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) 
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 . 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 .
FL is the second common form of NHL in the U.S with an estimated incidence of six new cases/ 100 000 persons/year . The rate of FL is higher in Caucasians compared to Asians and African Americans. FL is most common in the USA and Europe, but less so to the rest of the world. FL is a disease of older adults (median age 55 years) and relatively uncommon in children; rare under age 20 years. Exposure to pesticides and herbicides have been established as risk factors.
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 
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 .
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 . In children, FL majorly affects lymphoid tissues (tonsils and lymph nodes) of the head and neck .
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 . 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) .
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 . 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 . 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 .
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.
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) .
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, 
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 .
Prognosis and risk assessment of FL is determined based on the FLIP2 study risk factors that include: Beta2 microglobulin > upper limit of normal, Bone marrow involvement, Hemoglobin < 12g/dl, the diameter of the largest involved node > 6 cm and age > 60 years. The 5-year progression-free survival based on the risk factors is as follows: Low risk (0 risk factors): 80%; Intermediate risk (1 - 2 risk factors): 51%; High risk (3 - 5 risk factors): 19%. 
FL complications include BM suppression, organ dysfunction, and adverse effects related to high dose chemotherapy.
Patients should be educated about the prognosis and the possible adverse side effects from the chemotherapeutic regimes and hematopoietic stem cell transplantation before beginning treatment.
FL is the second most common type of non-Hodgkin lymphoma (NHL). FL typically presents with generalized painless lymphadenopathy. The disease is usually indolent with a favorable prognosis. Most cases of FL show at (14;18) (q32;q21), which leads to an overexpression of BCL2, an anti-apoptotic protein. The WHO (2017) has a pathological grading system (Grade 1, 2, or 3) for FL that depends on the evaluation of centroblasts. FL workup should include history, physical examination, and laboratory studies, and Imaging. The management of FL depends on the disease stage.
FL is the second most common form of NHL. The prognosis is overall favorable. FL needs an interprofessional management approach with a medical oncologist, pathologist, infectious disease physician, pharmacist, and oncology nurse all playing a role in management. Drug interventions have shown better outcomes than wait and watch in the treatment of follicular lymphoma . (level 1)
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