Epstein-Barr virus (EBV), defined as a group I carcinogen by the World Health Organization (WHO), is present in the tumour cells of patients with different forms of B-cell lymphoma, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorders, and, most recently, diffuse large B-cell lymphoma (DLBCL). Understanding how EBV contributes to the development of these different types of B-cell lymphoma has not only provided fundamental insights into the underlying mechanisms of viral oncogenesis, but has also highlighted potential new therapeutic opportunities. In this review, we describe the effects of EBV infection in normal B-cells and we address the germinal centre model of infection and how this can lead to lymphoma in some instances. We then explore the recent reclassification of EBV+ DLBCL as an established entity in the WHO fifth edition and ICC 2022 classifications, emphasising the unique nature of this entity. To that end, we also explore the unique genetic background of this entity and briefly discuss the potential role of the tumour microenvironment in lymphomagenesis and disease progression. Despite the recent progress in elucidating the mechanisms of this malignancy, much work remains to be done to improve patient stratification, treatment strategies, and outcomes.

BioScience and BioEngineering Research Bernal BioMaterials Cluster Bernal Institute University of Limerick V94 T9PX Limerick Ireland

Department of Clinical and Molecular Pathology Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olmouc 775 15 Olomouc Czech Republic

Department of Clinical and Molecular Pathology University Hospital Olomouc 779 00 Olomouc Czech Republic

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacky Univesity and University Hospital Olomouc 779 00 Olomouc Czech Republic

Department of Medical Biotechnologies Section of Pathology University of Siena 53100 Siena Italy

Health Research Institute and School of Medicine University of Limerick V94 T9PX Limerick Ireland

Institute of Immunology and Immunotherapy University of Birmingham Birmingham B15 2TT UK

See more in PubMed

Chabay P. Advances in the Pathogenesis of EBV-Associated Diffuse Large B Cell Lymphoma. Cancers. 2021;13:2717. doi: 10.3390/cancers13112717. PubMed DOI PMC

Soltani S., Zakeri A., Tabibzadeh A., Zakeri A.M., Zandi M., Siavoshi S., Seifpour S., Farahani A. A review on EBV encoded and EBV-induced host microRNAs expression profile in different lymphoma types. Mol. Biol. Rep. 2021;48:1801–1817. doi: 10.1007/s11033-021-06152-z. PubMed DOI

Alaggio R., Amador C., Anagnostopoulos I., Attygalle A.D., Araujo I.B.D.O., Berti E., Bhagat G., Borges A.M., Boyer D., Calaminici M. The 5th edition of the World Health Organization classification of haematolymphoid tumours: Lymphoid neoplasms. Leukemia. 2022;36:1720–1748. doi: 10.1038/s41375-022-01620-2. PubMed DOI PMC

Crump M., Neelapu S.S., Farooq U., Van Den Neste E., Kuruvilla J., Westin J., Link B.K., Hay A., Cerhan J.R., Zhu L. Outcomes in refractory diffuse large B-cell lymphoma: Results from the international SCHOLAR-1 study. Blood J. Am. Soc. Hematol. 2017;130:1800–1808. doi: 10.1182/blood-2017-03-769620. PubMed DOI PMC

Muris J., Ylstra B., Cillessen S., Ossenkoppele G., Kluin-Nelemans J., Eijk P., Nota B., Tijssen M., De Boer W., Van De Wiel M. Profiling of apoptosis genes allows for clinical stratification of primary nodal diffuse large B-cell lymphomas. Br. J. Haematol. 2007;136:38–47. doi: 10.1111/j.1365-2141.2006.06375.x. PubMed DOI

Nowakowski G.S., Czuczman M.S. ABC, GCB, and double-hit diffuse large B-cell lymphoma: Does subtype make a difference in therapy selection? Am. Soc. Clin. Oncol. Educ. Book. 2015;35:e449–e457. doi: 10.14694/EdBook_AM.2015.35.e449. PubMed DOI

Rickinson A.B., Kieff E. Epstein-Barr Virus. In: Field B.N., Knipe D.M., Howley P.M., editors. Fields Virology. 3rd ed. Lippincott-Raven Publishers; Philadelphia, PA, USA: 1996. pp. 2397–2446.

Baer R., Bankier A.T., Biggin M.D., Deininger P.L., Farrell P.J., Gibson T.J., Hatfull G., Hudson G.S., Satchwell S.C., Séguin C., et al. DNA sequence and expression of the B95-8 Epstein—Barr virus genome. Nature. 1984;310:207–211. doi: 10.1038/310207a0. PubMed DOI

de Jesus O., Smith P.R., Spender L.C., Karstegl C.E., Niller H.H., Huang D., Farrell P.J. Updated Epstein–Barr virus (EBV) DNA sequence and analysis of a promoter for the BART (CST, BARF0) RNAs of EBV. J. Gen. Virol. 2003;84:1443–1450. doi: 10.1099/vir.0.19054-0. PubMed DOI

Uner A., Akyurek N., Saglam A., Abdullazade S., Uzum N., Onder S., Barista I., Benekli M. The presence of Epstein–Barr virus (EBV) in diffuse large B-cell lymphomas (DLBCLs) in Turkey: Special emphasis on ‘EBV-positive DLBCL of the elderly’. Apmis. 2011;119:309–316. doi: 10.1111/j.1600-0463.2011.02736.x. PubMed DOI

Song C.-G., Huang J.-J., Li Y.-J., Xia Y., Wang Y., Bi X.-W., Jiang W.-Q., Huang H.-Q., Lin T.-Y., Li Z.-M. Epstein-barr virus-positive diffuse large B-cell lymphoma in the elderly: A matched case-control analysis. PLoS ONE. 2015;10:e0133973. doi: 10.1371/journal.pone.0133973. PubMed DOI PMC

Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J., Vardiman J.W. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Volume 2 IARC Press; Lyon, France: 2008.

Shannon-Lowe C., Rickinson A.B., Bell A.I. Epstein–Barr virus-associated lymphomas. Philos. Trans. R. Soc. B Biol. Sci. 2017;372:20160271. doi: 10.1098/rstb.2016.0271. PubMed DOI PMC

Malpica L., Marques-Piubelli M.L., Beltran B.E., Chavez J.C., Miranda R.N., Castillo J.J. EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk-stratification and management. Am. J. Hematol. 2022;97:951–965. doi: 10.1002/ajh.26579. PubMed DOI

Ehlers B., Spieß K., Leendertz F., Peeters M., Boesch C., Gatherer D., McGeoch D.J. Lymphocryptovirus phylogeny and the origins of Epstein-Barr virus. J. Gen. Virol. 2009;91:630–642. doi: 10.1099/vir.0.017251-0. PubMed DOI

Epstein M.A., Achong B.G., Barr Y.M. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;283:702–703. doi: 10.1016/S0140-6736(64)91524-7. PubMed DOI

Henle G., Henle W., Diehl V. Relation of Burkitt’s tumor-associated herpes-type virus to infectious mononucleosis. Proc. Natl. Acad. Sci. USA. 1968;59:94–101. doi: 10.1073/pnas.59.1.94. PubMed DOI PMC

Abate F., Ambrosio M.R., Mundo L., Laginestra M.A., Fuligni F., Rossi M., Zairis S., Gazaneo S., De Falco G., Lazzi S., et al. Distinct viral and mutational spectrum of endemic Burkitt lymphoma. PLoS Pathog. 2015;11:e1005158. doi: 10.1371/journal.ppat.1005158. PubMed DOI PMC

Henle G., Henle W., Clifford P., Diehl V., Kafuko G.W., Kirya B.G., Klein G., Morrow R.H., Munube G.M., Pike P. Antibodies to Epstein-Barr virus in Burkitt’s lymphoma and control groups. J. Natl. Cancer Inst. 1969;43:1147–1157. doi: 10.1093/jnci/43.5.1147. PubMed DOI

Niederman J.C., Miller G., Pearson H.A., Pagano J.S., Dowaliby J.M. Infectious Mononucleosis: Epstein–Barr-Virus Shedding in Saliva and the Oropharynx. N. Engl. J. Med. 1976;294:1355–1359. doi: 10.1056/NEJM197606172942501. PubMed DOI

Henle W., Diehl V., Kohn G., zur Hausen H., Henle G. Herpes-Type virus and chromosome marker in normal Leukocytes after growth with irradiated Burkitt cells. Science. 1967;157:1064–1065. doi: 10.1126/science.157.3792.1064. PubMed DOI

Pope J.H. Establishment of cell lines from peripheral Leucocytes in infectious Mononucleosis. Nature. 1967;216:810–811. doi: 10.1038/216810a0. PubMed DOI

Rowe M., Fitzsimmons L., Bell A.I. Epstein-Barr virus and Burkitt lymphoma. Chin. J. Cancer. 2014;33:609. doi: 10.5732/cjc.014.10190. PubMed DOI PMC

Neri A., Barriga F., Inghirami G., Knowles D.M., Neequaye J., Magrath I.T., Dalla-Favera R. Epstein-Barr virus infection precedes clonal expansion in Burkitt’s and acquired immunodeficiency syndrome-associated lymphoma [see comments] Blood. 1991;77:1092–1095. doi: 10.1182/blood.V77.5.1092.1092. PubMed DOI

Brady G., MacArthur G., Farrell P. Epstein–Barr virus and Burkitt lymphoma. Postgrad. Med. J. 2008;84:372–377. doi: 10.1136/jcp.2007.047977. PubMed DOI

Jha H.C., Pei Y., Robertson E.S. Epstein–Barr virus: Diseases linked to infection and transformation. Front. Microbiol. 2016;7:1602. doi: 10.3389/fmicb.2016.01602. PubMed DOI PMC

Thompson M.P., Kurzrock R. Epstein-Barr virus and cancer. Clin. Cancer Res. 2004;10:803–821. doi: 10.1158/1078-0432.CCR-0670-3. PubMed DOI

Kerr B.M., Lear A.L., Rowe M., Croom-Carter D., Young L.S., Rookes S.M., Gallimore P.H., Rickinson A.B. Three transcriptionally distinct forms of epstein-barr virus latency in somatic cell hybrids: Cell phenotype dependence of virus promoter usage. Virology. 1992;187:189–201. doi: 10.1016/0042-6822(92)90307-B. PubMed DOI

Pfeffer S. Identification of virus-encoded MicroRNAs. Science. 2004;304:734–736. doi: 10.1126/science.1096781. PubMed DOI

Barth S., Meister G., Grässer F.A. EBV-encoded miRNAs. Biochim. Biophys. Acta (BBA)-Gene Regul. Mech. 2011;1809:631–640. doi: 10.1016/j.bbagrm.2011.05.010. PubMed DOI

Raab-Traub N. Novel mechanisms of EBV-induced oncogenesis. Curr. Opin. Virol. 2012;2:453–458. doi: 10.1016/j.coviro.2012.07.001. PubMed DOI PMC

Ok C.Y., Papathomas T.G., Medeiros L.J., Young K.H. EBV-positive diffuse large B-cell lymphoma of the elderly. Blood J. Am. Soc. Hematol. 2013;122:328–340. doi: 10.1182/blood-2013-03-489708. PubMed DOI PMC

Wang W.-T., Guo J.-R., Wang L., Wu J.-Z., Shen H.-R., Kong Y.-L., Xia Y., Li J.-Y., Liang J.-H., Xu W. EBV-Mir-BART5-5p targets p53 independent pathway in cytoplasm: Potential role in EBV lymphomagenesis. Genes Dis. 2022 doi: 10.1016/j.gendis.2022.07.003. in press . PubMed DOI PMC

Crawford D.H., Macsween K.F., Higgins C.D., Thomas R., McAulay K., Williams H., Harrison N., Reid S., Conacher M., Douglas J., et al. A cohort study among university students: Identification of risk factors for Epstein-Barr virus Seroconversion and infectious Mononucleosis. Clin. Infect. Dis. 2006;43:276–282. doi: 10.1086/505400. PubMed DOI

Crawford D.H., Swerdlow A.J., Higgins C., McAulay K., Harrison N., Williams H., Britton K., Macsween K.F. Sexual history and Epstein-Barr virus infection. J. Infect. Dis. 2002;186:731–736. doi: 10.1086/342596. PubMed DOI

Higgins C.D., Swerdlow A.J., Macsween K.F., Harrison N., Williams H., McAulay K., Thomas R., Reid S., Conacher M., Britton K., et al. A study of risk factors for acquisition of Epstein-Barr virus and its subtypes. J. Infect. Dis. 2007;195:474–482. doi: 10.1086/510854. PubMed DOI

Nemerow G., Mold C., Schwend V.K., Tollefson V., Cooper N. Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-Barr virus (EBV) to the EBV/C3d receptor of B cells: Sequence homology of gp350 and C3 complement fragment C3d. J. Virol. 1987;61:1416–1420. doi: 10.1128/jvi.61.5.1416-1420.1987. PubMed DOI PMC

Li Q., Spriggs M.K., Kovats S., Turk S.M., Comeau M.R., Nepom B., Hutt-Fletcher L.M. Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. J. Virol. 1997;71:4657–4662. doi: 10.1128/jvi.71.6.4657-4662.1997. PubMed DOI PMC

Babcock G.J., Decker L.L., Volk M., Thorley-Lawson D.A. EBV persistence in memory B cells in vivo. Immunity. 1998;9:395–404. doi: 10.1016/S1074-7613(00)80622-6. PubMed DOI

Kurth J., Spieker T., Wustrow J., Strickler J.G., Hansmann M.-L., Rajewsky K., Küppers R. EBV-Infected B cells in infectious Mononucleosis. Immunity. 2000;13:485–495. doi: 10.1016/S1074-7613(00)00048-0. PubMed DOI

Kurth J., Hansmann M.L., Rajewsky K., Kuppers R. Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction. Proc. Natl. Acad. Sci. USA. 2003;100:4730–4735. doi: 10.1073/pnas.2627966100. PubMed DOI PMC

Dunmire S.K., Verghese P.S., Balfour Jr H.H. Primary epstein-barr virus infection. J. Clin. Virol. 2018;102:84–92. doi: 10.1016/j.jcv.2018.03.001. PubMed DOI

Odumade O.A., Hogquist K.A., Balfour Jr H.H. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin. Microbiol. Rev. 2011;24:193–209. doi: 10.1128/CMR.00044-10. PubMed DOI PMC

Altmann M., Hammerschmidt W. Epstein-Barr virus provides a new paradigm: A requirement for the immediate inhibition of apoptosis. PLoS Biol. 2005;3:e404. doi: 10.1371/journal.pbio.0030404. PubMed DOI PMC

Babcock G.J., Hochberg D., Thorley-Lawson D.A. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity. 2000;13:497–506. doi: 10.1016/S1074-7613(00)00049-2. PubMed DOI

Gires O., Zimber-Strobl U., Gonnella R., Ueffing M., Marschall G., Zeidler R., Pich D., Hammerschmidt W. Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J. 1997;16:6131–6140. doi: 10.1093/emboj/16.20.6131. PubMed DOI PMC

Caldwell R.G., Wilson J.B., Anderson S.J., Longnecker R. Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity. 1998;9:405–411. doi: 10.1016/S1074-7613(00)80623-8. PubMed DOI

Laichalk L.L., Thorley-Lawson D.A. Terminal differentiation into plasma cells initiates the Replicative cycle of Epstein-Barr virus in vivo. J. Virol. 2004;79:1296–1307. doi: 10.1128/JVI.79.2.1296-1307.2005. PubMed DOI PMC

Adam P., Bonzheim I., Fend F., Quintanilla-Martínez L. Epstein-Barr virus-positive diffuse large B-cell lymphomas of the elderly. Adv. Anat. Pathol. 2011;18:349–355. doi: 10.1097/PAP.0b013e318229bf08. PubMed DOI

Münz C. Epstein–Barr virus-specific immune control by innate lymphocytes. Front. Immunol. 2017;8:1658. doi: 10.3389/fimmu.2017.01658. PubMed DOI PMC

Marques-Piubelli M.L., Salas Y.I., Pachas C., Becker-Hecker R., Vega F., Miranda R.N. Epstein–Barr virus-associated B-cell lymphoproliferative disorders and lymphomas: A review. Pathology. 2020;52:40–52. doi: 10.1016/j.pathol.2019.09.006. PubMed DOI

Lu T.-X., Liang J.-H., Miao Y., Fan L., Wang L., Qu X.-Y., Cao L., Gong Q.-X., Wang Z., Zhang Z.-H. Epstein-Barr virus positive diffuse large B-cell lymphoma predict poor outcome, regardless of the age. Sci. Rep. 2015;5:12168. doi: 10.1038/srep12168. PubMed DOI PMC

Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Volume 2 IARC Press; Lyon, France: 2017.

Swerdlow S.H., Campo E., Pileri S.A., Harris N.L., Stein H., Siebert R., Advani R., Ghielmini M., Salles G.A., Zelenetz A.D. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood J. Am. Soc. Hematol. 2016;127:2375–2390. doi: 10.1182/blood-2016-01-643569. PubMed DOI PMC

Gatter K., Pezzella F. Diffuse large B-cell lymphoma. Diagn. Histopathol. 2010;16:69–81. doi: 10.1016/j.mpdhp.2009.12.002. DOI

Diebold J. World Health Organization classification of malignant lymphomas. Exp. Oncol. 2001;23:101–103.

Said J.W. Aggressive B-cell lymphomas: How many categories do we need? Mod. Pathol. 2013;26:S42–S56. doi: 10.1038/modpathol.2012.178. PubMed DOI PMC

Pittaluga S., Jaffe E.S. T-cell/histiocyte-rich large B-cell lymphoma. Haematologica. 2010;95:352. doi: 10.3324/haematol.2009.016931. PubMed DOI PMC

Vrzalikova K., Vockerodt M., Leonard S., Bell A., Wei W., Schrader A., Wright K.L., Kube D., Rowe M., Woodman C.B. Down-regulation of BLIMP1α by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: Implications for the pathogenesis of EBV-associated B-cell lymphomas. Blood J. Am. Soc. Hematol. 2011;117:5907–5917. doi: 10.1182/blood-2010-09-307710. PubMed DOI PMC

Vrzalikova K., Leonard S., Fan Y., Bell A., Vockerodt M., Flodr P., Wright K.L., Rowe M., Tao Q., Murray P.G. Hypomethylation and over-expression of the beta isoform of BLIMP1 is induced by Epstein-Barr virus infection of B cells; potential implications for the pathogenesis of EBV-associated lymphomas. Pathogens. 2012;1:83–101. doi: 10.3390/pathogens1020083. PubMed DOI PMC

Vrzalikova K., John Woodman C.B., Murray P.G. BLIMP1α, the master regulator of plasma cell differentiation is a tumor supressor gene in B cell lymphomas. Biomed. Pap. Med. Fac. Palacky Univ. Olomouc. 2012;156 doi: 10.5507/bp.2012.003. PubMed DOI

Choi W.W., Weisenburger D.D., Greiner T.C., Piris M.A., Banham A.H., Delabie J., Braziel R.M., Geng H., Iqbal J., Lenz G. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin. Cancer Res. 2009;15:5494–5502. doi: 10.1158/1078-0432.CCR-09-0113. PubMed DOI PMC

Van Roosbroeck K., Cools J., Dierickx D., Thomas J., Vandenberghe P., Stul M., Delabie J., De Wolf-Peeters C., Marynen P., Wlodarska I. ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions. Haematologica. 2010;95:509–513. doi: 10.3324/haematol.2009.014761. PubMed DOI PMC

Aukema S.M., Siebert R., Schuuring E., van Imhoff G.W., Kluin-Nelemans H.C., Boerma E.-J., Kluin P.M. Double-hit B-cell lymphomas. Blood J. Am. Soc. Hematol. 2011;117:2319–2331. doi: 10.1182/blood-2010-09-297879. PubMed DOI

Campo E., Jaffe E.S., Cook J.R., Quintanilla-Martinez L., Swerdlow S.H., Anderson K.C., Brousset P., Cerroni L., de Leval L., Dirnhofer S. The International Consensus Classification of Mature Lymphoid Neoplasms: A Report from the Clinical Advisory Committee. Blood J. Am. Soc. Hematol. 2022;140:1229–1253. doi: 10.1182/blood.2022015851. PubMed DOI PMC

Morin R.D., Arthur S.E., Hodson D.J. Molecular profiling in diffuse large B-cell lymphoma: Why so many types of subtypes? Br. J. Haematol. 2022;196:814–829. doi: 10.1111/bjh.17811. PubMed DOI

Kuze T., Nakamura N., Hashimoto Y., Sasaki Y., Abe M. The Characteristics of Epstein-Barr Virus (EBV)-positive Diffuse Large B-Cell Lymphoma: Comparison between EBV+ and EBV-Cases in Japanese Population. Jpn. J. Cancer Res. 2000;91:1233–1240. doi: 10.1111/j.1349-7006.2000.tb00909.x. PubMed DOI PMC

Oyama T., Ichimura K., Suzuki R., Suzumiya J., Ohshima K., Yatabe Y., Yokoi T., Kojima M., Kamiya Y., Taji H. Senile EBV+ B-cell lymphoproliferative disorders: A clinicopathologic study of 22 patients. Am. J. Surg. Pathol. 2003;27:16–26. doi: 10.1097/00000478-200301000-00003. PubMed DOI

Hong J., Yoon D., Suh C., Huh J., Do I.-G., Sohn I., Jo J., Jung S.-H., Hong M., Yoon H. EBV-positive diffuse large B-cell lymphoma in young adults: Is this a distinct disease entity? Ann. Oncol. 2015;26:548–555. doi: 10.1093/annonc/mdu556. PubMed DOI

Castillo J.J., Beltran B.E., Miranda R.N., Young K.H., Chavez J.C., Sotomayor E.M. EBV-positive diffuse large B-cell lymphoma of the elderly: 2016 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 2016;91:529–537. doi: 10.1002/ajh.24370. PubMed DOI

Beltran B.E., Castro D., Paredes S., Miranda R.N., Castillo J.J. EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2020 update on diagnosis, risk-stratification and management. Am. J. Hematol. 2020;95:435–445. doi: 10.1002/ajh.25760. PubMed DOI

Castillo J.J., Beltran B.E., Miranda R.N., Young K.H., Chavez J.C., Sotomayor E.M. EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2018 update on diagnosis, risk-stratification and management. Am. J. Hematol. 2018;93:953–962. doi: 10.1002/ajh.25112. PubMed DOI

Dojcinov S.D., Fend F., Quintanilla-Martinez L. EBV-positive lymphoproliferations of B-T-and NK-cell derivation in non-immunocompromised hosts. Pathogens. 2018;7:28. doi: 10.3390/pathogens7010028. PubMed DOI PMC

Falini B., Martino G., Lazzi S. A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas. Leukemia. 2022;37:18–34. doi: 10.1038/s41375-022-01764-1. PubMed DOI PMC

Ok C.Y., Li L., Xu-Monette Z.Y., Visco C., Tzankov A., Manyam G.C., Montes-Moreno S., Dybaer K., Chiu A., Orazi A. Prevalence and clinical implications of Epstein–Barr virus infection in de novo diffuse large B-cell lymphoma in Western countries. Clin. Cancer Res. 2014;20:2338–2349. doi: 10.1158/1078-0432.CCR-13-3157. PubMed DOI PMC

Donzel M., Bonjour M., Combes J.-D., Broussais F., Sesques P., Traverse-Glehen A., de Martel C. Lymphomas associated with Epstein-Barr virus infection in 2020: Results from a large, unselected case series in France. Eclinicalmedicine. 2022;54:101674. doi: 10.1016/j.eclinm.2022.101674. PubMed DOI PMC

Hwang J., Suh C.H., Won Kim K., Kim H.S., Armand P., Huang R.Y., Guenette J.P. The incidence of Epstein-Barr virus-positive diffuse large B-cell lymphoma: A systematic review and meta-analysis. Cancers. 2021;13:1785. doi: 10.3390/cancers13081785. PubMed DOI PMC

Gorodetskiy V., Probatova N., Obukhova T., Vasilyev V. Analysis of prognostic factors in diffuse large B-cell lymphoma associated with rheumatic diseases. Lupus Sci. Med. 2021;8:e000561. doi: 10.1136/lupus-2021-000561. PubMed DOI PMC

Gao X., Li J., Wang Y., Liu S., Yue B. Clinical characteristics and prognostic significance of EBER positivity in diffuse large B-cell lymphoma: A meta-analysis. PLoS ONE. 2018;13:e0199398. doi: 10.1371/journal.pone.0199398. PubMed DOI PMC

Mundo L., Del Porro L., Granai M., Siciliano M.C., Mancini V., Santi R., Marcar L., Vrzalikova K., Vergoni F., Di Stefano G. Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: Expanding the landscape of EBV-related lymphomas. Mod. Pathol. 2020;33:2407–2421. doi: 10.1038/s41379-020-0575-3. PubMed DOI PMC

Cohen M., De Matteo E., Narbaitz M., Carreño F.A., Preciado M.V., Chabay P.A. Epstein–Barr virus presence in pediatric diffuse large B-cell lymphoma reveals a particular association and latency patterns: Analysis of viral role in tumor microenvironment. Int. J. Cancer. 2013;132:1572–1580. doi: 10.1002/ijc.27845. PubMed DOI

Cohen M., Narbaitz M., Metrebian F., De Matteo E., Preciado M.V., Chabay P.A. Epstein-Barr virus-positive diffuse large B-cell lymphoma association is not only restricted to elderly patients. Int. J. Cancer. 2014;135:2816–2824. doi: 10.1002/ijc.28942. PubMed DOI

Nicolae A., Pittaluga S., Abdullah S., Steinberg S.M., Pham T.A., Davies-Hill T., Xi L., Raffeld M., Jaffe E.S. EBV-positive large B-cell lymphomas in young patients: A nodal lymphoma with evidence for a tolerogenic immune environment. Blood J. Am. Soc. Hematol. 2015;126:863–872. doi: 10.1182/blood-2015-02-630632. PubMed DOI PMC

Young L.S., Rickinson A.B. Epstein–Barr virus: 40 years on. Nat. Rev. Cancer. 2004;4:757–768. doi: 10.1038/nrc1452. PubMed DOI

Kelly G., Bell A., Rickinson A. Epstein–Barr virus–associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Nat. Med. 2002;8:1098–1104. doi: 10.1038/nm758. PubMed DOI

Kelly G.L., Milner A.E., Tierney R.J., Croom-Carter D.S., Altmann M., Hammerschmidt W., Bell A.I., Rickinson A.B. Epstein-Barr virus nuclear antigen 2 (EBNA2) gene deletion is consistently linked with EBNA3A,-3B, and-3C expression in Burkitt’s lymphoma cells and with increased resistance to apoptosis. J. Virol. 2005;79:10709–10717. doi: 10.1128/JVI.79.16.10709-10717.2005. PubMed DOI PMC

Kelly G.L., Long H.M., Stylianou J., Thomas W.A., Leese A., Bell A.I., Bornkamm G.W., Mautner J., Rickinson A.B., Rowe M. An Epstein-Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in burkitt lymphomagenesis: The Wp/BHRF1 link. PLoS Pathog. 2009;5:e1000341. doi: 10.1371/journal.ppat.1000341. PubMed DOI PMC

Anderton E., Yee J., Smith P., Crook T., White R., Allday M. Two Epstein–Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: Clues to the pathogenesis of Burkitt’s lymphoma. Oncogene. 2008;27:421–433. doi: 10.1038/sj.onc.1210668. PubMed DOI

Cohen J.I., Wang F., Mannick J., Kieff E. Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc. Natl. Acad. Sci. USA. 1989;86:9558–9562. doi: 10.1073/pnas.86.23.9558. PubMed DOI PMC

Li C., Romero-Masters J.C., Huebner S., Ohashi M., Hayes M., Bristol J.A., Nelson S.E., Eichelberg M.R., Van Sciver N., Ranheim E.A., et al. EBNA2-deleted Epstein-Barr virus (EBV) isolate, P3HR1, causes Hodgkin-like lymphomas and diffuse large B cell lymphomas with type II and Wp-restricted latency types in humanized mice. PLoS Pathog. 2020;16:e1008590. doi: 10.1371/journal.ppat.1008590. PubMed DOI PMC

Dirmeier U., Neuhierl B., Kilger E., Reisbach G., Sandberg M.L., Hammerschmidt W. Latent membrane protein 1 is critical for efficient growth transformation of human B cells by Epstein-Barr virus. Cancer Res. 2003;63:2982–2989. doi: 10.1128/JVI.01857-20. PubMed DOI

Ma S.-D., Xu X., Plowshay J., Ranheim E.A., Burlingham W.J., Jensen J.L., Asimakopoulos F., Tang W., Gulley M.L., Cesarman E., et al. LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis. J. Clin. Investig. 2015;125:304–315. doi: 10.1172/JCI76357. PubMed DOI PMC

Ma S.-D., Tsai M.-H., Romero-Masters J.C., Ranheim E.A., Huebner S.M., Bristol J.A., Delecluse H.-J., Kenney S.C. Latent membrane protein 1 (LMP1) and LMP2A collaborate to promote Epstein-Barr virus-induced B cell lymphomas in a cord blood-humanized mouse model but are not essential. J. Virol. 2017;91:e01928-16. doi: 10.1128/JVI.01928-16. PubMed DOI PMC

White R.E., Rämer P.C., Naresh K.N., Meixlsperger S., Pinaud L., Rooney C., Savoldo B., Coutinho R., Bödör C., Gribben J. EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J. Clin. Investig. 2012;122:1487–1502. doi: 10.1172/JCI58092. PubMed DOI PMC

Maruo S., Zhao B., Johannsen E., Kieff E., Zou J., Takada K. Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc. Natl. Acad. Sci. USA. 2011;108:1919–1924. doi: 10.1073/pnas.1019599108. PubMed DOI PMC

Price A.M., Dai J., Bazot Q., Patel L., Nikitin P.A., Djavadian R., Winter P.S., Salinas C.A., Barry A.P., Wood K.C. Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection. eLife. 2017;6:e22509. doi: 10.7554/eLife.22509. PubMed DOI PMC

Romero-Masters J.C., Ohashi M., Djavadian R., Eichelberg M.R., Hayes M., Zumwalde N.A., Bristol J.A., Nelson S.E., Ma S., Ranheim E.A., et al. An EBNA3A-mutated Epstein-Barr virus retains the capacity for lymphomagenesis in a cord blood-humanized mouse model. J. Virol. 2020;94:e02168-19. doi: 10.1128/JVI.02168-19. PubMed DOI PMC

Okuno Y., Murata T., Sato Y., Muramatsu H., Ito Y., Watanabe T., Okuno T., Murakami N., Yoshida K., Sawada A. Defective Epstein–Barr virus in chronic active infection and haematological malignancy. Nat. Microbiol. 2019;4:404–413. doi: 10.1038/s41564-018-0334-0. PubMed DOI

Kimura H., Okuno Y., Sato Y., Watanabe T., Murata T. Deletion of Viral microRNAs in the Oncogenesis of Epstein–Barr Virus-Associated Lymphoma. Front. Microbiol. 2021;12:667968. doi: 10.3389/fmicb.2021.667968. PubMed DOI PMC

Lin X., Tsai M.-H., Shumilov A., Poirey R., Bannert H., Middeldorp J.M., Feederle R., Delecluse H.-J. The Epstein-Barr virus BART miRNA cluster of the M81 strain modulates multiple functions in primary B cells. PLoS Pathog. 2015;11:e1005344. doi: 10.1371/journal.ppat.1005344. PubMed DOI PMC

Mabuchi S., Hijioka F., Watanabe T., Yanagi Y., Okuno Y., Masud H., Sato Y., Murata T., Kimura H. Role of Epstein–Barr Virus C Promoter Deletion in Diffuse Large B Cell Lymphoma. Cancers. 2021;13:561. doi: 10.3390/cancers13030561. PubMed DOI PMC

Wright G.W., Phelan J.D., Coulibaly Z.A., Roulland S., Young R.M., Wang J.Q., Schmitz R., Morin R.D., Tang J., Jiang A., et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37:551–568. doi: 10.1016/j.ccell.2020.03.015. PubMed DOI PMC

Frontzek F., Staiger A.M., Wullenkord R., Grau M., Zapukhlyak M., Kurz K.S., Horn H., Erdmann T., Fend F., Richter J., et al. Molecular profiling of EBV associated diffuse large B-cell lymphoma. Leukemia. 2023:1–10. doi: 10.1038/s41375-022-01804-w. PubMed DOI PMC

Crombie J.L., LaCasce A.S. Epstein Barr virus associated B-cell lymphomas and iatrogenic lymphoproliferative disorders. Front. Oncol. 2019;9:109. doi: 10.3389/fonc.2019.00109. PubMed DOI PMC

Gebauer N., Künstner A., Ketzer J., Witte H.M., Rausch T., Benes V., Zimmermann J., Gebauer J., Merz H., Bernard V. Genomic insights into the pathogenesis of Epstein–Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing. Blood Cancer J. 2021;11:102. doi: 10.1038/s41408-021-00493-5. PubMed DOI PMC

Gebauer N., Gebauer J., Hardel T.T., Bernard V., Biersack H., Lehnert H., Rades D., Feller A.C., Thorns C. Prevalence of targetable oncogenic mutations and genomic alterations in Epstein–Barr virus-associated diffuse large B-cell lymphoma of the elderly. Leuk. Lymphoma. 2015;56:1100–1106. doi: 10.3109/10428194.2014.944522. PubMed DOI

Ngo V.N., Young R.M., Schmitz R., Jhavar S., Xiao W., Lim K.-H., Kohlhammer H., Xu W., Yang Y., Zhao H. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470:115–119. doi: 10.1038/nature09671. PubMed DOI PMC

Jeelall Y.S., Horikawa K. Oncogenic MYD88 mutation drives Toll pathway to lymphoma. Immunol. Cell Biol. 2011;89:659–660. doi: 10.1038/icb.2011.31. PubMed DOI

Liu F., Wang Z., Zhou X., Liu Q., Chen G., Xiao H., Yin W., Nakamura S., Rao H. Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma. PLoS ONE. 2018;13:e0201546. doi: 10.1371/journal.pone.0201546. PubMed DOI PMC

Zhou Y., Xu Z., Lin W., Duan Y., Lu C., Liu W., Su W., Yan Y., Liu H., Liu L. Comprehensive genomic profiling of EBV-positive diffuse large B-cell lymphoma and the expression and clinicopathological correlations of some related genes. Front. Oncol. 2019;9:683. doi: 10.3389/fonc.2019.00683. PubMed DOI PMC

Schaefer A., Der C.J. RHOA takes the RHOad less traveled to cancer. Trends Cancer. 2022;8:655–669. doi: 10.1016/j.trecan.2022.04.005. PubMed DOI

Kataoka K., Miyoshi H., Sakata S., Dobashi A., Couronné L., Kogure Y., Sato Y., Nishida K., Gion Y., Shiraishi Y. Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. Leukemia. 2019;33:1687–1699. doi: 10.1038/s41375-019-0380-5. PubMed DOI PMC

Xia Y., Zhang X. The Spectrum of MYC alterations in diffuse large B-cell lymphoma. Acta Haematol. 2020;143:520–528. doi: 10.1159/000505892. PubMed DOI

Riedell P.A., Smith S.M. Double hit and double expressors in lymphoma: Definition and treatment. Cancer. 2018;124:4622–4632. doi: 10.1002/cncr.31646. PubMed DOI

Liu H., Xu-Monette Z.Y., Tang G., Wang W., Kim Y., Yuan J., Li Y., Chen W., Li Y., Fedoriw G.Y. EBV+ high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: A multi-institutional study. Histopathology. 2022;80:575–588. doi: 10.1111/his.14585. PubMed DOI

Beltran B.E., Morales D., Quiñones P., Medeiros L.J., Miranda R.N., Castillo J.J. EBV-positive diffuse large b-cell lymphoma in young immunocompetent individuals. Clin. Lymphoma Myeloma Leuk. 2011;11:512–516. doi: 10.1016/j.clml.2011.07.003. PubMed DOI

Keane C., Tobin J., Gunawardana J., Francis S., Gifford G., Gabrielli S., Gill A., Stevenson W., Talaulikar D., Gould C. The tumour microenvironment is immuno-tolerogenic and a principal determinant of patient outcome in EBV-positive diffuse large B-cell lymphoma. Eur. J. Haematol. 2019;103:200–207. doi: 10.1111/ejh.13274. PubMed DOI PMC

Cohen M., Vistarop A.G., Huaman F., Narbaitz M., Metrebian F., De Matteo E., Preciado M.V., Chabay P.A. Cytotoxic response against Epstein Barr virus coexists with diffuse large B-cell lymphoma tolerogenic microenvironment: Clinical features and survival impact. Sci. Rep. 2017;7:10813. doi: 10.1038/s41598-017-11052-z. PubMed DOI PMC

Carreras J., Kikuti Y.Y., Hiraiwa S., Miyaoka M., Tomita S., Ikoma H., Ito A., Kondo Y., Itoh J., Roncador G. High PTX3 expression is associated with a poor prognosis in diffuse large B-cell lymphoma. Cancer Sci. 2022;113:334. doi: 10.1111/cas.15179. PubMed DOI PMC

Ma S.-D., Xu X., Jones R., Delecluse H.-J., Zumwalde N.A., Sharma A., Gumperz J.E., Kenney S.C. PD-1/CTLA-4 blockade inhibits Epstein-Barr virus-induced lymphoma growth in a cord blood humanized-mouse model. PLoS Pathog. 2016;12:e1005642. doi: 10.1371/journal.ppat.1005642. PubMed DOI PMC