Chronic Lymphocytic Leukemia (CLL): Understanding Your Pathology Report

By Rosemarie Tremblay-LeMay MD FRCPC
April 16, 2026

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. It is a slow-growing (indolent) blood cancer that starts in B cells — the white blood cells that help the body fight infections by producing antibodies. In CLL, a single abnormal B cell multiplies uncontrollably, producing a large population of abnormal identical B cells that accumulate in the blood and bone marrow and crowd out normal blood cells. CLL usually progresses slowly, and many people live with the disease for years — sometimes decades — without requiring treatment. This article will help you understand the findings in your pathology report, what each term means, and why it matters for your care.

What are the symptoms of chronic lymphocytic leukemia?

Many people with CLL have no symptoms at diagnosis. The disease is often discovered incidentally when a routine blood test shows an abnormally high lymphocyte count — a finding called lymphocytosis — in someone who feels entirely well. When symptoms do develop, they tend to appear gradually as the abnormal cells accumulate.

The most common symptoms include painless swollen lymph nodes in the neck, armpits, or groin; enlargement of the spleen, causing a feeling of fullness or discomfort in the upper left abdomen; fatigue; and increased susceptibility to infections, because the abnormal B cells are unable to perform normal immune functions and because the bone marrow’s capacity to produce healthy immune cells is progressively reduced.

As the disease advances and the bone marrow becomes more heavily infiltrated, it produces fewer normal blood cells, leading to anemia (low red blood cells — causing fatigue, shortness of breath, and pale skin) and thrombocytopenia (low platelets — causing easy bruising and bleeding). Some people with CLL also develop autoimmune complications, in which the immune system — dysregulated by the disease — produces antibodies that attack the body’s own blood cells. The most common are autoimmune hemolytic anemia (in which the immune system destroys red blood cells) and immune thrombocytopenia (in which it destroys platelets). These autoimmune complications can occur at any stage of the disease and are sometimes the first sign of CLL.

General constitutional symptoms — fever, drenching night sweats, and unintentional weight loss of more than 10% of body weight over six months (B symptoms) — can occur at any stage. When these symptoms develop or worsen rapidly, particularly alongside rapidly enlarging lymph nodes that are asymmetrically enlarging (one area expanding much faster than others), they should prompt evaluation for Richter transformation — a change to a more aggressive lymphoma, discussed further below.

What causes chronic lymphocytic leukemia?

The exact cause of CLL is not fully known. The disease arises from acquired genetic changes in a single mature B cell that allow it to survive and proliferate abnormally, producing a clone of identical abnormal cells. These changes are not traditionally inherited in the way that some genetic diseases are, but family history plays a meaningful role: first-degree relatives of people with CLL have a 5 to 8 times higher risk of developing the disease, and more than 40 common genetic variants have been identified that collectively contribute to susceptibility. Despite this hereditary component, most cases occur without a family history. CLL is substantially more common in White populations than in Asian or African populations — a difference that reflects genetic rather than lifestyle factors.

Possible environmental contributions include exposure to certain pesticides, herbicides, and possibly Agent Orange (a defoliant used during the Vietnam War). Age is a strong risk factor: the median age at diagnosis in Western populations is above 70, and the disease becomes increasingly common with advancing age. CLL is about 1.5 to 2 times more common in men than in women. It is not caused by lifestyle choices such as diet or exercise.

What is the difference between CLL and small lymphocytic lymphoma?

CLL and small lymphocytic lymphoma (SLL) are the same disease — both involve the same abnormal B cell and share identical genetic features, prognosis, and treatment. The distinction is purely anatomical and is based on where the abnormal cells are most prominent. CLL is diagnosed when the abnormal B cell count in the blood reaches or exceeds 5 × 10⁹ per liter (5,000 cells per microliter) and the cells have the characteristic immunophenotype described below. SLL is used when the same abnormal B cells are primarily found in lymph nodes or other solid tissues, without meeting the blood count threshold for CLL. Because the two presentations can coexist and can change over time, the disease is often referred to as CLL/SLL.

If your diagnosis came from a lymph node biopsy rather than a blood test, you will likely have an SLL report. The companion article — Small Lymphocytic Lymphoma (SLL): Understanding Your Pathology Report — covers lymph node biopsy findings, proliferation centers, and Lugano staging specific to tissue-based diagnosis. This article focuses on the blood and bone marrow aspects of CLL.

How is the diagnosis made?

The diagnosis of CLL begins with a blood test showing an elevated lymphocyte count. When this finding is identified, flow cytometry is performed on blood to examine surface proteins on lymphocytes and confirm that they are the characteristic abnormal B cells of CLL. The formal diagnostic threshold for CLL requires a sustained B cell count of at least 5 × 10⁹ per liter in the blood — meaning at least 5,000 abnormal B cells per microliter — with the characteristic immunophenotype. Patients who have fewer circulating abnormal B cells but the same immunophenotype are considered to have a pre-malignant condition called monoclonal B cell lymphocytosis (MBL), which is monitored but not treated as CLL unless the count rises.

Once the blood diagnosis is established, a bone marrow biopsy may be performed to assess the degree of marrow involvement, particularly when the blood counts suggest marrow failure or when staging requires it. Immunohistochemistry (IHC) is performed on bone marrow biopsy tissue using the same protein markers used in flow cytometry. Molecular and genetic tests — including FISH for chromosomal changes and sequencing for IGHV mutation status and TP53 mutations — are performed on blood or bone marrow and provide critical information for prognosis and treatment selection. CT or PET/CT imaging may also be performed to assess lymph node and spleen size and to identify sites of concern for Richter transformation.

What does CLL look like under the microscope?

The microscopic appearance of CLL is examined in both the blood and the bone marrow.

On a blood smear (a thin preparation of blood examined under the microscope), the CLL cells appear as small lymphocytes with very little cytoplasm (the material surrounding the nucleus) and round nuclei containing densely clumped chromatin — the DNA-containing material inside the nucleus that gives it a “soccer ball” or “cracked-mud” appearance. These cells are fragile and often rupture during slide preparation, leaving behind shapeless remnants called smudge cells (also called basket cells). The presence of smudge cells alongside many small, uniform lymphocytes on a blood smear is a characteristic finding that alerts the examining pathologist to the possibility of CLL.

In a bone marrow biopsy, CLL cells infiltrate the marrow in one of several patterns: nodular (small clusters of cells), interstitial (cells scattered individually between normal marrow elements), diffuse (sheets of cells replacing normal marrow), or a combination. The diffuse pattern is associated with more advanced disease and a higher degree of marrow failure. The pathologist will describe the infiltration pattern in the report. Small pale-staining areas called proliferation centers — where CLL cells are actively dividing — may also be present in the bone marrow, though they are more prominent in lymph node biopsies.

Immunohistochemistry and flow cytometry results

The protein profile of CLL cells, as detected by immunohistochemistry and flow cytometry, is highly characteristic and confirms the diagnosis. The same markers are assessed whether the diagnosis is being made from blood, bone marrow, or lymph node tissue.

CD19, CD79a, PAX5 — Positive. Pan-B cell markers confirming that the cells are B lymphocytes.
CD20 — Positive but characteristically dim (weak). CD20 is a B cell surface protein expressed by almost all B cell lymphomas, but in CLL/SLL the expression is notably weaker than in normal B cells or most other B cell lymphomas. This dimness is diagnostically helpful.
CD5 — Positive. CD5 is normally found on T cells and a small subset of B cells. Its co-expression alongside B cell markers is the single most important finding in CLL, because it is absent in most other B cell lymphomas. The main CD5-positive B cell lymphoma to exclude is mantle cell lymphoma (see cyclin D1 below).
CD23 — Positive. The classic immunophenotype of CLL/SLL is CD5-positive and CD23-positive. CD23 is typically negative in mantle cell lymphoma, making this combination the key distinguishing pair between the two diagnoses.
LEF1 — Positive in approximately 95% of cases. A transcription factor (a protein that switches genes on or off) that is highly specific for CLL/SLL among small B cell lymphomas.
CD200 — Strongly positive. Strong CD200 expression is characteristic of CLL/SLL and is low or absent in mantle cell lymphoma, making it a useful differential marker.
CD10 — Negative. CD10 is a germinal center B cell marker expressed in follicular lymphoma but absent in CLL/SLL. Its absence helps exclude follicular lymphoma.
Cyclin D1 — Negative. Cyclin D1 is expressed in virtually all mantle cell lymphoma but not in CLL/SLL. Confirming its absence is one of the most important steps in the workup.
CD38 — Variable. CD38 expression in more than 30% of CLL cells, as assessed by flow cytometry, is associated with more aggressive disease and a less favorable prognosis.
CD49d — Variable. Similar to CD38, elevated CD49d expression is associated with more aggressive disease.

Molecular and genetic testing

Molecular and genetic testing provides critical prognostic information and guides treatment selection in CLL/SLL. These tests are recommended before initiating therapy and, for TP53 testing, should be repeated at disease progression.

FISH for chromosomal changes

FISH (fluorescence in situ hybridization) detects gains or losses of specific chromosomal regions in the CLL cells. Four changes are routinely tested and appear in more than 80% of CLL patients collectively:

13q deletion — The most common change, found in 50–60% of patients. When present as the sole chromosomal abnormality, it is associated with the most favorable prognosis and an indolent disease course.
Trisomy 12 — An extra copy of chromosome 12, found in 15–20% of patients and associated with an intermediate prognosis.
11q deletion — Deletion of part of chromosome 11, removing the ATM gene (which helps repair DNA damage), found in 10–20% of patients and associated with more extensive lymph node involvement and a less favorable prognosis.
17p deletion — Deletion of part of chromosome 17, removing the TP53 gene (the cell’s primary defense against uncontrolled growth), found in 5–10% of patients at diagnosis. This is the most clinically significant change because it predicts resistance to standard chemoimmunotherapy. Patients with 17p deletion require treatment with targeted therapies such as BTK inhibitors or venetoclax rather than chemotherapy.

TP53 mutation testing

In addition to the 17p deletion detected by FISH, the TP53 gene can also be mutated without deletion of the surrounding chromosomal region. Approximately 60% of patients with TP53 disruption have both the deletion and a mutation, and roughly 30% have a mutation without a detectable deletion. Because both mechanisms impair TP53 function and predict chemotherapy resistance, comprehensive TP53 assessment requires both FISH for 17p deletion and TP53 gene sequencing. Since TP53 abnormalities can emerge during the disease — particularly after chemoimmunotherapy — TP53 testing should be repeated at every relapse or disease progression in patients who were previously TP53 wild-type.

IGHV mutation status

IGHV stands for immunoglobulin heavy chain variable region — the part of the B cell’s antibody gene that undergoes normal editing as B cells mature and learn to recognize specific infections. This editing process is called somatic hypermutation. When the IGHV gene shows evidence of this editing, the disease is classified as IGHV-mutated CLL/SLL, which is associated with a more indolent course, a longer time to treatment, and better responses to certain therapies. When the IGHV gene is essentially identical to the unedited version (less than 2% different from germline), the disease is classified as IGHV-unmutated CLL/SLL, which tends to progress faster and require treatment sooner.

Because the IGHV mutation status does not change over time — it reflects the state of the cell at the time the clone originated — this test only needs to be performed once per patient. A specific IGHV gene configuration, subset #2 (using gene segments IGHV3-21 and IGLV3-21), behaves aggressively even when classified as mutated and carries a prognosis similar to unmutated CLL/SLL.

What are prolymphocytes, and why do they matter?

Prolymphocytes are slightly larger, more activated-looking lymphocytes that may appear in small numbers in CLL blood smears. Their abundance matters because it indicates how much the disease cells have changed from typical small lymphocytes toward a more activated state:

Less than 15% prolymphocytes — Typical CLL. No change in diagnosis.
15–55% prolymphocytes — Prolymphocytic progression of CLL/SLL. The disease may behave more aggressively than typical CLL and warrants closer monitoring and often treatment.
More than 55% prolymphocytes — Per the current WHO 2022 classification, this is now called prolymphocytic progression of CLL/SLL rather than the older term “B-cell prolymphocytic leukemia,” which is no longer used as a separate diagnosis for cases evolving from CLL. Mantle cell lymphoma (which can sometimes present with a similar blood picture) must be excluded. Cases at this end of the spectrum tend to behave aggressively.

Staging

CLL is staged using clinical staging systems based on blood counts and physical examination findings — specifically how far the abnormal cells have infiltrated the body and what complications have developed. Two systems are used: the Rai system (most commonly used in North America) and the Binet system (most commonly used in Europe). Your care team may refer to either.

The Rai staging system divides CLL into five stages (0–IV):

Stage 0 — High lymphocyte count in the blood and bone marrow only. No enlargement of lymph nodes, spleen, or liver. Normal blood counts. Lowest risk group.
Stage I — High lymphocyte count plus enlarged lymph nodes.
Stage II — High lymphocyte count plus enlarged spleen or liver (with or without enlarged lymph nodes).
Stage III — High lymphocyte count plus anemia (low red blood cells). Lymph nodes, spleen, and liver may or may not be enlarged.
Stage IV — High lymphocyte count plus thrombocytopenia (low platelets). Anemia may also be present.

Stages 0 is considered low risk; stages I and II are intermediate risk; stages III and IV are high risk based on blood count complications. The Rai system is particularly helpful for communicating the urgency of treatment: patients at stages III–IV typically require treatment, while those at stages 0–II may be managed with active surveillance.

The Binet staging system uses three groups (A, B, C): Group A has fewer than three enlarged lymph node areas and normal blood counts; Group B has three or more enlarged lymph node areas; Group C has anemia or thrombocytopenia. Group C corresponds approximately to Rai stages III–IV.

For patients whose disease is primarily expressed as lymph node involvement (SLL), the Lugano classification is used instead of Rai or Binet — this is described in detail in the SLL article.

Richter transformation

Approximately 5% of CLL patients develop Richter transformation — a change in which the slow-growing CLL acquires additional genetic changes and converts into a more aggressive cancer. In most cases (approximately 95%), transformation produces a diffuse large B cell lymphoma; in rare cases (less than 1%), it produces a classic Hodgkin lymphoma pattern.

Warning signs of Richter transformation include a sudden, rapid increase in the size of one or more lymph nodes (particularly asymmetric growth), new B symptoms, a sharp rise in LDH (a blood protein reflecting rapid cell turnover), or an area of unexpectedly high metabolic activity on PET/CT imaging. When these signs are present, a biopsy of the most suspicious site is needed to confirm transformation.

Richter transformation is treated as an aggressive lymphoma with intensive chemoimmunotherapy rather than with the targeted agents used for CLL. The prognosis is less favorable than that of de novo DLBCL, though outcomes vary depending on genetic features and prior treatment history. Cases that are clonally unrelated to the original CLL — meaning they arose independently rather than evolving from the CLL clone — tend to have better outcomes and may be cured.

What is the prognosis?

CLL is an indolent disease with a generally favorable prognosis. Many people live for 10–20 years or more after diagnosis, and some — particularly those with early-stage disease and favorable genetic features — may never require treatment during their lifetime. CLL is currently not curable with standard therapies in most patients. Still, modern targeted treatments have dramatically improved both quality of life and survival, and the disease can be managed effectively for many years.

Prognosis is primarily determined by genetic and molecular features rather than stage alone. The CLL International Prognostic Index (CLL-IPI) combines five factors to divide patients into four risk groups: IGHV mutation status, TP53 status, age, clinical stage, and the blood level of a protein called beta-2 microglobulin (B2M). Patients in the low-risk group have a 10-year overall survival of approximately 80%, while those in the very-high-risk group have a 10-year survival of approximately 20% with older treatment approaches. Importantly, the introduction of BTK inhibitors and venetoclax-based regimens has substantially improved outcomes even for high-risk patients, including those with 17p deletion or TP53 mutation who previously had very poor responses to chemotherapy.

What happens after the diagnosis?

Because CLL is typically slow-growing, most patients do not require immediate treatment at diagnosis. Active surveillance — watch and wait — is the standard initial approach for patients with early-stage disease (Rai 0–II or Binet A–B) who have no symptoms or signs of progressive disease and normal blood counts. During active surveillance, patients are seen regularly (typically every 3 to 6 months) for blood tests and physical examinations. Treatment is deferred until the disease meets established criteria, which include rapidly rising lymphocyte count, progressive enlargement of lymph nodes or spleen, worsening anemia or thrombocytopenia, or the development of significant disease-related symptoms.

When treatment is needed, the approach depends on the patient’s age, fitness, genetic features (particularly IGHV and TP53 status), and whether prior treatment has been given. The current standard first-line options include:

BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) — oral tablets taken daily that block a protein called Bruton’s tyrosine kinase, which is essential for CLL cell survival. These are now among the most widely used treatments for CLL at all stages and are preferred for patients with 17p deletion or TP53 mutation.
Venetoclax plus obinutuzumab — a time-limited combination (typically 12 months) of venetoclax (a BCL2 inhibitor that removes the CLL cell’s protection against programmed cell death) and obinutuzumab (an anti-CD20 antibody). This regimen achieves high rates of deep remission, including undetectable minimal residual disease (MRD) in many patients.
Fludarabine, cyclophosphamide, and rituximab (FCR) — a chemoimmunotherapy combination that may be considered for younger, fit patients with IGHV-mutated CLL/SLL, in whom it can achieve durable long-term remissions. It is generally not used in patients with 17p deletion or TP53 mutation.

The treatment landscape for CLL continues to evolve rapidly, and clinical trial participation is an important option for many patients. Your care team will recommend the most appropriate approach for your individual situation based on your genetic profile, stage, and overall health.

Questions to ask your doctor

Do I have CLL in the blood, SLL in the lymph nodes, or both — and does the distinction change anything about my management?
What was my B cell count on the blood test, and what does that tell you about the extent of the disease?
Was FISH testing performed, and what chromosomal changes were found — particularly, was 17p deletion detected?
Was TP53 mutation sequencing performed in addition to FISH?
What is my IGHV mutation status — mutated or unmutated — and what does that mean for my prognosis?
What is my Rai or Binet stage, and does my stage indicate I need treatment now, or can I be monitored?
What is my CLL-IPI score, and what risk group does it put me in?
If treatment is recommended, would you suggest a BTK inhibitor, venetoclax-based therapy, or another approach, and why?
What are the signs that the disease is progressing or transforming, and how quickly should I report them?
Do I have autoimmune complications — hemolytic anemia or immune thrombocytopenia — and how are they managed?
How will I be monitored during active surveillance, and how often should I have blood tests?
Are there clinical trials I should consider?