Follicular lymphoma (FL) is a cancer originating in the lymphatic system from B-lymphocytes, a type of white blood cell. It is the second most common form of non-Hodgkin lymphoma (NHL) in the United States and Europe. FL is characterized by slow growth, categorized as an indolent lymphoma. The cancerous B-cells accumulate in the lymph nodes, forming the “follicle-like” patterns that give the disease its name. This slow progression allows for a unique approach to management compared to more aggressive cancers.
Defining Follicular Lymphoma
Follicular lymphoma arises from B-lymphocytes within the germinal centers of lymph node follicles. The cancer develops when these B-cells undergo uncontrolled proliferation, accumulating primarily in the lymph nodes, spleen, and bone marrow. Because FL is indolent, it often behaves like a chronic condition that can wax and wane over many years.
The biological underpinning of most FL cases involves the translocation t(14;18). This chromosomal rearrangement results in the overexpression of the BCL2 gene, an anti-apoptosis protein. BCL2 regulates programmed cell death, but its overabundance prevents the cancerous B-cells from dying, giving them a survival advantage. This genetic abnormality is detected in 85% to 90% of conventional FL cases and is a hallmark of the disease.
Recognizing the Signs and Symptoms
The most common sign of follicular lymphoma is the painless swelling of lymph nodes, a condition known as lymphadenopathy. These enlarged nodes are often noticed in superficial areas like the neck, armpits, or groin. Because the disease is slow-growing, many patients are completely asymptomatic when the lymphoma is discovered during a routine physical examination or imaging for an unrelated condition.
When symptoms occur, they can be systemic, affecting the whole body. These are referred to as “B-symptoms” and include unexplained fevers, drenching night sweats, and unexplained weight loss of more than 10% of body weight over six months. Other non-specific symptoms may include fatigue, shortness of breath, or discomfort caused by enlarged lymph nodes pressing on nearby organs. The presence of B-symptoms signals a higher disease burden and is an important factor in deciding when to initiate treatment.
Diagnosis and Disease Staging
A definitive diagnosis of follicular lymphoma requires a tissue biopsy, typically of an enlarged lymph node. An excisional biopsy, where the entire node is removed, is preferred over a needle biopsy because it allows a pathologist to examine the architecture of the tissue and accurately determine the lymphoma subtype and grade. The histologic grading is based on the number of large, rapidly dividing cells, called centroblasts, observed under a microscope.
Once FL is confirmed, additional tests are performed to determine the extent of the disease, a process called staging. Imaging studies, such as computed tomography (CT) scans and positron emission tomography (PET) scans, are used to locate all areas of disease involvement throughout the body. A bone marrow biopsy is also commonly performed to check for the presence of lymphoma cells in the bone marrow.
The Ann Arbor staging system classifies the disease extent, ranging from Stage I (involvement of a single lymph node area) to Stage IV (widespread disease, often involving the bone marrow or an organ outside the lymphatic system). Because FL is often widespread at diagnosis, many patients present with Stage III or IV disease. Beyond staging, the Follicular Lymphoma International Prognostic Index (FLIPI) assesses a patient’s prognosis, incorporating factors such as age, Ann Arbor stage, hemoglobin levels, and the number of involved lymph node sites.
Managing Follicular Lymphoma Treatment Approaches
The management of follicular lymphoma is unique due to its indolent nature, and treatment is often deferred until the disease causes symptoms or threatens organ function. For patients with a low disease burden and no B-symptoms, the initial approach is “Watchful Waiting,” or Active Surveillance. This involves closely monitoring the patient without immediate active treatment, as delaying therapy until needed does not negatively impact overall survival.
Treatment is typically initiated if the disease burden is high, if the patient develops B-symptoms, or if the lymphoma is rapidly progressing or compressing vital organs. The primary goal of active treatment is to control the disease and improve the patient’s quality of life, as FL is considered incurable but manageable.
A mainstay of treatment is targeted therapy with a monoclonal antibody, most commonly Rituximab, which targets the CD20 protein found on the surface of FL B-cells. Rituximab can be used as a single agent for low-tumor-burden disease or in combination with chemotherapy, known as chemoimmunotherapy. Common chemoimmunotherapy regimens include R-CHOP (Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CVP (Rituximab combined with cyclophosphamide, vincristine, and prednisone).
Another common chemotherapy option is Bendamustine combined with Rituximab (BR), which has demonstrated high effectiveness and is often preferred for its favorable side-effect profile compared to R-CHOP in this disease setting. For localized Stage I or II disease, involved-site radiation therapy (ISRT) may be used as a curative option, though most patients are diagnosed at advanced stages. Following initial successful treatment, some patients may receive maintenance therapy with Rituximab to prolong the time before the disease progresses again.
The Risk of Transformation
A significant long-term risk for patients with follicular lymphoma is the potential for the disease to transform into a more aggressive form of cancer. This event, known as histologic transformation, occurs at a rate of approximately 2% to 3% per year. The most common transformation is into Diffuse Large B-cell Lymphoma (DLBCL), a fast-growing and aggressive NHL subtype.
Transformation is often signaled by the rapid, unexplained growth of a previously stable lymph node, the sudden reappearance of B-symptoms, or the development of new symptoms like elevated lactate dehydrogenase (LDH) levels. This shift indicates that the lymphoma cells have acquired additional genetic mutations, leading to a much more aggressive clinical course. When transformation is suspected, a new biopsy is required to confirm the change in histology. Transformed follicular lymphoma necessitates immediate and intensive treatment, typically using aggressive chemoimmunotherapy regimens similar to those used for de novo DLBCL.