How Is Chronic Lymphocytic Leukemia Diagnosed?

Signs and Symptoms of Chronic Lymphocytic Leukemia

Many people with chronic lymphocytic leukemia (CLL) do not have any symptoms when it is diagnosed. The leukemia is often found when their doctor orders blood tests for some unrelated health problem or during a routine checkup. Even when there are symptoms, they are often vague and non-specific.

Symptoms of CLL can include the following:

• weakness
• fatigue
• weight loss
• fever
• night sweats
• enlarged lymph nodes (felt as lumps under the skin)
• pain or a sense of "fullness" in the belly (especially after eating a small meal), which is caused by an enlarged spleen

But these symptoms aren't found only in CLL. They can also occur with other cancers, as well as many non-cancerous conditions.

Many of the signs and symptoms of advanced CLL occur because the leukemia cells replace the bone marrow's normal blood-making cells. As a result, people do not make enough red blood cells, properly functioning white blood cells, and blood platelets.

• Anemia is a shortage of red blood cells. It can cause tiredness, weakness, and shortness of breath.
  
• A shortage of normal white blood cells (leukopenia) increases the risk of infections. A common term you may hear is neutropenia, which refers specifically to low levels of neutrophils (a type of granulocyte). Although patients with CLL may have very high white blood cell counts due to excess numbers of lymphocytes (lymphocytosis), the leukemia cells do not protect against infection the way normal white blood cells do.
  
• A shortage of blood platelets (thrombocytopenia) can lead to excess bruising, bleeding, frequent or severe nosebleeds, and bleeding gums.

People with CLL are at higher risk for infections. This is mainly because their immune systems are not working as well as they should. CLL is a cancer of B lymphocytes, which normally make antibodies that help fight infection. But in CLL, these antibody-making cells don't work as they should, so they can't fight infections well. Infections may range from simple things like frequent colds or cold sores to pneumonia and other serious infections.

CLL may also affect the immune system in other ways. In some people with CLL, the immune system cells make abnormal antibodies that attack normal blood cells. This is known as autoimmunity. It can lead to hemolytic anemia (if the antibodies attack red blood cells), thrombocytopenia (if they attack the cells that make platelets), or leukopenia (if they attack white blood cells).

CLL often causes the liver or spleen to become enlarged. If these organs are enlarged, you may notice fullness or swelling of the belly. The spleen is on the left side, while the liver is on the right. These organs are usually covered by the lower ribs but when they are larger than normal, your doctor can feel them.

CLL will often invade the lymph nodes. If the nodes are close to the surface of the body (for instance, on the sides of the neck, in the groin, in the underarm area, or above the collarbone), you or your doctor may notice the swelling as a lump under the skin. Lymph nodes inside the chest or abdomen may also become swollen, but these can be found only by imaging tests such as a computed tomography (CT) scan.

Types of Samples Used to Test for Chronic Lymphocytic Leukemia

If signs and symptoms suggest you may have leukemia, the doctor will need to check samples of blood and bone marrow to be certain of this diagnosis. Other tissue and cell samples may also be taken in order to guide treatment.

Blood Samples

Blood samples for tests for CLL are generally taken from a vein in the arm.

Bone Marrow Samples

Bone marrow samples are obtained from a bone marrow aspiration and biopsy -- two tests that are usually done at the same time. The samples are usually taken from the back of the pelvic (hip) bone, although in some cases they may be taken from the sternum (breastbone) or other bones.

In bone marrow aspiration, you lie on a table (either on your side or on your belly). After cleaning the area, the skin over the hip and the surface of the bone are numbed with local anesthetic, which may cause a brief stinging or burning sensation. A thin, hollow needle is then inserted into the bone and a syringe is used to suck out a small amount of liquid bone marrow (about 1 teaspoon). Even with the anesthetic, most patients still have some brief pain when the marrow is removed.

A bone marrow biopsy is usually done just after the aspiration. A small piece of bone and marrow (about 1/16 inch in diameter and 1/2 inch long) is removed with a slightly larger needle that is twisted as it is pushed down into the bone. The biopsy may also cause some brief pain. Once the biopsy is done, pressure will be applied to the site to help prevent bleeding.

These tests are not usually needed to diagnose CLL, but may help tell how advanced it is. They are often done before starting treatment to see how much CLL is in the bone marrow. They may then be repeated during or after treatment to see if the treatment is effective.

Excisional Lymph Node Biopsy

In this procedure, a surgeon cuts through the skin to remove an entire lymph node. If the node is near the skin surface, this is a simple operation that can be done with local anesthesia, but if the node is inside the chest or abdomen, general anesthesia (where the patient is asleep) is used.

This type of biopsy is often used to diagnose lymphomas, but it is only rarely used in CLL. It may be used if a lymph node has grown very large and the doctor wants to know if the leukemia has changed (transformed) into a more aggressive lymphoma.

Lumbar Puncture (Spinal Tap)

This procedure is used to look for leukemia cells in the cerebrospinal fluid (CSF), which is the liquid that surrounds the brain and spinal cord. For this test, the doctor first numbs an area in the lower part of the back near the spine. A small needle is then placed between the bones of the spine to withdraw some of the fluid.

This is not a routine test for patients with CLL. It is only done if the doctor suspects leukemia cells may have spread to the brain or spinal cord (which is rare), or if there might be an infection in those areas.

Lab Tests Used to Diagnose and Classify Leukemia

One or more of the following lab tests may be used to diagnose CLL or to help determine how advanced the disease is.

Blood Cell Counts and Blood Cell Exam

These tests look at the numbers of lymphocytes in the blood and at how they look under the microscope. Patients with CLL have too many of these white blood cells (lymphocytosis). More than 10,000 lymphocytes/mm³ (per cubic millimeter) of blood (normal is less than 5,000) makes the diagnosis almost certain, although it may need to be confirmed by the more specialized tests discussed below. The patient will often have too few red blood cells and blood platelets as well.

Other Blood Tests

Other tests measure the amount of certain chemicals in the blood, but they are not used to diagnose leukemia. In patients already known to have CLL, these tests help detect liver or kidney problems caused by the spread of leukemia cells or due to the side effects of certain chemotherapy drugs. These tests also help determine if treatment is needed to correct low or high blood levels of certain minerals.

Blood immunoglobulin (antibody) levels may be tested to see if the patient has enough antibodies to fight infections, especially if they have had many recent infections. Another blood protein called beta-2-macroglobulin may be measured. High levels of this protein indicate a more advanced CLL.

Routine Microscopic Exam

Any samples taken (blood, bone marrow, lymph node tissue, or CSF) are looked at under a microscope by a pathologist (a doctor specializing in diagnosing diseases with lab tests) and may be reviewed by the patient's hematologist/oncologist (a doctor specializing in treating blood diseases and cancer).

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

An important factor is if the cells look mature (like normal circulating blood cells that can fight infections). Some leukemic cells can lack features of normal blood cells and are not effective in fighting infections. The most immature cells are called lymphoblasts (or "blasts" for short). Chronic lymphocytic leukemia cells usually appear mature.

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.

Doctors also look to see how much of the normal marrow has been replaced by CLL cells. The pattern of spread of CLL cells in the bone marrow is also important. A pattern where the cells are in small groups (nodular or interstitial pattern) often indicates a better outlook than if the cells are scattered throughout the marrow (a diffuse pattern).

Cytochemistry

Cytochemistry tests involve exposing cells to chemical stains (dyes) that react with only some types of leukemia cells. These stains cause color changes that can be seen under a microscope, which can help the doctor determine what types of cells are present.

Flow Cytometry

This test is important in diagnosing CLL. It looks for certain substances on the outside surface of cells that help identify what types of cells they are.

A sample of cells is treated with special antibodies 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 can be measured and analyzed by a computer.

Some doctors are now using flow cytometry (or immunocytochemistry) to test for substances called ZAP-70 and CD38. These substances seem to be linked to what type of B lymphocyte is involved in the leukemia. Some recent studies suggest that CLL with fewer cells that express these substances seem to have a better outlook. These tests are still fairly new and are not available in all labs. It's not yet clear if they accurate or helpful in all cases.

Immunocytochemistry

During this test, as in flow cytometry, cells from the blood or bone marrow samples are treated with special antibodies. But instead of using a laser and computer, the sample is treated so that certain types of cells change color. The color change can be seen only by using a microscope.

Cytogenetics

This test involves looking at chromosomes (pieces of DNA) under a microscope to detect any changes. Normal human cells contain 23 pairs of chromosomes, each of which is a certain size. Some cases of CLL have chromosome changes that can be seen under the microscope after the cells have been processed in a special way.

Fluorescent in situ hybridization (FISH): A type of cytogenetic test that uses special fluorescent dyes that only attach to specific parts of particular chromosomes. FISH can be used to look for specific changes in chromosomes. It can be used on regular blood or bone marrow samples and is very accurate, which is why this test is now used in many medical centers.

In some cases of CLL, part of a chromosome may be missing. This is called a deletion. The most commonly seen deletions involve parts of chromosomes 13, 11, or 17. Other, less common chromosome changes include having an extra copy of chromosome 12 (trisomy 12) or having a translocation (swapping of DNA) between chromosomes 11 and 14.

This information is sometimes helpful in determining a patient's prognosis (outlook), but it needs to be looked at along with other factors, such as the stage of CLL. The loss of part of chromosome 13 is usually linked with a slower growing disease and a better outlook, while defects in chromosomes 11 or 17 often indicate a poorer outlook. Trisomy 12 does not seem to have much of an effect on prognosis.

Imaging Tests

Imaging tests produce pictures of the inside of the body. There are several imaging tests that might be done in people with CLL. They are not needed to diagnose the leukemia, but they may be done to help determine the extent of the disease.

Computed Tomography (CT) Scan

The CT scan is a type of x-ray test that produces detailed, cross-sectional images of your 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 your body are enlarged. It isn't usually needed to diagnose CLL, but it may be done if your doctor suspects the leukemia is growing in an organ, like your spleen.

Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around you. A computer then combines these pictures into detailed images of the part of your body that is being studied.

Often after the first set of pictures is taken, you will receive an intravenous (IV) injection of a contrast dye or you may also be asked to drink a solution of contrast material. This helps to better outline blood vessels and internal organs. A second set of pictures is then taken.

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 you have ever had a reaction to any contrast material used for x-rays.

CT scans take longer than regular x-rays. You need to lie still on a table while they are being done. During the test, the table moves in and out of the scanner, a ring-shaped machine that completely surrounds the table. You might feel a bit confined by the ring you have to lay in when the pictures are being taken.

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 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. Not only does this create images of cross-sectional slices of the body like a CT scanner, it can also produce images of 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 take longer than CT scans -- often up to an hour. You may have to lie inside a narrow tube, which is confining and can upset people with a fear of enclosed spaces. Newer, "open" MRI machines can help with this if needed. The MRI machine makes loud buzzing noises that you may find disturbing. Some places provide headphones to 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 oil). It emits 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 for enlarged organs inside your abdomen.

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

Chest X-ray

A plain x-ray of your chest can be done in most outpatient settings. In patients with CLL, it isn't needed for a diagnosis, but it may be used to see if you have normal lungs or if you have an infection.