Approximately 3 out of every 1 million children are diagnosed with a tumor of the Ewing family annually. Ewing sarcoma is the second most common cancer of the bone in children. Males are more commonly affected than females. While this condition has been reported in adults and elderly individuals, it is most commonly diagnosed between the ages of 10-20. Ewing sarcoma is very rare in individuals of African or Asian descent while caucasians are affected more commonly.

All human cells carry the genetic material or DNA in 23 pairs of structures called chromosomes. 

Ewing sarcoma is associated with abnormalities in two genes: EWS RNA Binding Protein 1 (EWRS1) on chromosome 22 and Friend Leukemia Integration 1 (FLI1) on chromosome 11. Most cases of Ewing sarcoma occur due to a genetic event known as a reciprocal translocation between these two genes. In a reciprocal translocation, a piece of each of the two chromosomes breaks off and switches its location with the second piece on the other chromosome. As a result of reciprocal translocation, a part of the EWSR1 gene fuses with a part of the FLI1 gene. 

The protein synthesized from the FLI gene is involved in the regulation of growth and development of certain cell types by binding to their DNA. The protein encoded by the EWSR1 gene is also a regulatory protein and controls the activity of other proteins. When FLI1 and EWSR1 fuse, they encode a protein that abnormally increases or decreases the production of other proteins. This can ultimately result in an uncontrolled growth and proliferation of the cells and cause cancer. 

The EWSR1/FLI1 fusion is present in the majority of Ewing sarcomas. This is not an inherited mutation, and is only present in tumor cells. Less commonly, other fusions may occur between the EWSR1 and other genes that are functionally related to FLI1. 

Ewing sarcoma could be described as localized, metastatic, or recurrent. In localized Ewing sarcoma, the cancer is only found in the region where it began or has only invaded the nearby tissue. In metastatic Ewing sarcoma, the cancer has spread from the region where it began and can be found in other parts of the body. Ewing sarcoma most commonly spreads to other bones, bone marrow, or the lungs. Cancer can spread to the rest of the body via three routes:

1. Tissue: Cancerous cells can simply grow to adjacent tissues from where they began. 

2. Lymphatic system: They can also spread via the lymphatic system which is a network or lymphatic vessels and organs that have a number of functions including removing extra fluids from tissues and returning them to blood.

3. Blood: Cancerous cells can also spread throughout the body through blood. Recurrent Ewing sarcoma is when the tumor has been treated and it returns after some time.

Symptoms of Ewing sarcoma depend on the specific region affected. Generally, pain, tenderness and swelling, and a palpable lump near the affected area is noted. Weight loss, fever and tiredness with an unknown cause. If the bones are affected, bone pain and frequent fractures may occur. The pain may come and go initially and become consistent over time. If the lungs are affected, shortness of breath, pain in the chest, and a cough could also be present.

The Ewing family of tumors are diagnosed based on physical and clinical evaluations and a number of tests. These tests include imaging tests that visualize the affected region and can show the presence of a tumor, taking samples of the tissue that is suspected to be cancerous for further testing, and genetic tests to determine the presence of an abnormal EWSR1 gene in the tumor.

Imaging tests such as X-rays are often the first tests in the process of diagnosing Ewing sarcoma. Another imaging test used to diagnose Ewing sarcoma is Magnetic Resonance Imaging (MRI) in which a picture of the inside of the body is taken using magnetic and radio waves. Additionally, in a CT scan, pictures of the affected area are taken from different angles, creating a detailed image of the inside of the body. The individual may be injected with a dye to make the visualization more clear. A Positron Emission Tomography (PET) scan is an imaging technique commonly used to detect tumors in the body. The individual is injected with a small amount of radioactive glucose. Since tumors grow rapidly, their glucose uptake is much higher than healthy tissues. Since the injected glucose is radioactive, its location in the body can be tracked using the PET scanner. As the tumor takes up the glucose, the PET scanner creates a picture of the scanned region in which the tumor is brighter than normal tissues since there is a higher concentration of radioactive glucose there. A bone scan can be used to check cancer in the bone specifically. In a bone scan, a small amount of radioactive material is injected and the bone scanner detects the radioactive material in the bone. Depending on the stage and the location of the suspected tumor, one or a combination of these imaging tests may be selected.

A biopsy may then be performed for laboratory analysis of the suspicious tissue. A biopsy is a procedure in which a sample of the tissue is removed for further investigation. The sample can be removed using a needle that goes into the tumor or it could be removed surgically by making an incision. The choice of how the sample is collected depends on a number of factors including the location of the tumor. Once the sample is collected, a number of other tests can be done as listed below:

• Cytogenetic analysis: In this test, chromosomes of the cells are arranged and assessed to check for breaks in any of the chromosome or other chromosomal abnormalities. Certain chromosomal changes could indicate cancer.

• Immunohistochemistry: When a cell becomes cancerous, it may express certain markers called antigens that are not present in healthy cells or are present in larger or smaller amounts. In the context of cancer, immunohistochemistry allows for the detection of these cancer-specific antigens and the examination of the tissue by looking at gross structure and the shape of the cells. This test is helpful in diagnosing cancer or differentiating among different cancer types based on the specific antigen.

• Genetic test: the sample can be used to determine whether there are any abnormalities in the EWSR1 gene in the tumor.

Chemotherapy is usually the initial treatment for Ewing sarcoma. In chemotherapy, single drugs or a combination of them are administered directly to a vein (intravenously) or as a pill to kill the cancerous cells or reduce the size of the tumor to make its surgical removal or radiotherapy easier. 

Surgery usually follows chemotherapy. The goal of surgical treatment is the complete removal of the tumor. The size and the location of the tumor dictates how much of the tissue is removed in surgery. For instance, in Ewing sarcoma of the bone, the surgeons may be able to remove the tumor by removing a small portion of the bone or in more extreme cases, they may have to remove an entire limb. Sometimes, a graft may be used to replace the bone that was removed. This means that healthy bone or tissue is harvested from another part of the patient’s body and transplanted in the affected site. 

Sometimes, radiation therapy may be administered after surgery to kill any surviving cancer cells or instead of surgery if surgery is not possible due to the location of the tumor. In such cases, high energy radiation is directed towards the affected area to kill the cancerous cells.

Prognosis of Ewing sarcoma depends on a number of factors. For example, a metastatic Ewing sarcoma may have a poorer prognosis compared to a localized one. About 70% of individuals with a localized sarcoma live for more than five years after their diagnosis. This number drops to 15-30% for individuals with metastatic Ewing syndrome. In addition, the tissue in which the sarcoma started and the size of the tumor at diagnosis also affect that prognosis. Tumors of the bones or the lungs are associated with poorer prognosis. Diagnostic age is also a prognostic factor such that individuals who were under 18 years of age at diagnosis tend to have a better outcome.

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