Sunday, October 10, 2010

Leukemia, Childhood

Photograph of a male doctor with his stethoscope on the teddy bear of a young female patient

Leukemia is cancer of the white blood cells. It is the most common type of childhood cancer.

Your blood cells form in your bone marrow. White blood cells help your body fight infection. In leukemia, however, the bone marrow produces abnormal white blood cells. These cells crowd out the healthy blood cells, making it hard for blood to do its work. Leukemia can develop quickly or slowly. Acute leukemia is a fast growing type while chronic leukemia grows slowly. Children with leukemia usually have one of the acute types.

Risk factors for childhood leukemia include having a brother or sister with leukemia, having certain genetic disorders and having had radiation or chemotherapy. Treatment often cures childhood leukemia. Treatment options include chemotherapy, other drug therapy and radiation. In some cases bone marrow and blood stem cell transplantation might help.

NIH: National Cancer Institute

How is childhood leukemia classified?

For most cancers, staging is the process of finding out how advanced a cancer is. Most types of solid cancers are assigned a stage based on the size of the tumor and how far the cancer has spread in the body.
However, leukemia is not staged like most other cancers. It already involves the bone marrow and blood. But 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. For this reason, a spinal tap is done as part of the early diagnostic testing.
The most important factor for leukemias is determining the type (ALL vs. AML) and subtype of the leukemia. This is done by testing samples of the blood, bone marrow, and sometimes lymph nodes or CSF (as described in "How is childhood leukemia diagnosed?"). 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 cancer of the lymphocyte-forming cells called lymphoblasts.

Classification based on cell appearance (morphology)

In the past, ALL was divided into 3 major groups (L1, L2, or L3) based on the appearance of the cells under the microscope.
    L1 is the most common subtype in children. The lymphoblasts are small cells.
    L2 accounts for 10% of ALL cases. These cells are larger.
    L3 is the rarest subtype.
Some doctors may still refer to these categories. But newer lab tests now allow doctors to classify ALL based on more than just how it looks under the microscope.

Classification based on lymphocyte antigens (immunophenotypes)

It is more useful to classify subtypes of ALL by looking for certain substances, called antigens, on the cells. Tests for antigens can help determine whether the leukemia cells started in B cells or T cells, as well as how mature these cells are. Tests for abnormalities in the genes and chromosomes of leukemia cells are also used to determine their subtype.

here are 4 main subtypes as shown in the table 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 childhood ALL is 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 than most leukemias, it is discussed in detail in the American Cancer Society document, Non-Hodgkin Lymphoma in Children.
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 (which can sometimes cause breathing problems) and may 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). These are described in the section "Prognostic factors in childhood leukemia."
Acute myelogenous leukemia (AML)
Acute myelogenous leukemia (AML) is a cancer of one of the following types of early (immature) bone marrow cells:
  • myeloblasts: These cells normally form granulocytes (neutrophils, eosinophils, and basophils).
  • monoblasts: These cells normally become monocytes and macrophages.
  • erythroblasts: These cells mature into red blood cells.
  • megakaryoblasts: These cells normally become megakaryocytes, the cells that make platelets.
AML has several subtypes, based on the type of cell involved and how mature it is. Although several lab tests can help diagnose AML, the subtypes of AML are classified mainly by their morphology (appearance under the microscope) using routine and cytochemical stains. It may also be useful to look for changes in the genes or chromosomes of the leukemia cells.
There are 8 subtypes of AML: M0 to M7 (the "M" refers to myeloid).
    M0: This subtype of AML is made up of very immature cells -- so immature that they can't be labeled according to the types of cells listed above. This subtype can only be distinguished from ALL by flow cytometry because the cells lack any distinct features that can be seen by microscope. (Flow cytometry is explained in the section, "How is childhood leukemia diagnosed?") This type of leukemia is very rare in children.
    M1: This subtype is made up of immature myeloblasts. It can be recognized by the way the cells look under the microscope after using cytochemical stains.
    M2: This subtype is composed of slightly more mature forms of myeloblasts. It is the most common subtype of AML in children, making up a little more than 1 out of every 4 cases.
    M3: The M3 subtype is also known as acute promyelocytic leukemia (APL). It is made up of promyelocytes, which are a more mature form of myeloblast. Treatment of APL is different than for other subtypes of AML as it involves some newer drugs.
    M4: This subtype is known as acute myelomonocytic leukemia. The cells are an early form of monoblast. The M4 subtype is common in children less than 2 years of age.
    M5: This is known as acute monocytic leukemia. It is made up of monoblasts. Like the M4 subtype, it is more common in children less than 2 years of age.
    M6: This subtype of AML is known as acute erythroblastic leukemia (or acute erythroleukemia). It starts in erythroblasts, the cells that normally mature into red blood cells. It is very rare in children.
    M7: This subtype is also known as acute megakaryoblastic leukemia. The cells are megakaryoblasts, which normally mature into megakaryocytes (the cells that make platelets).
    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.
    Prognostic factors in childhood leukemia
Certain differences among patients that affect responses 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 acute lymphocytic leukemia (ALL)

These factors are used to help determine what risk group a child may fall into. There are different systems used to classify childhood ALL risk. In one of the more common systems, children with ALL are divided into low-risk, 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 keep in mind 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 T-cell or mature B-cell (Burkitt) leukemia.
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.
Race/ethnicity: African-American and Hispanic children with ALL tend to have a lower cure rate than children of other races.
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 more likely to be cured if their leukemia cells have more than 50 chromosomes (called hyperdiploidy), especially if there is an extra chromosome 4, 10, or 17. Hyperdiploidy can also be expressed as a "DNA index" of more than 1.16. Children whose leukemia cells have fewer chromosomes than the normal 46 (hypodiploidy) have a less favorable outlook.
Chromosome translocations: Translocations result from the swapping of genetic material (DNA) between chromosomes. Children whose leukemia cells have a translocation between chromosomes 12 and 21 are more likely to be cured. Those with a translocation between chromosomes 9 and 22 (the Philadelphia chromosome), 1 and 19, or 4 and 11 tend to have a less favorable prognosis. Some of these "poor" prognostic factors have become less important in recent years as treatment has improved.
Response to treatment: Children whose leukemia responds completely (major reduction of cancer cells in the bone marrow) within 1 to 2 weeks of chemotherapy have a better outlook than those whose leukemia does not. Children whose cancer does not respond may be given more intensive chemotherapy.

Prognostic factors for children with acute myelogenous leukemia (AML)

Prognostic factors do not seem to be quite as important in predicting outcome for AML as they are for ALL.
White blood cell (WBC) count: Children with AML whose WBC count is less than 100,000 cells per cubic millimeter at diagnosis are cured more often than those with higher counts.
Cytogenetics: Children with leukemia cell translocations between chromosomes 15 and 17 (seen in most cases of APL) or between 8 and 21, or with an inversion (rearrangement) of chromosome 16 have a better chance of being cured. Children whose leukemia cells have a chromosomal defect known as monosomy 7 have a poorer prognosis. Monosomy 7 means that the leukemia cells have lost one of the copies of chromosome 7.
Morphology: The morphology of the AML cells (how they look under a microscope) may affect the patient's outlook for survival in some cases. Auer rods are rod-like or needle-shaped granules that can be seen inside some patients' AML cells. They are mostly seen in the cells of M2 and M3 types of AML and are usually linked with a good prognosis.
Myelodysplastic syndrome or secondary AML: Children who first have myelodysplastic syndrome ("smoldering leukemia") or whose leukemia is the result of treatment for another cancer tend to have a less favorable prognosis.
Response to treatment: Children whose leukemia responds quickly to treatment (only one chemotherapy cycle needed to achieve remission) are more likely to be cured than those whose leukemia takes longer to respond or does not respond at all.
Status of acute lymphocytic leukemia after treatment
How well a leukemia responds to the initial (induction) treatment has an effect on long-term prognosis.
remission (complete remission) is usually defined as having no evidence of disease after the 4-6 weeks of induction treatment. This means the bone marrow contains fewer than 5% blast cells, the blood cell counts are within normal limits, and there are no signs or symptoms of the disease. A molecular complete remission means there is no evidence of leukemia cells in the bone marrow, even when using very sensitive lab tests, such as PCR.
Minimal residual disease is a term used after treatment when leukemia cells can't be found in the bone marrow using standard lab tests (such as looking at cells under a microscope), but more sensitive tests (such as flow cytometry or PCR) find evidence that leukemia cells remain in the bone marrow.
Active disease means that either there is evidence that the leukemia is still present during treatment or that the disease has relapsed (come back) after treatment. For a patient to be in relapse, they must have more than 5% blast cells present in the bone marrow.

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