CHILDHOOD LEUKEMIA

CHILDHOOD LEUKEMIA

What Is Cancer?

Cancer develops when cells in a part of the body begin to grow out of control. Although there
are many kinds of cancer, they all start because of out-of-control growth of abnormal cells.

Normal body cells grow, divide, and die in an orderly fashion. During the early years of a
person's life, normal cells divide more rapidly until the person becomes an adult. After that,
cells in most parts of the body divide only to replace worn-out or dying cells and to repair
injuries.

Because cancer cells continue to grow and divide, they are different from normal cells. Instead
of dying, they outlive normal cells and continue to form new abnormal cells.

Cancer cells often travel to other parts of the body where they begin to grow and replace
normal tissue. This process, called metastasis, occurs as the cancer cells get into the
bloodstream or lymph vessels of our body. When cells from a cancer like breast cancer spread
to another organ like the liver, the cancer is still called breast cancer, not liver cancer.

Cancer cells develop because of damage to DNA. This substance is in every cell and directs all
its activities. Most of the time when DNA becomes damaged the body is able to repair it. In
cancer cells, the damaged DNA is not repaired. People can inherit damaged DNA, which
accounts for inherited cancers. Many times though, a person's DNA becomes damaged by
exposure to something in the environment, like smoking. Scientists still do not understand
what damages person's DNA becomes damaged and leads to cancer.

Cancer usually forms as a tumor. Some cancers, like leukemia, do not form tumors. Instead,
these cancer cells involve the blood and blood-forming organs, and circulate through other
tissues where they grow.

Remember that not all tumors are cancerous. Benign (noncancerous) tumors do not spread to
other parts of the body (metastasize) and, with very rare exceptions, are not life-threatening.

Different types of cancer can behave very differently. For example, lung cancer and breast
cancer are very different diseases. They grow at different rates and respond to different
treatments. That is why people with cancer need treatment that is aimed at their particular kind
cancer.

Cancer is the second leading cause of death in the United States. Half of all men and one-third
of all women in the U.S. will develop cancer during their lifetimes. Today, millions of people
are living with cancer or have had cancer. The risk of developing most types of cancer can be
reduced by changes in a person's lifestyle, for example, by quitting smoking and eating a better
diet. The sooner a cancer is found and treatment begins, the better are the chances for living
for many years.

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What Are The Differences Between Cancers In Adults and Children?

The types of cancers that develop in children are different from the types that develop in
adults. Although there are exceptions, childhood cancers tend to respond better to
chemotherapy because these types of cancers grow rapidly and most forms of chemotherapy
specifically affect cells that are growing rapidly.

Childhood cancer patients and their families have special needs that can be best met by
specialized cancer centers for children and adolescents. Being treated in specialized centers
offers them the advantage of a team of specialists who know the differences between adult and
childhood cancers, as well as the unique needs of children with cancers. This team usually
includes pediatric oncologists, pathologists, surgeons, radiation oncologists, pediatric
oncology nurses, and nurse practitioners.

Many professionals other than nurses and doctors are involved in treating children and
adolescents with cancer. Children's cancer centers have psychologists, social workers, child
life specialists, nutritionists, rehabilitation and physical therapists, and educators who can
support and educate the entire family. Since the 1960s, most children with cancer have been
treated at specialized centers designed for them. Approximately 94% of children with cancer in
the United States are treated at a center that is a member of the Children's Oncology Group
(COG) (formerly the Children's Cancer Group [www.pog.ufl.edu] and the Pediatric Oncology
Group [www.nccf.org]). All of these centers are associated with a university or children's
hospital.


What Is Childhood Leukemia?

Leukemia is a cancer of the white blood cells. This cancer starts in the bone marrow but can
then spread to the blood, lymph nodes, the spleen, liver, central nervous system (the brain and
spinal cord), testes (testicles), or other organs. In contrast, other types of cancers develop in
various organs of children and adults and then spread to the bone marrow and other organs.
Some childhood cancers, such as neuroblastoma or Wilms’ tumor, can spread to bone marrow,
but these cancers are not leukemia.

Leukemia is divided into two types: acute (rapidly growing) and chronic (slowly growing),
with the vast majority of childhood leukemia being the acute form.

• Acute leukemia is divided into acute lymphocytic leukemia (ALL) and acute
nonlymphocytic leukemia (ANLL). Acute myelogenous leukemia or acute myeloid
leukemia (AML) is another name for ANLL.
• Chronic myelogenous leukemia (CML) will not be discussed in this document because it is
so rare, accounting for only about 2% of leukemias in children.

Bone Marrow

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The bone marrow is made up of hematopoietic (blood- forming) cells and supporting tissues
that aid the growth of hematopoietic cells. Bone marrow stem cells continually reproduce and
their "offspring" go through a multistep process of hematopoietic cell maturation, eventually
becoming 1 of 3 main types of blood cells: red blood cells, white blood cells, or platelets. In
infants, bone marrow is found in almost all bones of the body, but by the teenage years, it is
found primarily in the flat bones (skull, shoulder blade, ribs, pelvis) and vertebrae (back
bones).

• Red blood cells carry oxygen from the lungs to all other tissues of the body. Anemia (too
few red blood cells) typically causes weakness, pallor, tiredness, and shortness of breath.

• Platelets are usually classified as a type of blood cell, but they are actually fragments that
break off from a type of bone marrow cell called the megakaryocyte and are released into
the bloodstream. Blood platelets are important in plugging small areas of damage to small
blood vessels caused by cuts or bruises. Not having enough platelets is called
thrombocytopenia, and can result in excessive bleeding if small blood vessels are
damaged.

• White blood cells, also known as leukocytes defend the body against microorganisms
(germs). The three main types of white blood cells are lymphocytes (discussed in the
section on lymphoid tissue), granulocytes, and monocytes.

Granulocytes destroy such microorganisms as bacteria. There are three types of granulocytes:
neutrophils, basophils, and eosinophils, which are distinguished by the size and color of their
granules (spots seen inside the cells under the microscope). These granules can break down
chemicals that form invading microorganisms. Granulocytes undergo several changes as they
mature from the primitive myeloblast to infection- fighting cells. Once released into the
bloodstream as mature cells they circulate for a short period of time (from a few hours to a few
days).

Monocytes also protect the body against microorganisms. After circulating in the bloodstream,
they enter tissues to become macrophages, which can destroy some germs by surrounding and
digesting them. Macrophages help lymphocytes recognize germs and begin producing
antibodies to fight them.

Lymphoid Tissue

Lymphoid tissue, also known as lymphatic tissue, is the main component of the immune
system and is formed by several different types of cells that work together to resist infection.
Lymphoid tissue and the immune system may also fight some types of cancers. This system
also reacts to tissues received from other people, such as blood transfusions or organ
transplants. Lymphoid tissue is found in many places throughout the body including lymph
nodes, the thymus, the spleen, the tonsils and adenoids, the bone marrow, and scattered within
other systems, such as the digestive system and respiratory system. There is an extensive
interconnecting system between all lymphoid tissues called the lymphatic system.
Lymphocytes circulate in this system and eventually flow into the bloodstream.
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The lymphocyte is the main cell type that forms lymphoid tissue. These are the cells from
which acute lymphocytic leukemia (ALL) develops. There are two main types of lymphocytes,
B-lymphocytes (or B-cells) and T-lymphocytes (or T-cells). Although both can develop into
leukemia, B-cell leukemias are much more common than T-cell leukemias.

Normal T-cells and B-cells do different jobs in the immune system. B-cells help protect the
body against bacteria and viruses by maturing into plasma cells and producing
immunoglobulins (also called antibodies). The antibodies then attach to certain chemicals on
the surface of the virus or bacteria. This attracts another type of cell (the granulocyte,
discussed above) that swallows and digests the antibody-coated bacteria. Antibodies also
attract certain blood proteins that can destroy bacteria by causing holes to develop in the wall
surrounding the bacteria.

Normal T-cells help protect us against any foreign substance (a substance not normally present
in the body). They recognize specific chemicals such as those found on the outer surface of
virus- infected cells and destroy such cells by releasing substances that cause their outer
membranes to develop holes and become leaky. T-cells can also release substances called
cytokines that attract certain other types of white blood cells, such as macrophages, which then
surround and digest the infected cells. T-cells are also thought to destroy some types of cancer
cells as well as the cells of transplanted organs. Patients with transplanted organs must take
special medication to prevent this action by T-cells.

Normal B-cells and T-cells are recognized by laboratory tests that identify certain distinctive
chemicals on their sur faces. Certain chemical substances are found only on B-cells and others
are found only on T-cells. There are actually several types of T-cells, each with a specialized
job to do. There are also several stages of B-cell and T-cell development or maturation that
can be recognized.

Normal lymph nodes are pea-sized organs located throughout the body and connected by a
system of lymphatic vessels. These vessels are like veins, except that instead of carrying blood,
they carry lymph, a clear fluid containing waste products and excess fluid from tissues, and
immune system cells traveling between lymph nodes and other organs.

Lymph nodes enlarge when they are fighting an infection, especially in infants and children.
Lymph nodes that grow during a reaction to infection are called reactive nodes or hyperplastic
nodes. An enlarged lymph node is not usually serious in a child. But, a large lymph node may
rarely also be a sign of leukemia when the cancer has spread outside of the bone marrow.

The spleen is located under the lower part of the rib cage, on the left side of the body. An
average adult spleen weighs about 5 ounces, while the spleen of a 10-year-old is about 3
ounces. It is the largest collection of lymph tissue in the body. The spleen produces
lymphocytes and other immune system cells to help fight infections. It stores healthy blood
cells and filters out damaged blood cells, bacteria, and cell waste. Also, if certain diseases
cause the bone marrow to stop producing blood cells, the spleen may function in a back-up
role for this task.
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The thymus gland is an organ located in front of the heart. While a baby is developing in the
womb, this gland plays a vital role in development of the T- lymphocytes important to the
immune system. Although the thymus gland's size (¼ ounce in a 6-year-old child) and
importance peaks early in childhood it continues to function in the immune system throughout
life.

Adenoids and tonsils are collections of lymphoid tissue located at the back of the throat. They
are easy to see when they become enlarged during an infection or if they become cancerous.

Tests to Classify Types of Leukemia

Most childhood leukemias are classified by their appearance under the microscope. To help
doctors see them clearly under the microscope, the cells are stained, which changes the color
of different parts of the cells. Although some leukemias can be easily classified by routine
stains, most require special cytochemical stains that help identify certain substances inside the
leukemic cells.

In acute lymphocytic leukemias, more complex testing is needed to decide on the exact type of
leukemia a child has. This is important, because different types of leukemia have a different
prognosis (the outlook for chances of survival) and are treated differently. Tests used to further
classify leukemias include:
• Flow cytometry (a test that uses special antibodies to detect specific substances on the
cell surface or inside the cell), cytogenetics (studies to detect changes in the
chromosomes of cells)
• Molecular genetic tests (which show changes in the cell's DNA). These tests are done
on samples of leukemic cells from a child's blood or bone marrow, and are described
in the section "How Is Childhood Acute Leukemia Diagnosed?"

Acute Lymphocytic Leukemia

Acute lymphocytic leukemia (ALL) is a cancer of the lymphocyte-forming cells called
lymphoblasts, and is divided into 3 major categories (L1, L2, or L3) based predominantly on
its morphology (appearance under the microscope) and by its immunologic type (B-cell or T-
cell). L1 lymphoblasts, the most common in children, are smaller cells. L2, which accounts for
10% of ALL cases are larger. L3 lymphoblast is the rarest subtype.

Type
Frequency
Early Pre-B
57%-65%
Pre-B
20%-25%
B-Cell
2%-3%
T-Cell
13%-15%


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B-cell ALL: About 85% of ALL is B-cell ALL. The most common subtype of B-cell ALL is
early precursor B or early pre-B ALL. Mature B-cell leukemia accounts for about 2% to 3% of
childhood ALL and its cells have L3 morphology.

Also called Burkitt’s leukemia, this disease is closely related to Burkitt's lymphoma and is
discussed in greater detail in our document "Childhood non-Hodgkin's Lymphoma." Another
B-cell leukemia subtype is the "pre-B" form of ALL. This form of ALL occurs in 20% to 25%
of patients with B-cell ALL.

T-cell ALL: About 13% to 15% of ALL T-cell ALL. This type of leukemia affects boys more
than girls and generally affects children at an older age than B-cell ALL does. It is often
associated with an enlarged thymus (which can sometimes cause breathing difficulty) and
early spread to the spinal fluid (fluid that cushions and surrounds the brain and spinal cord).

Acute Myelogenous Leukemia: Acute myelogenous leukemia (AML; also called acute
nonlymphocytic leukemia or ANLL) is a cancer of the bone marrow cells that form
granulocytes (myeloblasts), monocytes (monoblasts), red blood cells (erythroblasts), and
platelets (megakaryoblasts). Like ALL, AML has several subtypes. Although tests are often
helpful in identifying AML, the subtypes of AML are classified almost exclusively by
morphology (appearance under the microscope), using routine and cytochemical stains.

There are 8 subtypes of AML: M0 to M7 (the "M" refers to myeloid).

• The M0 type of AML can only be distinguished from ALL by flow cytometry because the
leukemic cells lack any distinctive features that are apparent under the microscope. (Flow
cytometry is explained in the section, "How is Childhood Leukemia Diagnosed?").
• M1 - M3 are leukemias of granulocytes and are recognized by their appearance under the
microscope, particularly after treatment with cytochemical stains.
• M4 and M5 are two forms of monocytic leukemia with cytochemical features that differ
from other types of AML. These two types of AML are also more likely to occur in
children less than 2 years of age.
• M6 leukemia is known as erythroleukemia and is very rare in children.
• M7 or megakaryocytic leukemia cells may show a unique "budding" resembling the way
platelets (small cell fragments that help plug holes in blood vessels) form from normal
megakaryocytes. Special stains may be required to identify M6 and M7 leukemias.

Hybrid or Mixed Lineage Leukemias

Some leukemias have features of both ALL and AML when the cells are viewed under a
microscope and tested by flow cytometry or cytogenetics.


What Are The Key Statistics About Childhood Leukemia?

Leukemia is the most common cancer in children and adolescents. It accounts for almost 1/3 of
all cancers in children under age 15 and 1/4 of cancers occurring before age 20. The American
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Cancer Society predicts that about 2,700 children will be diagnosed with leukemia in the
United States during the year 2002.

Of the 2,700 children with leukemia, about 2,000 will be diagnosed with ALL. Many of the
remaining children will be diagnosed with AML. Chronic leukemias are very rare in children.
ALL is most common in early childhood, peaking between ages 2 and 3 years of age. AML is
most common during the first 2 years of life and is less common among older children. AML
cases start to inc rease again during the teenage years, with AML becoming the most common
acute leukemia in adults over 55 years of age. ALL is slightly more common among white
children than among African-American and Asian-American children, and is more common in
boys than in girls. AML is equally rare among boys and girls of all races.

The 5-year survival rate for ALL has greatly increased over time, and is now nearly 80%,
primarily due to advances in treatment. Five-year survival rates of children with AML have
also inc reased over time to about 40%. Of course, the outlook for each patient is different,
depending mostly on prognostic factors discussed in "How is Childhood Leukemia Staged?"
The 5-year survival rate refers to the percentage of patients who live at least 5 years after their
cancer is diagnosed. Many of these patients live much longer than 5 years after diagnosis, and
5-year rates are used to produce a standard way of discussing prognosis. Of course, 5-year
survival rates are based on patients diagnosed and initially treated more than 5 years ago.
Advances in treatment often result in a more favorable outlook for recently diagnosed patients.


What Are The Risk Factors For Childhood Leukemia?

A risk factor is anything that increases a person's chance of getting a disease such as cancer.
Different cancers have different risk factors. For example, exposing skin to strong sunlight is a
risk factor for skin cancer. Smoking is a risk factor for cancers of the lung, mouth, larynx,
bladder, kidney, and several other organs. But having a risk factor, or even several, does not
mean that a person will get the disease.

Lifestyle-related Risk Factors

Lifestyle-related risk factors include diet, harmful habits such as smoking and excessive
drinking of alcohol. In general, lifestyle-related factors are the most significant influence
contributing to cancers in adults, but are the least important part of childhood cancer risk.
There is some suggestion that drinking a lot of alcohol during pregnancy may increase the risk
of AML in the child.

Genetic Risk Factors

Certain genetic diseases cause children to be born with an abnormal or deficient immune
system. In addition to developing serious infections due to reduced immune defenses, these
children also have an increased risk of developing leukemia. Although these congenital
immune deficiency diseases can be passed on to children, adult leukemia survivors who do not
have these inherited diseases do not pass an increased risk of leukemia on to their children.
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• The Li-Fraumeni syndrome is a rare condition that increases a person's risk of developing
leukemia, bone or soft tissue sarcomas, breast cancer, and brain tumors.

• Children with Down's syndrome have an increased risk of developing leukemia. Instead of
having two copies of each chromosome, children with Down's syndrome have three copies
(one more than usual) 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's syndrome are 15 times more likely to develop either ALL or AML
than are other children. Down's syndrome is also associated with a leukemia- like condition
within the first month of life, which can resolve on its own without the use of
chemotherapy.

• Klinefelter’s syndrome is a genetic condition in which males have an extra "x"
chromosome. This causes infertility, prevents normal development of male features (such
as body hair, deep voice, etc.), and is also associated with an increased risk of developing
leukemia.

• Several other genetic disorders (neurofibromatosis, ataxia telangectasia, Wiscott-Aldrich
Syndrome, and Fanconi’s anemia) also carry an increased risk of developing leukemia, but
more commonly lead to non-Hodgkin’s lymphoma and other types of cancers.

• The sibling of an identical twin who develops ALL or AML before 6 years of age has a
20% to 25% chance of developing leukemia. Fraternal (not identical) twins and other
brothers and sisters have slightly increased chances (2 to 4 times) of developing leukemia.

Environmental Risk Factors

Environmental risk factors are influences, such as radiation and chemicals, in our surroundings
that increase the likelihood of developing diseases such as leukemias. Significant radiation
injury is a major environmental risk factor in developing childhood leukemia. Japanese
survivors of the atomic bomb had a 20-fold increased risk of developing AML, usually within
6-8 years after exposure. Similar risks occur after exposure to nuclear reactor accidents.
Exposure of the fetus to significant radiation within the first months of development may also
carry up to a 5- fold increased risk of developing ALL.

• Electromagnetic field exposure. There is conflicting evidence about electromagnetic field
exposure (such as tha t occurring near very high- voltage power lines) as a potential risk
factor for developing leukemia. The National Cancer Institute and others have undertaken
several large studies to answer this important question. The majority of studies published
so far suggest either no increased risk or a very slightly increased risk. The vast majority of
cases of leukemia are clearly not related to EMF exposure.
• Radiation therapy and chemotherapy. Children and adults treated with radiation therapy
and chemotherapy for other cancers have a slight risk of developing a second cancer,
usually AML, later in life. Alkylating agents (a class of chemotherapy drugs that includes
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cyclophosphamide) and epipodophyllotoxins are more likely than other chemotherapy
drugs to be associa ted with a second malignancy. These leukemias usually develop within
5 to 8 years of treatment and tend to be difficult to treat. Patients who are receiving
intensive therapy to suppress their immune function (mainly organ transplant patients) are
at increased risk of developing cancer, especially of the lymphoid system. This includes
ALL.

• Chemicals. Chemicals, such as benzene, may cause AML in adults and, rarely, in children.
ALL has not been linked to any cancer-causing chemicals. Other factors which ha ve been
studied for a possible association with ALL include exposure to insecticides; maternal age;
maternal use of alcohol, cigarettes, diethylstilbestrol (DES), or contraceptives; paternal
occupational exposure to chemicals and solvents; and chemical contamination of ground
water. These factors have not been definitely linked to ALL.


Do We Know What Causes Childhood Leukemia?

The exact cause of most cases of leukemia is not known. However, doctors have found that
this cancer is associated with a number of other conditions, which are described in the section
on risk factors. It is important to remember that most children with leukemia do not have any
known risk factors, and the cause of their cancer is not known at this time.

During the past few years, doctors have made great progress in understanding how certain
changes in DNA can cause bone marrow stem cells to develop into leukemia. DNA is the
chemical that carries the instructions for nearly everything our cells do. We usually resemble
our parents because they are the source of our DNA. However, DNA affects more than our
outward appearance. Some genes (parts of our DNA) contain instructions for controlling when
our cells grow and divide. Certain genes that promote cell division are called oncogenes. Other
genes that slow down cell division or cause cells to die at the appropriate time are called tumor
suppressor genes. It is known that leukemia can be caused by DNA mutations (defects) that
turn on oncogenes or turn off tumor suppressor genes.

Some people with certain types of cancer have DNA mutations they inherited from a parent.
These changes increased their risk for the disease but leukemia is not one of the cancers
usually caused by these inherited mutations. A condition called Li-Fraumeni syndrome,
resulting from inherited mutations of the p53 tumor suppressor gene, increases a person's risk
of developing leukemia, as well as bone and soft tissue sarcomas, breast cancer, and brain
tumors.

Usually, DNA mutations related to leukemia develop after conception rather than having been
inherited. Recently, it has been shown that some of these acquired mutations are present at
birth, and are presumed to have occurred inside the mother's womb. Acquired mutations may
result from exposure to radiation or cancer-causing chemicals, but usually they occur for no
apparent reason. Every time a cell prepares to divide into two new cells, it must duplicate its
DNA. This process is not perfect and copying errors occur sometimes. Fortunately, cells have
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repair enzymes that "proofread" DNA, but some errors may slip past, especially when the cells
are growing rapidly.

Translocations are another type of DNA abnormality that can lead to leukemia. Human DNA
is packaged in 23 pairs of chromosomes. A translocation means that DNA from one
chromosome is switched or exchanged with a different chromosome. Translocations can cause
oncogenes to be activated or tumor suppressor genes to be turned off. Doctors have found that
some of these translocations can be found in blood cells at birth. Most children who have these
translocations do not develop leukemia, but some do.


Can Childhood Leukemia Be Prevented?

Although many adult cancers can be prevented by lifestyle changes that reduce certain risk
factors, there is currently no known way to prevent most childhood cancers. In addition, most
adults and children with leukemia have no known risk factors and, at the present time, there is
no way to prevent their leukemias from developing. Children with a known increased risk of
developing leukemia (because of Li-Fraumeni syndrome or Down's syndrome, for example)
should receive careful, periodic medical checkups. The frequency of leukemia in children with
these syndromes, although greater than in the general population, is still extreme ly rare.

Treating cancers with radiation and chemotherapy and the use of immune system-suppressing
drugs to avoid rejection of transplanted organs also causes some leukemias. Doctors are
currently studying ways to treat patients with cancer and organ transplants that minimize the
risk of leukemia. However, the obvious benefits of treating life-threatening diseases with
chemotherapy, radiation therapy, or organ transplantation must be balanced against the small
chance of developing leukemia several years la ter.


Can Childhood Leukemia Be Found Early?

There are no special tests that can detect leukemia early. The best strategy for early diagnosis
is prompt attention to the signs and symptoms of this disease (see "How is Childhood
Leukemia Diagnosed?"). Close observation is important for children with a known genetic
abnormality that 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.


How Is Childhood Leukemia Diagnosed?

Signs and Symptoms of Childhood Leukemia

Most of the signs and symptoms that children with leukemia develop result from a lack of
normal blood cells caused by crowding out of normal blood cell-producing bone marrow by
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