Last updated:
7/18/2025
Years published: 2019, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and James Armitage, MD, The Joe Shapiro Professor of Medicine, Division of Oncology & Hematology, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, for assistance in the preparation of this report.
Follicular lymphoma (FL) is a form of cancer that belongs to a broader group of diseases called non-Hodgkin lymphomas (NHL) which affect the lymphatic system, a part of the immune system that helps fight infections.
The lymphatic system consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that trap viruses, bacteria and other harmful substances. Groups of lymph nodes are located throughout the body, including, but not limited to, the neck, under the arms (axillae), at the elbows, and in the chest, abdomen and groin. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body.
FL is usually indolent, meaning it progresses slowly and can often be monitored before treatment is needed. However, in some people, it transforms into a more aggressive lymphoma, typically diffuse large B-cell lymphoma (DLBCL).
There are two main types of lymphocytes: B-lymphocytes (B-cells) which may produce specific antibodies to “neutralize” certain invading microorganisms and T-lymphocytes (T-cells) which may directly destroy microorganisms or cancer cells or assist in the activities of other lymphocytes. Follicular lymphoma is a B-cell lymphoma. It is characterized by the transformation of a B-cell into a malignant (cancerous) cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant B-cells can lead to enlargement of specific lymph node regions, involvement of other lymphatic tissues such as the spleen or bone marrow and spread to other bodily tissues and organs.
While not usually curable, FL is often manageable with treatment, which varies among affected people.
The term follicular lymphoma comes from the observation that the cancer cells are grouped in clusters (or follicles) within the lymph nodes.
Non-Hodgkin lymphoma including follicular lymphoma can be characterized as “low-grade” (or indolent), meaning the cancer tends to grow slowly and results in few associated symptoms or “high-grade” (aggressive), meaning the cancer typically grows rapidly.
The signs and symptoms of follicular lymphoma (FL) can vary. Most people experience cycles of disease progression and remission. For some, symptoms may be absent for years.
Common findings include:
“B symptoms” may occur, especially in aggressive or transformed FL:
Other symptoms may include:
Transformed follicular lymphoma
About 40% of the people with follicular lymphoma have cancer that can go under a transformation from a slow-growing (indolent) form into a more aggressive form called diffuse large B-cell lymphoma (DLBCL). This is often associated with worsening symptoms and rapid progression. Transformation requires a biopsy to confirm and usually leads to a change in treatment strategy.
Primary gastrointestinal follicular lymphoma
This variant of FL typically affects the first part of the small intestine (duodenum) and is usually asymptomatic. It is considered to have a good outlook. Some symptoms may include heartburn, abdominal discomfort, or gastrointestinal bleeding.
Pediatric follicular lymphoma
This rare subtype presents differently from adult FL and is considered a distinct type of lymphoma by many researchers. Different genetic factors have been shown to play a role in the pediatric form than are seen in follicular lymphoma in adults. Pediatric follicular lymphoma is characterized by the cancer remaining in the area where it first develops (localized presentation) and is generally benign. Enlargement of the lymph nodes is the most common symptom. The lymph nodes found in the neck (cervical area) and the tonsils are most often affected. The gastrointestinal tract, salivary duct, kidney and skin can also be affected.
The exact, underlying cause of follicular lymphoma is not fully understood. The reason why cancer develops is a complex question and researchers speculate that multiple factors are involved in the development of follicular lymphoma. These factors include genetic, environmental and immunologic factors, which all may play a role in the development of this cancer. About 85% of affected adults have a genetic abnormality that is not inherited and found only within the cancer cells called a translocation.
A translocation is a genetic abnormality in which regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. In follicular lymphoma, regions of chromosome 14 and 18 break off and trade places. Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.
The genetic translocation involving chromosomes 14 and 18 leads to the overexpression of a gene called BCL-2. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a change (variant) of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Overexpression means that the protein product of the BCL-2 gene is overproduced. The protein produced by this gene is thought to play a role in inhibiting apoptosis, the normal process by which cells grow and then die (programmed cell death). Because the BCL-2 gene is overexpressed, it prevents cells from going through apoptosis, causing cells to not die off when they are supposed to. This contributes to the development of cancer.
Although most adults with follicular lymphoma have this specific genetic translocation, there are people in the general population who also have this specific translocation but never develop follicular lymphoma. This suggests that additional factors, including other genetic alterations or changes, are required for the development of follicular lymphoma.
For example, variants in a gene called EZH2 have been reported in more than 25% of people with follicular lymphoma and may play a role in the development of cancer. More research is necessary to fully understand the complex genetic interactions that contribute to the development of follicular lymphoma.
In a small number of people, another gene called BCL-6 is affected. BCL-6 normally helps B-cells grow and develop properly, so when it doesn’t work right, it may lead to cancer. BCL6 translocations are also observed and can be associated with unique characteristics and potential progression to more aggressive lymphoma. Other genes and proteins also get out of balance, and some become too active and push the cells to grow or avoid normal controls (like p21, p16, and IL-4 receptors). Others become less active and reduce the cells’ ability to stay in place or respond to inflammation (like MRP14 and MRP8). Altogether, these changes let the B-cells grow uncontrollably resulting in cancer.
Environmental factors that have been suggested to possibly play a role in the development of follicular lymphoma include exposure to toxic substances like benzene, occupational exposure to pesticides, certain infections and smoking including passive smoking.
The underlying genetic factors differ between the adult and pediatric forms. Children with follicular lymphoma do not have a translocation involving chromosomes 14 and 18. The genetic factors involved in pediatric follicular lymphoma are not fully known. Variants in the MAP2K1 gene and variants or deletions in the TNFRSF14 gene have been commonly reported in the medical literature. More research is necessary to determine the complex genetic factors that are involved in pediatric follicular lymphoma
The rate of new cases of follicular lymphoma is 2.4 per 100,000 males and females per year. In the United States and Western Europe, follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma accounting for about 30%-35% of people with non-Hodgkin lymphoma and almost 75% of people with indolent forms of lymphoma. Each year, 15-20,000 people in the U.S. are diagnosed with follicular lymphoma. Pediatric follicular lymphoma is an extremely rare subtype that makes up only 1-2% of all malignant lymphomas in children. Non-Hodgkin lymphoma, as a group, accounts for about 4.3% of people with cancer in the United States. Follicular lymphoma affects both males and females but is slightly more common in females. This form of cancer is found all over the world and can affect people of all races. It is less common in individuals of Asian or African heritage than it is in other ethnicities. The mean age at diagnosis is 65.
A diagnosis of follicular lymphoma is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Such testing is necessary to confirm the specific type (and subtype) of non-Hodgkin lymphoma, determine the nature and extent of the cancer and to determine the most appropriate treatments.
During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck, tonsil and adenoidal region, under the arms, and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.
For people with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. These may include blood tests, biopsies, specialized imaging tests, bone marrow examination and/or other tests.
Clinical Testing and Workup
A diagnosis of follicular lymphoma requires the review of an adequate biopsy sample by an expert medical pathologist. Pathologists are physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis.
Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node–or, in some instances, removal of an entire, enlarged lymph node–that is suspected of being cancerous. Depending upon the specific type of biopsy performed, the procedure may be conducted under local or whole body (general) anesthesia. In addition, in some instances, such as when involvement appears to be restricted to the abdominal or pelvic region, laparoscopy or laparotomy may be necessary to obtain biopsy samples. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease and samples of tissue are removed for microscopic examination. Sometimes, doctors may recommend a bone marrow biopsy to determine whether lymphoma is in the bone marrow.
Blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells and platelets, liver enzyme studies, tests to measure levels of the enzyme lactate dehydrogenase (LDH), and/or other studies. High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies, but only 25% of affected individuals have elevated LDH.
Advanced imaging (X-ray) techniques can also be recommended and can include a combined positron emission tomography (PET) and computerized tomography (CT) scan known as a PET/CT scan. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer that is combined with sugar (glucose). This radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Cancer requires a lot of energy to keep growing and spreading and will soak up the radioactive sugar. These areas will show up on the PET scan brighter than the surrounding areas. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan can show enlarged organs or lymph nodes. A PET/CT allows physicians to assess the metabolic and structural (anatomic) in one session and can return a more accurate image or picture of cancer than either test can by itself.
A test known as fluorescent in situ hybridization (FISH) may also be used to help diagnose follicular lymphoma. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing researchers to better view a specific region of that chromosome. The test allows physicians to detect alterations in the genetic material of chromosomes including translocations such as a translocation of chromosomes 14 and 18. This can help distinguish follicular lymphoma from other forms of indolent lymphoma.
A test called polymerase chain reaction or PCR may also be used to help diagnose follicular lymphoma. PCR is a test technique for identifying and making copies of specific segments of deoxyribonucleic acid (DNA). The test can identify tiny amounts of DNA including genetic material to detect alterations such as a translocation of chromosomes 14 and 18. This test tends to be less reliable in diagnosing follicular lymphoma than FISH.
Staging
When someone is diagnosed with a non-Hodgkin lymphoma (NHL) such as follicular lymphoma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging NHL (e.g., blood tests, CT scanning, bone marrow biopsy, PET scan). In addition, in some people, additional biopsies may be obtained to assist in lymphoma staging.
The specific stage of NHL may be based upon the number of lymph node regions involved, whether such lymph nodes are located above, below, or on both sides of the diaphragm and/or whether the malignancy has infiltrated other lymphatic tissues such as the spleen or bone marrow or spread to involve other organs outside the lymphatic system such as the liver. (The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)
The Ann Arbor system is used to classify disease extent:
Each stage is further labeled A (no B symptoms) or B (presence of B symptoms).
Category E refers to involvement of nearby organs and S denotes spleen involvement.
Various additional elements may be considered as physicians determine the stage of NHL, potential disease course and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, disease outside the lymph nodes and other factors.
Treatment
The diagnosis and therapeutic management of follicular lymphoma may require the coordinated efforts of a team of medical professionals such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists), oncology nurses, surgeons, dietitians and/or other healthcare professionals. Psychosocial support for the entire family is essential as well. Genetic counseling may be recommended for affected individuals and their families.
The course of follicular lymphoma is highly variable. The average survival rate is greater than 20 years. Some individuals do not develop symptoms or only require one therapeutic option, while other people develop severe, recurrent and life-threatening complications and may require repeated and multiple therapies. Consequently, specific therapeutic procedures and interventions will vary, depending upon numerous factors, such as disease stage, tumor size, tumor grade (which is related to how abnormal the tumor cells look under a microscope), the presence or absence of certain symptoms, an individual’s age and general health and/or other elements.
Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case, a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preference and other appropriate factors. Therapies used to treat individuals with follicular lymphoma include watch and wait, radiation therapy, immunotherapy, single-agent chemotherapy and multiagent chemotherapy.
For many people with early-stage or low-volume disease that is not causing symptoms, immediate treatment may not be necessary. This approach is known as “watch and wait” or active surveillance.
Recent studies show that many people under active surveillance do not need therapy for years, and some may never need systemic treatment.
When symptoms develop or the disease shows signs of progression such as bulky tumors, low blood counts, or organ involvement, systemic therapy is usually recommended.
Immunochemotherapy combines chemotherapy drugs with monoclonal antibodies targeting cancerous B-cells.
These combinations are known as R-CHOP, O-CHOP, R-bendamustine and O-bendamustine depending on which antibody (rituximab or obinutuzumab) is used.
It has been shown that obinutuzumab plus chemotherapy improved progression-free survival (PFS, the time before the disease worsens) compared to rituximab-chemotherapy, though overall survival (OS) was similar. Obinutuzumab may have more side effects in older or frail patients, especially infections when combined with bendamustine.
R2 regimen (rituximab and lenalidomide) is a chemotherapy-free approach that uses:
The R2 have been shown to be as effective as rituximab-chemotherapy in previously untreated FL.
Maintenance therapy
After initial successful treatment, some people receive ongoing therapy to maintain remission, known as maintenance therapy. Commonly used agents are rituximab or obinutuzumab, given every 2–3 months for up to 2 years. The goal is to delay disease recurrence.
Maintenance therapy does not improve overall survival. It can suppress the immune system, increasing the risk of infections and reduced vaccine responses.
When the disease comes back (relapses) or does not respond to initial therapy (refractory), new treatment options are considered.
CAR-T cell therapy: CAR-T (chimeric antigen receptor T-cell) therapy re-engineers a patient’s own immune cells to target and destroy lymphoma cells.
Bispecific antibodies (BsAbs): BsAbs are a newer form of immunotherapy that bind to CD3 on T-cells and CD20 on lymphoma cells, bringing them together so the immune system can kill the cancer.
It is approved for people after at least two prior therapies, and it show 60–80% response rates. Ongoing trials are evaluating their use in earlier lines of therapy.
Targeted therapies may include:
EZH2 inhibitors: Tazemetostat is approved for people who have FL with variants in the EZH2 gene. EZH2 is a gene involved in gene expression regulation.
PI3K (phosphoinositide 3-kinase) inhibitors: Idelalisib and copanlisib target PI3K, a protein involved in cancer cell growth and survival. It is used in relapsed settings. Risks include diarrhea, liver inflammation and lung issues. Both idelalisib (Zydelig), approved in 2014 by the FDA, and copanlisib (Aliqopa) were approved for the treatment of adults with relapsed follicular lymphoma who have received at least two other systemic treatments. PI3K protein plays a role in the activation, growth and spread, and survival of B-cells.
BTK Inhibitors: Zanubrutinib, when combined with obinutuzumab, has shown superior results compared to obinutuzumab alone in the ROSEWOOD trial.
Radioimmunotherapy may include:
Stem cell transplant
In certain high-risk or relapsed cases, especially those with progression of disease within 24 months, a stem cell transplant may be considered.
People with stage 1 FL are candidates for radiation therapy, which achieves prolonged progression-free survival in many people. The treatment of patients with more advanced disease (stage 2 to 4) depends on the presence of symptoms, the burden and aggressiveness of disease and patient characteristics. Stem cell transplants are generally reserved for younger people with FL or those with aggressive disease courses.
For information about non-Hodgkin lymphoma treatment visit the NCI website.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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INTERNET
SEER Cancer Stat Facts: Follicular Lymphoma. National Cancer Institute. https://seer.cancer.gov/statfacts/html/follicular.html Accessed June 30, 2025.
PDQ® Adult Treatment Editorial Board. PDQ Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated August 22, 2024. Available at: https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq. Accessed June 30, 2025.
Kaseb H, Ali MA, Gasalberti DP, et al. Follicular Lymphoma. [Updated 2024 Mar 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538206/ Accessed June 30, 2025.
Freedman AS and Aster JC. Clinical manifestations, pathologic features, diagnosis and prognosis of follicular lymphoma. UpToDate, Inc. Apr 02, 2025. Available at: https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-diagnosis-and-prognosis-of-follicular-lymphoma Accessed June 30, 2025.
Freedman AS and Friedberg JW. Treatment of relapsed or refractory follicular lymphoma. UpToDate, Inc. Mar 25, 2025. Available at: https://www.uptodate.com/contents/treatment-of-relapsed-or-refractory-follicular-lymphoma?search=follicular Accessed June 30, 2025.
Freedman AS and Salles G. Initial treatment of stage 2 to 4 follicular lymphoma. UpToDate, Inc. Jun 12, 2025. Available at: https://www.uptodate.com/contents/initial-treatment-of-advanced-stage-iii-iv-follicular-lymphoma Accessed June 30, 2025.
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