55 Kenosia Avenue
Danbury, CT 06810
Phone: 203.744.0100
Toll Free: 1.800.999.6673
http://rarediseases.org

Ewing Sarcoma

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1990, 1995, 1997, 1998, 2005, 2013

NORD is very grateful to Patrick J. Grohar, MD, PhD, Assistant Professor of Pediatrics, Division of Hematology-Oncology, Monroe Carell Jr. Children's Hospital & Vanderbilt Ingram Cancer Center, Vanderbilt University, for assistance in the preparation of this report.

Synonyms of Ewing Sarcoma

Disorder Subdivisions

General Discussion

Ewing sarcoma is a rare bone tumor that occurs most often in adolescents. It can also arise outside of the bone in soft tissue (extraosseous Ewing sarcoma). Ewing sarcoma is related to another type of tumor known as primitive neuroectodermal tumor (PNET). Researchers have learned that these tumors are associated with the same chromosomal abnormality (balanced reciprocal translocation) and share many physiological characteristics. Consequently, these tumors are sometimes collectively classified as the Ewing family of tumors (EFT). This general term encompasses Ewing sarcoma of bone, extraosseous Ewing sarcoma, primitive neuroectodermal tumor, and Askin’s tumor (a tumor of the chest wall). Ewing sarcoma of bone accounts for approximately 70 percent of the tumors in this family. Generally, the term Ewing sarcoma is preferred because, despite the different names, it is one tumor, molecularly. Ewing sarcoma of bone most often affects the long bone of the legs (femur) and flat bones such as those found in the pelvis and chest well. Ewing sarcoma is an aggressive cancer that may spread (metastasize) to the lungs, other bones, and bone marrow potentially causing life-threatening complications. The exact cause of these tumors is unknown.

Ewing sarcoma was first described in the medical literature in 1921 by Dr. James Ewing. Ewing sarcoma is the second most common primary bone tumor in children and accounts for approximately 2% of all childhood cancer diagnoses.

NORD’s report on Ewing sarcoma is a detailed summary of the main aspects of this rare disorder. The National Cancer Institute offers comprehensive, in-depth information on this disorder, which is available at,

For patients: http://www.cancer.gov/cancertopics/pdq/treatment/ewings/Patient

For healthcare professionals: http://www.cancer.gov/cancertopics/pdq/treatment/ewings/HealthProfessional

Symptoms

Individuals with a tumor in the Ewing family of tumors may exhibit pain, tenderness, and swelling near the affected part of the body. Pain often comes and goes (intermittent) initially, eventually progressing to be more consistent. Weakness and numbness in the affected area can also occur. In some cases, affected individuals may also experience fever, lack of energy, weight loss, low levels of circulating red blood cells (anemia), and increased levels of circulating white blood cells (leukocytosis). A palpable mass is often present.

Ewing sarcoma most often affects the middle portion (diaphyseal region) of the long bones of the arms and legs, especially the long bone of the leg (femur). These tumors also commonly affect flat bones such as those found in the pelvis, chest wall, and spinal column (vertebrae). Ewing sarcoma may occur in any bone of the body such as the bones of the foot, the hand, the lower jaw (mandible), the skull, and/or additional locations. Soft tissue tumors develop most often in the trunk and chest. However, the most common site of presentation is the pelvis accounting for about 25% of cases. Ewing sarcoma may weaken bones sometimes resulting in fractures.

These tumors are often aggressive and may spread (metastasize) to additional areas of the body, especially to other bones and the lungs. In rare cases, the bone marrow may become involved.

Symptoms associated with these tumors are secondary to their location. For example, a tumor of the leg may result in a limp, a tumor in the lungs may result in breathing problems and an accumulation of fluid in the tissue layers that line the lungs and chest cavity (pleural effusion), or a tumor in the spinal column may cause weakness or paralysis of affected muscles (paraplegia).

Causes

The exact cause of Ewing sarcoma is unknown and the underlying cell type has not been identified. Most cases are thought to occur randomly, for no specific reason (sporadically).

Chromosomal (cytogenetic) studies have found that Ewing sarcoma cells are often characterized by an abnormal change in their genetic makeup known as a reciprocal translocation. A reciprocal translocation means pieces of two separate chromosomes break off and "trade places". Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered.

In Ewing sarcoma, the chromosomal areas involved are the long arms (q) of chromosome 11 and 22 (11q24-22q12). These pieces break off and trade places. In most cases, this results in the abnormal fusion of two genes, usually the EWS and FLI genes. Genes normally produce (encode) proteins that have several functions within the body. The abnormal fusion of the EWS and FLI genes results in a "fusion" gene that produces an abnormal protein product. Researchers believe that this abnormal protein may contribute to or influence the development of Ewing sarcoma, although, currently, the exact functions or impact of this protein is not fully understood. The reason that the chromosomal translocation between chromosomes 11 and 22 occurs is also unknown. According to some estimates, however, more than 85 percent of tumors in the Ewing family of tumors have this translocation. Less often, the EWS gene may fuse with another gene other than the FLI gene; these are often genes from the same family as FLI1, most often involving the gene ERG.

In extremely rare cases, Ewing sarcoma may develop as a second malignancy, which means that the disorder develops as a late-onset complication of earlier treatment for another form of cancer.

Affected Populations

Ewing sarcoma affects males more often than females. It may affect individuals of any age, but most often occurs in individuals between 10 and 20 years of age. The annual incidence of Ewing sarcoma is 2.93 children per 1,000,000. Approximately 200-250 children and adolescents in the United States are diagnosed with a tumor in the Ewing family of tumors each year. Two-thirds will be long-term survivors (more than five years). The tumor occurs with greater frequency in Caucasians. It is extremely rare in African Americans and Asians.

Studies have shown that there are distinct differences between extraosseous (extraskeletal) Ewing sarcoma (EOE) and Ewing sarcoma of bone. EOE is more likely to occur in individuals above the age of 35 or below the age of 5, with a higher mean age than Ewing sarcoma of bone.

Related Disorders

Symptoms of the following disorders can be similar to those of Ewing sarcoma. Comparisons may be useful for a differential diagnosis:

Osteosarcoma is a tumor affecting the bones. It is the most common form of bone cancer. Approximately 60 percent of cases occur in children and adolescents during the second decade of life. Osteosarcomas affect males twice as often as females. The bones most commonly affected are the long bones of the arms and legs. Symptoms may vary depending upon the location and extent of the disease. Pain, swelling, tenderness and eventually the formation of a lump may occur in the affected area. General symptoms may include fever, weight loss, anemia, and lack of energy. Osteosarcomas may weaken the surrounding bone resulting in fractures. Osteosarcomas may spread (metastasize) to other areas of the body. The exact cause of osteosarcoma is unknown.

Additional tumors must also be differentiated from Ewing sarcoma including chondrosarcomas, osteochondromas, medulloblastomas, neuroblastoma, rhabdomyosarcoma, and lymphoma of bone. (For more information on these tumors, choose the specific tumor name as your search term in the Rare Disease Database.)

Osteomyelitis is a bone infection, usually caused by bacteria. Osteomyelitis can be either acute or chronic. The disorder usually occurs as a result of an infection in one part of the body that is transported through the bloodstream to a bone in a distant location. Among children and teens, the long bones of the legs and arms are most frequently affected. In adults, osteomyelitis most often affects the vertebrae of the spine and/or the hips. Initially there may be several days of fever and a generalized feeling of ill health (malaise). This may be followed by an increase in fever, deep localized bone pain, chills, sweating, swelling and painful or limited movement of the nearby joints. The skin near the affected bone may be red (erythema) and there may be pus, destruction of the surrounding tissue (necrosis) and bone deterioration or deformity. (For more information on this disorder, choose "osteomyelitis" as your search term in the Rare Disease Database.)

Eosinophilic granuloma is a subdivision of a rare spectrum of disorders known as Langherhans cell histiocytosis (LCH). LCH is characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body. These may include certain distinctive granule-containing cells (Langerhans cells) involved in certain immune responses, as well as other white blood cells (e.g., monocytes, eosinophils). Most individuals with LCH develop single or multiple bone lesions (eosinophilic granulomas) caused by the abnormal accumulation of Langerhans cells and eosinophils. In some cases, these lesions may be not by accompanied by any symptoms (asymptomatic). However, in most cases, the lesions are associated with bone pain and swelling of adjacent tissue. In many cases, loss of the calcium of bone (osteolysis) may also occur. The skull, spine, and long bones of the arms and legs are most often affected. Secondary complications may also occur including spontaneous fractures of the long bones or vertebral collapse and compression of the spinal cord. (For more information on this disorder, choose "Langerhans cell histiocytosis" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
The diagnosis of a tumor in the Ewing family of tumors is based upon a thorough clinical evaluation, the identification of characteristic symptoms and physical findings, a detailed patient history, and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells and affected tissue (histopathology) and molecular analysis looking for the EWS-FLI1 translocation.

Clinical Testing and Work-up
X-rays may be taken initially, especially if there is a palpable mass. X-rays are used to obtain images of the tumor or affected area. More specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor (e.g. into the soft tissue or bone marrow), to determine whether the tumor has spread (metastasized) to other areas of the body (for example, the lungs and other bones), and to serve as an aid for future surgical procedures. Such imaging techniques may include computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and bone scans. A biopsy of the bone marrow may reveal whether the tumor has spread to the bone marrow.

The diagnosis of Ewing sarcoma may be made through the surgical removal (biopsy) and microscopic evaluation of a portion of affected tissue. A specialized surface protein known as CD99 is found on most tumors in the Ewing family of tumors. Detecting the presence of this protein may aid in making a diagnosis of Ewing sarcoma.

Another test used to diagnose Ewing sarcoma is polymerase chain reaction (PCR). PCR is a laboratory technique that has been described as "photocopying". It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes such as the reciprocal translocation that characterizes Ewing sarcoma. This test is available on a research basis.

Treatment
The therapeutic management of individuals with Ewing sarcoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), adult oncologists, specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, (orthopedic surgeons), oncology nurses, and other specialists (depending upon the primary tumor site).

Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.

Individuals with Ewing sarcoma and their families are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families.

Individuals with a tumor in the Ewing family of tumors are treated with multiple anticancer drugs (chemotherapy) in combination with surgical procedures and/or radiation. Surgical removal of the malignancy and affected tissue or radiation is used to treat the primary tumor site. Chemotherapy kills cancer cells in the primary site as well as hidden cancer cells that may have spread into other areas of the body. Generally, systemic chemotherapy is administered first, followed by surgery or radiation. Surgery or radiation therapy without adjuvant chemotherapy has been far less effective than combination therapy. Radiation is often used to treat tumors that are inoperable and sometimes for metastatic disease.

Physicians use multiple chemotherapeutic drugs because different drugs have different modes of action in destroying tumor cells and/or preventing them from multiplying. Chemotherapy drugs often used to treat individuals with Ewing sarcoma include doxorubicin, vincristine, cyclophosphamide, dactinomycin, ifosfamide, and etoposide.

Investigational Therapies

Numerous treatment options are being studied for the Ewing family of tumors including various combinations of chemotherapeutic agents, targeted therapies, and stem cell transplantation.

Targeted therapies such as insulin-like growth factor receptors and tyrosine kinase inhibitors are being studied for the treatment of individuals with Ewing sarcoma. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (often proteins) that are involved in the development of specific cancers. Generally, targeted therapies are less toxic than other treatments for cancer. More research is necessary to determine the long-term safety and effectiveness of specific targeted therapies for the treatment of individuals with Ewing sarcoma.

The drug gemcitabine has shown promise as a treatment for individuals with soft tissue sarcomas. The drug is being studied alone or in conjunction with other drugs and/or therapies for the treatment of individuals with sarcomas including Ewing sarcoma. More research is necessary to determine the long-term safety and effectiveness of this potential treatment for Ewing sarcoma.

Some individuals with Ewing sarcoma have been treated with allogeneic or autologous stem cell transplantation. Stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, platelets). In autologous stem cell transplantation, an affected individual’s stem cells are removed after prior treatment, usually with drugs. These healthy stem cells are later re-infused into the bone marrow after the disorder has progressed. In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member. These procedures have generally been used as a last resort for individuals who have failed to respond to other forms of treatment.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Contact for additional information about Ewing sarcoma:

Patrick J. Grohar, MD, PhD
Assistant Professor of Pediatrics
Division of Hematology-Oncology
Monroe Carell Jr. Children's Hospital &
Vanderbilt Ingram Cancer Center
Vanderbilt University, Nashville, TN 37212
Email: patrick.grohar@vanderbilt.edu

Organizations related to Ewing Sarcoma

References

TEXTBOOKS
Devita VT, Lawrence TS, Rosenberg SA. Ewing’s sarcoma. In: Cancer Principles & Practice of Oncology, 8th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2008;2061-2067.

Trent J. Ewing Syndrome of Bone. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:380-381.

JOURNAL ARTICLES
Fox E, Patel S, Wathen JK, et al. Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research through Collaboration Study 003. Oncologist. 2012;17:321-e329. http://www.ncbi.nlm.nih.gov/pubmed/22665455

Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/23091096

Kovar H, Alonso J, Aman P, et al. The first European Interdisciplinary Ewing Sarcoma Research Summit. Front Oncol. 2012;2:54. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361960/

Lissat A, Chao MM, Kontny U. Targeted therapy in Ewing sarcoma. ISRN Oncol. 2012;1-9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368441/

Sankar S, Lessnick SL. Promiscuous partnerships in Ewing’s sarcoma. Cancer Genet. 2011;204;351-365. http://www.ncbi.nlm.nih.gov/pubmed/21872822

Applebaum MA, Worch J, Matthay KK, et al. Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. Cancer. 2011;117:3027-3032. http://www.ncbi.nlm.nih.gov/pubmed/21692057

Ginsberg JP, Goodman P, Leisenring W, et al. Long-term survivors of childhood Ewing sarcoma: report from Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010;102:1272-1283. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948841/

Ordonez JL, Osuna D, Herrero D, de Alava E, Madoz-Gurpide J. Advances in Ewing’s sarcoma research: where are we now and what lies ahead? Cancer Res. 2009;69:7140-7150. http://www.ncbi.nlm.nih.gov/pubmed/19738075

Folpe AL, Goldblum JR, Rubin BP, et al., Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol. 2005;29:1025-33. http://www.ncbi.nlm.nih.gov/pubmed/16006796

Carvajal R, Meyers P. Ewing’s sarcoma and primitive neuroectodermal family of tumors. Hematol Oncol Clin North Am. 2005;19:501-25.
http://www.ncbi.nlm.nih.gov/pubmed/15939194

Barker LM, Pendergrass TW, Sanders JE, Hawkins DS. Survival after recurrence of Ewing’s sarcoma family of tumors. J Clin Oncol. 2005;23:4354-62.
http://jco.ascopubs.org/content/23/19/4354.full.pdf

Grier HE, Krailo MD, Tarbell NJ. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348:694-701. http://www.nejm.org/doi/full/10.1056/NEJMoa020890

FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:612219; Last Update:08/05/2009. Available at: http://omim.org/entry/612219 Accessed On: November 1, 2012.

Toretsky JA. Ewing Sarcoma and Primitive Neuroectodermal Tumors. eMedicine Journal. November 2, 2012. Available at: http://www.emedicine.com/ped/topic2589.htm Accessed On: November 2, 2012.

Oberlin O. Ewing Sarcoma. Orphanet Encyclopedia, February 2009. Available at: http://www.orpha.net/ Accessed on: November 2, 2012.

Ewing’s Sarcoma. Wheeless’ Textbook of Orthopaedics. June 7, 2012. Available at: http://www.wheelessonline.com/ortho/ewings_sarcoma Accessed On: November 1, 2012.

National Cancer Institute. Ewing Sarcoma. Available at: http://www.cancer.gov/cancertopics/types/ewing Accessed On: November 2, 2012.

Report last updated: 2013/01/14 00:00:00 GMT+0