Follicular Lymphoma – Causes, Symptoms, Treatment

Follicular Lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) and accounts for almost 30% of all lymphomas. It is number one among clinically indolent non-Hodgkin lymphomas. FL is a slow-growing B cell lymphoproliferative disorder, and survival is calculated in years. Based on histology FL is graded as 1 – 3 (low grade to high grade) [rx][rx]

Follicular lymphoma (FL) is cancer that involves certain types of white blood cells known as lymphocytes. Cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles (nodular swirls of various types of lymphocytes) in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle-like structures (see adjacent Figure) in the tissues they invade. These structures are usually the dominant histological feature of this cancer.^[rx]

Most people who have follicular lymphoma do not have a particular type. However, there are some rare variants of follicular lymphoma that behave and are treated, differently. These include:

• duodenal-type follicular lymphoma
• pediatric-type follicular lymphoma.

We have separate information on primary cutaneous follicle center lymphoma. This is a type of low-grade B-cell skin lymphoma that used to be classified as a type of follicular lymphoma.

Causes of Follicular Lymphoma

FL originates from germinal/follicular center B cells. Most cases of FL show at (14;18) (q32;q21), which leads to an overexpression of BCL2, an anti-apoptotic protein. About 5% of FL have BCL-6 deregulating mutations. BCL-6 is required for germinal center formation. BCL-6 related protein is a repressor of transcription and modulates the interleukin-4 response of B-cells [rx]. Other upregulated genes thought to play a role in follicular lymphoma are associated with p21, p16, and G1 arrest. Similarly, regulatory proteins (p120, p16, CKD10, p21), transcription factors (Id-2 and PAX5), and cell-cell interaction (TNF, IL4RA, and IL2RG) related genes are also upregulated. Adhesion related genes MRP14 and MRP8 are downregulated [rx].

• unexplained weight loss
• fevers (temperature above 38ºC)
• drenching sweats, especially at night
• frequent infections, or having difficulty getting over infections
• fatigue (overwhelming tiredness).

Symptoms of Follicular Lymphoma

You may have no symptoms of follicular lymphoma.

If you do have symptoms, you may have:

• Painless swelling of the lymph nodes in your neck, groin, stomach, or armpits
• Shortness of breath
• Fatigue
• Night sweats
• Weight loss

Diagnosis of Follicular Lymphoma

Histopathology

Morphological assessment of a lymph node excision/biopsy is crucial for the diagnosis of FL. Lymph node will show variable-sized closely packed follicles containing small cleaved cells without nucleoli (centrocytes) and larger noncleaved cells with moderate cytoplasm, open chromatin, and multiple nucleoli (centroblasts). The morphology will also show minimal apoptotic cells or tingible body macrophages. The mantle zones are typically absent, necrosis is rare. Usually, there is interfollicular involvement or capsular infiltration. Different patterns include Diffuse pattern, floral pattern, and Incipient pattern. There are 4 FL variants: (1) In situ follicular neoplasia (formerly called FL in situ) (2) Duodenal-type FL (3) Testicular FL and (4) Diffuse variant of FL. Pediatric FL has been split off FL into an independent entity in the WHO 2017 [rx][rx]

FL typically involves the paratrabecular areas of the bone marrow. Centroblasts are enlarged rapidly dividing B-cells in a lymphoid follicle. The WHO (2017) has a grading system (Grade 1, 2 or 3) for FL that depends on the percentage of centroblasts, and is as follows: grade 1 (follicular small cleaved): 0 – 5 centroblasts/HPF, grade 2 (follicular mixed): 6 – 15 centroblasts/HPF, grade 3 (follicular large cell): > 15 centroblasts/HPF (grade 3A – centrocytes present, grade 3B – solid sheets of centroblasts). It is clinically important to differentiate grades 1/2 vs. grade 3. If in areas of diffuse large B cell lymphoma exist with FL, the exact percentage of DLBCL should be reported. IHC is useful in confirming the FL diagnosis. Positive stains supporting FL include CD10, CD19, CD20 (strong), CD79a, BCL2 within follicles, and BCL6. Variable stains include CD30, CD11c, CD23, CD25, CD43 and surface immunoglobulin. Negative stains include T cell markers such as CD5 (although mixed T cells are often present) and cyclin D1 [rx][rx][rx].

History and Physical

Follicular lymphoma typically presents with generalized painless lymphadenopathy. Lymphadenopathy is waxing and waning in nature. FL commonly involves axillary, cervical, femoral, and inguinal lymph nodes. Rarely, it may present with an asymptomatic large mediastinal mass. Only 20% of the patients experience B symptoms (night sweats, fever, weight loss). Increased serum LDH is also seen in 20% of the patients. Usually, FL only involves bone marrow and lymphoid organs [rx][rx].[rx] In children, FL majorly affects lymphoid tissues (tonsils and lymph nodes) of the head and neck [rx].

The disease is usually indolent with a favorable prognosis. Marrow involvement occurs in most of the cases (>50%); the paratrabecular pattern of infiltration is the most common pattern of bone marrow infiltration. Some examples show lymphocytosis with atypical forms that show deeply cleft nuclei. Spleen infiltration presents as lymphocyte aggregates in the white pulp. There are some subtypes of FL, such as double-hit follicular lymphoma (MYC and BCL2 translocations) and low-grade FL with a high proliferation index that presents with low-grade morphology and a relatively aggressive course; more research on these and other rare subtypes is underway [rx][rx]. Transformation of FL to different aggressive NHL such as diffuse large B cell lymphoma, Burkitt/Burkitt-like lymphoma, high-grade B-cell lymphoma (not otherwise specified or with double-hit/triple-hit genetics) and B-Acute lymphoblastic leukemia (B-ALL) occurs and is associated with an unfavorable outcome. Transformation of FL can be suspected clinically when there is rapidly enlarging disproportionate masses, B symptoms, abnormal laboratory tests (such as elevated serum lactate dehydrogenase (LDH), or calcium) [rx][rx][rx].

Evaluation

Evaluation of FL should include history, physical examination, laboratory studies (complete blood count with differential, routine chemistries, and lactate dehydrogenase) and imaging (including CT, MRI and whole-body combined fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET/CT)). Diagnosis of FL will usually require a lymph node morphological assessment and flow cytometry. Sometimes genetic testing is incorporated to confirm the diagnosis. Peripheral blood smear rarely shows atypical lymphocytes that have scant cytoplasm and deeply cleaved nucleus [rx]. Effacement of nodal architecture with CD20+ CD10+ BCL2+ cells small/medium-sized cells supports FL diagnosis. In some cases, it is hard to differentiate FL from reactive hyperplasia. For these cases, the assessment of CD10 will be helpful, since the expression if the stain supports FL. Bone marrow biopsy should be performed before the initiation of therapy to confirm staging. Genetics is a useful tool for assessing FL. Most cases will show clonally rearranged immunoglobulin genes.

Further, the majority of the cases will show at (14;18) (q32;q21); the translocation affects the IgH and BCL2. The translocation leads to an overexpression of BCL2, which prevents cells in the follicular center from undergoing apoptosis. BCL2 is sensitive but not specific for FL and can be present in other NHL such as DLBCL [13]. After the achievement of remission, follow-up of patients should be planned every three months during the first year and then every three to six months [rx].

Staging

• Non-Hodgkin lymphomas are divided into the following stages,
• Stage I: Single lymph node group or single extra lymphatic organ involved without lymph node involvement.
• Stage II: Two or more lymph node regions involved on the same side of the diaphragm with or without the involvement of an extra lymphatic organ.
• Stage III: Lymph nodes on both sides of the diaphragm involved.
• Stage IV: One or more extra lymphoid organs diffusely involved with or without lymph node involvement [rx].

Treatment of Follicular Lymphoma

The management of FL depends on the disease stage. Options available for the treatment of follicular lymphoma include radiation (RT), immunochemotherapy (Rituximab plus chemotherapy), Bundamustine with immunotherapy, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), immunochemotherapy plus RT, CVP (cyclophosphamide, vincristine, and prednisolone), single-agent rituximab, and observation until progression. The choice of regimen depends on the stage of the disease, preference of physician, and preference of the patient.

In stage 1 lymphomas, radiation therapy is preferred in grades 1, 2, and 3a lymphomas. In contrast, patients with grade 3b FL are treated with aggressive regimens (such as R-CHOP) used for other aggressive lymphomas (e.g., diffuse large B cell lymphoma).

Treatment of stage II-IV FL is mainly focused on the improvement of life, alleviation of symptoms, and reversal of cytopenias. Asymptomatic patients are mostly observed closely without any intervention. Anti-CD20 antibodies (obinutuzumab, rituximab) are combined with chemotherapy regimens for the treatment of symptomatic advanced follicular lymphomas.

• New antibody therapies – including antibodies that bind to two different targets (one on lymphoma cells and one on T cells, which helps the T cells find and destroy the lymphoma cells). These are called ‘bispecific’ antibodies.
• Antibody-drug conjugates – (antibodies joined to chemotherapy drugs). The antibody sticks to a protein on the surface of lymphoma cells and carries the chemotherapy drug directly to it.
• Checkpoint inhibitors – which stop lymphoma cells from blocking the pathways your immune system uses to recognize and destroy cancer cells.
• Cell signal blockers – which block signals that B cells send to help them divide or stay alive. Cell signal blockers include targeted drugs such as BTK inhibitors, PI3K inhibitors and BCL-2 inhibitors, named after the particular proteins they block.
• CAR T-cell therapy –  which involves genetically modifying your own T cells so they can recognise and kill lymphoma cells.
• Drugs that block proteins – linked to particular genetic changes in lymphoma cells.
• 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 patients with follicular lymphoma will relapse multiple times and be treated with many available drugs at some point during their disease course. Novel agents, as referred to here, include small molecules designed to target signaling pathways that are abnormally expressed in the cancer cells. Agents that may be used to treat follicular lymphoma that has relapsed multiple times include lenalidomide, idelalisib, copanlisib, and duvelisib.
• Radioimmunotherapy — Radioimmunotherapy (RIT) uses antibodies to deliver radiation to the tumor cells. This reduces the amount of radiation delivered to healthy tissues. However, administering RIT is cumbersome and there are potentially serious short- and long-term side effects of the treatment; as a result, it is used much less frequently than the other treatment options.
• Stem cell transplantation — Stem cell transplantation (also called bone marrow transplantation or hematopoietic stem cell transplantation) is generally reserved for people whose lymphoma has recurred after treatment.
• Radiation – It kills cancer cells. The radiation comes from a high-energy beam, similar to an X-ray, or from material put inside your body in or near cancer. Follicular lymphoma responds well to radiation. In some cases, it can cure cancer. If yours is at an early stage, you may only need radiation. If it’s advanced, you may get other treatments as well.
• Monoclonal antibodies – These are drugs that act like your body’s disease-fighting cells. For most people, rituximab (Rituxan) and obinutuzumab (Gazyva) works well to kill lymphoma cells while doing little damage to normal body tissues. It also has fewer side effects than chemotherapy. You may also take rituximab as maintenance therapy, to slow the growth of lymphoma. You get it by IV in your doctor’s office or at an infusion center. Your dosing schedule will depend on your particular case. Because it must be given slowly, expect it to take several hours at first.
• Chemotherapy – Usually, you get this treatment by IV or as a pill. Because it enters the bloodstream and reaches most parts of the body, it works very well for lymphoma.?
• Radioimmunotherapy – You get this medication — Y90 ibritumomab tiuxetan (Zevalin) — through an IV. It delivers radiation straight to a protein on cancer cells. Your doctor may recommend it if your lymphoma comes back or doesn’t respond to chemotherapy.?
• Stem cell transplant – This is used mainly when follicular lymphoma returns. These aren’t the “embryonic” stem cells that you may have heard about. They come from either your own stem cells or a donor’s bone marrow.
• 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.  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 patients with follicular lymphoma will relapse multiple times and be treated with many available drugs at some point during their disease course. Novel agents, as referred to here, include small molecules designed to target signaling pathways that are abnormally expressed in the cancer cells. Agents that may be used to treat follicular lymphoma that has relapsed multiple times include lenalidomide, idelalisib, copanlisib, and duvelisib.
  Radioimmunotherapy — Radioimmunotherapy (RIT) uses antibodies to deliver radiation to the tumor cells. This reduces the amount of radiation delivered to healthy tissues. However, administering RIT is cumbersome and there are potentially serious short- and long-term side effects of the treatment; as a result, it is used much less frequently than the other treatment options.

Autologous hematopoietic stem cell transplantation is the preferred management for recurrent/relapsed patients or patients who have undergone a transformation to higher grade lymphoma. Patients with advanced, relapsed, or refractory disease are encouraged to take part in clinical trials of new therapies like CAR-T cell therapy (chimeric antigen receptor T cells) [rx][rx][rx].

Differential Diagnosis

Follicular lymphoma is differentiated from other types of lymphomas based on nodular pattern, absence of tangible body macrophages, monoclonal cells, and immunophenotyping (i-e, CD10, BCL-2, BCL-6). Following are the differential diagnosis of follicular lymphoma, [rx][rx][rx][rx]

• Follicular colonization by other low-grade lymphomas
• Mantle cell lymphoma with a diffuse pattern
• Marginal zone B cell lymphoma
• Peripheral T cell lymphoma
• Reactive hyperplasia
• Small lymphocytic lymphoma/ chronic lymphocytic leukemia (SLL / CLL)

Complications

FL complications include BM suppression, organ dysfunction, and adverse effects related to high dose chemotherapy

References