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Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma

Jennifer R Brown, MD, PhD
Arnold S Freedman, MD
Jon C Aster, MD
Section Editor
Andrew Lister, MD, FRCP, FRCPath, FRCR
Deputy Editor
Alan G Rosmarin, MD


Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 25 percent of adult NHL cases. (See "Classification of the hematopoietic neoplasms".)

The molecular pathogenesis of DLBCL is a complex, multistep process that ultimately results in the transformation and expansion of a malignant clone of germinal or post-germinal B cell origin. While some steps in this pathway have been elucidated, many remain unknown. The best-characterized oncogenic events are acquired genetic lesions (eg, rearrangements of BCL6, BCL2, and MYC), many of which are also seen in other NHL variants. This may reflect in part the not uncommon evolution of low-grade lymphoma into DLBCL. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Histologic transformation of follicular lymphoma" and "Pathobiology and treatment of Richter's transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)

The following sections will describe genetic changes, aberrant gene and protein expression, and other alterations that are thought to play a role in the development of DLBCL. It is increasingly appreciated that the diagnostic category of "DLBCL" is heterogeneous in terms of morphology, genetics, and biologic behavior. The 2016 World Health Organization classification of lymphoid neoplasms recommends that immunohistochemistry and/or gene expression profiling be used to subclassify "typical" DLBCL into tumors of germinal center and non-germinal center origin, in recognition that these two classes of tumors have different prognoses with current therapies [1]. Most of the non-germinal center tumors fall into a specific category, termed the activated B cell (ABC) type, so named based on a resemblance in terms of gene expression to normal activated B cells, whereas others into an unclassifiable category. In addition, a number of clinicopathologic entities are recognized that are sufficiently distinct to be considered separate diagnostic and/or therapeutic categories:

T cell rich large B cell lymphoma. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Initial treatment of advanced stage diffuse large B cell lymphoma".)

Primary diffuse large B cell lymphoma of the mediastinum, also called primary mediastinal large B cell lymphoma. (See "Primary mediastinal large B cell lymphoma".)

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Literature review current through: Nov 2017. | This topic last updated: Dec 05, 2017.
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  1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127:2375.
  2. Stevenson F, Sahota S, Zhu D, et al. Insight into the origin and clonal history of B-cell tumors as revealed by analysis of immunoglobulin variable region genes. Immunol Rev 1998; 162:247.
  3. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010; 362:1417.
  4. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463:88.
  5. Migliazza A, Martinotti S, Chen W, et al. Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma. Proc Natl Acad Sci U S A 1995; 92:12520.
  6. 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.
  7. Chang CC, Ye BH, Chaganti RS, Dalla-Favera R. BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proc Natl Acad Sci U S A 1996; 93:6947.
  8. Parekh S, Polo JM, Shaknovich R, et al. BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms. Blood 2007; 110:2067.
  9. Phan RT, Saito M, Basso K, et al. BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells. Nat Immunol 2005; 6:1054.
  10. Shen HM, Peters A, Baron B, et al. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 1998; 280:1750.
  11. Pasqualucci L, Migliazza A, Fracchiolla N, et al. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci U S A 1998; 95:11816.
  12. Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 2004; 432:635.
  13. Basso K, Dalla-Favera R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol 2015; 15:172.
  14. Cattoretti G, Chang CC, Cechova K, et al. BCL-6 protein is expressed in germinal-center B cells. Blood 1995; 86:45.
  15. Tunyaplin C, Shaffer AL, Angelin-Duclos CD, et al. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol 2004; 173:1158.
  16. Fearon DT, Manders PM, Wagner SD. Bcl-6 uncouples B lymphocyte proliferation from differentiation. Adv Exp Med Biol 2002; 512:21.
  17. Ye BH, Cattoretti G, Shen Q, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997; 16:161.
  18. Cattoretti G, Pasqualucci L, Ballon G, et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 2005; 7:445.
  19. Basso K, Saito M, Sumazin P, et al. Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells. Blood 2010; 115:975.
  20. Ci W, Polo JM, Cerchietti L, et al. The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood 2009; 113:5536.
  21. Capello D, Vitolo U, Pasqualucci L, et al. Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. Blood 2000; 95:651.
  22. Jardin F, Bastard C, Contentin N, et al. Intronic BCL-6 mutations are preferentially targeted to the translocated allele in t(3;14)(q27;q32) non-Hodgkin B-cell lymphoma. Blood 2003; 102:1872.
  23. Lo Coco F, Ye BH, Lista F, et al. Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. Blood 1994; 83:1757.
  24. Gaidano G, Lo Coco F, Ye BH, et al. Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype. Blood 1994; 84:397.
  25. Dalla-Favera R, Migliazza A, Chang CC, et al. Molecular pathogenesis of B cell malignancy: the role of BCL-6. Curr Top Microbiol Immunol 1999; 246:257.
  26. Ye BH, Chaganti S, Chang CC, et al. Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J 1995; 14:6209.
  27. Kaneita Y, Yoshida S, Ishiguro N, et al. Detection of reciprocal fusion 5'-BCL6/partner-3' transcripts in lymphomas exhibiting reciprocal BCL6 translocations. Br J Haematol 2001; 113:803.
  28. Ying CY, Dominguez-Sola D, Fabi M, et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat Immunol 2013; 14:1084.
  29. Savage KJ, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 2003; 102:3871.
  30. Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011; 471:189.
  31. Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inactivates the transcriptional repressor BCL6. Nat Genet 2002; 32:606.
  32. Koduru PR, Raju K, Vadmal V, et al. Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma. Blood 1997; 90:4078.
  33. Ichikawa A, Kinoshita T, Watanabe T, et al. Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma. N Engl J Med 1997; 337:529.
  34. Young KH, Leroy K, Møller MB, et al. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 2008; 112:3088.
  35. Winter JN, Li S, Aurora V, et al. Expression of p21 protein predicts clinical outcome in DLBCL patients older than 60 years treated with R-CHOP but not CHOP: a prospective ECOG and Southwest Oncology Group correlative study on E4494. Clin Cancer Res 2010; 16:2435.
  36. Reddy A, Zhang J, Davis NS, et al. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell 2017; 171:481.
  37. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 2011; 476:298.
  38. Pasqualucci L, Dalla-Favera R. The genetic landscape of diffuse large B-cell lymphoma. Semin Hematol 2015; 52:67.
  39. Morin RD, Mungall K, Pleasance E, et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 2013; 122:1256.
  40. Müschen M, Re D, Jungnickel B, et al. Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction. J Exp Med 2000; 192:1833.
  41. Gordon MS, Kanegai CM, Doerr JR, Wall R. Somatic hypermutation of the B cell receptor genes B29 (Igbeta, CD79b) and mb1 (Igalpha, CD79a). Proc Natl Acad Sci U S A 2003; 100:4126.
  42. Pasqualucci L, Neumeister P, Goossens T, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 2001; 412:341.
  43. Mottok A, Renné C, Seifert M, et al. Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities. Blood 2009; 114:4503.
  44. Pasqualucci L, Bhagat G, Jankovic M, et al. AID is required for germinal center-derived lymphomagenesis. Nat Genet 2008; 40:108.
  45. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol 2010; 28:3360.
  46. Akasaka T, Akasaka H, Ueda C, et al. Molecular and clinical features of non-Burkitt's, diffuse large-cell lymphoma of B-cell type associated with the c-MYC/immunoglobulin heavy-chain fusion gene. J Clin Oncol 2000; 18:510.
  47. Kawasaki C, Ohshim K, Suzumiya J, et al. Rearrangements of bcl-1, bcl-2, bcl-6, and c-myc in diffuse large B-cell lymphomas. Leuk Lymphoma 2001; 42:1099.
  48. Sáez AI, Artiga MJ, Romero C, et al. Development of a real-time reverse transcription polymerase chain reaction assay for c-myc expression that allows the identification of a subset of c-myc+ diffuse large B-cell lymphoma. Lab Invest 2003; 83:143.
  49. Stasik CJ, Nitta H, Zhang W, et al. Increased MYC gene copy number correlates with increased mRNA levels in diffuse large B-cell lymphoma. Haematologica 2010; 95:597.
  50. Challa-Malladi M, Lieu YK, Califano O, et al. Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 2011; 20:728.
  51. Fangazio M, Dominguez-Sola D, Tabbo F, et al. Genetic mechanisms of immune escape in diffuse large B cell lymphoma. Blood (ASH Annual Meeting Abstracts) 2014; 124:1692.
  52. Cattoretti G, Mandelbaum J, Lee N, et al. Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation. Cancer Res 2009; 69:8686.
  53. Muppidi JR, Schmitz R, Green JA, et al. Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma. Nature 2014; 516:254.
  54. Flori M, Schmid CA, Sumrall ET, et al. The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling. Blood 2016; 127:1438.
  55. 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.
  56. Offit K, Lo Coco F, Louie DC, et al. Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med 1994; 331:74.
  57. 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.
  58. Morgensztern D, Martin MG, Lossos IS. Gene expression profiling in diffuse large B-cell lymphoma. Leuk Lymphoma 2007; 48:669.
  59. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403:503.
  60. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346:1937.
  61. Klapper W, Kreuz M, Kohler CW, et al. Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. Blood 2012; 119:1882.
  62. Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 2009; 15:5494.
  63. Lossos IS, Alizadeh AA, Eisen MB, et al. Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas. Proc Natl Acad Sci U S A 2000; 97:10209.
  64. Bea S, Zettl A, Wright G, et al. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 2005; 106:3183.
  65. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010; 42:181.
  66. Tam W, Gomez M, Chadburn A, et al. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood 2006; 107:4090.
  67. Smith PG, Wang F, Wilkinson KN, et al. The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma. Blood 2005; 105:308.
  68. Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001; 194:1861.
  69. Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 2009; 459:717.
  70. Monti S, Savage KJ, Kutok JL, et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 2005; 105:1851.
  71. Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood 2008; 111:2230.
  72. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115:2578.
  73. Shipp MA, Ross KN, Tamayo P, et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 2002; 8:68.
  74. Hans CP, Weisenburger DD, Greiner TC, et al. Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Mod Pathol 2005; 18:1377.
  75. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 2014; 123:1214.
  76. Steidl C, Gascoyne RD. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood 2011; 118:2659.
  77. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 2003; 198:851.
  78. Kanavaros P, Gaulard P, Charlotte F, et al. Discordant expression of immunoglobulin and its associated molecule mb-1/CD79a is frequently found in mediastinal large B cell lymphomas. Am J Pathol 1995; 146:735.
  79. Bentz M, Barth TF, Brüderlein S, et al. Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line. Genes Chromosomes Cancer 2001; 30:393.
  80. Joos S, Otaño-Joos MI, Ziegler S, et al. Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 1996; 87:1571.
  81. Rodig SJ, Savage KJ, LaCasce AS, et al. Expression of TRAF1 and nuclear c-Rel distinguishes primary mediastinal large cell lymphoma from other types of diffuse large B-cell lymphoma. Am J Surg Pathol 2007; 31:106.
  82. Dunphy CH, O'Malley DP, Cheng L, et al. Primary mediastinal B-cell lymphoma: detection of BCL2 gene rearrangements by PCR analysis and FISH. J Hematop 2008; 1:77.
  83. Iqbal J, Greiner TC, Patel K, et al. Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. Leukemia 2007; 21:2332.