Diffuse large B cell lymphoma: Using pathologic and molecular biomarkers to define subgroups for novel therapy

Annals of Hematology

Volumn 93, Issue 8, 2014, Pages 1263-1277

  Carbone, Antonino ^a   Gloghini, Annunziata ^b   Kwong, Yok Lam ^c   Younes, Anas ^d  

^a CENTRO DI RIFERIMENTO ONCOLOGICO   (Italy)

^b NATIONAL CANCER INSTITUTE   (Italy)

^c QUEEN MARY HOSPITAL   (Hong Kong)

^d MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

Biomarkers; Diagnosis; DLBCL; Prognosis; Treatment

Indexed keywords

BIOLOGICAL MARKER; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MYELOID DIFFERENTIATION FACTOR 88;

CANCER DIAGNOSIS; CANCER PROGNOSIS; DIAGNOSTIC TEST ACCURACY STUDY; GENE EXPRESSION PROFILING; GENE MUTATION; HUMAN; IMMUNOHISTOCHEMISTRY; LARGE CELL LYMPHOMA; LOSS OF FUNCTION MUTATION; PRIORITY JOURNAL; REVIEW;

B-LYMPHOCYTE SUBSETS; CELL TRANSFORMATION, NEOPLASTIC; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; LYMPHOMA, LARGE B-CELL, DIFFUSE; MOLECULAR TARGETED THERAPY; NEOPLASM PROTEINS; NEOPLASTIC STEM CELLS; NF-KAPPA B; THERAPIES, INVESTIGATIONAL; TUMOR MARKERS, BIOLOGICAL; TUMOR MICROENVIRONMENT; TUMOR VIRUS INFECTIONS;

EID: 84904743618     PISSN: 09395555     EISSN: 14320584     Source Type: Journal    
DOI: 10.1007/s00277-014-2116-y     Document Type: Review

References (113)

1. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC, Lyon
2. Stein H, Warnke RA, Chan WC, Jaffe ES, Chan JKC, Gatter KC, Campo E (2008) Diffuse large B-cell lymphoma, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopietic and lymphoid tissues, 4th edn. IARC press, Lyon, pp 233-237
3. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES (2011) The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117(19):5019-5032. doi:10.1182/blood-2011-01- 293050
4. Shankland KR, Armitage JO, Hancock BW (2012) Non-Hodgkin lymphoma. Lancet 380(9844):848 - 857. doi:10.1016/S0140-6736(12)60605-9
5. Cheson BD (2013) Therapy for diffuse large B-cell lymphoma: getting personal. Lancet 381(9880):1793-1794. doi:10.1016/S0140-6736(13)60849-1
6. Campo E (2013) Whole genome profiling and other high throughput technologies in lymphoid neoplasms - current contributions and future hopes. Mod Pathol 26(Suppl):1S97-S110. doi:10.1038/modpathol.2012.179
7. Staudt LM(2013) Therapy of DLBCL based on genomics. Hematol Oncol 31(Suppl):126-128. doi:10.1002/hon.2062
8. Slack GW, Gascoyne RD (2013) Next-generation sequencing discoveries in lymphoma. Adv Anat Pathol 20(2):110-116. doi:10.1097/PAP.0b013e3182862724
9. Menon MP, Pittaluga S, Jaffe ES (2012) The histological and biological spectrum of diffuse large B-cell lymphoma in the World Health Organization classification. Cancer J 18(5):411-420. doi:10.1097/PPO.0b013e31826aee97
10. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC (1994) A revised european-american classification of lymphoid neoplasms: A proposal from the international lymphoma study group. Blood 84(5):1361-1392
11. Rappaport H (1966) Tumors of the hematopoietic system. Series I ed. Armed Forces Institute of Pathology, Washington
12. Gérard-Marchant R, Hamlin I, Lennert K, Rilke F, Stansfeld A, van Unnik J (1974) Classification of non-Hodgkin's lymphomas. Lancet 406-408
13. Lukes RJ, Collins RD (1974) Immunologic characterization of human malignant lymphomas. Cancer 34(4 Supp):suppl:1488-suppl:1503
14. Stansfeld AG, Diebold J, Noel H, Kapanci Y, Rilke F, Kelenyi G, Sundstrom C, Lennert K, van Unnik JA, Mioduszewska O (1988) Updated kiel classification for lymphomas. Lancet 1(8580):292-293
15. [Anonymous] (1982) National cancer institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The non-Hodgkin's lymphoma pathologic classification project. Cancer 49(10):2112-2135
16. Rosenberg SA (1994) Classification of lymphoid neoplasms. Blood 84(5):1359-1360
17. Mounier N, Briere J, Gisselbrecht C, Emile JF, Lederlin P, Sebban C, Berger F, Bosly A, Morel P, Tilly H, Bouabdallah R, Reyes F, Gaulard P, Coiffier B (2003) Rituximab plus CHOP (R-CHOP) overcomes bcl-2-associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood 101(11):4279-4284. doi:10.1182/blood-2002-11-3442
18. Ott G, Ziepert M, Klapper W, Horn H, Szczepanowski M, Bernd HW, Thorns C, Feller AC, Lenze D, Hummel M, Stein H, Muller-Hermelink HK, Frank M, Hansmann ML, Barth TF, Moller P, Cogliatti S, Pfreundschuh M, Schmitz N, Trumper L, Loeffler M, Rosenwald A (2010) 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 116(23):4916-4925. doi:10.1182/blood-2010-03-276766
19. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403(6769):503-511. doi:10.1038/35000501
20. Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander ES, Aster JC, Golub TR (2002) Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8(1):68-74. doi:10.1038/nm0102-68
21. Lossos IS, Czerwinski DK, Alizadeh AA,Wechser MA, Tibshirani R, Botstein D, Levy R (2004) Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350(18):1828-1837. doi:10.1056/NEJMoa032520
22. Alizadeh AA, Gentles AJ, Alencar AJ, Liu CL, Kohrt HE, Houot R, Goldstein MJ, Zhao S, Natkunam Y, Advani RH, Gascoyne RD, Briones J, Tibshirani RJ, Myklebust JH, Plevritis SK, Lossos IS, Levy R (2011) Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment. Blood 118(5):1350-1358. doi:10.1182/blood-2011-03- 345272
23. Scott DW, Wright GW, Williams PM, Lih CJ, Walsh W, Jaffe ES, Rosenwald A, Campo E, Chan WC, Connors JM, Smeland EB, Mottok A, Braziel RM, Ott G, Delabie J, Tubbs RR, Cook JR, Weisenburger DD,Greiner TC,Glinsmann-Gibson BJ, Fu K, Staudt LM, Gascoyne RD, Rimsza LM (2014) Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123(8):1214-1217. doi:10.1182/blood-2013-11- 536433
24. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM, Lymphoma/Leukemia Molecular Profiling Project (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346(25):1937-1947. doi:10.1056/NEJMoa012914
25. Carbone A, Gloghini A, Larocca LM, Capello D, Pierconti F, Canzonieri V, Tirelli U, Dalla-Favera R, Gaidano G (2001) Expression profile of MUM1/IRF4, BCL-6, and CD138/syndecan-1 defines novel histogenetic subsets of human immunodeficiency virus-related lymphomas. Blood 97(3):744-751
26. Said JW (2013) Aggressive B-cell lymphomas: how many categories do we need? Mod Pathol 26(Suppl):1S42-1S56. doi:10.1038/modpathol.2012.178
27. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Muller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, Pan Z, Farinha P, Smith LM, Falini B, Banham AH, Rosenwald A, Staudt LM, Connors JM, Armitage JO, Chan WC (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103(1):275-282. doi:10.1182/blood-2003-05-1545
28. Salles G, de Jong D, Xie W, Rosenwald A, Chhanabhai M, Gaulard P, Klapper W, Calaminici M, Sander B, Thorns C, Campo E, Molina T, Lee A, Pfreundschuh M, Horning S, Lister A, Sehn LH, Raemaekers J, Hagenbeek A, Gascoyne RD, Weller E (2011) Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: A study from the lunenburg lymphoma biomarker consortium. Blood 117(26):7070-7078. doi:10.1182/blood-2011-04-345256
29. Meyer PN, Fu K, Greiner TC, Smith LM, Delabie J, Gascoyne RD, Ott G, Rosenwald A, Braziel RM, Campo E, Vose JM, Lenz G, Staudt LM, Chan WC, Weisenburger DD (2011) Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol 29(2):200-207. doi:10.1200/JCO.2010.30.0368
30. Choi WW, Weisenburger DD, Greiner TC, Piris MA, Banham AH, Delabie J, Braziel RM, Geng H, Iqbal J, Lenz G, Vose JM, Hans CP, Fu K, Smith LM, Li M, Liu Z, Gascoyne RD, Rosenwald A, Ott G, Rimsza LM, Campo E, Jaffe ES, Jaye DL, Staudt LM, Chan WC (2009) A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 15(17):5494-5502. doi:10.1158/1078-0432.CCR-09-0113
31. Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, Shovlin M, Jaffe ES, Janik JE, Staudt LM, Wilson WH (2009) Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113(24):6069-6076. doi:10.1182/blood-2009-01-199679
32. Perry AM, Cardesa-Salzmann TM, Meyer PN, Colomo L, Smith LM, Fu K, Greiner TC, Delabie J, Gascoyne RD, Rimsza L, Jaffe ES, Ott G, Rosenwald A, Braziel RM, Tubbs R, Cook JR, Staudt LM, Connors JM, Sehn LH, Vose JM, Lopez-Guillermo A, Campo E, Chan WC, Weisenburger DD (2012) A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma. Blood 120(11):2290-2296. doi:10.1182/blood-2012-05-430389
33. Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, Banham AH, Leppa S (2009) Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod Pathol 22(8):1094-1101. doi:10.1038/modpathol.2009.73
34. Barrans SL, Crouch S, Care MA, Worrillow L, Smith A, Patmore R, Westhead DR, Tooze R, Roman E, Jack AS (2012) Whole genome expression profiling based on paraffin embedded tissue can be used to classify diffuse large B-cell lymphoma and predict clinical outcome. Br J Haematol 159(4):441-453. doi:10.1111/bjh. 12045
35. Gaidano G, Carbone A (2000) MUM1: a step ahead toward the understanding of lymphoma histogenesis. Leukemia 14(4):563-566
36. Chadburn A, Chiu A, Lee JY, Chen X, Hyjek E, Banham AH, Noy A, Kaplan LD, Sparano JA, Bhatia K, Cesarman E (2009) Immunophenotypic analysis of AIDS-related diffuse large B-cell lymphoma and clinical implications in patients from AIDS malignancies consortium clinical trials 010 and 034. J Clin Oncol 27(30):5039-5048. doi:10.1200/JCO.2008.20.5450
37. Dunleavy K, Little RF, Pittaluga S, Grant N, Wayne AS, Carrasquillo JA, Steinberg SM, Yarchoan R, Jaffe ES, Wilson WH (2010) The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood 115(15):3017-3024. doi:10.1182/blood-2009-11-253039
38. Capello D, Gloghini A, Martini M, Spina M, Tirelli U, Bertoni F, Rinaldi A, Morra E, Rambaldi A, Sinigaglia F, Larocca LM, Carbone A (2011) Mutations of CD79A, CD79B and EZH2 genes in immunodeficiency-related non-Hodgkin lymphomas. Br J Haematol 152(6):777-780. doi:10.1111/j.1365-2141.2010.08445.x
39. IARC (2012) IARC monograph on the evaluation of carcinogenic risk to humans. vol. 100. A review of human carcinogens. part B: biological agents. IARC, Lyon
40. Coutinho R, Clear AJ, Owen A, Wilson A, Matthews J, Lee A, Alvarez R, da Silva MG, Cabecadas J, Calaminici M, Gribben JG (2013) Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: implications for therapeutic strategies. Clin Cancer Res 19(24):6686-6695. doi:10.1158/1078-0432.CCR-13-1482
41. Culpin RE, Sieniawski M, Angus B, Menon GK, Proctor SJ, Milne P, McCabe K, Mainou-Fowler T (2013) Prognostic significance of immunohistochemistry-based markers and algorithms in immunochemotherapy-treated diffuse large B cell lymphoma patients. Histopathology 63(6):788-801. doi:10.1111/his.12223
42. Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW, Dave SS, Zhao H, Xu W, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Chan WC, Staudt LM (2008) Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319(5870):1676-1679. doi:10.1126/science.1153629
43. Milhollen MA, Traore T, Adams-Duffy J, Thomas MP, Berger AJ, Dang L, Dick LR, Garnsey JJ, Koenig E, Langston SP, Manfredi M, Narayanan U, Rolfe M, Staudt LM, Soucy TA, Yu J, Zhang J, Bolen JB, Smith PG (2010) MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood 116(9):1515-1523. doi:10.1182/blood-2010-03-272567
44. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large Bcell lymphomas of germinal-center origin. Nat Genet 42(2):181-185. doi:10.1038/ng.518
45. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, Cruz-Gordillo P, Knoechel B, Asmann YW, Slager SL, Novak AJ, Dogan A, Ansell SM, Link BK, Zou L, Gould J, Saksena G, Stransky N, Rangel-Escareno C, Fernandez-Lopez JC, Hidalgo- Miranda A, Melendez-Zajgla J, Hernandez-Lemus E, Schwarz- Cruz y Celis A, Imaz-Rosshandler I, Ojesina AI, Jung J, Pedamallu CS, Lander ES, Habermann TM, Cerhan JR, Shipp MA, Getz G, Golub TR (2012) Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A 109(10):3879-3884. doi:10.1073/pnas.1121343109
46. Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM (2011) Oncogenically active MYD88 mutations in human lymphoma. Nature 470(7332):115-119. doi:10.1038/nature09671
47. Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, Kasper LH, Lerach S, Tang H, Ma J, Rossi D, Chadburn A, Murty VV, Mullighan CG, Gaidano G, Rabadan R, Brindle PK, Dalla-Favera R (2011) Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471(7337):189-195. doi:10.1038/nature09730
48. Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA (2011) Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476(7360):298-303. doi:10.1038/nature10351
49. Iqbal J, Greiner TC, Patel K, Dave BJ, Smith L, Ji J, Wright G, Sanger WG, Pickering DL, Jain S, Horsman DE, Shen Y, Fu K, Weisenburger DD, Hans CP, Campo E, Gascoyne RD, Rosenwald A, Jaffe ES, Delabie J, Rimsza L, Ott G, Muller-Hermelink HK, Connors JM, Vose JM, McKeithan T, Staudt LM, Chan WC, Leukemia/Lymphoma Molecular Profiling Project (2007) Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. Leukemia 21(11):2332- 2343. doi:10.1038/sj.leu.2404856
50. Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, Carty S, Lam LT, Shaffer AL, Xiao W, Powell J, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Campo E, Jaffe ES, Delabie J, Smeland EB, Rimsza LM, Fisher RI, Weisenburger DD, Chan WC, Staudt LM (2008) Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A 105(36):13520-13525. doi:10.1073/pnas.0804295105
51. Pasqualucci L, Compagno M, Houldsworth J, Monti S, Grunn A, Nandula SV, Aster JC, Murty VV, Shipp MA, Dalla-Favera R (2006) Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med 203(2):311-317
52. Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, Bertoni F, Ponzoni M, Scandurra M, Califano A, Bhagat G, Chadburn A, Dalla-Favera R, Pasqualucci L (2009) Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 459(7247):717-721. doi:10.1038/nature07968
53. Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, Wells VA, Grunn A, Messina M, Elliot O, Chan J, Bhagat G, Chadburn A, Gaidano G, Mullighan CG, Rabadan R, Dalla-Favera R (2011) Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 43(9):830-837. doi:10.1038/ng.892
54. Johnson NA, Savage KJ, Ludkovski O, Ben-Neriah S, Woods R, Steidl C, Dyer MJ, Siebert R, Kuruvilla J, Klasa R, Connors JM, Gascoyne RD, Horsman DE (2009) Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 114(11):2273-2279. doi:10.1182/blood-2009-03- 212191
55. Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, Horsman DE, Gascoyne RD (2009) MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood 114(17):3533-3537. doi:10.1182/blood-2009-05-220095
56. Scott DW, Mungall KL, Ben-Neriah S, Rogic S, Morin RD, Slack GW, Tan KL, Chan FC, Lim RS, Connors JM, Marra MA, Mungall AJ, Steidl C, Gascoyne RD (2012) TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma. Blood 119(21):4949-4952. doi:10.1182/blood-2012-02-414441
57. Lee SY, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto G, Nannya Y, Suzuki R, Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M, Hangaishi A, Yagita H, Fukayama M, Seto M, Kurokawa M, Ogawa S, Chiba S (2009) Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci 100(5):920-926
58. Xu-Monette ZY, Medeiros LJ, Li Y, Orlowski RZ, Andreeff M, Bueso-Ramos CE, Greiner TC, McDonnell TJ, Young KH (2012) Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood 119(16):3668-3683. doi:10.1182/blood-2011-11-366062
59. Davis RE, Brown KD, Siebenlist U, Staudt LM (2001) Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 194(12):1861-1874
60. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang JK, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463(7277):88-92. doi:10.1038/nature08638
61. Barton S, Hawkes EA,Wotherspoon A, Cunningham D (2012) Are we ready to stratify treatment for diffuse large B-cell lymphoma using molecular hallmarks? Oncologist 17(12):1562-1573. doi:10.1634/theoncologist.2012-0218
62. Rossi D, Ciardullo C, Gaidano G (2013) Genetic aberrations of signaling pathways in lymphomagenesis: revelations from next generation sequencing studies. Semin Cancer Biol. doi:10.1016/j.semcancer.2013.04.002
63. Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam A, Liu WM, Visco C, Li Y, Miranda RN, Montes-Moreno S, Dybkaer K, Chiu A, Orazi A, Zu Y, Bhagat G, Richards KL, Hsi ED, Choi WW, Zhao X, van Krieken JH, Huang Q, Huh J, Ai W, Ponzoni M, Ferreri AJ, Zhou F, Slack GW, Gascoyne RD, Tu M, Variakojis D, Chen W, Go RS, Piris MA, Moller MB, Medeiros LJ, Young KH (2013) MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates highrisk gene expression signatures: a report from the international DLBCL rituximab-CHOP consortium program. Blood 121(20): 4021-4031. doi:10.1182/blood-2012-10-460063, quiz 4250
64. Younes A (2011) Beyond chemotherapy: new agents for targeted treatment of lymphoma. Nat Rev, Clin Oncol 8(2):85-96. doi:10.1038/nrclinonc.2010.189
65. Younes A, Berry DA (2012) From drug discovery to biomarkerdriven clinical trials in lymphoma. Nat Rev, Clin Oncol 9(11):643-653. doi:10.1038/nrclinonc. 2012.156
66. Chau CH, Rixe O, McLeod H, Figg WD (2008)Validation of analytic methods for biomarkers used in drug development. Clin Cancer Res 14(19):5967-5976. doi:10.1158/1078-0432.CCR-07-4535
67. Dancey JE, Dobbin KK, Groshen S, Jessup JM, Hruszkewycz AH, Koehler M, Parchment R, Ratain MJ, Shankar LK, Stadler WM, True LD, Gravell A, Grever MR, Biomarkers Task Force of the NCI Investigational Drug Steering Committee (2010) Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin Cancer Res 16(6):1745-1755. doi:10.1158/1078-0432.CCR-09-2167
68. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356(6366):215-221. doi:10.1038/356215a0
69. Jardin F, Coiffier B (2013) TP53 and outcome in DLBCL: not only the coding region. Blood 121(22):4433-4434. doi:10.1182/blood-2013-04-493486
70. Monti S, Chapuy B, Takeyama K, Rodig SJ, Hao Y, Yeda KT, Inguilizian H, Mermel C, Currie T, Dogan A, Kutok JL, Beroukhim R, Neuberg D, Habermann TM, Getz G, Kung AL, Golub TR, Shipp MA (2012) Integrative analysis reveals an outcomeassociated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma. Cancer Cell 22(3):359-372. doi:10.1016/j.ccr. 2012.07.014
71. Young KH, Weisenburger DD, Dave BJ, Smith L, Sanger W, Iqbal J, Campo E, Delabie J, Gascoyne RD, Ott G, Rimsza L, Muller-Hermelink HK, Jaffe ES, Rosenwald A, Staudt LM, Chan WC, Greiner TC (2007) Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma. Blood 110(13):4396-4405. doi:10.1182/blood-2007-02-072082
72. Leroy K, Haioun C, Lepage E, Le Metayer N, Berger F, Labouyrie E, Meignin V, Petit B, Bastard C, Salles G, Gisselbrecht C, Reyes F, Gaulard P, Groupe d'Etude des Lymphomes de l'Adulte (2002) p53 gene mutations are associated with poor survival in low and lowintermediate risk diffuse large B-cell lymphomas. Ann Oncol 13(7):1108-1115
73. Xu-Monette ZY, Wu L, Visco C, Tai YC, Tzankov A, Liu WM, Montes-Moreno S, Dybkaer K, Chiu A, Orazi A, Zu Y, Bhagat G, Richards KL, Hsi ED, Zhao XF, Choi WW, Zhao X, van Krieken JH, Huang Q, Huh J, Ai W, Ponzoni M, Ferreri AJ, Zhou F, Kahl BS, Winter JN, Xu W, Li J,Go RS, Li Y, Piris MA, Moller MB, Miranda RN, Abruzzo LV, Medeiros LJ, Young KH (2012) Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an international DLBCL rituximab-CHOP consortium program study. Blood 120(19):3986-3996. doi:10.1182/blood-2012-05-433334
74. Meyer N, Penn LZ (2008) Reflecting on 25 years with MYC. Nat Rev Cancer 8(12):976-990. doi:10.1038/nrc2231
75. Ott G, Rosenwald A, Campo E (2013) Understanding MYC driven aggressive B-cell lymphomas: pathogenesis and classification. Blood. doi:10.1182/blood- 2013-05-498329
76. Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, Roman E, Jack A (2010) 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 28(20):3360-3365. doi:10.1200/JCO.2009.26.3947
77. Green TM, Nielsen O, de Stricker K, Xu-Monette ZY, Young KH, Moller MB (2012) High levels of nuclear MYC protein predict the presence of MYC rearrangement in diffuse large B-cell lymphoma. Am J Surg Pathol 36(4):612-619. doi:10.1097/PAS.0b013e318244e2ba
78. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, Korsmeyer SJ (1989) Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57(1):79-88
79. Reed JC (1997) Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologicmalignancies. Semin Hematol 34(4 Suppl 5):9-19
80. Hermine O, Haioun C, Lepage E, d'Agay MF, Briere J, Lavignac C, Fillet G, Salles G, Marolleau JP, Diebold J, Reyas F, Gaulard P (1996) Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. groupe d'etude des lymphomes de l'adulte (GELA). Blood 87(1):265-272
81. Gascoyne RD, Adomat SA, Krajewski S, Krajewska M, Horsman DE, Tolcher AW, O'Reilly SE, Hoskins P, Coldman AJ, Reed JC, Connors JM (1997) Prognostic significance of bcl-2 protein expression and bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma. Blood 90(1):244-251
82. Hill ME, MacLennan KA, Cunningham DC, Vaughan Hudson B, Burke M, Clarke P, Di Stefano F, Anderson L, Vaughan Hudson G, Mason D, Selby P, Linch DC (1996) Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a British national lymphoma investigation study. Blood 88(3):1046-1051
83. Iqbal J, Neppalli VT, Wright G, Dave BJ, Horsman DE, Rosenwald A, Lynch J, Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Campo E, Ott G, Muller-Hermelink HK, Delabie J, Jaffe ES, Grogan TM, Connors JM, Vose JM, Armitage JO, Staudt LM, Chan WC (2006) BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol 24(6):961-968. doi:10.1200/JCO.2005.03.4264
84. Copie-Bergman C, Gaulard P, Leroy K, Briere J, Baia M, Jais JP, Salles GA, Berger F, Haioun C, Tilly H, Emile JF, Banham AH, Mounier N, Gisselbrecht C, Feugier P, Coiffier B, Molina TJ (2009) Immuno-fluorescence in situ hybridization index predicts survival in patients with diffuse large B-cell lymphoma treated with R-CHOP: a GELA study. J Clin Oncol 27(33):5573-5579. doi:10.1200/JCO.2009.22.7058
85. Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, Scott DW, Tan KL, Steidl C, Sehn LH, Chan WC, Iqbal J, Meyer PN, Lenz G, Wright G, Rimsza LM, Valentino C, Brunhoeber P, Grogan TM, Braziel RM, Cook JR, Tubbs RR, Weisenburger DD, Campo E, Rosenwald A, Ott G, Delabie J, Holcroft C, Jaffe ES, Staudt LM, Gascoyne RD (2012) Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30(28):3452-3459. doi:10.1200/JCO.2011.41.0985
86. Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, Nielsen O, Gadeberg OV, Mourits-Andersen T, Frederiksen M, Pedersen LM, Moller MB (2012) Immunohistochemical doublehit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30(28):3460-3467. doi:10.1200/JCO.2011.41.4342
87. Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS, Dalla-Favera R (1993) Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262(5134):747-750
88. Lossos IS, Jones CD, Warnke R, Natkunam Y, Kaizer H, Zehnder JL, Tibshirani R, Levy R (2001) Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood 98(4):945-951
89. Horn H, Ziepert M, Becher C, Barth TF, Bernd HW, Feller AC, Klapper W, Hummel M, Stein H, Hansmann ML, Schmelter C, Moller P, Cogliatti S, Pfreundschuh M, Schmitz N, Trumper L, Siebert R, Loeffler M, Rosenwald A, Ott G, German High-Grade Non-Hodgkin Lymphoma Study Group (2013) MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 121(12):2253-2263. doi:10.1182/blood-2012-06-435842
90. Yamaguchi M, Nakamura N, Suzuki R, Kagami Y, Okamoto M, Ichinohasama R, Yoshino T, Suzumiya J, Murase T, Miura I, Ohshima K, Nishikori M, Tamaru J, Taniwaki M, Hirano M, Morishima Y, Ueda R, Shiku H, Nakamura S (2008) De novo CD5+ diffuse large B-cell lymphoma: results of a detailed clinicopathological review in 120 patients. Haematologica 93(8):1195-1202. doi:10.3324/haematol. 12810
91. Miller TP, Grogan TM, Dahlberg S, Spier CM, Braziel RM, Banks PM, Foucar K, Kjeldsberg CR, Levy N, Nathwani BN (1994) Prognostic significance of the ki-67-associated proliferative antigen in aggressive non-Hodgkin's lymphomas: a prospective southwest oncology group trial. Blood 83(6):1460-1466
92. Armitage JO, Weisenburger DD (1998) New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. non-Hodgkin's lymphoma classification project. J Clin Oncol 16(8):2780-2795
93. Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J, Gascoyne RD, Connors JM (2007) The revised international prognostic index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109(5):1857-1861
94. Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, Vanderplas A, Zelenetz AD, Abel GA, Rodriguez MA, Nademanee A, Kaminski MS, Czuczman MS, Millenson M, Niland J, Gascoyne RD, Connors JM, Friedberg JW, Winter JN (2014) An enhanced international prognostic index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123(6):837-842. doi:10.1182/blood-2013-09-524108
95. Dolcetti R, Dal Col J, Martorelli D, Carbone A, Klein E (2013) Interplay among viral antigens, cellular pathways and tumor microenvironment in the pathogenesis of EBV-driven lymphomas. Semin Cancer Biol. doi:10.1016/j. semcancer.2013.07.005
96. Carbone A, Tripodo C, Carlo-Stella C, Santoro A, Gloghini A (2013) Inflammation and lymphoma. In: Gupta SC, Sung B, Aggarwal BB (eds) Inflammation and cancer. Springer, Basel
97. Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B, Goldschmidt N, Iqbal J, Vose J, Bast M, Fu K, Weisenburger DD, Greiner TC, Armitage JO, Kyle A, May L, Gascoyne RD, Connors JM, Troen G, Holte H, Kvaloy S, Dierickx D, Verhoef G, Delabie J, Smeland EB, Jares P, Martinez A, Lopez-Guillermo A, Montserrat E, Campo E, Braziel RM, Miller TP, Rimsza LM, Cook JR, Pohlman B, Sweetenham J, Tubbs RR, Fisher RI, Hartmann E, Rosenwald A, Ott G, Muller-Hermelink HK, Wrench D, Lister TA, Jaffe ES, Wilson WH, Chan WC, Staudt LM, Lymphoma/Leukemia Molecular Profiling Project (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359(22):2313-2323. doi:10.1056/NEJMoa0802885
98. Liapis K, Clear A, Owen A, Coutinho R, Greaves P, Lee AM, Montoto S, Calaminici M, Gribben JG (2013) The microenvironment of AIDS-related diffuse large B-cell lymphoma provides insight into the pathophysiology and indicates possible therapeutic strategies. Blood 122(3):424-433. doi:10.1182/blood-2013- 03-488171
99. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, Cogliano V, WHO International Agency for Research on Cancer Monograph Working Group (2009) A review of human carcinogens-part B: biological agents. Lancet Oncol 10(4):321-322
100. Carbone A, Cesarman E, Spina M, Gloghini A, Schulz TF (2009) HIV-associated lymphomas and gamma-herpesviruses. Blood 113(6):1213-1224. doi:10.1182/blood-2008-09-180315
101. Aozasa K (2006) Pyothorax-associated lymphoma. J Clin Exp Hematop 46(1):5-10
102. Fukayama M, Ibuka T, Hayashi Y, Ooba T, Koike M, Mizutani S (1993) Epstein-barr virus in pyothorax-associated pleural lymphoma. Am J Pathol 143(4):1044-1049
103. Chan JKC, Aozasa K, Gaulard P (2008) DLBCL associated with chronic inflammation. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC press, Lyon, pp 245-246
104. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, Ralfkiaer E, Chimenti S, Diaz-Perez JL, Duncan LM, Grange F, Harris NL, Kempf W, Kerl H, Kurrer M, Knobler R, Pimpinelli N, Sander C, Santucci M, Sterry W, Vermeer MH, Wechsler J, Whittaker S, Meijer CJ (2005) WHO-EORTC classification for cutaneous lymphomas. Blood 105(10):3768-3785
105. Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De Leval L, Kurtin P, Dal Cin P, Ladd C, Feuerhake F, Aguiar RC, Li S, Salles G, Berger F, Jing W, Pinkus GS, Habermann T, Dalla-Favera R, Harris NL, Aster JC, Golub TR, Shipp MA (2003) 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 102(12):3871-3879. doi:10.1182/blood-2003-06- 1841
106. Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M, Jaffe ES (2005) Mediastinal gray zone lymphoma: the missing link between classic Hodgkin's lymphoma and mediastinal large B-cell lymphoma. Am J Surg Pathol 29(11):1411-1421
107. Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD, Chan WC, Zhao T, Haioun C, Greiner TC, Weisenburger DD, Lynch JC, Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Campo E, Montserrat E, Lopez-Guillermo A, Ott G, Muller-Hermelink HK, Connors JM, Braziel R, Grogan TM, Fisher RI, Miller TP, LeBlanc M, Chiorazzi M, Zhao H, Yang L, Powell J, Wilson WH, Jaffe ES, Simon R, Klausner RD, Staudt LM (2003) 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 198(6):851-862. doi:10.1084/jem.20031074
108. Ferreri AJ (2011) How I treat primary CNS lymphoma. Blood 118(3):510-522. doi:10.1182/blood-2011-03-321349
109. Sung CO, Kim SC, Karnan S, Karube K, Shin HJ, Nam DH, Suh YL, Kim SH, Kim JY, Kim SJ, Kim WS, Seto M, Ko YH (2011) Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma. Blood 117(4):1291-1300. doi:10.1182/blood-2010-07-297861
110. Martinez A, Ponzoni M, Agostinelli C, Hebeda KM, Matutes E, Peccatori J, Campidelli C, Espinet B, Perea G, Acevedo A, Mehrjardi AZ, Martinez-Bernal M, Gelemur M, Zucca E, Pileri S, Campo E, Lopez-Guillermo A, Rozman M, International Extranodal Lymphoma Study Group (2012) Primary bone marrow lymphoma: an uncommon extranodal presentation of aggressive non-Hodgkin lymphomas. Am J Surg Pathol 36(2):296-304. doi:10.1097/PAS.0b013e31823ea106
111. Bruno Ventre M, Ferreri AJ, Gospodarowicz M, Govi S, Messina C, Porter D, Radford J, Heo DS, Park Y, Martinelli G, Taylor E, Lucraft H, Hong A, Scarfo L, Zucca E, Christie D, International Extranodal Lymphoma Study Group (2014) Clinical features, management, and prognosis of an international series of 161 patients with limited-stage diffuse large B-cell lymphoma of the bone (the IELSG-14 study). Oncologist 19(3):291 - 298. doi:10.1634/theoncologist.2013-0249
112. Gloghini A, De Leval L (2013) Immunophenotyping of non-Hodgkin lymphomas. In: Carbone A, Younes A (eds) Non-Hodgkin lymphomas: advanced diagnostics and personalized therapies, Future Medicine, pp 32-55. doi:10.2217/9781780841717
113. Younes A (2013) XIV. the rationale for combining targeted and biological anti-lymphoma drugs. Hematol Oncol 31(Suppl):181-183. doi:10.1002/hon.2072