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.

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.

Tests used to diagnose and classify leukemia

If symptoms and/or the results of the physical exam suggest you could 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 tests

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

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. These tests are often the first ones done on patients with a suspected blood problem.

People with CLL have too many lymphocytes (called lymphocytosis). Having more than 10,000 lymphocytes/mm³ (per cubic millimeter) of blood strongly suggests that CLL is present, but other tests are needed to know for certain. You might also 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. If you have CLL, the blood smear could show many abnormal looking lymphocytes called smudge cells.

Flow cytometry

This test is important in diagnosing CLL. It uses a machine that looks for certain substances on or in cells that help identify what types of cells they are (markers).

This test can be used to see if the lymphocytes in a sample of blood contain CLL cells. It can also be used to look for CLL cells in bone marrow or other fluids. CLL cells can have many of the same markers as normal B-cells. However, they also have a marker called CD5 that is normally found on T-cells, but not on normal B cells. For someone to have CLL, there must be at least 5,000 of these cells (per mm3) in the blood.

Flow cytometry can also be used to test for substances called ZAP-70 and CD38 on the cells. Studies suggest that CLL with fewer cells that have these substances seem to have a better outlook. This is discussed in more detail in How Is Chronic Lymphocytic Leukemia Staged?

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 Monoclonal Antibodies for Chronic Lymphocytic Leukemia).

Blood immunoglobulin (antibody) levels may be tested to check if you enough antibodies to fight infections, especially if you have recently had many infections. Another blood protein called beta-2-microglobulin may be measured. High levels of this protein generally indicate a more advanced CLL.

Bone marrow tests

Blood tests are often enough to diagnose CLL, but testing the bone marrow is helpful to tell how advanced it is. Bone marrow tests are often done before starting treatment for that reason. They might also be repeated during or after treatment to see if the treatment is effective.

Bone marrow aspiration and biopsy

Bone marrow aspiration and biopsy are done to get bone marrow samples for testing. They are usually done together, as part of the same procedure. The samples are usually taken from the back of the pelvic (hip) bone, but sometimes they may be taken from other bones.

For a 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 (about 1 teaspoon) of liquid bone marrow. Even with the anesthetic, most people 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. With the local anesthetic, this most often causes a feeling of pressure or tugging, but is not often painful. Once the biopsy is done, pressure will be applied to the site to help prevent bleeding.

Routine microscopic exams

The bone marrow samples 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). Chronic lymphocytic leukemia cells usually appear mature, while cells of acute leukemias look immature.

A key feature of a bone marrow sample is its cellularity. Normal bone marrow has a certain number of blood-forming cells and fat cells. Marrow with too many blood-forming cells is said to be hypercellular. This is often seen in bone marrow of CLL patients. Doctors also look to see how much of the normal cells in the bone marrow have 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).

Stains and/or antibody tests such as cytochemistry, immunocytochemistry, immunohistochemistry, and flow cytometry may be used on the bone marrow samples to diagnose CLL.

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 (written as t[11;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 genes or 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: Immunoglobulins, the antibodies that help your body fight infections, are made up of light chains and heavy chains. Whether the gene for the immunoglobulin heavy chain variable region (IGHV or IgVH) has changed (mutated) can help your doctor know how aggressive your CLL is. That gene is looked at in a test called cDNA sequencing.

Lymph node biopsy

In a lymph node biopsy, all or part of a lymph node is removed so that it can be examined under the microscope to see if it contains cancer cells. Although this is often done to diagnose lymphomas, 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.

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. If the lymph node is very large, only part of it may be removed. This is called an incisional biopsy.

Lumbar puncture (or spinal tap)

This procedure is used to take samples of the fluid that surrounds the brain and spinal cord (the cerebrospinal fluid or CSF) for testing. This is not a routine test for people 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.

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 and into the space around the spinal cord to collect some of the fluid.

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 other reasons, including to help find a suspicious area that might be cancerous, to learn how far a cancer may have spread, or to help determine if treatment has been effective.

Computed tomography (CT) scan

The CT scan 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.

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 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

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 might 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 can be used to look at lymph nodes near the surface of the body or to look for enlarged organs (like the liver and spleen) inside your abdomen.

This is an easy test to have, 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.

The American Cancer Society medical and editorial content team
Our team is made up of doctors and master’s-prepared nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing.

Last Medical Review: January 6, 2015 Last Revised: April 11, 2016

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