Ewing Family of Tumors
Ewing Family of Tumors encompasses osseous and extraosseous Ewing sarcoma, peripheral primitive neuroectodermal tumor, and Askin tumor and is a prime example of how cytogenetic and genetic data have influenced histologic classification. EFT occurs most often in the second decade of life but may occur in both young children and adults.
For extraosseous sites, chest wall, trunk, extremities, abdomen or pelvis, and head and neck are common sites, although EFT has been described just about everywhere. EFT is a small round blue cell tumor and is characterized by a monomorphic population of round cells with finely dispersed chromatin and inconspicuous nucleoli. Cytoplasm is scant and may be slightly eosinophilic, amphophilic, or cleared out. Cytoplasmic glycogen can be demonstrated with periodic acid Schiff.
EFT may be difficult to differentiate from undifferentiated NB or poorly differentiated synovial sarcoma. Strong membranous immunoreactivity toward cell-surface glycoprotein CD99 has greatly aided in this diagnosis but may also be present in lymphoblastic lymphoma, RMS, and synovial sarcoma (Figure 30-8). EFT is characterized by a translocation leading to a fusion of Ewing sarcoma gene (EWS) on 22q12 to a member of the ETS family of transcription factors, most commonly FLI1.
The chimeric gene juxtaposes the potent transcriptional activation domain of EWS to the DNA-binding domain of ETS. This creates an aberrant transcription factor that is oncogenic, although the downstream targets are not well characterized. EWS/FLI1 tumorigenesis is likely a result of induction of genes involved in cell proliferation and survival, as well as a repression of genes involved in apoptosis and growth inhibition.
Ewing sarcoma is a rare malignancy that most often presents as an undifferentiated primary bone tumor; less commonly, it arises in soft tissue (extraosseous Ewing sarcoma). Both are part of a spectrum of neoplastic diseases known as the Ewing sarcoma family of tumors (EFT), which also includes the more-differentiated peripheral primitive neuroectodermal tumor (PNET; previously called peripheral neuroepithelioma and Askin’s tumor of the chest wall.
PNET can also present either in bone or soft tissue. Because these tumors share similar histological and immunohistochemical characteristics and unique nonrandom chromosomal translocations, they are considered to have a common origin [2-5].
In addition to their immunohistochemical and cytogenetic similarities, the EFT share important clinical features. These include a peak incidence between the age of 10 and 20 (70 percent of affected patients are under the age of 20), a tendency towards early dissemination to the lungs, bone, and bone marrow, and responsiveness to chemotherapy and radiation therapy (RT).
Advances in multidisciplinary management over the past 30 years have resulted in a marked improvement in long-term survival. In data derived from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, five-year survival rates for patients with Ewing sarcoma rose from 36 to 56 percent during the periods 1975 to 1984 and 1985 to 1994 . (See “Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management”.)
About 1% of all childhood tumors are Ewing tumors. About 225 children and teens are diagnosed with Ewing tumors in North America each year.
Most Ewing tumors occur in teens, but they can also affect younger children, as well as adults (mainly in their 20s and 30s).
Slightly more males than females develop these cancers. These tumors are much more common among whites, either non-Hispanic or Hispanic. This disease is very rare among African Americans, and it also seldom occurs in other racial groups.
Survival statistics for these tumors are discussed in the section “ Survival rates for Ewing tumors, by stage.”
Here we will discuss the management of the EFT. The epidemiology, pathology, molecular genetics, clinical presentation, and diagnosis of these tumors, surgical principles, indications for limb-sparing surgery, and indications for RT are discussed elsewhere.
In addition, central nervous system (supratentorial) PNET tumors and undifferentiated sarcomas lacking classic Ewing sarcoma chromosomal translocations (so-called Ewing-like sarcomas) are biologically distinct from Ewing sarcoma and peripheral PNET. Management of these tumors is discussed elsewhere.
A risk factor is anything that affects a person’s chance of getting a disease such as cancer. Different cancers have different risk factors.
Lifestyle-related risk factors such as body weight, physical activity, diet, and tobacco use play a major role in many adult cancers. But these factors usually take many years to influence cancer risk, and they are not thought to play much of a role in childhood cancers, including Ewing tumors.
Studies of children with Ewing tumors have not found links to radiation, chemicals, or any other environmental exposures.
Certain childhood cancers tend to run in some families. But genetic changes passed along within families are not an important risk factor for Ewing tumors. Although the gene changes that cause most Ewing tumors are known (see the section “ Do we know what causes Ewing tumors?”), they are not inherited.
The cause of Ewing tumors is not fully understood, but researchers are learning how certain changes in a cell’s DNA can cause the cell to become cancerous. DNA is the chemical in each of our cells that makes up our genes. Genes tell our cells how to function.
They are packaged in chromosomes, which are long strands of DNA in each cell. We normally have 23 pairs of chromosomes in each cell (one set of chromosomes comes from each parent). We usually look like our parents because they are the source of our DNA. But DNA affects more than how we look.
Some genes control when our cells grow, divide into new cells, and die. Genes that help cells grow, divide, or stay alive are called oncogenes. Others that slow down cell division or make cells die at the right time are called tumor suppressor genes. Cancers can be caused by changes in the cell’s DNA that turn on oncogenes or turn off tumor suppressor genes.
Researchers have found chromosome changes that lead to Ewing tumors, but these changes are not inherited. Instead, they develop in a single cell after a child is born, for unknown reasons.
Nearly all Ewing tumor cells have changes that involve the EWS gene, which is found on chromosome 22. In most cases, the change is a swapping of pieces of DNA (called a translocation) between chromosomes 22 and 11. Less often, the swap is between chromosomes 22 and 21, or rarely between 22 and another chromosome.
The translocation moves a certain piece of chromosome 11 (or another chromosome) just next to the EWS gene on chromosome 22, causing the EWS gene to be turned on all the time. Activation of the EWS gene leads to overgrowth of the cells and to the development of this cancer, but the exact way in which this happens is not yet clear.
Lab tests can be used to find chromosome translocations in Ewing tumor cells (see the section, “ How are Ewing tumors diagnosed?”). If doctors are not sure if a tumor belongs to the Ewing family, they can use these tests on tumor samples to look for translocations and confirm the diagnosis.
The gene changes that lead to Ewing tumors are now fairly well known, but it’s still not clear what causes these changes. It might just be a random event that sometimes happens inside a cell, without having an outside cause. There are no known lifestyle-related or environmental causes of Ewing tumors, so it is important to remember that at this time, nothing could have been done to prevent these cancers.
The risk of many adult cancers can be reduced with certain lifestyle changes (such as staying at a healthy weight or quitting smoking), but at this time there are no known ways to prevent most cancers in children.
The only known risk factors for Ewing tumors (age, gender, and race/ethnicity) can’t be changed. There are no known lifestyle-related or environmental causes of Ewing tumors, so at this time there is no way to protect against these cancers.
Signs and Symptoms
Most children and teens with Ewing tumors will have pain in the area of the tumor. Bone pain can be caused by the tumor spreading under the outer covering of the bone (periosteum), or the pain can be from a break (fracture) in a bone that has been weakened by the tumor.
Lump or swelling
Over time, most Ewing bone tumors and almost all non-bone (soft tissue) Ewing tumors cause a lump or swelling, which is more likely to be noticed in tumors in the arms or legs. The lump is often soft and feels warm. Tumors in the chest wall or pelvis (hip bones) might not be noticed until they have grown quite large.
Ewing tumors can also cause other symptoms, some of which are more common in tumors that have spread:
- Feeling tired
- Weight loss
Rarely, tumors near the spine can cause weakness, numbness, or paralysis in the arms or legs, while tumors that have spread to the lungs can cause shortness of breath.
Many of the signs and symptoms of Ewing tumors are more likely to be caused by something else. Still, if your child has any of these symptoms, see a doctor so that the cause can be found and treated, if needed.
Because many of these signs and symptoms can be confused with normal bumps and bruises or bone infections, Ewing tumors might not be recognized right away. For example, the doctor might try giving antibiotics first if an infection is suspected. The correct diagnosis might not be made until the signs and symptoms don’t go away (or get worse) and the bone is then x-rayed.
Medical history and physical exam
If your child has signs or symptoms that could be from a tumor, the doctor will want to get a complete medical history to find out more about the symptoms and how long they have been present. The doctor will also do a complete physical exam, paying special attention to any areas causing pain or swelling.
If a doctor suspects the child might have a bone tumor (or another type of tumor), more tests will be done to find out. These might include imaging tests, biopsies, and/or lab tests.
Imaging tests (such as x-rays, MRI scans, CT scans, bone scans, and PET scans) create pictures of the inside of the body. Imaging tests can be done for many reasons, including:
To help find out if a suspicious area might be cancer
To determine the extent of a tumor or learn how far a cancer may have spread
To help determine if treatment is working
Patients who have or may have a Ewing tumor will have one or more of these tests.
If a bone lump doesn’t go away or the doctor suspects a bone tumor for some other reason, an x-ray of the area will probably be the first test done. A radiologist (doctor who specializes in reading imaging tests) can usually spot a bone tumor on an x-ray and can often tell if it is likely to be a Ewing tumor. But other imaging tests may be needed as well.
Even if an x-ray strongly suggests a Ewing bone tumor, a biopsy (described below) is still needed to confirm that it is cancer rather than some other problem, such as an infection.
Magnetic resonance imaging (MRI) scan
Often, an MRI scan is done to get a better look an abnormal area seen on an x-ray. MRI scans usually can show if it is likely to be a tumor, an infection, or some type of bone damage from other causes. MRI scans can also help determine the extent of a tumor, as they show in detail the marrow inside bones and the muscle, fat, and connective tissue around the tumor. Knowing the extent of the tumor is very important when planning surgery or radiation therapy.
MRI scans might also be done to see if the cancer has spread to other areas, such as the spine or pelvis (hip area). MRI scans can also be used during and after treatment to see how well the tumor is responding.
MRI scans create detailed images using radio waves and strong magnets instead of x-rays, so there is no radiation involved. A contrast material called gadolinium may be injected into a vein before the scan to help see details better.
MRI scans may take up to an hour. Your child may have to lie on a table that slides inside a narrow tube, which is confining and can be distressing. The test also requires a person to stay still for several minutes at a time. Open MRI machines, which are less confining, might be another option, but they still require staying still for long periods of time. The machines also make buzzing and clicking noises that may be disturbing. Sometimes, younger children are given medicine to help keep them calm or even asleep during the test.
Computed tomography (CT or CAT) scan
CT scans of the chest are often used to see if a Ewing tumor has spread to the lungs. MRI scans are usually a bit better at defining the extent of the main tumor itself, but a CT scan of the tumor may be done as well.
The CT scan uses x-rays to make detailed cross-sectional images of parts of the body, including soft tissues such as muscles. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around your child while he or she lies on a table. A computer then combines these pictures into images of slices of the part of the body being studied.
Before the scan, your child may be asked to drink a contrast solution and/or get an intravenous (IV) injection of a contrast dye that helps better outline abnormal areas in the body. If a contrast dye is to be injected, your child may need an IV line. The contrast can cause some flushing (a feeling of warmth, especially in the face). Some people are allergic and get hives. Rarely, more serious reactions like trouble breathing or low blood pressure can occur. Be sure to tell the doctor if your child has any allergies (especially to iodine or shellfish) or has ever had a reaction to any contrast material used for x-rays.
CT scans take longer than regular x-rays, but not as long as MRI scans. A CT scanner has been described as a large donut, with a narrow table that slides in and out of the middle opening. Your child will need to lie still on the table while the scan is being done. Some people feel a bit confined while the pictures are being taken, although it is not as narrow as an MRI tube. Some children may need to be sedated before the test to stay still and help make sure the pictures come out well.
A bone scan can help show if a cancer has metastasized (spread) to bones in other parts of the body, and might be part of the workup for a child with a Ewing tumor. This test is useful because it can show the entire skeleton at once. (A positron emission tomography [PET] scan can often provide similar information, so a bone scan might not be needed if a PET scan is done.)
For this test, a small amount of low-level radioactive material is injected into a vein (intravenously, or IV). (The amount of radioactivity used is very low and will pass out of the body within a day or so.) The substance settles in abnormal areas of bone throughout the body over the course of a couple of hours. Your child then lies on a table for about 30 minutes while a special camera detects the radioactivity and creates a picture of the skeleton. Younger children might be given medicine to help keep them calm or even asleep during the test.
Areas of active bone changes appear as “hot spots” on the skeleton because they attract the radioactivity. These areas may suggest the presence of cancer, but other bone diseases can also cause the same pattern. To be sure, other tests such as plain x-rays or MRI scans, or even a bone biopsy might be needed.
Positron emission tomography (PET) scan
For a PET scan, a form of radioactive sugar (known as fluorodeoxyglucose or FDG) is injected into the blood. The amount of radioactivity used is very low and will pass out of the body within a day or so. Because cancer cells in the body are growing quickly, they absorb large amounts of the sugar. After about an hour, your child will lie on a table in the PET scanner for about 30 minutes while a special camera creates a picture of areas of radioactivity in the body. The picture is not detailed like a CT or MRI scan, but it provides helpful information about the whole body.
PET scans can be very helpful in showing the spread of Ewing tumors and in finding out whether abnormal areas seen on other imaging tests (such as a bone scan or CT scan) are tumors. PET scans can also be repeated during treatment to monitor the cancer over time.
Some newer machines can do a PET and CT scan at the same time (PET/CT scan). This lets the doctor compare areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT scan.
To learn more about these and other imaging tests, see our document Imaging (Radiology) Tests.
The results of imaging tests might strongly suggest a Ewing tumor, but a biopsy (removing some of the tumor for viewing under a microscope and other lab testing) is the only way to be certain. A biopsy is also the best way to tell Ewing tumors from other types of cancer.
If the tumor is in a bone, it is very important that a surgeon experienced in treating bone tumors does the biopsy. Whenever possible, the biopsy and the surgery to treat the cancer should be planned together, and the same surgeon should do both. Proper planning of the biopsy can help prevent later complications and might reduce the amount of surgery needed later on.
There are a few ways to get a sample of the tumor to diagnose Ewing tumors.
In very rare cases, if the tumor is small enough and in a good location, the surgeon can completely remove it while the child is under general anesthesia (asleep). This is called an excisional biopsy.
In most cases of suspected Ewing tumors, an incisional biopsy (taking only a piece of the tumor) is more likely to be done. This can be done in a couple of ways:
Surgical (open) biopsy: For this type of biopsy, the surgeon cuts away a piece of the tumor through an opening on the skin.
Needle (closed) biopsy: In this type of biopsy, the surgeon puts a large, hollow needle through the skin and into the tumor to remove a piece of it.
Incisional biopsies are often done while the patient is under general anesthesia (in a deep sleep), but in older teens and adults they are sometimes done using sedation and a local anesthetic (numbing medicine).
If general anesthesia is going to be used for the biopsy, the surgeon may also plan other procedures while the child is asleep to avoid having to do them as separate operations later on. For example, if the tumor is thought to have spread to the chest or elsewhere, the surgeon may take biopsy samples of these suspected tumors when the child is still asleep. The doctor might also do a bone marrow biopsy (see next section) at this time to see if the cancer has spread to the bone marrow spaces.
During the biopsy (while the child is still asleep), a pathologist (a doctor specializing in lab tests to diagnose diseases) can take a quick look at the biopsy samples under a microscope. If it looks like a Ewing tumor, the child will very likely need chemotherapy as part of treatment, so the surgeon may place a small flexible tube, known as a central venous catheter, into a large vein in the chest area during the same operation. The catheter end lies just under or outside on the skin. It can stay in place for several months during treatment. The catheter gives doctors and nurses easier access to the vein, which is allows the child to get fewer needle sticks when chemotherapy is given or blood needs to be drawn at a later time.
Bone marrow aspiration and biopsy
These tests are used to see if the cancer cells have spread into the bone marrow, the soft inner parts of certain bones. The tests aren’t usually done to diagnose Ewing tumors, but they may be done once the diagnosis is made because it is important to know if the tumor has spread to the bone marrow.
Bone marrow aspiration and biopsy are usually done at the same time. In most cases the marrow samples are taken from the back of both of the pelvic (hip) bones.
These tests may be done during the surgery to biopsy or treat the main tumor (while the child is still under anesthesia), or they may be done as a separate procedure.
If the bone marrow aspiration is being done as a separate procedure, the child lies on a table (on his or her side or belly). The area over the hip is cleaned, and the skin and the surface of the bone are numbed with a local anesthetic, which may cause a brief stinging or burning sensation. In most cases, the child is also given other medicines to make them sleepy, or they might even be asleep during the procedure. A thin, hollow needle is then inserted into the bone, and a syringe is used to suck out a small amount of liquid bone marrow.
A bone marrow biopsy is usually done just after the aspiration. A small piece of bone and marrow is removed with a slightly larger needle that is pushed down into the bone. Once the biopsy is done, pressure is applied to the site to help stop any bleeding.
Samples from the bone marrow are sent to a pathology lab, where they are looked at and tested for cancer cells.
Testing biopsy samples
A doctor called a pathologist looks at all biopsy specimens under a microscope to see if they contain cancer cells. If cancer is found, the specific type of cancer can often be determined as well. But because cells from Ewing tumors share many of the same features as cells from other types of childhood cancer, more lab tests are often needed.
For this test, a portion of the biopsy sample is treated with special proteins (antibodies) that attach to substances found on Ewing tumor cells but not on other cancers. Chemicals (stains) are then added so that cells containing these substances change color and can be seen under a microscope. This lets the pathologist know that the cells are from a Ewing tumor.
For this test, chromosomes (pieces of DNA) from the tumor cells are looked at under a microscope to detect any changes. Ewing tumor cells almost always have chromosome translocations, where 2 chromosomes swap pieces of their DNA. In most cases, the cells have translocations between chromosomes 22 and 11. Less often, the translocation is between other chromosomes. Finding these changes can help doctors tell Ewing tumors from other types of cancer. Other types of chromosome changes can also be found in some Ewing tumors.
Getting the results of cytogenetic testing usually takes about 2 to 3 weeks because the cancer cells must be grown in lab dishes for a couple of weeks before their chromosomes can be seen under the microscope.
Fluorescence in situ hybridization (FISH) is a type of cytogenetic test that uses special fluorescent dyes to spot specific chromosome changes in Ewing tumors. FISH can find most chromosome changes (such as translocations) that are visible under a microscope in standard cytogenetic tests, as well as some changes too small to be seen with usual cytogenetic testing.
FISH can be used to look for specific changes in chromosomes. It is very accurate and can usually provide results within a couple of days.
Reverse transcription polymerase chain reaction (RT-PCR)
This test is another way to find translocations in tumor cells to confirm the type of tumor. RT-PCR is a very sensitive test that is often able to detect very small numbers of cells with translocations, which wouldn’t be detected by cytogenetics.
RT-PCR is also useful in looking for leftover or recurrent cancer after treatment. For example, if RT-PCR testing of a bone marrow sample after treatment finds cells with a typical Ewing tumor translocation, it is likely that the cancer has not been cured, so more treatment is needed.
No blood test can be used to diagnose Ewing tumors. But certain blood tests may be helpful once a diagnosis has been made.
A complete blood count (CBC) measures the levels of white blood cells, red blood cells, and platelets in the blood. An abnormal CBC result at the time of diagnosis might suggest the cancer has spread to the bone marrow, where these blood cells are made.
A blood test for levels of an enzyme called lactate dehydrogenase (LDH) is typically done at diagnosis. A high LDH level indicates the cancer may be harder to treat.
Standard blood tests are done often to check a child’s general health both before treatment (especially before surgery) and during treatment (such as chemotherapy) to look for possible problems or side effects. These tests often include a CBC to monitor bone marrow function and blood chemistry tests to measure how well the liver and kidneys are working.
Once a Ewing tumor has been found and staged, the cancer care team will talk with you about treatment options. It’s important to be sure you understand your child’s options as well as their possible side effects to help make the decision that’s the best fit for your child. If there is anything you don’t understand, ask to have it explained. You can find some good questions to ask in “ What should you ask the doctor about Ewing tumors?”
- The main goals of treatment of Ewing tumors are:
- To try to cure the patient
- To keep as much function in affected parts of the body as possible
- To limit the long-term complications of treatment as much as possible
For children and teens, a team approach is recommended that includes the child’s pediatrician as well as children’s cancer specialists. Treatment for children and teens is best done at a children’s cancer center. For adults with Ewing tumors, the treatment team typically includes the patient’s primary care doctor, as well as specialists at a major cancer center. Doctors on the treatment team might include:
- An orthopedic surgeon (a surgeon who specializes in muscles and bones) who is experienced in treating bone tumors
- A medical or pediatric oncologist (a doctor who treats cancer with chemotherapy and other drugs)
- A radiation oncologist (a doctor who treats cancer with radiation therapy)
- A pathologist (a doctor specializing in lab tests to diagnose and classify diseases)
- A physiatrist (a doctor who directs a person’s rehabilitation and physical therapy)
For adults and children, the team will also include other doctors, physician assistants (PAs), nurse practitioners (NPs), nurses, psychologists, social workers, physical therapists and other rehabilitation specialists, and other health professionals. Going through cancer treatment often means meeting lots of specialists and learning about parts of the medical system you probably haven’t been exposed to before. For more information, see Children Diagnosed With Cancer: Understanding the Health Care System.
Before treatment, the doctors and other members of the team will help you, as a parent, understand the tests that will need to be done. The team’s social worker will also counsel you about the problems you and your child might have during and after treatments such as surgery, and might be able to help you find housing and financial aid if needed.
The types of treatment that can be used in Ewing tumors include:
- Radiation therapy
- High-dose chemotherapy followed by a stem cell transplant
Chemotherapy is almost always the first treatment. Localized therapy (surgery and/or radiation therapy) is next, often followed by more chemotherapy. A stem cell transplant might be an option for some patients with Ewing tumors that are unlikely to be cured with other treatments.
Your child’s treatment will depend on the stage of the cancer and other factors. See “Treatment of Ewing tumors by stage” for information about the most common approaches.0 200