Leukemia in Children

(Harry Kochat)

EARLY DETECTION

At this time, there are no special tests recommended for the early detection of leukemia. The best strategy for early diagnosis is prompt attention to the signs and symptoms of this disease. Close follow-up is important for children with a known genetic abnormality which might increase their risk of leukemia, children who have had another cancer treated with chemotherapy or combined chemotherapy and radiation therapy, and children who have received organ transplants and are taking immune system-suppressing drugs.

DIAGNOSIS

Signs and symptoms of childhood leukemia

The usual signs and symptoms of childhood leukemia result from a lack of normal blood cells due to crowding out of normal blood cell-producing bone marrow by the leukemia cells. Anemia, a shortage of red blood cells causes shortness of breath, excessive tiredness and a "pale" color to the skin. A deficiency of normal white blood cells, particularly mature granuloctyes, can lead to fever and increases susceptibility to infections. Although leukemia is a cancer of white blood cells and 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. Finally, insufficient production of blood platelets, important for plugging holes in damaged blood vessels, can lead to excessive bruising and bleeding. About one third of the children will have bone pain. A smaller number will have joint pain. This is due to the cells moving to the surface of the bone or into the joint from the marrow cavity.

Leukemia usually causes enlargement of the liver and spleen, two organs located on the right and left side respectively, of the abdomen. Enlargement of these organs would be noticed as a fullness, or even swelling, of the belly. The lower ribs usually cover these organs but when enlarged, they can be felt by the doctor examining the child.

Leukemia can also spread to lymph nodes. If the affected nodes are close to the surface of the body (lymph nodes on the sides of the neck, in the groin, underarm areas, above the collarbone, etc.), their swelling may be noticed by the patient, parent, or health care provider. Swelling of lymph nodes inside the chest or abdomen may also occur but can be detected only by imaging tests such as CT or MRI scans.

The T-cell type of ALL often involves the thymus. Enlargement of the thymus can compress the nearby trachea (windpipe) leading to cough, shortness of breath, or even suffocation. The superior Venn 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 leukemia cells may compress the SVC and cause swelling of the head and arms known as SVC syndrome. This can also affect the brain and can be life-threatening. Patients with SVC syndrome need immediate treatment.

Spread of leukemia cells outside the bone marrow, so-called "extramedullary spread," may involve the central nervous system (brain and spinal cord), the testicles, ovaries, kidneys, and other organs. Spread to the central nervous system (CNS) at the time of initial diagnosis occurs in 10% -12% of patients with AML, about twice as often as in ALL. Symptoms of CNS leukemia included headache, poor work or school performance, weakness, seizures, vomiting, difficulty in maintaining balance, and blurred vision. Spread to other extramedullary sites rarely occurs, but is more common in ALL compared with AML. Spread of leukemia cells may cause an enlarged, painless testicle, but often only a few leukemia cells are present in the testicles and can be detected only if a biopsy (tissue sample) is examined in the laboratory.

AML may also cause some unique symptoms. Leukemia cells may spread to the gums, causing swelling, pain and bleeding. Spread to the skin can cause small pigmented (colored) spots which can resemble common rashes. A collection of ANLL cells under the skin or other parts of the body is called a chloroma or granulocytic sarcoma.

In addition, leukemia can also produce generalized symptoms such as fatigue, lack of appetite, and fever.

Types of specimens used in diagnosis and evaluation of children with leukemia

Most of the symptoms of leukemia are not unique enough to say for certain whether or not cancer is present. Some of these symptoms can also be caused by noncancerous problems like infections or by other kinds of cancers. For these reasons, an accurate diagnosis is needed and the best way to do this is to sample cells from the patient's blood or bone marrow.

Blood cell counts and blood cell examination: Changes in the numbers of different cell types in the blood and the appearance of these cells under the microscope are often highly suggestive of leukemia. Most children with acute leukemia (ALL or AML) will have either too many white cells in their blood and not enough red blood cells (oxygen-carrying cells) and/or not enough platelets (cells that help plug up small holes in blood vessels and stop bleeding from cuts and bruises). In addition, many of the white blood cells in these children’s blood will be blasts, a type of cell normally found in the bone marrow but not in circulating blood.

Even though these findings raise the doctor's suspicion that leukemia is present, usually the disease cannot be diagnosed for sure without obtaining a sample of bone marrow cells.

Other blood tests: Children with leukemia will have tests done to measure the amount of certain chemicals in the blood, in order to evaluate how well their liver and kidneys are working. These tests are not used to diagnose leukemia. But, in children already known to have leukemia, these tests help detect liver or kidney problems due to damage caused by the spread of leukemia cells or the side effects of certain chemotherapy drugs.

Bone marrow biopsy and aspiration: Bone marrow aspiration involves removing a small amount of bone marrow. During a biopsy, a small cylindrical piece of bone and bone marrow (about 1/16-inch in diameter and 1/2-inch long) is removed. Both samples generally are taken at the same time. They are usually taken from the back of the hipbone. These tests are used for the initial diagnosis and are repeated later to tell if the leukemia is responding to therapy.

Excisional lymph node biopsy: A surgeon cuts through the skin to remove the entire lymph node (excisional biopsy). If the node is near the skin surface, this is a simple operation that can be done with local anesthesia (numbing medication) in the older cooperative child. But if the node is inside the chest or abdomen, general anesthesia is

used (the patient is asleep). This procedure is important in diagnosing lymphomas, but is rarely needed for children with leukemias.

Lumbar puncture: A small needle is inserted into the spinal cavity in the lower back (below the level of the spinal cord) to withdraw some cerebrospinal fluid (CSF) and to look for leukemia cells.

Laboratory tests used to diagnose and classify leukemia

All bone marrow aspirate and biopsy specimens, all lymph node biopsy specimens, and any blood smears with significant abnormalities are examined under a microscope by a doctor with special training in recognizing cells from blood and lymphoid tissue diseases. The samples are usually examined by a pathologist (doctor specializing in diagnosis of disease by laboratory tests) and are often also reviewed by the patient's hematologist/oncologist (doctor specializing in medical treatment of cancer and blood diseases). The doctors will look at the size and shape of the cells and whether their cytoplasm contains granules (microscopic collections of enzymes and other chemicals which help white blood cells fight infections). Sometimes this examination does not provide a definite answer, and other laboratory tests are needed.

Cytochemistry: After cells from the sample are placed on glass microscope slides, they are exposed to stains (dyes) that are attracted to certain chemicals only present in some types of leukemia cells. For example, one stain causes the granules of most AML cells to appear as a black spot under the microscope, but it does not cause ALL cells to change colors.

Flow cytometry: This technique is sometimes used to examine the cells from bone marrow, lymph nodes and blood samples. It is very accurate in determining the exact type of leukemia. This test is expensive and may not be needed if the child has AML. The cells being examined by flow cytometry are treated with special laboratory antibodies and passed in front of a laser beam. Each antibody sticks only to certain types of leukemia cells. If the sample contains those cells, the laser light will cause them to give off light that is measured and analyzed by a computer. Flow cytometry is also used to estimate the amount of DNA in the leukemia cells. ALL cells with DNA content more than 16% above normal are more sensitive to chemotherapy.

Immunocytochemistry: As in flow cytometry, cells from the bone marrow aspiration or biopsy sample are treated with special laboratory 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 detectable under a microscope. Like flow cytometry, it is helpful in distinguishing different types of leukemia from one another and from other diseases.

Cytogenetics: Normal human cells contain 46 chromosomes (pieces of DNA and protein that control cell growth and metabolism). In certain types of leukemia, part of one chromosome may be attached to part of a different chromosome. This change, called a translocation, can usually be detected under a microscope. Recognizing these translocations helps in identifying certain types of ALL and AML and is important in determining prognosis. Some types of leukemia have an abnormal number of chromosomes. For example, ALL cells with over 50 chromosomes are more sensitive and those with less than 46 are more resistant to chemotherapy.

Molecular genetic studies: Certain substances, called antigen receptors, occur on the surface of lymphocytes. These receptors are important in initiating a response from the immune system. Normal lymphoid cells have many different antigen receptors, which help the body respond to many types of infection. Lymphocytic leukemias, such as ALL, however, start from a single abnormal lymphocyte, so all cells in each patient's leukemia have the same antigen receptor.

Laboratory tests of the DNA which contain information on each cell's antigen receptors are a very sensitive way to diagnose ALL. Because different subtypes of ALL cells have different antigen receptor features, this test is sometimes helpful in ALL classification.

However, the test is a quite complex and expensive, and it is not necessary in most cases.

Tests of leukemia cell DNA can also detect most translocations that are visible under a microscope in cytogenetic tests. DNA tests can also find some translocations involving parts of chromosomes too small to be seen with usual cytogenetic testing under a microscope. This sophisticated testing is also not needed in most cases of leukemia, but it is sometimes helpful in leukemia classification because many subtypes of ALL and AML have distinctive translocations. Information about these translocations may be useful in predicting response to treatment.

Imaging studies

X-rays: During the course of diagnosis and evaluating of a child with leukemia, a chest x-ray and bone films are frequently obtained. These may show a mass in the chest, or evidence of leukemic invasion of the bone or rarely the joint.

Ultrasound: This test uses sound waves (like sonar) which, when reflected by organs, allow a mass to be identified or other abnormalities detected. It is useful in determining leukemic involvement of the kidney.

Computed tomography (CT scan): This is a modified x-ray procedure, in which the x-ray beam moves around the body, taking pictures from different angles. These images are then combined by a computer to produce a detailed cross-sectional picture of the inside of the body. This study is rarely obtained but can show involvement of lymph nodes around the heart and trachea (windpipe) or in the back of the abdomen.

Magnetic resonance imaging (MRI): This procedure uses large magnets and radio waves to produce computer-generated pictures of internal organs. The pictures look very similar to a CT scan, but are more detailed. This scan will be used when there is concern about leukemia involving the brain.

Gallium scan and bone scan: For this procedure, the radiologist injects a radioactive chemical which accumulates in areas of cancer or infection in the body. This accumulation of radioactivity can then be viewed by a special camera. These tests are useful when a patient has bone pain that might be due to bone infection or cancer involving bones. If the diagnosis of leukemia is known there would be no indication for this study.

STAGING

Staging is the process of determining how advanced a cancer is. Most types of cancers are given stages of I, II, III, or IV, based on the size of the tumor and how far from the original site in the body the cancer has spread.

Leukemia, by definition, is a cancer of the white blood cell-forming bone marrow cells which involves at least 25% of all of normal bone marrow cells. When diagnosed, most cases of leukemia have crowded out most (70% - 95%) normal cells in the bone marrow. There is no need to stage leukemia, as one would do in other cancers, because leukemia already involves all the bone marrow in the body, and, in most cases, has also spread to other organs such as the liver, spleen, lymph nodes, testes, and central nervous system. For leukemia, laboratory testing focuses on determining the prognosis of the specific disease and predicting which treatments will get the best response.

As leukemia treatment has improved over the last 20 years, research has focused on why some patients have a better chance of cure than others. Certain consistently observed differences among patients with good and poor responses to treatment are called prognostic features and are essential in helping doctors decide if a certain type of leukemia should receive more or less treatment.

ALL prognostic features

Children with ALL are divided into low-risk or high-risk categories, with more intensive treatment given for higher risk patients.

Age: Children younger than 1 year or older than 10 years are higher risk patients.

White blood cell count (WBC): Children with ALL who, at the time of diagnosis, have WBC counts greater than 50,000 cells per cubic millimeters usually do worse with standard treatment.

Cytogenetics: Patients are at lower risk (more likely to be cured) if their leukemia cells have an increased number of chromosomes (called hyperdiploidy), especially if there is an extra chromosome 4 and 10. A translocation between the 12th and 21st chromosomes also suggests lower risk. Children with a translocation between 9 and 22 or 1 and 19 have a higher risk. Children with a translocation involving 11:23 also have a higher risk.

Sex: Girls have a greater chance of cure compared to boys.

Immunology of the leukemia cells: Children with precursor B-cell ALL do better than those with T-cell or mature B-cell (Burkitt's) leukemia.

Central nervous system (CNS) disease: At higher risk and likely to do worse are patients with involvement of the CNS (ALL cells detected in samples of spinal fluid).

Response to therapy: Children without evidence of leukemia in the bone marrow after 7 or 14 days of therapy have a higher long term cure rate.

AML prognostic features

Doctors can often predict before treatment starts, which patients with AML will do better with standard treatment.

White blood cell count (WBC): Patients with a WBC count greater than 100,000 cells per cubic millimeter at diagnosis do worse with standard treatment.

Cytogenetics: Patients with myelodysplastic syndrome (smoldering leukemia) or with a chromosomal defect known as monosomy 7 have a poor prognosis. Monosomy 7 means that the leukemic cells have lost one of the two copies of chromosome 7.

Morphology: The absence of Auer rods in AML is a feature associated with a worse prognosis. These are rod-like or needle-shaped granules most numerous in the cells of M2 and M3 types of AML.

Down's syndrome: Children with Down's syndrome have a higher cure rate compared to those without this genetic condition.

Response to treatment: Children with a slow response to treatment (more than one chemotherapy cycle to achieve remission) do worse than those who respond after receiving just, one course of chemotherapy.

HARRY KOCHAT
BioNumerik Pharmaceuticals Inc.
(An oncology based company based in San Antonio, Texas, USA)


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