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
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). 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. 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: 0 - 5, grade 2: 6 - 15, grade 3: > 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 .
FL typically presents with generalized painless lymphadenopathy. The disease is usually indolent with 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 clefted 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 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, 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 .
Management of FL depends on the disease stage. Options available for control of stage I disease include radiation (RT), immunochemotherapy (Rituximab plus chemotherapy), immunochemotherapy plus RT, single-agent rituximab, and observation until progression. The most established and evidence-based chemotherapeutic regimen in FL is the cyclophosphamide, vincristine, and prednisolone (CVP) regimen. Stage II disease is managed by RT or immunochemotherapy. Patients with grade 3b FL are treated with aggressive regimens (such as R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) used for other aggressive lymphomas (e.g., diffuse large B cell lymphoma). Autologous hematopoietic stem cell transplantation is the preferred management for recurrent/relapsed patients or patients who have undergone transformation to higher grade lymphoma .
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) and accounts for up 30% of all lymphomas. FL typically presents with generalized painless lymphadenopathy. The disease is usually indolent with 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. Management of FL depends on the disease stage.
FL is the second most common form of NHL. The prognosis is overall favorable. FL needs a multidisciplinary management approach with a medical oncologist, pathologist, infectious disease physician, pharmacist, and oncology nurse all playing a role in management.
|||Freedman A, Follicular lymphoma: 2015 update on diagnosis and management. American journal of hematology. 2015 Dec; [PubMed PMID: 26769125]|
|||Swerdlow SH,Campo E,Pileri SA,Harris NL,Stein H,Siebert R,Advani R,Ghielmini M,Salles GA,Zelenetz AD,Jaffe ES, The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19; [PubMed PMID: 26980727]|
|||Kridel R,Sehn LH,Gascoyne RD, Can histologic transformation of follicular lymphoma be predicted and prevented? Blood. 2017 Jul 20; [PubMed PMID: 28408460]|
|||Martin AR,Weisenburger DD,Chan WC,Ruby EI,Anderson JR,Vose JM,Bierman PJ,Bast MA,Daley DT,Armitage JO, Prognostic value of cellular proliferation and histologic grade in follicular lymphoma. Blood. 1995 Jun 15; [PubMed PMID: 7780151]|
|||Miao Y,Hu S,Lu X,Li S,Wang W,Medeiros LJ,Lin P, Double-hit follicular lymphoma with MYC and BCL2 translocations: a study of 7 cases with a review of literature. Human pathology. 2016 Dec; [PubMed PMID: 27544800]|
|||Wang SA,Wang L,Hochberg EP,Muzikansky A,Harris NL,Hasserjian RP, Low histologic grade follicular lymphoma with high proliferation index: morphologic and clinical features. The American journal of surgical pathology. 2005 Nov; [PubMed PMID: 16224216]|
|||Sarkozy C,Baseggio L,Feugier P,Callet-Bauchu E,Karlin L,Seymour JF,Lebras L,Michallet AS,Offner F,Dumas O,Traverse-Glehen A,Ffrench M,Lopez-Guillermo A,Berger F,Coiffier B,Felman P,Salles G, Peripheral blood involvement in patients with follicular lymphoma: a rare disease manifestation associated with poor prognosis. British journal of haematology. 2014 Mar; [PubMed PMID: 24274024]|
|||McNamara C,Davies J,Dyer M,Hoskin P,Illidge T,Lyttelton M,Marcus R,Montoto S,Ramsay A,Wong WL,Ardeshna K, Guidelines on the investigation and management of follicular lymphoma. British journal of haematology. 2012 Feb; [PubMed PMID: 22211428]|
|||Solal-Céligny P,Roy P,Colombat P,White J,Armitage JO,Arranz-Saez R,Au WY,Bellei M,Brice P,Caballero D,Coiffier B,Conde-Garcia E,Doyen C,Federico M,Fisher RI,Garcia-Conde JF,Guglielmi C,Hagenbeek A,Haïoun C,LeBlanc M,Lister AT,Lopez-Guillermo A,McLaughlin P,Milpied N,Morel P,Mounier N,Proctor SJ,Rohatiner A,Smith P,Soubeyran P,Tilly H,Vitolo U,Zinzani PL,Zucca E,Montserrat E, Follicular lymphoma international prognostic index. Blood. 2004 Sep 1; [PubMed PMID: 15126323]|
|||Relander T,Johnson NA,Farinha P,Connors JM,Sehn LH,Gascoyne RD, Prognostic factors in follicular lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 Jun 10; [PubMed PMID: 20385990]|