INTRODUCTION — Follicular lymphoma (FL, previously called follicle center lymphoma and nodular lymphoma) is a heterogeneous clinicopathologic entity that includes tumors derived from germinal center B cells, both centrocytes (small cleaved follicular center cells) and centroblasts (large noncleaved follicular center cells). FL virtually always has a growth pattern that is partially follicular, giving it a nodular appearance both grossly and microscopically. It is the second most common subtype of non-Hodgkin lymphoma (NHL) and is the most common of the clinically indolent NHLs, defined as those lymphomas in which survival of the untreated patient is measured in years. (See "Classification of the hematopoietic neoplasms".)
The epidemiology, clinical presentation, pathologic features, diagnosis, and prognosis of FL will be reviewed here. The pathobiology and treatment of this disorder are discussed separately.
EPIDEMIOLOGY — FL is one of the most common forms of non-Hodgkin lymphoma (NHL). FL occurs in all races and geographic locations. The exact worldwide incidence of FL is not known, as epidemiologic data are limited in some countries by a lack of resources that are needed for case ascertainment and accurate diagnosis. As a consequence, most epidemiologic data come from retrospective analyses of patients treated at major centers in the United States and Europe.
In the United States as a whole, FL accounts for approximately 35 percent of NHLs and has an estimated incidence of 3.18 cases per 100,000 people . The estimated incidence in Europe is 2.18 cases per 100,000 persons per year . The incidence is stable over time, but varies, with the incidence in White populations being more than twice that in African and Asian populations [1,3,4]. FL appears to be less common in Central and South America, where it accounts for approximately 20 percent of NHL . There is no strong sex predilection. The incidence increases with age; FL most frequently presents in middle-aged individuals and the elderly; the median age at diagnosis is 65 years [6,7]. Rarely, FL arises in children or adolescents [8-11]. (See 'Children' below.)
While numerous potential risk factors have been proposed, most have not been validated in independent studies. As such, there is a lack of consensus regarding risk factors for the development of FL. A small number of cases appear to be familial [12,13]. While the risk of developing FL is slightly increased among relatives of persons with FL, the absolute risk remains low [14,15]. Diseases, infectious agents, and drugs or toxins associated with the development of NHL in general are discussed in more detail separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Past medical history'.)
PATHOGENESIS — FL is thought to arise from germinal center B cells, which include both centrocytes (small cleaved follicular center cells) and centroblasts (large noncleaved follicular center cells) [16,17].
The pathogenesis of FL is incompletely understood. Approximately 85 percent of FL have the t(14;18), which results in juxtaposition of the B cell leukemia/lymphoma 2 (BCL2) gene with regulatory elements of the immunoglobulin heavy chain gene (IGH). The resulting overexpression of BCL2, an oncogene that blocks programmed cell death (apoptosis), leads to prolonged cell survival. However, it is clear that multiple genetic events are required for the development of FL since the (14;18) translocation can be identified in a small subset of B cells in reactive lymphoid tissues and peripheral blood in a sizable fraction of normal individuals, few of whom go on to develop FL. Many of these additional, complementary acquired mutations involve genes that encode chromatin-modifying enzymes [18,19]. In addition, most FLs express surface immunoglobulin (typically IgM), even after treatment with anti-idiotype antibodies [20,21], suggesting that Ig-mediated B cell receptor signaling also is important in the growth/survival of FL cells. The pathogenesis of FL is discussed in more detail separately. (See "Pathobiology of follicular lymphoma".)
Adults — Most patients with FL present with painless peripheral adenopathy in the cervical, axillary, inguinal, and/or femoral regions [6,22,23]. The adenopathy commonly waxes and wanes spontaneously, but does not altogether disappear. While hilar and mediastinal nodes are often involved, large mediastinal masses are rare . Some patients present with relatively asymptomatic large abdominal masses, with or without evidence of gastrointestinal and/or urinary tract obstruction. Staging studies usually demonstrate widely disseminated disease with overt involvement of the spleen, liver, and/or bone marrow in approximately 40, 50, and 80 percent of cases, respectively .
Despite the presence of widespread disease at diagnosis, most patients are asymptomatic, with lymph node enlargement being the only evident abnormality. Only approximately 20 percent present with B symptoms (ie, fevers, night sweats, or unintentional weight loss) . There are no characteristic laboratory abnormality specifically associated with FL and, despite the large tumor burden, fewer than 25 percent of patients present with an increased serum lactate dehydrogenase (LDH) or cytopenias in the peripheral blood . Staging of lymphoma and the definitions of systemic symptoms associated with lymphoma are presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Systemic "B" symptoms'.)
Involvement of organs other than the lymphatic organs or bone marrow is uncommon [26,27]. Central nervous system involvement is rare, but peripheral nerve compression and epidural tumor masses causing cord compression may develop. Other patients have disease localized to the small intestine, most commonly the second portion of the duodenum, frequently identified as an incidental finding during endoscopy performed for other reasons . The morphology, immunophenotype, and genetic features of such primary "duodenal-type follicular lymphomas" are similar to those of nodal FL. The clinical presentation of gastrointestinal lymphoma is presented in more detail separately. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas" and 'Duodenal-type FL' below.)
Children — Rarely, FL arises in children or adolescents [8-11,29]. A substantial proportion of these pediatric FL tumors appear to be biologically distinct from typical adult FL. (See 'Pediatric-type FL' below.)
Characteristics of pediatric-type FL include:
●Low stage disease (generally stage I/II)
●Frequent involvement of the head and neck region
●Predominance of grade 3 histology
●Absence of BCL2 rearrangements and infrequent presence of BCL2 protein expression (approximately 30 percent)
●The presence of activating mutations involving MAP2K1 (a serine/threonine kinase that also is mutated in certain other lymphoid neoplasms, particularly hairy cell leukemia variant) and mutations affecting TNFRSF14, a member of the tumor necrosis factor receptor family 
●A high rate of apparent cure
Rarely, adults may present with tumors that resemble childhood FL (low-stage, grade 3, BCL2-negative disease with a high proliferation index) [29,31,32]. Such cases appear to have a high rate of cure following localized therapy. Conversely, childhood tumors with BCL2 rearrangements appear to be more likely to pursue a course like typical adult FL [11,29].
Morphologic features — On histology, the growth pattern and cell morphology can help to identify FL. Enumeration of centroblasts is used to determine the tumor grade, which has therapeutic implications.
Growth pattern — One of the most notable morphologic features of FL is its nodular growth pattern (picture 1), which recapitulates the normal germinal centers of secondary lymphoid follicles (picture 2) and effaces the normal lymphoid architecture . Unlike normal reactive follicles, the nodules in FL are typically closely packed and vary in size and shape. There is often artifactual cracking around the nodules in tissue sections, presumably because the follicles lack the normal stromal elements that surround and support reactive follicles. When necessary, staining for follicular dendritic cells (eg, with markers such as CD21, CD23, and CD35) can aid in the identification of follicular growth patterns.
The neoplastic follicles may be present throughout the tumor tissue, or in only a portion, with a diffuse component occupying the rest of the tumor (picture 3). Similar to normal germinal centers, T cells and tightly organized meshworks of follicular dendritic cells are present within the malignant follicles; however, unlike in normal follicles, so-called tingible body macrophages (cells laden with the remnants of B cells that have died by apoptosis) are typically absent [33-35]. Neoplastic follicles also lack polarization into centroblast-rich dark zones and centrocyte-rich light zones, which is a feature of normal reactive germinal centers.
The interfollicular areas of FLs, although compressed, also resemble normal lymph nodes in that large numbers of normal T cells are often located there, mixed with variable numbers of neoplastic cells. The Ki-67+ fraction, a marker of proliferation, is generally lower in neoplastic follicles than it is in reactive follicles. The number of Ki-67+ cells and mitotic figures increases with grade (picture 4 and picture 5).
Rarely, biopsy of involved tissue demonstrates a diffuse infiltration of tumor cells without a nodular growth pattern . Most of these cases are thought to represent a sampling error in which a small biopsy misses areas of nodular growth. A diagnosis of FL may be made in these cases if other criteria for the diagnosis are present, including a classic immunophenotype (ie, germinal center cell phenotype) and genetic features (ie, 14;18 translocation) associated with FL. A minority represent the provisional entity "predominantly diffuse FL with 1p36 deletion," which lacks BCL2 rearrangement and often presents as a localized inguinal mass .
●Centrocytes (cleaved follicle center cells) are small to medium sized cells with elongated or cleaved nuclei, inconspicuous nucleoli and scant pale cytoplasm (picture 6).
●Centroblasts (noncleaved follicle center cells) are large cells with round or oval nuclei, vesicular chromatin, often multiple peripheral nucleoli and a narrow rim of basophilic cytoplasm (picture 7).
Centrocytes typically predominate in FL; centroblasts are usually in the minority, but by definition are always present. Uncommonly, lymphomas with a follicular growth pattern consist almost entirely of centroblasts (grade 3b FL). Occasional cases may show plasmacytoid differentiation or foci of marginal zone or monocytoid B cells .
Grade — The proportion of centroblasts (large cells) varies from case to case, and the clinical aggressiveness of the tumor increases with increasing numbers of centroblasts. Numerous criteria have been proposed for grading FL. The World Health Organization classification has adopted the following cell-counting method [22,38-41]:
●Grade 1 – 0 to 5 centroblasts/high power field (hpf) (follicular small cleaved) (picture 6)
●Grade 2 – 6 to 15 centroblasts/hpf (follicular mixed) (picture 8A-B)
●Grade 3 – More than 15 centroblasts/hpf (follicular large cell) (picture 7). Grade 3 has been subdivided for investigational purposes into grade 3a, in which centrocytes are present, and grade 3b, in which there are solid sheets of centroblasts .
The prognostic value of FL grade is discussed below. (See 'Tumor grade' below.)
Blood and bone marrow — Bone marrow involvement is common and mainly takes the form of paratrabecular lymphoid aggregates (picture 9) . Low-level involvement of the peripheral blood is often detected by flow cytometry, but overt involvement of the blood (eg, sufficient to be appreciated on the peripheral smears) is unusual . Morphologically, these circulating cells usually have notches or clefts and correspond to centrocytes (picture 10).
Immunophenotype — The immunophenotype of FL is confirmed by immunohistochemistry (picture 11) or flow cytometry (figure 1). FL is a B cell malignancy thought to arise from germinal center B cells. The key features are the presence of germinal center B cell markers and lack of T cell markers (table 1):
●The tumor cells usually demonstrate surface immunoglobulin ; approximately 50 to 60 percent express IgM, 40 percent express IgG, and rare cases express IgA. Either kappa or lambda light chains should be present, but not both.
●Virtually all cases express HLA-DR and are positive for certain B cell antigens (CD19, CD20, CD79a), CD21, and CD10 (60 percent), and lack expression of CD5, CD43 (most cases), and CD11c. CD23 expression is variable [46,47].
●Cytoplasmic staining for BCL2 protein is strongly positive in almost all grade 1/2 tumors, which is in contrast to hyperplastic normal germinal center B cells, which are BCL2 negative (picture 12). However, a high fraction of cutaneous FL, childhood FL, and grade 3B FL is BCL2 negative. The transcription factor B cell lymphoma 6 (BCL6) is expressed by at least some of the neoplastic cells in all FL tumors [48,49].
Molecular genetics — Molecular genetics can help confirm the presence of clonal immunoglobulin gene rearrangements and an IGH::BCL2 fusion gene, which is the product of the t(14;18). "Deep" sequencing of FL genomes has revealed that most tumors (approximately 80 to 90 percent) have mutations in KMT2D (formerly MLL2) [18,50], a gene encoding a histone methyltransferase that stimulates RNA elongation; in contrast, KMT2D mutations are found in only about half of duodenal-type FL. The functional and clinical significance of KMT2D mutations remains to be determined.
Recurrent mutations have also been observed in a number of other genes encoding proteins that regulate the epigenome, including EZH2, ARID1A, EP300, as well as the transcription factors MEF2B and FOXO1, suggesting that dysregulation of chromatin and associated transcription factors has an important pathogenic role in FL .
Immunoglobulin genes — Immunoglobulin heavy and light chain genes are rearranged, and analysis of the immunoglobulin variable region genes shows that most cases have extensive somatic mutations and a high frequency of intraclonal diversity, indicating ongoing somatic mutation, similar to normal germinal center cells [52,53].
Cytogenetics — Patients with FL frequently have chromosomal abnormalities, but there is no single chromosomal change that is diagnostic of this disease. In the vast majority of cases, FL is associated with a translocation between the long arm of chromosome 18, the site of the BCL2 oncogene (18q21), and one of three immunoglobulin (Ig) gene loci [54,55]:
●The Ig heavy chain gene on chromosome 14 – Resulting in the t(14;18)(q32;q21) found in approximately 85 percent of FL
●The kappa light chain gene on chromosome 2 – Resulting in the t(2;18)(p11;q21), which is uncommon but considered a biologic equivalent
●The lambda light chain gene on chromosome 22 – Resulting in the t(18;22)(q21;q21), which is uncommon but considered a biologic equivalent
The consequence of these translocations is high-level "mis-expression" of BCL-2 protein, resulting in resistance to apoptosis [54-58]. The (14;18) translocation is not specific for FL, as it is also found in up to 30 percent of diffuse large B cell lymphomas and in a small number of reactive germinal center B cells in many lymph nodes undergoing follicular hyperplasia [57,59-63]. The pathogenesis of FL and the role of BCL2 in the development of FL are presented separately. (See "Pathobiology of follicular lymphoma", section on 'Introduction' and "Pathobiology of follicular lymphoma".)
Approximately 5 to 15 percent of FL tumors have 3q27 abnormalities involving the BCL6 gene, which encodes a transcription factor that is essential for normal germinal center development [42,64]. The incidence of BCL6 rearrangement increases with histologic grade, being most common in tumors with grade 3b histology, and appears to be associated with a more aggressive clinical course. Although some series have suggested that BCL6 rearrangements and BCL2 rearrangements are mutually exclusive , tumors with both rearrangements have been identified . BCL6 gene rearrangements associated with abnormalities of chromosome 3q27 are also seen in a subset of diffuse large B cell lymphomas .
DIAGNOSIS — The diagnosis of FL is best made by excisional tissue biopsy, most commonly a lymph node. The histologic examination is essential, while immunophenotypic and molecular genetic studies can help to support a suspected diagnosis. A discussion of lymph node and tissue biopsy, including the selection of a lymph node to biopsy, is presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)
Most patients will have systemic FL. The 2016 World Health Organization classification of tumors of hematopoietic and lymphoid tissues recognizes four additional clinical variants of FL :
●Intrafollicular neoplasia/"in situ" follicular neoplasm – (See 'Intrafollicular neoplasia' below.)
●Duodenal-type follicular lymphoma – (See 'Duodenal-type FL' below.)
●Predominantly diffuse follicular lymphoma with IRF4 rearrangement – (See 'Pediatric-type FL' below.)
In contrast, primary cutaneous follicle center lymphoma is considered a distinct clinicopathologic entity. (See 'Primary cutaneous follicle center lymphoma' below.)
Follicular lymphoma — The diagnosis of systemic FL is made based on the evaluation of a lymph node biopsy, typically in a patient with a history of waxing and waning lymphadenopathy . Bone marrow examination is an important component of staging, but is not a reliable means of primary diagnosis.
In classic cases, the histologic appearance of nodal FL is so characteristic that it is one of the few forms of non-Hodgkin lymphoma that pathologists can consistently diagnose accurately based on morphology alone. Typically, the tumor has a distinctly nodular growth pattern and is comprised of a mixture of centrocytes and centroblasts (picture 1 and picture 8A). Mitoses and apoptotic cells, which are common in reactive follicles, are infrequently seen.
However, FL has many less common morphologic variants, and sometimes lymph nodes are only partially involved. Also, on rare occasions, FL has an entirely diffuse growth pattern. In these situations, the diagnosis is based on a combination of morphologic and immunophenotypic findings. The diagnosis can also be made by fine needle aspiration of involved lymph nodes, with the caveat that it does not allow for assessment of growth pattern, and that grading is problematic. With this modality, immunophenotypic analysis (generally carried out by flow cytometry) plays a central role in establishing the diagnosis.
Characteristically, the tumor cells express monotypic immunoglobulin light chain, CD19, CD20, CD10, and BCL6, and are negative for CD5 and CD23. The vast majority (>85 percent) of tumors express BCL2 as a result of the t(14;18), which can be detected by fluorescence in situ hybridization (FISH) or by polymerase chain reaction (PCR).
Intrafollicular neoplasia — Intrafollicular neoplasia/"in situ" follicular neoplasia is a pathologic diagnosis used to describe the identification of follicles, typically several in number, that have a high content of BCL2-rearrangement-positive B cells within a lymph node that otherwise lacks the diagnostic features of FL [22,32]. Some patients with this finding will prove to have disseminated FL on further work-up; the intrafollicular component in such cases presumably represents early seeding of FL to a partially involved node. Most patients, however, will not have evidence of FL on further evaluation [66-70]. Little is known about the natural history of this second group of patients. A retrospective analysis of 34 cases of in situ FL with a median follow-up of 41 months reported only one case of progression to disseminated FL . It is possible that the BCL2-rearrangement-positive cells in such cases are a hyperplastic B cell clone that has acquired the t(14;18), but lacks the other genetic or epigenetic lesions that are required for full-blown FL to arise; if true, such patients may not be at any higher risk of FL than other members of the general population.
Duodenal-type FL — Duodenal-type FL is a clinical variant of FL confined to the intestine (usually duodenum) that typically presents as multiple small polyps [22,32,71]. It is a rare entity described in small case series and diagnosed approximately once in every 3000 to 7000 gastroduodenoscopies [72-80]. Duodenal-type FL is typically confined to the mucosa, shows at least a partial follicular growth pattern, and has grade 1 or 2 cytologic features . Lymphoid infiltrates may be found outside of follicular structures and extend into duodenal villi but do not infiltrate deeper structures. Unlike MALT lymphoma, marginal zone differentiation is not seen. The mutational landscape and immune microenvironment are different from that seen in nodal FL . Duodenal-type FL is often discovered incidentally and appears to follow a very indolent course. The clinical evaluation of duodenal-type FL is discussed in more detail separately. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)
Duodenal-type FL should be differentiated from systemic FL involving the gastrointestinal tract. Features that point to systemic FL include transmural infiltration of the organ wall, regional lymph node involvement, and involvement of the large intestine. Ultimately, the distinction relies on careful staging following diagnosis.
Pediatric-type FL — Pediatric-type FL is considered a distinct clinicopathologic entity that is usually seen in children and rarely presents in adults [8-11,29,31,32]. It usually presents with localized lymphadenopathy as early stage (I/II) disease. (See 'Children' above.)
Morphologically the tumor is comprised of large, highly proliferative, expansile follicles with prominent blastoid follicular center cells (rather than classic centroblasts and centrocytes). There are no foci of diffuse involvement. Rearrangements of BCL2, BCL6, and MYC are absent. These tumors are often associated with activating mutations involving MAP2K1 (encoding a serine/threonine kinase) and TNFRSF14, a member of the tumor necrosis factor receptor gene family [30,81,82].
Pediatric-type FL should be distinguished from the more aggressive provisional entity "large B-cell lymphoma with IRF4 rearrangement," which can also present in children and young adults with a follicular growth pattern . Unlike pediatric-type FL, such cases have strong IRF4/MUM1 expression due to the presence of rearrangements involving this gene.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for FL includes other malignant and non-malignant causes of lymphadenopathy. A general approach to adults and children who present with lymphadenopathy is presented separately. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach" and "Evaluation of peripheral lymphadenopathy in adults".)
The most common pathologic entities that are difficult to differentiate from FL are reactive follicular hyperplasia, cutaneous follicle center cell lymphoma, T cell rich large B cell lymphoma, mantle cell lymphoma, and nodal marginal zone lymphoma (table 2). The latter is particularly relevant due to the existence of unusual FL variants that exhibit plasmacytic or "monocytoid B cell" differentiation, features that are common in marginal zone B cell lymphoma. In addition, the identification of histologic transformation to diffuse large B cell lymphoma is extremely important. The differential diagnosis and evaluation of peripheral adenopathy in adults is presented separately. (See "Evaluation of peripheral lymphadenopathy in adults".)
The differential diagnosis of patients presenting with primary intestinal FL includes benign and malignant growths of the gastrointestinal tract. (See "Epidemiology, clinical features, and types of small bowel neoplasms" and "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)
Reactive follicular hyperplasia — FL recapitulates the normal germinal centers of secondary lymphoid follicles seen in reactive follicular hyperplasia. As such, it can be difficult to distinguish these two entities morphologically, but subtle differences usually are present that can be discerned readily by experienced hematopathologists. Reactive follicular hyperplasia is marked by the presence of discrete follicles of varying sizes and shapes that are separated from one another by interfollicular regions rich in T cells within the lymph node cortex. By contrast, the neoplastic follicles of FL tend to show little variation in size and shape, and are typically found back-to-back, with little interfollicular tissue, throughout the node (picture 2).
In both reactive follicular hyperplasia and FL, T cells and follicular dendritic cells are present; however, tingible body (debris-laden) macrophages are not typically observed in FL but are prominent in reactive follicular hyperplasia . A further clue is that neoplastic follicles do not exhibit polarization, whereas reactive follicles are typically polarized into centroblast-rich dark zones and centrocyte-rich light zones. In addition, the Ki-67+ fraction is generally lower in FL than in reactive follicles.
Perhaps the most useful differentiating characteristic is that cytoplasmic staining for BCL2 protein is strongly positive in almost all grade 1/2 FL, and is universally negative in reactive follicular hyperplasia (picture 12). However, a high fraction of cutaneous FL, childhood FL, and systemic grade 3 FL tumors do not express BCL2. As such, the presence of cytoplasmic BCL2 rules out reactive follicular hyperplasia, but its absence is not as straightforward to interpret.
Primary cutaneous follicle center lymphoma — Patients with FL often present with painless peripheral adenopathy. Extralymphatic tissues can be involved secondarily. In contrast, primary cutaneous lymphomas present in the skin and do not involve other tissues. Primary cutaneous lymphomas of germinal center B cell origin are classified separately as primary cutaneous follicle center lymphoma. Primary cutaneous follicle center lymphomas typically lack BCL2 rearrangements and BCL2 protein expression, which can help to discriminate these tumors from systemic FL. Primary cutaneous follicle center lymphoma is discussed in more detail separately. (See "Primary cutaneous follicle center lymphoma".)
Mantle cell lymphoma — FL is usually easily distinguished from mantle cell lymphoma (MCL) by the presence of a nodular growth pattern in FL. Rarely, FL has an entirely diffuse pattern of growth and a cell morphology that resembles MCL. In such cases, immunophenotyping is needed to confirm the diagnosis of FL and exclude MCL and chronic lymphocytic leukemia/small lymphocytic lymphoma. MCLs with a predominantly mantle zone growth pattern may also take on a nodular appearance, but in contrast to FL, MCL cells express cyclin D1 and CD5, and do not express BCL6 or CD10 (table 1). (See "Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma".)
T cell rich large B cell lymphoma — All cases of diffuse large B cell lymphoma (DLBCL) have some infiltrating reactive T cells and macrophages (histiocytes), but in some DLBCLs classified as T cell/histiocyte-rich large B cell lymphoma, small T cells predominate. On initial evaluation, the infiltrating T cells may resemble the small centrocytes of FL, while the scattered neoplastic B cells are fewer in number and resemble large centroblasts. Once the T cell origin of the small cells is identified, such cases are best classified as T cell rich large B cell lymphoma, a variant of diffuse large B cell lymphoma. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'T cell histiocyte-rich large B cell lymphoma'.)
Marginal zone lymphoma — Marginal zone lymphomas (MZL), both splenic and extranodal, can demonstrate a partially nodular pattern of growth that may resemble FL. MZL can usually be differentiated from FL by immunophenotype since, unlike FL, MZL does not usually express CD10, BCL2, or BCL6 (table 1). (See "Splenic marginal zone lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)
Histologic transformation — Histologic transformation of FL to a DLBCL occurs in up to 70 percent of patients over time and is associated with rapid progression of lymphadenopathy, infiltration of extranodal sites, development of systemic symptoms, elevated serum LDH, and often a poor prognosis.
Histology can vary greatly in different sections of the same lymph node. As such, careful examination of the sampled lymph node is key to determining whether a component of DLBCL is present. Discordant histologic features suggest histologic transformation of a previously undiagnosed indolent lymphoma. As an example, a small B cell proliferation may be identified in the bone marrow in a patient with large B cell involvement in a lymph node. The detection of areas of DLBCL within the lymph node denotes transformation to an aggressive phase of disease. This subject is discussed in detail separately. (See "Histologic transformation of follicular lymphoma".)
PROGNOSIS — The course of FL is variable. Some patients have waxing and waning disease for five years or more without therapy . Others with more disseminated disease and rapid tumor growth require treatment because massive nodal or organ enlargement leads to pain, lymphatic obstruction, or organ dysfunction .
At the time of diagnosis, the two best measures of outcome are the FL international prognostic index (FLIPI) and the PRIMA prognostic index (PRIMA-PI). Initial work suggests that the presence of particular acquired pathogenic mutations in FL has prognostic value [19,85,86], but further study is needed to support the incorporation of sequencing of FL genomes into routine care [19,85,86]. Prognostic features that aid in the decision to initiate therapy have been proposed by the Groupe d-Etude des Lymphomes Folliculaires (GELF)  and the British National Lymphoma Investigation (BNLI) . Our approach, described separately, incorporates factors of each. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Indications for treatment'.)
At the time of relapse, the best predictor of tumor aggressiveness is the duration of remission following initial treatment. This is discussed in more detail separately. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Recognize early treatment failure'.)
In addition, a subset of cases will undergo histologic transformation to a more aggressive lymphoma. Patients with histologic transformation generally have a worse prognosis and require more aggressive therapy. Prognostic factors for patients with histologic transformation are discussed in more detail separately. (See "Histologic transformation of follicular lymphoma", section on 'Prognosis and prognostic factors'.)
There is also evidence that the quality and quantity of the reactive cell response to the FL tumor cells influences biological behavior and outcome. Specifically, multiple studies indicate that an immune response rich in T cells predicts a better outcome, whereas an immune response dominated by macrophages is associated with a worse outcome [89-92]. (See 'Microenvironment' below.)
Follicular lymphoma IPI (FLIPI) — The Follicular Lymphoma International Prognostic Index (FLIPI) was devised based on an international study of long-term survival in >4000 patients with FL diagnosed between 1985 and 1992 and treated without rituximab (table 3) . The following five adverse prognostic factors were identified and used to identify risk groups with significantly different overall survival (OS):
●Age >60 years
●Stage III or IV (table 4)
●Hemoglobin level <12.0 g/dL
●Number of involved nodal areas >4 (figure 2)
●Serum lactate dehydrogenase level greater than the upper limit of normal
Several studies have validated the FLIPI in patients treated with rituximab-containing therapy [93-95]. In a prospective observational study of >2000 patients diagnosed with FL between 2004 and 2007 and managed by academic or community practices, rituximab was included in the initial management of the majority (68 percent), while a minority was managed initially with watchful waiting (17 percent) or non-rituximab-containing therapy (15 percent) . The three FLIPI risk groups differed significantly from each other in their estimates for progression-free survival (PFS) and OS:
●High-risk FLIPI (three or more adverse factors) – median PFS 42 months, two-year OS 87 percent
●Intermediate-risk FLIPI (two adverse factors) – median PFS 70 months, two-year OS 94 percent
●Low-risk FLIPI (zero to one adverse factors) – median PFS 84 months, two-year OS 98 percent
At a median follow-up of 58 months, median OS had not been reached. However, OS between the three arms was significantly different. As an example, when compared with low-risk disease, OS was significantly shorter for patients with intermediate (HR 2.37; 95% CI 1.64-3.41) or high (HR 6.17; 95% CI 4.47-8.53) risk disease.
PRIMA prognostic index (PRIMA-PI) — The PRIMA prognostic index (PRIMA-PI) was created using data from 1135 patients with advanced stage FL treated with initial chemoimmunotherapy with or without maintenance rituximab as part of the prospective PRIMA trial, and validated in another cohort of patients treated with chemoimmunotherapy [95,96].
The score uses beta-2 microglobulin and bone marrow involvement to identify three groups with different PFS after chemoimmunotherapy:
●High-risk PRIMA-PI – Beta-2 microglobulin >3 mg/L; five-year PFS 37 percent
●Intermediate-risk PRIMA-PI – Beta-2 microglobulin ≤3 mg/L with bone marrow involvement; five-year PFS 55 percent
●Low-risk PRIMA-PI – Beta-2 microglobulin ≤3 mg/L without bone marrow involvement; five-year PFS 69 percent
The PRIMA-PI has also been evaluated in a cohort of patients with advanced FL treated without chemotherapy ; In this cohort, the PRIMA-PI risk groups demonstrated the following rates of failure-free survival (FFS) and OS after initial rituximab with or without interferon:
●High-risk PRIMA-PI – five-year FFS 17 percent; five-year OS 78 percent
●Intermediate-risk PRIMA-PI – five-year FFS 39 percent; five-year OS 91 percent
●Low-risk PRIMA-PI – five-year FFS 41 percent; five-year OS 95 percent
The similar outcomes for the intermediate- and low-risk groups in this cohort question the prognostic value of bone marrow evaluation in patients treated with single-agent rituximab.
Tumor grade — FL tumors are graded on a scale from 1 to 3, and this grade appears to have some prognostic value. There has been poor consensus among pathologists on the determination of the grade of FL. However, the most commonly used grading system is presented above. (See 'Grade' above.)
The minor differences in clinical behavior and response to treatment have not supported a different treatment approach toward grade 1 versus grade 2 FL. Thus, although the grading system remains in place, for clinical decision making, grade 1 and 2 FL should be approached similarly and considered to be clinically indolent lymphomas . Molecular genetics as well as clinical behavior suggest that FL grade 3a is also an indolent disease [42,98-101].
By contrast, FL grade 3b is synonymous with what is often referred to as follicular large cell lymphoma . Unlike lower grade FLs, this histologic variant has a lesser tendency to involve the bone marrow or peripheral blood and often presents with larger lymphoid masses. Although follicular architecture is preserved, the clinical presentation, behavior, and outcome with treatment more closely approximates that of diffuse large B cell lymphoma (DLBCL) [100,102,103]. In contrast to DLBCL, the relapse rate of FL grade 3b is higher following combination chemotherapy, but the survival is longer [104,105]. The diagnosis of DLBCL is discussed in more detail separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)
Microenvironment — Studies point to the possibility that variation in the host immune response to cancer cells in the local microenvironment influences prognosis in a number of malignancies, including FL. These associations suggest that "crosstalk" between the neoplastic B cells and benign immune cells in the microenvironment has a strong bearing on the pathobiology of FL [106,107]. In some instances, interaction of FL cells with stromal cells may directly stimulate the growth and survival of FL cells. For example, over 80 percent of FLs acquire somatic mutations in rearranged, expressed IgM heavy chain alleles that create N-glycosylation sites [108,109], which are proposed to promote interactions between IgM on FL cells and CD206 and/or CD209 expressed on the surface of tumor infiltrating macrophages that stimulate B cell receptor signaling in FL cells [109,110].
The following observations illustrate findings that point to the importance of interactions between FL cells and immune cells in determining prognosis in FL [90,91,111-118]:
●Using gene expression profiling on tumor specimens obtained from 191 previously untreated patients with FL, the length of survival correlated with the molecular features of nonmalignant immune cells (eg, T cells, monocytes/macrophages, dendritic cells) present in the tumor at the time of diagnosis [90,111]. A two-signature model based on these results and divided into quartiles yielded median survivals of 14, 11, 11, and 4 years, respectively. These survival values were independent of the clinical variables included in the IPI. (See "Prognosis of diffuse large B cell lymphoma", section on 'International Prognostic Index'.)
●In a study of 139 patients with FL in whom flow cytometry had been performed on an involved lymph node, higher CD8+ T cell levels correlated with longer overall survival and disease-specific survival . Patients who had not required treatment within six months of diagnosis had significantly more CD8+ T cells than those who required treatment. The statistical significance of CD8+ T cells was independent of the FLIPI. (See 'Follicular lymphoma IPI (FLIPI)' above.)
●Among 97 and 37 patients with FL studied at diagnosis or first relapse, respectively, higher percentages of FOXP3+ regulatory T (Treg) cells correlated directly with higher rates of OS at five years, while very low numbers were associated with refractory disease or histologic transformation to DLBCL . The prognostic significance of Treg cell numbers was independent of the FLIPI.
●In another study, FL with reduced immune infiltration on biopsy was more likely to experience progression within 24 months of initial therapy, a finding associated with inferior survival . The impact of immune infiltration appeared to be independent from the tumor mutational profile.
Major challenges in this field include the limited reproducibility of the techniques used, variability of antibodies used, and interobserver variability in scoring . Increased reliance on small samples (eg, needle core biopsies) for diagnosis may also negatively affect the predictive value of these analyses. Ongoing studies will help to expand upon and clarify these observations, which have potentially important implications for the pathobiology of FL, but have yet to yield actionable predictive biomarkers.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Follicular lymphoma (The Basics)")
●Beyond the Basics topics (see "Patient education: Follicular lymphoma in adults (Beyond the Basics)")
●Epidemiology and clinical presentation – Follicular lymphoma (FL) is the second most common lymphoma in the United States and Western Europe. It most frequently presents in middle-aged White individuals. (See 'Epidemiology' above.)
Patients with FL usually present with painless peripheral adenopathy, often with a long history of waxing and waning lymph node enlargement. Widespread disseminated disease is usually present at baseline, but patients are typically asymptomatic aside from their lymphadenopathy. There are no characteristic laboratory abnormalities and, despite the large tumor burden, the majority has a normal serum lactate dehydrogenase (LDH) level. (See 'Adults' above.)
●Pathologic features – On histology, a nodular growth pattern and cell morphology consisting of a mixture of centrocytes and centroblasts is characteristic. The proportion of centroblasts found in the sample determines the tumor grade, which has therapeutic implications. Involvement of the bone marrow and peripheral blood is often seen but may not be prominent. (See 'Morphologic features' above.)
The tumor cells express monotypic immunoglobulin light chain, CD20 (or CD19), CD10, and BCL-6 and are negative for CD5 and CD23 (table 1). The vast majority (>85 percent) of tumors express BCL-2. (See 'Immunophenotype' above.)
Molecular genetics can confirm the presence of immunoglobulin gene rearrangements and the t(14;18) involving BCL2, which is not specific for FL. (See 'Molecular genetics' above.)
●Diagnosis – The diagnosis of FL is primarily made based on the evaluation of a lymph node biopsy in a patient who has had a history of waxing and waning lymphadenopathy. In classic cases, the histologic appearance of FL is so characteristic that it is one of the few forms of non-Hodgkin lymphoma that pathologists can diagnose based on morphology alone. (See 'Diagnosis' above.)
Typically, the tumor has a distinctly nodular growth pattern and is comprised of a mixture of centrocytes and centroblasts (picture 1 and picture 8A). However, FL has many less common morphologic variants, and sometimes lymph nodes are only partially involved. In these situations, the diagnosis is based on a combination of morphologic and immunophenotypic findings.
●Differential diagnosis – The differential diagnosis for FL is comprised of other malignant and non-malignant diseases that result in lymphadenopathy (table 2). (See 'Differential diagnosis' above and "Evaluation of peripheral lymphadenopathy in adults".)
●Prognosis – The course of FL is quite variable. The two best measures of outcome are the Follicular Lymphoma International Prognostic Index (FLIPI) (table 3) and the PRIMA prognostic index (PRIMA-PI). There is also increasing evidence that the immune response to the tumor influences clinical behavior and outcome. (See 'Prognosis' above.)