Orthopaedic Surgery - Ewing Sarcoma

Basics

Ewing sarcoma is a high-grade malignant small round-cell tumor that most commonly arises in bone during childhood and adolescence.

It frequently affects the long bones, pelvis, and spine, with the diaphysis or metadiaphysis of long bones being characteristic locations.

Bone pain is the most common presenting symptom.

Systemic Features

Unlike many other primary bone tumors, Ewing sarcoma may produce systemic manifestations.

Patients may develop fever, malaise, weight loss, leukocytosis, and an elevated erythrocyte sedimentation rate, sometimes creating a clinical picture that resembles infection.

Spinal Disease

When the tumor involves the spine, patients may develop nerve-root irritation, radicular symptoms, or neurologic dysfunction from local extension.

Classification

Ewing sarcoma has traditionally been staged using the Musculoskeletal Tumor Society, or Enneking, staging system.

Because Ewing sarcoma is considered a high-grade malignancy, localized lesions are frequently classified as high-grade tumors, and many extend beyond the original bone compartment.

Metastatic Disease at Presentation

Approximately 20–25% of patients may have detectable metastatic disease at diagnosis.

The lungs and other bones are the most common metastatic sites.

Synonym

Ewing sarcoma has historically been categorized among the small round-cell sarcomas.

Epidemiology

Frequency

Ewing sarcoma is the second most common primary malignant bone tumor of childhood, after osteosarcoma.

Age

The disease occurs predominantly in children, adolescents, and young adults.

Most patients are younger than 25 years, while occurrence in children younger than 3 years is uncommon.

Sex

Males are affected somewhat more frequently than females.

Ethnic Distribution

Ewing sarcoma is considerably more common in individuals of European ancestry and is rare in many non-Caucasian populations.

Genetics

A characteristic molecular abnormality is a reciprocal chromosomal translocation, most commonly t(11;22)(q24;q12).

This rearrangement produces an EWSR1-FLI1 fusion gene, which encodes an abnormal transcription factor involved in tumor development.

Other Molecular Rearrangements

Less common EWSR1-related fusion partners can occur, but EWSR1-FLI1 is the classic and most frequent abnormality.

Molecular testing is useful in confirming the diagnosis when the histologic appearance is uncertain.

Etiology

The exact cause of Ewing sarcoma is unknown.

There is no established environmental exposure or inherited syndrome responsible for most cases.

The characteristic chromosomal rearrangement is acquired within the tumor cells rather than usually being inherited.

Diagnosis

Signs and Symptoms

The typical patient presents with localized bone pain and tenderness that have been present for several weeks or months.

Symptoms may initially be attributed to a sports injury or musculoskeletal strain.

Soft-Tissue Mass

As the tumor enlarges and extends beyond the cortex, a palpable soft-tissue mass may develop.

The mass may be firm, tender, and associated with local warmth or swelling.

Constitutional Symptoms

Some patients develop fever, fatigue, malaise, anorexia, or weight loss.

These symptoms, together with elevated inflammatory markers, can make Ewing sarcoma difficult to distinguish initially from osteomyelitis.

Pathologic Fracture

Occasionally, the tumor weakens the involved bone sufficiently to produce a pathologic fracture.

Physical Examination

Early Disease

The physical examination may be relatively normal during the early stages.

Pain can precede a palpable mass or visible swelling.

Advanced Local Disease

As the soft-tissue component enlarges, the examiner may identify swelling, tenderness, warmth, or a palpable mass over the involved bone.

Neurologic Examination

Patients with spinal or pelvic tumors should undergo careful neurologic examination because nerve roots, the spinal cord, or major peripheral nerves may be affected by local extension.

Laboratory Tests

Complete Blood Count

A complete blood count should be obtained.

Leukocytosis may occur, although it is nonspecific.

ESR and Other Studies

The erythrocyte sedimentation rate may be elevated.

Electrolytes and general baseline laboratory studies are also obtained before systemic therapy.

Bone Marrow Evaluation

Bone marrow aspiration and biopsy have historically been included in staging because marrow involvement may occur.

Their use depends on contemporary staging protocols and the presence of other evidence suggesting disseminated disease.

Biopsy

Tissue diagnosis is mandatory before definitive treatment.

When the tumor has a substantial soft-tissue component, biopsy can often be performed through the extraosseous portion, avoiding unnecessary penetration of additional uninvolved bone.

Biopsy should be carefully planned with the orthopedic oncology team so that the biopsy tract can be removed during definitive resection.

Imaging

Plain Radiographs

Plain radiographs are essential for initial evaluation.

They commonly demonstrate an aggressive lytic lesion arising in the diaphysis or metadiaphysis, although appearances vary.

The fibula is one of the characteristic long-bone sites.

Bone Destruction

Radiographs may show a large region of permeative or destructive bone loss.

The margins are often poorly defined, reflecting aggressive tumor growth.

Reactive Bone Formation

Variable amounts of reactive new bone may be present.

This can create a mixed lytic and sclerotic appearance.

Periosteal Reaction

A characteristic feature is a layered periosteal reaction sometimes described as an “onion-skin” appearance.

Other aggressive periosteal patterns may also occur.

Soft-Tissue Extension

The tumor commonly extends through the cortex into adjacent soft tissue.

A large soft-tissue mass may be present despite relatively modest radiographic bone destruction.

Early Radiographs

Very early disease may occasionally be subtle or even appear relatively normal on plain radiographs.

Persistent unexplained bone pain therefore warrants further evaluation when clinical concern remains high.

MRI

MRI is the most important modality for defining the local extent of the primary tumor.

It demonstrates medullary involvement, soft-tissue extension, neurovascular relationships, adjacent joint involvement, and the longitudinal extent of disease.

MRI is also essential for surgical planning.

Chest Imaging

Because the lung is a common site of metastasis, staging includes chest imaging.

Chest CT is more sensitive than plain chest radiography for detecting pulmonary metastases.

Skeletal Staging

Whole-body skeletal imaging is performed to search for bone metastases.

Historically, technetium bone scintigraphy has been used, although current staging may incorporate additional whole-body imaging according to institutional protocols.

Pathological Findings

Small Round Blue Cells

Histologically, Ewing sarcoma consists of numerous small, round, relatively uniform malignant cells that stain deeply blue on hematoxylin and eosin preparations.

Cellular Appearance

The cells are densely packed and contain scant cytoplasm.

Cell borders may be indistinct, giving the microscopic field a somewhat blurred or “out-of-focus” appearance.

Immunohistochemistry

Immunohistochemical staining is used to support the diagnosis.

Strong membranous expression of CD99 is characteristic but not completely specific.

Molecular demonstration of an EWSR1-related fusion provides additional diagnostic confirmation.

Differential Diagnosis

Osteomyelitis

Ewing sarcoma is most commonly confused clinically with osteomyelitis.

Both can present with pain, fever, elevated inflammatory markers, and an aggressive-appearing bone lesion.

Biopsy is often necessary when the distinction is uncertain.

Neuroblastoma

Metastatic neuroblastoma can mimic Ewing sarcoma histologically, particularly in children younger than 5 years.

Age, clinical context, immunohistochemical staining, and molecular testing help distinguish the two.

Lymphoma

Primary or secondary lymphoma involving bone may also resemble Ewing sarcoma.

This is especially important in younger children.

Appropriate lymphoid markers help establish the diagnosis.

Rhabdomyosarcoma

Rhabdomyosarcoma is another small round-cell malignancy that may enter the differential diagnosis.

Muscle-specific markers such as desmin and myogenic regulatory proteins help distinguish it.

Eosinophilic Granuloma

Langerhans cell histiocytosis, particularly eosinophilic granuloma, may produce a destructive bone lesion and should be considered in children and young adults.

Metastatic Disease

In adults, particularly those older than approximately 30 years, metastatic carcinoma and other secondary malignancies should also be considered.

Treatment

General Principles

Treatment requires multimodal therapy.

Systemic chemotherapy is essential because Ewing sarcoma is regarded as a systemic disease even when metastases are not detectable at diagnosis.

Local control is achieved with surgery, radiotherapy, or a combination of both.

Chemotherapy

Multiagent chemotherapy is a central component of treatment.

Specific agents and treatment schedules vary according to current pediatric or adult oncology protocols.

The goals are to treat micrometastatic disease, shrink the primary tumor, and reduce the risk of recurrence.

Radiotherapy

Ewing sarcoma is relatively radiosensitive.

External-beam radiotherapy may be used as definitive local treatment when surgery would cause unacceptable morbidity, or it may be combined with surgery when margins are inadequate or local control remains uncertain.

Radiation Planning

The treatment field must encompass the involved tumor volume while protecting surrounding normal structures as much as possible.

Long-term radiation effects are especially important in children.

Surgery

Role of Surgery

Surgery has become an important method of obtaining local control whenever the tumor can be removed safely with an acceptable functional result.

Surgical Margin

When resection is performed, the objective is a wide surgical margin with complete removal of the tumor.

Limb Salvage

Limb-salvage surgery is possible in the great majority of extremity cases.

Amputation is now uncommon and is reserved for selected unresectable or severely complicated lesions.

Expendable Bones

Wide resection is particularly suitable when the tumor involves relatively expendable bones such as the fibula, iliac wing, or clavicle, where removal may produce less functional loss.

Physical Therapy

Physical therapy is used during and after treatment to maintain joint range of motion, muscle strength, mobility, and functional independence.

Rehabilitation requirements vary substantially according to tumor location and the reconstructive procedure performed.

Follow-Up

Prognosis

Modern multimodal treatment has substantially improved survival.

Historical series report approximately 60–70% 5-year survival for patients treated with contemporary chemotherapy and local control, with outcomes being best for localized disease.

Adverse Prognostic Sites

Tumors arising in the pelvis or spine generally have a less favorable prognosis than tumors of the extremities.

This relates partly to larger tumor size, difficulty obtaining wide surgical margins, and proximity to critical structures.

Metastatic Disease

Patients presenting with metastases have a substantially worse prognosis than those with localized tumors.

Pulmonary-only metastases generally carry a better prognosis than widespread bone or bone-marrow metastases.

Complications

Radiation-Associated Sarcoma

A secondary sarcoma may rarely arise within a previous radiation field several years after treatment.

Historical rates of post-radiation sarcoma have been approximately 2–4% in some series.

Pathologic or Treatment-Related Fracture

Fracture may occur in irradiated or surgically reconstructed bone.

The proximal femur is particularly vulnerable after treatment involving this region.

Osteonecrosis

Patients treated for pelvic or proximal femoral tumors may develop osteonecrosis of the femoral head, particularly after radiation or extensive local therapy.

Functional Impairment

Muscle weakness, joint stiffness, growth disturbance, limb-length discrepancy, and gait abnormalities may develop following surgery or radiation in skeletally immature patients.

Metastatic Surveillance

Pulmonary Metastases

The lungs are a common site of recurrence.

Historically, chest CT has been obtained every 3–4 months for the first 2–3 years, then approximately every 6 months until 5 years, with less frequent long-term surveillance thereafter.

The exact schedule should follow the treating oncology protocol.

Bone Metastases

Bone metastases have traditionally been monitored using radionuclide bone scanning or other whole-body imaging.

Surveillance is most intensive during the first several years after treatment, when recurrence risk is greatest.

Local Recurrence

Local recurrence may occur despite therapy.

Historical rates have been approximately 10–30% after chemotherapy combined with radiation and lower, around 5–10%, after chemotherapy combined with complete surgical resection, although rates vary substantially according to tumor site, stage, and margin status.

Imaging for Local Recurrence

MRI or CT can be used to evaluate the primary site when no large metallic prosthesis interferes with imaging.

In patients with reconstructive implants, surveillance may rely more heavily on plain radiographs, physical examination, and appropriately selected cross-sectional imaging.

Patient Monitoring

Follow-up should include surveillance for local recurrence, pulmonary metastases, skeletal metastases, treatment toxicity, secondary malignancy, growth disturbance, fracture, and functional impairment.

The first several years after treatment require the most intensive surveillance because the risk of recurrence is highest during this period.