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Overview of the pathobiology of the non-Hodgkin lymphomas

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


Non-Hodgkin lymphoma (NHL) consists of a diverse group of malignant tumors of the lymphoid tissues variously derived from the clonal expansion of B cells, T cells, natural killer (NK) cells or precursors of these cells. This topic will review the most common mechanisms underlying the pathobiology of the NHLs.

Specifics regarding the pathobiology of the more common lymphoma subtypes are discussed separately:

Diffuse large B cell lymphoma (see "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma")

Mantle cell lymphoma (see "Pathobiology of mantle cell lymphoma")

Burkitt lymphoma (see "Pathobiology of Burkitt lymphoma")


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Literature review current through: Sep 2016. | This topic last updated: Jan 19, 2016.
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  1. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010; 362:1417.
  2. Coupland SE. The challenge of the microenvironment in B-cell lymphomas. Histopathology 2011; 58:69.
  3. Gamberi B, Gaidano G, Parsa N, et al. Microsatellite instability is rare in B-cell non-Hodgkin's lymphomas. Blood 1997; 89:975.
  4. Duval A, Raphael M, Brennetot C, et al. The mutator pathway is a feature of immunodeficiency-related lymphomas. Proc Natl Acad Sci U S A 2004; 101:5002.
  5. Offit K, Wong G, Filippa DA, et al. Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: clinical correlations. Blood 1991; 77:1508.
  6. Johansson B, Mertens F, Mitelman F. Cytogenetic evolution patterns in non-Hodgkin's lymphoma. Blood 1995; 86:3905.
  7. Ouillette P, Collins R, Shakhan S, et al. Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 2011; 118:3051.
  8. 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.
  9. Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008; 319:1676.
  10. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470:115.
  11. Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 2012; 44:47.
  12. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365:2497.
  13. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475:101.
  14. Rossi D, Trifonov V, Fangazio M, et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med 2012; 209:1537.
  15. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 2011; 43:830.
  16. 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.
  17. Proschek D, Kafchitsas K, Kurth AA, et al. The quality of applied bone cement depends on the chemical composition of the application system. Eur Surg Res 2011; 47:189.
  18. 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.
  19. Couronné L, Bastard C, Bernard OA. TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med 2012; 366:95.
  20. Rossi D, Bruscaggin A, Spina V, et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 2011; 118:6904.
  21. 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.
  22. Lo Coco F, Gaidano G, Louie DC, et al. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood 1993; 82:2289.
  23. Sander CA, Yano T, Clark HM, et al. p53 mutation is associated with progression in follicular lymphomas. Blood 1993; 82:1994.
  24. Gaidano G, Hauptschein RS, Parsa NZ, et al. Deletions involving two distinct regions of 6q in B-cell non-Hodgkin lymphoma. Blood 1992; 80:1781.
  25. Kalachikov S, Migliazza A, Cayanis E, et al. Cloning and gene mapping of the chromosome 13q14 region deleted in chronic lymphocytic leukemia. Genomics 1997; 42:369.
  26. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002; 99:15524.
  27. Calin GA, Ferracin M, Cimmino A, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353:1793.
  28. Di Lisio L, Martinez N, Montes-Moreno S, et al. The role of miRNAs in the pathogenesis and diagnosis of B-cell lymphomas. Blood 2012; 120:1782.
  29. Küppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 2005; 5:251.
  30. Jacobs H, Bross L. Towards an understanding of somatic hypermutation. Curr Opin Immunol 2001; 13:208.
  31. Ramiro AR, Jankovic M, Callen E, et al. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 2006; 440:105.
  32. Klein U, Goossens T, Fischer M, et al. Somatic hypermutation in normal and transformed human B cells. Immunol Rev 1998; 162:261.
  33. Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 2004; 432:635.
  34. 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.
  35. Peng HZ, Du MQ, Koulis A, et al. Nonimmunoglobulin gene hypermutation in germinal center B cells. Blood 1999; 93:2167.
  36. Pasqualucci L, Bhagat G, Jankovic M, et al. AID is required for germinal center-derived lymphomagenesis. Nat Genet 2008; 40:108.
  37. Montesinos-Rongen M, Van Roost D, Schaller C, et al. Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation. Blood 2004; 103:1869.
  38. Gaidano G, Pasqualucci L, Capello D, et al. Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma. Blood 2003; 102:1833.
  39. Cerri M, Capello D, Muti G, et al. Aberrant somatic hypermutation in post-transplant lymphoproliferative disorders. Br J Haematol 2004; 127:362.
  40. Dijkman R, Tensen CP, Buettner M, et al. Primary cutaneous follicle center lymphoma and primary cutaneous large B-cell lymphoma, leg type, are both targeted by aberrant somatic hypermutation but demonstrate differential expression of AID. Blood 2006; 107:4926.
  41. Rossi D, Berra E, Cerri M, et al. Aberrant somatic hypermutation in transformation of follicular lymphoma and chronic lymphocytic leukemia to diffuse large B-cell lymphoma. Haematologica 2006; 91:1405.
  42. Deutsch AJ, Aigelsreiter A, Staber PB, et al. MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation. Blood 2007; 109:3500.
  43. Liso A, Capello D, Marafioti T, et al. Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma. Blood 2006; 108:1013.
  44. Kasar S, Kim J, Improgo R, et al. Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution. Nat Commun 2015; 6:8866.
  45. Khalidi HS, Chang KL, Medeiros LJ, et al. Acute lymphoblastic leukemia. Survey of immunophenotype, French-American-British classification, frequency of myeloid antigen expression, and karyotypic abnormalities in 210 pediatric and adult cases. Am J Clin Pathol 1999; 111:467.
  46. Uckun FM, Sensel MG, Sun L, et al. Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 1998; 91:735.
  47. Lyons SF, Liebowitz DN. The roles of human viruses in the pathogenesis of lymphoma. Semin Oncol 1998; 25:461.
  49. Tao Q, Robertson KD, Manns A, et al. Epstein-Barr virus (EBV) in endemic Burkitt's lymphoma: molecular analysis of primary tumor tissue. Blood 1998; 91:1373.
  50. Davi F, Delecluse HJ, Guiet P, et al. Burkitt-like lymphomas in AIDS patients: characterization within a series of 103 human immunodeficiency virus-associated non-Hodgkin's lymphomas. Burkitt's Lymphoma Study Group. J Clin Oncol 1998; 16:3788.
  51. Gutiérrez MI, Bhatia K, Barriga F, et al. Molecular epidemiology of Burkitt's lymphoma from South America: differences in breakpoint location and Epstein-Barr virus association from tumors in other world regions. Blood 1992; 79:3261.
  52. Subar M, Neri A, Inghirami G, et al. Frequent c-myc oncogene activation and infrequent presence of Epstein-Barr virus genome in AIDS-associated lymphoma. Blood 1988; 72:667.
  53. Neri A, Barriga F, Inghirami G, et al. Epstein-Barr virus infection precedes clonal expansion in Burkitt's and acquired immunodeficiency syndrome-associated lymphoma. Blood 1991; 77:1092.
  54. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 2004; 350:1328.
  55. Mariette X, Cazals-Hatem D, Warszawki J, et al. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002; 99:3909.
  56. Smith MR, Greene WC. Molecular biology of the type I human T-cell leukemia virus (HTLV-I) and adult T-cell leukemia. J Clin Invest 1991; 87:761.
  57. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994; 266:1865.
  58. Cesarman E, Chang Y, Moore PS, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995; 332:1186.
  59. Gaidano G, Capello D, Fassone L, et al. Molecular characterization of HHV-8 positive primary effusion lymphoma reveals pathogenetic and histogenetic features of the disease. J Clin Virol 2000; 16:215.
  60. Järviluoma A, Koopal S, Räsänen S, et al. KSHV viral cyclin binds to p27KIP1 in primary effusion lymphomas. Blood 2004; 104:3349.
  61. Asou H, Said JW, Yang R, et al. Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. Blood 1998; 91:2475.
  62. Rizzo P, Di Resta I, Powers A, et al. Unique strains of SV40 in commercial poliovaccines from 1955 not readily identifiable with current testing for SV40 infection. Cancer Res 1999; 59:6103.
  63. Engels EA, Rodman LH, Frisch M, et al. Childhood exposure to simian virus 40-contaminated poliovirus vaccine and risk of AIDS-associated non-Hodgkin's lymphoma. Int J Cancer 2003; 106:283.
  64. Engels EA, Viscidi RP, Galloway DA, et al. Case-control study of simian virus 40 and non-Hodgkin lymphoma in the United States. J Natl Cancer Inst 2004; 96:1368.
  65. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds), IARC Press, Lyon 2008.
  66. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994; 263:1281.
  67. Horsman DE, Connors JM, Pantzar T, Gascoyne RD. Analysis of secondary chromosomal alterations in 165 cases of follicular lymphoma with t(14;18). Genes Chromosomes Cancer 2001; 30:375.
  68. Lestou VS, Gascoyne RD, Sehn L, et al. Multicolour fluorescence in situ hybridization analysis of t(14;18)-positive follicular lymphoma and correlation with gene expression data and clinical outcome. Br J Haematol 2003; 122:745.
  69. Viardot A, Möller P, Högel J, et al. Clinicopathologic correlations of genomic gains and losses in follicular lymphoma. J Clin Oncol 2002; 20:4523.
  70. Landau DA, Carter SL, Stojanov P, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013; 152:714.
  71. 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.