Sarcoma, Ewing

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    Ewing sarcoma is a type of cancer that forms in bone or soft tissue. It is also called peripheral primitive neuroectodermal tumor or pPNET. Learn about Ewing sarcoma and find information on how we support and care for children and teens with Ewing sarcoma before, during, and after treatment.

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Ewing Sarcoma

What is Ewing sarcoma (ES)?

Ewing sarcoma is a cancer that occurs primarily in the bone or soft tissue. Ewing sarcoma can occur in any bone, but most often it is found in the long bones such as the femur (thigh), tibia (shin), or humerus (upper arm). It can involve the muscle and the soft tissues around the tumor site as well. Ewing sarcoma cells can also spread (metastasize) to other areas of the body including the bone marrow, lungs, kidneys, heart, adrenal gland, and other soft tissues.

As you read further below, you will find general information about Ewing sarcoma. If you would like to view summary information about cancer first, see the cancer overview.

Ewing sarcoma accounts for about 2 to 3 percent of childhood cancers. About 250 children and adolescents are diagnosed with Ewing sarcoma each year in the US. It is the second most common malignant bone tumor in children and adolescents. Ewing sarcoma most often occurs in children between the ages of ten and 20. The number of males affected is slightly higher than the number of females.

What causes Ewing sarcoma?

The exact cause of Ewing sarcoma is not fully understood. There seems to be no known risk factors or prevention measures avaliable. However, researchers have discovered chromosomal changes in a cell's DNA that can lead to Ewing sarcoma formation. These changes are not inherited. They develop in children after they are born for no apparent reason.

In nearly 85 percent of these cases, the change involved the fusing of genetic material between chromosomes #11 and #22. When a certain piece of chromosome #11 is placed next to the EWS gene on chromosome #22, the EWS gene gets "switched on." This activation leads to an overgrowth of the cells and eventually the development of cancer. The exact mechanism remains unclear, but this important discovery has led to improvements in diagnosing Ewing sarcoma.

Some physicians classify Ewing sarcoma as a primitive neuroectodermal tumor (PNET). This means the tumor may have started in fetal, or embryonic, tissue that has developed into nerve tissue.

What are the symptoms of Ewing sarcoma?

The following are the most common symptoms of Ewing sarcoma. However, each child may experience symptoms differently. Symptoms may include, but are not limited, to the following:

  • pain around the site of the tumor
  • swelling (mass) and/or redness around the site of the tumor
  • fever
  • weight loss, decreased appetite
  • fatigue
  • paralysis and/or incontinence (if the tumor is in the spinal region )
  • symptoms related to nerve compression from tumor (i.e., numbness, tingling, paralysis, etc.)

The symptoms of Ewing sarcoma may resemble other conditions or medical problems. Always consult your child's physician for a diagnosis.

How is Ewing sarcoma diagnosed?

In addition to a complete medical history and physical examination of your child, diagnostic procedures for Ewing sarcoma may include:

  • multiple imaging studies, such as:
    • x-rays — a diagnostic test which uses invisible electromagnetic energy beams to produce images of internal tissues, bones, and organs onto film. X-rays are very useful in the diagnosis of bone tumors and frequently they allow the physician to distinguish benign from malignant bone tumors. It is the first diagnostic study, and often gives the doctor information regarding the need for further testing.
    • bone scans — a nuclear imaging method to detect bone and metastatic tumors. It will determine if there are any abnormalities in other bones.
    • magnetic resonance imaging (MRI) — a diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body. This test outlines the extent of the tumor within the bone and joint and the relationship of the tumor to the muscles, nerves and blood vessels.
    • computerized tomography scan (also called a CT or CAT scan) — a diagnostic imaging procedure that uses a combination of x-rays and computer technology to produce cross-sectional images (often called slices), both horizontally and vertically, of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general x-rays. They are used primarily to assess the chest and lung for metastatic tumors.
     
  • biopsy of the tumor — a sample of tissue removed from the tumor and examined under a microscope. This procedure establishes the diagnosis and distinguishes a Ewing sarcoma from other bone tumors.
  • bone marrow aspiration/biopsy (to detect cancer cells) — a procedure that involves a small amount of bone marrow fluid and tissue to be taken, usually from part of the hip bones, to further examine the number, size, and maturity of blood cells and/or abnormal cells.

Ewing sarcoma is difficult to distinguish from other similar tumors. Diagnosis is often made by excluding all other common solid tumors, and by the use of genetic studies.

How is Ewing sarcoma staged?

Once Ewing sarcoma has been diagnosed, the tumor is staged. This process indicates how far the tumor has spread from its original location. The stage of a tumor suggests which form of treatment is most appropriate, and gives some indication as to prognosis.

A Ewing sarcoma may be localized, meaning it has not spread beyond the bone where it arose or beyond nearby tissues, or metastatic, meaning it has spread to lungs, bones other than the bone that the tumor originated in, or to other organs or structures of the body.

What are the treatments for Ewing sarcoma?

Specific treatment for Ewing sarcoma will be determined by your child's physician based on: 

  • your child's age, overall health, and medical history
  • extent and location of the disease
  • your child's tolerance of specific medications, procedures, or therapies
  • how your child's physician expects the disease may progress
  • your opinion or preference

Treatment may include one or more of the following:

Surgery

Surgery for Ewing sarcoma involves the biopsy, surgical removal of the tumor, bone/skin grafts, limb salvage procedures, amputation, and/or reconstruction, all performed by a surgeon. The type of surgery will depend on the size and location of the tumor, and whether the cancer has spread.

Types of Surgery

  • Limb-salvage surgery: It is sometime necessary to remove all or part of a limb. In most cases, however, limb-sparing surgery is used to avoid amputation. This however is considered only if the orthopedic surgeon determines that it is possible that the tumor, and wide margins of healthy tissue surrounding the tumor, can be removed.

    Through limb-sparing surgery, all of the bone and cartilage involved with the tumor, including some degree of muscle surrounding it, is removed, while nearby tendons, nerves and vessels are saved. The bone that is removed is replaced with a bone graft or with a metal prosthesis. Subsequent surgery may be needed to repair or replace the reconstruction, which can become loose or break. Patients who have undergone limb-salvage surgery need intensive rehabilitation. It may take as long as a year for a patient to regain full use of a limb following limb-salvage surgery. Rarely, patients who have limb salvage procedures may eventually have to undergo amputation because of a severe complication or tumor recurrence. Radiation therapy is occasionally given either before surgery to shrink the tumor or after surgery to kill remaining cancer cells.
  • Amputation — In many cases, if your child's orthopedic surgeon determines that the tumor cannot be removed because, for example, it involves the nerves and blood vessels, amputation is the only surgical option. (This is rarely needed in Ewing sarcoma; however, because radiation is an acceptable means to treat the local tumor.)

    During the operation, doctors ensure that muscles and skin form a cuff around the amputated bone. A cast may be applied in the operating room which permits a temporary artificial leg (prosthesis) to be applied during the first few post-operative days for walking. Crutches are used for several weeks. As the swelling decreases (10 to 14 days) the patient is fitted for a plastic, temporary socket and prosthesis, which is used for 2 to 4 months until the stump is healed sufficiently to accept a permanent artificial leg.

    The advantages of an amputation are that it is a simple operation with minimal chances of surgical complication and it definitively removes the local tumor. The functional outcome is good with the modern prostheses available today and with "immediate-fit" prostheses applied in the operating room. Although the patient will probably have a limp with above-the-knee amputations, the procedure is functional and stable. He/she will be able to walk, climb stairs, swim (with the prosthesis on or off) and participate in many sports such as skiing, basketball, baseball, and tennis although running will be limited. The functional limitations are left to the imagination and determination of the patient.
Chemotherapy

Chemotherapy is a drug treatment that works by interfering with the cancer cell's ability to grow or reproduce. Different groups of drugs work in different ways to fight cancer cells and shrink tumors. Chemotherapy may be used alone for some types of cancer or in conjunction with other therapy such as radiation or surgery. Often, a combination of chemotherapy drugs is used to fight a specific cancer. Certain chemotherapy drugs may be given in a specific order depending on the type of cancer it is being used to treat. While chemotherapy can be quite effective in treating certain cancers, the agents do not differentiate normal healthy cells from cancer cells. Because of this, there can be many adverse side effects during treatment. Being able to anticipate these side effects can help the care team, parents, and child prepare, and, in some cases, prevent these symptoms from occurring, if possible

Chemotherapy is systemic treatment, meaning it is introduced to the bloodstream and travels throughout the body to kill cancer cells. Chemotherapy can be given:

  • as a pill to swallow
  • as an injection into the muscle or fat tissue
  • intravenously (directly to the bloodstream; also called IV)
  • intrathecally — chemotherapy given directly into the spinal column with a needle
Radiation Therapy

Radiation therapy uses high-energy rays from a specialized machine to damage or kill cancer cells and shrink tumors. Radiotherapy is a standard treatment method for control of the primary tumor and at times is used instead of or in addition to surgery. The specific method of treating the primary tumor is decided upon by the treatment team. Radiation may have side effects, especially in growing children, and patients who survive Ewing sarcoma are at a small risk for developing a second malignant tumor several years later. For that reason, the primary tumor is surgically removed without using radiation therapy whenever possible.

Stem Cell Transplant

Stem cell transplant is a treatment involving stem cells, a specific type of cell from which all blood cells develop. Stem cells develop into red blood cells to carry oxygen, white blood cells to fight disease and infection, and platelets to aid in blood clotting. Transplantation of normal stem cells from another person is used to help restore normal blood production in patients whose own ability to make any or all of these blood cells has been compromised by cancer, intensive cancer treatment, or other types of damage or abnormality. The use of cells from another individual is called allogeneic transplantation. Stem cells collected form patients themselves prior to intensive treatment can also be used to supplement the recovery of the patient's own cells after particularly aggressive course of chemotherapy or radiation therapy. The use of a patient's own cells is referred to as autologous transplantation. Stem cell transplantation and the treatment needed to manage its effects are complex. Your physician will give you more detailed information on what to expect.

Rehabilitation

Rehabilitation includes the following:

  • physical/occupational therapy and psychosocial adaptation
  • prosthesis fitting and training
  • supportive care — any type of treatment to prevent and treat infections, side effects of treatments, and complications, and to keep your child comfortable during treatment
  • continuous follow-up care — a schedule of follow-up care determined by your child's physician and other members of your care team to monitor ongoing response to treatment and possible late effects of treatment

Prognosis for Ewing sarcoma greatly depends on:

  • the extent of the disease
  • the size and location of the tumor
  • presence or absence of metastasis
  • the tumor's response to therapy
  • the age and overall health of your child
  • your child's tolerance of specific medications, procedures, or therapies
  • new developments in treatment

As with any cancer, prognosis and long-term survival can vary greatly from child to child. Every child is unique and treatment and prognosis is structured around the child's needs. Prompt medical attention and aggressive therapy are important for the best prognosis. Continuous follow-up care is essential for a child diagnosed with Ewing sarcoma. Late effects of radiation and chemotherapy, as well as second malignancies, can occur in survivors of Ewing sarcoma. New methods are continually being discovered to improve treatment and to decrease side effects.

What is the latest research on Ewing sarcoma?

Dana-Farber/Boston Children's Cancer and Blood Disorders Center is conducting numerous research studies that will help clinicians better understand and treat Ewing sarcoma. One current national study in which Boston Children's Hospital and Dana-Farber are participating involves dose compression, a way of giving more chemotherapy in hopes of improving outcomes for Ewing sarcoma patients. With the help of hematopoietic growth factors (proteins that stimulate marrow cells to grow and produce blood cells), patients can receive chemotherapy every two weeks instead of every three weeks, increasing the amount of therapy over a given time period.

In the area of stem cell transplantation, the Dana-Farber/Boston Children's Transplant Program is one of only eight institutions around the country that are investigating the use of umbilical cord transplantation. Also under study is a novel method for preventing graft versus host disease, a serious complication that occurs when transplanted cells do not recognize the tissues and organs of the recipient's body and react against the recipient's tissue. The result of this treatment approach, if it continues to be as successful, will be that the degree of match between donor and the recipient will not need to be particularly close, greatly increasing the pool of potential donors for each patient. This could also eliminate the need for long-term drug therapy traditionally needed to treat graft versus host disease.

Other types of treatment currently being studied include:

  • angiogenesis inhibitors — substances that may be able to prevent the growth of tumors by blocking the formation of new blood vessels that feed the tumors
  • biological therapies — a wide range of substances that may be able to involve the body's own immune system to fight cancer or lessen harmful side effects of some treatments
  • the functional outcomes of bone allografts and metallic prostheses for limb salvage in Ewing sarcoma.

Childhood Ewing Sarcoma

General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For Ewing sarcoma, the 5-year survival rate has increased over the same time from 59% to 76% for children younger than 15 years and from 20% to 49% for adolescents aged 15 to 19 years. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment.

Origin and Incidence of Ewing Sarcoma Family of Tumors

Studies using immunohistochemical markers, cytogenetics, molecular genetics, and tissue culture indicate that classic Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumor (chest wall), as well as extraosseous Ewing sarcoma (EOE) are all derived from the same primordial bone marrow-derived mesenchymal stem cell.The incidence of Ewing sarcoma family of tumors (ESFTs) is approximately three per 1,000,000 per year and remained unchanged for 30 years. Data from the Surveillance, Epidemiology, and End Results (SEER) registries reports an overall incidence of ESFT of one per 1,000,000 in the U.S. population. The incidence in patients aged 10 to 19 years is between nine and ten per 1,000,000. The same analysis suggests that the incidence of Ewing sarcoma is nine times greater in U.S. Caucasians than African Americans.

The median age of patients with ESFT is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of ESFT in neonates and infants have been described. Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies (EI-CESS), 59% of patients are male and 41% are female. Primary sites of bone disease include the following:

  • Lower extremity (41%).
  • Pelvis (26%).
  • Chest wall (16%).
  • Upper extremity (9%).
  • Spine (6%).
  • Skull (2%).

For EOE, the most common primary sites of disease are the following:

  • Trunk (32%).
  • Extremity (26%).
  • Head and neck (18%).
  • Retroperitoneum (16%).
  • Other sites (9%).

Approximately 25% of patients will have metastatic disease at diagnosis.

Prognostic Factors for Ewing Sarcoma

There are two major types of prognostic factors for patients with Ewing sarcoma: pretreatment factors and treatment response factors.

Pretreatment factors 
  • Site: Patients with Ewing sarcoma in the distal extremities have the best prognosis. Patients with Ewing sarcoma in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites. Patients with tumors of the sacrum have a very poor prognosis.
  • Size: Tumor volume has been shown to be an important prognostic factor in most studies. Cutoffs of either 100 mL or 200 mL are used to define larger tumors. Larger tumors tend to occur in unfavorable sites.
     
  • Age: Infants and younger patients (<15 years) have a better prognosis than adolescents aged 15 years or older, young adults, or adults.
     
  • Gender: Girls with Ewing sarcoma have a better prognosis than boys.
     
  • Serum lactate dehydrogenase: Increased serum lactate dehydrogenase (LDH) levels prior to treatment are associated with inferior prognosis. Increased LDH levels are also correlated with large primary tumors and metastatic disease.
     
  • Metastases: Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. The presence or absence of metastatic disease is the single most powerful predictor of outcome. Patients with metastatic disease confined to lung have a better prognosis than patients with extrapulmonary metastatic sites. The number of pulmonary lesions does not seem to correlate with outcome, but patients with unilateral lung involvement do better than patients with bilateral lung involvement. Patients with metastasis to bone only seem to have a better outcome than patients with metastases to both bone and lung. Positron emission tomography (PET) scans using fluorine-18-fluorodeoxyglucose (FDG) are under investigation as a staging tool that may provide additional information and alter therapy planning. Whole body MRI may provide additional information which could potentially alter therapy planning.
     
  • Standard cytogenetics: Complex karyotype (defined as the presence of 5 or more independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 appear to have adverse prognostic significance.
     
  • Detectable fusion transcripts in morphologically normal marrow: Reverse transcription polymerase chain reaction can be used to detect fusion transcripts in bone marrow. In a single retrospective study utilizing patients with normal marrow morphology and no other metastatic site, fusion transcript detection in marrow was associated with an increased risk of relapse.
     
  • Other biological factors: Overexpression of the p53 protein and loss of 16q may be adverse prognostic factors. High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma.

The following are not considered to be adverse prognostic factors for ESFT:  

  • Pathologic fracture: Pathologic fractures do not appear to be a prognostic factor for ETB.
     
  • Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.
     
  • Molecular pathology: The EWS-FL1 translocation associated with ESFT can occur at several potential breakpoints in each of the genes which join to form the novel segment of DNA. Once thought to be significant, two large series have shown the EWS-FL1 translocation is not an adverse prognostic factor.
Treatment response factors to preoperative therapy

Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better event-free survival compared with patients with larger amounts of viable tumor. Female gender and younger age predict a good histologic response to preoperative therapy. Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence. For patients who receive preinduction and postinduction chemotherapy PET scans, decreased PET uptake following chemotherapy correlated with good histologic response.

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