Saturday, October 13, 2007

Follicular lymphoma

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 (show figure 1).

There are two main types of lymphoma: Hodgkin's lymphoma (also called Hodgkin's disease) Non-Hodgkin's 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. Because of its slow growth characteristics, follicular lymphoma is referred to as being an indolent (rather than aggressive or highly aggressive) lymphoma.

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

RISK FACTORS — Age, gender, and race/ethnicity affect a person's likelihood of developing follicular lymphoma, although most persons have no known risk factors. Follicular lymphoma is slightly more likely to be diagnosed in women than men, and is less commonly found in persons of Asian and black ethnicity. Nearly all persons diagnosed with follicular lymphoma are adults, with the average age at diagnosis being 60 years.

SYMPTOMS — The initial symptoms of follicular lymphoma include painless swelling in one or more of the body's lymph nodes, particularly in the neck, armpit, or groin areas; this is called adenopathy. Often, patients with follicular lymphoma complain that their lymph nodes have been swollen for a long time; the size may increase and decrease several times before the patient seeks medical attention.

Some persons with follicular lymphoma develop large tumors in the abdomen. These may cause no symptoms, but can cause obstruction of the gastrointestinal, vascular, or urinary tract.

In the early stages, only one or two lymph nodes may be involved with the lymphoma. However, staging studies typically show that follicular lymphoma affects lymph node sites throughout the body:

DIAGNOSIS — 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. Additional diagnostic tests are used to obtain more information about the type of lymphoma and 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 history and physical examination will help determine the extent of the disease. The physical exam may reveal swollen lymph nodes in various locations (show figure 1).

Diagnostic tests — A number of diagnostic tests are available to help determine which areas of the body have been affected. Tests that may be done include: CT scan of the chest, abdomen, and pelvis Blood tests Bone marrow biopsy: Removal of tissue from the bone marrow, the spongy area in the middle of large bones, for analysis. PET scan: This test uses a small amount of a radioactive substance, which is injected into a vein; the radioactive substance is absorbed by the cancer cells and can be viewed with a special camera.

STAGING — 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 (show table 1).

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 (show figure 2), the axillary nodes in the armpit, the inguinal nodes in the groin, or the mediastinal nodes in the chest (show 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 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 liver, lung, or bone marrow.

Subclassifications — Additional criteria help clinicians further identify subgroups within each stage, as follows: A or B — The letter "A," as in stage IIA, means that symptoms of unexplained fever, night sweats, or weight loss (at least 10 percent of the body weight) were NOT present during the six months prior to diagnosis. The letter "B," as in stage IIIB, means that these symptoms were present. These symptoms are therefore referred to as "B symptoms". About one in five patients with follicular lymphoma experiences systemic "B" symptoms E — The presence of local spread of the disease from one nodal area or structure to surrounding tissue in the same area of the body is indicated by the letter "e," as in stage IIe.

For example, a patient with follicular lymphoma involving lymph nodes in the neck, mediastinum, and groin (ie, involvement above and below the diaphragm) who also has symptoms of fever, night sweats, and weight loss (ie, systemic symptoms), would be in stage IIIB.

CLASSIFICATION — The World Health Organization (WHO) classifies follicular lymphoma into three different grades, according to the number of large cells they contain. This is determined by a pathologist, who looks at tumor sections under a microscope. A high-power field refers to what the pathologist sees in one area of the tissue using high-power magnification. Grade I: Fewer than five large cells are seen per high power field. Grade I is the most common type of follicular lymphoma. Generally, physicians consider grades I and II to be indolent or slow growing. Grade II: Between 6 and 15 large cells are seen per high power field. Grade III: More than 15 large cells are seen per high power field. This is also referred to as follicular large cell lymphoma. Unlike other grades of follicular lymphoma, this variant is less likely to invade the bone marrow and more likely to occur as large masses in the lymph tissues. Although this is similar to the lower grades of lymphoma, the symptoms and growth pattern of follicular large cell lymphoma is similar to that seen in patients with diffuse large B-cell lymphoma. (See "Patient information: Diffuse large B-cell lymphoma").

DISEASE PROGRESSION — The disease 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 patients with the disease have no symptoms for many years and do not need treatment. In other patients, treatment may be required for symptoms such as fever, night sweats, weight loss, pain, obstruction of organs, or the development of anemia and other changes in blood counts.

Treatment for follicular lymphoma depends on the patient's symptoms, tumor grade, age and general health. Early treatment does not always improve overall survival if a patient has no symptoms and the disease is not affecting their organs. Thus, close observation (a "watch and wait" approach) is often recommended.

Because of follicular lymphoma's ability to change into a more aggressive, widespread form of lymphoma (an aggressive B-cell lymphoma that occurs in 10 to 70 percent of patients), continued follow-up is required. (See "Patient information: Diffuse large B-cell lymphoma").

TREATMENT — The majority of patients with follicular lymphoma have widespread, advanced-stage disease when first diagnosed. However, because follicular lymphoma is slow-growing, it may take many years for the disease to progress, during which time patients may not need any form of treatment. Furthermore, the slow-growth characteristics make the tumors relatively less responsive to standard forms of cancer treatment (compared to 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

Patients without these features are usually monitored with frequent physical examination and blood testing. For older patients who have symptoms but have no evidence of organ obstruction, monoclonal antibody therapy with rituximab (Rituxan®) may be recommended (see "Monoclonal antibody treatment" below).

Early stage disease — Patients with early stage disease (stage I or II) who develop symptoms may be treated with radiation therapy alone.

Radiation therapy — Radiation therapy uses high-energy beams (gamma rays) 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 persons with stage II, III and IV 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 disease is treated with either a single chemotherapy drug or combination of chemotherapy drugs.

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 treatment 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.

Monoclonal antibody treatment — 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 to traditional chemotherapy.

Rituximab (Rituxan®) is a monoclonal antibody treatment that may be used for patients with follicular lymphoma who have relapsed or not responded to other treatments. Rituximab is frequently combined with chemotherapy treatments, and is being tested as a long-term maintenance treatment after chemotherapy. It has also been tested as an initial treatment for follicular lymphoma; follow-up trials are needed to determine if this treatment can prolong overall survival.

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 exposure of healthy tissues to radiation. The radioimmunotherapy treatments used for follicular lymphoma includes 90 Y-ibritumomab tiuxetan (Zevalin®) or 131I-tositumomab (Bexxar®), both of which are administered through a vein. The patient is usually given treatment in a hospital-based setting, but may go home after treatment is completed.

RIT is currently reserved for patients who have relapsed or failed to respond to other treatments. 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 cell (bone marrow) transplantation is generally reserved for patients whose lymphoma has recurred after treatment. (See "Patient information: Overview of bone marrow transplantation").

Summary — For patients with advanced stage follicular lymphoma that has never been treated, the following table summarizes treatment recommendations (show table 2). For patients who have received treatment and relapsed, the following table summarizes treatment recommendations (show table 3).

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

National Library of Medicine


PROGNOSIS — For patients with advanced forms of follicular lymphoma (ie, stages III and IV disease, show table 1), the average survival is approximately 10 years. Despite its slow-growing nature, most cases of follicular lymphoma are not curable with currently available therapies.

The Follicular Lymphoma International Prognostic Index (FLIPI) has identified five factors that are useful for predicting survival (prognosis). In addition, physicians can use these data to predict which patients benefit from specific chemotherapy treatments. Age >60 years Advanced clinical stages (ie, stages III or IV, show table 1) Low hemoglobin level More than 4 involved lymph node areas (show figure 1) Serum lactate dehydrogenase level greater than the upper limit of normal

Persons with zero to one of these factors are considered to have a low risk of dying; on average, 91 percent of this group is alive at 5 years after diagnosis, and 71 percent are alive 10 years after diagnosis.

Persons with 2 of these factors are considered to have an intermediate risk of dying; on average, 78 percent of this group is alive at 5 years after diagnosis, and 51 percent are alive 10 years after diagnosis.

Persons with 3 or more of these factors are considered to have a higher risk of dying; on average, 52 percent of this group is alive at 5 years after diagnosis, and 36 percent are alive 10 years after diagnosis.

It is important to remember that these numbers represent averages, and do not necessarily predict which persons with follicular lymphoma will live or die.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site ( Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. American Cancer Society

National Cancer Institute

People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
National Library of Medicine


The Leukemia & Lymphoma Society



Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. The Non-Hodgkin's Classification Project. Blood 1997; 89:3909.
2. Glass, A, Karnell, L, Menck, H. The National Cancer Data Base report on non-Hodgkin's lymphoma. Cancer 1997; 80:2311.
3. American Cancer Society. What is non-Hodgkin's lymphoma? (Accessed 3/7/05).

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