Ewing sarcoma

is a malignant round-cell tumour. It is a rare disease in which cancer cells are found in the bone or in soft tissue. The most common areas in which it occurs are the pelvis, the femur, the humerus, the ribs and clavicle. Because a common genetic locus is responsible for a large percentage of Ewing sarcoma and primitive neuroectodermal tumors, these are sometimes grouped together in a category known as the Ewing family of tumors. The diseases are, however, considered to be different: peripheral primitive neuroectodermal tumours are generally not associated with bones, while Ewing sarcomas are most commonly related to bone. Ewing sarcoma occurs most frequently in teenagers, with a male/female ratio of 1.6:1. Although usually classified as a bone tumour, Ewing sarcoma can have characteristics of both mesodermal and ectodermal origin, making it difficult to classify. James Ewing (18661943) first described the tumour, establishing that the disease was separate from lymphoma and other types of cancer known at that time

Causes
In all Ewing Family Tumors, a change occurs in a cell to move a gene called EWS on chromosome No. 22 next to a section of DNA on one of several other chromosomes that causes the EWS gene to turn on. No one knows why this happens. It is not inherited; rather it occurs after the child is born. This change can be tested for in a piece of the tumor to confirm the diagnosis

Risk Factors
There are approximately 250 new cases of Ewing's Sarcoma -- primarily involving children older than 10 and young adolescents -- diagnosed in the U.S. each year. Although it can occur in younger children and in adults, it rarely does; slightly more boys than girls get the disease. For unknown reasons, it occurs most often in whites and is extremely rare in African-Americans or Asian-Americans. Unlike with adult cancers, the risk of most childhood cancers, including Ewing's sarcoma, cannot be affected by making lifestyle changes. Nor has Ewing's sarcoma been associated with any environmental risks such as exposure to chemicals or radiation. There are genetic changes that appear in the cells of people with Ewing's sarcoma. But these happen after birth and are not inherited from the parents.

Because there are no known risk factors that can be changed and because there is no screening test that can effectively identify someone who might develop this cancer, there is no way to prevent it.

Symptoms
Many things, ranging from infections to accidental injuries, can cause symptoms that resemble the symptoms caused by Ewing's sarcoma. Because early diagnosis is important for successful treatment, any child with any of the following symptoms should be evaluated by a doctor.

pain or swelling, most commonly in an arm or leg, chest, back, or pelvis a lump, which may or may not feel warm fever for no known reason a bone that breaks with no apparent cause

Children often get lumps from play. But any lump that doesn't quickly go away should be seen by a doctor. A tumor that has spread can cause a child to feel very tired and to lose weight. If it has spread to the lungs, it can also cause breathlessness. Tumors near the spine can cause unexplained weakness or even paralysis. If Ewing's sarcoma develops inside the chest wall, it's possible for the tumor to progress with no apparent symptoms until it has gotten very large and possibly spread.

Diagnosis
Ewing's sarcoma can only be confirmed with a biopsy of the tumor and testing for the change in DNA. But first the doctor will perform a series of procedures and tests. The results will be useful in determining the extent of the cancer if it is confirmed and the appropriate treatment. The doctor will start with a physical exam and medical history to check for symptoms and other health issues. The doctor may ask for a complete blood count or CBC. If a tumor is eventually confirmed, abnormal levels of red blood cells and white blood cells will help determine whether or not the cancer has spread to the bone marrow. The doctor will also ask for imaging tests if a lump has been found or other symptoms of a possible tumor have been identified during the exam. The tests might include:

X-rays to locate and identify a potential bone tumor.

Magnetic resonance imaging (MRI) scan, which uses radio waves and strong magnets to create a more detailed image of a potential tumor seen on an X-ray. Computed tomography (CT or CAT) scan to see if a tumor has spread to the lungs, liver, or lymph nodes. Bone scan, which uses an injected radioactive material and a special camera to identify potential spots in the skeleton where the cancer may have spread. Positron emission tomography (PET) scan, which also uses a radioactive material and special camera to identify other spots in the body that may have a tumor.

If a potential tumor has been found, the doctor will then ask for a biopsy to confirm the presence of Ewing's sarcoma. During a biopsy, cells and tissue are removed and then examined in a lab. If your child is going to have a biopsy, the specialists who will be involved in treating the cancer should take part in planning it. That way, the incision that's made to remove the tissue won't interfere with later surgery or treatment with radiation. For children, biopsies are usually done under general anesthesia. Finally, if Ewing's sarcoma is confirmed, the results of the biopsy, lab tests, imaging tests, and physical exam will all be used to determine the stage of the cancer.

Imaging

X-Ray of a child with Ewing sarcoma of the tibia.

Magnetic resonance imaging slice showing Ewing's sarcoma of the left hip (white area shown right).

On conventional radiographs, the most common osseous presentation is a permeative lytic lesion with periosteal reaction. The classic description of lamellated or "onion skin" type periosteal reaction is often associated with this lesion. Plain films add valuable information in the initial evaluation or screening. The wide zone of transition (e.g. permeative) is the most useful plain film characteristic in differentiation of benign versus aggressive or malignant lytic lesions. MRI should be routinely used in the work-up of malignant tumours. MRI will show the full bony and soft tissue extent and relate the tumour to other nearby anatomic structures (e.g. vessels). Gadolinium contrast is not necessary as it does not give additional information over noncontrast studies, though some current researchers argue that dynamic, contrast enhanced MRI may help determine the amount of necrosis within the tumour, thus help in determining response to treatment prior to surgery. CT can also be used to define the extraosseous extent of the tumour, especially in the skull, spine, ribs and pelvis. Both CT and MRI can be used to follow response to radiation and/or chemotherapy. Bone scintigraphy can also be used to follow tumour response to therapy. In the group of malignant small round cell tumours which include Ewing's sarcoma, bone lymphoma and small cell osteosarcoma, the cortex may appear almost normal radiographically, while there is permeative growth throughout the Haversian channels. These tumours may be accompanied by a large soft tissue mass while there is almost no visible bone destruction. The radiographs frequently do not shown any signs of cortical destruction. Radiographically Ewing's Sarcoma presents as "Moth-eaten" destructive radiolucencies of the medulla and erosion of the cortex with expansion.

Biopsy, Pathology, and Molecular Pathology

As for other malignant diseases, the definitive diagnostic test is the biopsy. Although the diagnosis can be made by fine needle aspiration biopsy or by core needle biopsy, the most adequate sampling is achieved by open biopsy. The initial biopsy is usually incisional rather than excisional, and usually from the soft tissue extension of the primary bone mass, except in the rare case of a small lesion in an expendable bone such as the proximal fibula. The biopsy incision is usually longitudinal, so as to not

violate tissue flap planes and neurovascular structures. A longitudinal incision can thus facilitate eventual complete excision and limb salvage if surgery is to be the primary mode of local control. The biopsy is best performed by an experienced orthopedic oncologist, especially by one working as part of a multidisciplinary oncology team. Frozen section to confirm the adequacy of the tissue sample should be organized beforehand, and the tissue should be rapidly sent in a fresh state to the pathology department. Assessment of viability is accomplished by visual inspection, complemented by touch preparations for rapid microscopic evaluation as deemed necessary.

[EWINGS SARCOMA/PNET, BONE] The tumor cells are rather undifferentiated morphologically and are arranged in large sheets and clusters separated by thick fibrous bands. Necrosis may be focal or extensive (arrowhead) and may render diagnosis difficult in small biopsy specimens with few viable cells. FISH study for typical t(11;22) may prove diagnostic in smaller samples.

[EWINGS SARCOMA/PNET, BONE] Ewings sarcoma/PNET is one of several socalled Small blue round cell tumors. Included among these tumors are lymphoma (especially lymphoblastic lymphoma), small cell neuroendocrine carcinomas (lung and other sites), desmoplastic small round cell tumor (abdominal and extraabdominal), embryonal rhabdomyosarcoma, small cell variant of melanoma, and many other tumors with similar morphology. A correct diagnosis would require correlation of clinical, radiographic, morphologic, immunohistochemical, and molecular findings.

Staging
Staging is a process used to determine the extent of the cancer -- whether it has spread and if so, how far. The system used for staging Ewing's Sarcoma is simpler than for a lot of other cancers. Ewing's sarcoma is classified as either localized Ewing tumors or metastatic Ewing tumors. A tumor is said to be localized only if there is no evidence of distant spread to other organs. That means it's confined to its site of origin with perhaps some spread to nearby tissues. Metastatic tumors have clearly spread to other organs. The most common sites include the lungs, other bones, and bone marrow. It can, though, spread to other organs, including the liver and the lymph nodes. The stage is used to help determine both the prognosis and the appropriate treatment options. The prognosis is an indication of what the likely course of the disease is and the chances that treatment will be effective. It's often stated in terms of a five-year survival rate. For patients with localized Ewing tumors, the five-year survival rate is close to 70%. For metastatic tumors, the five-year survival rate is 20% to 30%. If the cancer has spread only to the lungs, the rate is slightly better. But survival rate is only a statistic. It does not predict what is going to happen for any one person. If your child is diagnosed with Ewing's sarcoma, keep in mind that other things beside stage can affect the prognosis. They include:

size of the tumor where the main tumor is located how the tumor responds to chemotherapy the child's age

How Is Ewing's Sarcoma Treated?

For localized Ewing tumor, treatment usually begins with chemotherapy to shrink the tumor before it's treated with surgery or radiation. Chemotherapy uses anticancer drugs that enter the bloodstream and reach all parts of the body. So in

addition to shrinking the main tumor, the chemotherapy is intended to kill cancer cells that may have already spread but have not yet been detected. Between 8-12 weeks after chemotherapy starts, imaging tests are used to determine whether the tumor is able to be removed by surgery. If for some reason surgery can't be done or if surgery leaves some cancer cells behind, radiation is used to kill the cells. This course of treatment then is usually followed by several more months of chemotherapy to kill any remaining cells. Chemotherapy is also the first treatment step for metastatic Ewing tumors. The regimen, though, is more intense and continues for several months. Then a series of imaging tests is done to see what effect the chemotherapy has had on the main tumor as well as the cancer that has metastasized. The next step is to remove the primary and all known secondary tumors either by surgery, radiation therapy, or a combination of surgery and radiation. Chemotherapy is then resumed for several more months.
Treatment

Chemotherapy

In most cases, chemotherapy is used before surgery to kill the tumour cells. This helps control any spread of the tumour outside the bone and usually makes it easier for the surgeon to remove the primary tumour. It is also used after surgery to kill any remaining cancer cells. Chemotherapy may be given as part of a clinical trial - a study used to investigate new or different treatments or side effects of treatments.

In some patients, chemotherapy is given to help slow down the growth of the tumour and decrease symptoms when their cancer is advanced and unable to be cured. This is known as palliative chemotherapy. Types of chemotherapy drugs used to treat Ewing's sarcoma:

Doxorubicin (dox-oh-ROOB-issin) Etoposide (ee-tow-POH-side) Vincristine (vin-KRIS-teen) Actinomycin D (AK-tin-oh-MY-sin) Cyclophosphamide (SY-kloh-FOSS-fam-ide) Ifosfamide (eye-FOSS-fam-ide)

Surgery

Surgery is used to remove the primary tumour.

If a joint has to be removed it is usually possible to replace it using an implant with a joint replacement. Limb sparing surgery: is complex surgery, which aims to keep as much normal function in the limb as possible. Autologous (aw-TOH-low-gus) bone graft: this is bone , which is taken from another part of the body to replace the bone that has been removed. Other surgical techniques include resection alone, allografts (donated tissue), irradiation/ reimplantation. Amputation: sometimes because of the position or size of the tumour, the surgery involves removal of the whole limb. If possible, then a prosthetic (false) arm or leg can be made for the patient. Amputation may also be needed if the cancer has spread to major blood vessels or nerves or if the patient develops a bad infection or other serious complications after limb-sparing surgery. For many patients the main tumour is not easily removable by surgery, for example, if the tumour is in the pelvis or spine. Compared with other sarcomas, Ewing's tumours respond well to radiotherapy. Sometimes when surgical removal is not reasonable, radiotherapy can be used alone. Surgery may also be used to remove tumour that has spread to the lungs. Surgery may be needed in future if the reconstruction of the limb wears out or if the tumour comes back.

Radiotherapy

Radiotherapy is administered by a radiation oncologist. Radiotherapy involves the patient receiving high doses of concentrated radiation. Radiotherapy is usually given as a single dose each day (a few minutes) for approximately 5 - 6 weeks. It is used alone when removal of the primary tumour may not be possible, for example if it is in the pelvis or spine. Radiotherapy may also be used after surgery if not all the tumour is completely removed or more than 10% of the tumour is still alive when examined under a microscope.

After Treatment

When a child is treated for cancer, conditions can develop later in life that stem from that treatment. These "late effects" vary from child to child and depend largely on the kind of treatment received. Radiation and the drugs used in chemotherapy damage normal cells as well as the cancer cells, and over the long term that can have an effect on the brain -- for example creating learning difficulties -- hearing and vision, growth and development, the heart and respiratory system, and other organs and functions.

Children can also develop second cancers. For example, some chemotherapy drugs can cause leukemia, or a new cancer can develop at the site of radiation therapy. In addition there is always the possibility of a recurrence of Ewing's sarcoma. All this means it's important to work closely with your child's health care team and get regular checkups to watch out for possible problems. The American Cancer Society also recommends that you keep accurate records of the treatment your child receives and make sure any doctor your child sees in the future has a copy of those records. At the minimum, those records should include:

copies of any pathology or postoperative reports copies of any hospital discharge summaries a list of the drugs used for chemotherapy a summary of the radiation type and doses

When your child becomes an adult, he or she should be given a copy of those records.