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leukemia-in-children

Leukemia in Children

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What is childhood leukemia?

Leukemia is a cancer of the early blood-forming cells. Most often, leukemia is a cancer of the white blood cells, but some leukemias start in other blood cell types.

Leukemia starts in the bone marrow (the soft inner part of certain bones, where new blood cells are made). In most cases, the leukemia invades the blood fairly quickly. From there it can go to other parts of the body such as the lymph nodes, spleen, liver, central nervous system (the brain and spinal cord), testicles, or other organs.

Some other childhood cancers, such as neuroblastoma or Wilms tumor, start in other organs and can spread to bone marrow, but these cancers are not leukemia.

Normal bone marrow, blood, and lymphoid tissue: To understand the different types of leukemia, it helps to know about the blood and lymph systems.

Bone marrow:Bone marrow is the soft inner part of bones. It is where new blood cells (red blood cells, white blood cells, and platelets) are made. In infants, active bone marrow is found in almost all bones of the body, but by the teenage years it is found mainly in the flat bones (skull, shoulder blades, ribs, and pelvis) and vertebrae (the bones that make up the spine).

Bone marrow is made up of a small number of blood stem cells, more mature blood-forming cells, fat cells, and supporting tissues that help cells grow. Blood stem cells go through a series of changes to make new blood cells. During this process, the cells develop into 1 of the 3 main types of blood cell components: Red blood cells, Platelets, White blood cells (which include lymphocytes, granulocytes, and monocytes)

Red blood cells:Red blood cells carry oxygen from the lungs to all other tissues of the body, and take carbon dioxide back to the lungs to be removed.

Platelets:Platelets are actually cell fragments that are made by a type of bone marrow cell called a megakaryocyte. They are released into the blood, where they are important in stopping bleeding by plugging holes in blood vessels caused by cuts or bruises.

White blood cells:White blood cells, also known as leukocytes, help the body fight infections. The 3 main types of white blood cells are lymphocytes, granulocytes, and monocytes.

Lymphocytes: These are the main cells that make up lymphoid tissue, a major part of the body's immune system. Lymphoid tissue is found in many places in the body, including the lymph nodes, thymus, spleen, tonsils and adenoids, and bone marrow. It is also scattered through the digestive system and respiratory system.

Lymphocytes develop from cells called lymphoblasts to become mature, infection-fighting cells. There are 2 main types of lymphocytes:

B lymphocytes (B cells) help protect the body against germs such as bacteria and viruses. When a B cell comes into contact with one of these germs, it matures into a plasma cell, which releases proteins called antibodies. The antibodies attach to the germ, marking it for destruction by other parts of the immune system.

T lymphocytes (T cells) also help protect the body against germs. There are several types of T cells, each with a special job. Some T cells can destroy germs directly, while others play a role in either boosting or slowing the activity of other immune system cells.

Acute lymphocytic (lymphoblastic) leukemia (ALL), the most common type of childhood leukemia, develops from early forms of lymphocytes. It can start in either early B cells or T cells at different stages of maturity. Although both B cells and T cells can develop into leukemia, B-cell leukemias are much more common than T-cell leukemias. 

Granulocytes: These white blood cells have granules in them, which are spots that can be seen under the microscope. These granules contain enzymes and other substances that can destroy germs, such as bacteria. The 3 types of granulocytes – neutrophils, basophils, and eosinophils – are distinguished by the size and color of their granules. Granulocytes develop from blood-forming cells called myeloblasts to become mature, infection-fighting cells.

Monocytes: These white blood cells, which are related to granulocytes, also help protect the body against bacteria. They start in the bone marrow as blood-forming monoblasts and develop into mature monocytes. After circulating in the bloodstream for about a day, monocytes enter body tissues to become macrophages, which can destroy some germs by surrounding and digesting them.

Development of leukemia:Any of the cells from the bone marrow can turn into a leukemia cell. Once this change takes place, the leukemia cells fail to go through the normal process of maturing. Leukemia cells might reproduce quickly, and not die when they should. They survive and build up in the bone marrow. Over time, these cells spill into the bloodstream and spread to other organs, where they can keep other cells in the body from functioning normally.

Types of leukemia in children: Leukemia is often described as being either acute (fast growing) or chronic (slow growing). Almost all childhood leukemia is acute.

Acute leukemias:There are 2 main types of acute leukemia:

Acute lymphocytic (lymphoblastic) leukemia (ALL): About 3 out of 4 cases of childhood leukemia are ALL. This leukemia starts from the lymphoid cells in the bone marrow.

Acute myelogenous leukemia (AML): This type of leukemia, also called acute myeloid leukemia, acute myelocytic leukemia, or acute non-lymphocytic leukemia), accounts for most of the remaining cases. AML starts from the myeloid cells that form white blood cells (other than lymphocytes), red blood cells, or platelets.

Hybrid or mixed lineage leukemias: In these rare leukemias, the cells have features of both ALL and AML. In children, they are generally treated like ALL and respond to treatment like ALL.

Both ALL and AML can be further divided into different subtypes.

Chronic leukemias:Chronic leukemias are much more common in adults than in children. They tend to grow more slowly than acute leukemias, but they are also harder to cure. Chronic leukemias can also be divided into 2 types. 

Chronic myelogenous leukemia (CML): This leukemia rarely occurs in children. Treatment is similar to treatment in adults. 

Chronic lymphocytic leukemia (CLL): This leukemia is extremely rare in children, so it is not discussed further in this document. 

Juvenile myelomonocytic leukemia (JMML):This rare type of leukemia is neither chronic nor acute. It begins from myeloid cells, but it doesn’t grow as fast as AML or as slow as CML. It occurs most often in young children (under age 4). Symptoms can include pale skin, fever, cough, easy bruising or bleeding, trouble breathing (from too many white blood cells in the lungs), and an enlarged spleen and lymph nodes.

What are the risk factors for childhood leukemia?

A risk factor is anything that affects your chance of getting a disease such as cancer. Different cancers have different risk factors. For example, smoking is a risk factor for several types of cancer in adults.

There are a few known risk factors for childhood leukemia.

Genetic risk factors:Genetic risk factors are those that are part of our DNA (the substance that makes up our genes). They are most often inherited from our parents. While some genetic factors increase the risk of childhood leukemia, most cases of leukemia are not linked to any known genetic causes.

Inherited syndromes:There are several inherited disorders that increase a child's risk of developing leukemia:

Li-Fraumeni syndrome: This is a rare condition caused by change in the TP53 tumor suppressor gene. People with this change have an increased risk of developing several kinds of cancer, including leukemia, bone or soft tissue sarcomas, breast cancer, adrenal gland cancer, and brain tumors.

Down syndrome (trisomy 21): Children with Down syndrome have an extra (third) copy of chromosome 21. In ways that are not completely understood, this extra chromosome 21 causes mental retardation and a characteristic facial appearance. Children with Down syndrome are many times more likely to develop either acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) than are other children, with an overall risk of about 2% to 3%. Down syndrome has also been linked with transient leukemia – a leukemia-like condition within the first month of life, which often resolves on its own without the use of chemotherapy.

Klinefelter syndrome: This is a genetic condition in which males have an extra "X" chromosome. This causes infertility, prevents normal development of some male features (such as body hair, deep voice, etc.), and is linked to a slightly increased risk of developing leukemia.

Several other genetic disorders (such as neurofibromatosis and Fanconi anemia) also carry an increased risk of leukemia, as well as some other types of cancers.

Inherited immune system problems:Certain inherited diseases such as ataxia telangiectasia, Wiskott-Aldrich syndrome, and Bloom syndrome cause children to be born with immune system problems. Along with being at increased risk of getting serious infections from reduced immune defenses, these children might also have an increased risk of leukemia.

Having a brother or sister with leukemia:Siblings (brothers and sisters) of children with leukemia have a slightly increased chance (2 to 4 times normal) of developing leukemia, but the overall risk is still low. The risk is much higher among identical twins. If an identical twin develops childhood leukemia, the other twin has about a 1 in 5 chance of getting leukemia as well. This risk is even higher if the leukemia develops in the first year of life.

Having a parent who develops leukemia as an adult does not seem to raise a child's risk of leukemia.

Lifestyle-related risk factors:Lifestyle-related risk factors for some adult cancers include being overweight, smoking, drinking excessive amounts of alcohol, and getting too much sun exposure. While lifestyle-related factors are important in many adult cancers, they are unlikely to play a role in most childhood cancers.

Some studies have suggested that if a mother drinks a lot of alcohol during pregnancy it might increase the risk of leukemia in her child, but not all studies have found such a link.

Environmental risk factors:Environmental risk factors are influences in our surroundings, such as radiation and certain chemicals, that increase the risk of getting diseases such as leukemias.

Radiation exposure:Exposure to high levels of radiation is a risk factor for childhood leukemia. Japanese atomic bomb survivors had a greatly increased risk of developing AML, usually within 6 to 8 years after exposure. If a fetus is exposed to radiation within the first months of development, there may also be an increased risk of childhood leukemia, but the extent of the risk is not clear.

The possible risks from fetal or childhood exposure to lower levels of radiation, such as from x-rays or CT scans, is not well defined. Some studies have found a slight increase in risk, while others have found no increased risk. Any risk increase is likely to be small, but to be safe, most doctors recommend that pregnant women and children not get these tests unless they are absolutely necessary.

Exposure to chemotherapy and certain other chemicals:Children and adults treated for other cancers with certain chemotherapy drugs have a higher risk of getting a second cancer, usually AML, later in life. Drugs such as alkylating agents (a class that includes cyclophosphamide and chlorambucil) and epipodophyllotoxins (such as etoposide and teniposide) have been linked to a higher risk of leukemia. These leukemias usually develop within 5 to 10 years of treatment and tend to be hard to treat.

Exposure to chemicals such as benzene (a solvent used in the cleaning industry and to manufacture some drugs, plastics, and dyes) may cause AML in adults and, rarely, in children. Chemical exposure is more strongly linked to an increased risk of AML than to ALL.

Several studies have found a possible link between childhood leukemia and household exposure to pesticides, either during pregnancy or early childhood. Some studies have also found a possible increased risk among mothers with workplace exposure to pesticides before birth. However, most of these studies had serious limitations in the way they were done. More research is needed to try to confirm these findings and to provide more specific information about the possible risks.

Immune system suppression:Patients getting intensive treatment to suppress their immune function (mainly organ transplant patients) have an increased risk of certain cancers, such as lymphoma and ALL.

Uncertain, unproven, or controversial risk factors

Other factors that have been studied for a possible link to childhood leukemia include: Exposure to electromagnetic fields (such as living near power lines), Living near a nuclear power plant, Infections early in life, Mother's age when child was born, Parent's smoking history, Fetal exposure to hormones such as diethylstilbestrol (DES) or birth control pills, Father's workplace exposure to chemicals and solvents, Chemical contamination of ground water

Do we know what causes childhood leukemia?

The exact cause of most cases of childhood leukemia is not known. Doctors have found that the risk of this cancer is increased in a number of genetic conditions, which are described in the section "What are the risk factors for childhood leukemia?" But it is important to note that most children with leukemia do not have any known risk factors.

Scientists have made great progress in understanding how certain changes in DNA can cause normal bone marrow cells to become leukemia cells. Normal human cells grow and function based mainly on the information contained in each cell's chromosomes. Chromosomes are long strands of DNA in each cell. DNA is the chemical that makes up our genes – the instructions for how our cells function. We usually look like our parents because they are the source of our DNA. But our genes affect more than the way we look.

Some genes have instructions for controlling when our cells grow, divide into new cells, and die. Certain genes that help cells grow and divide are called oncogenes. Others that slow down cell division or cause cells to die at the right time are called tumor suppressor genes.

Cancers can be caused by DNA changes (mutations) that turn on oncogenes or turn off tumor suppressor genes. These gene changes can be inherited from a parent (as is sometimes the case with childhood leukemias), or they may happen spontaneously during a person's lifetime if cells in the body make mistakes as they divide to form 2 new cells.

A common type of DNA abnormality that can lead to leukemia is known as a translocation. Human DNA is packaged in 23 pairs of chromosomes. A translocation means that DNA from one chromosome breaks off and becomes attached to a different chromosome. The point at which the break occurs can affect oncogenes or tumor suppressor genes. For example, a translocation seen in nearly all cases of childhood chronic myeloid leukemia (CML) and in some cases of childhood acute lymphocytic leukemia (ALL) is a swapping of DNA between chromosomes 9 and 22, which leads to what is known as the Philadelphia chromosome. This creates an oncogene known as BCR-ABL. Many other changes in chromosomes or in specific genes have been found in childhood leukemias as well.

Some children inherit DNA mutations from a parent that may increase their risk for cancer. For instance, a condition called Li-Fraumeni syndrome, which results from an inherited mutation of the TP53 tumor suppressor gene, increases a person's risk of developing leukemia, as well as some other cancers.

Certain inherited diseases can increase the risk of developing leukemia, but most cases of childhood leukemia do not seem to be caused by inherited mutations. Usually, DNA mutations related to leukemia develop after conception rather than having been inherited. Some of these acquired mutations may occur early, even before birth. In rare cases, acquired mutations may result from exposure to radiation or cancer-causing chemicals, but usually they occur for no apparent reason.

A few studies have suggested that some childhood leukemias may be caused by a combination of genetic and environmental factors. For example, certain genes normally control how our bodies break down and get rid of harmful chemicals. Some people have different versions of these genes that make them less effective. Children who inherit these genes may not be as able to break down harmful chemicals if they are exposed to them. The combination of genetics and exposure might increase their risk for leukemia.

Can childhood leukemia be found early?

At this time there are no widely recommended blood tests or other screening exams for most children to look for leukemia before it starts to cause symptoms. Childhood leukemia is often found because a child has symptoms that prompt a visit to the doctor. Blood test results are abnormal, which then points to the diagnosis. The best way to find these cancers early is prompt attention to the possible signs and symptoms of this disease.

For children with a known increased risk of leukemia (because of Li-Fraumeni syndrome or Down syndrome, for example), most doctors recommend careful, regular medical checkups and possibly other tests. The same is true for children who have had other cancers treated with chemotherapy and/or radiation therapy, and for children who have received organ transplants and are taking immune system-suppressing drugs. The risk of leukemia in these children, although higher than in the general population, is still small.

How is childhood leukemia diagnosed?

It is very important to diagnose childhood leukemia as early as possible and to determine what type of leukemia it is so that treatment can be tailored to provide the best chance of success. The exams and tests below are used to diagnose the disease, to help determine what type of leukemia it is, and to measure how advanced it may be.

Signs and symptoms of childhood leukemia: Many of the signs and symptoms of childhood leukemia are caused by a lack of normal blood cells, a result of the leukemia cells crowding out the normal blood cell-making cells in the bone marrow. As a result, a child may not have enough normal red blood cells, white blood cells, and blood platelets. These shortages show up on blood tests, but they can also cause symptoms. The leukemia cells may also invade other areas of the body, which can also cause symptoms.

Many of these symptoms have other causes as well, and most often they are not due to leukemia. Still, it's important to let your child's doctor know about them so that the cause can be found and treated, if needed.

Fatigue, pale skin: Anemia (a shortage of red blood cells) may cause a child to feel tired, weak, dizzy, or short of breath. It may also cause the skin to appear pale.

Infections and fever: A child with leukemia may develop fever. This is often caused by an infection, which may not improve even with antibiotics. This is because of a lack of normal white blood cells, which would normally help fight the infection. Although children with leukemia may have very high white blood cell counts, the leukemia cells do not protect against infection the way normal white blood cells do. Fever is also sometimes caused by the leukemia cells themselves releasing certain chemicals into the body.

Easy bleeding or bruising: A child with leukemia may bruise easily, have frequent nosebleeds and bleeding gums, or bleed excessively from small cuts. There may be pinhead-sized red spots on the skin caused by bleeding from tiny blood vessels. This comes from a lack of blood platelets, which normally stop bleeding by plugging holes in damaged blood vessels.

Bone or joint pain: Some children with leukemia will have bone pain or joint pain. This is from the buildup of leukemia cells near the surface of the bone or inside the joint.

Swelling of the abdomen: Leukemia cells may collect in the liver and spleen, causing them to enlarge. This may be noticed as a fullness or swelling of the belly. The lower ribs usually cover these organs, but when they are enlarged the doctor can often feel them.

Loss of appetite, weight loss: If the spleen and/or liver become large enough, they may press against other organs like the stomach. This can limit the amount of food that can be eaten, leading to a loss of appetite and weight loss over time.

Swollen lymph nodes: Some leukemias may spread to lymph nodes. The child, a parent, or a health care professional may notice swollen nodes as lumps under the skin in certain areas of the body (such as on the sides of the neck, in underarm areas, above the collarbone, or in the groin). Lymph nodes inside the chest or abdomen may also swell, but these can only be detected by imaging tests, such as CT or MRI scans.

Lymph nodes often enlarge when they are fighting an infection, especially in infants and children. Lymph nodes that grow as a reaction to infection are called reactive nodes or hyperplastic nodes. An enlarged lymph node in a child is more often a sign of infection than leukemia, but it should be checked by a doctor and followed closely.

Coughing or trouble breathing: The T-cell type of acute lymphocytic leukemia (ALL) often involves the thymus, which is a small organ in the chest behind the breastbone (sternum) and in front of the windpipe (trachea). Enlargement of the thymus or of lymph nodes inside the chest can press on the trachea. This can lead to coughing or trouble breathing.

Swelling of the face and arms: The superior vena cava (SVC), a large vein that carries blood from the head and arms back to the heart, passes next to the thymus. Growth of the thymus due to excess leukemia cells may press on the SVC, causing the blood to "back up" in the veins. This is known as SVC syndrome. It can cause swelling in the face, neck, arms, and upper chest (sometimes with a bluish-red skin color). It can also cause headaches, dizziness, and a change in consciousness if it affects the brain. The SVC syndrome can be life-threatening, and needs to be treated right away.

Headache, seizures, vomiting: Leukemia can spread outside the bone marrow. It may spread to the central nervous system (brain and spinal cord), the testicles, ovaries, kidneys, lungs, heart, intestines, or other organs. A small portion of children have leukemia that has already spread to the central nervous system when they are first diagnosed. Headache, trouble concentrating, weakness, seizures, vomiting, problems with balance, and blurred vision can be symptoms of central nervous system leukemia.

Rashes, gum problems: In children with acute myelogenous leukemia (AML), leukemia cells may spread to the gums, causing swelling, pain, and bleeding. Spread to the skin can cause small, darkly colored spots that can resemble common rashes. A collection of AML cells under the skin or in other parts of the body is called a chloromaor granulocytic sarcoma.

Extreme fatigue, weakness: One rare but very serious consequence of AML is extreme tiredness, weakness, and slurring of speech. This can occur when very high numbers of leukemia cells make the blood too "thick" and slow the circulation through small blood vessels of the brain.

Medical history and physical exam:If your child has signs and symptoms that suggest they may have leukemia, the doctor will want to get a thorough medical history, including how long the symptoms have been present and whether or not there is any history of exposure to risk factors. A family history of cancer, especially leukemia, may also be important.

During the physical exam, the doctor will focus on any enlarged lymph nodes, areas of bleeding or bruising, or possible signs of infection. The eyes, mouth, and skin will likely be looked at carefully, and a nervous system exam may be done. The abdomen will be felt for signs of an enlarged spleen or liver.

The doctor may also get blood samples to test your child's blood cell counts. If these are abnormal, the doctor may refer you to a pediatric oncologist, a doctor who specializes in treating cancers (like leukemia) in children. This doctor may run one or more of the tests described below.

Types of tests used to look for leukemia in children: If the doctor thinks your child might have leukemia, he or she will need to check samples of cells from your child's blood and bone marrow to be sure of the diagnosis. Other tissue and cell samples may also be taken to help guide treatment.

Blood tests:Blood samples for tests for leukemia are taken as they are for other tests – usually from a vein in the arm. In infants and younger children, they may be taken from other veins (such as in the feet or scalp) or from a "finger stick."

Blood counts and blood smears are the usual tests done on these samples. A complete blood count (CBC) is done to determine how many of each type of blood cell are present in the blood. For a blood smear, a small sample of blood is spread on a glass slide and looked at under a microscope. Abnormal numbers of different blood cell types and changes in the way these cells look may make the doctor suspect leukemia.

Most children with acute leukemia — lymphocytic or myeloid — will have too many white blood cells and not enough red blood cells and/or platelets. Many of the white blood cells in the blood will be blasts, an early type of blood cell normally found only in the bone marrow. Even though these findings may make a doctor suspect that a child has leukemia, usually the disease cannot be diagnosed for sure without looking at a sample of bone marrow cells.

Bone marrow aspiration and biopsy:Bone marrow samples are obtained from a bone marrow aspiration and biopsy – 2 tests that are usually done at the same time. The samples are usually taken from the back of the pelvic (hip) bones, but in some cases they may be taken from the front of the pelvic bones, the breastbone (sternum [very rarely in children]), or other bones.

For a bone marrow aspiration, the skin over the hip and the surface of the bone is cleaned and numbed with local anesthetic. In most cases, the child is also given other medicines to reduce pain or even be asleep during the procedure. A thin, hollow needle is then inserted into the bone and a syringe is used to suck out (aspirate) 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 twisted as it is pushed down into the bone. Once the biopsy is done, pressure will be applied to the site to help prevent any bleeding.

These bone marrow tests are used to diagnose leukemia and may be repeated later to tell if the leukemia is responding to treatment.

Lumbar puncture (spinal tap):This test is used to look for leukemia cells in the cerebrospinal fluid (CSF), which is the liquid that bathes the brain and spinal cord.

For this test, the doctor first numbs an area in the lower part of the back over the spine. The doctor usually also gives the child medicine to make him or her sleep during the procedure. A small, hollow needle is then placed between the bones of the spine to withdraw some of the fluid.

This test is routinely done in children with leukemia, but it is important that it is done by an expert. Doctors have found that if the spinal tap isn't performed expertly and some blood leaks into the CSF, in some cases leukemia cells may escape into the fluid and grow there.

In children already diagnosed with leukemia, a lumbar puncture can also be used to give chemotherapy drugs into the CSF to try to prevent or treat the spread of leukemia to the spinal cord and brain.

Lymph node biopsy:This type of biopsy is important in diagnosing lymphomas, but it is rarely needed for children with leukemias.

During this procedure, a surgeon cuts through the skin to remove an entire lymph node (excisional biopsy). If the node is near the skin surface, this is a simple operation. But it may be more involved if the node is inside the chest or abdomen. Most often the child will need general anesthesia (where the child is asleep).

Lab tests used to diagnose and classify leukemia

Routine microscopic exams:As mentioned above, blood counts and smears are usually the first tests done when leukemia is a possible diagnosis. Any other samples taken (bone marrow, lymph node tissue, or CSF) are also looked at under a microscope by a pathologist (a doctor specializing in lab tests) and may be reviewed by the patient's hematologist/oncologist (a doctor specializing in blood diseases and cancer).

The doctors will look at the size, shape, and staining patterns of the blood cells in the samples to classify them into specific types.

A key element is whether the cells look mature (like normal blood cells) or immature (lacking features of normal blood cells). The most immature cells are called blasts. Having too many blasts in the sample, especially in the blood, is a typical sign of leukemia.

An important feature of a bone marrow sample is its cellularity. Normal bone marrow contains a certain number of blood-forming cells and fat cells. Marrow with too many blood-forming cells is said to be hypercellular. If too few blood-forming cells are found, the marrow is called hypocellular.

Cytochemistry:In cytochemistry tests, cells from the sample are put on a microscope slide and exposed to chemical stains (dyes) that react only with some types of leukemia cells. These stains cause color changes that can be seen under a microscope. This can help the doctor determine what types of cells are present. For example, one stain causes the granules of most AML cells to appear as black spots under the microscope, but it does not cause ALL cells to change colors.

Flow cytometry and immunohistochemistry:Flow cytometry is used to test the cells from bone marrow, lymph nodes, and blood samples to determine more accurately the exact type of leukemia. It is a very important tool because it may help define the unique traits of the leukemia. It can also be used to measure the response to treatment and the existence of minimal residual disease  in some types of leukemias.

The test checks for certain substances on the surface of cells that help identify what types of cells they are. The cells in the sample are treated with special antibodies (man-made versions of immune system proteins) that stick only to these substances. The cells are then passed in front of a laser beam. If the cells now have antibodies attached to them, the laser will cause them to give off light, which is measured and analyzed by a computer.

Flow cytometry can also be used to estimate the amount of DNA in the leukemia cells. This is important to know, especially in ALL, because cells with a high DNA index (more than 16% above normal) are often more sensitive to chemotherapy, and these leukemias have a better prognosis (outlook).

For immunohistochemistry tests, cells from the bone marrow or other samples are treated with special man-made antibodies. But instead of using a laser and computer for analysis, the sample is treated so that certain types of cells change color. The color change is visible under a microscope. Like flow cytometry, it is helpful in distinguishing different types of leukemia from one another and from other diseases.

These tests are used for immunophenotyping – classifying leukemia cells according to the substances (antigens) on their surfaces. Different types of cells have different antigens on their surface. These antigens also change as the cells mature. Each patient's leukemia cells should all have the same antigens because they are all derived from the same cell. Lab testing for antigens is a very sensitive way to diagnose and classify leukemias.

Cytogenetics:For this test, chromosomes (pieces of DNA) from leukemia cells are looked at under a microscope to detect any changes. Normal human cells contain 23 pairs of chromosomes, each of which is a certain size and stains a certain way. In some types of leukemia, chromosome changes may be seen.

For instance, sometimes 2 chromosomes swap some of their DNA, so that part of one chromosome becomes attached to part of a different chromosome. This change, called a translocation, can usually be seen under a microscope. Recognizing these changes can help identify certain types of acute leukemias and can help determine prognosis (outlook).

Some types of leukemia have cells with an abnormal number of chromosomes (instead of the usual 46) – they may be missing some chromosomes or have extra copies of some. This can also affect a patient's outlook. For example, chemotherapy is more likely to work in cases of ALL where the cells have more than 50 chromosomes and is less likely to be effective if the cells have fewer than 46 chromosomes. (Counting the number of chromosomes by cytogenetics provides similar information to measuring the DNA index by flow cytometry, as described above.)

Cytogenetic testing usually takes about 2 to 3 weeks because the leukemia cells must grow in lab dishes for a couple of weeks before their chromosomes are ready to be looked at under the microscope.

Not all chromosome changes can be seen under a microscope. Other lab tests can often help detect these changes.

Fluorescent in situ hybridization (FISH):This is similar to cytogenetic testing. It uses special fluorescent dyes that only attach to specific parts of particular chromosomes. 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 can be used on blood or bone marrow samples. It is very accurate and can usually provide results within a couple of days.

Polymerase chain reaction (PCR):This is a very sensitive DNA test that can also find some chromosome changes too small to be seen under a microscope, even if very few leukemia cells are present in a sample. Like flow cytometry, it can be a very useful tool to look for small numbers of leukemia cells (minimal residual disease, or MRD) during and after treatment.

These tests may also be used after treatment to see if even small numbers of leukemia cells, which would not be detected by other tests, are still there.

Other blood tests:Children with leukemia will have tests to measure certain chemicals in the blood to evaluate how well their body systems are working.

These tests are not used to diagnose leukemia, but in children already known to have it, they can help find damage to the liver, kidneys, or other organs caused by the spread of leukemia cells or by certain chemotherapy drugs. Tests are also often done to measure blood levels of important minerals, as well as to ensure the blood is clotting properly.

Children might also be tested for blood infections. It is important to quickly diagnose and treat infections in children with leukemia because their weakened immune systems can allow infections to spread quickly.

Imaging tests:Imaging tests use x-rays, sound waves, magnetic fields, or radioactive particles to produce pictures of the inside of the body. Leukemia does not usually form tumors, so imaging tests aren't as useful as they are for other types of cancer. But if leukemia is suspected or has been diagnosed, your child's doctor may order some of the following imaging tests to get a better idea of the extent of the disease or to look for other problems, such as infections.

Chest x-rays:A chest x-ray can help detect an enlarged thymus or lymph nodes in the chest. If this test is abnormal, a computed tomography (CT) scan may be done to get a more detailed view. Chest x-rays can also help look for pneumonia if your child seems to have a lung infection.

Computed tomography (CT) scan:The CT scan is a type of x-ray test that produces detailed, cross-sectional images of the body. Unlike a regular x-ray, CT scans can show the detail in soft tissues such as internal organs.

This test can help tell if any lymph nodes or organs in the body are enlarged. It isn't usually needed to diagnose leukemia, but it may be done if the doctor suspects the leukemia is growing in lymph nodes in the chest or in organs like the spleen or liver. It is also sometimes used to look at the brain and spinal cord, but MRI may also be used for this.

Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around your child. A computer then combines these pictures into detailed images of the part of the body that is 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. He or she may need an IV line through which the contrast dye is injected.

The IV injection of contrast dye can cause a feeling of flushing or warmth in the face or elsewhere. Some people are allergic and get hives or, rarely, more serious reactions like trouble breathing and low blood pressure. Be sure to tell the doctor if your child has any allergies or has ever had a reaction to any contrast material used for x-rays.

CT scans take longer than regular x-rays. Your child will need to lie still on a table while the scan is being done. During the test, the table slides in and out of the scanner, a ring-shaped machine that completely surrounds the table. Some children may need to be sedated before the test. Spiral CT (also known as helical CT) is now used in many medical centers. This type of CT scan uses a faster machine with a lower dose of radiation, but gives more detailed pictures.

PET/CT scan: In recent years, newer devices have been developed that combine the CT scan with a positron emission tomography (PET) scan. For a PET scan, a form of radioactive sugar (known as fluorodeoxyglucose or FDG) is injected into the blood. Because cancer cells in the body grow rapidly, they absorb large amounts of the radioactive sugar. A special camera can then create a picture of areas of radioactivity in the body. The PET/CT scan lets the doctor compare areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT.

Magnetic resonance imaging (MRI) scans:Like CT scans, MRI scans give detailed images of soft tissues in the body. But MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed by the body and then released in a pattern formed by the type of body tissue and by certain diseases. A computer translates the pattern into a very detailed image of parts of the body.

A contrast material called gadolinium is often injected into a vein before the scan to better show details. The contrast material usually does not cause allergic reactions.

MRI scans are most helpful in looking at the brain and spinal cord.

MRI scans take longer than CT scans – often up to an hour. Your child may have to lie inside a narrow tube, which is confining and can be distressing, so sedation is sometimes needed. Newer, more open MRI machines may be another option, although they still require that your child be able to lie still. All MRI machines make loud buzzing and clicking noises that your child may find disturbing. Some places provide headphones or earplugs to help block this out.

Ultrasound:Ultrasound uses sound waves and their echoes to produce a picture of internal organs or masses. For this test, a small, microphone-like instrument called a transducer is placed on the skin (which is first lubricated with gel). It gives off sound waves and picks up the echoes as they bounce off the organs. The echoes are converted by a computer into an image that is displayed on a computer screen.

Ultrasound can be used to look at lymph nodes near the surface of the body or to look for enlarged organs inside the abdomen such as the kidneys, liver, and spleen. (It can't be used to look at organs or lymph nodes in the chest because the ribs block the sound waves.)

This is an easy test to have, and it uses no radiation. Your child simply lies on a table, and a technician moves the transducer over the part of the body being looked at.

Gallium scan and bone scan:These tests are not often done for childhood leukemias, but they may be useful if your child has bone pain that might be from either an infection or cancer in the bones. If your child has already been diagnosed with leukemia or if a PET scan (described above) has already been done, there is usually no need for these tests.

For these tests, the doctor or nurse injects a small amount of a slightly radioactive chemical into the bloodstream, which collects in areas of cancer or infection in the body. These areas can then be looked at with a special type of camera. The images from these scans are seen as "hot spots" in the body, but they don't provide much detail. If an area lights up on the scan, other imaging tests such as x-rays or CT or MRI scans may be done to get a more detailed look at the area. If leukemia is a possibility, a biopsy of the area may be needed to confirm this.

How is childhood leukemia classified?

Most types of cancers are assigned numbered stages to describe their extent in the body, based on the size of the tumor and how far the cancer has spread.

But leukemia is not staged like most other cancers. It starts in the bone marrow and quickly spreads to the blood, so leukemia cells are already scattered throughout the body. Still, it is important to know whether the leukemia cells have started to collect in other organs such as the liver, spleen, lymph nodes, testicles, or central nervous system.

For instance, if the leukemia cells have spread to the central nervous system in large numbers, they can be seen in samples of cerebrospinal fluid (CSF). Treatment must be more intense in order to kill the leukemia cells in the central nervous system. This is why a spinal tap (lumbar puncture) is done as part of the early diagnostic testing.

The most important factor for leukemias is determining the type (acute lymphocytic, acute myeloid, etc.) and subtype of the leukemia. This is done by testing samples of the blood, bone marrow, and sometimes lymph nodes or CSF. Classification of the leukemia plays a major role in determining both treatment options and a child's outlook (prognosis).

Acute lymphocytic (lymphoblastic) leukemia (ALL):Acute lymphocytic leukemia (ALL) is a fast-growing cancer of the lymphocyte-forming cells called lymphoblasts.

Classification based on cell appearance (morphology):In the past, doctors used the French-American-British (FAB) classification to divide ALL into 3 major groups (L1, L2, or L3) based on how the cells looked under the microscope. Some doctors may still refer to these categories. But newer lab tests now let doctors classify ALL based on more than just how the cells look under the microscope.

Classification based on immunophenotype:Doctors have found that cytogenetic tests, flow cytometry, and other lab tests provide more detailed information about the subtype of ALL and the patient's prognosis. These tests help divide ALL into groups based on theimmunophenotype of the leukemia, which takes into account: The type of lymphocyte (B cell or T cell) the leukemia cells come from, How mature these leukemia cells are

There are 4 main subtypes of ALL, as shown  below:

Subtype                     Frequency

Early Pre-B cell           60%-65%

Pre-B cell                    20%-25%

Mature B cell               2%-3%

T cell                          15%-18%

B-cell ALL: About 85% of children with ALL have B-cell ALL.

The most common subtype of B-cell ALL is "early precursor B" (early pre-B) ALL.

The "pre-B" form of ALL accounts for 20% to 25% of patients with B-cell ALL.

Mature B-cell leukemia accounts for about 2% to 3% of childhood ALL. It is also called Burkitt leukemia. Because this disease is essentially the same as Burkitt lymphoma and is treated differently from most leukemias.

T-cell ALL: About 15% to 18% of children with ALL have T-cell ALL. This type of leukemia affects boys more than girls and generally affects older children more than does B-cell ALL. It often causes an enlarged thymus (a small organ in front of the windpipe), which can sometimes cause breathing problems. It may also spread to the cerebrospinal fluid (the fluid that surrounds the brain and spinal cord) early in the course of the disease.

Aside from the subtypes of ALL, other factors are important in determining outlook (prognosis). 

Acute myelogenous leukemia (AML):Acute myelogenous leukemia (AML) is typically a fast-growing cancer of one of the following types of early (immature) bone marrow cells:   (a) Myeloblasts: These cells normally form white blood cells called granulocytes (neutrophils, eosinophils, and basophils), (b) Monoblasts: These cells normally become white blood cells called monocytes and macrophages, (c) Erythroblasts: These cells mature into red blood cells, (d) Megakaryoblasts: These cells normally become megakaryocytes, the cells that make platelets.

Two systems have been used to classify AML into subtypes – the French-American-British (FAB) classification and the newer World Health Organization (WHO) classification.

World Health Organization (WHO) classification of AML: The FAB classification system is useful and is still commonly used to group AML into subtypes. But it doesn't take into account many other prognostic factors that doctors have learned about in recent years, such as chromosome changes in the leukemia cells. The newer WHO system includes some of these factors to try to help better classify cases of AML based on a person's outlook. Not all doctors use this new system.

The WHO system divides AML into several broad groups:

AML with certain genetic abnormalities: AML with a translocation between chromosomes 8 and 21, AML with a translocation or inversion in chromosome 16, AML with changes in chromosome 11, APL (M3), which usually has translocation between chromosomes 15 and 17

AML with multilineage dysplasia (more than one abnormal myeloid cell type is involved)

AML related to previous chemotherapy or radiation

AML not otherwise specified (includes cases of AML that don't fall into one of the above groups; similar to the FAB classification): Undifferentiated AML (M0), AML with minimal maturation (M1), AML with maturation (M2), Acute myelomonocytic leukemia (M4), Acute monocytic leukemia (M5), Acute erythroid leukemia (M6), Acute megakaryoblastic leukemia (M7), Acute basophilic leukemia, Acute panmyelosis with fibrosis, Myeloid sarcoma (also known as granulocytic sarcoma or chloroma)

Hybrid or mixed lineage leukemias:These leukemias have cells with features of both ALL and AML when they are subjected to lab tests. In children, these leukemias are generally treated like ALL and respond to treatment like ALL.

Chronic myelogenous leukemia (CML):Chronic myelogenous leukemia (CML) is typically a slower-growing cancer of early (immature) myeloid bone marrow cells. CML is not common in children, but it can occur.

The course of CML is divided into 3 phases, based mainly on the number of immature white blood cells – myeloblasts ("blasts") – that are seen in the blood or bone marrow. Different groups of experts have suggested slightly different cutoffs to define the phases, but a common system (proposed by the World Health Organization) is described below.

If the leukemia is not cured with treatment, it can progress to more advanced phases over time.

Chronic phase:This is the earliest phase, in which patients typically have less than 10% blasts in their blood or bone marrow samples. These children usually have fairly mild symptoms (if any), and the leukemia usually responds well to standard treatments. Most patients are in the chronic phase when they are diagnosed.

Accelerated phase:Patients are considered to be in accelerated phase if bone marrow or blood samples have more than 10% but fewer than 20% blasts, or if levels of certain other blood cells are too high or too low.

Children whose CML is in accelerated phase may have symptoms such as fever, poor appetite, and weight loss. CML in the accelerated phase does not respond as well to treatment as CML in the chronic phase.

Blast phase (also called acute phase or blast crisis):Bone marrow and/or blood samples from a patient in this phase have more than 20% blasts. The blast cells often spread to tissues and organs beyond the bone marrow. These children often have fever, poor appetite, and weight loss. At this point the CML acts much like an aggressive acute leukemia (AML or, less often, ALL).

Not all doctors may agree with or follow these cutoff points for the different phases. If you have questions about what phase your child's CML is in, be sure to have the doctor explain it to you.

Prognostic factors in childhood leukemia (ALL or AML):Certain differences among patients that affect the leukemia’s response to treatment are called prognostic factors. They help doctors decide whether a child with leukemia should receive standard treatment or more intensive treatment. Prognostic factors seem to be more important in acute lymphocytic leukemia (ALL) than in acute myelogenous leukemia (AML).

Prognostic factors for children with ALL:Different systems are used to classify childhood ALL risk. In one of the more common systems, children with ALL are divided into standard-risk, high-risk, or very high-risk groups, with more intensive treatment given for higher risk patients. Generally, children at low risk have a better outlook than those at very high risk.

While all of the following are prognostic factors, only certain ones are used to determine which risk group a child falls into. (The first 2 factors – age at diagnosis and initial white blood cell count – are generally considered the most important.) It's important to know that many children with one or more poor prognostic factors can still be cured.

Age at diagnosis: Children with B-cell ALL between the ages of 1 and 9 tend to have better cure rates. Children younger than 1 year and children 10 years or older are considered high-risk patients. The outlook in T-cell ALL isn't affected much by age.

White blood cell (WBC) count: Children with ALL who have especially high WBC counts (greater than 50,000 cells per cubic millimeter) when they are diagnosed are classified as high risk and need more intensive treatment.

Subtype of ALL: Children with pre-B or early pre-B-cell ALL generally do better than those with mature B-cell (Burkitt) leukemia. The outlook for T-cell ALL seems to be about the same as that for B-cell ALL as long as treatment is intense enough.

Gender: Girls with ALL may have a slightly higher chance of being cured than do boys. As treatments have improved in recent years, this difference has shrunk.

Spread to certain organs: Spread of the leukemia into the spinal fluid, or the testicles in boys, increases the chance of a poor outcome. Enlargement of the spleen and liver is usually linked to a high WBC count, but some doctors view this as a separate sign that the outlook is not as favorable.

Number of chromosomes: Patients are mo

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