Pathobiology of follicular lymphoma
- Jennifer R Brown, MD, PhD
Jennifer R Brown, MD, PhD
- Associate Professor
- Harvard Medical School
- Arnold S Freedman, MD
Arnold S Freedman, MD
- Section Editor — Lymphoproliferative Disorders
- Professor of Medicine
- Harvard Medical School
- Jon C Aster, MD
Jon C Aster, MD
- Professor of Pathology
- Harvard Medical School
Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphomas. It is defined as a lymphoma of follicle center B cells, and virtually always demonstrates a growth pattern that is partially follicular. (See "Classification of the hematopoietic neoplasms".)
The molecular pathogenesis of FL is a complex, multistep process during which a single follicular B cell acquires all of the genetic and epigenetic alterations needed for malignant transformation. The resultant tumor is usually comprised of a mixture of centrocytes (small cleaved follicular center cells) and centroblasts (large noncleaved follicular center cells). Some common steps in this pathway have been elucidated, particularly chromosomal rearrangements involving BCL-2 and certain somatic mutations, some of which are also seen in other non-Hodgkin lymphoma variants. These lesions typically persist and are joined by other acquired lesions in the not uncommon instance in which FL evolves into a more aggressive lymphoma, usually diffuse large B cell lymphoma, an event referred to as histologic transformation. (See "Histologic transformation of follicular lymphoma".)
This review will discuss the pathobiology of FL in adults. In contrast, a different form of FL that mainly develops in children and adolescents appears to have distinctive clinical and pathologic features. The epidemiology, clinical presentation, pathologic features, diagnosis, treatment, and prognosis of FL are discussed separately. General aspects of the pathobiology of non-Hodgkin lymphoma are also discussed separately. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma" and "Initial treatment of limited stage (I/II) follicular lymphoma" and "Treatment of relapsed or refractory follicular lymphoma" and "Overview of the pathobiology of the non-Hodgkin lymphomas".)
CELL OF ORIGIN
Follicular lymphoma (FL) is a heterogeneous clinicopathologic entity that has as a common feature an origin from germinal center B cells . The tumor is comprised of variable numbers of small, cleaved cells (centrocytes) and larger, blastoid cells (centroblasts) that morphologically resemble cells found in the light and dark zones of normal germinal centers, respectively. The germinal center ancestry of these cells is principally supported by the identification of somatic mutations in the variable region of the immunoglobulin genes (IgVH), which serves as a marker of germinal center transit , the follicular growth pattern of the tumor cells in most cases, and the immunophenotype of the tumor cells, which in most respects closely resembles that of normal follicle center B cells. (See "Overview of the pathobiology of the non-Hodgkin lymphomas", section on 'B cell lymphoma'.)
Overview — The development of the majority of follicular lymphoma (FL) tumors in adults is dependent upon the overexpression of B cell leukemia/lymphoma 2 (BCL-2) located on chromosome band 18q21. BCL-2 is an oncogene that blocks programmed cell death (apoptosis). As such, overexpression results in prolonged cell survival. BCL-2 overexpression in itself is not sufficient for FL development and other genetic lesions or host factors are required (figure 1). (See 'Other genetic lesions' below.)
- Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
- Ottensmeier CH, Thompsett AR, Zhu D, et al. Analysis of VH genes in follicular and diffuse lymphoma shows ongoing somatic mutation and multiple isotype transcripts in early disease with changes during disease progression. Blood 1998; 91:4292.
- Raghavan SC, Swanson PC, Wu X, et al. A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex. Nature 2004; 428:88.
- Korsmeyer SJ. Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 1992; 80:879.
- Nuñez G, Hockenbery D, McDonnell TJ, et al. Bcl-2 maintains B cell memory. Nature 1991; 353:71.
- McDonnell TJ, Deane N, Platt FM, et al. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 1989; 57:79.
- Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2002; 2:647.
- Cory S, Adams JM. Killing cancer cells by flipping the Bcl-2/Bax switch. Cancer Cell 2005; 8:5.
- Boise LH, González-García M, Postema CE, et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993; 74:597.
- Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74:609.
- Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 1996; 88:386.
- Ghia P, Boussiotis VA, Schultze JL, et al. Unbalanced expression of bcl-2 family proteins in follicular lymphoma: contribution of CD40 signaling in promoting survival. Blood 1998; 91:244.
- Limpens J, de Jong D, van Krieken JH, et al. Bcl-2/JH rearrangements in benign lymphoid tissues with follicular hyperplasia. Oncogene 1991; 6:2271.
- Aster JC, Kobayashi Y, Shiota M, et al. Detection of the t(14;18) at similar frequencies in hyperplastic lymphoid tissues from American and Japanese patients. Am J Pathol 1992; 141:291.
- Limpens J, Stad R, Vos C, et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 1995; 85:2528.
- Dölken G, Illerhaus G, Hirt C, Mertelsmann R. BCL-2/JH rearrangements in circulating B cells of healthy blood donors and patients with nonmalignant diseases. J Clin Oncol 1996; 14:1333.
- Roulland S, Navarro JM, Grenot P, et al. Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis. J Exp Med 2006; 203:2425.
- Roulland S, Kelly RS, Morgado E, et al. t(14;18) Translocation: A predictive blood biomarker for follicular lymphoma. J Clin Oncol 2014; 32:1347.
- Bloomfield CD, Arthur DC, Frizzera G, et al. Nonrandom chromosome abnormalities in lymphoma. Cancer Res 1983; 43:2975.
- Rowley JD. Chromosome studies in the non-Hodgkin's lymphomas: the role of the 14;18 translocation. J Clin Oncol 1988; 6:919.
- Graninger WB, Seto M, Boutain B, et al. Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. J Clin Invest 1987; 80:1512.
- Ngan BY, Chen-Levy Z, Weiss LM, et al. Expression in non-Hodgkin's lymphoma of the bcl-2 protein associated with the t(14;18) chromosomal translocation. N Engl J Med 1988; 318:1638.
- Schraders M, de Jong D, Kluin P, et al. Lack of Bcl-2 expression in follicular lymphoma may be caused by mutations in the BCL2 gene or by absence of the t(14;18) translocation. J Pathol 2005; 205:329.
- Leich E, Salaverria I, Bea S, et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood 2009; 114:826.
- Ott G, Katzenberger T, Lohr A, et al. Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 2002; 99:3806.
- Bosga-Bouwer AG, van Imhoff GW, Boonstra R, et al. Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive. Blood 2003; 101:1149.
- Díaz-Alderete A, Doval A, Camacho F, et al. Frequency of BCL2 and BCL6 translocations in follicular lymphoma: relation with histological and clinical features. Leuk Lymphoma 2008; 49:95.
- Ye BH, Lista F, Lo Coco F, et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 1993; 262:747.
- Gaidano G, Ballerini P, Gong JZ, et al. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 1991; 88:5413.
- Schwaenen C, Viardot A, Berger H, et al. Microarray-based genomic profiling reveals novel genomic aberrations in follicular lymphoma which associate with patient survival and gene expression status. Genes Chromosomes Cancer 2009; 48:39.
- Cheung KJ, Shah SP, Steidl C, et al. Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances. Blood 2009; 113:137.
- Launay E, Pangault C, Bertrand P, et al. High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 2012; 26:559.
- Green MR, Gentles AJ, Nair RV, et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood 2013; 121:1604.
- Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011; 471:189.
- Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 2011; 476:298.
- Bödör C, Grossmann V, Popov N, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood 2013; 122:3165.
- Zhang J, Dominguez-Sola D, Hussein S, et al. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat Med 2015; 21:1190.
- Okosun J, Wolfson RL, Wang J, et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat Genet 2016; 48:183.
- Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361.
- Lo Coco F, Gaidano G, Louie DC, et al. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood 1993; 82:2289.
- Sander CA, Yano T, Clark HM, et al. p53 mutation is associated with progression in follicular lymphomas. Blood 1993; 82:1994.
- O'Shea D, O'Riain C, Taylor C, et al. The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival. Blood 2008; 112:3126.
- Callanan MB, Le Baccon P, Mossuz P, et al. The IgG Fc receptor, FcgammaRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma. Proc Natl Acad Sci U S A 2000; 97:309.
- Bende RJ, Smit LA, van Noesel CJ. Molecular pathways in follicular lymphoma. Leukemia 2007; 21:18.
- de Jong D. Molecular pathogenesis of follicular lymphoma: a cross talk of genetic and immunologic factors. J Clin Oncol 2005; 23:6358.
- Carbone A, Gloghini A, Gruss HJ, Pinto A. CD40 ligand is constitutively expressed in a subset of T cell lymphomas and on the microenvironmental reactive T cells of follicular lymphomas and Hodgkin's disease. Am J Pathol 1995; 147:912.
- Petrasch S, Kosco M, Schmitz J, et al. Follicular dendritic cells in non-Hodgkin-lymphoma express adhesion molecules complementary to ligands on neoplastic B-cells. Br J Haematol 1992; 82:695.
- Lindhout E, Mevissen ML, Kwekkeboom J, et al. Direct evidence that human follicular dendritic cells (FDC) rescue germinal centre B cells from death by apoptosis. Clin Exp Immunol 1993; 91:330.
- Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004; 351:2159.
- Alvaro T, Lejeune M, Salvadó MT, et al. Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol 2006; 24:5350.
- Farinha P, Masoudi H, Skinnider BF, et al. Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 2005; 106:2169.
- Glas AM, Knoops L, Delahaye L, et al. Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma. J Clin Oncol 2007; 25:390.
- Coupland SE. The challenge of the microenvironment in B-cell lymphomas. Histopathology 2011; 58:69.
- Laurent C, Müller S, Do C, et al. Distribution, function, and prognostic value of cytotoxic T lymphocytes in follicular lymphoma: a 3-D tissue-imaging study. Blood 2011; 118:5371.
- Amin R, Mourcin F, Uhel F, et al. DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma. Blood 2015; 126:1911.
- Linley A, Krysov S, Ponzoni M, et al. Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells. Blood 2015; 126:1902.
- Ansell SM. Malignant B cells at the helm in follicular lymphoma. J Clin Oncol 2013; 31:2641.
- Kiaii S, Clear AJ, Ramsay AG, et al. Follicular lymphoma cells induce changes in T-cell gene expression and function: potential impact on survival and risk of transformation. J Clin Oncol 2013; 31:2654.
- Husson H, Carideo EG, Neuberg D, et al. Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arrays. Blood 2002; 99:282.