. Chemotherapy delays healing, so close without tension, keep drains away from the prosthesis, and allow for postoperative radiotherapy if the margins are close.

Reconstruction follows the defect:

• Endoprosthetic replacement with a modular tumour prosthesis, the commonest choice for long bones
• Structural allograft, or an allograft-prosthetic composite
• Vascularised fibula for an intercalary defect
• Rotationplasty as a specialised limb-sparing option
• Amputation where limb salvage is not safe

Tumour prostheses, custom or modular, allow the length to be set on the table, are cemented or press-fit, and come as growing designs for the skeletally immature. The sequence is fixed: resect en bloc with wide margins, measure the resection length precisely, prepare the bone, assemble the modular components, fix them, reconstruct the soft tissues around the prosthesis, and close over drains.

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Rotationplasty (the Van Nes procedure) is for the young patient with a distal femoral or proximal tibial tumour in whom conventional limb salvage would give poor function. The tumour-bearing segment is resected and the distal limb rotated 180 degrees, so that the knee becomes the new hip and the ankle the new knee: plantarflexion now does the work of knee flexion, and the patient is fitted with a below-knee type prosthesis. Function is better than after an above-knee amputation, and the cosmetic price is the reason it needs discussing honestly.

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With modern technique and multimodal therapy, limb salvage achieves oncological outcomes equivalent to amputation, which is exactly why the margin can never be traded for the reconstruction.

Treatment is long, and the chemotherapy complications are predictable from the agents, which is why the regimen is worth knowing drug by drug.

Radiotherapy's complications follow the field and the age of the patient: growth arrest where the field crosses a physis in a skeletally immature patient, radiation-induced sarcoma in 1-2% at 10 years with a latency of 5-20 years, pathological fracture through weakened bone in 5-10%, and soft-tissue fibrosis with chronic pain and reduced movement. IMRT and proton therapy reduce all of these significantly compared with older techniques.

Late effects outlive the treatment. Infertility follows alkylating agents and pelvic radiotherapy in 20-40%, which is why fertility preservation is discussed before the first cycle rather than after it. Ifosfamide leaves nephrotoxicity in 10-20%, and second malignancies reach 5-10% at 20 years after radiotherapy and alkylating agents, so surveillance is lifelong. Growth disturbance in a child irradiated across a physis needs limb-length monitoring.

Metastatic progression is the disease's own complication, and the lung is where it happens.

• Lung: metastases in 15% at diagnosis, and a further 30% develop them during treatment. Detected on three-monthly CT chest. Treated with intensified chemotherapy, surgical resection if oligometastatic (under 5 nodules), or whole lung radiation if unresectable. Five-year survival 30%
• Bone and bone marrow: 10% bone and 5% marrow at diagnosis, found on PET-CT or bone scan and bilateral marrow biopsy. Treated with systemic chemotherapy and radiotherapy to symptomatic sites. Five-year survival 25%, similar to lung metastases
• Local progression: pathological fracture in 10%, neurovascular compression, and rarely compartment syndrome

Metastatic disease at presentation is the worst prognostic factor, reducing five-year survival from 70% to 25-30%.

The wound sets the pace. Closed suction drainage comes out when the output falls under 30 mL/24h, and the wound is inspected daily for haematoma and infection. Analgesia and mobilisation are the other tasks of the first few days. Perioperative antibiotics cover 24-48 hours, dressings are changed cleanly, and the threshold for suspecting infection stays low, because these patients are immunosuppressed and an endoprosthesis is unforgiving.

Rehabilitation is dictated by the reconstruction. After an endoprosthesis, partial weight-bearing with crutches starts immediately and progresses to full over 4-6 weeks, earlier than any biological reconstruction allows; high-impact activity is avoided for life, and the implant is watched for the rest of the patient's life for loosening, infection and implant failure, with revision for wear or loosening in a proportion of patients. An allograft is protected for 3-6 months until serial radiographs show incorporation, and it carries its own risks: nonunion 10-20%, allograft fracture 15-25%, infection 10-15%, and resorption over time. Range of motion begins when the wound is stable, under physiotherapy, with occupational therapy for an upper limb reconstruction and walking aids for as long as they are needed.

Chemotherapy restarts within 2-4 weeks, once the wound has healed and the counts have recovered, taking the total treatment duration to approximately 12 months, and the resected specimen is reported before then: percent necrosis, which grades the response, and margin status, which decides whether radiotherapy is added. Both change what happens next, so chase the report.

Surveillance is intensive early because the lung is the site that fails. CT chest and MRI of the local site run every 3 months for 2 years, every 6 months to year 5, then annually thereafter, or as the institutional protocol dictates, with the first reassessment at about three months. Alongside it, monitor cardiac function for doxorubicin, renal function for ifosfamide, fertility, and second malignancy, particularly after radiotherapy.

Survival tracks two things: whether there were metastases at diagnosis, and how the tumour answered the chemotherapy.

Function after limb salvage is good rather than normal: most patients reach 70-85% of the MSTS functional score (Enneking) (Enneking), an upper limb reconstruction preserves hand function, and a lower limb reconstruction leaves the patient walking with or without aids, with quality of life comparable to amputation. The long-term costs are an endoprosthesis needing revision in 10-20% at 10 years, leg length discrepancy in a growing child, a permanent ban on high-impact activity, and chronic pain in some patients.

After amputation survival is oncologically equivalent, prosthetic function is generally good, and some studies report higher rates of activity participation; there are no implant-related complications and the solution is more durable. What it costs is body image, and that deserves the same honest conversation as the functional gain.

Recurrence declares itself locally or distantly, and the distant pattern dominates. Local recurrence runs 10-15% where the margins were adequate and radiation was given, and is higher with inadequate margins; it is treated with re-resection where possible, radiotherapy and chemotherapy, with 20-30% long-term survival afterwards. Distant recurrence goes to the lungs in 50-60% of cases, and also to bone, bone marrow and other soft tissues; treatment is systemic chemotherapy with or without local control of the metastases, and five-year survival is 15-25%.

With modern multimodal therapy most patients with localised Ewing sarcoma are cured, and metastatic disease remains a significant challenge. Completing the chemotherapy is what controls the disease systemically.

Global Epidemiology

Ewing sarcoma is the second most common primary bone malignancy in children and adolescents, with an annual incidence of approximately 1 to 3 per million in populations of European ancestry. It is markedly less common in populations of African and East Asian ancestry, a disparity now attributed in part to germline variation at the EGR2 locus and ancestry-related differences in regulatory microsatellites. Population-based registry data (SEER) confirm a male predominance and a peak in the second decade, and identify pelvic/axial site, tumour size over 8cm, older age and metastatic extent as the principal adverse-risk factors (Shi 2020).

Practice Variation

The principal axis of international variation is high-dose chemotherapy with autologous stem-cell rescue: European protocols (EE2008/R2) incorporate busulfan-melphalan consolidation for selected high-risk localised patients, whereas North American practice has not adopted routine high-dose consolidation. Interval-compressed chemotherapy is standard in paediatric North American practice but is applied more selectively in adults. Relapsed/refractory disease is increasingly managed within the international rEECur platform, which is establishing the most active salvage regimen. Across all systems, care is mandated within designated bone-sarcoma reference centres with a specialist multidisciplinary team (orthopaedic oncologist, paediatric/medical oncologist, radiation oncologist, radiologist, pathologist).