How Is Acute Lymphocytic Leukemia Diagnosed?

Signs and Symptoms of Acute Lymphocytic Leukemia

Acute lymphocytic leukemia can cause many different signs and symptoms. Most of these occur in all kinds of ALL, but some are particularly common with certain subtypes.
 
Patients with ALL often have several generalized symptoms. These can include weight loss, fever, and loss of appetite. Of course, these are not just symptoms of ALL and are more often caused by something other than cancer.

Most signs and symptoms of ALL result from a shortage of normal blood cells due to crowding out of normal blood cell-producing bone marrow by the leukemia cells. As a result, people do not have enough properly functioning red blood cells, white blood cells, and blood platelets.

Anemia, a shortage of red blood cells, causes shortness of breath, excessive tiredness, and weakness.

A shortage of normal white blood cells (leukopenia), and, in particular, too few mature granulocytes (neutropenia or granulocytopenia), increases the risk of infections. Although leukemia is a cancer of white blood cells and patients with leukemia may have very high white blood cell counts (leukocytosis), the abnormal leukemia cells do not protect against infection.

Thrombocytopenia (not having enough platelets needed for plugging holes in damaged blood vessels) can lead to excessive bruising, bleeding, frequent or severe nosebleeds, and bleeding from the gums.

Leukemia cells  may spread outside the bone marrow, (called extramedullary spread), to  the brain and spinal cord (central nervous system, or CNS), the testicles, ovaries, kidneys, or other organs. Symptoms of CNS leukemia include headache, weakness, seizures, vomiting, difficulty in maintaining balance, and blurred vision.

Some patients have bone pain or joint pain caused by the spread of leukemic cells to the surface of the bone or into the joint from the marrow cavity.

Acute lymphocytic leukemia sometimes causes the liver and spleen, located on the right and left side, respectively, of the abdomen to enlarge. Enlargement of these organs would be noticed as a fullness, or even swelling, of the belly. These organs are usually covered by the lower ribs but when enlarged, they can be felt by the doctor examining the patient.

Acute lymphocytic leukemia may 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.), a person or his or her health care provider may notice the swelling. Swelling of lymph nodes inside the chest or abdomen may also occur, but can be detected only by imaging tests such as computed tomography (CT) or magnetic resonance imaging (MRI) scans.

The T-cell type of ALL often involves the thymus, which is a small gland located behind the sternum (breastbone) and in front of the trachea (windpipe). An enlarged thymus can press on the trachea, causing coughing, shortness of breath, or even suffocation. 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 leukemia cells may compress the SVC and prevent blood from getting back to the heart, causing the head and arms to swell. This is known as SVC syndrome. It can also affect the brain and can be life-threatening. Patients with SVC syndrome need immediate treatment.

Types of Specimens Used to Diagnose and Evaluate Acute Lymphocytic Leukemia

If signs and symptoms suggest that a patient has leukemia, the doctor will need to check samples of cells from the patient's blood and bone marrow to be sure of the diagnosis. Other tissue and cell samples may also be taken in order to guide treatment.

Bone marrow aspiration and biopsy: The bone marrow sample is taken from the pelvic (hip) bone. The patient lies face down and the doctor feels the bones at the top of the buttocks. The area is cleaned with a special soap. Before the sampling, the doctor injects a local anesthetic, usually lidocaine, into the back of the pelvic bone about an inch or two from the middle of the back. This causes some very brief stinging. Once this has had a few moments to take effect, the doctor  inserts a needle, which is about one-third as wide as a pencil and has a handle on one end that the doctor holds while moving it into the bone. The needle is moved through the bone with a twisting motion.

In bone marrow aspiration, a syringe is used to suck out a small amount of liquid bone marrow (about 1 teaspoon). Sometimes the needle going into the bone is painful, but it only lasts a short time. The sucking out is often painful or at least uncomfortable for a brief moment.

Usually this is followed by a bone marrow biopsy in the same area. The doctor carefully moves the needle further into the bone marrow to collect a second sample called a core biopsy. This contains a small solid piece of bone and marrow (about 1/16 inch in diameter and ½ inch long) and is removed with a slightly larger needle. You may also feel some pressure as the doctor removes the marrow specimen.  After the biopsy needle is pulled out, this solid sample is pushed out of the needle with a wire so that it can be examined under a microscope. You will have pressure held against your buttock at the biopsy site for a few minutes and a pressure dressing applied to help prevent bleeding.

These bone marrow tests are used to diagnose leukemia and, later, to tell if the leukemia is responding to therapy.

Excisional lymph node biopsy: In this procedure, the doctor removes an entire lymph node (excisional biopsy). If the node is near the skin surface, this is a simple operation that can be done using a local anesthetic (numbing medication), but if the node is inside the chest or abdomen, general anesthesia (the patient is asleep) is used.

This procedure is important in diagnosing lymphomas, but is only rarely needed with leukemias.

Lumbar puncture (spinal tap): In this procedure, a small needle is placed into the spinal cavity in the lower back (below the level of the spinal cord) to withdraw cerebrospinal fluid (CSF) to be examined for leukemia cells. The patient may be lying on their side or sitting up. The doctor usually numbs the area with a local anesthetic and slides a long thin needle between the lower lumbar vertebrae into the spinal canal. This allows the doctors to withdraw fluid to test for leukemia cells and to inject chemotherapy.

Lab Tests Used to Diagnose and Classify Acute Lymphocytic Leukemia

One or more of the following lab tests may be used.

Blood chemistry tests: These tests measure the amounts of certain chemicals in the blood but are not used to diagnose leukemia. In patients already known to have leukemia, these tests help detect liver or kidney problems due to damage caused by the spread of leukemic cells or due to the side effects of certain chemotherapy drugs. These tests also help determine whether treatment is needed to correct abnormally low or high blood levels of certain minerals.

Blood cell counts and blood cell examination: Changes in the numbers of different types of blood cells and the appearance of these cells under the microscope help in the diagnosis of leukemia. Most patients with ALL have too many white cells in their blood, not enough red blood cells, and not enough platelets. In addition, many of these white blood cells will be lymphoblasts, an immature type of lymphocyte normally found only in the bone marrow. These immature cells do not function normally. Even though these findings suggest leukemia, usually the disease cannot be diagnosed without a sample of bone marrow cells.

Routine microscopic exam: Any samples taken (blood, bone marrow, lymph node tissue, or CSF) are examined under a microscope 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).

Based on the bone marrow cells' size, shape, and granules, doctors can classify them into specific types. A key element of this cell classification is whether the cells appear mature (resembling normal cells of circulating blood), or immature (lacking features of normal circulating blood cells). The most immature cells are called blasts.

The percentage of cells in the bone marrow that are blasts is particularly important. Having at least 20%-30% blasts in the marrow is generally required for a diagnosis of acute lymphocytic leukemia. In order for a patient to be considered in remission after treatment, the blast percentage must be no higher than 5%.

Sometimes this examination does not provide a definite answer, and other lab tests are needed.

Cytochemistry After cells from the sample are placed on glass microscope slides, they are exposed to chemical stains (dyes) that are attracted to or react with only some types of leukemia cells. These stains cause color changes that can be seen only under a microscope, and these changes can help the doctor determine what types of cells are present. For example, one stain distinguishes acute lymphocytic leukemia (ALL) from acute myelogenous leukemia (AML). The 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: This technique is often used to examine the cells from bone marrow, lymph nodes, and blood samples. It is very accurate in determining the exact type of leukemia.

Leukemia cells can be distinguished by the kinds of molecules on their surface. A sample of cells is treated with special antibodies that stick to the cells only if certain molecules are present on their surfaces. The cells are then passed in front of a laser beam. If the sample contains cells that now have antibodies attached to them, the laser will cause them to give off light, which is measured and analyzed by a computer.  

Immunocytochemistry: During this test, as in flow cytometry, cells from the bone marrow aspiration or biopsy sample are treated with special antibodies that react only to certain molecules. 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 can be seen only by using a microscope. Like flow cytometry, it is helpful in distinguishing different types of leukemia from one another and from other diseases.

Cytogenetics: This is a study to detect changes in chromosomes (pieces of DNA). . Normal human cells contain 23 pairs (46) of chromosomes, pieces of DNA that control cell growth and metabolism. In certain types of leukemia, 2 chromosomes may exchange 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 translocations helps to identify certain types of ALL and is important in determining the survival outlook for the patient.

Some types of leukemia have an abnormal total number of chromosomes (more or less than 46). This may also affect a patient's prognosis (outlook for survival). For example, ALL cells with more than 50 chromosomes are more sensitive to chemotherapy.

The testing usually takes about 3 weeks because the leukemic cells must grow in laboratory dishes for a couple of weeks before their chromosomes are ready to be viewed under the microscope.

Almost all the chromosome abnormalities in ALL are translocations. The most common one is a translocation between chromosomes 9 and 22 (the Philadelphia chromosome). About 20%-25% of adults with ALL have this abnormality in their leukemia cells. It is usually associated with a poorer outcome.

Molecular genetic studies: Special tests of leukemia cell DNA can also find most translocations that are visible under a microscope in cytogenetic tests, as well as some translocations too small to be seen with usual cytogenetic testing under a microscope.

This sophisticated testing, called FISH (fluorescent in situ hybridization), is helpful in leukemia classification because some subtypes of ALL have distinctive translocations. Information about these translocations may be useful in predicting response to treatment. Treatment will also depend on the genetic changes. For this reason, most doctors will test for genetic changes in the leukemia cells of all patients with ALL.

These tests may also be used after treatment to detect small numbers of leukemia cells that can be missed under a microscope.

Gene-expression profiling: This is a new experimental technique that is being used for many cancers. It produces a pattern of many different genes in the cancer cells. This creates a unique fingerprint that can distinguish different kinds of cancer cells. It is also being used to classify the different kinds of ALL into different risk categories. This may add to the information that comes from the standard molecular genetic studies.

Imaging Studies

Imaging studies are ways of producing pictures of the inside of the body. Because leukemia does not usually form visible tumors, imaging tests are of limited value. There are several imaging studies that might be done in people with ALL, but they are done more often to look for infections or other problems, rather than for the leukemia itself.

X-rays: Routine chest x-rays may be done if a lung infection is suspected. These also may spot enlarged lymph nodes in the chest.

Computed tomography (CT) scan: The CT scan is an x-ray procedure that produces detailed cross-sectional images of your body. Instead of taking one picture, as does a conventional x-ray, a CT scanner takes many pictures of the part of your body being studied as it rotates around you. A computer then combines these pictures into an image of a slice of your body.

CT scans are helpful in looking at internal organs. They can spot abscesses (pockets of infection), enlarged organs, and any large accumulation of leukemia cells. They are often better than routine chest x-rays for finding enlarged lymph nodes in the chest or anywhere else.

If you are having a CT of the abdomen, after a set of pictures is taken you may be asked to drink 1 or 2 pints of a radiocontrast agent, or dye. This helps outline the intestine so that certain areas are not mistaken for tumors. You may also receive an IV (intravenous) line through which the contrast dye is injected. This helps better outline structures in your body. A second set of pictures is then taken.

The injection can cause some flushing (feeling of warmth, especially in the face). Some people are allergic and get hives; rarely more serious reactions like trouble breathing and low blood pressure can occur. Be sure to tell the doctor if you have ever had a reaction to any contrast material used for x-rays.

CT scans take longer than regular x-rays, and you need to lie still on a table while they are being done. The part of your body being examined is placed within the scanner, a doughnut-shaped machine that completely surrounds the table. The test is painless, but you may find it uncomfortable to hold still in certain positions for minutes at a time.

CT scans can also be used to guide a biopsy needle precisely into a suspected abnormality, such as an abscess. For this procedure, called a CT-guided needle biopsy, you remain on the CT scanning table while a radiologist moves a biopsy needle toward the location of the mass. CT scans are repeated until the doctors are confident that the needle is within the mass. A fine needle biopsy sample (tiny fragment of tissue) or a core needle biopsy sample (a thin cylinder of tissue about ½-inch long and less than 1/8-inch in diameter) is then removed and examined under a microscope.

Magnetic resonance imaging (MRI) scan: MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed by tissues in the body and then released in a pattern formed by the type of tissue and by certain diseases. A computer translates the pattern of radio waves given off by the tissues into a very detailed image of parts of the body. Not only does this produce cross-sectional slices of the body like a CT scanner, it can also produce slices that are parallel with the length of your body. A contrast material might be injected just as with CT scans, but is used less often.  

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

MRI scans are a little more uncomfortable than CT scans. First, they take longer - often up to an hour. Also, you have to be placed inside a tube, which is confining and can upset people with claustrophobia. The machine also makes a thumping noise that you may find disturbing. Some places provide headphones with music to block this out.

Gallium scan and bone scan: For this procedure, the doctor injects a slightly radioactive chemical into the bloodstream that collects in areas of cancer or infection. 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 infection or cancer.

Ultrasound: This test uses sound waves to produce images of internal organs. The test can distinguish solid from fluid-filled masses. It can help to show whether the kidneys, liver, or spleen are enlarged.

This is an easy test to have done. It uses no radiation, which is why it is often used to look at developing fetuses. For an ultrasound examination, you simply lie on a table, and a technician moves the transducer over the part of your body being examined. Usually the skin is first lubricated with oil.