follicular lymphoma follicular lymphoma follicular lymphoma (fl) is a cancer that involves certain types of white blood cells known as lymphocytes. the 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. follicular lymphomamicrograph of a follicular lymphoma, showing the characteristically abnormal lymphoid follicles that gave the condition its name. h&e stain.specialtyhematology and oncology there are several synonymous and obsolete terms for fl such as cb/cc lymphoma (centroblastic and centrocytic lymphoma), nodular lymphoma, brill-symmers disease, and the subtype designation, follicular large-cell lymphoma. in the us and europe, this disease is the second most common form of non-hodgkin's lymphomas, exceeded only by diffuse large b-cell lymphoma. fl accounts for 10–20% of non-hodgkin's lymphomas with ~15,000 new cases of it being newly diagnosed each year in the us and europe. recent studies indicate that fl is similarly prevalent in japan. fl is a broad and extremely complex clinical entity with a wide range of manifestations which have not yet been fully systematized. it is commonly preceded by a benign precancerous disorder in which abnormal centrocytes and/or centroblasts accumulate in lymphoid tissue. they may then circulate in the blood to cause an asymptomatic condition termed in situ lymphoid neoplasia of the follicular lymphoma type (i.e. isfl). a small percentage of these cases progress to fl. most commonly, however, fl presents as a swelling of lymph nodes in the neck, armpits, and/or groin. less often, it presents as a gastrointestinal tract cancer, a cancer in children involving lymphoid tissues of the head and neck area (e.g. tonsils), or one or more masses in non-lymphoid tissues such as the testes. fl typically has a slow disease course which persists essentially unchanged for years. however, each year 2–3% of fl cases progress to a highly aggressive form often termed stage 3b fl, to an aggressive diffuse large b-cell lymphoma, or to another type of aggressive b-cell cancer. these transformed follicular lymphomas (t-fl) are essentially incurable. however, recent advancements in the treatment of t-fl (e.g. the addition to standard chemotherapy of agents such as rituximab) have improved overall survival times. these newer regimens may also delay the transformation of fl to t-fl. additional advances in understanding fl may lead to further improvements in treating the disease. pathophysiology genomic alterations the serial progressions of in situ fl to fl and fl to t-fl appear to involve the accumulation of increasing numbers of genomic alterations (i.e. chromosome abnormalities and gene mutations) in the formative b-cell precursors to these disorders. at least some of these alterations appear to cause the over-expression or under-expression of the products of genes that regulate these cells' susceptibility to develop further genomic alterations, to survive, to proliferate, and/or to spread to other tissues. in consequence, multiple b-cell clones that exhibit increasing genomic alterations and malignant behaviors populate the disorder. no single genomic alteration seems responsible for the development of each of the spectrum of fl disorders. rather, interactions between multiple genomic alterations appear to underlie this serial progression. in situ follicular lymphoma in situ follicular lymphoma is an accumulation of monoclonal b cells (i.e. cells descendent from a single ancestral cell) in the germinal centers of lymphoid tissue. these cells commonly bear a pathological genomic abnormality, i.e. a translocation between position 32 on the long (i.e. "q") arm of chromosome 14 and position 21 on chromosome 18's q arm. this translocation juxtaposes the b-cell lymphoma 2 (bcl2) gene on chromosome 18 at position q21.33 near to the immunoglobulin heavy chain locus (igh@) on chromosome 14 at position q21. in consequence, bcl2 overexpresses its product, bcl2 apoptosis regulator (i.e. bcl2). bcl2 functions to inhibit programmed cell death thereby prolonging cell survival. the overexpression of bcl2 in the b-cells of isfl is thought to be a critical factor in their pathological accumulation and subsequent malignant progression. small numbers (e.g. 1 in 100,000) of circulating nucleated blood cells bearing this t(14:18)q32:q21) translocation are found in 50–67% of otherwise healthy individuals. the prevalence of this finding increases with age and years of tobacco smoking. since most individuals with this translocation in their blood cells do not develop isfl, the t(14:18)(q32:q21) translocation, while prolonging cell survival, must be just one step in the development of isfn. this translocation is proposed to occur during the early development of immature bone marrow b-cells (i.e. pre-b-cells/pro-b-cells) after which these cells circulate freely and in rare cases accumulate and mature to centrocytes and/or centroblasts in the germinal centers of lymphoid follicles to form isfl. the mechanism favoring this localization and further accumulation is unclear. individuals with isfl progress to fl at a rate of 2–3%/year for at least the first 10 years following diagnosis. this progression likely involves the acquisition of genomic aberrations besides the t(14:18)q32:q21) translocation in the isfl b-cells. suspect mutations include those in the following genes: 1) ezh2 (encodes polycomb repressive complex 2 family protein which is involved in maintaining the transcriptional repressive state of various genes and is found in up to 27% of fl cases); 2) crebbp (encodes creb-binding protein which contributes to the activation of various genes); 3) tnfsf14 (encodes tumor necrosis factor superfamily member 14, a member of the tumor necrosis factor superfamily which may function as a co-stimulatory factor for the activation of lymphoid cells); and 4) kmt2d (encodes histone-lysine n-methyltransferase 2d, a histone methyltransferase which regulates the expression of various genes). isfl may also acquire numerous copy-number variations (i.e. duplications and deletions of a portion of a chromosome along with any of the genes contained therein) that may contribute to fl. in all cases, the number of genetic abnormalities acquired in the b-cells of isfl are much less than those in fl. follicular lymphoma the genomic alterations found in fl include 1) the t(14:18)(q32:q21.3) translocation (85–90% of cases); 2) 1p36 deletions (i.e. deletions in the q arm of chromosome 1 at position 36, ) that lead to lose of tnfaip3 (encodes tumor necrosis factor, alpha-induced protein 3 which inhibits the activation of nf-κb, blocks cell death due to apoptosis, and regulates lymphocyte-based immune responses through its ubiquitin ligase activity); 3) mutations in prdm1 (encodes the pr domain zinc finger protein which promotes the maturation and proliferation of b-cells); and 4) the same mutations seen in isfl including kmt2d (85–90% of cases), creebp (40–65% of cases), bcl2 (40–65% of cases), and ezh2 (20–30% of cases) as well as other mutations such as those in the histone-modifying gene hist1h1e (20–30% of cases), the rragc gene (~17% of cases) which regulates cell growth, survival, death, and proliferation, and, in ≤15% of cases several other genes including mef2b, stat6, ep300, arid1a, slc22a2, card11, foxo1, gna12, b2m (i.e. the gene for beta-2 microglobulin), and sgk1. except for the t(14:18)(q32:q21.3) translocation and ezh2 mutations which lead to gains in the expression and function, respectively, of their products, the genetic alterations generally lead to a loss in the production or function of the cited genes products. however, the exact roles, if any, of these genomic abnormalities in promoting the progression of isfl to fl are unclear. transformed follicular lymphoma the transformation of fl to a more aggressive state or other type of aggressive lymphoma is associated with: 1) primarily gene-activating mutations in creebp, kmt2d, stat6, card11 (encoding a guanylate kinase which interacts with bcl10 and activates nf-κb to regulate cell survival); 2) changes in the expression of diverse genes; 3) the overproduction of various cell-activating cytokines and cd79b (encoding the ig-beta protein component of the b-cell receptor); 4) gene-inactivating mutations in tnfaip3, cd58 (encoding the cell adhesion molecule, lymphocyte function-associated antigen 3, that is involved in activating t-cells), cdkn2a (encoding p16ink4a and p14arf tumor suppressor proteins) or cdkn2b (encoding cyclin dependent kinase inhibitor 2b multiple tumor suppressor 2) (inactivation of either cdkn2 gene causes genome instability, i.e. increased frequency of other gene mutations), and tnfrsf4 (encoding one type of tumor necrosis factor receptor); and 5) gene-activating or -inactivating mutations in, or other causes for the under- or over-expression of, c-myc ((encoding the c-myc proto-oncogene transcription factor that regulates the expression of diverse genes many of which promote cell proliferation). tumor environment the non-neoplastic immune and stromal cells as well as the extracellular matrix in tissues may enable neoplastic follicular cells to survive, proliferate, and avoid surveillance by the immune system. for example, laboratory studies show that: 1) follicular dendritic cells, fibroblastic reticular cells, and t helper cells provide growth and survival signals to neoplastic follicular b-cells; 2) neoplastic follicular b-cells recruit regulatory t cells that act to suppress immune responses to them; 3) the cytotoxic t-cells which normally kill neoplastic cells become dysfunctional in the presence of neoplastic follicular cells that are embedded in this multicellular environment; and 4) bone marrow stromal cells directly support the growth of neoplastic follicular cells. reduced levels of immune-infiltration has been shown to be strongly associated with early progression of disease. presentation and course in situ follicular lymphoma fl is commonly preceded by but uncommonly progresses to isfl, an asymptomatic disorder that usually is discovered in tissues which are biopsied for other reasons. fl lymphoma may be diagnosed in the uncommon cases in which individuals with isfl are found to have fl on follow-up examinations. similarly, individuals with >1 in 10,000 circulating lymphocytes containing the t(14:18)q32:q21) translocation are at increased but still small risk of developing fl and being diagnosed as having fl on follow up examinations. follicular lymphoma fl commonly presents as an otherwise asymptomatic enlargement of lymph nodes in the neck, armpit, groin, femoral canal, or other sites in individuals (median age 65) without a known history of isfl or abnormal numbers of circulating t(14:18)q32:q21-conatianing lymphocytes. these enlargements may have been present for months to years and during this time waxed and waned in size. less commonly, fl presents as extra-nodal masses in the skin, thyroid gland, salivary gland, breast, testicles. spleen, liver, and/or lung. regardless of the type of presentation, fl is usually (~80% of cases) at an advanced stage at diagnosis as indicated by involvement of the bone marrow (50% to 70% of cases), multiple lymph nodes in different parts of the body, and/or other tissues. a minority (<33%) of fl patients present with b symptoms, i.e. recurrent unexplained fevers, recurrent night sweats, and/or weight loss ≥10% in the past 6 months. generally, the disease has an indolent and prolonged course with a median life expectancy of 15–20 years: a large percentage of patients die from other causes than their fl disease. however, each year, including the early years after diagnosis, some 2–3% of fl cases transform to t-fl; median survival has been ~4.5 years after the onset of this transformation. there are less common subtypes of fl that differ not only in their presentation but also in their histopathology, genetic abnormalities, and course. these subtypes, which are now (i.e. primary gastrointestinal tract fl) or may in the future (pediatric-type fl) be considered distinctive diseases, are: duodenal-type follicular lymphoma main article: duodenal-type follicular lymphoma duodenal-type follicular lymphoma (dfl) was initially considered to be a type of primary gastrointestinal tract (gi tract) follicular lymphoma (pgtfl), i.e. a follicular lymphoma in which gi tract lesions were prominent parts of the disease. however, a subset of pgtfl cases had lesions that were localized to the duodenum and other parts of the small intestine usually without involving other parts of the gi tract or tissues outside of the gi tract. this contrasts with the other cases of pgtfl which were systemic diseases involving a wide range of gi tract and non-gi tract tissues. consequently, the world health organization (2017) removed the localized disease from the primary gastrointestinal tract follicular lymphoma category, reclassified it as a distinct disease entity, and termed it duodenal-type follicular lymphoma. dfl is most often an asymptomatic disease that is diagnosed on endoscopic examination of the gi tract conducted for other reasons. less commonly, it presents with vague abdominal symptoms. in one review of former studies, the lesions in 85% of primary duodenal follicular lymphoma were located not only in the