Patient education: Follicular lymphoma in adults (Beyond the Basics)

INTRODUCTION — Lymphoma is a cancer of lymphocytes, a type of white blood cell. Lymphocytes circulate in the body through a network referred to as the lymphatic system, which includes the bone marrow, spleen, thymus, and lymph nodes. The organs and vessels of the lymphatic system work together to produce and store cells that fight infection (figure 1).

There are two main types of lymphoma:

●Hodgkin lymphoma (HL)

●Non-Hodgkin lymphoma (NHL)

NHL is the most common type of lymphoma. Follicular lymphoma is one form of NHL. In contrast to some of the other forms of NHL, follicular lymphoma usually grows slowly and thus may not require treatment for many years. Up to 30 percent of people may never need treatment.

The following discussion will review the risk factors, classification, symptoms, and treatment of follicular lymphoma.

CANCER CARE DURING THE COVID-19 PANDEMIC — COVID-19 stands for "coronavirus disease 2019." It is an infection caused by a virus called SARS-CoV-2. The virus first appeared in late 2019 and has since spread throughout the world. Getting vaccinated lowers the risk of severe illness; experts recommend COVID-19 vaccination for anyone with cancer or a history of cancer.

In some cases, if you live in an area with a lot of cases of COVID-19, your doctor might suggest rescheduling or delaying medical appointments. But this decision must be balanced against the importance of getting care to screen for, monitor, and treat cancer. Your doctor can talk to you about whether to make any changes to your appointment schedule. They can also advise you on what to do if you test positive or were exposed to the virus.

RISK FACTORS — Age, gender, and ethnicity affect a person's likelihood of developing follicular lymphoma. Follicular lymphoma is slightly more likely to be diagnosed in women than men, and is less common among people of Asian or African descent than among people of other ethnicities. Nearly everyone diagnosed with follicular lymphoma is an adult, with the average age at diagnosis being 65 years.

Follicular lymphoma is not an inherited disease. However, 5 to 10 percent of the siblings and children of people with follicular lymphoma may also develop a lymphoma.

SYMPTOMS — The initial symptoms of follicular lymphoma include painless swelling in one or more lymph nodes, particularly in the neck, armpit, or groin areas. Often, people with follicular lymphoma complain that their lymph nodes have been swollen for a long time; the size may increase and decrease several times before they seek medical attention.

Some people with follicular lymphoma develop large tumors in the abdomen. These may cause no symptoms, but can block normal flow in the digestive or urinary system or in a blood vessel.

DIAGNOSIS AND STAGING — The diagnosis of follicular lymphoma is confirmed by removing all or part of an enlarged lymph node to examine its cells under a microscope, a procedure known as a biopsy.

Once the diagnosis is confirmed, additional tests are performed to obtain more information about the extent to which the disease has spread in the body. This process is called staging. The results of these tests will help determine the most effective course of treatment.

History and physical exam — A careful interview and physical examination will help determine the extent of the disease. The physical exam may reveal swollen lymph nodes in various locations (figure 1).

Staging tests — A number of tests are available to help determine which areas of the body have been affected by follicular lymphoma. Tests that may be done include:

●Blood tests

●Computed tomography (CT) scan

●Positron emission tomography (PET) scan

Bone marrow biopsy is usually not necessary for staging. However, it may be included in the evaluation if a person is otherwise thought to have stage I disease and is considering treatment with radiation therapy.

Staging terms — The following are terms used in the staging criteria:

●Lymph node regions – An area of lymph nodes and the surrounding tissue. Examples include the cervical nodes in the neck (figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (figure 3).

●Lymph structures – Organs or structures that are part of the lymphatic system, such as the lymph nodes, spleen, and thymus gland.

●Diaphragm – A large muscle that separates the chest cavity from the abdominal cavity.

Stage grouping — Staging involves dividing people into groups (stages) based on how much of the lymphatic system is involved at the time of diagnosis. Staging helps determine a person's prognosis and treatment options (table 1).

The stages of lymphoma are defined as follows:

●Stage I – Only one lymph node region is involved, or only one lymph structure is involved.

●Stage II – Two or more lymph node regions or lymph node structures on the same side of the diaphragm are involved.

●Stage III – Lymph node regions or structures on both sides of the diaphragm are involved.

●Stage IV – There is widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the bone marrow.

When a stage is assigned, it also includes a letter, A or B, to denote whether fever, weight loss, or night sweats are present. "A" means these symptoms are not present; "B" means they are. For example, a person with stage IB disease has evidence of cancer in one lymph node region and has "B" symptoms (fever, weight loss, or night sweats). (See 'Symptoms' above.)

DISEASE PROGRESSION — The progression of follicular lymphoma varies from one person to another, depending on the speed of the tumor's growth and the involvement of other organs. Sometimes, people with follicular lymphoma have no symptoms for many years and do not need treatment. Some may never need treatment. In other people, treatment may be required for symptoms. Examples of symptoms that may lead to treatment include fever, night sweats, weight loss, pain, blockage of organs, and anemia or other changes in blood counts.

Some cases of follicular lymphoma either behave like or transform into a more aggressive form of lymphoma, such as diffuse large B cell lymphoma, which grows more rapidly and requires more intensive treatment. (See "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)".)

TREATMENT — Treatment for follicular lymphoma depends on the person's symptoms, the aggressiveness of the tumor, age, and general health. The majority of people with follicular lymphoma already have widespread disease by the time they are diagnosed. It is unclear whether these people can be cured of the lymphoma with standard treatment. As such, treatment usually focuses on relieving symptoms and delaying relapse.

Since follicular lymphoma is slow growing, it may take many years for the disease to progress, during which time treatment may not be needed. Early treatment does not always improve overall survival if a person has no symptoms and the disease is not affecting their organs. Thus, close observation (a "watch and wait" approach) is often recommended.

Features that may warrant treatment include one or more of the following:

●Progressively enlarging lymph nodes

●Fever, weight loss, or night sweats

●Low blood counts

People without these features are usually monitored with periodic physical examination and blood testing.

Stage I disease — Some people with stage I follicular lymphoma may be treated with radiation therapy alone. This approach can lead to long term remission in approximately half of people in this situation.

Radiation therapy — Radiation therapy uses high-energy beams to slow or stop the growth of cancer cells and is administered to the region of affected lymph nodes (called involved-site radiation). Radiation therapy must be given in small daily doses over a period of weeks to minimize the side effects; the number of weeks depends on the amount of radiation to be administered.

Stage II to IV disease — There are many treatment options for people with stage II to IV follicular lymphoma. The choice of treatment depends on the person's preference and the need for the treatment to act quickly (if organ function is threatened by the follicular lymphoma). People with stage II to IV disease are generally treated first with chemotherapy plus anti-CD20 antibodies, sometimes called chemoimmunotherapy. The most common antibodies used are rituximab (brand name: Rituxan) and obinutuzumab (brand name: Gazyva), which selectively target follicular lymphoma tumor cells. For older people who have symptoms but have no evidence of organ dysfunction, treatment with rituximab alone may be recommended. (See 'Anti-CD20 antibodies' below.)

People with follicular lymphoma that decreases in size after being treated with chemoimmunotherapy may choose to receive further antibody treatments as "maintenance therapy." Maintenance therapy postpones progression of the lymphoma, but does not improve survival.

Stem cell (bone marrow) transplantation is reserved for people with relapsed disease. Newly developed drugs for treating follicular lymphoma ("novel agents") are most commonly reserved for people with relapsed disease, although they may be used as initial therapy in selected cases. (See 'Novel agents' below.)

Anti-CD20 antibodies — These are medications that target a particular protein (CD20) that is found on the surface of tumor cells. The most frequently used anti-CD20 antibodies are rituximab (brand name: Rituxan) and obinutuzumab (brand name: Gazyva); however, there are other drugs in this category as well. An anti-CD20 antibody is often combined with chemotherapy treatments.

Because the anti-CD20 antibodies preferably target cancer cells, they have advantages over other cancer treatments such as chemotherapy, which targets all rapidly growing cells (see 'Chemotherapy' below). There are usually fewer side effects and long-term risks associated with anti-CD20 antibody therapies than with traditional chemotherapy.

Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide or multiply. Because most of an adult's normal cells are not actively dividing or multiplying, they are not affected by chemotherapy. However, the bone marrow (where the blood cells are produced), the hair follicles, and the lining of the gastrointestinal (GI) tract are all growing. The side effects of chemotherapy drugs are related to effects on these and other normal tissues.

A chemotherapy drug or combination of drugs is referred to as a regimen. Regimens used for the initial treatment of follicular lymphoma are usually given intravenously in cycles. A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover. For example, a typical chemotherapy regimen is a one-hour intravenous infusion of chemotherapy given two days in a row and repeated every four weeks. This four-week period is one cycle of therapy. If this regimen were repeated for a total of six cycles, it would take six months to complete.

Novel agents — Most people with follicular lymphoma will relapse multiple times and be treated with many available drugs at some point during their disease course. There are several newer medications available to treat follicular lymphoma that are not traditional chemotherapy drugs. These "novel agents" include small molecules designed to target signaling pathways that are abnormally expressed in the cancer cells.

Novel agents are most commonly reserved for people with relapsed disease, although some may be used as initial therapy in selected situations. Novel agents that may be used to treat follicular lymphoma include lenalidomide and tazemetostat.

Stem cell transplantation, CAR-T therapy, and bispecific antibodies — Stem cell transplantation (also called bone marrow transplantation or hematopoietic stem cell transplantation) is generally reserved for people whose lymphoma has recurred after treatment. More information about stem cell transplantation is available separately. (See "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)".)

In some cases, newer forms of immunotherapy, such as "CAR-T" therapy, may be effective for relapsed follicular lymphoma. CAR-T therapy involves genetically modifying specific cells from a person's immune system; this enables the cells to directly target the cancer cells.

Mosunetuzumab is a "bispecific" antibody that targets both CD20 (on the tumor cell) and CD3 (on normal T cells) to activate and use the T cells to help fight the cancer cells. Where available, it is an option for people whose lymphoma has recurred after at least two treatments.

Clinical trials — A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Clinical trials are especially important for persons with follicular lymphoma since there is no treatment currently available to cure this disease. Ask a health care provider for more information, or read about clinical trials at:

●https://www.cancer.gov/about-cancer/treatment/clinical-trials

●http://clinicaltrials.gov/

Videos addressing common questions about clinical trials are available from the American Society of Clinical Oncology (https://www.cancer.net/research-and-advocacy/clinical-trials/welcome-pre-act).

PROGNOSIS — As discussed above, people with stage I follicular lymphoma can achieve long-term remissions with radiation therapy (see 'Radiation therapy' above). For people with stage II, III, or IV disease (table 1), the average survival is greater than 20 years. Despite its slow-growing nature, it is unclear whether most cases of follicular lymphoma can be cured with currently available therapies.

Researchers have developed a way to estimate how long a person with lymphoma is likely to live based on what they call the "Follicular Lymphoma International Prognostic Index" (FLIPI). This index takes into account five factors that affect prognosis. The index can also help doctors identify who will benefit from specific chemotherapy treatments.

The five factors involved in the FLIPI are:

●Age older than 60 years

●Stage III or IV disease (table 1)

●Low red blood cell count

●More than four involved lymph node areas (figure 1)

●Lactate dehydrogenase level higher than normal (lactate dehydrogenase is a protein found in blood whose levels increase when tissues have been damaged)

On average, the more of these risk factors a person has, the worse his or her prognosis.

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Lymphoma (The Basics)
Patient education: Follicular lymphoma (The Basics)
Patient education: Neutropenia and fever in people being treated for cancer (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)
Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Classification of hematopoietic neoplasms
Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma
Clinical presentation and initial evaluation of non-Hodgkin lymphoma
Pretreatment evaluation and staging of non-Hodgkin lymphomas
Autologous hematopoietic cell transplantation in follicular lymphoma
Initial treatment of stage I follicular lymphoma
Histologic transformation of follicular lymphoma

The following organizations also provide reliable health information:

●American Cancer Society

     (www.cancer.org)

●National Cancer Institute

     (www.cancer.gov)

●The American Society of Clinical Oncology

     (www.cancer.net)

●National Library of Medicine

     (medlineplus.gov/healthtopics.html)

●The Leukemia & Lymphoma Society

     (www.lls.org)