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 be sure.

Medical history and physical exam

If you might have leukemia, your doctor will want to take a complete medical history to check for symptoms and possible risk factors. You'll also be asked about your family medical history and your general health.

A physical exam will be done to look for possible signs of leukemia and other health problems. During the exam, your doctor will pay close attention to your lymph nodes, abdomen (belly), and other areas that might be affected.

Your doctor may also order tests to check your blood cell counts. If the results suggest leukemia, you may be referred to a hematologist, a doctor who specializes in treating blood disorders (including blood cancers like leukemia). This doctor may do one or more of the tests described below.

Tests used to diagnose and classify leukemia

Tests will need to be done on your blood and bone marrow to be certain of a leukemia diagnosis. Other tissue and cell samples may also be needed to help guide treatment.

Blood tests

Blood samples for tests for CLL will be taken from a vein in your arm. Many different tests are done.

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

The complete blood count or CBC measures the different cells in your 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 when a blood problem is suspected.

People with CLL have too many lymphocytes. (This may be called lymphocytosis.) Having more than 10,000 lymphocytes/mm³ (per cubic millimeter) of blood strongly suggests CLL, but other tests are needed to know for sure. You might also have low levels of red blood cells and platelets.

A sample of blood is looked at under the microscope (called a peripheral blood smear). 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 (markers) on or in cells that help identify what types of cells they are.

This test can be used to see if the lymphocytes in a sample of blood contain CLL cells. Flow cytometry can also be used to look for CLL cells in bone marrow or other fluids.

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

Other blood tests

Other tests may be done to measure the amount of certain chemicals in your blood, but they're not used to diagnose leukemia. In people already known to have CLL, these tests can help find liver or kidney problems caused by the spread of leukemia cells or certain chemotherapy (chemo) drugs. These tests also can check the levels of certain minerals so any imbalances can be treated. If you're going to be treated with the drug rituximab (Rituxan®), your doctor may order blood tests to check for previous hepatitis infection. (You can find more on this in Monoclonal Antibodies for Chronic Lymphocytic Leukemia.)

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

Bone marrow tests

Blood tests are often enough to diagnose CLL, but testing the bone marrow can help tell how advanced it is. Because of this, bone marrow tests are often done before starting treatment. They might also be repeated during or after treatment to see if treatment is working.

Bone marrow aspiration and biopsy are done to get bone marrow samples for testing. They're usually done together. 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 your hip, the doctor uses a long thin needle to put in a drug that numbs the area and the surface of the bone. This may cause brief stinging or burning. A hollow needle is then put into the bone, and a syringe is used to suck out a small amount (about 1 teaspoon) of the thick, liquid bone marrow. Even with the numbing medicine, 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 (core) of bone and marrow (about 1/16 inch in diameter and 1/2 inch long) is removed with a larger needle that's twisted as it's pushed down into the bone. Even with the numbing medicine, this can cause a feeling of pressure or tugging, but it usually doesn't hurt. After the biopsy is done, pressure will be put the site to help prevent bleeding.

Routine microscopic exams

A pathologist (a doctor specializing in lab tests) looks at the bone marrow samples under a microscope. They may also be reviewed by your 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. This helps to classify them into specific types.

An important factor is if the cells look mature (like normal blood cells that can fight infections). CLL cells usually look mature, while cells of acute leukemias look immature.

A key feature of a bone marrow sample is its cellularity or cellular makeup. 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 a person with CLL. Doctors also look to see how much of the normal cells in the bone marrow are replaced by CLL cells.

The pattern of spread of CLL cells in the bone marrow is important, too. A pattern where the cells are in small groups (called a nodular or interstitial pattern) often means 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. You can learn more about these tests at Tests Used on Biopsy and Cytology Specimens to Diagnose Cancer.

Gene tests

Cytogenetics

For this test, bone marrow cells (or sometimes cells from the blood or other tissues) are grown in the lab, then their 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 sometimes CLL cells 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 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 doesn't seem to have much of an effect on prognosis.

Fluorescent in situ hybridization (FISH)

This chromosome test 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, too. Because the cells don’t have to grow in the lab first, you can usually get the results more quickly than cytogenetics, often within a few 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 it can be examined under the microscope to see if it contains cancer cells. This is often done to diagnose lymphomas, but only rarely needed for CLL. It may be done 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 by first numbing the sikn, but if the node is inside the chest or abdomen (belly), 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 test the fluid that surrounds the brain and spinal cord (the cerebrospinal fluid or CSF). It's not often needed for people with CLL. It's 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 CLL, but they may be done for other reasons, for instance to help find a suspicious area that might be cancer, to learn how far a cancer may have spread, or to help see if treatment working.

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're not often needed in people with CLL.

Ultrasound

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.

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.

American Society of Clinical Oncology. Leukemia - Chronic Lymphocytic - CLL: Diagnosis (06/2016). Accessed at www.cancer.net/cancer-types/leukemia-chronic-lymphocytic-cll/diagnosis on April 12, 2018.

National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version. March 28, 2018. Accessed at www.cancer.gov/types/leukemia/patient/cll-treatment-pdq on April 12, 2018.

National Comprehensive Cancer Network, Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 5.2018 -- March 26, 2018. Accessed at www.nccn.org/professionals/physician_gls/pdf/cll.pdf on April 12, 2018.

Last Medical Review: May 10, 2018 Last Revised: May 10, 2018

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