Advertisement

Pathology and Molecular Pathogenesis of DLBCL and Related Entities

  • Laura PasqualucciEmail author
  • German Ott
Chapter
Part of the Hematologic Malignancies book series (HEMATOLOGIC)

Abstract

Diffuse large B-cell lymphomas (DLBCLs) comprise a diverse group of aggressive lymphoid tumors characterized by distinct genetic, phenotypic, and clinical features, with over ten entities recognized in the updated WHO classification of hematopoietic and lymphoid tissues. Among them, DLBCL not otherwise specified (NOS) represents the most common diagnosis, accounting for 25–30% of all B cell lymphoma cases. In recent years, significant progress has been made in our understanding of the molecular pathogenesis of these diseases, thanks to the development of powerful genomic technologies that enabled the definition of multiple phenotypic and molecular subtypes of the disease, often associated with discrete clinical outcomes. These studies revealed a multitude of genetic alterations that contribute to the malignant transformation process by disrupting functional programs critical for the biology of normal germinal center B cells, i.e., the normal counterpart of most DLBCL types. These include epigenetic remodeling, blockade of B-cell differentiation, escape from immune surveillance, and the dysregulated expression of several transcription factors/signal transduction pathways. This wealth of new information is offering unique opportunities for the development of improved diagnostic and prognostic tools that could assist in the clinical management of DLBCL patients. Importantly, a number of the identified mutated genes are potentially actionable targets that are currently being explored for the development of novel therapeutic strategies. In this chapter, we summarize current knowledge on the pathology, biology, and genetic basis of these diseases, with emphasis on its most common types.

Keywords

Diffuse large B-cell lymphoma Double-hit lymphoma Central nervous system Primary mediastinal B-cell lymphoma Germinal center Immunophenotype Genetic alterations BCL6 NF-κB Immune escape Epigenetic modifications 

Notes

Acknowledgments

The authors wish to thank Drs. Annette Staiger and Heike Horn for helpful discussions and editorial help and Dr. Marco Fangazio for help with Figs. 2.5 and 2.6.

References

  1. 1.
    Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Swerdlow SH Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO classification of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC; 2017.Google Scholar
  3. 3.
    Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumors of haematopoietic and lymphoid tissues. In: Bosman FT, Jaffe ES, Lakhani SR, Ohgaki H, editors. World Health Organization of tumor. Lyon: International Agency for Research on Cancer (IARC); 2008.Google Scholar
  4. 4.
    Jaffe ES, Arber DA, Campo E, Harris NL, Quintanilla-Fend L. Hematopathology. Philadelphia: Saunders/Elsevier; 2017.Google Scholar
  5. 5.
    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;346:1937–47.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Engelhard M, Brittinger G, Huhn D, et al. Subclassification of diffuse large B-cell lymphomas according to the Kiel classification: distinction of centroblastic and immunoblastic lymphomas is a significant prognostic risk factor. Blood. 1997;89:2291–7.PubMedGoogle Scholar
  7. 7.
    Lennert K, Feller AC. High grade malignant lymphoma of B-cell type. Histopathology of non-Hodgkin’s lymphoma. Berlin: Springer; 1990.Google Scholar
  8. 8.
    Ott G, Ziepert M, Klapper W, et al. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood. 2010;116:4916–25.PubMedGoogle Scholar
  9. 9.
    Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121:2253–63.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452–9.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Perry AM, Alvarado-Bernal Y, Laurini JA, et al. MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol. 2014;165:382–91.PubMedGoogle Scholar
  12. 12.
    Petrella T, Copie-Bergman C, Briere J, et al. BCL2 expression but not MYC and BCL2 coexpression predicts survival in elderly patients with diffuse large B-cell lymphoma independently of cell of origin in the phase 3 LNH03-6B trial. Ann Oncol. 2017;28(5):1042–9.PubMedGoogle Scholar
  13. 13.
    Valera A, Lopez-Guillermo A, Cardesa-Salzmann T, et al. MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica. 2013;98:1554–62.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Kuppers R, Klein U, Hansmann ML, Rajewsky K. Cellular origin of human B-cell lymphomas. N Engl J Med. 1999;341:1520–9.PubMedGoogle Scholar
  15. 15.
    Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla-Favera R, Nussenzweig MC. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood. 2012;120:2240–8.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Lenz G, Wright GW, Emre NC, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A. 2008;105:13520–5.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Pasqualucci L, Dalla-Favera R. The genetic landscape of diffuse large B-cell lymphoma. Semin Hematol. 2015;52:67–76.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Horn H, Staiger AM, Ott G. New targeted therapies for malignant lymphoma based on molecular heterogeneity. Expert Rev Hematol. 2017;10:39–51.PubMedGoogle Scholar
  20. 20.
    Rovira J, Karube K, Valera A, et al. MYD88 L265P mutations, but no other variants, identify a subpopulation of DLBCL patients of activated B-cell origin, extranodal involvement, and poor outcome. Clin Cancer Res. 2016;22:2755–64.PubMedGoogle Scholar
  21. 21.
    Paul U, Richter J, Stuhlmann-Laiesz C, et al. Advanced patient age at diagnosis of diffuse large B-cell lymphoma is associated with molecular characteristics including ABC-subtype and high expression of MYC. Leuk Lymphoma. 2018;59(5):1213–21.PubMedGoogle Scholar
  22. 22.
    Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–82.PubMedPubMedCentralGoogle Scholar
  23. 23.
    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;15:5494–502.PubMedGoogle Scholar
  24. 24.
    Salles G, Dd J, Xie W, et al. Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium. Blood. 2011;117:7070–8.PubMedGoogle Scholar
  25. 25.
    Coutinho R, Clear AJ, Owen A, et al. Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: implications for therapeutic strategies. Clin Cancer Res. 2013;19:6686–95.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33:2848–56.PubMedPubMedCentralGoogle Scholar
  27. 27.
    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;123:1214–7.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43:830–7.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012;109:3879–84.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhang J, Grubor V, Love CL, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110:1398–403.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171:481–94 e15.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Meng FL, Du Z, Federation A, et al. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell. 2014;159:1538–48.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Qian J, Wang Q, Dose M, et al. B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell. 2014;159:1524–37.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Green MR, Gentles AJ, Nair RV, et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood. 2013;121:1604–11.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Green MR, Kihira S, Liu CL, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci U S A. 2015;112:E1116–25.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Okosun J, Bodor C, Wang J, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014;46:176–81.PubMedGoogle Scholar
  38. 38.
    Pasqualucci L, Khiabanian H, Fangazio M, et al. Genetics of follicular lymphoma transformation. Cell Rep. 2014;6:130–40.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471:189–95.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 2000;14:1553–77.PubMedGoogle Scholar
  41. 41.
    Zhang J, Vlasevska S, Wells VA, et al. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B-cell lymphoma. Cancer Discov. 2017;7:322–37.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inactivates the transcriptional repressor BCL6. Nat Genet. 2002;32:606–13.PubMedGoogle Scholar
  43. 43.
    Gu W, Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell. 1997;90:595–606.PubMedGoogle Scholar
  44. 44.
    Tang Y, Zhao W, Chen Y, Zhao Y, Gu W. Acetylation is indispensable for p53 activation. Cell. 2008;133:612–26.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature. 2004;432:635–9.PubMedGoogle Scholar
  46. 46.
    Shilatifard A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem. 2012;81:65–95.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Ortega-Molina A, Boss IW, Canela A, et al. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat Med. 2015;21:1199–208.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Zhang J, Dominguez-Sola D, Hussein S, et al. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat Med. 2015;21:1190–8.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Hatzi K, Melnick A. Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis. Trends Mol Med. 2014;20:343–52.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Basso K, Dalla-Favera R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev. 2012;247:172–83.PubMedGoogle Scholar
  51. 51.
    Phan RT, Saito M, Basso K, Niu H, Dalla-Favera R. 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;6:1054–60.PubMedGoogle Scholar
  52. 52.
    Ranuncolo SM, Polo JM, Dierov J, et al. Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. Nat Immunol. 2007;8:705–14.PubMedGoogle Scholar
  53. 53.
    Ranuncolo SM, Polo JM, Melnick A. BCL6 represses CHEK1 and suppresses DNA damage pathways in normal and malignant B-cells. Blood Cells Mol Dis. 2008;41:95–9.PubMedPubMedCentralGoogle Scholar
  54. 54.
    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;115:975–84.PubMedPubMedCentralGoogle Scholar
  55. 55.
    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;113:5536–48.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Tunyaplin C, Shaffer AL, Angelin-Duclos CD, Yu X, Staudt LM, Calame KL. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol. 2004;173:1158–65.PubMedGoogle Scholar
  57. 57.
    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;21:2332–43.PubMedPubMedCentralGoogle Scholar
  58. 58.
    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;262:747–50.PubMedGoogle Scholar
  59. 59.
    Ye BH, Rao PH, Chaganti RS, Dalla-Favera R. Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma. Cancer Res. 1993;53:2732–5.PubMedGoogle Scholar
  60. 60.
    Baron BW, Nucifora G, McCabe N, Espinosa R 3rd, Le Beau MM, McKeithan TW. Identification of the gene associated with the recurring chromosomal translocations t(3;14)(q27;q32) and t(3;22)(q27;q11) in B-cell lymphomas. Proc Natl Acad Sci U S A. 1993;90:5262–6.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G, Bastard C. LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nat Genet. 1993;5:66–70.PubMedGoogle Scholar
  62. 62.
    Butler MP, Iida S, Capello D, et al. Alternative translocation breakpoint cluster region 5′ to BCL-6 in B-cell non-Hodgkin’s lymphoma. Cancer Res. 2002;62:4089–94.PubMedGoogle Scholar
  63. 63.
    Ye BH, Chaganti S, Chang CC, et al. Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J. 1995;14:6209–17.PubMedPubMedCentralGoogle Scholar
  64. 64.
    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;95:11816–21.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Shen HM, Peters A, Baron B, Zhu X, Storb U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science. 1998;280:1750–2.PubMedGoogle Scholar
  66. 66.
    Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti RS, Dalla-Favera R. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood. 2003;101:2914–23.PubMedGoogle Scholar
  67. 67.
    Wang X, Li Z, Naganuma A, Ye BH. Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas. Proc Natl Acad Sci U S A. 2002;99:15018–23.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Saito M, Gao J, Basso K, et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell. 2007;12:280–92.PubMedGoogle Scholar
  69. 69.
    Jiang Y, Ortega-Molina A, Geng H, et al. CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. Cancer Discov. 2017;7:38–53.PubMedGoogle Scholar
  70. 70.
    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;14:1084–92.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Brescia P, Schneider C, Holmes AB, et al. MEF2B instructs germinal center development and acts as an oncogene in B cell lymphomagenesis. Cancer Cell. 2018;34:453–65.PubMedGoogle Scholar
  72. 72.
    Duan S, Cermak L, Pagan JK, et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature. 2012;481:90–3.PubMedPubMedCentralGoogle Scholar
  73. 73.
    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;7:445–55.PubMedGoogle Scholar
  74. 74.
    Schneider C, Kon N, Amadori L, et al. FBXO11 inactivation leads to abnormal germinal-center formation and lymphoproliferative disease. Blood. 2016;128:660–6.PubMedGoogle Scholar
  75. 75.
    Cerchietti LC, Ghetu AF, Zhu X, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell. 2010;17:400–11.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Cerchietti LC, Lopes EC, Yang SN, et al. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nat Med. 2009;15:1369–76.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Fangazio M, Dominguez-Sola D, Tabbo F, et al. Genetic mechanisms of immune escape in diffuse large B cell lymphoma. Blood. 2014;124:1692.Google Scholar
  78. 78.
    Challa-Malladi M, Lieu YK, Califano O, et al. Combined genetic inactivation of beta2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell. 2011;20:728–40.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Kridel R, Chan FC, Mottok A, et al. Histological transformation and progression in follicular lymphoma: a clonal evolution study. PLoS Med. 2016;13:e1002197.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Moingeon P, Chang HC, Wallner BP, Stebbins C, Frey AZ, Reinherz EL. CD2-mediated adhesion facilitates T lymphocyte antigen recognition function. Nature. 1989;339:312–4.PubMedGoogle Scholar
  81. 81.
    Rimsza LM, Roberts RA, Miller TP, et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood. 2004;103:4251–8.PubMedGoogle Scholar
  82. 82.
    Mottok A, Woolcock B, Chan FC, et al. Genomic alterations in CIITA are frequent in primary mediastinal large B cell lymphoma and are associated with diminished MHC class II expression. Cell Rep. 2015;13:1418–31.PubMedGoogle Scholar
  83. 83.
    Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature. 2011;471:377–81.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Hashwah H, Schmid CA, Kasser S, et al. Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth. Proc Natl Acad Sci U S A. 2017;114:9701–6.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Dominguez-Sola D, Kung J, Wells VA, et al. Role of FOXO1 in germinal center development and lymphomagenesis. Blood. 2014;124:3536.Google Scholar
  86. 86.
    Sander S, Chu VT, Yasuda T, et al. PI3 kinase and FOXO1 transcription factor activity differentially control B cells in the germinal center light and dark zones. Immunity. 2015;43:1075–86.PubMedGoogle Scholar
  87. 87.
    Trinh DL, Scott DW, Morin RD, et al. Analysis of FOXO1 mutations in diffuse large B-cell lymphoma. Blood. 2013;121:3666–74.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Morin RD, Assouline S, Alcaide M, et al. Genetic landscapes of relapsed and refractory diffuse large B-cell lymphomas. Clin Cancer Res. 2016;22:2290–300.PubMedGoogle Scholar
  89. 89.
    Hata AN, Engelman JA, Faber AC. The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov. 2015;5:475–87.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Saito M, Novak U, Piovan E, et al. BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2009;106:11294–9.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Iqbal J, Sanger WG, Horsman DE, et al. BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma. Am J Pathol. 2004;165:159–66.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Schuetz JM, Johnson NA, Morin RD, et al. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia. 2012;26:1383–90.PubMedGoogle Scholar
  93. 93.
    Barrans SL, Evans PA, O’Connor SJ, et al. The t(14;18) is associated with germinal center-derived diffuse large B-cell lymphoma and is a strong predictor of outcome. Clin Cancer Res. 2003;9:2133–9.PubMedGoogle Scholar
  94. 94.
    Conacci-Sorrell M, McFerrin L, Eisenman RN. An overview of MYC and its interactome. Cold Spring Harb Perspect Med. 2014;4:a014357.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Dominguez-Sola D, Ying CY, Grandori C, et al. Non-transcriptional control of DNA replication by c-Myc. Nature. 2007;448:445–51.PubMedGoogle Scholar
  96. 96.
    Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci U S A. 1982;79:7824–7.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Dalla-Favera R, Martinotti S, Gallo RC, Erikson J, Croce CM. Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science. 1983;219:963–7.Google Scholar
  98. 98.
    Ladanyi M, Offit K, Jhanwar SC, Filippa DA, Chaganti RS. MYC rearrangement and translocations involving band 8q24 in diffuse large cell lymphomas. Blood. 1991;77:1057–63.PubMedGoogle Scholar
  99. 99.
    Karube K, Campo E. MYC alterations in diffuse large B-cell lymphomas. Semin Hematol. 2015;52:97–106.PubMedGoogle Scholar
  100. 100.
    Dominguez-Sola D, Victora GD, Ying CY, et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat Immunol. 2012;13:1083–91.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Copie-Bergman C, Cuillière-Dartigues P, Baia M, et al. MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study. Blood. 2015;126:2466–74.  https://doi.org/10.1182/blood-2015-05-647602.CrossRefPubMedGoogle Scholar
  102. 102.
    Mahmoudi T, Verrijzer CP. Chromatin silencing and activation by Polycomb and trithorax group proteins. Oncogene. 2001;20:3055–66.PubMedGoogle Scholar
  103. 103.
    Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 2002;111:185–96.PubMedGoogle Scholar
  104. 104.
    Cao R, Wang L, Wang H, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–43.PubMedGoogle Scholar
  105. 105.
    Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–26.PubMedGoogle Scholar
  106. 106.
    Beguelin W, Popovic R, Teater M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23:677–92.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Caganova M, Carrisi C, Varano G, et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest. 2013;123:5009–22.PubMedPubMedCentralGoogle Scholar
  108. 108.
    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;42:181–5.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Sneeringer CJ, Scott MP, Kuntz KW, et al. 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. 2010;107:20980–5.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Yap DB, Chu J, Berg T, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117:2451–9.PubMedPubMedCentralGoogle Scholar
  111. 111.
    McCabe MT, Graves AP, Ganji G, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A. 2012;109:2989–94.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Knutson SK, Wigle TJ, Warholic NM, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8:890–6.PubMedGoogle Scholar
  113. 113.
    McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12.PubMedGoogle Scholar
  114. 114.
    Morschhauser F, Salles GA, McKay P, et al. Interim report from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphomas. Hematol Oncol. 2017;35(suppl S2):24–5.  https://doi.org/10.1002/hon.2437_3.CrossRefGoogle Scholar
  115. 115.
    Green JA, Cyster JG. S1PR2 links germinal center confinement and growth regulation. Immunol Rev. 2012;247:36–51.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Muppidi JR, Schmitz R, Green JA, et al. Loss of signalling via Galpha13 in germinal centre B-cell-derived lymphoma. Nature. 2014;516(7530):254–8.PubMedPubMedCentralGoogle Scholar
  117. 117.
    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;69:8686–92.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Steinberg MW, Cheung TC, Ware CF. The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol Rev. 2011;244:169–87.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Boice M, Salloum D, Mourcin F, et al. Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T Cells. Cell. 2016;167:405–18 e13.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Pfeifer M, Grau M, Lenze D, et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110:12420–5.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol. 2001;21:952–65.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Tai DJ, Su CC, Ma YL, Lee EH. SGK1 phosphorylation of IkappaB Kinase alpha and p300 Up-regulates NF-kappaB activity and increases N-Methyl-D-aspartate receptor NR2A and NR2B expression. J Biol Chem. 2009;284:4073–89.PubMedGoogle Scholar
  123. 123.
    Mo JS, Ann EJ, Yoon JH, et al. Serum- and glucocorticoid-inducible kinase 1 (SGK1) controls Notch1 signaling by downregulation of protein stability through Fbw7 ubiquitin ligase. J Cell Sci. 2011;124:100–12.PubMedGoogle Scholar
  124. 124.
    Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88–92.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319:1676–9.PubMedGoogle Scholar
  126. 126.
    Thome M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nat Rev Immunol. 2004;4:348–59.PubMedGoogle Scholar
  127. 127.
    Young RM, Wu T, Schmitz R, et al. Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens. Proc Natl Acad Sci U S A. 2015;112:13447–54.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:922–6.Google Scholar
  129. 129.
    Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature. 2010;465:885–90.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–9.PubMedGoogle Scholar
  131. 131.
    Lam LT, Wright G, Davis RE, et al. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. Blood. 2008;111:3701–13.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Boone DL, Turer EE, Lee EG, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 2004;5:1052–60.PubMedGoogle Scholar
  133. 133.
    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;459:717–21.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009;459:712–6.PubMedGoogle Scholar
  135. 135.
    Mandelbaum J, Bhagat G, Tang H, et al. BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell. 2010;18:568–79.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Pasqualucci L, Compagno M, Houldsworth J, et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med. 2006;203:311–7.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Tam W, Gomez M, Chadburn A, Lee JW, Chan WC, Knowles DM. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood. 2006;107:4090–100.PubMedGoogle Scholar
  138. 138.
    Calado DP, Zhang B, Srinivasan L, et al. Constitutive canonical NF-kappaB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. Cancer Cell. 2010;18:580–9.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoetic and lymphoid tissues. Lyon: IARC Press; 2008.Google Scholar
  140. 140.
    Kluk MJ, Ho C, Yu H, et al. MYC immunohistochemistry to identify MYC-driven B-cell lymphomas in clinical practice. Am J Clin Pathol. 2016;145:166–79.PubMedGoogle Scholar
  141. 141.
    Pillai RK, Sathanoori M, van Oss SB, Swerdlow SH. Double-hit B-cell lymphomas with BCL6 and MYC translocations are aggressive, frequently extranodal lymphomas distinct from BCL2 double-hit B-cell lymphomas. Am J Surg Pathol. 2013;37:323–32.PubMedGoogle Scholar
  142. 142.
    Turakhia SK, Hill BT, Dufresne SD, Nakashima MO, Cotta CV. Aggressive B-cell lymphomas with translocations involving BCL6 and MYC have distinct clinical-pathologic characteristics. Am J Clin Pathol. 2014;142:339–46.PubMedGoogle Scholar
  143. 143.
    Delabie J, Vandenberghe E, Kennes C, et al. Histiocyte-rich B-cell lymphoma. A distinct clinicopathologic entity possibly related to lymphocyte predominant Hodgkin’s disease, paragranuloma subtype. Am J Surg Pathol. 1992;16:37–48.PubMedGoogle Scholar
  144. 144.
    Boudova L, Torlakovic E, Delabie J, et al. Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma. Blood. 2003;102:3753–8.PubMedGoogle Scholar
  145. 145.
    Hartmann S, Doring C, Jakobus C, et al. Nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma—endpoints of a spectrum of one disease? PLoS One. 2013;8:e78812.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Ponzoni M, Ferreri AJ, Campo E, et al. Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting. J Clin Oncol. 2007;25:3168–73.PubMedGoogle Scholar
  147. 147.
    Delecluse HJ, Anagnostopoulos I, Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood. 1997;89:1413–20.PubMedGoogle Scholar
  148. 148.
    Montes-Moreno S, Gonzalez-Medina AR, Rodriguez-Pinilla SM, et al. Aggressive large B-cell lymphoma with plasma cell differentiation: immunohistochemical characterization of plasmablastic lymphoma and diffuse large B-cell lymphoma with partial plasmablastic phenotype. Haematologica. 2010;95:1342–9.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Valera A, Balague O, Colomo L, et al. IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. Am J Surg Pathol. 2010;34:1686–94.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Laurent C, Do C, Gascoyne RD, et al. Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis. J Clin Oncol. 2009;27:4211–6.PubMedGoogle Scholar
  151. 151.
    Gascoyne RD, Lamant L, Martin-Subero JI, et al. ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood. 2003;102:2568–73.PubMedGoogle Scholar
  152. 152.
    Pd P, Baens M, van Krieken H, et al. ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma. Blood. 2003;102:2638–41.Google Scholar
  153. 153.
    Valera A, Colomo L, Martinez A, et al. ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements. Mod Pathol. 2013;26:1329–37.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Yuan J, Wright G, Rosenwald A, et al. Identification of primary mediastinal large B-cell lymphoma at nonmediastinal sites by gene expression profiling. Am J Surg Pathol. 2015;39:1322–30.PubMedGoogle Scholar
  155. 155.
    Paulli M, Strater J, Gianelli U, et al. Mediastinal B-cell lymphoma: A study of its histomorphologic spectrum based on 109 cases. Hum Pathol. 1999;30:178–87.PubMedGoogle Scholar
  156. 156.
    Moller P, Lammler B, Eberlein-Gonska M, et al. Primary mediastinal clear cell lymphoma of B-cell type. Virchows Arch A Pathol Anat Histopathol. 1986;409:79–92.PubMedGoogle Scholar
  157. 157.
    Copie-Bergman C, Plonquet A, Alonso MA, et al. MAL expression in lymphoid cells: further evidence for MAL as a distinct molecular marker of primary mediastinal large B-cell lymphomas. Mod Pathol. 2002;15:1172–80.PubMedGoogle Scholar
  158. 158.
    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;198:851–62.PubMedPubMedCentralGoogle Scholar
  159. 159.
    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;102:3871–9.PubMedGoogle Scholar
  160. 160.
    Gunawardana J, Chan FC, Telenius A, et al. Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet. 2014;46:329–35.PubMedGoogle Scholar
  161. 161.
    Steidl C, Gascoyne RD. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood. 2011;118:2659–69.PubMedGoogle Scholar
  162. 162.
    Twa DD, Chan FC, Ben-Neriah S, et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood. 2014;123:2062–5.Google Scholar
  163. 163.
    Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268–77.PubMedPubMedCentralGoogle Scholar
  164. 164.
    Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–21.PubMedGoogle Scholar
  165. 165.
    Joos S, Otano-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;87:1571–8.PubMedGoogle Scholar
  166. 166.
    Melzner I, Bucur AJ, Bruderlein S, et al. Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood. 2005;105:2535–42.PubMedGoogle Scholar
  167. 167.
    Rui L, Emre NC, Kruhlak MJ, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell. 2010;18:590–605.PubMedPubMedCentralGoogle Scholar
  168. 168.
    Dawson MA, Bannister AJ, Gottgens B, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature. 2009;461:819–22.PubMedPubMedCentralGoogle Scholar
  169. 169.
    Guiter C, Dusanter-Fourt I, Copie-Bergman C, et al. Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma. Blood. 2004;104:543–9.PubMedGoogle Scholar
  170. 170.
    Weniger MA, Gesk S, Ehrlich S, et al. Gains of REL in primary mediastinal B-cell lymphoma coincide with nuclear accumulation of REL protein. Genes Chromosomes Cancer. 2007;46:406–15.PubMedGoogle Scholar
  171. 171.
    Schmitz R, Hansmann ML, Bohle V, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med. 2009;206:981–9.PubMedPubMedCentralGoogle Scholar
  172. 172.
    Wessendorf S, Barth TF, Viardot A, et al. Further delineation of chromosomal consensus regions in primary mediastinal B-cell lymphomas: an analysis of 37 tumor samples using high-resolution genomic profiling (array-CGH). Leukemia. 2007;21:2463–9.PubMedGoogle Scholar
  173. 173.
    Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517–34.PubMedGoogle Scholar
  174. 174.
    Rigaud G, Moore PS, Taruscio D, et al. Alteration of chromosome arm 6p is characteristic of primary mediastinal B-cell lymphoma, as identified by genome-wide allelotyping. Genes Chromosomes Cancer. 2001;31:191–5.PubMedGoogle Scholar
  175. 175.
    Roberts RA, Wright G, Rosenwald AR, et al. Loss of major histocompatibility class II gene and protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient survival. Blood. 2006;108:311–8.PubMedPubMedCentralGoogle Scholar
  176. 176.
    Wilson WH, Pittaluga S, Nicolae A, et al. A prospective study of mediastinal gray-zone lymphoma. Blood. 2014;124:1563–9.PubMedPubMedCentralGoogle Scholar
  177. 177.
    Harris NL. Shades of gray between large B-cell lymphomas and Hodgkin lymphomas: differential diagnosis and biological implications. Mod Pathol. 2013;26(Suppl 1):S57–70.PubMedGoogle Scholar
  178. 178.
    Vermeer MH, Geelen FA, van Haselen CW, et al. Primary cutaneous large B-cell lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis. Dutch Cutaneous Lymphoma Working Group. Arch Dermatol. 1996;132:1304–8.PubMedGoogle Scholar
  179. 179.
    Pham-Ledard A, Prochazkova-Carlotti M, Andrique L, et al. Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma. Mod Pathol. 2014;27:402–11.PubMedGoogle Scholar
  180. 180.
    Camilleri-Broet S, Criniere E, Broet P, et al. A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood. 2006;107:190–6.PubMedGoogle Scholar
  181. 181.
    Riemersma SA, Jordanova ES, Schop RF, et al. Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites. Blood. 2000;96:3569–77.PubMedGoogle Scholar
  182. 182.
    Rubenstein JL, Treseler P, O’Brien JM. Pathology and genetics of primary central nervous system and intraocular lymphoma. Hematol Oncol Clin North Am. 2005;19:705–17, vii.PubMedGoogle Scholar
  183. 183.
    Vater I, Montesinos-Rongen M, Schlesner M, et al. The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing. Leukemia. 2015;29:677–85.PubMedGoogle Scholar
  184. 184.
    Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M. Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma. Acta Neuropathol. 2011;122:791–2.PubMedGoogle Scholar
  185. 185.
    Gonzalez-Aguilar A, Idbaih A, Boisselier B, et al. Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res. 2012;18:5203–11.PubMedGoogle Scholar
  186. 186.
    Montesinos-Rongen M, Schafer E, Siebert R, Deckert M. Genes regulating the B cell receptor pathway are recurrently mutated in primary central nervous system lymphoma. Acta Neuropathol. 2012;124:905–6.PubMedGoogle Scholar
  187. 187.
    Montesinos-Rongen M, Van Roost D, Schaller C, Wiestler OD, Deckert M. Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation. Blood. 2004;103:1869–75.PubMedGoogle Scholar
  188. 188.
    Cady FM, O’Neill BP, Law ME, et al. Del(6)(q22) and BCL6 rearrangements in primary CNS lymphoma are indicators of an aggressive clinical course. J Clin Oncol. 2008;26:4814–9.PubMedPubMedCentralGoogle Scholar
  189. 189.
    Schwindt H, Vater I, Kreuz M, et al. Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma. Leukemia. 2009;23:1875–84.PubMedGoogle Scholar
  190. 190.
    Harada K, Nishizaki T, Kubota H, Harada K, Suzuki M, Sasaki K. Distinct primary central nervous system lymphoma defined by comparative genomic hybridization and laser scanning cytometry. Cancer Genet Cytogenet. 2001;125:147–50.PubMedGoogle Scholar
  191. 191.
    Courts C, Montesinos-Rongen M, Brunn A, et al. Recurrent inactivation of the PRDM1 gene in primary central nervous system lymphoma. J Neuropathol Exp Neurol. 2008;67:720–7.PubMedGoogle Scholar
  192. 192.
    Nakamura M, Kishi M, Sakaki T, et al. Novel tumor suppressor loci on 6q22-23 in primary central nervous system lymphomas. Cancer Res. 2003;63:737–41.PubMedGoogle Scholar
  193. 193.
    Nicolae A, Pittaluga S, Abdullah S, et al. EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood. 2015;126:863–72.PubMedPubMedCentralGoogle Scholar
  194. 194.
    Sansoni P, Vescovini R, Fagnoni F, et al. The immune system in extreme longevity. Exp Gerontol. 2008;43:61–5.PubMedGoogle Scholar
  195. 195.
    Oyama T, Yamamoto K, Asano N, et al. Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res. 2007;13:5124–32.PubMedGoogle Scholar
  196. 196.
    Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19:3462–73.PubMedPubMedCentralGoogle Scholar
  197. 197.
    Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995;332:1186–91.Google Scholar
  198. 198.
    Nador RG, Cesarman E, Chadburn A, et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi’s sarcoma-associated herpes virus. Blood. 1996;88:645–56.PubMedGoogle Scholar
  199. 199.
    Said JW, Tasaka T, Takeuchi S, et al. Primary effusion lymphoma in women: report of two cases of Kaposi’s sarcoma herpes virus-associated effusion-based lymphoma in human immunodeficiency virus-negative women. Blood. 1996;88:3124–8.PubMedGoogle Scholar
  200. 200.
    Hermine O, Michel M, Buzyn-Veil A, Gessain A. Body-cavity-based lymphoma in an HIV-seronegative patient without Kaposi’s sarcoma-associated herpesvirus-like DNA sequences. N Engl J Med. 1996;334:272–3.PubMedGoogle Scholar
  201. 201.
    Chadburn A, Hyjek E, Mathew S, Cesarman E, Said J, Knowles DM. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Am J Surg Pathol. 2004;28:1401–16.PubMedGoogle Scholar
  202. 202.
    Nakatsuka S, Yao M, Hoshida Y, Yamamoto S, Iuchi K, Aozasa K. Pyothorax-associated lymphoma: a review of 106 cases. J Clin Oncol. 2002;20:4255–60.PubMedGoogle Scholar
  203. 203.
    Narimatsu H, Ota Y, Kami M, et al. Clinicopathological features of pyothorax-associated lymphoma; a retrospective survey involving 98 patients. Ann Oncol. 2007;18:122–8.PubMedGoogle Scholar
  204. 204.
    Petitjean B, Jardin F, Joly B, et al. Pyothorax-associated lymphoma: a peculiar clinicopathologic entity derived from B cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype. Am J Surg Pathol. 2002;26:724–32.PubMedGoogle Scholar
  205. 205.
    Ando M, Sato Y, Takata K, et al. A20 (TNFAIP3) deletion in Epstein-Barr virus-associated lymphoproliferative disorders/lymphomas. PLoS One. 2013;8:e56741.PubMedPubMedCentralGoogle Scholar
  206. 206.
    Yamato H, Ohshima K, Suzumiya J, Kikuchi M. Evidence for local immunosuppression and demonstration of c-myc amplification in pyothorax-associated lymphoma. Histopathology. 2001;39:163–71.PubMedGoogle Scholar
  207. 207.
    Guinee D, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol. 1994;18:753–64.PubMedGoogle Scholar
  208. 208.
    Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol. 2010;34:e35–48.PubMedGoogle Scholar
  209. 209.
    Roschewski M, Wilson WH. Lymphomatoid granulomatosis. Cancer J. 2012;18:469–74.PubMedGoogle Scholar
  210. 210.
    Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood. 2000;95:1406–12.PubMedGoogle Scholar
  211. 211.
    Du MQ, Liu H, Diss TC, et al. Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood. 2001;97:2130–6.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institute for Cancer Genetics, Columbia UniversityNew YorkUSA
  2. 2.Department of Clinical PathologyRobert-Bosch-KrankenhausStuttgartGermany

Personalised recommendations