Advertisement

Clinical Impact of the 2016 Update to the WHO Lymphoma Classification

  • Ryan C. Lynch
  • Dita Gratzinger
  • Ranjana H. Advani
Lymphoma (JW Sweetenham, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Lymphoma

Opinion statement

The 2016 revision of the WHO classification of lymphoid neoplasms includes new entities along with a clearer definition of provisional and definitive subtypes based on better understanding of the molecular drivers of lymphomas. These changes impact current treatment paradigms and provide a framework for future clinical trials. Additionally, this update recognizes several premalignant or predominantly indolent entities and underscores the importance of avoiding unnecessarily aggressive treatment in the latter subsets.

Keywords

Non-Hodgkin lymphoma Chronic lymphocytic leukemia (CLL) Lymphoplasmacytic lymphoma Waldenström macroglobulinemia Follicular lymphoma Mantle cell lymphoma Diffuse large B cell lymphoma (DLBCL) BCL6 translocations Double hit lymphoma Burkitt lymphoma High grade B cell lymphoma NOS ALK-negative anaplastic large cell lymphoma (ALCL) 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

Although no new studies with human or animal subjects were performed by the authors for this article, this article does contain two cited studies (references 37 and 99) where Dr. Advani was a coinvestigator.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  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. This is the original manuscript highlighting the molecular and pathological changes in the 2016 WHO revisionPubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Zelenetz AD, Gordon LI, Wierda WG, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Hodgkin’s Lymphoma Version 3.2016. 2016.Google Scholar
  3. 3.
    Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Landgren O, Albitar M, Ma W, et al. B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 2009;360:659–67.PubMedCrossRefGoogle Scholar
  5. 5.
    Vardi A, Dagklis A, Scarfò L, et al. Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL. Blood. 2013;121:4521–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359:575–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Gibson SE, Swerdlow SH, Ferry JA, et al. Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis. Haematologica. 2011;96:1144–52.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Giné E, Martinez A, Villamor N, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica. 2010;95:1526–33.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ciccone M, Agostinelli C, Rigolin GM, et al. Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays. Leukemia. 2012;26:499–508.PubMedCrossRefGoogle Scholar
  10. 10.
    Falchi L, Keating MJ, Marom EM, et al. Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia. Blood. 2014;123:2783–90.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Gradowski JF, Sargent RL, Craig FE, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma with cyclin D1 positive proliferation centers do not have CCND1 translocations or gains and lack SOX11 expression. Am J Clin Pathol. 2012;138:132–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Gibson SE, Leeman-Neill RJ, Jain S, et al. Proliferation centres of chronic lymphocytic leukaemia/small lymphocytic lymphoma have enhanced expression of MYC protein, which does not result from rearrangement or gain of the MYC gene. Br J Haematol. 2016;175:173–5.Google Scholar
  13. 13.
    Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013;121:1403–12.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123:3247–54.PubMedCrossRefGoogle Scholar
  16. 16.
    Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16:169–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:768–78.PubMedCrossRefGoogle Scholar
  19. 19.
    Swerdlow SH, Campo E, Harris NL, et al: WHO classification of tumours of haematopoietic and lymphoid tissues, fourth edition, World Health Organization, 2008.Google Scholar
  20. 20.
    Swerdlow SH, Kuzu I, Dogan A, et al. The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing. Virchows Arch. 2016;468:259–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367:826–33.PubMedCrossRefGoogle Scholar
  22. 22.
    King RL, Gonsalves WI, Ansell SM, et al. Lymphoplasmacytic lymphoma with a non-IgM paraprotein shows clinical and pathologic heterogeneity and may harbor MYD88 L265P mutations. Am J Clin Pathol. 2016;145:843–51.PubMedCrossRefGoogle Scholar
  23. 23.
    Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood. 2013;121:2051–8.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Peveling-Oberhag J, Wolters F, Döring C, et al. Whole exome sequencing of microdissected splenic marginal zone lymphoma: a study to discover novel tumor-specific mutations. BMC Cancer. 2015;15:773.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Cani AK, Soliman M, Hovelson DH, et al. Comprehensive genomic profiling of orbital and ocular adnexal lymphomas identifies frequent alterations in MYD88 and chromatin modifiers: new routes to targeted therapies. Mod Pathol. 2016;29:685–97.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Nakamura T, Tateishi K, Niwa T, et al. Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol Appl Neurobiol. 2016;42:279–90.PubMedCrossRefGoogle Scholar
  28. 28.
    Oishi N, Kondo T, Nakazawa T, et al. High prevalence of the MYD88 mutation in testicular lymphoma: immunohistochemical and genetic analyses. Pathol Int. 2015;65:528–35.PubMedCrossRefGoogle Scholar
  29. 29.
    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
  30. 30.
    Pham-Ledard A, Beylot-Barry M, Barbe C, et al. High frequency and clinical prognostic value of MYD88 L265P mutation in primary cutaneous diffuse large B-cell lymphoma, leg-type. JAMA Dermatol. 2014;150:1173–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood. 2013;122:1222–32.PubMedCrossRefGoogle Scholar
  32. 32.
    Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenström macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014;123:1637–46.PubMedCrossRefGoogle Scholar
  33. 33.
    Roccaro AM, Sacco A, Jimenez C, et al. C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood. 2014;123:4120–31.PubMedCrossRefGoogle Scholar
  34. 34.
    Schmidt J, Federmann B, Schindler N, et al. MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity. Br J Haematol. 2015;169:795–803.PubMedCrossRefGoogle Scholar
  35. 35.
    Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s macroglobulinemia. Leukemia. 2015;29:169–76.PubMedCrossRefGoogle Scholar
  36. 36.
    Cao Y, Hunter ZR, Liu X, et al. CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88(L265P)-directed survival signalling in Waldenstrom macroglobulinaemia cells. Br J Haematol. 2015;168:701–7.PubMedCrossRefGoogle Scholar
  37. 37.
    •• Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015;372:1430–40. This paper is the study that led to the approval of ibrutinib for WM. It is a good example of the therapeutic implications of somatic mutations in lymphoma. It identifies two separate mutations and demonstrates that response to ibrutinib is dependent on mutation statusPubMedCrossRefGoogle Scholar
  38. 38.
    Horn H, Schmelter C, Leich E, et al. Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica. 2011;96:1327–34.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015;16:1111–22.PubMedCrossRefGoogle Scholar
  40. 40.
    Tellier J, Menard C, Roulland S, et al. Human t(14;18)positive germinal center B cells: a new step in follicular lymphoma pathogenesis? Blood. 2014;123:3462–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Roulland S, Kelly RS, Morgado E, et al. t(14;18) Translocation: a predictive blood biomarker for follicular lymphoma. J Clin Oncol. 2014;32:1347–55.PubMedCrossRefGoogle Scholar
  42. 42.
    Pillai RK, Surti U, Swerdlow SH. Follicular lymphoma-like B cells of uncertain significance (in situ follicular lymphoma) may infrequently progress, but precedes follicular lymphoma, is associated with other overt lymphomas and mimics follicular lymphoma in flow cytometric studies. Haematologica. 2013;98:1571–80.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Jegalian AG, Eberle FC, Pack SD, et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood. 2011;118:2976–84.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Bödör C, Grossmann V, Popov N, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013;122:3165–8.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Okosun J, Bödör 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.PubMedCrossRefGoogle Scholar
  48. 48.
    Katzenberger T, Kalla J, Leich E, et al. A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36. Blood. 2009;113:1053–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Mori M, Kobayashi Y, Maeshima AM, et al. The indolent course and high incidence of t(14;18) in primary duodenal follicular lymphoma. Ann Oncol. 2010;21:1500–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Schmatz AI, Streubel B, Kretschmer-Chott E, et al. Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. J Clin Oncol. 2011;29:1445–51.PubMedCrossRefGoogle Scholar
  51. 51.
    Liu Q, Salaverria I, Pittaluga S, et al. Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma. Am J Surg Pathol. 2013;37:333–43.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Louissaint A, Ackerman AM, Dias-Santagata D, et al. Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement. Blood. 2012;120:2395–404.PubMedCrossRefGoogle Scholar
  53. 53.
    Orchard J, Garand R, Davis Z, et al. A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease. Blood. 2003;101:4975–81.PubMedCrossRefGoogle Scholar
  54. 54.
    Royo C, Navarro A, Clot G, et al. Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease. Leukemia. 2012;26:1895–8.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Ondrejka SL, Lai R, Smith SD, et al. Indolent mantle cell leukemia: a clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica. 2011;96:1121–7.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Carvajal-Cuenca A, Sua LF, Silva NM, et al. In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior. Haematologica. 2012;97:270–8.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest. 2012;122:3416–23.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res. 2012;72:5307–16.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Mozos A, Royo C, Hartmann E, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica. 2009;94:1555–62.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Determann O, Hoster E, Ott G, et al. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008;111:2385–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Fernandez V, Salamero O, Espinet B, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70:1408–18.PubMedCrossRefGoogle Scholar
  62. 62.
    Del Giudice I, Messina M, Chiaretti S, et al. Behind the scenes of non-nodal MCL: downmodulation of genes involved in actin cytoskeleton organization, cell projection, cell adhesion, tumour invasion, TP53 pathway and mutated status of immunoglobulin heavy chain genes. Br J Haematol. 2012;156:601–11.PubMedCrossRefGoogle Scholar
  63. 63.
    Rule SA, Poplar S, Evans PA, et al. Indolent mantle-cell lymphoma: immunoglobulin variable region heavy chain sequence analysis reveals evidence of disease 10 years prior to symptomatic clinical presentation. J Clin Oncol. 2011;29:e437–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Bea S, Valdes-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A. 2013;110:18250–5.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood. 2012;119:1963–71.PubMedCrossRefGoogle Scholar
  66. 66.
    Salaverria I, Royo C, Carvajal-Cuenca A, et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1(−) mantle cell lymphoma. Blood. 2013;121:1394–402.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Dunleavy K, Fanale M, LaCasce A, et al. Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. Blood. 2014;124:395.Google Scholar
  68. 68.
    Sun H, Savage KJ, Karsan A, et al. Outcome of patients with non-Hodgkin lymphomas with concurrent MYC and BCL2 rearrangements treated with CODOX-M/IVAC with rituximab followed by hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2015;15:341–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Savage KJ, Slack GW, Mottok A, et al. Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL. Blood. 2016;127:2182–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Li S, Lin P, Fayad LE, et al. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol. 2012;25:145–56.PubMedCrossRefGoogle Scholar
  71. 71.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    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.PubMedCrossRefGoogle Scholar
  74. 74.
    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.PubMedCrossRefGoogle Scholar
  75. 75.
    Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471:189–95.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Pasqualucci L, Khiabanian H, Fangazio M, et al. Genetics of follicular lymphoma transformation. Cell Rep. 2014;6:130–40.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    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.PubMedCrossRefGoogle Scholar
  79. 79.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Monti S, Chapuy B, Takeyama K, et al. Integrative analysis reveals an outcome-associated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma. Cancer Cell. 2012;22:359–72.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Muppidi JR, Schmitz R, Green JA, et al. Loss of signalling via Galpha13 in germinal centre B-cell-derived lymphoma. Nature. 2014;516:254–8.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009;459:712–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat Rev Clin Oncol. 2014;11:12–23.PubMedCrossRefGoogle Scholar
  88. 88.
    Intlekofer AM, Younes A. Precision therapy for lymphoma—current state and future directions. Nat Rev Clin Oncol. 2014;11:585–96.PubMedCrossRefGoogle Scholar
  89. 89.
    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.PubMedCrossRefGoogle Scholar
  90. 90.
    Wright G, Tan B, Rosenwald A, et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2003;100:9991–6.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol. 2015;33:251–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Vitolo U, Chiappella A, Franceschetti S, et al. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol. 2014;15:730–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Molina TJ, Canioni D, Copie-Bergman C, et al. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d’Etudes des Lymphomes de l’Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014;32:3996–4003.PubMedCrossRefGoogle Scholar
  94. 94.
    Younes A, Thieblemont C, Morschhauser F, et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol. 2014;15:1019–26.PubMedCrossRefGoogle Scholar
  95. 95.
    Offner F, Samoilova O, Osmanov E, et al. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood. 2015;126:1893–901.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Ruan J, Martin P, Furman RR, et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29:690–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113:6069–76.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell–like than in germinal center B-cell–like phenotype. Cancer. 2011;117:5058–66.PubMedCrossRefGoogle Scholar
  99. 99.
    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.PubMedCrossRefGoogle Scholar
  100. 100.
    Leonard JP, Kolibaba K, Reeves Ja, et al: Randomized phase 2 open-label study of R-CHOP ± bortezomib in patients (Pts) with untreated non-germinal center B-cell-like (non-GCB) subtype diffuse large cell lymphoma (DLBCL): results from the pyramid trial (NCT00931918) Blood 126, 2015.Google Scholar
  101. 101.
    Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114:3533–7.PubMedCrossRefGoogle Scholar
  102. 102.
    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;28:3360–5.PubMedCrossRefGoogle Scholar
  103. 103.
    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.PubMedCrossRefGoogle Scholar
  104. 104.
    Sesques P, Johnson NA. Approach to the diagnosis and treatment of high-grade B cell lymphomas with <em>MYC</em> and <em>BCL2</em> and/or <em>BCL6</em> rearrangements. Blood, 2016.Google Scholar
  105. 105.
    Swerdlow SH. Diagnosis of ‘double hit’ diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC. Hematology Am Soc Hematol Educ Program. 2014;2014:90–9.PubMedGoogle Scholar
  106. 106.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Salaverria I, Martin-Guerrero I, Wagener R, et al. A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma. Blood. 2014;123:1187–98.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Ferreiro JF, Morscio J, Dierickx D, et al. Post-transplant molecularly defined Burkitt lymphomas are frequently MYC-negative and characterized by the 11q-gain/loss pattern. Haematologica. 2015;100:e275–9.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Campo E. MYC in DLBCL: partners matter. Blood. 2015;126:2439–40.PubMedCrossRefGoogle Scholar
  110. 110.
    Momose S, Weißbach S, Pischimarov J, et al. The diagnostic gray zone between Burkitt lymphoma and diffuse large B-cell lymphoma is also a gray zone of the mutational spectrum. Leukemia. 2015;29:1789–91.PubMedCrossRefGoogle Scholar
  111. 111.
    Love C, Sun Z, Jima D, et al. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet. 2012;44:1321–5.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Richter J, Schlesner M, Hoffmann S, et al. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet. 2012;44:1316–20.PubMedCrossRefGoogle Scholar
  113. 113.
    Schmitz R, Young RM, Ceribelli M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012;490:116–20.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Sander S, Calado DP, Srinivasan L, et al. Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer Cell. 2012;22:167–79.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Howlett C, Snedecor SJ, Landsburg DJ, et al. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015;170:504–14.PubMedCrossRefGoogle Scholar
  116. 116.
    Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124:2354–61.PubMedCrossRefGoogle Scholar
  117. 117.
    Dojcinov SD, Venkataraman G, Pittaluga S, et al. Age-related EBV-associated lymphoproliferative disorders in the Western population: a spectrum of reactive lymphoid hyperplasia and lymphoma. Blood. 2011;117:4726–35.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Dojcinov SD, Venkataraman G, Raffeld M, et al. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010;34:405–17.PubMedCrossRefGoogle Scholar
  120. 120.
    Hart M, Thakral B, Yohe S, et al. EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder. Am J Surg Pathol. 2014;38:1522–9.PubMedCrossRefGoogle Scholar
  121. 121.
    Salaverria I, Philipp C, Oschlies I, et al. Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood. 2011;118:139–47.PubMedCrossRefGoogle Scholar
  122. 122.
    Karube K, Guo Y, Suzumiya J, et al. CD10-MUM1+ follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features. Blood. 2007;109:3076–9.PubMedGoogle Scholar
  123. 123.
    Iqbal J, Weisenburger DD, Greiner TC, et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood. 2010;115:1026–36.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Odejide O, Weigert O, Lane AA, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood. 2014;123:1293–6.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Lemonnier F, Couronné L, Parrens M, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;120:1466–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Sakata-Yanagimoto M, Enami T, Yoshida K, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46:171–5.PubMedCrossRefGoogle Scholar
  127. 127.
    Cairns RA, Iqbal J, Lemonnier F, et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012;119:1901–3.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Nicolae A, Pittaluga S, Venkataraman G, et al. Peripheral T-cell lymphomas of follicular T-helper cell derivation with Hodgkin/Reed-Sternberg cells of B-cell lineage: both EBV-positive and EBV-negative variants exist. Am J Surg Pathol. 2013;37:816–26.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Moroch J, Copie-Bergman C, de Leval L, et al. Follicular peripheral T-cell lymphoma expands the spectrum of classical Hodgkin lymphoma mimics. Am J Surg Pathol. 2012;36:1636–46.PubMedCrossRefGoogle Scholar
  130. 130.
    Balagué O, Martínez A, Colomo L, et al. Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: a phenomenon with distinctive clinicopathologic features. Am J Surg Pathol. 2007;31:1310–22.PubMedCrossRefGoogle Scholar
  131. 131.
    Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014;123:2915–23.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Palomero T, Couronné L, Khiabanian H, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46:166–70.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Wang T, Feldman AL, Wada DA, et al. GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features. Blood. 2014;123:3007–15.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Marquard L, Poulsen CB, Gjerdrum LM, et al. Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas. Histopathology. 2009;54:688–98.PubMedCrossRefGoogle Scholar
  135. 135.
    Attygalle AD, Cabecadas J, Gaulard P, et al. Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward—report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology. Histopathology. 2014;64:171–99.PubMedCrossRefGoogle Scholar
  136. 136.
    Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111:5496–504.PubMedCrossRefGoogle Scholar
  137. 137.
    Gascoyne RD, Aoun P, Wu D, et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood. 1999;93:3913–21.PubMedGoogle Scholar
  138. 138.
    Sibon D, Fournier M, Brière J, et al. Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l’Adulte trials. J Clin Oncol. 2012;30:3939–46.PubMedCrossRefGoogle Scholar
  139. 139.
    • Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124:1473–80. This study highlights the heterogeneity of ALK− ALCL, with rearragements in DUSP22 highlighting a group with improved prognosis, and rearrangements in TP63 highlighting a group with worse prognosisPubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Agnelli L, Mereu E, Pellegrino E, et al. Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma. Blood. 2012;120:1274–81.PubMedCrossRefGoogle Scholar
  141. 141.
    Piccaluga PP, Fuligni F, De Leo A, et al. Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study. J Clin Oncol. 2013;31:3019–25.PubMedCrossRefGoogle Scholar
  142. 142.
    Crescenzo R, Abate F, Lasorsa E, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27:516–32.PubMedCrossRefGoogle Scholar
  143. 143.
    Thompson PA, Lade S, Webster H, et al. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Haematologica. 2010;95:1977–9.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Keech JA, Creech BJ. Anaplastic T-cell lymphoma in proximity to a saline-filled breast implant. Plast Reconstr Surg. 1997;100:554–5.PubMedCrossRefGoogle Scholar
  145. 145.
    Miranda RN, Aladily TN, Prince HM, et al. Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients. J Clin Oncol. 2014;32:114–20.PubMedCrossRefGoogle Scholar
  146. 146.
    Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical excision is essential for the management of patients with breast implant-associated anaplastic large-cell lymphoma. J Clin Oncol. 2016;34:160–8.PubMedCrossRefGoogle Scholar
  147. 147.
    Laurent C, Delas A, Gaulard P, et al. Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes. Ann Oncol. 2016;27:306–14.PubMedCrossRefGoogle Scholar
  148. 148.
    Perry AM, Warnke RA, Hu Q, et al. Indolent T-cell lymphoproliferative disease of the gastrointestinal tract. Blood. 2013;122:3599–606.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Petrella T, Maubec E, Cornillet-Lefebvre P, et al. Indolent CD8-positive lymphoid proliferation of the ear: a distinct primary cutaneous T-cell lymphoma? Am J Surg Pathol. 2007;31:1887–92.PubMedCrossRefGoogle Scholar
  150. 150.
    Deleeuw RJ, Zettl A, Klinker E, et al. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology. 2007;132:1902–11.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017, corrected publication July/2017 2017
corrected publication July/2017

Authors and Affiliations

  • Ryan C. Lynch
    • 1
  • Dita Gratzinger
    • 2
  • Ranjana H. Advani
    • 1
    • 3
  1. 1.Division of Oncology, Department of MedicineStanford University School of MedicineStanfordUSA
  2. 2.Department of PathologyStanford University School of MedicineStanfordUSA
  3. 3.Stanford University Medical CenterStanfordUSA

Personalised recommendations