How Leukemia Is Diagnosed

Diagnosis of leukemia involves a number of steps. It often begins with a complete blood count (CBC) and peripheral blood smear. A bone marrow aspiration and biopsy are also done with most types of leukemia.

After diagnosis, the cancer is staged based on factors such as symptoms, the subtype of leukemia, and the number of abnormal cells in the blood or bone marrow.

Additional tests might identify surface markers on the cells (flow cytometry) as well as genetic changes (cytogenetic testing.) With some leukemias, a lumbar puncture (spinal tap), or lymph node biopsy may be needed as well.

There are many different variations of leukemia and an accurate diagnosis is important for choosing the best treatment options.

Physical Exam and History

The history and physical are the starting point in the diagnosis of leukemia, but they aren't used alone to make the diagnosis.

Your doctor will ask you about symptoms of leukemia and risk factors for the disease that you may have. A physical examination may reveal signs of possible leukemia, such as lymph node swelling, pale skin, or bruising. These issues can occur with many medical conditions and they aren't specifically diagnostic of leukemia.

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Blood Tests

A CBC and peripheral smear are blood tests that can show abnormalities characteristic of leukemia and are also used to guide further evaluation. 

Complete Blood Cell Count and Peripheral Blood Smear

A CBC provides an estimate of your blood concentration of each of the major types of blood cells made by the bone marrow: the white blood cells (WBCs), red blood cells (RBCs), and platelets. It can also identify whether your RBCs are large or small.

There is often an increase in WBCs with leukemia, which may sometimes be associated with a decrease in RBC and platelet count. In some cases, acute leukemia may also be associated with a decrease in all of the types of blood cells—a condition referred to pancytopenia.

A CBC can determine if the WBC number is low or high, but it doesn't give enough information about the type of WBCs that are increased or decreased. A CBC also can't identify blasts (immature WBCs) in the peripheral blood—these cells are normally only found in significant numbers in the bone marrow.

A peripheral smear can provide more details about the type of WBCs in the blood.

Typical findings (these can vary) on a CBC and blood smear for the four main types of leukemia include:

Bone Marrow Aspiration and Biopsy

The bone marrow is the source of all of the blood cells found in the peripheral blood, as well as the cancer cells in leukemia. With most types of leukemia, blood tests are not enough to conclusively diagnose the disease, and a bone marrow aspiration and biopsy are done.

During a bone marrow aspiration, a long, thin needle is inserted into the bone marrow in the hip (or sometimes the breastbone) after the skin is numbed locally with lidocaine. After a sample of the bone marrow is aspirated, a biopsy sample is also taken.

With CLL, the diagnosis can sometimes be made based on blood tests, but a bone marrow aspiration can be helpful in determining how advanced the cancer is.  

In the normal bone marrow, between 1 and 5% of cells are blast cells (immature WBCs) that are expected to mature into those normally found in the blood.

If leukemia is diagnosed, the ratio of leukemia cells to healthy blood-forming cells can also be an important part of the diagnostic process.

In addition to looking at the number of different cells present in the bone marrow, doctors also look at the pattern of the cells. For example, with CLL, the prognosis of the disease is better if the cancer cells are found in groups (nodular or interstitial pattern) than if they are found diffusely scattered around the bone marrow.

Cytochemistry

Cytochemistry looks at how the cells in the bone marrow take up certain stains, and it can be helpful in distinguishing ALL from AML. Tests can include both flow cytometry and immunohistochemistry.

• In flow cytometry, the bone marrow cells or peripheral blood cells are coated with antibodies to look for the presence of certain proteins found on the surface of the cells. The antibodies will stick to these proteins and can be detected by the light they give off when a laser is introduced.
• With immunohistochemistry, the color of the antibody-marked proteins can be detected by examination of the cells with a microscope.
• This process of looking for unique proteins on the surface of cells is referred to as immunophenotyping. In genetics, genotype refers to the characteristics of a gene, whereas phenotype describes physical characteristics (such as blue eyes). Different types of leukemia differ in these phenotypes.

In addition, these tests can be helpful in confirming a diagnosis of CLL by identifying proteins called ZAP-70 and CD38.

Flow cytometry can also be used to determine the amount of DNA in leukemia cells, which can be helpful in planning treatment. ALL cells that have more DNA than an average cell tend to respond better to chemotherapy.

Chromosome and Gene Studies

Leukemia cells very often have changes in the chromosomes or genes found in the DNA of each cell. Each of our cells normally has 46 chromosomes that contain many genes. Some studies look primarily at chromosomal changes, whereas others look for changes in specific genes.

Cytogenetics

Cytogenetics involves microscopic examination of the chromosomes of cancer cells.

The cancer cells need time to be grown in the lab after being retrieved, so the results of these studies are often not available for two to three weeks after a bone marrow biopsy is done. 

Chromosomal changes that may be seen in the leukemia cells include:

• Deletions: Part of a chromosome is missing.
• Translocations: Pieces of two chromosomes are exchanged. For example, DNA may be swapped between chromosomes 9 and 22. Chromosome translocations are very common in leukemia, occurring in up to 50% of these cancers.
• Inversion: Part of a chromosome remains present, but is turned around (as if a piece of a puzzle is removed and replaced, but backward).
• Addition or duplication: Extra copies of all or part of a chromosome are found.
• Trisomy: There are three copies of one of the chromosomes, rather than two.

Cytogenetics can help with planning treatment. For example, in ALL, leukemia cells that have more than 50 chromosomes respond better to treatment.

Fluorescent In Situ Hybridization (FISH)

Fluorescent in situ hybridization (FISH) is a procedure in which special dyes are used to look for changes in specific genes.

With CML, this test can be used to look for pieces of the BCR/ABL1 fusion gene on chromosome 22 (Philadelphia chromosome).

With CLL, cytogenetics is less helpful, and FISH and PCR are more important for finding genetic changes. There are many genetic abnormalities that may be seen with these studies, including deletions in the long arm of chromosome 13 (in half of the people with the disease), an extra copy of chromosome 12 (trisomy 12), deletions in the 17th and 11th chromosome, and specific mutations in genes such as NOTCH1, SF3B1, and more.

Polymerase Chain Reaction (PCR)

Like FISH, polymerase chain reaction (PCR) can find changes in chromosomes and genes that can't be identified through cytogenetics. PCR is also helpful in finding changes that are present in just a few, but not all, of the cancer cells.

PCR is very sensitive for finding the BCR/ABL gene, even when other signs of CML aren't found on chromosome testing.

Other Procedures

In addition to evaluating WBCs in the blood and bone marrow, other procedures are sometimes done.

Lumbar Puncture (Spinal Tap)

With some types of leukemia, a spinal tap (lumbar puncture) may be done to look for the presence of leukemia cells that have spread into the cerebrospinal fluid (CSF) surrounding the brain and spinal cord. It may be done for those with ALL, as well as people with AML who have any neurological symptoms suggesting this spread.

During a lumbar puncture, a person lies on a table on their side with knees up and head down. After cleaning and numbing the area, a doctor inserts a long thin needle into the lower back, between the vertebrae, and into the space surrounding the spinal cord. Fluid is then withdrawn and sent to a pathologist to be analyzed.

Lymph Node Biopsy

Lymph node biopsies, in which part or all of a lymph node are removed, are done infrequently with leukemia. A lymph node biopsy may be done with CLL if large lymph nodes are present, or if it's thought that CLL may have transformed into a lymphoma.

Imaging

Imaging tests are not usually used as a diagnostic method for leukemia, as blood-related cancers like leukemia don't often form tumors. It may be helpful, however, in staging some leukemias, such as CLL.

X-Rays

X-rays, such as a chest X-ray or bone X-ray are not used to diagnose leukemia but may give the first signs that something is wrong. An X-ray may show enlargement of lymph nodes or osteopenia (thinning of the bone).

Computed Tomography (CT Scan)

A CT scan uses a series of X-rays to create a 3-dimensional picture of the inside of the body. CT may be helpful in looking at nodes in the chest or other regions of the body, as well as noting enlargement of the spleen or liver.

Magnetic Resonance Imaging (MRI)

An MRI uses magnets to create a picture of the inside of the body and does not involve radiation. It may be helpful in leukemias that involve the brain or spinal cord.

Positron Emission Tomography (PET/CT or PET/MRI)

Before a PET scan, radioactive glucose is injected into the body, where it is taken up by cells that are more metabolically active (such as cancer cells). PET is more helpful with solid tumors than with leukemia but may be helpful with some chronic leukemias, especially when there is concern about transformation into a lymphoma.

Differential Diagnosis

There are some diseases that may resemble leukemia.

Some of these include:

• Certain viral infections: Epstein-Barr virus (the cause of infectious mononucleosis), cytomegalovirus, and HIV may cause an elevated number of atypical lymphocytes that are detected with blood tests.
• Myelodysplastic syndromes: These are diseases of the bone marrow that have a predilection for developing into AML and are sometimes referred to as preleukemia.
• Myeloproliferative disorders: Conditions such as polycythemia vera, essential thrombocytosis, and primary myelofibrosis may resemble leukemia.
• Aplastic anemia: This is a condition in which the bone marrow stops making all of the types of blood cells.

Staging

Once leukemia has been confirmed, it must be staged. Staging refers to the system used by doctors to categorize a cancer. Determining the stage of a cancer, in general, can help doctors select the most appropriate treatment as well as estimate the prognosis of the disease.

A number of factors are taken into consideration in assigning a stage, such as the number of immature WBCs found in the blood or bone marrow, tumor markers, chromosome studies, and more.

People with the same kind of leukemia and the same stage may have very different responses to therapy, as well as different prognoses.

Chronic Lymphocytic Leukemia (CLL)

For CLL, there are a number of different staging systems that may be used. Most common is the Rai system in which a stage between 0 and 4 is assigned based on the presence of several findings:

• Number of lymphocytes
• Enlarged lymph nodes
• An enlarged liver and/or spleen
• Anemia
• Number of platelets

Based on these stages, the cancers are then separated into low, intermediate, and high-risk categories.

In contrast, the Binet system used in Europe separates these leukemias into only three stages:

• Stage A: Less than 3 lymph node regions
• Stage B: Greater than 3 affected lymph node regions
• Stage C: Any number of lymph nodes, but combined with either anemia or a low level of platelets.

Acute Lymphocytic Leukemia (ALL)

For ALL, staging is different, as the disease does not form tumor masses that extend incrementally from an original tumor. 

This usually involves cytogenetic tests, flow cytometry, and other lab tests.

ALL is often defined by the phases of the disease:

• Untreated ALL
• ALL in remission
• Minimal residual disease
• Refractory ALL
• Relapsed (recurrent) ALL

Acute Myelogenous Leukemia (AML)

Similar to ALL, AML is usually not detected until it has spread to other organs, and traditional cancer staging is not applicable. Staging is determined by characteristics such as the subtype of the leukemia, a person's age, and more.

An older staging system, the French-American-British (FAB) classification, classified AML into eight subtypes, M0 through M7, based on the microscopic appearance of the cells.

In this system, these leukemias are separated by characteristics such as chromosomal abnormalities (some chromosome changes are associated with a better-than-average prognosis, while others are associated with poorer outcomes), whether the cancer arose after previous chemotherapy or radiation (secondary cancers), those related to Down syndrome, and more.

Chronic Myelogenous Leukemia (CML)

For CML, the presence of an increased number of mature cells belonging to the myeloid lineage (like neutrophils) is common. Staging is determined based on the number of immature myeloid cells at different stages of maturation:

• Chronic phase: In this earliest stage, there are less than 10% blasts in the blood or bone marrow and symptoms are either mild or absent. People in the chronic phase of CML usually respond well to treatment.
• Accelerated phase: In the next phase, 10 to 19% of the cells in the blood or bone marrow are blasts. Symptoms become more pronounced, particularly fever and weight loss. Testing may reveal new chromosomal changes in addition to the Philadelphia chromosome. People in the accelerated phase of CML may not respond to treatment.
• Blast phase (aggressive phase): In the blast phase of CML, 20% or more of the cells in the blood or bone marrow are blasts, and blast cells may also spread to areas of the body outside of the bone marrow. During this phase, symptoms include fatigue, fever, and an enlarged spleen (blast crisis).