Abstract
Follicular lymphoma (FL) is a B-cell lymphoma that recapitulates the germinal center (GC)-B-cell stage of differentiation and in most cases form neoplastic follicles that resemble the normal GC. Normal GCB-cells do not express the anti-apoptotic protein B-cell leukemia/lymphoma 2 (BCL2) and they readily undergo apoptosis if they do not have a high affinity antigen receptor that will transmit survival signals on recognition of the antigen. The vast majority of FL has a translocation that leads to an inappropriate constitutive expression of the BCL2 protein that protects the cell from apoptosis. This cell can survive for long periods in the GC environment and undergoes further genetic alterations that eventually establish the neoplastic clonal population as a FL. These critical secondary changes are of great interest in understanding the evolution of a pre-neoplastic clone with BCL2 translocation to a malignant lymphoma.
Alyssa Bouska and SharathKumar Bagvati contributed equally.
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References
Ansari KI, Mandal SS (2010) Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J 277(8):1790–1804
Ardeshna KM, Smith P et al (2003) Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362(9383):516–522
Ardeshna KM, Qian W et al (2010) An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with Stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (Grades 1, 2 and 3a). A preliminary analysis. ASH Annu Meet Abstr 116(21):6
Bodor C, O’Riain C et al (2011) EZH2 Y641 mutations in follicular lymphoma. Leukemia 25(4):726–729
Butler MP, Iida S et al (2002) Alternative translocation breakpoint cluster region 5′ to BCL-6 in B-cell non-Hodgkin’s lymphoma. Cancer Res 62(14):4089–4094
Butsch R, Lukas Waelti S et al (2011) Intratumoral plasmacytoid dendritic cells associate with increased survival in patients with follicular lymphoma. Leuk Lymphoma 52(7):1230–1238
Camacho FI, Bellas C et al (2011) Improved demonstration of immunohistochemical prognostic markers for survival in follicular lymphoma cells. Mod Pathol 24(5):698–707
Carlotti E, Wrench D et al (2009) Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone. Blood 113(15):3553–3557
Cerroni L, Kerl H (2001) Primary cutaneous follicle center cell lymphoma. Leuk Lymphoma 42(5):891–900
Cheung KJ, Shah SP et al (2009) Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances. Blood 113(1):137–148
Cheung KJ, Delaney A et al (2010a) High resolution analysis of follicular lymphoma genomes reveals somatic recurrent sites of copy-neutral loss of heterozygosity and copy number alterations that target single genes. Genes Chromosom Cancer 49(8):669–681
Cheung KJ, Johnson NA et al (2010b) Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis. Cancer Res 70(22):9166–9174
Chim CS, Wong KY et al (2004) SOCS1 and SHP1 hypermethylation in mantle cell lymphoma and follicular lymphoma: implications for epigenetic activation of the Jak/STAT pathway. Leukemia 18(2):356–358
Chim CS, Wong KY et al (2007) Frequent epigenetic inactivation of Rb1 in addition to p15 and p16 in mantle cell and follicular lymphoma. Hum Pathol 38(12):1849–1857
Coe BP, Ylstra B et al (2007) Resolving the resolution of array CGH. Genomics 89(5):647–653
Coelho V, Krysov S et al (2010) Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc Natl Acad Sci U S A 107(43):18587–18592
d’Amore F, Chan E et al (2008) Clonal evolution in t(14;18)-positive follicular lymphoma, evidence for multiple common pathways, and frequent parallel clonal evolution. Clin Cancer Res 14(22):7180–7187
Dave SS, Wright G et al (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21):2159–2169
Davies AJ, Rosenwald A et al (2007) Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms. Br J Haematol 136(2):286–293
Eide MB, Liestol K et al (2010) Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallel evolution of tumor cell clones. Blood 116(9):1489–1497
Elenitoba-Johnson KS, Jenson SD et al (2003) Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc Natl Acad Sci U S A 100(12):7259–7264
Farinha P, Masoudi H et al (2005) Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 106(6):2169–2174
Federico M, Bellei M et al (2009) Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27(27):4555–4562
Fitzgibbon J, Iqbal S et al (2007) Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma. Leukemia 21(7):1514–1520
Freedman A, Aster J (2010) Clinical manifestations, pathologic features, and diagnosis of follicular lymphoma. UptoDate. D. Basow. Waltham, Wolters Kluwer
Frizzera G, Murphy SB (1979) Follicular (nodular) lymphoma in childhood: a rare clinical-pathological entity. Report of eight cases from four cancer centers. Cancer 44(6):2218–2235
Ganti AK, Weisenburger DD et al (2006) Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska lymphoma study group experience. Ann Oncol 17(6):920–927
Gronbaek K, Ralfkiaer U et al (2008) Frequent hypermethylation of DBC1 in malignant lymphoproliferative neoplasms. Mod Pathol 21(5):632–638
Gu K, Fu K et al (2009) t(14;18)-negative follicular lymphomas are associated with a high frequency of BCL6 rearrangement at the alternative breakpoint region. Mod Pathol 22(9):1251–1257
Hagiwara K, Nagai H et al (2007) Frequent DNA methylation but not mutation of the ID4 gene in malignant lymphoma. J Clin Exp Hematop 47(1):15–18
Hainsworth JD, Burris HA 3rd et al (2000) Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood 95(10):3052–3056
Hainsworth JD, Litchy S et al (2002) Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J Clin Oncol 20(20):4261–4267
Hannibal MC, Buckingham KJ et al (2011) Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. Am J Med Genet A 155(7):1511–1516
Hayslip J, Montero A (2006) Tumor suppressor gene methylation in follicular lymphoma: a comprehensive review. Mol Cancer 5:44
Hiddemann W, Kneba M et al (2005) Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German low-grade lymphoma study group. Blood 106(12):3725–3732
Hoglund M, Sehn L et al (2004) Identification of cytogenetic subgroups and karyotypic pathways of clonal evolution in follicular lymphomas. Genes Chromosom Cancer 39(3):195–204
Horn H, Schmelter C et al (2011) Follicular lymphoma grade 3b is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica 96(9):1327–1334
Irish JM, Czerwinski DK et al (2006) Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. Blood 108(9):3135–3142
Jin MK, Hoster E et al (2011) Follicular dendritic cells in follicular lymphoma and types of non-Hodgkin lymphoma show reduced expression of CD23, CD35 and CD54 but no association with clinical outcome. Histopathology 58(4):586–592
Juweid ME, Stroobants S et al (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the imaging subcommittee of international harmonization project in lymphoma. J Clin Oncol 25(5):571–578
Kallioniemi A, Kallioniemi OP et al (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258(5083):818–821
Kelley T, Beck R et al (2007) Biologic predictors in follicular lymphoma: importance of markers of immune response. Leuk Lymphoma 48(12):2403–2411
Koyama M, Oka T et al (2003) Activated proliferation of B-cell lymphomas/leukemias with the SHP1 gene silencing by aberrant CpG methylation. Lab Invest 83(12):1849–1858
Krivtsov AV, Armstrong SA (2007) MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7(11):823–833
Lee AM, Clear AJ et al (2006) Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol 24(31):5052–5059
Leich E, Salaverria I et al (2009) Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood 114(4):826–834
Limpens J, Stad R et al (1995) Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 85(9):2528–2536
Lossos IS, Alizadeh AA et al (2002) Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci U S A 99(13):8886–8891
Lu D, Medeiros LJ et al (2001) Primary follicular large cell lymphoma of the testis in a child. Arch Pathol Lab Med 125(4):551–554
Mac Manus MP, Hoppe RT (1996) Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14(4):1282–1290
Martinez-Climent JA, Alizadeh AA et al (2003) Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations. Blood 101(8):3109–3117
Matolcsy A, Casali P et al (1996) Morphologic transformation of follicular lymphoma is associated with somatic mutation of the translocated Bcl-2 gene. Blood 88(10):3937–3944
Matolcsy A, Schattner EJ et al (1999) Clonal evolution of B cells in transformation from low- to high-grade lymphoma. Eur J Immunol 29(4):1253–1264
Montes-Moreno S, Castro Y et al (2010) Intrafollicular neoplasia/in situ follicular lymphoma: review of a series of 13 cases. Histopathology 56(5):658–662
Moormeier JA, Williams SF et al (1990) The staging of non-Hodgkin’s lymphomas. Semin Oncol 17(1):43–50
Morin RD, Johnson NA et al (2010a) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 42(2):181–185
Morin RD, Mungall AJ et al (2010b) Mutations in MLL2 and MEF2B genes in follicular lymphoma and diffuse large B-cell lymphoma 2010. American Society of Hematology (ASH). https://ash.confex.com/ash/2010/webprogram/Paper30713.html
Nagy M, Balazs M et al (2000) Genetic instability is associated with histological transformation of follicle center lymphoma. Leukemia 14(12):2142–2148
Nanjangud G, Rao PH et al (2007) Molecular cytogenetic analysis of follicular lymphoma (FL) provides detailed characterization of chromosomal instability associated with the t(14;18)(q32;q21) positive and negative subsets and histologic progression. Cytogenet Genome Res 118(2–4):337–344
O’Shea D, O’Riain C et al (2008) 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 112(8):3126–3129
O’Shea D, O’Riain C et al (2009) Regions of acquired uniparental disomy at diagnosis of follicular lymphoma are associated with both overall survival and risk of transformation. Blood 113(10):2298–2301
Ott G, Katzenberger T et al (2002) Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 99(10):3806–3812
Pasqualucci L, Dominguez-Sola D et al (2011) Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471(7337):189–195
Pinto A, Hutchison RE et al (1990) Follicular lymphomas in pediatric patients. Mod Pathol 3(3):308–313
Pinyol M, Cobo F et al (1998) p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin’s lymphomas. Blood 91(8):2977–2984
Rambaldi A, Carlotti E et al (2005) Quantitative PCR of bone marrow BCL2/IgH+  cells at diagnosis predicts treatment response and long-term outcome in follicular non-Hodgkin lymphoma. Blood 105(9):3428–3433
Rosenberg SA (1977) Validity of the Ann Arbor staging classification for the non-Hodgkin’s lymphomas. Cancer Treat Rep 61(6):1023–1027
Ross CW, Ouillette PD et al (2007) Comprehensive analysis of copy number and allele status identifies multiple chromosome defects underlying follicular lymphoma pathogenesis. Clin Cancer Res 13(16):4777–4785
Salles GA, Seymour JF et al (2010) Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy. J Clin Oncol Meet Abstr 28(15_Suppl):8004
Sander CA, Yano T et al (1993) p53 mutation is associated with progression in follicular lymphomas. Blood 82(7):1994–2004
Schraders M, de Jong D et al (2005) 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 205(3):329–335
Schwaenen C, Viardot A et al (2009) Microarray-based genomic profiling reveals novel genomic aberrations in follicular lymphoma which associate with patient survival and gene expression status. Genes Chromosom Cancer 48(1):39–54
Sneeringer CJ, Scott MP et al (2010) Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A 107(49):20980–20985
Stamatopoulos K, Kosmas C et al (1997) Follicular lymphoma immunoglobulin kappa light chains are affected by the antigen selection process, but to a lesser degree than their partner heavy chains. Br J Haematol 96(1):132–146
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (2008) Follicular lymphoma. WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, Lyon. WHO press
Szereday Z, Csernus B et al (2000) Somatic mutation of the 5′ noncoding region of the BCL-6 gene is associated with intraclonal diversity and clonal selection in histological transformation of follicular lymphoma. Am J Pathol 156(3):1017–1024
Tari A, Asaoku H et al (2011) Clinical features of gastrointestinal follicular lymphoma: comparison with nodal follicular lymphoma and gastrointestinal MALT lymphoma. Digestion 83(3):191–197
Tomita N (2011) BCL2 And MYC dual-hit lymphoma/leukemia. J Clin Exp Hematop 51(1):7–12
Torlakovic EE, Bilalovic N et al (2006) Prognostic significance of PU.1 in follicular lymphoma. J Pathol 209(3):352–359
van Oers MH, Tonnissen E et al (2010) BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC 20981 phase III intergroup study. J Clin Oncol 28(13):2246–2252
Velichutina I, Shaknovich R et al (2010) EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116(24):5247–5255
Vire E, Brenner C et al (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439(7078):871–874
Wahlin BE, Sander B et al (2007) CD8+ T-cell content in diagnostic lymph nodes measured by flow cytometry is a predictor of survival in follicular lymphoma. Clin Cancer Res 13(2 Pt 1):388–397
Wahlin BE, Aggarwal M et al (2010) A unifying microenvironment model in follicular lymphoma: outcome is predicted by programmed death-1–positive, regulatory, cytotoxic, and helper T cells and macrophages. Clin Cancer Res 16(2):637–650
Wang SA, Wang L et al (2005) Low histologic grade follicular lymphoma with high proliferation index: morphologic and clinical features. Am J Surg Pathol 29(11):1490–1496
William BM, Bierman PJ (2010) I-131 tositumomab. Expert Opin Biol Ther 10(8):1271–1278
Wilson WH, Armitage JO (2008) Non-Hodgkin’s lymphoma. In: Abeloff MDA, Armitage JO, Niederhuber JE, Kastan MB, Gillies McKenna WG (eds) Abeloff’s clinical oncology, 4th edn. Churchill Livingstone, Philadelphia, pp 2371–2404
Yang H, Chen CM et al (2003) The androgen receptor gene is preferentially hypermethylated in follicular non-Hodgkin’s lymphomas. Clin Cancer Res 9(11):4034–4042
Yano T, Jaffe ES et al (1992) MYC rearrangements in histologically progressed follicular lymphomas. Blood 80(3):758–767
Ye BH, Lista F et al (1993) Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262(5134):747–750
Ylstra B, van den Ijssel P et al (2006) BAC to the future! or oligonucleotides: a perspective for micro array comparative genomic hybridization (array CGH). Nucleic Acids Res 34(2):445–450
Young RC, Longo DL et al (1988) The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 25(2 Suppl 2):11–16
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Bouska, A., Bagvati, S., Iqbal, J., William, B.M., Chan, W.C. (2012). Follicular Lymphoma: Recent Advances. In: Tao, J., Sotomayor, E. (eds) Hematologic Cancers: From Molecular Pathobiology to Targeted Therapeutics. Cancer Growth and Progression, vol 14. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5028-9_2
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