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Follicular Lymphoma


Last updated: June 07, 2019
Years published: 2019


NORD gratefully acknowledges 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.

Disease Overview

Follicular lymphoma is a form of cancer. It is a type of non-Hodgkin lymphoma (NHL), which is a group of related cancers that affect the lymphatic system (lymphomas). The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It 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 help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. 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. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. 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. 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. The term follicular lymphoma comes from the observation that the cancer cells are group 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.

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  • pediatric follicular lymphoma
  • primary gastrointestinal follicular lymphoma
  • transformed follicular lymphoma
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Signs & Symptoms

The specific symptoms and physical findings of follicular lymphoma can vary from one person to another, depending upon the extent and region(s) of involvement and other factors. Follicular lymphoma is described as having a relapsing and remitting course; the cancer alternates between flaring up or worsening for a period of time often requiring treatment, and periods of time where the cancer is in remission or levels off. For many people, follicular lymphoma is a slow-growing cancer that develops over many years.

A common finding is the enlargement of affected lymph nodes (lymphadenopathy). Lymph nodes may become hard and can be felt (palpable) underneath the skin. Lymph nodes in the neck, the armpit (axilla), and groin are most commonly affected. Lymph nodes in the abdomen can also become enlarged, but cannot be felt. Lymph node enlargement is mostly painless. The enlargement of a lymph node may come and go for several years before a diagnosis of follicular lymphoma is made.

Follicular lymphoma can affect the bone marrow and the spleen, causing abnormal enlargement of the spleen (splenomegaly). When follicular lymphoma affects the bone marrow or the spleen, it can lead to low levels of the three main blood cell types: red blood cells, white blood cells, and platelets. This is called cytopenia. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding. A low levels of red blood cells is called anemia and can be characterized by tiredness, shortness of breath, weakness, lightheadedness, headaches, and pale skin color. A low levels of white blood cells (neutropenia) increases the risk of contracting bacterial and fungal infections. A low levels of platelets (thrombocytopenia) makes the individual more susceptible to excessive bruising following minimal injury and spontaneous bleeding from the gums and nose.

Less often, affected individuals develop symptoms that are vague and can be nonspecific, which means that the symptoms are common to many different disorders or conditions. When dealing with lymphoma, these symptoms may come and go and are sometimes referred to as ‘B symptoms.’ These symptoms can include a persistent, chronic fever; unintended weight loss, and excessive sweating, especially at night (night sweats).

Follicular lymphoma affecting organs other than those in the lymphatic system or the bone morrow is rare. Sometimes, large tumors may form in the abdomen.

Transformed Follicular Lymphoma
There is a risk in individuals with follicular lymphoma that the cancer can go under a transformation from a slow-growing (indolent) form into a more aggressive form called diffuse large B-cell lymphoma (DLBCL). As many as 30-40% of individuals may experience aggressive transformation of indolent follicular lymphoma. DLBCL can progress rapidly and spread to areas and organs outside of the lymphatic system (extranodal) and the bone marrow. ‘B’ symptoms are more common in transformed follicular lymphoma.

Primary Gastrointestinal Follicular Lymphoma
Primary gastrointestinal follicular lymphoma often does not cause any apparent symptoms (asymptomatic). This form is generally considered to be a distinct variant of follicular lymphoma that has a better prognosis. Cancer often arises in the first section of the small intestines (duodenum), which connects to the stomach. Affected individuals can develop abdominal discomfort and heartburn. Less often, affected individuals can develop nausea, vomiting, diarrhea, abdominal pain, and intestinal bleeding, which can cause black, tarry stools.

Pediatric Follicular Lymphoma
Pediatric follicular lymphoma is different from the adult form 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. Pediatric follicular lymphoma is characterized by the cancer remaining in the area where it first develops (localized presentation). Enlargement of the lymph nodes is the most common symptom. Overall, pediatric follicular lymphoma shows a generally benign behavior. 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. Some researchers use the term pediatric-type follicular lymphoma because adults with this form of follicular lymphoma have been identified.

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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, but 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 the 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 mutation 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 believed 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 that do not die off when they are supposed to. This contributes to the development of cancer.

Although the majority of adults with follicular lymphoma have this specific genetic translocation, there are people in the general population who also have this specific translocation, but who 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, alterations (mutations) in a gene called EZH2 have been reported in more than 25% of people with follicular lymphoma and may play a role in the cancer’s development. More research is necessary to fully understand the complex genetic interactions that contribute to the development of follicular lymphoma.

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 genetics 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. Mutations in the MAP2K1 gene and mutations 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.

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Affected populations

Follicular lymphoma affects both men and women, but is slightly more common in women. 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. 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 extremely rare variant 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.

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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, to 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 those 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 require 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 as 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 or 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 fluorescent in situ hybridization (FISH).

When an individual 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.)

Although various staging systems have been described, a system commonly used for adult NHL is the Ann Arbor staging system, which includes the following stages:

Stage I – indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extralymphatic organ or site).

Stage II – indicates locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extralymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).

Stage III – indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extralymphatic organ or site.

Stage IV – indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extralymphatic organs or sites with or without associated lymph node involvement. Follicular lymphoma in the bone marrow and liver is always stage IV.

Each stage of NHL may be further divided into categories A or B, based upon whether or not affected individuals have symptoms. More specifically:

A indicates that no generalized (systemic) symptoms are present upon diagnosis.

B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis).

In addition, category E may indicate that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ. Category S may indicate involvement of the spleen.

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, extranodal site involvement, and other factors.

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Standard Therapies

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 particular 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.

In select individuals with no symptoms of follicular lymphoma (asymptomatic), physicians may recommend waiting before starting treatment until the disease leads to certain symptoms or progresses. In such instances, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called “watch and wait” or “watchful waiting.” Most affected individuals eventually require systemic treatment.

If follicular lymphoma is detected early enough, some affected individuals may be treated with radiation therapy, in which radiation is used to destroy cancerous tissue. Radiation therapy often produces prolonged periods of remission in individuals in early stage (tage I) disease and is frequently used for individuals with early stage disease.

Most affected individuals are diagnosed with advanced disease. Advanced disease includes individuals with stage III or IV disease (see Staging above). Affected individuals receive treatment regimens that include a medication known as an anti-CD20 monoclonal antibody. A monoclonal antibody is a type of immune therapy; it uses the immune system to help fight off cancer. CD20 is a substance found on the surface of B-cells. Anti-CD20 monoclonal antibodies are medications that target CD20 and, therefore, target the B-cells in the body, including the cancerous B-cells that make up follicular lymphoma. Two types of anti-CD20 monoclonal antibodies are used to treat adults with follicular lymphoma and are known as rituximab (Rituxan®) and obinutuzumab (Gazyva®).

In 1997, the U.S. Food and Drug Administration (FDA) approved rituximab (Rituxan®) for the treatment of individuals with follicular lymphoma that did not respond to other treatments (refractory) or returned after treatment (relapsed). In 2006, rituximab was approved as a first-line therapy for affected individuals. Rituximab can be used alone (as a single agent) as a single-agent therapy. In individuals with bulkier disease or who require a more rapid response (often due to specific symptoms or manifestations), rituximab is used as part of a drug regimen (multiagent chemotherapy) that includes other more traditional chemotherapeutic drugs.

The two most popular chemotherapeutic regimens used for follicular lymphoma are bendamustine plus rituximab and CHOP-R. CHOP-R is a common chemotherapeutic regimen used to treat NHL and includes cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone given along with rituximab. Sometimes, other medications may be tried along with rituximab including chlorambucil (Leukeran®) or lenalidomide (Revlimid®).

In 2017, the FDA approved obinutuzumab (Gazyva®) along with chemotherapy for the treatment of previously untreated individuals with stage II bulky, stage III, or stage IV follicular lymphoma.

While some individuals with follicular lymphoma are cured, the majority of affected individuals will not be cured with initial or follow up therapy. Follicular lymphoma often recurs (relapses). Affected individuals require maintenance therapy. Maintenance therapy is designed to help maintain the effectiveness of a primary therapy in order to keep cancer in remission (i.e. prevent a relapse) and to help minimize side effects of therapy. Both rituximab and obinutuzumab can be used for maintenance therapy. Rituximab and obinutuzumab can also be used to treat follicular lymphoma when the cancer returns after treatment (relapse), or when the cancer does not respond to another type of treatment (refractory).

There are additional medications that have been approved for the treatment of relapsed or refractory lymphoma. In 2014, the FDA approved the drug, idelalisib (Zydelig®), for the treatment of adults with follicular lymphoma who have received at least two other therapies. The FDA has also approved the drug copanlisib (Aliqopa®) for the treatment of adults with relapsed follicular lymphoma who have received at least two other systemic treatments. Idelalisib and copanlisib are drugs that inhibit or block that activity of a protein called phosphoinositide 3-kinase. This protein plays a role in the activation, growth and spread, and survival of B-cells.

Radioimmunotherapy is also used to treat relapsed or refractory follicular lymphoma. Radioimmunotherapy uses radiation along with cancer-specific antibodies to attack cancer cells. Ibritumomab tiuxetan (Zevalin®) is a monoclonal antibody radioimmunotherapy that was approved by the FDA in 2002 for the treatment of relapsed or refractory, low-grade, follicular or transformed B-cell lymphoma. Ibritumomab tiuxetan has also been used as the sole initial therapy for some people.

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Clinical Trials and Studies

Researchers are studying chemotherapy with autologous or allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of individuals, particularly younger individuals, who have relapsed or refractory follicular lymphoma. Affected individuals undergo high-doses of chemotherapy (often Rituxan therapy) followed by an autologous stem cell transplant. Stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, platelets). In autologous stem cell transplantation, an affected individual’s stem cells are removed after prior treatment. These healthy stem cells are later re-infused into the bone marrow to restore the child’s immune system that was damaged by the intense chemotherapy. In allogenic stem cell transplantation, affected individuals, after treatment with chemotherapy, receive hematopoietic stem cells from a healthy donor. These are major medical procedures that carries significant risk. Generally, HSCT is reserved for individuals, usually younger individuals, with refractory and sometimes relapsed follicular lymphoma. Research indicates that these treatments can lead to long-lasting remission and potentially even a cure in some people. Affected individuals transplanted in their first or second relapse have a better prognosis than individuals treated later in the course of the disease. More research is necessary to determine the long-term safety and effectiveness of this therapy.

Research is underway to develop additional anti-CD20 monoclonal antibodies for treating follicular lymphoma. These medications would be for individuals who did not respond to therapy with rituximab or obinutuzumab, or could not tolerate those medications, or that may prove more effective.

Additional medications that are being studied for relapsed follicular lymphoma include ibrutinib (Imbruvica®), lenalidomide (Revlimid®), BCL-2 inhibitors, and inhibitors of programmed cell death protein 1 (PD1) or PD1 ligand 1 (PDL1). More research is necessary to determine the long-term safety and effectiveness of these therapies.

Drugs are also being studied that can stimulate the immune system to act in order to enhance the effectiveness of rituximab. These drugs are sometimes called immunostimulatory drugs.

Information on current clinical trials is posted on the Internet at https://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:

Toll-free: (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:

For information about clinical trials sponsored by private sources, contact:

For information about clinical trials conducted in Europe, contact:

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