FOLLICULAR LYMPHOMA OVERVIEW

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)

Non-Hodgkin lymphoma (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.

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

FOLLICULAR LYMPHOMA 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 Asians and Blacks than among people of other ethnicities. Nearly everyone diagnosed with follicular lymphoma is an adult, with the average age at diagnosis being 60 years.

Follicular lymphoma is not an inherited disease. Siblings and children of patients with follicular lymphoma do not have a substantially increased risk of developing follicular lymphoma.

FOLLICULAR 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.

FOLLICULAR LYMPHOMA 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
• Bone marrow biopsy (removal of a small sample of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis)
• CT scan
• PET scan

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 patients into groups (stages) based upon how much of the lymphatic system is involved at the time of diagnosis. Staging helps determine a person's prognosis and whether treatment is required (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 1B disease has evidence of cancer in one lymph node region and has "B" symptoms (fever, weight loss, or night sweats). (See 'Follicular lymphoma symptoms' above.)

FOLLICULAR LYMPHOMA DISEASE PROGRESSION

The progression of follicular lymphoma varies from one person to another, depending upon 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. 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 information: Diffuse large B cell lymphoma in adults (Beyond the Basics)".)

FOLLICULAR LYMPHOMA TREATMENT

Treatment for follicular lymphoma depends on the person's symptoms, tumor grade, age, and general health. The majority of people with follicular lymphoma have widespread disease when first diagnosed. However, because 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.

Furthermore, the slow-growth characteristics make the tumors relatively less responsive to standard forms of cancer treatment (compared with the more aggressive lymphomas). As a result, a cure is not usually possible; the main reason to treat is to improve symptoms.

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.

Early-stage disease — Some patients with early-stage follicular lymphoma (stage I or II) who develop symptoms may be treated with radiation therapy alone.

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 field radiation) or to the affected and surrounding lymph nodes (called extended-field 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 upon the amount of radiation to be administered.

Advanced-stage disease — Advanced-stage disease includes stage III and IV follicular lymphoma. Some patients with stage II disease will be treated as though they have advanced-stage disease.

There are many treatment options for patients with advanced-stage disease. The choice of treatment depends upon the patient's preference and the need for the treatment to act quickly (if organ function is threatened by the follicular lymphoma). Most advanced-stage follicular lymphoma is treated with rituximab (Rituxan®) plus chemotherapy. For older people who have symptoms but have no evidence of organ blockage, monoclonal antibody therapy with rituximab (Rituxan®) may be recommended (see 'Monoclonal antibody treatment' below).

Patients with follicular lymphoma that decreases in size after being treated with rituximab may choose to receive further treatments with rituximab as “maintenance therapy.” Maintenance therapy postpones progression of the lymphoma. It is not yet clear whether maintenance therapy improves survival.

Monoclonal antibody treatment — Rituximab (Rituxan®) is a monoclonal antibody used to treat follicular lymphoma. Rituximab is frequently combined with chemotherapy treatments.

A monoclonal antibody is a purified protein that targets a specific group of cells (usually cancer cells). This has advantages over other cancer treatments such as chemotherapy, which targets all rapidly growing cells. There are usually fewer side effects and long-term risks of monoclonal antibody therapies as compared 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 treatment of follicular lymphoma may include a single agent taken by mouth on a daily basis, while other regimens are 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 IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three- or four-week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.

Radioimmunotherapy — Radioimmunotherapy (RIT) uses radioactive isotopes that are linked to monoclonal antibodies. As a result, radiation therapy can be delivered directly to proteins on cancer cells, which reduces the amount of radiation delivered to healthy tissues. The radioimmunotherapy treatments used for follicular lymphoma include 90 Y-ibritumomab tiuxetan (Zevalin®) or 131I-tositumomab (Bexxar®), both of which are given through a vein. The person is usually given treatment in a hospital-based setting but may go home after treatment is completed.

Administering RIT requires specialized equipment and additional training of physicians, nurses, and other involved personnel. The cost of RIT is quite high, and there are potentially serious short- and long-term side effects of the treatment.

Bone marrow transplantation — Hematopoietic stem cell (bone marrow) transplantation is generally reserved for people whose lymphoma has recurred after treatment. (See "Patient information: Bone marrow transplantation (stem cell transplantation) (Beyond the Basics)".)

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 healthcare provider for more information, or read about clinical trials at:

• National Cancer Institute

     (www.cancer.gov/clinicaltrials/)

• National Library of Medicine

     (http://clinicaltrials.gov/)

FOLLICULAR LYMPHOMA PROGNOSIS

For patients with advanced forms of follicular lymphoma (ie, stages III and IV disease) (table 1), the average survival is more than 10 years. Despite its slow-growing nature, most cases of follicular lymphoma are not curable 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 which patients 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 healthcare 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 web site (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 information: Lymphoma (The Basics)
Patient information: Follicular lymphoma (The Basics)
Patient information: 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 information: Diffuse large B cell lymphoma in adults (Beyond the Basics)
Patient information: Bone marrow transplantation (stem cell 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 the hematopoietic neoplasms
Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma
Clinical presentation and diagnosis of non-Hodgkin lymphoma
Initial evaluation and staging of non-Hodgkin lymphoma
Hematopoietic cell transplantation in follicular lymphoma
Initial treatment of limited stage (I/II) 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/portal/site/patient)

• National Library of Medicine

     (www.nlm.nih.gov/medlineplus/healthtopics.html)

• The Leukemia & Lymphoma Society

     (www.leukemia-lymphoma.org)

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