Ewing sarcoma – Early Signs, Staging, and Prognosis

March 2, 2025

What is Ewing Sarcoma?

Ewing Sarcoma is a malignant tumor that develops in your bones and, less commonly, in soft tissues. It mainly affects people at a young age when the bones are in a growing phase. The major reason is a chromosomal translocation that ultimately impacts transcription factors. It mostly involves your pelvis, femur, axial skeleton, and soft tissues. Symptoms often include persistent bone pain, stiffness, swelling, and, in some cases, fractures or systemic signs like fever and weight loss.

Epidemiology of Ewing Sarcoma

This tumor very infrequently affects older people. The mean age to develop this tumor is 10-15 years, mostly affecting males. Studies show that in the years between 1973 and 2004, there were 2.93 per million cases of Ewing sarcoma, making it the second most common primary tumor of the bones. The incidence of this tumor is higher in White people than in Blacks and Asians.¹

Why does Ewing Sarcoma occur?

The primary cause of Ewing sarcoma is a genetic translocation that leads to the abnormal rearrangement of EWS and FLI1 genes. EWS is present on the 22q11 chromosome and FLI1 on 11q24, and the genetic defect leads to the fusion of these two genes, which is t(11;22)(q24;q12). This rearrangement results in the formation of a fusion protein, EWS-FLI1, which is the main culprit behind the pathogenesis of Ewing sarcoma.

Although other translocations involving EWSR1 and different members of the ETS gene family (such as ERG, ETV1, ETV4, and FEV) have been identified, the EWS-FLI1 fusion is the most common and accounts for approximately 85% of Ewing sarcoma cases.
Unlike many other cancers, Ewing sarcoma is not linked to inherited genetic mutations, environmental factors, prior radiation exposure, or other cancers. Its occurrence is primarily attributed to these specific chromosomal rearrangements.²

Ewing Sarcoma Vs. Osteosarcoma

Osteosarcoma is more common than Ewing sarcoma and is the most prevalent primary bone cancer worldwide. While both tumors can metastasize to the lungs, they differ in several key aspects. Ewing sarcoma primarily affects children and adolescents, with the highest incidence between 10 and 15 years of age, whereas osteosarcoma is more common between 10 and 30 years of age.

Osteosarcoma mostly affects the metaphysis (lower end) of the bones in your extremities, and Ewing sarcoma affects the diaphysis (shaft) of large bones like the femur and your axial skeleton. Another important difference is that there is no predisposing factor behind Ewing sarcoma, but osteosarcoma has some predisposing and associated factors like Paget disease of bones or retinoblastoma.³

Stages of Ewing Sarcoma

Ewing sarcoma is staged using two primary systems: a practical classification (localized vs. metastatic) and the TNM staging system from the American Joint Committee on Cancer (AJCC). These classifications help guide treatment and predict outcomes.

Localized vs. Metastatic Ewing Sarcoma

This simpler classification is often used for treatment planning:

Localized Ewing Sarcoma:

The tumor is confined to its original site (bone or soft tissue) and may involve nearby structures but has not spread to distant organs. Imaging tests and bone marrow biopsies confirm no detectable metastases. However, microscopic cancer cells may still be present elsewhere, which is why chemotherapy is always included in treatment.

Metastatic Ewing Sarcoma:

The cancer has spread to other areas such as the lungs, bones, bone marrow, or less commonly, lymph nodes and the liver.

TNM Staging System for Ewing Sarcoma

In TNM system, T indicates the size of the tumor, N denotes the involvement of lymph nodes, and M indicates the extent and spread of Ewing sarcoma. In the TNM system, Ewing sarcoma has the following stages:

Stage l – Not used

Since all Ewing sarcomas are high-grade, Stage I is not used for this cancer.

Stage II – Localized Disease

IIA: The tumor is ≤8 cm, high-grade, and has not spread to lymph nodes or distant organs.
IIB: The tumor is >8 cm, high-grade, and remains localized.

Stage III – Locally Advanced Disease

The tumor is present in multiple locations within the same bone but has not spread to distant organs or lymph nodes.

Stage IV – Metastatic Disease

IVA: The tumor has spread to the lungs but not to lymph nodes or other organs.
IVB: The tumor has either:
- Spread to lymph nodes, possibly with or without distant organ involvement.
- Spread to distant organs other than the lungs, such as the liver or other bones, but not to the lungs.

The higher the stage, the more advanced the disease, impacting treatment strategies and prognosis.

Symptoms of Ewing Sarcoma

Initially, this tumor presents as pain and swelling at the affected site that may exacerbate at night. When this tumor involves your bones, like the femur or pelvis, it may cause fractures due to the weakening of your bones. Ewing sarcoma most commonly spreads to your lungs with symptoms like dyspnea or rales in your chest. Involvement of your bone marrow causes bleeding or purpura formation in your skin. In stage lVA or IVB, when the tumor metastasizes to your nearby organs or lymph nodes, you may get symptoms like fever or weight loss. In some patients, there is also CNS involvement, which your physician diagnoses based on signs like seizures or memory loss.⁴

How to diagnose Ewing Sarcoma?

After taking a thorough history of your symptoms and doing your physical examination, your physician may instruct you on the following diagnostic tests to diagnose it:

X-rays:

It is the initial investigation into the diagnosis of Ewing sarcoma, and it shows important findings that help to make the diagnosis:

Onion skin appearance: It is a significant finding of Ewing sarcoma, and the reason behind this is that the layers of your affected bone are arranged in a circle on the outer surface of the particular bone.
Moth-eaten lesion: The x-ray shows large holes in the affected bones, just like holes in your clothes eaten by any moth.
Codman triangle: When this tumor impacts your bones, a periosteal reaction takes place in which the tumor elevates your periosteum (membrane of your blood vessels and nerves) from the bone, and this appearance is known as the Codman triangle.⁵

Ill-defined lucency in the distal femur is noted, with a wide zone of transition and onion-skin periosteal reaction.Case courtesy of Frank Gaillard, <a href=”https://radiopaedia.org/?lang=gb”>Radiopaedia.org</a>. From the case <a href=”https://radiopaedia.org/cases/7844?lang=gb”>rID: 7844</a>

MRI of the Primary Site:

MRI (with or without contrast) of the primary site of the tumor helps your physician to find out the extent of the disease to your nearby organs or to determine the degree of severity of the tumor.

Biopsy & the Histopathology Findings:

For diagnostic purposes, your doctor suggests a core needle biopsy in which a needle takes cells from your affected bone and is then sent to the laboratory for histopathology. The histopathology of Ewing sarcoma shows small round blue cells with excessive glycogen in their cytoplasm.⁶

Bone marrow Aspiration:

The surgeon takes the spongy liquid from your bone marrow with a biopsy needle to see the presence of cancerous cells in the bone marrow aspiration.

A surgeon using an aspiration needle for bone marrow extraction

LDH Levels:

Lactate dehydrogenase goes beyond its normal value in your blood in Ewing sarcoma. Hence, it is also a crucial test in diagnosing Ewing sarcoma.
If there is a suspicion of tumor metastasis to your lungs, lymph nodes, or other sites, consider the following imaging modalities:

CT thorax
MRI of the spine and pelvis
Positron emission tomography scan
Bone scan⁷

How to Treat Ewing Sarcoma?

There are varied treatment modalities for Ewing sarcoma, which are effective in their way, along with some drawbacks. These are:

Chemotherapy:

You can take one of the following recommended regimens of medicines to treat this sarcoma:

VACA ( Vincristine, dactinomycin, cyclophosphamide, and doxorubicin )
VIEA ( Vincristine, dactinomycin, and cyclophosphamide )

Vials of chemotherapy drugs with a syringe

Radiotherapy:

It is a reasonable option if the Ewing sarcoma has become metastatic or cannot be treated with other treatment modalities. There are several alternatives for radiotherapy: preoperative, adjuvant, definitive, intraoperative, or postoperative radiotherapy. Definitive radiotherapy is recommended when surgery is contraindicated to treat this sarcoma. The adjuvant therapy is done after your surgery to clear out the remaining cancerous cells in the nearby areas.

Woman receiving radiotherapy treatment for cancer

Surgery:

Before considering surgery to treat this tumor, it is crucial to confirm its extent, spread to other organs, involvement of lymph nodes, and the amount of edema caused by the tumor.
Surgical possibilities for the treatment are:

Limb-Sparing Surgery

The resection of Ewing sarcoma depends upon its location. If it affects the bones of the spine, it is easily resectable. Tumors involving your lungs need resectioning of your chest wall and pleura if affected; occasionally, a rib is also resected. Your surgeon can easily cut out the Ewing sarcoma involving your sternum and clavicle (lateral fourth fifth). Cases in which Ewing sarcoma affects the bones of your upper limb, which are the proximal humerus, radius, and ulna, are easily dealt with resection. Still, you need an allograft (tissue from another person) or implant after their resection.

Amputation

When the tumor has just spread locally, does not involve lymph nodes or other organs, and the involved limb already has a poor prognosis, consider amputation to treat this tumor.

Palliative Treatment:

It is a treatment that concentrates on your physical and emotional well-being. It mainly helps to relieve your symptoms of chronic diseases like cancer. Palliative treatment helps to alleviate symptoms like pain, anxiety, depression, fatigue, and insomnia by providing you with basic management. The basic management is painkillers, massages, sleep therapy, and meditation. You can get palliative treatment even at home with the help of a team involving your physician, nurses, nutritionists, and spiritual advisers. You also receive emotional and financial support with palliative treatment if you have a life-threatening disease.⁸

Complications of Ewing Sarcoma

Ewing sarcoma and its treatment can lead to several complications, affecting different body systems. These complications arise from the cancer itself, chemotherapy, radiation therapy, and surgery.

Metastasis (Cancer Spread)

Ewing sarcoma is aggressive and can spread to other parts of the body, most commonly the lungs, other bones, and bone marrow. Metastatic disease makes treatment more challenging and significantly impacts survival rates.

Complications due to Chemotherapy & Radiotherapy:

Radiotherapy and chemotherapy wipe out cancerous cells in your body. Still, along with cancerous cells, they also harm your healthy cells, leading to complications like hair loss, mouth sores, vomiting, nausea, fatigue, taste changes, dryness, and weight loss. Chemotherapy alone may cause serious problems in the heart, lungs, or liver, and it also leads to decreased overall immunity. Moreover, the prolonged use of chemotherapy severely affects your gastrointestinal system as well as increases the risk of dental problems. The radiation also disrupts the normal growth of your bones, causing stunted growth and shortening of limbs in young patients.

Complications due to Surgery:

Surgical complications occur due to inappropriate methods of surgery, inexperienced staff, or poor postoperative care. You may undergo poor wound healing, infections, abscess formation, thrombosis, or fibrosis. So, you’ll need to take care of the surgical wound after the operation to avoid adverse effects. A good diet is also beneficial for you to heal properly after the surgery.⁹

Differentials of Ewing Sarcoma

The histopathological findings of Ewing sarcoma (small round blue cells) also resemble the findings of other carcinomas. These are:

Rhabdomyosarcoma
Lymphoma
Neuroblastoma
Synovial sarcoma

Proper clinical history, histochemical tests, morphological findings, and laboratory tests make it manageable to differentiate this tumor from other disorders.

Prognosis of Ewing Sarcoma

The prognosis relies on your age and the stage of the tumor. Involvement of both of your lungs has a worse prognosis than involvement of only one lung. Ewing sarcoma that affects your distal bones is more destructive than the proximal tumor. Moreover, if Ewing sarcoma spreads outside the pulmonary system, the prognosis worsens.¹⁰

Conclusion

In conclusion, Ewing sarcoma is a high-grade tumor that may involve your bones and soft tissues. An abnormal genetic translocation is the main cause of this tumor. You suffer from localized symptoms like pain and stiffness of joints. When the tumor affects your lungs and other organs, you experience shortness of breath, bleeding, or weight loss. Treatment revolves around radiotherapy, chemotherapy, and surgery, and the choice of treatment depends upon your age and tumor stage. As it is an aggressive tumor, the prognosis is not promising. Stay in contact with your surgeon even after the treatment to avoid additional complications.

Refrences

1
Khan S, Abid Z, Haider G, Bukhari N, Zehra D, Hashmi M, Abid M, Ibrahim U. Incidence of Ewing’s Sarcoma in Different Age Groups, Their Associated Features, and Its Correlation With Primary Care Interval. Cureus. 2021 Mar 18;13(3):e13986. doi: 10.7759/cureus.13986. PMID: 33884237; PMCID: PMC8054948.
2
Durer, S., Gasalberti, D. P., & Shaikh, H. (2024). Ewing Sarcoma. In StatPearls. StatPearls Publishing.
3
Cillo, A. R., Mukherjee, E., Bailey, N. G., Onkar, S., Daley, J., Salgado, C., Li, X., Liu, D., Ranganathan, S., Burgess, M., Sembrat, J., Weiss, K., Watters, R., Bruno, T. C., Vignali, D. A. A., & Bailey, K. M. (2022). Ewing Sarcoma and Osteosarcoma Have Distinct Immune Signatures and Intercellular Communication Networks. Clinical cancer research: an official journal of the American Association for Cancer Research, 28(22), 4968–4982. https://doi.org/10.1158/1078-0432.CCR-22-1471
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Widhe, B., & Widhe, T. (2000). Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. The Journal of bone and joint surgery. American volume, 82(5), 667–674. https://doi.org/10.2106/00004623-200005000-00007
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Baraga, J. J., Amrami, K. K., Swee, R. G., Wold, L., & Unni, K. K. (2001). Radiographic features of Ewing’s sarcoma of the bones of the hands and feet. Skeletal radiology, 30(3), 121–126. https://doi.org/10.1007/s002560100349
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Cesari, M., Righi, A., Colangeli, M., Gambarotti, M., Spinnato, P., Ferraro, A., Longhi, A., Abate, M. E., Palmerini, E., Paioli, A., Ferrari, C., Donati, D. M., Picci, P., & Ferrari, S. (2019). Bone marrow biopsy in the initial staging of Ewing sarcoma: Experience from a single institution. Pediatric blood & cancer, 66(6), e27653. https://doi.org/10.1002/pbc.27653
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Ozaki T. (2015). Diagnosis and treatment of Ewing sarcoma of the bone: a review article. Journal of orthopaedic science: official journal of the Japanese Orthopaedic Association, 20(2), 250–263. https://doi.org/10.1007/s00776-014-0687-z
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Kaçmaz, İ. E., Keçeci, B., Basa, C. D., & Sabah, D. (2020). Treatment of pelvic Ewing’s sarcoma: Pros and cons of chemotherapy plus definitive radiotherapy versus surgery. Acta orthopaedica et traumatologica turcica, 54(1), 42–48. https://doi.org/10.5152/j.aott.2020.01.601
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Fuchs, B., Valenzuela, R. G., Inwards, C., Sim, F. H., & Rock, M. G. (2003). Complications in long-term survivors of Ewing sarcoma. Cancer, 98(12), 2687–2692. https://doi.org/10.1002/cncr.11891
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Bellan, D. G., Filho, R. J., Garcia, J. G., de Toledo Petrilli, M., Maia Viola, D. C., Schoedl, M. F., & Petrilli, A. S. (2015). EWING’S SARCOMA: EPIDEMIOLOGY AND PROGNOSIS FOR PATIENTS TREATED AT THE PEDIATRIC ONCOLOGY INSTITUTE, IOP-GRAACC-UNIFESP. Revista brasileira de ortopedia, 47(4), 446–450. https://doi.org/10.1016/S2255-4971(15)30126-9

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Ewing sarcoma – Early Signs, Staging, and Prognosis

What is Ewing Sarcoma?

Epidemiology of Ewing Sarcoma

Why does Ewing Sarcoma occur?

Ewing Sarcoma Vs. Osteosarcoma