Ewing Sarcoma Explained: Causes, Symptoms, and Treatment

Medically Reviewed by Dr. Sony Sherpa, (MBBS)

Fact Checked by Dr. Rae Osborn, Ph.D.

Ewing sarcoma is a rare and aggressive cancer that forms in the bones or soft tissues surrounding them, such as cartilage or muscle. It most often develops in the long bones of the arms and legs, pelvis, or chest wall, though it can occur anywhere in the body.

This cancer primarily affects children, teenagers, and young adults between the ages of 10 and 20, with a slightly higher incidence in males. In the United States, more than 200 new cases are diagnosed each year, making up less than 2% of all childhood cancers. Despite its rarity, Ewing sarcoma requires prompt diagnosis and specialized care due to its rapid growth and potential to spread to the lungs, other bones, or bone marrow.

Understanding Ewing Sarcoma

What Is Ewing Sarcoma?

Ewing sarcoma is a small-round-blue-cell malignancy defined by EWSR1-ETS fusions; its precise cell of origin is uncertain, but evidence now favors a mesenchymal stem/progenitor cell (with neural-crest–like features reported in some models). These abnormal cells multiply uncontrollably, forming a malignant tumor that destroys surrounding healthy bone or tissue. Depending on its site of origin, it may appear as a bone tumor or a soft tissue tumor.

Most cases are linked to a specific chromosomal translocation between chromosomes 11 and 22, known as the EWSR1-FLI1 fusion gene. This genetic rearrangement triggers the overproduction of abnormal proteins that promote cancer cell growth.

Stages of Ewing Sarcoma

Ewing sarcoma can be staged using the American Joint Committee on Cancer (AJCC) TNM system, which formally evaluates:

• T (Tumor): Size and extent of the primary tumor
• N (Node): Involvement of regional lymph nodes
• M (Metastasis): Presence of distant metastasis
• G (Grade): How abnormal (atypical) the tumor cells appear under the microscope

However, in clinical practice — particularly for pediatric and adolescent patients — Ewing sarcoma is more simply classified as either:

• Localized: Cancer confined to the bone or surrounding soft tissue, without detectable metastasis
• Metastatic: Cancer that has spread to distant organs, such as the lungs, other bones, or bone marrow

This practical two-tier system (localized vs. metastatic) is favored by oncologists and research protocols because it better reflects disease behavior and treatment planning in Ewing sarcoma.

Importance of Accurate Staging

Accurate staging (local extent, nodal status if relevant, bone marrow, and distant metastases) is critical because treatment intensity and prognosis differ substantially between localized and metastatic disease. Multimodality staging is recommended in contemporary practice and ideally coordinated by a multidisciplinary sarcoma team.

Where Does Ewing Sarcoma Typically Occur?

Ewing sarcoma most often affects the:

• Pelvis
• Long bones of the legs and arms (femur, tibia, humerus)
• Ribs and chest wall
• Spine
• Jaw or facial bones
• Shoulder blades and vertebrae

Extraosseous (soft tissue) forms may occur in the trunk, limbs, or, less commonly, in organs such as the kidney or adrenal gland.

How Fast Does Ewing Sarcoma Grow?

Ewing sarcoma is known for being highly aggressive and fast-growing. It can double in size within weeks, which is why early detection and treatment are critical. Delays in diagnosis can allow the cancer to metastasize, often to the lungs or other bones.

Causes and Risk Factors

The exact cause of Ewing sarcoma remains unknown, but researchers have identified several contributing factors:

• Genetic changes: Nearly all cases involve the EWSR1 gene translocation, which is not inherited but occurs spontaneously during cell division.
• Age: Most common in adolescents and young adults due to active bone growth.
• Gender: Slightly more frequent in males than females.
• Ethnicity: Higher incidence in Caucasians; it is extremely rare in people of African or Asian descent.

Types of Ewing Sarcoma

Ewing sarcoma encompasses a family of related tumors that share similar genetic features. The primary subtypes include:

• Ewing Sarcoma of Bone: This is the most common type, typically forming in long bones like the femur, tibia, or humerus, as well as in flat bones such as the pelvis and ribs.
• Extraosseous (Extraskeletal) Ewing Tumor: Occurs in soft tissues such as muscle, tendons, or connective tissue rather than bone. Though rarer, it behaves similarly to bone-based Ewing sarcoma.
• Peripheral Primitive Neuroectodermal Tumor (PNET): A closely related tumor that arises from immature nerve cells in bone or soft tissue. Ewing sarcoma was historically grouped with peripheral primitive neuroectodermal tumor (PNET), but modern WHO classifications now recognize it as a single molecularly defined tumor that may show variable neural differentiation.
• Adamantinoma-like Ewing Sarcoma: A recently recognized variant that shows features of both Ewing sarcoma and epithelial tumors, most often found in the head and neck region.

Symptoms of Ewing Sarcoma

The symptoms vary depending on the tumor’s location, size, and whether it has spread.
 Common early signs include:

• Pain and swelling around the affected area (often mistaken for a sports injury)
• A tender lump or mass that may feel warm to the touch
• Restricted movement if the tumor involves a joint
• Fever, fatigue, or weight loss
• Bone fragility or fractures from minimal trauma (“pathological fractures”)

Symptoms in Adults

Ewing sarcoma in adults tends to present later and may have more subtle symptoms, leading to delayed diagnosis. Adults might experience deep, persistent bone pain, swelling, or limited mobility for months before medical evaluation.

Complications of Ewing Sarcoma

If untreated or advanced, Ewing sarcoma can lead to several serious complications:

• Recurrent cancer: Even after successful treatment, relapse can occur, sometimes years later.
• Long-term effects: Chemotherapy and radiation may cause growth issues, fertility problems, or secondary cancers (like acute myeloid leukemia).
• Organ involvement: Rarely, Ewing sarcoma has been linked with retinoblastoma and other malignancies in individuals with specific genetic backgrounds.

Where Does Ewing Sarcoma Spread to?

Metastatic spread is another possible complication. When it metastasizes, Ewing sarcoma typically spreads via the bloodstream to:

• Lungs (most common site)
• Other bones
• Bone marrow
• Uncommon metastatic sites include the central nervous system, kidneys, or other soft tissues

Once metastasis occurs, treatment becomes more complex, and outcomes depend on the extent of spread and response to chemotherapy.

• Radiation exposure: Rarely, individuals who have previously undergone radiation therapy may have a higher risk.
• Not inherited: Unlike some cancers, Ewing sarcoma does not run in families and is not associated with known hereditary cancer syndromes. However, further research is needed to investigate genetic predisposition.

Although these risk factors provide clues, most patients diagnosed with Ewing sarcoma have no identifiable cause, underscoring the role of random genetic mutations rather than inherited traits.

Diagnosis of Ewing Sarcoma

Clinical Assessment

The diagnostic process starts with a detailed medical history and physical examination. Early signs such as progressive bone pain, swelling, a palpable mass, fever, or a pathological fracture prompt imaging and specialist referral. As Ewing sarcoma can mimic infection or benign bone conditions, early referral to a sarcoma center is recommended when imaging or symptoms are suspicious.

Imaging Studies

Imaging both characterizes the primary tumor and looks for spread.

• Plain Radiograph (X-ray): This is usually the first test done. It may show an area of bone damage that looks patchy or “moth-eaten,” where the cancer is destroying bone tissue. The bone’s outer covering (called the periosteum) may react by forming new layers of bone, creating a distinctive “onion-skin” appearance on the X-ray.
• Magnetic Resonance Imaging (MRI): A primary modality for local staging, this defines intraosseous extent, soft-tissue component, and relationship to neurovascular structures and joints, and is required before biopsy to plan the approach. MRI is essential for surgical and radiation planning.
• CT Chest: Required to evaluate pulmonary metastases (lungs are the most common metastatic site).
• 18F-FDG PET/CT (or PET/MRI): Increasingly used for whole-body staging because it can detect both osseous and soft-tissue metastases and helps assess treatment response; PET/CT often performs better than conventional bone scans for detecting osseous metastases. PET/MRI is emerging as a useful combined tool in pediatric patients.
• Bone Scan (Technetium): Historically used for skeletal staging, but PET/CT is more sensitive for Ewing sarcoma in many series.

Blood Tests

There are no blood tests that confirm Ewing sarcoma, but routine labs (CBC, ESR/CRP, liver and renal panels) are performed to assess overall health, look for infection/inflammation, and establish baselines prior to chemotherapy. Markers like ESR/CRP may be elevated and can sometimes confuse the picture with osteomyelitis.

Biopsy and Pathology

A tissue biopsy is mandatory for diagnosis. Adequate, well-planned sampling (usually image-guided core biopsy) is essential and should be performed after local staging MRI and with input from the sarcoma team to avoid compromising future surgery. Open biopsy may be used when core biopsy is non-diagnostic, but poorly planned biopsies increase the risk of tumor seeding and complicate limb-sparing surgery.

On light microscopy, Ewing sarcoma is classically a small round blue-cell tumor. Immunohistochemistry typically shows strong membranous CD99 (MIC2) positivity; newer markers such as NKX2-2 help increase diagnostic specificity when combined with CD99. However, immunostains alone are insufficient, and molecular confirmation is recommended.

Genetic/ Molecular Testing

Molecular confirmation of characteristic gene fusions (most commonly EWSR1–FLI1, resulting from t(11;22)(q24;q12) is a cornerstone of modern diagnosis. Testing options include FISH (break-apart probes), RT-PCR for fusion transcripts, or next-generation sequencing (NGS) panels. Molecular testing both confirms diagnosis and can help distinguish Ewing sarcoma from look-alike small round cell tumors and EWSR1-rearranged sarcoma variants. Emerging liquid-biopsy approaches are being investigated but are not yet standard for initial diagnosis.

Bone Marrow Evaluation

Since Ewing sarcoma can involve bone marrow, bone marrow aspiration and biopsy are often performed as part of staging to detect marrow involvement, especially in advanced disease.

Differential Diagnosis

Ewing sarcoma shares clinical and radiologic features with several other bone and soft tissue conditions. Accurate differentiation is crucial for appropriate management.

Osteosarcoma vs. Ewing Sarcoma

• Age of Onset: Osteosarcoma typically affects adolescents and young adults, whereas Ewing sarcoma primarily occurs in children and young adults.
• Location: Osteosarcoma often arises in the metaphysis of long bones, particularly around the knee. Ewing sarcoma commonly affects the diaphysis of long bones, pelvis, and ribs.
• Radiologic Features: Osteosarcoma most commonly presents with a sunburst pattern and Codman's triangle on imaging. Ewing sarcoma is characterized by a periosteal reaction forming an "onion skin" appearance and a large soft tissue mass.
• Histology: Ewing sarcoma cells are small, round, and blue with scant cytoplasm, and they express the FLI-1 protein, which is absent in osteosarcoma.

Osteomyelitis vs. Ewing Sarcoma

• Clinical Presentation: Both conditions can present with localized bone pain, stiffness, swelling, and fever.
• Imaging Findings: MRI of Ewing sarcoma typically shows a sharply defined bone lesion with a large soft tissue mass and cortical destruction. In contrast, osteomyelitis may present with ill-defined margins, bone marrow swelling, and less aggressive bone involvement.
• Biopsy: Histopathological examination is essential, as osteomyelitis shows inflammatory infiltrates, whereas Ewing sarcoma shows malignant small round cells.

Osteoid Osteoma vs. Ewing Sarcoma

• Age Group: Osteoid osteoma typically affects adolescents and young adults, whereas Ewing sarcoma occurs in children and young adults.
• Location: Osteoid osteoma commonly involves the cortex of long bones, especially the femur and tibia. Ewing sarcoma often affects the diaphysis of long bones and the pelvis.
• Imaging Characteristics: Osteoid osteoma presents as a small, well-circumscribed lesion with a central nidus surrounded by reactive bone sclerosis. Ewing sarcoma appears as a large, aggressive lesion with a soft tissue mass and periosteal reaction.
• Clinical Features: Osteoid osteoma is characterized by nocturnal pain relieved by nonsteroidal anti-inflammatory drugs (NSAIDs), whereas Ewing sarcoma presents with persistent pain and systemic symptoms.

Treatment of Ewing Sarcoma

Overview of the Multimodal Approach

Ewing sarcoma is treated with a multimodal strategy that combines systemic chemotherapy (to treat microscopic/metastatic disease), local control (surgery and/or radiotherapy), and supportive care. Multidisciplinary management at a sarcoma center (pediatric or adult, as appropriate) is essential because treatment sequencing, surgical planning, and reconstructive options markedly affect outcomes and functional preservation.

Chemotherapy — The Backbone of Treatment

Chemotherapy is the core of Ewing sarcoma therapy for both localized and metastatic disease. Common, evidence-based regimens include VDC/IE — Vincristine, Doxorubicin (Adriamycin), Cyclophosphamide alternating with Ifosfamide and Etoposide. Chemotherapy is given in phases: induction (to shrink the tumor), local control (surgery/radiation), and consolidation/intensification to eradicate residual disease. Contemporary protocols use multi-agent and dose-intensive schedules.

• Interval-compressed (every-2-week) chemotherapy: Trials and pooled analyses show that administering VDC/IE at 2-week intervals improves event-free survival compared with 3-week intervals in many cooperative-group protocols and is widely used where supportive care permits. This is sometimes referred to colloquially as the “two-week” or interval-compression approach. The intensified schedule requires proactive growth-factor support and close toxicity monitoring.
• Side effects
  • Myelosuppression (neutropenia, thrombocytopenia, anemia)
  • Infection risk
  • Mucositis
  • Nausea/vomiting
  • Cardiotoxicity (anthracyclines like doxorubicin)
  • Hemorrhagic cystitis (ifosfamide/cyclophosphamide)
  • Neurotoxicity (vincristine)
  • Infertility risk

Long-term survivorship issues (cardiac, endocrine, growth) must be discussed before therapy begins.

Local Control: Surgery and Radiotherapy

Local control (removing or eradicating the primary tumor) is typically performed after initial chemotherapy when the tumor has shrunk and surgical margins can be optimized. The choice between surgery, radiation therapy, or both depends on tumor location, response to chemo, resectability, and expected functional outcome.

Surgery

• Limb-sparing (limb-salvage) surgery is preferred for extremity tumors when complete (wide) resection with acceptable function is feasible. Modern reconstructive options include endoprostheses, allografts, allograft–prosthesis composites, rotationplasty, and biologic reconstructions, depending on patient age and anatomic site. Reconstructive surgery is integral to restoring function after tumor resection.
• Importance of clear margins: Achieving negative (clear) surgical margins is strongly associated with lower local recurrence risk. Close coordination between the surgeon and the sarcoma team (and planning biopsy tract removal if needed) reduces local failure and preserves limb function. In some anatomic sites (pelvis, spine, chest wall), wide resection may be difficult; multidisciplinary planning is essential.
• Amputation: Rarely required today, reserved for tumors that cannot be controlled with limb-sparing surgery without unacceptable compromise of oncologic margins or function.

Radiation Therapy

• Radiosensitivity: Ewing sarcoma is relatively radiosensitive, and radiotherapy is a mainstay for patients with unresectable disease, positive margins after surgery, or as part of combined modality therapy for local control.
• Side effects
  • Skin irritation
  • Fatigue
  • Mucositis when in the head/neck or chest
  • Growth disturbance in children
  • Fibrosis
  • Secondary malignancy risk
  • Organ-specific toxicity

Targeted Therapies and Immunotherapy (Emerging Options)

Since Ewing sarcoma is driven by characteristic fusion oncogenes (e.g., EWSR1–FLI1), research has focused on targeted strategies that disrupt fusion protein biology, DNA repair pathways, or tumor microenvironment.

Early-phase trials and preclinical studies include small molecules, PARP inhibitors (combined approaches), IGF1R inhibitors, and agents targeting downstream pathways, as well as immunotherapy approaches (checkpoint inhibitors, engineered T-cells, and vaccines).

Results so far are preliminary; many strategies are under active clinical investigation and available via clinical trials for relapsed/refractory disease. Participation in trials at specialized centers is encouraged when standard options are exhausted.

Can Ewing Sarcoma Be Completely Cured or Prevented?

In the context of localized disease, many patients can achieve durable remission and, effectively, a cure. The term “cure” is used cautiously because late relapse is possible, but long-term survivors (10+ years) exist.

Metastatic or relapsed disease is much harder to cure; outcomes are worse, and complete remission is more challenging. There is no known preventive measure for Ewing sarcoma since the causes are largely sporadic genetic rearrangements rather than modifiable risk factors.

Living With Ewing Sarcoma

Prognosis & Survival Rates

The prognosis for patients with Ewing sarcoma depends strongly on whether the disease is localized or metastatic, the site and size of the tumor, patient age, response to therapy, and the presence of certain biomarkers.

• For localized disease (no distant metastasis at diagnosis), 5-year survival rates typically range from 70 % to 80 % in modern series.
• In contrast, patients who present with metastatic disease (e.g., lung, bone, bone-marrow spread) have much worse outcomes, with 5-year survival often around 20 % to 30 %
• After relapse, prognosis is generally poor. Across studies, 5-year post-relapse survival is often 15 % to 25 %, though outcomes vary depending on how soon relapse occurs and whether salvage therapy (including surgery or radiotherapy) is possible.
• The timing of relapse is prognostic: relapses more than 2 years after diagnosis tend to have somewhat better outcomes (e.g., ~30 % 5-year post-relapse survival) versus relapses <2 years, when survival is much lower.
• Meta-analyses and guideline reviews note that although therapy advances have plateaued for high-risk and metastatic cases, improvements in surgical techniques, imaging, supportive care, and investigational therapies offer incremental gains.

Other Factors Influencing Prognosis:

• Tumor Location: Centrally located or pelvic tumors fare worse than tumors in the limbs.
• Tumor Size/ Burden: Larger tumors or high tumor volume at presentation are associated with poorer outcomes.
• Age: Older adolescents and adults may have worse outcomes compared to children (as reported in some studies), possibly due to differences in biology or therapy tolerability.
• Treatment Response: A good histologic response (high degree of necrosis) after induction chemotherapy is favorable.
• LDH and Biomarkers: Elevated lactate dehydrogenase (LDH) at diagnosis associates with worse prognosis in several reports.

Since factors can vary among patients, the individual prognosis should be discussed with the treating oncology team, taking into account imaging response, biomarkers, and risk stratification.

Recurrence & Follow-up Care

• Among patients with initially localised disease, approximately 25 % eventually relapse despite curative intent therapy.
• Relapse is mostly systemic rather than purely local. Local-only relapse occurs less frequently, and combined locoregional and systemic relapse occurs in a minority of cases.
• Most relapses happen within the first 2 years following the end of treatment.
• Late recurrences, even beyond 5–10 years, though rare, are documented. Hence, there is a need for long-term surveillance.

Follow-up Surveillance

After treatment, close follow-up is critical to detect recurrences early, monitor late toxicities, and support rehabilitation.

Common surveillance protocols include:

• Periodic imaging of the prior tumor site (X-ray, MRI) and chest (CT) every 3 to 6 months in the first 2–3 years, then at reduced frequency over time.
• Laboratory assessments and evaluation of organ functions (cardiac, renal, hepatic) related to therapy.
• Functional assessments / physical exams to monitor limb strength, mobility, growth (in children), and detect complications (e.g., fracture risk, bone health).
• Survivorship care programs involving endocrinology, cardiology, neurology, fertility counseling, neuropsychology, and late-effect monitoring.

Rehabilitation, Quality of Life, and Long-Term Support

Surviving Ewing sarcoma involves more than just disease control; quality of life, rehabilitation, and long-term support are essential:

Physical Therapy & Rehabilitation

• Early mobilization after surgery and radiation helps preserve joint function, muscle strength, and flexibility.
• Gait training, prosthetic fitting (if needed), and orthotic support when structural changes occur.
• Long-term monitoring of limb length discrepancies, especially in children whose bones are still growing.

Psychosocial Support & Counseling

• Emotional and psychological support is critical, particularly because the disease often affects adolescents and young adults.
• Peer support groups, counseling, educational, and vocational planning.

Monitoring & Managing Late Effects

• Cardiac monitoring due to anthracycline chemotherapy cardiotoxicity.
• Endocrine and growth assessments, particularly in children exposed to radiotherapy or chemotherapy, affecting growth plates.
• Fertility preservation counseling before therapy; ongoing reproductive health monitoring.
• Secondary malignancy risk: lifetime surveillance for therapy-related cancers (e.g., leukemia).
• Bone health: risk of osteoporosis, fracture, and joint degeneration.

Lifestyle & Wellness

• Encouraging safe physical activity, nutritional support, and smoking avoidance to optimize long-term health.
• Regular screening for cardiovascular risk, endocrinologic problems, and general health.

Educational and Vocational Integration

• Support to return to school/work, accommodations if needed, and rehabilitation of functional deficits.

Research & Advancements in Ewing Sarcoma

Recent research in Ewing sarcoma focuses on enhancing treatment efficacy and exploring novel therapeutic avenues:

• INTER-EWING-1 Trial: This international, all-age study aims to transform Ewing sarcoma treatment by testing various strategies, including optimized chemotherapy and novel agents.
• Targeted Therapies: Researchers have developed a small molecule that selectively degrades a protein implicated in Ewing sarcoma, offering a potential new therapeutic approach.
• DNA Damage Response: A new combination therapy targets the DNA damage response pathway, potentially enhancing tumor sensitivity to radiation therapy.
• Immunotherapy: "Off-the-shelf" immunotherapy approaches to treat Ewing sarcoma, particularly in cases with lung metastases, are being investigated.
• Clinical Trials: Numerous clinical trials are underway, exploring treatments like TK216 and combinations of onivyde with talazoparib or temozolomide for relapsed or refractory Ewing sarcoma.

Currently, there is no preventive vaccine for Ewing sarcoma. However, therapeutic vaccines are being explored in clinical trials. For patients exploring clinical trials, resources like Cancer.gov provide detailed information and current listings.

These developments have the potential to support more targeted therapies and better management of Ewing sarcoma.

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