Small Lymphocytic Lymphoma (SLL): Understanding Your Pathology Report

by Rosemarie Tremblay-LeMay MD FRCPC
April 16, 2026

Small lymphocytic lymphoma (SLL) is a slow-growing (indolent) blood cancer that starts in B cells — the white blood cells that help the body fight infections. It is defined by the accumulation of abnormal small B cells in the lymph nodes, spleen, bone marrow, and other tissues.

SLL is biologically identical to chronic lymphocytic leukemia (CLL) — both are caused by the same type of abnormal B cell and share the same genetic features, prognosis, and treatment approach. The difference is where the abnormal cells are most prominent: in SLL, they are found primarily in lymph node tissue and solid organs, while in CLL, they circulate in the blood in large numbers. Because of this, a pathology report for a lymph node biopsy will typically use the term SLL, while a blood test result will use CLL. Your care team may refer to your disease as CLL/SLL, which reflects this unified classification.

This article will help you understand the findings in your SLL pathology report, what each term means, and why it matters for your care.

What are the symptoms of small lymphocytic lymphoma?

Many people with SLL feel completely well at the time of diagnosis. The most common finding is one or more painless, slowly enlarging lumps caused by swollen lymph nodes, most often in the neck, armpits, or groin. Enlargement of the spleen — an organ in the upper left abdomen that is part of the immune system — can cause a feeling of fullness or discomfort in the left side of the abdomen. Some people also have an enlarged liver.

As the disease progresses, the accumulation of abnormal B cells in the bone marrow can reduce production of normal blood cells, causing anemia (low red blood cells), which leads to fatigue, shortness of breath, and pale skin; thrombocytopenia (low platelets), which leads to easy bruising or bleeding; or increased susceptibility to infections, because the abnormal B cells do not function properly as immune cells. Some people develop autoimmune complications — a condition in which the immune system produces proteins that attack the body’s own blood cells — causing anemia or low platelet counts even in the absence of extensive bone marrow involvement.

General constitutional symptoms — persistent fatigue, fever, drenching night sweats, and significant unintentional weight loss (more than 10% of body weight over six months) — can occur at any stage. When these symptoms appear or worsen rapidly, particularly alongside rapidly enlarging lymph nodes, they may indicate disease progression or transformation to a more aggressive lymphoma, and should prompt re-evaluation.

What causes small lymphocytic lymphoma?

The exact cause of SLL is not known. Like all lymphomas, it arises from acquired genetic changes in a single B cell that cause it to survive and multiply abnormally, producing a population of identical abnormal cells — a process called clonal expansion. These changes are not inherited in the traditional sense. However, family history is a recognized risk factor: first-degree relatives of people with CLL/SLL have a 5 to 8 times higher risk of developing the disease, and more than 40 common genetic variants have been identified that together contribute to susceptibility. Despite this hereditary contribution, most cases occur without a family history. SLL is most common in older adults (median age at diagnosis in Western populations is above 70) and is more common in men than women. It is substantially more common in White populations than in Asian or African populations, suggesting that genetic background influences risk.

No specific environmental, dietary, or lifestyle risk factor has been consistently identified as a cause of CLL/SLL.

How is the diagnosis made?

The diagnosis of SLL is made by examining lymph node tissue under the microscope. An excisional biopsy — removal of an entire lymph node — is the preferred approach because the full architecture of the node, including the characteristic proliferation centers described below, needs to be assessed. A core needle biopsy may be used when an excisional biopsy is not accessible, though it provides less tissue and makes some features harder to evaluate.

The pathologist examines the tissue under the microscope and then performs immunohistochemistry (IHC) to identify the specific protein profile of the lymphoma cells, and often flow cytometry to characterize cell surface proteins in detail. Both tests are essential for distinguishing SLL from other small B cell lymphomas that can look very similar under the microscope. Additional molecular and genetic tests — including FISH (fluorescence in situ hybridization) for chromosomal changes and sequencing of the IGHV gene — are typically performed at the time of diagnosis or before treatment begins, because they provide critical prognostic information and guide treatment selection. Blood tests, including a complete blood count, are also performed to assess for circulating abnormal lymphocytes and to determine whether the disease meets criteria for CLL in addition to SLL.

What does small lymphocytic lymphoma look like under the microscope?

Under the microscope, SLL shows a characteristic appearance that the pathologist uses to identify the diagnosis. The lymph node is typically replaced — either partially or completely — by a uniform population of small B cells. These cells are slightly larger than normal resting lymphocytes and have round nuclei with densely clumped chromatin (the DNA-containing material inside the nucleus), giving the nucleus a “soccer-ball” or “cracked mud” appearance. The cells have very little cytoplasm (the material surrounding the nucleus). Mitoses — cells caught in the act of dividing — are rare, reflecting the slow-growing nature of the disease.

One of the most diagnostically important and characteristic features of SLL in lymph node tissue is the presence of proliferation centers — also called pseudofollicles. These are pale-staining, round-to-oval areas scattered throughout the otherwise dark lymph node tissue. Under the microscope, they appear lighter than the surrounding small cells because they contain a mixture of slightly larger cells called prolymphocytes and paraimmunoblasts, which have more open chromatin (looser, less condensed DNA) and visible nucleoli (dense structures inside the nucleus). Proliferation centers are present in the majority of SLL cases and are one of the disease’s defining microscopic features — their identification by the pathologist strongly supports the diagnosis. When they are very large or confluent (fused), this may indicate a more aggressive variant of the disease.

Immunohistochemistry and flow cytometry results

Immunohistochemistry (IHC) and flow cytometry are essential for confirming the diagnosis and excluding other small B cell lymphomas. The characteristic protein profile of SLL/CLL is described below.

CD20 — Positive but characteristically dim (weak). CD20 is a B cell surface marker expressed in almost all B cell lymphomas, but in CLL/SLL, the expression is notably weaker than in normal B cells and most other B cell lymphomas. This dimness is a diagnostically helpful feature.
CD19, CD79a, PAX5 — Positive. Pan-B cell markers confirming B cell lineage.
CD5 — Positive. CD5 is a protein normally found on T cells and a subset of B cells. Its co-expression with B cell markers is the most important single IHC finding in CLL/SLL, because most other B cell lymphomas are CD5-negative. The combination of B cell markers plus CD5 positivity distinguishes CLL/SLL from follicular lymphoma, marginal zone lymphoma, and most other small B cell lymphomas. The main CD5-positive B cell lymphoma to exclude is mantle cell lymphoma, which is distinguished by its cyclin D1 positivity (see below).
CD23 — Positive. Co-expression of both CD5 and CD23 is the classic immunophenotype of CLL/SLL. CD23 is typically negative in mantle cell lymphoma, which is the most important differential diagnosis when CD5 is positive.
LEF1 — Positive in approximately 95% of cases. LEF1 is a transcription factor (a protein that switches genes on or off) that is rarely expressed in other small B cell lymphomas, making it a highly specific marker for CLL/SLL when positive.
CD43 — Positive in most cases.
CD200 — Strongly positive. CD200 expression is characteristically strong in CLL/SLL and helps differentiate it from mantle cell lymphoma, which typically shows low or absent CD200 expression.
CD10 — Negative. CD10 is a germinal center marker expressed in follicular lymphoma and some other B-cell lymphomas, but absent in CLL/SLL. Its absence helps exclude follicular lymphoma.
Cyclin D1 — Negative. Cyclin D1 is expressed in mantle cell lymphoma (the main CD5-positive B cell lymphoma that must be excluded) but is consistently negative in CLL/SLL. Confirming cyclin D1 negativity is one of the most important steps in the diagnosis.
CD38 — Variable. CD38 expression in more than 30% of tumor cells, as assessed by flow cytometry, is associated with more aggressive disease behavior and a worse prognosis.

Molecular and genetic testing

Molecular and genetic testing is an essential part of the workup for SLL/CLL and provides critical information about prognosis and treatment selection. These tests may be performed at the time of initial diagnosis or deferred until treatment is needed. Your pathology report or clinical correspondence may include results from these tests, and your care team will use them, along with your clinical stage, to make treatment decisions.

FISH for chromosomal changes

FISH (fluorescence in situ hybridization) uses fluorescent probes to detect whether specific chromosomal changes — gains or deletions of DNA — are present in the lymphoma cells. In CLL/SLL, four chromosomal changes are routinely tested and are among the most important prognostic markers:

13q deletion — The most common chromosomal change in CLL/SLL, found in approximately 50–60% of patients. When present as the sole chromosomal change, a 13q deletion is associated with an indolent (slow-growing) disease course and the most favorable prognosis among the four main chromosomal changes.
Trisomy 12 — An extra copy of chromosome 12, found in approximately 15–20% of patients (and somewhat more commonly in SLL than CLL). Associated with an intermediate prognosis.
11q deletion — Deletion of part of chromosome 11, affecting a gene called ATM (which helps repair DNA damage), found in approximately 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 a gene called TP53 (the cell’s primary defense against uncontrolled growth), found in approximately 5–10% of patients. This is the most clinically significant chromosomal change because it predicts resistance to standard chemotherapy. Patients with 17p deletion require treatment with targeted agents (BTK inhibitors or venetoclax) rather than chemoimmunotherapy.

It is important to note that 17p deletion and TP53 mutation can emerge or become more prominent over time, particularly after treatment. For this reason, testing is often repeated during disease progression or before each new treatment course.

TP53 mutation testing

In addition to 17p deletion, the TP53 gene itself can be mutated (changed) without deletion of the surrounding chromosomal region. Approximately 60% of patients with TP53 disruption have both the deletion and a mutation, while about 30% have a mutation without a detectable deletion. Because both mechanisms impair TP53 function and predict chemotherapy resistance, comprehensive testing requires FISH for 17p deletion and TP53 sequencing.

IGHV mutation status

IGHV stands for immunoglobulin heavy chain variable region — part of the gene that B cells use to build antibodies. In CLL/SLL, the IGHV gene mutation status is one of the most important prognostic markers. When the IGHV gene carries evidence of somatic hypermutation (normal editing that B cells undergo as they mature), the disease is called IGHV-mutated CLL/SLL. It is associated with a more indolent course, a slower time to first treatment, and a better response to certain therapies. When the IGHV gene is essentially identical to the unedited germline sequence (with less than a 2% difference), the disease is called IGHV-unmutated CLL/SLL. It is associated with a more aggressive course and a shorter time to treatment. Because the IGHV mutation status does not change over time, this test only needs to be performed once per patient.

A specific IGHV gene configuration, subset #2 (using particular gene segments, IGHV3-21 and IGLV3-21), is associated with an aggressive clinical course even when the IGHV gene would otherwise be classified as mutated, and is treated similarly to unmutated CLL/SLL in terms of prognosis.

Proliferation centers and what they mean

Proliferation centers are a characteristic microscopic feature of SLL in lymph node and other tissue biopsies. They appear as pale-staining areas within the otherwise dense small-lymphocyte population and represent sites where CLL/SLL cells are actively dividing. The pathologist will note whether proliferation centers are present and, when relevant, whether they are unusually large or confluent (merged).

The size and activity of proliferation centers can have prognostic significance. Cases with very large or confluent proliferation centers — sometimes called histologically aggressive CLL/SLL — may behave more aggressively than typical SLL and are often associated with TP53 abnormalities and complex chromosomal changes. This feature may prompt more comprehensive genetic testing and closer clinical monitoring. If your report mentions large or prominent proliferation centers, ask your care team what this means for your follow-up and treatment planning.

What is Richter transformation?

One of the most important long-term considerations in SLL/CLL is Richter transformation — the process in which the slow-growing lymphoma acquires additional genetic changes and becomes more aggressive. This occurs in approximately 5% of patients over the course of their disease. In most cases, transformation produces a diffuse large B cell lymphoma; in rare cases (less than 1%), transformation produces a classic Hodgkin lymphoma pattern.

Richter transformation should be suspected when there is a sudden rapid increase in the size of one or more lymph nodes (particularly if growth is asymmetric — one side growing much faster than others), new B symptoms (fever, night sweats, weight loss), a sharp rise in LDH (a blood marker of cell turnover), or a PET/CT scan showing an area of unexpectedly high metabolic activity. A new excisional biopsy of the most rapidly growing or metabolically active site is needed to confirm transformation. PET/CT is useful for identifying the best biopsy target.

The genetic changes underlying transformation most commonly include TP53 mutations or deletions, NOTCH1 mutations, MYC rearrangements or amplification, and CDKN2A deletions — changes that together are found in approximately 90% of transformed cases. Transformed SLL/CLL is treated with intensive chemoimmunotherapy appropriate for aggressive lymphoma and has a less favorable prognosis than de novo aggressive lymphoma. However, outcomes depend heavily on the specifics of the genetic changes and prior treatment history.

Staging

SLL is staged using the Lugano classification (a modification of the Ann Arbor staging system), which describes the extent of lymphoma spread. Staging is based on CT or PET/CT imaging and bone marrow biopsy.

Stage I — A single lymph node region or a single extranodal site is involved.
Stage II — Two or more lymph node regions on the same side of the diaphragm are involved.
Stage III — Lymph node regions on both sides of the diaphragm are involved.
Stage IV — The lymphoma has spread to one or more extranodal organs such as the bone marrow, liver, or spleen.

It is worth noting that clinical staging for CLL (the blood-based form of the same disease) uses different systems — the Rai staging system (used primarily in North America) and the Binet staging system (used primarily in Europe) — both based on blood counts, lymph node involvement, and whether the spleen and liver are enlarged. Because SLL is diagnosed by lymph node biopsy rather than blood tests, the Lugano system is used for SLL, though your care team may also refer to Rai or Binet staging if blood involvement is also present. Staging in CLL/SLL is particularly important for deciding when to start treatment, as many patients with early-stage disease are managed with active surveillance (watch and wait) rather than immediate therapy.

What is the prognosis?

SLL/CLL is an indolent disease, and the prognosis is generally favorable compared to many other lymphomas. Many people live for 10–20 years or more after diagnosis, and some patients — particularly those with early-stage disease and favorable genetic features — may never require treatment during their lifetime.

Prognosis in CLL/SLL is primarily determined by genetic and molecular features rather than stage alone. The most important prognostic markers are IGHV mutation status and TP53/17p status. Patients with IGHV-mutated CLL/SLL and favorable chromosomal features (particularly isolated 13q deletion) have the most favorable outcomes, with median time to first treatment often exceeding 10 years and excellent responses to modern targeted therapies when treatment is needed. Patients with IGHV-unmutated CLL/SLL or TP53 disruption tend to require treatment sooner and may need more intensive or different therapeutic approaches.

The CLL International Prognostic Index (CLL-IPI) combines five factors — IGHV mutation status, TP53 status, age, stage, and beta-2 microglobulin (a blood protein) — to divide patients into low-, intermediate-, high-, and very-high-risk groups. Your care team will calculate your CLL-IPI score to give you a more individualized estimate of prognosis.

It is important to know that the treatment landscape for CLL/SLL has been transformed by the development of targeted oral therapies — particularly BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib, and the BCL2 inhibitor venetoclax — which have dramatically improved outcomes even for patients with adverse genetic features such as 17p deletion or TP53 mutation who previously had poor responses to standard chemotherapy.

What happens after the diagnosis?

Because SLL/CLL is typically slow-growing, many patients do not require immediate treatment at diagnosis. Active surveillance — also called watch-and-wait — is the standard initial approach for patients with early-stage disease who have no symptoms, no signs of progressive disease, and no evidence of bone marrow failure. During active surveillance, patients are monitored regularly with blood tests and clinical examinations, and treatment is deferred until the disease meets established criteria for requiring therapy.

When treatment is needed, the choice of regimen depends on the patient’s age, overall health, genetic features (particularly IGHV and TP53 status), and whether prior treatment has been given. Modern first-line options include BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib), the combination of venetoclax plus obinutuzumab (a time-limited regimen), or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) in younger, fit patients with IGHV-mutated disease. Patients with 17p deletion or TP53 mutation are treated with BTK inhibitors or venetoclax-based combinations rather than chemoimmunotherapy, which is largely ineffective in this setting.

For patients with Richter transformation, treatment follows protocols for the transformed lymphoma type rather than for CLL/SLL.

For more information about the blood-based aspects of this disease — including the CLL blood test criteria, Rai and Binet staging, and blood count-related complications — see the companion article: Chronic Lymphocytic Leukemia (CLL): Understanding Your Pathology Report.

Questions to ask your doctor

My report says small lymphocytic lymphoma — does this mean I also have CLL in my blood, or is the disease currently limited to the lymph nodes?
Was FISH testing performed, and what chromosomal changes were found — in particular, was 17p deletion detected?
Was TP53 mutation testing performed, and what was the result?
What is my IGHV mutation status — mutated or unmutated — and what does that mean for my prognosis?
Were proliferation centers seen in my biopsy, and were they described as large or prominent?
What is my stage, and do I need treatment now, or can I be monitored?
What is my CLL-IPI score, and what risk group does it place me in?
If I do need treatment, would you recommend a BTK inhibitor, venetoclax-based therapy, or another approach?
How will you monitor me for Richter transformation, and what signs should I watch for?
What symptoms between appointments should prompt me to contact you urgently?
Are there clinical trials I should consider?