Classic Follicular Lymphoma: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 14, 2026

Classic follicular lymphoma is a type of blood cancer that starts in B cells — specialized white blood cells that normally help the body fight infection. It is the second most common lymphoma in adults and is considered an indolent, or slow-growing, cancer. Most people are diagnosed when they notice a painless lump or swelling, often in the neck, armpit, or groin. Although classic follicular lymphoma can rarely be cured with standard treatment, many people live for many years with well-controlled disease. 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 classic follicular lymphoma?

Many people with classic follicular lymphoma feel well at the time of diagnosis. The most common finding is one or more painless, slowly enlarging lumps caused by swollen lymph nodes — small bean-shaped glands that are part of the immune system and are found throughout the body. Swollen nodes are most often noticed in the neck, armpits, or groin.

Some people also experience general symptoms sometimes called B symptoms — unintentional weight loss, fever, and drenching night sweats. Fatigue and loss of appetite are also common. In some people, lymphoma involves the spleen, liver, or bone marrow, which can cause abdominal fullness, anemia, or increased susceptibility to infection. Because the disease often grows slowly, symptoms may be present for months or years before a diagnosis is made.

What causes classic follicular lymphoma?

The exact cause of classic follicular lymphoma is not known. Most cases arise from an acquired genetic change — a chromosomal rearrangement called t(14;18) — that occurs by chance in a single B cell during its normal development in the lymph node germinal center. This rearrangement places the BCL2 gene next to a powerful growth-promoting region, causing the cell to produce too much of the BCL2 protein. BCL2 normally prevents cells from dying when they should; in classic follicular lymphoma, its overproduction allows abnormal B cells to accumulate rather than dying off naturally. Over time, additional genetic changes accumulate in these cells, driving lymphoma growth.

Several factors have been associated with an increased risk of developing classic follicular lymphoma. These include cigarette smoking, hepatitis C infection, Sjögren’s syndrome (an autoimmune condition), obesity, and having a first-degree relative previously diagnosed with follicular lymphoma. In most people, however, no clear cause is identified, and the disease is not considered inherited.

How is the diagnosis made?

The diagnosis of classic follicular lymphoma can only be made by examining tissue under the microscope. A biopsy is performed to remove a piece of a swollen lymph node or affected tissue, which is then examined by a pathologist. An excisional biopsy — removal of an entire lymph node — is preferred when possible, because it preserves the architectural pattern of the tissue, which is essential for accurate diagnosis and grading. A core needle biopsy may be used when an excisional biopsy is not feasible, though it provides less tissue for evaluation. Under the microscope, the pathologist identifies the characteristic follicular growth pattern, the types of cells present, and the proportion of large cells. Additional tests, including immunohistochemistry, flow cytometry, and genetic tests such as FISH, are routinely performed to confirm the diagnosis, characterize the lymphoma cells, and distinguish classic follicular lymphoma from other lymphomas that can look similar. Once the diagnosis is confirmed, imaging — typically a PET/CT scan — is used to determine how widely the lymphoma has spread in the body.

What does classic follicular lymphoma look like under the microscope?

Under the microscope, classic follicular lymphoma is typically made up of two types of abnormal B cells: centrocytes and centroblasts. Centrocytes are small, irregularly shaped cells with folded or cleaved nuclei (the central compartment of each cell that contains its DNA). Centroblasts are larger, rounder cells with more prominent nuclei. Both cell types are normally found in the germinal centers of healthy lymph nodes — the areas where B cells mature and learn to recognize infections. In classic follicular lymphoma, these cells escape normal growth control and form abnormal clusters.

The pattern of growth describes how the lymphoma cells are arranged in the tissue. Two main patterns can be seen:

Follicular pattern — The lymphoma cells are arranged in round or oval clusters called follicles, resembling the germinal centers of normal lymph nodes. A predominantly follicular pattern is the most common finding and is associated with the typical indolent behavior of classic follicular lymphoma.
Diffuse pattern — The lymphoma cells grow in large, shapeless sheets without forming follicles. A significant diffuse component — particularly when it makes up more than 25% of the tumor — is associated with a somewhat worse prognosis and is an important finding that your pathologist will note.

Most tumors show a predominantly follicular pattern. When more than 75% of the tumor is follicular, the report may describe the pattern as “follicular” or “predominantly follicular.” When substantial areas of diffuse growth are present alongside follicular areas, the report may describe the tumor as “follicular and diffuse.”

Is classic follicular lymphoma graded?

Classic follicular lymphoma is not assigned a grade in the traditional sense. This requires some explanation, because older reports — and some current reports in centers that have not yet adopted the most recent classification — may still use grades 1, 2, and 3A.

In the past, follicular lymphoma was divided into grades 1 through 3B based on the number of large cells called centroblasts per high-power field under the microscope. Grade 1 had the fewest large cells; grade 3B had the most. However, long-term studies showed that grades 1, 2, and 3A behave similarly and respond to similar treatments. The current World Health Organization classification (2022) groups grades 1, 2, and 3A into a single category, “classic follicular lymphoma,” which is no longer subdivided by grade.

What was previously called grade 3B follicular lymphoma — a subtype in which virtually all the cells are large centroblasts and sheets of cells are seen — is now classified as a separate disease called follicular large B cell lymphoma. This subtype behaves more aggressively and is treated differently from classic follicular lymphoma.

If your report uses grade 1, 2, or 3A, this means the same thing as classic follicular lymphoma. If your report says grade 3B or follicular large B cell lymphoma, this is a different and more aggressive diagnosis.

Immunohistochemistry and other diagnostic tests

Immunohistochemistry (IHC) is a laboratory test that detects specific proteins inside or on the surface of cells, allowing the pathologist to confirm the cell type and distinguish classic follicular lymphoma from other conditions that can look similar under the microscope. Flow cytometry is a related test that identifies proteins on the surface of cells in suspension and is often performed on fresh tissue or blood samples. Together, these tests provide a detailed protein profile of the lymphoma cells.

Classic follicular lymphoma typically shows the following results:

CD20 — Positive. CD20 is a protein found on the surface of normal and malignant B cells. Its presence confirms the lymphoma is of B cell origin and is also important because CD20 is the target of rituximab, the antibody used in treatment.
CD10 — Positive. CD10 is a marker of germinal center B cells. Its presence in follicular lymphoma confirms that the cells originated in the germinal center.
BCL2 — Positive. BCL2 is a survival protein that is overproduced in most cases of classic follicular lymphoma due to the t(14;18) chromosomal rearrangement. BCL2 positivity in follicular-pattern lymphoma is a key distinguishing feature that helps separate classic follicular lymphoma from reactive (non-cancerous) follicular hyperplasia, in which BCL2 is negative inside the follicles.
BCL6 — Positive. BCL6 is a protein that drives germinal center development and is expressed in most lymphoma cells.
CD23 — Negative.
CD3 — Negative. CD3 is a T cell marker. Its absence confirms the lymphoma cells are not T cells.
CD5 — Negative. CD5 negativity helps distinguish classic follicular lymphoma from other B cell lymphomas such as small lymphocytic lymphoma and mantle cell lymphoma, which are CD5 positive.
Cyclin D1 — Negative. Cyclin D1 negativity helps exclude mantle cell lymphoma, which can occasionally have a follicular growth pattern.

Occasionally, classic follicular lymphoma lacks BCL2 expression or CD10 — this does not exclude the diagnosis, as a minority of cases are negative for one or both markers, and the overall pattern of findings is used to reach the diagnosis.

Ki-67 and the proliferation rate

The Ki-67 labeling index is a measure of how quickly the lymphoma cells are dividing. Ki-67 is a protein expressed only in cells actively making new copies of themselves; a higher Ki-67 percentage indicates more cells are actively dividing, indicating a more rapidly growing tumor.

In classic follicular lymphoma, the Ki-67 index is typically low — often below 20–30% — reflecting the indolent nature of the disease. A higher Ki-67 index can be a sign that the lymphoma is growing more aggressively or, in some cases, that transformation to a more aggressive lymphoma such as diffuse large B cell lymphoma may be occurring. Your pathologist will record the Ki-67 result in the report, and your care team will consider it alongside other findings when assessing prognosis and deciding on treatment.

Biomarker and molecular testing

In addition to immunohistochemistry, several molecular and genetic tests are commonly performed on tissue from classic follicular lymphoma. These tests help confirm the diagnosis, assess risk, and in some cases, guide treatment decisions.

BCL2 rearrangement — t(14;18)

The t(14;18) chromosomal rearrangement — a swap of genetic material between chromosomes 14 and 18 — is present in approximately 85–90% of classic follicular lymphoma cases. This rearrangement places the BCL2 gene under the control of the immunoglobulin heavy chain gene promoter, a powerful genetic switch that is permanently active in B cells. The result is continuous overproduction of BCL2 protein, which prevents the lymphoma cells from undergoing normal programmed cell death. Detection of this rearrangement by FISH or PCR supports the diagnosis of follicular lymphoma and, in some centers, is used to monitor for residual disease after treatment.

BCL6 rearrangement

Rearrangements of the BCL6 gene are found in a minority of classic follicular lymphoma cases, more commonly in those with a higher proportion of large cells. BCL6 rearrangement can also be seen at the time of transformation to diffuse large B cell lymphoma and is one of the markers assessed when transformation is suspected.

MYC

MYC is a gene that drives rapid cell proliferation. MYC rearrangements or strong MYC protein expression are not typical of classic follicular lymphoma but may be seen at the time of transformation to a more aggressive lymphoma. When MYC rearrangement is detected alongside BCL2 rearrangement, the diagnosis may change to a higher-grade entity. If your report mentions MYC, ask your care team what this means in your specific situation.

Next-generation sequencing and recurrent mutations

Comprehensive molecular profiling by next-generation sequencing is increasingly used in classic follicular lymphoma to identify mutations that may affect prognosis or treatment. Mutations in genes such as EZH2, CREBBP, KMT2D, and EP300 are among the most common, occurring in 40–80% of cases depending on the gene. EZH2 mutations are of particular interest because they are targetable — tazemetostat, an EZH2 inhibitor, is approved for relapsed or refractory follicular lymphoma in patients with EZH2 mutations (and also in patients without EZH2 mutations who have no other satisfactory treatment options). Mutations in TP53 and certain other genes are associated with a higher risk of transformation and a less favorable prognosis.

For more information about biomarkers and molecular testing in blood cancers, visit the Biomarkers and Genetic Testing section.

Lymph node involvement and staging

Classic follicular lymphoma is staged using the Lugano classification, which describes how widely the lymphoma has spread throughout the body. Unlike solid tumors, lymphoma staging does not use TNM criteria; instead, it is based on the number and location of affected lymph node groups and whether the disease has spread to organs outside the lymphatic system. Staging is determined primarily by PET/CT imaging and, in some cases, 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 (the muscle separating the chest from the abdomen) are involved, or a single extranodal site plus one or more regional lymph node regions on the same side of the diaphragm.
Stage III — Lymph node regions on both sides of the diaphragm are involved.
Stage IV — The lymphoma has spread to one or more organs outside the lymphatic system, such as the bone marrow, liver, or lung.

The letter A or B is added to the stage to indicate whether B symptoms (fever, drenching night sweats, and weight loss of more than 10% of body weight over six months) are absent (A) or present (B). Most people with classic follicular lymphoma are diagnosed at an advanced stage (stage III or IV) because the disease spreads widely before causing significant symptoms, yet this advanced stage does not necessarily mean the outlook is poor, given the indolent nature of the disease.

Transformation to a more aggressive lymphoma

One of the most important concepts in classic follicular lymphoma is transformation — the process by which the indolent lymphoma changes into a faster-growing, more aggressive type. In most cases, transformation produces a diffuse large B cell lymphoma, though other aggressive lymphomas can occasionally arise. Transformation occurs in approximately 2–3% of people per year, meaning the cumulative risk over 10–15 years is approximately 25–30%.

Transformation should be suspected when there is a rapid increase in the size of one or more nodes, the emergence of new B symptoms, a sharp rise in LDH (a blood marker of cell turnover), or unexplained changes in blood counts. A new biopsy of the most clinically concerning site is needed to confirm transformation, as the transformed cells may be present only in part of the disease. PET/CT scanning is used to identify areas of high metabolic activity that are most likely to harbor transformed disease and, therefore, most informative for rebiopsy.

Transformed follicular lymphoma is treated as an aggressive lymphoma — typically with intensive chemotherapy and anti-CD20 immunotherapy — rather than with the watch-and-wait or gentler approaches used for indolent disease. The prognosis after transformation is generally less favorable than for de novo aggressive lymphoma, though some patients achieve durable remissions, particularly when transformation occurs late in the disease course or has not been heavily pre-treated.

All lymphoma tissue is examined carefully for evidence of transformation at the time of diagnosis and at any subsequent biopsy. If transformation is identified, it will be described in your pathology report.

What is the prognosis?

Classic follicular lymphoma is an indolent disease, and many people live for 15–20 years or more after diagnosis. The median overall survival in clinical trials using modern treatment is often greater than 20 years for early-stage disease, and 12–18 years even for advanced-stage disease. However, this must be understood alongside the reality that classic follicular lymphoma is rarely cured with standard treatment — most people experience a pattern of response and relapse over many years. With each relapse, the disease is generally still manageable with different treatments, and newer therapies continue to improve the outlook.

The most widely used prognostic tool for classic follicular lymphoma is the Follicular Lymphoma International Prognostic Index (FLIPI), which assigns a score based on five factors: age over 60, Ann Arbor stage III–IV, hemoglobin below 12 g/dL, more than four nodal sites involved, and elevated LDH. Patients are divided into low-risk (0–1 factors), intermediate-risk (2 factors), and high-risk (3–5 factors) groups. A newer version, FLIPI-2, incorporates bone marrow involvement, the longest diameter of the largest lymph node, and beta-2 microglobulin level.

Features associated with a worse prognosis include a high FLIPI score, a significant diffuse component in the growth pattern, a high Ki-67 index, TP53 mutation, transformation to aggressive lymphoma, and early relapse or progression within 24 months of first treatment (called POD24). POD24 is one of the strongest adverse prognostic markers in classic follicular lymphoma — people whose disease progresses within 24 months of first-line chemoimmunotherapy have a substantially lower overall survival than those who maintain a longer remission. Conversely, achieving a deep and durable response to first treatment is an important predictor of long-term outcomes.

What happens after the diagnosis?

Treatment for classic follicular lymphoma depends primarily on stage, FLIPI score, symptom status, and disease progression. A multidisciplinary team, including a hematologist or lymphoma specialist, radiation oncologist, and other specialists, will guide decision-making.

For limited-stage disease (stage I–II), radiation therapy to the involved lymph node regions is often used with curative intent, and long-term disease control is achieved in a significant proportion of patients.

For advanced-stage disease (stage III–IV) without symptoms or with slow-growing disease, active surveillance — sometimes called watch-and-wait — is a standard initial approach. Because classic follicular lymphoma grows slowly and treatment is not curative, starting therapy before symptoms develop does not improve overall survival. Patients on watch-and-wait are monitored with regular blood tests and imaging, and treatment begins when the disease causes symptoms, grows rapidly, involves critical organs, or meets criteria established by clinical guidelines.

When treatment is needed, the standard first-line approach is chemoimmunotherapy — most commonly bendamustine or CHOP-based chemotherapy combined with rituximab (an anti-CD20 antibody) or obinutuzumab (a newer-generation anti-CD20 antibody). Response rates to first-line chemoimmunotherapy are high — approximately 80–90% of patients achieve a response, with complete response rates of 50–70%. Rituximab maintenance therapy after chemoimmunotherapy has been shown to prolong remission. For patients unsuitable for chemotherapy, rituximab alone or lenalidomide plus rituximab (the R2 regimen) are alternatives. For relapsed disease, options include different chemoimmunotherapy combinations, tazemetostat (particularly for EZH2-mutated disease), PI3K inhibitors such as idelalisib or copanlisib, CAR T cell therapy (axicabtagene ciloleucel or lisocabtagene maraleucel), or autologous stem cell transplantation in eligible patients.

Questions to ask your doctor

What stage is my classic follicular lymphoma, and what does that mean for my treatment options?
What is my FLIPI score, and what does it tell you about my prognosis?
Does my report show any diffuse areas of growth, and does that affect my treatment plan?
What is the Ki-67 score, and is it consistent with typical indolent follicular lymphoma?
Was a BCL2 rearrangement detected, and was testing done for other genetic changes such as EZH2 or TP53 mutations?
Is watch-and-wait an option for me, and if so, what signs or symptoms should prompt me to contact you between appointments?
If treatment is recommended, what regimen are you proposing, and why?
What is the goal of treatment: remission, symptom control, or something else?
What are the signs that my lymphoma might be transforming to a more aggressive type, and what would happen then?
How will you monitor my response to treatment, and what tests will be used?
What happens if the lymphoma comes back after treatment?
Are there clinical trials I should consider?