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Ewing's Sarcoma

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Description: Ewing's sarcoma is a rare and aggressive type of cancer that primarily affects the bones and the soft tissue surrounding bones, typically occurring in children and young adults.
Type: Ewing's sarcoma is a type of cancer that occurs in bones or in the soft tissue around the bones. It typically affects children and young adults. The type of genetic transmission for Ewing's sarcoma is not hereditary, but rather it is associated with specific chromosomal translocations, most commonly between chromosomes 11 and 22. This translocation leads to the fusion of the EWSR1 gene on chromosome 22 with the FLI1 gene on chromosome 11, creating an abnormal gene that contributes to cancer development.
Signs And Symptoms: Ewing sarcoma is more common in males (1.6 male:1 female) and usually presents in childhood or early adulthood, with a peak between 10 and 20 years of age. It can occur anywhere in the body but most commonly in the pelvis and proximal long tubular bones, especially around the growth plates. The diaphyses of the femur are the most common sites, followed by the tibia and the humerus. Thirty percent are overtly metastatic at presentation, while 10–15% of people present with a pathologic fracture at the time of diagnosis. People usually experience extreme bone pain. Rarely, it can develop in the vagina.Signs and symptoms include intermittent fevers, anemia, leukocytosis, increased sedimentation rate, and other symptoms of inflammatory systemic illness.According to the Bone Cancer Research Trust (BCRT), the most common symptoms are localized pain, swelling, and sporadic bone pain with variable intensity. The swelling is most likely to be visible if the sarcoma is located on a bone near the surface of the body, but when it occurs in other places deeper in the body, like on the pelvis, it may not be visible.
Prognosis: Staging attempts to distinguish people with localized from those with metastatic disease. The most common areas of metastasis are the lungs, bone and bone marrow with less common areas of metastasis being the lymph nodes, liver and brain. The presence of metastatic disease is the most important prognostic factor in Ewing Sarcoma with the 5 year survival rate being only 30% when metastasis is present at the time of diagnosis as compared to a 70% 5 year survival rate with no metastasis present. Another important prognostic factor is the location of the primary tumor; proximal tumors (located in the pelvis and sacrum) are worse prognostic indicators as compared to more distal tumors. Other factors associated with a poor prognosis include a large primary neoplasm, older age at diagnosis (older than 18 years of age) and increased lactate dehydrogenase (LDH) levels.Five-year survival for localized disease is greater than 70% after therapy. Prior to the use of multi-drug chemotherapy, long-term survival was less than 10%. The development of multi-disciplinary therapy with chemotherapy, irradiation, and surgery has increased current long-term survival rates in most clinical centers to greater than 50%. However, some sources state it is 25–30%.Retrospective research showed that two chemokine receptors, CXCR4 and CXCR7, can be used as molecular prognosis factors. People who express low levels of both chemokine receptors have the highest odds of long-term survival with >90% survival at five years post-diagnosis versus <30% survival at five years for patients with very high expression levels of both receptors. A recent study also suggested a role for SOX2 as an independent prognostic biomarker that can be used to identify patients at high risk for tumor relapse.
Onset: Ewing's sarcoma typically occurs in children and young adults, with the peak incidence between the ages of 10 and 20 years old.
Prevalence: Ewing's sarcoma is a rare type of cancer that primarily affects children and adolescents. The prevalence is approximately 1 to 3 cases per million people annually. It accounts for about 1% of all childhood cancers.
Epidemiology: Ewing sarcomas represent 16% of primary bone sarcomas. In the United States, they are most common in the second decade of life, with a rate of 0.3 cases per million in children under 3 years of age, and as high as 4.6 cases per million in adolescents aged 15–19 years. Nearly 80% of patients are aged less than 20 years of age. It is uncommon in patients younger than 5 years and older than 30 years.Internationally, the annual incidence rate averages less than 2 cases per million children. In the United Kingdom, an average of six children per year are diagnosed; mainly males in early stages of puberty. With occurrences primarily arising in older children and teenagers, one causal theory is puberty, e.g. its rapid growth spurts making bone tissue more cancer susceptible during development years.A grouping of three unrelated teenagers in Wake Forest, North Carolina, have been diagnosed with Ewing sarcoma. All three children were diagnosed in 2011 and all attended the same temporary classroom together while the school underwent renovation. A fourth teenager living nearby was diagnosed in 2009. The odds of this grouping are considered significant. Ewing sarcoma occurs about 10- to 20-fold more commonly in people of European descent compared to people of African descent.Ewing sarcoma is the second most common bone cancer in children and adolescents, with poor prognosis and outcome in ~70% of initial diagnoses and 10–15% of relapses.
Intractability: Ewing's sarcoma is considered a challenging and aggressive form of cancer, primarily affecting children and adolescents. While it is not necessarily intractable, meaning that it's not impossible to treat, the disease requires intensive treatment, which typically includes a combination of surgery, chemotherapy, and radiation therapy. Outcomes can vary significantly based on factors such as the stage at diagnosis, the location of the tumor, and the patient's overall health. Early detection and advances in therapy have improved prognosis, but it remains a serious and potentially life-threatening condition.
Disease Severity: Ewing's sarcoma is a rare and aggressive type of cancer that typically affects the bones or the soft tissue surrounding the bones. The disease severity can vary, but it's generally considered serious due to its rapid growth and potential to spread (metastasize) to other parts of the body. Adequate and timely treatment is crucial for better outcomes.
Healthcare Professionals: Disease Ontology ID - DOID:3369
Pathophysiology: Ewing's sarcoma is a type of malignant bone tumor that primarily affects children and young adults. The pathophysiology involves a specific genetic mutation, typically a translocation between chromosomes 11 and 22 (t(11;22)(q24;q12)), which creates a fusion gene known as EWS-FLI1. This fusion gene functions as an abnormal transcription factor that disrupts normal cell regulation, leading to uncontrolled cell growth and the development of a tumor. The tumor cells are small, round, and blue under a microscope and can arise in any bone or soft tissue. The exact mechanism by which the EWS-FLI1 fusion protein leads to malignancy is complex and involves the deregulation of multiple cellular pathways.
Carrier Status: Ewing's sarcoma is a type of cancer that forms in bone or soft tissue. It is not attributed to carrier status because it is typically not inherited through a single-gene mutation in a manner similar to genetic disorders. Instead, Ewing's sarcoma is usually caused by a chromosomal translocation between chromosomes 11 and 22. There is no "carrier" state for this type of cancer.
Mechanism: Ewing's sarcoma is a malignant bone and soft tissue tumor that primarily affects children and adolescents. The mechanisms and molecular mechanisms involved in its development are as follows:

### Mechanism:
1. **Oncogenic Transformation**: Ewing's sarcoma arises from primitive neuroectodermal cells, which undergo oncogenic transformation.
2. **Cell Proliferation**: The malignancy is characterized by aggressive cell proliferation, invasion of surrounding tissues, and potential for distant metastasis.

### Molecular Mechanisms:
1. **EWS-FLI1 Fusion Gene**: The hallmark of Ewing's sarcoma is a specific chromosomal translocation, most commonly t(11;22)(q24;q12), which fuses the EWSR1 gene on chromosome 22 with the FLI1 gene on chromosome 11. This results in the EWS-FLI1 fusion protein.
2. **Transcriptional Dysregulation**: The EWS-FLI1 fusion protein functions as an aberrant transcription factor, dysregulating the expression of target genes responsible for cell growth, differentiation, and apoptosis.
3. **Epigenetic Changes**: The EWS-FLI1 fusion protein also interacts with chromatin remodeling complexes, leading to widespread epigenetic changes that contribute to oncogenesis.
4. **Other Genetic Alterations**: Secondary genetic alterations, such as mutations in TP53 or CDKN2A, may also play a role in tumor progression and chemoresistance.

Understanding these mechanisms is essential for developing targeted therapies that can improve outcomes for patients with Ewing's sarcoma.
Treatment: Almost all people receive multidrug chemotherapy (most often vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide), as well as local disease control with surgery and/or radiation. An aggressive approach is necessary because almost all people with apparently localized disease at the time of diagnosis actually have asymptomatic metastatic disease.The surgical resection may involve limb salvage or amputation. Complete excision at the time of biopsy may be performed if malignancy is confirmed at the time it is examined. Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as six treatments at three-week cycles, but most people undergo chemotherapy for 6–12 months and radiation therapy for 5–8 weeks. Radiotherapy has been used for localized disease. The tumor has a unique property of being highly sensitive to radiation, sometimes acknowledged by the phrase "melting like snow", but the main drawback is that it recurs dramatically after some time.Antisense oligodeoxynucleotides have been proposed as possible treatment by down-regulating the expression of the oncogenic fusion protein associated with the development of Ewing sarcoma resulting from the EWS-ETS gene translocation. In addition, the synthetic retinoid derivative fenretinide (4-hydroxy(phenyl)retinamide) has been reported to induce high levels of cell death in Ewing sarcoma cell lines in vitro and to delay growth of xenografts in in vivo mouse models.In most pediatric cancers including sarcoma, proton beam radiation (also known as proton therapy) delivers an equally effective dose to the tumor with less damage to the surrounding normal tissue compared to photon radiation.
Compassionate Use Treatment: Ewing's sarcoma is a type of bone or soft tissue cancer that primarily affects children and adolescents. For cases where standard treatments are not effective, compassionate use, off-label, or experimental treatments may be considered. Here are some options:

1. **Compassionate Use:** This involves the use of drugs that are not yet approved by regulatory authorities, but are still in clinical trials. Patients with Ewing's sarcoma who have not responded to standard therapies might be eligible for these treatments through the compassionate use programs offered by pharmaceutical companies.

2. **Off-Label Treatments:** These are FDA-approved drugs used for conditions other than what they were initially approved for. For Ewing’s sarcoma, one such drug may be Temozolomide, which is traditionally used to treat brain tumors. Cyclophosphamide, a chemotherapy drug, may also be used off-label in combination with other therapies.

3. **Experimental Treatments:** These involve clinical trials of new drugs, therapies, or treatment regimens. Targeted therapies such as tyrosine kinase inhibitors (e.g., TK216) or immune checkpoint inhibitors (e.g., pembrolizumab) are being investigated for their efficacy in treating Ewing's sarcoma. Patients may participate in these clinical trials to gain access to the latest experimental treatments.

These options should always be discussed with a healthcare professional to weigh potential benefits and risks.
Lifestyle Recommendations: For individuals with Ewing's sarcoma, lifestyle recommendations may include the following:

1. **Nutrition**: Maintain a balanced diet rich in fruits, vegetables, lean proteins, and whole grains to support overall health and strength.
2. **Exercise**: Engage in appropriate levels of physical activity as advised by a healthcare professional to maintain strength and endurance, while avoiding excessive strain on affected bones.
3. **Stress Management**: Utilize mindfulness techniques, counseling, or support groups to manage the emotional stress associated with cancer treatment.
4. **Infection Prevention**: Practice good hygiene and avoid large crowds or people who are sick, especially during periods of immunosuppression due to chemotherapy.
5. **Follow-Up Care**: Adhere to scheduled medical appointments for monitoring and managing side effects or recurrence.
6. **Avoid Tobacco and Alcohol**: These can complicate treatment and recovery.

Consult with a healthcare provider for personalized recommendations tailored to individual health status and treatment plan.
Medication: Ewing's sarcoma is typically treated with a combination of therapies rather than relying on a single medication. Options often include:

1. **Chemotherapy**: Common drugs include vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide.
2. **Surgery**: To remove the tumor.
3. **Radiation Therapy**: Often used if surgery isn't an option or to kill any remaining cancer cells post-surgery.

These treatments are often tailored to the individual patient's needs based on the stage and location of the tumor. Always consult with a specialized healthcare provider for the most appropriate treatment plan.
Repurposable Drugs: For Ewing's sarcoma, some repurposable drugs that have shown potential include:

1. **Celecoxib**: a COX-2 inhibitor with potential anti-tumor effects.
2. **Temozolomide**: an alkylating agent used in brain cancers, showing promise in combination therapies.
3. **Valproic acid**: an anti-epileptic drug that may inhibit tumor growth by affecting histone deacetylase.

Research in this area is ongoing, and these drugs are typically used in combination with standard chemotherapy or targeted treatments for Ewing's sarcoma.
Metabolites: Ewing's sarcoma is a rare type of cancer that most commonly occurs in the bones or the soft tissue around the bones. Metabolites associated with Ewing's sarcoma include lactate, due to increased glycolytic activity, and other markers such as choline-containing compounds, which can be detected through metabolic profiling and advanced imaging techniques. These metabolites play a role in identifying the metabolic alterations that occur in the tumor cells.
Nutraceuticals: Ewing's sarcoma is a rare type of cancer that typically affects bones or the soft tissue around bones. Nutraceuticals, which include foods or food products that provide health benefits, are not currently established as a primary treatment for Ewing's sarcoma. Conventional treatment typically involves a combination of surgery, chemotherapy, and radiation therapy. However, nutraceuticals might play a role in supporting overall health and well-being during and after treatment. Always consult healthcare providers before using any nutraceuticals in conjunction with conventional cancer treatments.
Peptides: Ewing's sarcoma is a rare and aggressive form of bone or soft tissue cancer primarily affecting children and adolescents. In the context of peptides and nanotechnology, research is ongoing to develop targeted therapies that utilize these advanced approaches to improve treatment outcomes.

1. **Peptides**: Peptides can be engineered to specifically bind to cancer cells. In Ewing's sarcoma, peptide-based therapies may involve designing molecules that target specific proteins or receptors overexpressed on the surface of the cancer cells, possibly enhancing drug delivery and reducing side effects.

2. **Nanotechnology (Nan)**: Nanotechnology can be employed to design nanoparticle-based drug delivery systems, which can encapsulate chemotherapeutic agents or genetic material. These nanoparticles can be functionalized to target cancer cells more effectively, improving drug accumulation at the tumor site and minimizing exposure to healthy tissues.

These approaches are at varying stages of research and development and hold the potential for more effective and less toxic treatments for Ewing's sarcoma in the future.