How is chronic lymphocytic leukemia diagnosed?

Certain signs and symptoms might suggest that a person has chronic lymphocytic leukemia (CLL), but tests are needed to confirm the diagnosis.

Many people with 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.

Signs and symptoms

Even when people with CLL have symptoms, they are often vague and non-specific. Symptoms can include the following:

• Weakness
• Feeling tired
• 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

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). Patients with CLL may have very high white blood cell counts because of excess numbers of lymphocytes (lymphocytosis), but 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 have a higher risk of 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 low blood counts. If the antibodies attack red blood cells, it is known as autoimmune hemolytic anemia. Less often, the antibodies attack platelets and the cells that make them, leading to low platelet counts (thrombocytopenia). Rarely, the antibodies attack white blood cells, leading to leukopenia (low white blood cell counts).

CLL often causes the liver or spleen to become enlarged. If these organs are enlarged, you may notice fullness or swelling of the belly. You may also notice that you feel full after only a small meal. 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.

The symptoms and signs above may be caused by CLL, but they can also be caused by other conditions. Still, if you have any of these problems, it's important to see your doctor right away so the cause can be found and treated, if needed.

Medical history and physical exam

If you have any signs or symptoms that suggest you might have leukemia, your doctor will want to take a complete medical history to check for symptoms and possible risk factors. You will also be asked about your general health.

A physical exam provides information about your general health, possible signs of leukemia, and other health problems. During the physical exam, your doctor will pay close attention to your lymph nodes and other areas that might be affected.

Types of samples used to test for chronic lymphocytic leukemia

If symptoms and/or the results of the physical exam 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 to help 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, usually at the same time. The samples are usually taken from the back of the pelvic (hip) bone, but sometimes 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 skin over the hip, the doctor numbs the area and the surface of the bone 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 they 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.

Lymph nodes

In an excisional lymph node biopsy, an entire lymph node is removed through a cut in the skin. 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 needed 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.

Spinal fluid

The procedure used to take samples of spinal fluid (also called cerebrospinal fluid or CSF) is called a lumbar puncture (or spinal tap). CSF 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 over the spine. A small, hollow 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 area around 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 done on the samples to diagnose CLL or to help determine how advanced the disease is.

Complete blood count and blood cell exam (peripheral blood smear)

The complete blood count (CBC) is a test that measures the different cells in the blood, such as the red blood cells, the white blood cells, and the platelets. This test is often done along with a differential (or diff) which looks at the numbers of the different types of white blood cells. Patients with CLL have too many lymphocytes (called lymphocytosis). Having more than 10,000 lymphocytes/mm³ (per cubic millimeter) of blood makes the diagnosis almost certain, but 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. For the peripheral blood smear, a sample of blood is looked at under the microscope. In patients with CLL, the blood smear often shows many abnormal looking lymphocytes called smudge cells.

Other blood tests

Other tests may be done to 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 (chemo) drugs. These tests also help determine if treatment is needed to correct low or high blood levels of certain minerals. If treatment with the drug rituximab (Rituxan^®) is planned, the doctor may order blood tests to check for previous hepatitis infection (this is discussed further in the "Monoclonal antibodies" section).

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 exams

Any samples taken (blood, bone marrow, lymph node tissue, or CSF) are looked at under a microscope by a pathologist (a doctor specializing in lab tests) and may be reviewed by the patient's hematologist/oncologist (a doctor specializing in 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 blood cells that can fight infections). Some leukemia cells can lack features of normal blood cells and are not effective in fighting infections. The most immature cells are called lymphoblasts (or blasts). Chronic lymphocytic leukemia cells usually appear mature.

A key 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

For cytochemistry tests, cells are exposed 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 on the cells. These substances seem to be linked to the type of B lymphocyte involved in the leukemia. Studies suggest that CLL with fewer cells that have these substances seem to have a better outlook. This is discussed in more detail in the section about prognostic factors called “How is chronic lymphocytic leukemia staged?”

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 when seen under a microscope.

Gene tests

Cytogenetics: For this test, bone marrow cells (or sometimes cells from the blood or other tissues) are grown in the lab, and the chromosomes are examined under a microscope. Because it takes time for the cells to start dividing, this test usually takes weeks to complete. Normal human cells contain 23 pairs of chromosomes, but some cases of CLL have chromosome changes that can be seen under the microscope.

In some cases of CLL, part of a chromosome may be missing. This is called a deletion. The most common deletions occur in parts of chromosomes 13, 11, or 17. Deletion of part of chromosome 17 (often written as del[17p]) is linked to a poor outlook. Other, less common chromosome changes include an extra copy of chromosome 12 (trisomy 12) or a translocation (swapping of DNA) between chromosomes 11 and 14.

This information may be helpful to determine 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.

Fluorescent in situ hybridization (FISH): This is a type of chromosome test that can be used to look at the cells’ chromosomes and DNA without having to grow the cells in the lab. It uses special fluorescent dyes that only attach to specific parts of particular chromosomes. FISH is used to look for certain chromosome changes (not just any change). It can be used on regular blood or bone marrow samples. Because the cells don’t have to grow in the lab first, it can usually provide results more quickly than cytogenetics, often within a couple of days.

Molecular tests: Whether the gene for the immunoglobulin heavy chain variable region (IgV_H) has changed (mutated) can help your doctor know how aggressive your CLL is. In order to check for the change, that gene is looked at in a test called DNA sequencing.

Imaging tests

Imaging tests use x-rays, sound waves, or magnetic fields to create pictures of the inside of the body. Imaging tests are not done to diagnose the leukemia, but they may be done for a number of reasons, including to help find a suspicious area that might be cancerous, to learn how far a cancer may have spread, and to help determine if treatment has been effective.

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.

Before the scan, you may be asked to drink a contrast solution and/or get an intravenous (IV) injection of a contrast dye that helps better outline abnormal areas in the body. You may need an IV line through which the contrast dye is injected. The 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.

Sometimes a CT scan is combined with a PET scan in a test known as a PET/CT scan. For a PET scan, glucose (a form of sugar) containing a radioactive atom is injected into the blood. Because cancer cells in the body grow rapidly, they absorb large amounts of the radioactive sugar. A special camera can then create a picture of the areas of radioactivity in the body. The PET/CT scan combines both tests in one machine. This test allows the doctor to compare areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT.

Magnetic resonance imaging (MRI) scan

Like CT scans, MRI scans provide detailed images of soft tissues in the body. But MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed and then released in a pattern formed by the type of body tissue and by certain diseases. A computer translates the pattern into very detailed images of parts of the body. A contrast material called gadolinium may be injected into a vein before the scan to better see details.

MRI scans are most useful in looking the brain and spinal cord, but they are not often needed in people with CLL.

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 be distressing to some people. Newer, more open MRI machines may be another option. The MRI machine makes loud buzzing and clicking noises that you may find disturbing. Some places provide headphones or earplugs to help block this noise out.

Ultrasound

Ultrasound uses sound waves and their echoes to produce a picture of internal organs or masses. Most often for this test, a small, microphone-like instrument called a transducer is placed on the skin over the area to be examined (which is first lubricated with gel). 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 on a computer screen.

Ultrasound can be used to look at lymph nodes near the surface of the body or to look for enlarged organs inside your abdomen.

This is an easy test to have done, and it uses no radiation. For most ultrasound exams, 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.