Received: 28 July 2023 | Accepted: 29 November 2023

DOI: 10.1111/bjh.19255

REVIEW

Epstein–Barr virus-­associated lymphomas decoded

Karolina Bednarska1 | Rakin Chowdhury2,3 | Joshua W. D. Tobin1,3 |

2,3 2,3 4 4
Fiona Swain | Colm Keane | Stephen Boyle | Rajiv Khanna |
1,3
Maher K. Gandhi

1
Mater Research Institute, University of
Queensland, Brisbane, Queensland, Australia Summary
2
Frazer Institute, University of Queensland, Epstein–Barr virus (EBV)-­associated lymphomas cover a range of histological B-­and
Brisbane, Queensland, Australia T-­cell non-­Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-­cell
3
Department of Haematology, Princess malignant pathogenesis and its impact on the tumour microenvironment are intrigu-
Alexandra Hospital, Brisbane, Queensland,
Australia ing but incompletely understood. Both the International Consensus Classification
4
QIMR Berghofer Medical Research Institute, (ICC) and 5th Edition of the World Health Organization (WHO-­HAEM5) proposals
Brisbane, Queensland, Australia give prominence to the distinct clinical, prognostic, genetic and tumour microenvi-
ronmental features of EBV in lymphoproliferative disorders. There have been major
Correspondence
Maher K. Gandhi, Level 7, Translational advances in our biological understanding, in how to harness features of EBV and its
Research Institute, Brisbane, QLD 4102, host immune response for targeted therapy, and in using EBV as a method to moni-
Australia. tor disease response. In this article, we showcase the latest developments and how
Email: [email protected]
they may be integrated to stimulate new and innovative approaches for further lines
Funding information of investigation and therapy.
Mater Foundation; Medical Research Future
Fund
K EY WOR DS
EBV, EBV-­associated lymphoma, EBV latency, EBV-­specific T cells, Hodgkin lymphoma, PTLD

SU M M A RY E BV BACKGROU N D

Epstein–Barr virus (EBV) infects most people worldwide Epstein–Barr virus is a large (∼175 kb) gamma-­herpesvirus
and persists for life. While usually asymptomatic, EBV that establishes life-­long infection. EBV seroprevalence
is a causative agent in several types of lymphoprolifera- increases with age, from approximately 50% between 6
tive diseases (LPDs). The pathogenesis of EBV-­associated and 8 years to 90%–95% in adults.1 Acquisition of EBV
lymphomas involves a complex interplay between differ- in early childhood is usually asymptomatic, but in ado-
ent patterns of viral gene expression and cellular genetic lescents and young adults, it can manifest clinically with
changes. EBV infection has three main latency patterns symptoms such as fever, painless swollen glands and sore
(types III, II and I). Each LPD displays a different latency throat known as infectious mononucleosis (IM). EBV is
pattern that impacts pathogenesis and host EBV-­specific transmitted orally, via infected saliva and enters host B
T-­cell recognition. The intent of this paper is not to discuss cells via the binding of EBV-­g lycoprotein gp350/220 to
standard of care management. Rather, this review provides CD21. EBV-­i nfected B cells proliferate via an atypical ger-
an update on recent major advances in the EBV immunobi- minal centre-­t ype reaction to differentiate into memory B
ology that have implications for new treatment approaches cells, in which the virus establishes a persistent and anti-
for EBV-­associated lymphomas (see video summary). genically silent infection. 2

Karolina Bednarska and Rakin Chowdhury—equal contribution as first authors.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Br J Haematol. 2024;204:415–433.  wileyonlinelibrary.com/journal/bjh | 415

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416 |    EBV-­A SSOCIATED LYMPHOMAS

Both the International Consensus Classification (ICC) within host DNA. The host cell provides the machinery that
and 5th Edition of the World Health Organization (WHO-­ regulates the viral genome's replicative capability during the
HAEM5) proposals give prominence to the distinct clini- host cell cycle.
cal, prognostic, genetic and tumour microenvironmental There are four distinct EBV-­latent gene expression
features of EBV in lymphoproliferative disorders (Table 1). patterns (Types 0, I, II and III; Figure 1) defined by the
Approximately 90% of EBV-­ driven LPDs involve EBV-­ expression of specific sets of viral genes and promoters.
infected B cells. Although EBV is primarily a B-­cell lympho- The unique functions and role in lymphomagenesis of the
tropic virus, it can, under poorly understood circumstances, EBV-­latency proteins (Figure 2) impact the pathogenesis
also infect T cell and natural killer (NK) cell.3 Several lines of distinct EBV-­d riven disorders. Latency III exhibits the
of evidence suggest that EBV infects CD21-­positive T-­cell most complex viral expression pattern, characterised by
precursors during thymic differentiation.4 Unlike B-­ cell EBV-­encoded RNA (EBER)1, EBER2 (both these RNAs
infection (which is nearly always benign), T-­and NK-­cell are not translated into proteins) and the EBV-­nuclear an-
infection always results in serious diseases ranging from tigen proteins EBNA1, EBNA-­L P, EBNA2, EBNA3A/B/C,
chronic active EBV ‘CAEBV’ to highly aggressive malig- latent membrane protein (LMP)1, LPM2A and LMP2B. It
nancies (e.g. extra-­nodal NK/T-­cell lymphoma ‘ENKTL’). is the latency pattern seen in vitro in EBV-­transformed
Interestingly, EBV-­v irions on the B-­cell surface that remain lymphoblastoid cell lines (LCLs) and is the profile ob-
non-­internalised are believed to be involved in infection of served in many but not all cases of B-­c ell post-­t ransplant
(CD21-­negative) epithelial cells.5 EBV infection is also asso- lymphoproliferative disorder (PTLD). Latency II displays
ciated with a variety of non-­haematological epithelial can- a more restrictive EBV-­e xpression pattern that is EBER1,
cers, which are beyond the scope of this review. EBER2, EBNA1, LMP1 and LMP2A, with the archetypal
There are two major EBV genotypes in humans: EBV1 latency II LPDs being classical Hodgkin lymphoma (cHL).
and EBV2, which were distinguished based on the differ- Latency I is the most restrictive latency programme, ex-
ences in the EBNA2 gene. EBV genotypes differ in their pressing only EBER1, EBER2 and EBNA1, and is typi-
transformation ability, with EBV1 being more efficient in cally associated with endemic Burkitt lymphoma (eBL).
immortalising B cells in vitro than EBV2.6 Persistence of EBV in the quiescent memory B-­c ell pool
without viral protein expression (hence antigenically si-
lent) is termed latency 0 and is a feature of healthy B cells
LY M PHOM AGE N E SIS , E BV L AT E NC Y and not LPDs, with the exception of plasmablastic lym-
A N D T H E A BORT I V E LY T IC C YC L E phoma (PBL).
Stimulation of the B-­cell receptor of EBV-­infected B cells
Epstein–Barr virus-­infected lymphocytes display a latent expressing latency type 0/I leads to lytic cycle reactivation.
(i.e. lying dormant) or lytic (i.e. actively replicating and It has long been known that in some EBV-­associated B-­cell
disseminating among cells) infection profile. Latent virus lymphomas, both a latent and a truncated lytic gene expres-
is maintained in a circular chromatinised (episomal) state sion pattern may coincide within the same cell.7 More re-
within the nucleus of a host cell and is not known to integrate cently, this phenomenon has been gaining attention. A state

TA BL E 1 Major updates relating to EBV in lymphoma and related disorders in the WHO HAEM5 2022 and ICC histopathology classifications.

WHO HAEM4R WHO HAEM5 ICC

Tumour-­like lesions with B-­cell proliferation
Not included Not included EBV-­associated polymorphic B-­cell LPD—NOS is a new entity
to describe EBV-­associated B-­cell lesions with altered nodal
architecture that are not diagnostic of lymphoma
Large B-­cell lymphoma
EBV-­associated mucocutaneous ulcera EBV-­associated mucocutaneous ulcer EBV-­associated mucocutaneous ulcer
EBV-­associated DLBCL and NOS EBV-­associated DLBCL EBV-­associated DLBCL-­NOS
Not included Fluid overload-­associated large B-­cell HHV8-­and EBV8-­negative primary effusion-­based lymphomaa
lymphoma (previously included in
primary effusion lymphoma)
High-­g rade B-­cell lymphomas
BL BL—recommended subtyping of BL BL
based on EBV status rather than
epidemiological context

Abbreviations: BL, Burkitt lymphoma; DLBCL, diffuse large B-­cell lymphoma; EBV, Epstein–Barr virus; HHV8, Herpes Virus Type 8; ICC, International Consensus
Classification; KSHV, Kaposi's sarcoma-­associated herpesvirus; LPD, lymphoproliferative disease; NOS, not otherwise specified; WHO HAEM5, World Health Organization
5th edition.
a
Denotes a provisional entity.
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BEDNARSKA et al.    | 417

F I G U R E 1 The Epstein–Barr virus (EBV) lifecycle and latency types are displayed in EBV-­associated lymphoproliferative diseases. Figure generated
in Biorender. CAEBV, chronic active EBV; DLBCL, diffuse large B-­cell lymphoma; ENKT, extra-­nodal NK/T-­cell; PBL, plasmablastic lymphoma; PEL,
Primary effusion lymphoma; PTLD, post-­t ransplant lymphoproliferative disorder.

of EBV infection, in which the full lytic programme is not deacetylase inhibitors (HDACi) can not only induce lytic
induced due to incomplete expression of viral lytic genes gene expression, but the addition of ganciclovir increases
(and therefore without formation of infective viral particles), cytotoxic activity compared to treatment with the lytic in-
is termed the abortive lytic cycle.8 ducers alone.12 In a patient with a refractory EBV-­associated
Emerging evidence suggests the regulation of cellular diffuse large B-­ cell lymphoma (DLBCL)-­ not otherwise
oncogenic pathways can be mediated in the abortive lytic specified (NOS), treatment with valproic acid and ganci-
cycle via the early lytic genes. The EBV BCL-­2 homologue clovir was associated with a rise in unencapsulated cell-­free
BHRF1, expressed in several EBV-­LPDs, is known to pro- EBV-­DNA, indicating the tumour-­derived EBV-­DNA.13 In
mote anti-­apoptosis.9 A study in NOD/Shi-­scid-­ILR2 null a small-­scale clinical trial in patients with refractory EBV-­
(NOD) mice used silencing of the late lytic gene BALF5 to associated lymphomas, two thirds responded to treatment
engineer EBV to enter but not complete the lytic cycle. There with arginine butyrate (an HDACi) in combination with
was an increased frequency of engineered EBV-­infected cells ganciclovir.14 A study of the HDACi nanatinostat with val-
compared to the wild-­t ype strain, an observation consistent ganciclovir (NCT05011058) is ongoing.
with EBV's early lytic phase being important in tumouri- Methylation also plays a critical role in regulating EBV-­
genesis.10 This is also supported by viral genome analysis in gene expression and transition between latency types,15 with
EBV-­associated LPDs, which showed that some patients har- the EBV genome becoming gradually methylated at differ-
boured intragenic deletions in regions essential to produce ent regions, including latency and lytic gene promoters.16
infectious viral particles.11 Hence, another therapeutic approach involves using epigen-
etic modifying agents such as decitabine to induce lytic gene
expression and a more immunogenic viral antigen profile,
E PIGE N ET IC MODI F IC AT ION thereby potentially sensitising resistant tumours to EBV-­
directed immunotherapy.17
Upon infection, both EBV and the host cell undergo a vari- MicroRNAs (miRNAs) are a large class of evolutionarily
ety of epigenetic changes, each of which provides therapeu- conserved small non-­coding RNAs generated from either
tic opportunities. These include histone modification, DNA exons or introns of both protein-­coding and non-­coding
methylation and RNA silencing. Viral thymidine kinase is a transcripts. Their role is to modulate gene expression by both
lytic protein that is not produced during latency. As a result, degrading target messenger RNA and by post-­transcriptional
anti-­v iral agents (e.g. ganciclovir) that require phosphoryla- repression. EBV-­latent genes can upregulate host oncomiRs
tion by viral thymidine kinase for conversion of the prod- or limit the expression of host miRNAs with tumour sup-
rug into its active form are ineffective in EBV-­associated pressive activity. The first virus-­encoded miRNAs detected
LPDs. An alternate strategy would be lytic reactivation to were in EBV, and to date, the virus is known to encode at
render EBV-­infected tumour cells susceptible to ganciclovir least 44 miRNAs.18 They are distributed in three clusters: the
(Figure 3). This approach might also make the infected cells BamH I fragment A rightward transcript (BART) cluster 1,
more susceptible to T-­cell recognition and killing due to the BART cluster 2 and the BamH I fragment H rightward open
expression of more immunogenic viral proteins. Histone reading frame 1 (BHRF1)-­cluster. The BHRF1 miRNAs are
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
418 |    EBV-­A SSOCIATED LYMPHOMAS

F I G U R E 2 Function of EBV-­encoded latent proteins. BRLF1 is an immediate early lytic protein transcriptional activator that mediates the switch
from latent to lytic viral replication. Figure generated in Biorender. EBV, Epstein–Barr virus; TR, terminal repeat; vIL-­10, viral interleukin 10.

expressed during EBV-­latency III-­t ype infection and in the the EBV-­positive Akata cell line, but not those from the
lytic cycle, while the BART miRNAs are expressed in all EBV-­positive B95-­8 cell line (which has a deletion in the
phases of the EBV-­life cycle, including all latency types. It BART cluster 2 region) caused severe LPDs in a human-
is beyond the scope of this review to discuss other classes ised mouse model. 23
of non-­coding viral RNAs that increase the latent and viral Studies have shown that T-­cell recognition of LCLs trans-
transcriptome repertoires. formed by EBV deficient in EBV-­miRNAs is increased.24
Individual EBV-­ m iRNAs can target multiple tran- This is due to the downregulation of components of the
scripts to have a broad impact on fine-­ t uning trans- protein degradation and antigen presentation machinery by
formation, proliferation and apoptosis that are known EBV-­miRNAs.24 Moreover, cytokines such as IL-­12 and IL-­
to be dysregulated in EBV-­ a ssociated lymphomas.19–21 23 that are instrumental for effector T-­and NK-­cell activa-
EBV-­m iRNAs are released into the circulation via exo- tion are targeted by EBV-­miRNAs.24 NK-­cell recognition is
somes (microvesicles that protect against degradation further compromised by the downregulation of MICA and
by RNases). 22 Emphasising the role of exosomal BART MICB (ligands for the activating NKG2D molecule present
miRNAs in lymphomagenesis, exosomes derived from on NK cells) by EBV-­miRNAs.25
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BEDNARSKA et al.    | 419

F I G U R E 3 Potential therapeutic approaches in patients with EBV-­associated lymphoma. Figure generated in Biorender. BTKi, Bruton tyrosine
kinase inhibitors; CTL, cytotoxic T lymphocyte; EBV, Epstein–Barr virus; HDACi, histone deacetylase inhibitor.

A particularly notable example of how EBV has evolved E BV-­SPE CI F IC T-­C E L L I M M U N I T Y

to utilise distinct strategies involving an interplay of viral A N D A DOP T I V E I M M U NOT H E R A PY
genes with viral and host miRNAs is the regulation of the
immune checkpoint PD-­1/PD-­L1/PD-­L2 axis.26 Disruption Following primary EBV infection, both humoral and cellu-
of the PD-­L1 and/or PD-­L2 3′UTR results in significant ele- lar immunity play a crucial role in limiting replicative and
vation of PD-­L1/PD-­L2 expression in human B-­cell lympho- latent infection.33 While the control of acute EBV infection
mas.27 Structural alterations of PD-­L1 and PD-­L2, including is primarily mediated by neutralising antibodies directed to
truncation of this 3′UTR, are seen in EBV-­associated lym- the major virus envelope glycoprotein gp350, once latent in-
phomas.28 LMP1 is known to induce PD-­L1/PD-­L2 in ma- fection is established, these antibodies do not play a major
lignant B cells.29 EBNA2 also increases PD-­L1, which it role in controlling the outgrowth of EBV-­infected B cells,
achieves indirectly by downregulating EBF1 expression and although it has been postulated that this humoral immune
thereby suppressing miR-­34a, which represses PD-­L1.30 In response may be important to prevent reinfection with dif-
an in vitro model of EBV-­driven transformation,31 there ferent strains of EBV.
was a steady increase in EBNA2 and miR-­34a during the The emergence of EBV-­associated lymphomas and rep-
germinal centre-­like reaction that peaks in the activated B-­ licative lesions in individuals with compromised cellular
cell phase. This is preceded by a rise in LMP1 and PD-­L1 immunity strongly argues for the critical role of cellular
and PD-­L2 expression. Further fine-­tuning is achieved by immunity in controlling persistent EBV infection and EBV-­
miR-­BHRF1-­2-­5p, which has been demonstrated to bind associated diseases.33 This includes both innate and adap-
to PD-­L1 and PD-­L2 3′UTRs to reduce their surface pro- tive immune cells, which either directly contribute to the
tein expression.31 Furthermore, it has been shown in non-­ elimination of virus-­infected cells or promote long-­term
lymphoid EBV-­associated malignancies that EBV-­miRNAs immunological memory.34 Early studies conducted by Moss
inhibit FOXP1 and PBRM1 respectively. These host genes et al. provided the first evidence of cytotoxic T lymphocytes
bind to the enhancer region of PD-­L1 to inhibit its expres- (CTLs)-­mediated immune surveillance in controlling the
sion, thereby amplifying the transcription of PD-­L1.32 It re- outgrowth of EBV-­infected B cells.35 Initial data supporting
mains to be established if similar mechanisms are operative this concept was generated using in vitro EBV-­driven B-­cell
in EBV-­associated lymphomas. Advances in miRNA tech- transformation inhibition by CTLs.
nologies suggest there may be potential utility of mimics or One of the classic features of acute EBV infection is
antagomiRs of cellular and/or EBV-­miRNAs as novel ther- the massive expansion of both CD4+ and CD8+ T cells. 36
apeutics to overcome the PD-­1/PD-­L1/PD-­L2 axis in EBV-­ In-­depth analysis of these activated T cells has shown
associated lymphomas (Figure 3). that the majority of these cells are directed to EBV-­lytic
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420 |    EBV-­A SSOCIATED LYMPHOMAS

antigens, and these T cells express an oligoclonal T-­cell of the blood–brain barrier was confirmed, indicating the
repertoire with a single dominant T-­cell receptor (TCR). 33 suitability of this approach for EBV-­associated primary CNS
Ex vivo analyses show that these T cells predominantly lymphoma (PCNSL)-­PTLD.47 Commercialisation of third-­
recognise early lytic antigens, while late structural anti- party EBV-­specific CTL is being actively pursued in ongoing
gens are rarely recognised. Remarkably, T-­cell responses clinical trials (NCT03394365; NCT4554914). Chimeric anti-
to early antigens can reach up to 40% of the total CD8+ gen receptor (CAR) T cells combined with EBV-­specific TCR
T-­cell population, while T-­cell responses to latent anti- therapy are in development.48
gens are much lower, ranging between 0.1% and 5% of the
CD8+ T cells. 37 Following recovery from acute EBV infec-
tion, there is a dramatic reduction in these early antigen-­ E BV-­A S SO CI AT E D P T L Ds
specific T-­cell populations that are maintained at much
lower levels during latent infection. On the other hand, Post-­transplant lymphoproliferative disorders are a hetero-
latent antigen-­specific T cells are largely maintained with geneous group of LPDs that occur in the setting of a prior
minimal reduction, and some of these T cells may increase organ or HSCT. The incidence varies from 1% to 18% of
in frequency. organ transplant recipients depending on the organ trans-
Much of our understanding of T-­ cell immunity has planted and the depth and duration of immunosuppression,
emerged from studies carried out on healthy virus carri- with the highest incidence in lung and then intestinal trans-
ers. Memory T cells from these individuals can be readily plantation, followed by heart, liver and kidney.49
expanded following stimulation with autologous LCLs. The WHO (Table 1)50 recognises distinct histological
Generally, these T cells are predominantly directed at EBV-­ subtypes ranging from less overtly malignant processes
latent antigens, with dominant reactivity to EBNA3A/B/C, (plasmacytic hyperplasia, IM and florid follicular hyper-
while other latent antigens are less frequently recognised. In plasia) through to polymorphic PTLD (comprised of lym-
contrast to acute EBV infection, latent antigen-­specific T-­cell phoid cells of varying sizes and morphologies), cHL PTLD
frequencies range from 0.2% to 2.0% and are generally main- and finally monomorphic PTLD, which shows a more ho-
tained at static levels. An intriguing aspect of these T-­cell mogenous lymphoid infiltrate and comprises the majority
responses is that the overall pattern of antigen specificity is of cases. Within monomorphic PTLD, the disease is further
disproportionately influenced by select HLA alleles, includ- categorised by the disease it morphologically resembles; typ-
ing A2, A11, B7, B8 and B44, which are relatively common ically, cases are monomorphic-­DLBCL PTLD.
in Caucasian populations, while HLA-­A1-­restricted T-­cell The development of the lymphoproliferative process
responses are only minimally detected. In addition, HLA B occurs in the setting of iatrogenic immunosuppression,
alleles are more efficient at presenting EBV epitopes when which is required for immune tolerance of the trans-
compared to HLA-­A alleles.38 Sequence variation in EBV planted organ, and in most cases (excluding HSCT), the
epitopes and polymorphisms in the TCR loci may also con- malignant cells are B cells of host origin. EBV infection,
tribute towards variability in EBV-­specific T-­cell immunity occurring in the setting of reduced EBV-­specific T-­cell im-
and the outcome of infection.39 munosurveillance due to immunosuppressive therapy, is
While earlier studies suggested that the EBNA1 protein the major driver of oncogenesis in the majority of cases. 51
is not recognised by EBV-­specific T cells, subsequent anal- This is supported by the fact that EBER1 in situ hybridi-
ysis showed that T-­cell epitopes from this protein can be sation (EBER-­ISH) positivity on biopsy is almost univer-
presented on EBV-­infected B cells through an unusual an- sal in many subtypes, including plasmacytic hyperplasia,
tigen processing mechanism.40 While the EBNA1 protein polymorphic PTLD and cHL PTLD. EBV-­positivity is also
can block proteasomal degradation of mature protein, T-­cell present in ~60% of monomorphic PTLDs, with good evi-
epitopes from this protein can be generated from newly syn- dence that EBV-­negative cases have a different pathophys-
thesised, defective ribosomal products.41 In fact, more recent iology and clinical behaviour, including EBV-­a ssociated
studies have shown that in vitro expanded EBNA1-­specific T monomorphic-­DLBCL PTLD having fewer genetic aberra-
cells can be effectively used for the treatment of EBV-­driven tions than EBV-­negative cases. 52 Evidence regarding the
lymphoproliferative disorder after transplantation.42 relative risks imparted by different immunosuppressive
Restoration of EBV-­specific CTL immunity (Figure 3) regimens is inconsistent, but it appears the use of T-­cell-­
with autologous or partially HLA-­matched third-­party do- depleting antibodies and calcineurin inhibitors confers
nors (as well as allogeneic haematopoietic stem cell trans- greater risk. 53 Systemic EBV-­ a ssociated monomorphic
plantation [HSCT] donors) has been shown to be beneficial PTLD commonly presents early (within 1 year of trans-
in a variety of settings.43,44 Autologous EBV-­specific CTL plantation) and may occur due to reactivation of the la-
provides the advantage of durable engraftment and immune tent virus or as a result of a new infection, with patients
reconstitution, whereas third-­party approaches offer rapid who are EBV seronegative prior to transplant at the high-
‘off-­the-­shelf’ access (but not long-­term reconstitution).45 est risk. 54 EBV can be transmitted conventionally via the
Notably, a multicentre trial showed >50% sustained response oropharynx or via latently infected B cells present in the
at 6 months.46 Despite the HLA disparity, there was negligible allograft. With polymorphic PTLD and DLBCL-­t ype his-
toxicity. Homing of donor CTL to the tumour site crossing tology, an EBV-­latency III pattern is commonly observed. 55
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BEDNARSKA et al.    | 421

Intriguingly, there is also data suggesting EBV-­a ssociated recipients appears to improve outcomes compared to his-
monomorphic PTLD entities such as cHL and BL may also torical controls.60 Another approach involving prophylactic
be latency III, although this needs confirmation in a larger infusion of donor EBV-­specific CTL in high-­risk HSCT pa-
series. 55 EBV-­a ssociated disease may be driven in part by tients has been shown to be feasible and safe and is likely to
a defective CD4+ Th1 response to EBV followed by failure be effective.61 For further information, a recent update on
of CD8+ T cells to appropriately recognise viral antigens, novel therapies in PTLD is recommended.62
leading to a highly activated but ineffective CD8+ T-­cell Post-­transplant lymphoproliferative disorder involving
population that overexpresses PD-­1, creating a tumour mi- the CNS is almost invariably EBV-­associated and may occur
croenvironment (TME) rich in exhausted CD8+ T cells. 56 alongside systemic monomorphic PTLD but more com-
EBV-­negative PTLD, on the other hand, typically pres- monly presents as an isolated PCNSL. Compared with other
ents later (after 1 year) and is characterised by more promi- EBV-­associated PTLD, PCNSL-­PTLD tends to occur much
nent CD4+ T-­cell lymphopenia and high levels of expression later, at a median of around 54 months post-­transplant,72
of TIM-­3 on both CD4+ T cells and NK cells.56 The DLBCL-­ and most commonly affects kidney transplant recipients.58
type shows frequent lack of expression of CDKN2A and en- EBV-­associated PCNSL appears to represent a unique bio-
richment for recurrent cytogenetic abnormalities involving logical entity characterised by retention of antigen presenta-
deletions of parts of chromosome 7p and gains of 7q (11q24-­ tion (in contrast to EBV-­negative PCNSL) and a tolerogenic
q25).57 EBV-­ negative cases are more frequently TP53-­ TME comprising overexpression of the inhibitory cell sur-
mutated or p53-­positive and CD30-­negative. However, the face molecules PDL-­1, PDL-­2, LAG3 and TIM-­3.73
prognosis appears to be similar between the two groups.58 The prognosis for patients with PTLD involving the CNS
Table 2 outlines current first-line approaches. In those has been shown to be inferior to that of other PCNSL pa-
with PTLD following solid organ transplantation, check- tients74 but appears to be better for those with isolated CNS
point blockade is contraindicated due to a high risk of al- involvement and may have improved in the modern era.58
lograft rejection (41% rejection, with 81% graft loss in those Treatment of these patients tends to involve combinations of
patients).59 The PREVALE study (NCT01075321) will evalu- radiotherapy, chemotherapy and rituximab, with recent ev-
ate PD-­1 blockade (and hence the risk of graft rejection) with idence showing potential for improved outcomes with both
EBV-­specific CTL for the treatment of PTLD after HSCT and modifications of existing regimens to involve higher doses of
is yet to be reported. Serial monitoring of EBV-­v iral loads to- methotrexate,74 and with novel approaches more directed to
gether with pre-­emptive rituximab in T-­cell-­depleted HSCT the underlying biology, such as BTK inhibition.75 A study of

TA BL E 2 Current therapy options for EBV-­associated LPDs.

EBV-­associated lymphoma First-­line treatment

EBV-­associated CD20+ post-­t ransplant Reduction in immunosuppression followed by rituximab given weekly for 4 weeks, then
lymphoproliferative disorder restaging. Patients in complete remission receive four rituximab consolidation cycles.
Patients not in complete remission receive R-­CHOP chemotherapy 62,63
EBV-­associated classical Hodgkin lymphoma Combination chemotherapy with either ABVD (doxorubicin, bleomycin, vinblastine
and dacarbazine) or escalated BEACOPP (bleomycin, etoposide, doxorubicin,
cyclophosphamide, vincristine, procarbazine and prednisone) depending on stage and
risk factors and modified by interim PET imaging. Involved field therapy in select. Older
patients receive reduced-­intensity chemotherapy 64
EBV-­associated DLBCL-­NOS R-­CHOP (rituximab, cyclophosphamide, doxorubicin and prednisone)
Polatuzumab with rituximab and cyclophosphamide, doxorubicin and prednisone 65
Immune-­deficiency lymphoproliferative disorder Ceasing maintenance therapy, rituximab monotherapy, rituximab with chemotherapy and
associated with paediatric ALL maintenance chemotherapy alone66
therapy
Burkitt lymphoma Intensive chemotherapy, including R-­CODOX-­M-­I VAC (rituximab), DA-­R-­EPOCH (dose-­
adjusted) and infusional chemotherapy of rituximab, etoposide, prednisone, vincristine,
cyclophosphamide and doxorubicin67
Chronic active EBV Immune suppression includes corticosteroids, ciclosporin and azathioprine. Chemotherapy
(CHOP); allogenic stem cell transplant68
Extra-­nodal NK/T-­cell lymphoma, nasal type Sequential sandwich therapy for advanced-­stage disease. Includes chemotherapy (SMILE:
methotrexate, ifosfamide, peg-­asparaginase and etoposide) followed by radiation or
autologous stem cell transplantation69
Plasmablastic lymphoma DA-­EPOCH or CHOP with bortezomib consolidated with an autologous stem cell
transplant70
Primary effusion lymphoma Chemotherapy (CHOP, DA-­EPOCH) consolidated with an autologous stem cell transplant71

Note: Novel agents are discussed within the main text.

Abbreviations: ALL, acute lymphoblastic leukaemia; DLBCL, diffuse large B-­cell lymphoma; EBV, Epstein–Barr virus; NK, natural killer; NOS, not otherwise specified.
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
422 |    EBV-­A SSOCIATED LYMPHOMAS

ibrutinib, third-­party EBV-­specific CTL and rituximab for pathway, such as TNFAIP3, are rare in EBV-­associated cHL.80
EBV-­associated PCNSL or secondary CNSL in the immuno- LMP2A has been shown to rescue BCR-­deficient B cells and
suppressed is ongoing (ACTRN12618001541291). Utilisation may allow the development of HRS cells in the absence of
of novel therapies such as EBV-­specific CTL and CAR-­T BCR signalling.82
therapy is much lower in those with CNS disease, with such Antigen presentation of viral peptides is preserved in
patients often being excluded from clinical trials, and re- EBV-­associated cHL because of higher expression of HLA-­
lapsed/refractory PCNSL-­PTLD remains a significant area class I molecules in HRS cells due to less frequent muta-
of unmet need. tions in β2-­microglobulin compared to EBV-­negative cHL.83
Immune evasion in EBV-­associated cHL is achieved through
the recruitment of an immunosuppressive TME, which also
E BV-­A S SO CI AT E D cH L leads to diminished EBV-­specific T-­cell immunity. HRS are
surrounded by immunosuppressive CD4+ regulatory T cells
Classical Hodgkin lymphoma accounts for 10% of LPDs, and and tissue-­associated macrophages (TAMs).84 EBNA1 can
EBV is identified in 30%–50% of these cases.76 However, the stimulate HRS cells to express CCL20, resulting in the re-
incidence of EBV-­associated cHL is higher in older patients, cruitment of CD4+ T regulatory cells to the TME.85 A unique
in children and in patients from developing nations (>90% of regulatory T-­cell subset that expresses LAG3 has been asso-
cases).76 Human immune deficiency virus (HIV)-­associated ciated with HRS cells that surprisingly have reduced MHC
cHL is associated with latent EBV infection in >95% of cases. Class II expression.86 Interestingly, high levels of LAG3+ T
A recent meta-­analysis pooled the data of 9570 patients with cells in the tumour correlated with diminished LMP1 and
EBV-­associated cHL and found that disease-­specific and LMP2-­specific CD8+ T-­cell responses in peripheral blood.78
overall survival (OS) were worse when compared to EBV-­ Galectin-­1, a carbohydrate-­binding protein that modulates
negative cHL.77 However, there was considerable heteroge- innate and adaptive immune responses, is known to be over-
neity in terms of clinical outcomes between the studies. In expressed by HRS and is associated with impaired latency
subgroup analysis, older patients with EBV-­associated cHL II-­specific CD8+ T-­cell response ex vivo.87 Frequently, cHL
(>45 years) had poorer clinical outcomes compared to their has increased expression of PD-­L1, which further contrib-
EBV-­negative counterparts, but the opposite was observed utes to T-­cell anergy. It is known that in many instances,
for young patients with EBV-­associated cHL.77 Patients from this is due to copy number changes and amplifications in
Africa, where rates of EBV-­associated cHL are considerably the 9p24.1 encoding for this gene, along with upregulation
higher, also had better outcomes compared to their EBV-­ of the JAK/STAT pathway that is involved in the regulation
negative counterparts.77 of PD-­L1.88 However, cHLs with normal 9p24.1 copy num-
The malignant Hodgkin Reed-­Sternberg (HRS) cell ac- bers also expressed detectable PD-­L1, with EBV shown to be
counts for 1%–2% of the tumour mass and is surrounded by an alternative mechanism for PD-­L1 induction in cHLs with
an immunosuppressive TME enriched in immunosuppres- diploid 9p24.1.29
sive molecules.78 EBV-­associated cHL accounts for a higher Conventional first-­line therapies are not stratified by
proportion (~75%) of mixed cellularity and is least frequent EBV-­tissue status (Table 2). Patients who enter remission
in the nodular sclerosing subtype. EBV is also implicated demonstrate a significant reduction in EBV-­v iral load to low
in the HL type of Richter's transformation in chronic lym- or undetectable levels, in contrast to persistent or escalating
phocytic leukaemia.78 The presence of clonal EBV-­DNA in levels in those with disease progression.78
HRS cells strongly argues for a pathogenic role of the virus
in EBV-­associated cHL tumour development.79
The rates of driver mutations and the total mutational E BV-­A S SO CI AT E D DL BC L -­N OS
burden are significantly lower in EBV-­associated cHL com-
pared to EBV-­negative cHL.80 Thus, the EBV-­related changes Epstein–Barr virus-­ associated DLBCL-­ NOS is a well-­
contribute to the molecular pathogenesis of cHL, resulting established subgroup of DLBCL-­NOS that is distinct from
in less reliance on mutationally driven changes to cellular DLBCL occurring in patients with immunosuppression. It
pathways compared to EBV-­negative cHL. EBV-­associated accounts for between 3% and 15% of all DLBCL-­NOS with
cHL has distinct molecular characteristics compared to significant geographical variances apparent, with western
EBV-­negative cHL. HRS in EBV-­associated cHL displays Europe and the United States having lower rates but higher
type II latency. Deletions clustered near the 3′ end of the occurrence in Asia and South America, and intermediate
LMP1 gene occur in some cases and are believed to be histo- rates in Australasia.89,90 Initial reports indicated that this
logically associated with numerous HRS cells.81 A hallmark was a disease of the elderly, but while it more commonly oc-
of cHL is a constitutively activated NF-­κB pathway. Distinct curs in patients over 45, cases in younger patients occur.91
mechanisms are involved in pathway activation in EBV-­ Patients with EBV-­associated DLBCL-­NOS are more likely
associated and EBV-­negative diseases. In EBV-­associated to present with advanced disease, poor performance status,
cHL, LMP1 functions as a CD40 homologue that constitu- B symptoms and in some series haemophagocytic lympho-
tively activates multiple downstream pathways, including histiocytosis (HLH).90 EBV-­v iral loads are frequently but
NF-­κB. Consequently, mutations in regulators of the NF-­κB not invariably detected in the peripheral blood.90 In patients
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BEDNARSKA et al.    | 423

over 45 years, it is associated with an inferior outcome com- The viral and mutational differences in EBV-­a ssociated
pared to EBV-­negative DLBCL-­NOS receiving conventional DLBCL-­NOS have a significant inf luence on immune
chemoimmunotherapy, with outcomes generally 10%–15% evasion strategies. Copy number alterations show that
lower in most series.89,90 approximately 20% of cases have gains at 9p24.1, which
The percentage of positive EBER-­ISH cells required for covers the locus of PD-­L1/PD-­L1 and JAK2.92 This level
the diagnosis of EBV-­associated DLBCL-­NOS is not clearly of mutation is significantly higher than the levels found
defined, with levels varying between 20% and 90% de- in EBV-­negative DLBCL-­NOS. It is possible that EBV-­
scribed.89,90,92 The WHO 2016 criteria set the level at 80%, infected B cells that gain PD-­L1/L2 amplifications are
and this is currently endorsed by the ICC.93 However, a at a significant advantage for neoplastic transformation.
50% cut-­off is utilised by some studies, and it is likely that However, some patients without PD-­L1 amplifications
EBV-­ positive levels below arbitrary thresholds still play still have high PD-­L1 expression, illustrating that there are
a significant part in the pathogenesis of the disease.92,94 likely independent mechanisms that lead to this method
Histologically, it can occur in a polymorphic form not dis- of immune evasion in this disease. Truncating lesions in
similar to cHL, with the remaining cases presenting as a the 3′ UTR of PD-­L1 and PD-­L 2 have also been described
monomorphic form resembling de-­novo DLBCL.90 Perhaps in 19% of EBV-­a ssociated DLBCL cases from Japan. 28
uniquely in EBV-­associated DLBCL-­NOS, almost all cases The TME of EBV-­a ssociated DLBCL-­NOS is also unique
demonstrate malignant cell CD30 and PD-­ L1 positivity. with enrichment for immune checkpoints such as PD-­L1,
The majority of cases show a type II latency (~90%), which PD-­L 2, LAG3 and TIM-­3 and higher levels of TAMs that
contrasts with latency-­ III pattern, which predominates strongly correlated with expression of LMP1. 89 These
in PTLD.90 EBV-­gene expression levels appear to be re- findings could have a significant impact on how we ap-
duced compared to EBV-­associated monomorphic-­DLBCL proach the treatment of this unique entity. Clearly, anti-­
PTLD.55 PD-­1 holds promise as a potential therapy (Figure 4), and
Most cases are non-­G CB subtype by immunohisto- there are some early indicators that this approach may be
chemistry, but gene expression analysis challenges this highly effective in this disorder due to the increased lev-
concept.89,92 Within GCB cases, levels of the GCB-­related els of PD-­1+ T cells in the TME.97 Although conventional
gene BCL- ­6 are consistently lower in EBV-­ a ssociated first-­l ine therapies are not stratified by EBV-­t issue status
DLBCL-­ NOS relative to EBV-­ negative GCB, consistent (Table 2), a trial of PD-­1 blockade in combination with
with the known ability of EBV-­m iRNAs to downregu- R-­CHOP and autologous EBV-­specific CTL is ongoing
late BCL- ­6 expression.95 Potentially, the concept of cell-­ ACTRN12622001189718.
of-­origin as applied to EBV-­negative DLBCL-­NOS is not
applicable to the EBV-­ d riven atypical germinal centre
reaction. I M M U N E DE F ICI E NC Y
Recently, targeted DNA sequencing and copy num- LY M PH​O PR​O L I​F E R ​A T I V E
ber analysis of EBV-­ associated DLBCL-­ NOS have been DISOR DE R A S SO CI AT E D
performed.92,94,96 Studies have not demonstrated consis- W I T H PA E DI AT R IC AC U T E
tent results, perhaps indicating the different methodolog- LY M PHOBL A ST IC L EU K A E M I A
ical approaches as well as the heterogeneity of the disease. M A I N T E NA NC E T H E R A PY
However, although marked variations in many individual
mutation frequencies occurred, some common features were Recently, Elitzur et al. reported on the development of lym-
present, including frequent mutations in genes involved in phoid neoplasms following paediatric acute lymphoblastic
the JAK/STAT pathway, NOTCH2 signalling and epigene- leukaemia (ALL) therapy.66 The study included 12 interna-
tic regulators, whereas mutations involving the NF-­κB and tional collaborative paediatric ALL trials between 1980 and
DNA repair pathways and immune evasion genes were typ- 2018 and excluded stem cell transplantation. Most of the
ically less frequent. MYC translocation does not appear to patients developed immune deficiency lymphoproliferative
be increased in EBV-­associated DLBCL cases. However, as disorder (IA-­LPD) within 6 months of maintenance ther-
most studies performed used limited whole exome, or WGS, apy (typically prednisolone, vincristine, methotrexate and
and highly targeted sequencing, our knowledge is still likely 6-­mercaptopurine ‘POMP’) or shortly after its cessation.
somewhat incomplete. All these studies indicate that EBV Approximately two thirds of these lymphoid neoplasms
is a significant contributor to lymphoma pathogenesis given were mature B-­cell LPD, 26% with lymphoblastic lym-
that EBV-­associated DLBCL-­NOS has a significantly lower phoma and the remainder were peripheral T-­cell lympho-
mutational burden, either indicating that this disease needs mas or NHL-­NOS. They were predominantly EBV-­d riven.
a reduced number of driver mutations and/or EBV is capable They were classified as polymorphic B-­cell lymphoprolif-
of upregulating key oncology pathways required for tumour erative disorders, monomorphic B-­cell LPD, monomorphic
propagation. To date, it is not entirely clear if polymorphic T-­cell LPD, lymphomatoid granulomatosis and EBV-­
subtypes differ from monomorphic subtypes, and larger associated mucocutaneous ulcer. Patients were generally
studies are required to establish this. at an advanced stage. The 5-­year event-­free survival and
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
424 |    EBV-­A SSOCIATED LYMPHOMAS

F I G U R E 4 Anti-­PD-­1 monoclonal antibody enhances Epstein–Barr virus (EBV)-­infected B-­cell killing. (A) Time course following EBV infection
of naïve B cells, showing upregulation of PD-­L1 and PD-­L2 protein expression. (B) In vitro expanded EBV-­specific cytotoxic T lymphocytes kill EBV-­
infected B cells more efficiently upon PD-­1 blockade with the anti-­PD-­1 monoclonal antibody pembrolizumab (Bednarska and Gandhi, unpublished
data).

OS from the lymphoid neoplasm diagnosis were 66.6% and of great interest. Importantly, more research is required to
67.4% respectively.66 By multivariable analysis, the presence establish if these neoplasms are also present in adult ALL
of HLH was the only variable associated with an increased patients receiving maintenance therapy. Furthermore,
risk of mortality. Treatment varied and typically involved without prospective trials, the optimal management is un-
stopping maintenance therapy. Interventions included certain (Table 2).
rituximab, rituximab plus low-­intensity chemotherapy or
chemotherapy alone.
The aetiology of IA-­LPD in this setting remains un- E BV-­A S SO CI AT E D
clear. One possibility is that paediatric patients have a BU R K I T T LY M PHOM A
subtle primary immunodeficiency that contributes to the
development of both primary ALL and secondary IA-­LPD. Burkitt lymphoma (BL) was the first EBV-­a ssociated ma-
Perhaps more likely (or as well as) are the iatrogenic immu- lignancy identified.98 It is an aggressive B-­cell lymphoma
nosuppressive effects of maintenance therapy. In line with that is most common in children (one third of all paedi-
this, both methotrexate and thiopurines have previously atric lymphomas) but can occur in adults. BL is divided
been associated with LPDs in patients with rheumatoid into three clinical subtypes: eBL, sporadic BL (sBL) and
arthritis treated with methotrexate and in patients treated immunodeficiency-­ related BL (iBL).99 EBL is closely
with thiopurines due to inflammatory bowel disease.78 linked to EBV (~95% of cases), although with some geo-
Other potential underlying factors of secondary neo- graphical variation, whereas EBV-­a ssociated tumour cells
plasms include chemotherapy-­induced T-­cell or NK-­cell are present in ~20% of sBL and 25%–40% of adult patients
lymphopenia or dysfunction. Hence, rapid restoration of with iBL.100 iBL occurs in association with the HIV infec-
the host's immune system is important to prevent the de- tion and less commonly in patients with other causes of
velopment of these IA-­lymphoid neoplasms. Approaches immunodeficiency, for example recipients of organ trans-
to achieve this include the implementation of alternative plants.101 Unlike other AIDS-­related NHLs, despite the
treatment regiments and/or revision of maintenance ther- introduction of anti-­retroviral therapy, the incidence of
apy durations that have reduced immunosuppressive ac- iBL in patients with HIV has not declined.102 It is the most
tivity or EBV-­specific CTLs to restore EBV-­specific T-­cell rapidly growing of all lymphomas; extra-­nodal presenta-
immunity. tion is frequent (jaw presentation is typical of eBL) and
Given that this entity was only recently described, it is can present as an acute leukaemia if bone marrow infil-
likely that IA-­LPD in the context of paediatric ALL main- tration is present. First-­l ine therapies are not stratified by
tenance therapy is underreported. Prospective studies with EBV-­t issue status (Table 2).
modern therapeutic strategies incorporating a central re- The genetic hallmark of BL is MYC translocation, which
view of histopathological IA-­LPD specimens are of great brings the MYC gene into juxtaposition with immuno-
importance to obtain meaningful data to determine future globulin genes (typically the heavy chain, causing a t(8;14)
treatment strategies. Biomarker-­d irected studies exploring (q24;q32) translocation, seen in 80%), which places it under
the possibility of stratifying patients into groups that may the regulation of a strong enhancer, causing its overexpres-
or may not require maintenance treatment would also be sion. The immunoglobulin-­ MYC translocation does not
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BEDNARSKA et al.    | 425

appear to vary by EBV-­tissue status, whereas breakpoints are, diagnostic criteria for CAEBV preclude known syndromes
with more breakpoints upstream of MYC in EBV-­associated of immunodeficiency, defects in cellular immunity are re-
cases.31,39,48,103 The overexpression of MYC reprogrammed ported, including mutations in PRF1,110,111 IL2RG,112 PI3K,113
cells for maximum proliferative capacity. Protection against STXBP2110 and GATA2.113
apoptosis is achieved through mutations in p53 and the pro-­ More recently, whole exome sequencing (WES) of a co-
apoptotic BH3-­only genes PUMA and BIM.104 Although hort of CAEBV samples confirmed that germline mutations
BL more typically exhibits latency type 1, up to 15% of eBL rarely contribute to the pathogenesis of CAEBV. Rather,
express an atypical EBV latency that is driven by the Wp somatic mutations, particularly DDX3X (present in 87% of
promoter associated with expression of the anti-­apoptotic patients) and other driver mutations associated with hae-
BCL-­2 homologue BHRF1.105 matological malignancies (TET2, KMT2D and BCOR), have
A study by Grande and colleagues demonstrated a been shown to accumulate in EBV-­infected lymphocytes and
striking genome-­w ide increase in aberrant somatic hyper- are strongly associated with survival.91 Furthermore, serial
mutation (SHM) in EBV-­associated tumours, supporting sampling from one case demonstrated evidence of clonal
a link between EBV and activation-­induced cytidine de- evolution in a DDX3X-­ mutated population, which pro-
aminase activity. This is consistent with SHM-­ mediated gressed to frank lymphoma, demonstrating the continuum
breakpoints being predominant among EBV-­ associated connecting CAEBV with malignancy.11
BLs.103 Sequencing indicates fewer driver mutations in The prognosis of CAEBV is generally poor, particularly
EBV-­associated BL.103,106 The Vancouver group used whole when diagnosed in adulthood, and the 3-­year OS in patients
genome sequencing to classify DLBCL and BL and found with uncontrolled active disease is only 16.7%.114 While
a strong association between EBV status and a subgroup- immunosuppressive agents (ciclosporin, prednisone) and
ing they termed DGG-­BL (characterised by mutations in chemotherapy may yield transient symptomatic improve-
DDX3X, GNA13 and GNAI2).103 These studies highlight the ments (Table 2), HSCT remains the only curative treatment
strong influence that EBV has on BL biology. option.114 Although approximately two thirds of patients
treated with HSCT are alive at 15 years of age, many patients
are unable to receive this option, and effective alternatives
CH RON IC AC T I V E E BV remain an unmet need. Recent data from an early-­phase
study suggests PD-­1 blockade combined with lenalidomide
Chronic active EBV is a rare and life-­ t hreatening LPD. is effective in some patients.115 Notably, restoration of CD8+
Presentation is more frequent in East Asian and Latin T-­cell function was associated with response, whereas non-­
American countries and is rare in Western countries. It usu- responders were characterised by a higher somatic muta-
ally occurs in paediatric and adolescent patients. Although tional load.
definitions differ, CAEBV is broadly characterised by persis-
tent IM-­like symptoms for more than 3 months, high-­level
EBV-­v iraemia in peripheral blood, as well as abnormally E N K T L , NA SA L T Y PE
high levels of EBV-­antibodies and evidence of tissue infil-
tration by EBV-­infected lymphocytes (typically T cells and Extra-­ nodal NK T-­ cell lymphoma is characterised by lo-
less often NK cells) in the absence of known immunodefi- cally destructive extra-­nodal masses of EBV-­positive NK-­or
ciency.50 Infected lymphocytes exhibit type II latency.107 T-­cell lineage lymphoma cells and angiocentric growth/de-
Cases with EBV-­infected B cells have been described in struction.50 It occurs in adults (male > female) and occurs in
south/central American populations.108 3%–10% of East Asian and Latin American but <1% of North
Clinically, this heterogeneous entity is divided into sys- American and European populations and is enriched for
temic and localised subtypes, with the later manifesting as predisposing HLA genotypes.116 Most patients present with
isolated cutaneous presentations: severe mosquito bite al- limited-­stage disease, commonly nasal; however, the most
lergy and hydroa vacciniforme LPD.50 Lesions located in the recent WHO classification recognises ENKTL as a single en-
sun-­exposed area and photosensitivity are most common. tity with nasal (80%) and non-­nasal (20%) presentations.50
Systemic CAEBV most often presents with an aggressive Advanced-­ stage deposits most often occur in extra-­ nodal
clinical course marked by constitutional symptoms, lymph- sites such as the skin, gastrointestinal tract, testis, liver, spleen
adenopathy, hepatosplenomegaly and cytopenias reflecting and bone marrow. Symptoms are refer to local involvement
hypercytokinaemia, as well as uncommon but serious com- or reflect constitutional symptoms, with 3% of cases compli-
plications such as HLH, multiorgan failure and progression cated by HLH. Several prognostic systems have been reported;
to lymphoma/leukaemia.109 PINK-­E is widely used and incorporates age >60, stage III/IV,
While the precise aetiology of CAEBV remains elusive, non-­nasal primary location and distant lymph node involve-
there appears to be a complex interplay between immune ment with detectable plasma EBV-­DNA as markers of poor
dysfunction, the acquisition of somatic mutations and viral prognosis.117 Circulating-­DNA and EBV-­DNA clearance may
characteristics. Geographic restriction as well as rare in- improve the assessment of disease response.
stances of familial syndromes are strongly suggestive of Genomic alterations, including chromosomal deletions
inheritable genetic susceptibility to CAEBV. Although the (typically 6q21-­ 25 deletion), mutations (e.g. BIM, TET2,
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
426 |    EBV-­A SSOCIATED LYMPHOMAS

ASNS, PRDM1, MLL2/MLL3 and BCOR) and altered gene a median OS of less than 2 years.126 Table 2 outlines current
expression (EZH2 overexpression), have been identified in first-­line approaches.
significant minorities of cases, with epigenetic modification Some studies observe frequent mutations in the tumour
being the most common pathogenic mechanism of disease, suppressor gene PRDM1, which plays a major role in plasma
suggesting potential roles for hypomethylating agents and cell differentiation.127 A combined WES and extended tar-
novel miRNA inhibitors. Cell survival/proliferation path- geted sequencing study in South African HIV-­associated PBL
ways are frequently upregulated, including the JAK/STAT, by Liu et al. identified recurrent mutations in genes of the
NF-­κB, RAS/MAPK and PDGFRa pathways.118 JAK/STAT (particularly STAT3) and RAS-­MAPK pathways
As a rare entity, there are no prospective randomised tri- leading to their constitutive activation.128 They also found
als to guide optimal management. Traditionally, treatment copy number gains encompassing the CD44 gene, involved in
is intensive multiagent chemotherapy for advanced-­stage lymphocyte activation and homing. However, all WES cases
disease and/or local radiation for limited-­ stage disease. were EBV-­associated, with no information on the EBV status
Anthracycline-­ based regimens are inadequate due to P-­ of the cases that underwent targeted sequencing. This pre-
glycoprotein-­ mediated drug resistance.119 l-­Asparaginase vents an evaluation of whether the pattern of mutated genes
is the backbone of chemotherapy regimens, and a consol- in PBL is linked to EBV infection of the lymphoma cells.128
idative autologous or allogeneic transplant may be consid- More recently, PBL tumours were tested by WES and RNA-­
ered for selected patients (Table 2). Outcomes for relapsed/ sequencing. Cases were stratified by EBV (and HIV) sta-
refractory disease are dismal, necessitating novel approaches tus. In addition to confirming many of the findings by Liu
translated from an improved characterisation of the biologi- et al., they also showed that HLA-­class I antigen processing
cal underpinnings of ENKTL, including therapy directed at and cell cycle regulation were significantly upregulated in
rational targets based on common genetic drivers and dys- EBV-­associated PBL (Kunster and Gebauer, personal com-
regulated signalling pathways, the TME, targetable surface munication). An almost exclusive upregulation of phosphati-
proteins and EBV infection. dylinositol 3-­kinase/AKT/mTOR signalling in EBV-­associated
Ruxolitinib (a JAK1/2 inhibitor) has been investigated PBL and a significantly induced expression of NTRK3 in
in other T-­cell lymphomas and warrants consideration concert with recurrent oncogenic mutations in EBV-­negative
in ENKTL.120 PD-­L1 expression is common in ENKTL121 PBL hint at a specific therapeutically targetable mechanism
and checkpoint inhibitors have been used with reasonable in PBL subgroups. Further, RNA-­sequencing revealed several
efficacy in the up front and relapse/refractory settings.122 significantly upregulated genes in EBV-­associated PBL (in-
Recent transcriptomic studies have sought to subclassify cluding MET, BCL2 and NRAS), while EBV-­negative PBL was
ENKTL into immune subgroups, which could further significantly enriched for downregulated tumour suppressors
guide the optimal use of checkpoint inhibitors in immune-­ (including FLT3, MEN1, MSH2 and NPM1).129
responsive categories.123 Other novel approaches include
targeting surface proteins or directing therapy against
EBV. CD38 and CD30 are surface proteins expressed in PR I M A RY E F F USION LY M PHOM A
roughly half of cases. Daratumumab (an anti-­CD38 mono-
clonal antibody) and brentuximab vedotin (an anti-­CD30 Primary effusion lymphoma (PEL) is a rare, aggressive
antibody-­d rug conjugate) have been investigated, respec- lymphoproliferative disorder of B-­cell origin, most com-
tively, in relapsed/refractory settings, though limited re- monly presenting in patients with HIV. It accounts for
sponse rates were observed.124 The role of EBV-­specific 2%–4% of HIV-­ a ssociated non-­Hodgkin lymphomas.
CTLs remains uncertain. PEL may also present after immunosuppression for organ
transplantation and in older patients due to immune se-
nescence. The presence of human herpes virus 8 (HHV8)
E BV-­A S SO CI AT E D PBL is a requirement for diagnosis of the disease, and there is
frequent coinfection with EBV in 50%–80% of cases.130
Plasmablastic lymphoma is a rare B-­cell lymphoma associ- The immunophenotype of PEL cells shows plasma cell
ated with immunosuppression, particularly when mediated markers but lacks mature B-­cell antigen expression, in-
by HIV infection. It accounts for ∼2% of all AIDS-­related cluding CD20.130 Patients present with an accumulation
lymphomas.125 PBL is typified by the presence of large plas- of effusions in body cavities without identifiable tumour
mablastic or immunoblastic cells, loss of B-­cell lineage mark- masses. A rare extra-­c avitary subtype presents with extra-­
ers (CD20, PAX5), expression of plasmacytic differentiation nodal masses and nodal disease.130
markers (CD38, CD138, IRF4/MUM1, BLIMP1), a high The coinfection with two DNA herpes viruses, HHV8
proliferation index and frequent expression of EBV (with a and EBV, in PEL raises the possibility of viral cooperation
restricted latency profile, typically latency 0 but also I and in this disease.131 EBV infection in PEL has a latency type
II latencies). Activating MYC translocations (mostly involv- 1 pattern of antigen expression.132 Genomic analysis of
ing the immunoglobulin loci as the translocation partner) EBV-­DNA in HIV+ PEL did not show any predilection of
are frequently but not always observed and are not neces- a particular EBV strain.133 However, each PEL case con-
sary for overexpression of MYC. It is highly aggressive, with tained only a single EBV variant, indicating infection of
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BEDNARSKA et al.    | 427

precursor cells prior to clonal expansion. HHV8 has a more Patients with XLP1 have a specific vulnerability to EBV-­
extensive expression of viral proteins in PEL, including associated conditions, including severe IM, HLH and EBV-­
LANA-­1 (latency-­a ssociated nuclear antigen 1), Kaposin associated LPDs. However, curiously, immunity to other
B, viral homologues of cyclin D and FLICE-­inhibitory viral pathogens such as influenza or varicella zoster is not
protein.130 Each of the HHV8 viral proteins is implicated affected.139 The disease is caused by inactivating mutations
in the pathogenesis of the disease. For instance, LANA-­1 in SH2D1A, resulting in dysfunction of SLAM-­associated
binds to the tumour suppressor proteins retina-­blastoma proteins (SAP), which link SLAM receptors with intracel-
tumour and p53, leading to increased cell cycle progres- lular pathways.139 Studies in asymptomatic female carriers
sion and survival. However, infection with HHV8 alone in with SH2D1A mutations showed CD8+ T cells that are SAP+
the absence of EBV is insufficient to transform B cells. A retain immune responsiveness to EBV-­infected B cells, but
study using PEL cell lines showed that HHV8 coinfection those cells that are SAP− do not exhibit any immune re-
with EBV was required for ongoing cell proliferation, and sponse when EBV-­ antigens are presented by B cells.140
inhibition of EBNA-­1 reduced cell growth.134 The interac- However, SAP− cells retain responses to EBV-­antigens if pre-
tion between EBV and HHV8 microRNAs within infected sented by monocytes and fibroblasts. This suggests that the
B cells and epigenetic mechanisms may contribute to the loss of EBV-­specific immunity in patients with XLP1 is due
pathogenesis of PEL.131 However, the exact mechanisms to a loss of antigen response to B cells. This is likely due to the
underlying viral cooperation in PEL remain to be better inhibitory effects of receptors 2B4 and NTB-­A in SAP− cells
explored. when binding to their associated ligands on EBV-­infected B
Survival and response to treatment for PEL are poor, even cells.140 In addition to the changes to CD8+ T cells, muta-
in HIV+ cases treated with chemoimmunotherapy and anti-­ tions in SH2D1A result in a deficiency in NKT cells, which
retroviral therapy (ART) (Table 2). CHOP-­based regimens may also contribute to a reduction in EBV-­specific immu-
have been used with a complete response rate of 62% and a me- nity.137 A recent multicentre retrospective review explored
dian survival of 10 months.71 Improved outcomes have been the outcomes of 91 patients with XLP1. Patients had a me-
observed in studies using dose-­adjusted EPOCH (etoposide, dian age of presentation of between 3 and 4 years. In this
prednisone, vincristine, cyclophosphamide and doxorubi- cohort, lymphoma developed in 24.2% of patients and was
cin).135 There is also evidence of increased PD-­L1 expression in the cause of mortality in 9% of patients.141 The prognosis for
patients with PEL, and one small case series has shown prom- patients who develop HLH is poor, and stem cell transplan-
ising efficacy using pembrolizumab with or without poma- tation is strongly recommended in these cases.141
lidomide in patients with HIV+ PEL.136 The absence of EBV,
increased IL-­6 and IL-­10 levels, multiple cavitary involvement
and absence of ART at diagnosis (in HIV-­positive cases) are I M M U N​O SE​N E S​C E NC E A N D
associated with inferior outcomes in PEL.130 AGE -­R E L AT E D LY M PHOI D
PROL I F E R AT IONS

I N BOR N E R ROR S OF I M M U N I T Y Immunosenescence is a constellation of changes to adaptive

A N D E BV-­A S SO CI AT E D LY M PHOM A S and innate immune cells leading to increased susceptibil-
ity to infections, autoimmune diseases and malignancy.142
Inborn errors of immunity (IEI) are rare, typically mono- EBV-­associated DLBCL and EBV-­associated cHL are more
genetic inherited conditions that affect the function of common in older patients, and this raises the possibility that
immune cells against pathogens.137 There is increasing immunosenescence contributes to a defective response to
recognition of IEIs, particularly with the more wide- EBV infection and to lymphomagenesis.143 There are substan-
spread availability of genomic tests. In EBV-­associated tial changes to T cells with ageing and these include a loss of
lymphomas, knowledge of IEI is important in patient TCR diversity, reduced numbers of naïve T cells, increased
management because allogenic stem cell transplants to immune checkpoint expression, reduced expression of the
address immunodeficiency may be curative in many of costimulatory CD28 and functional changes to CD4+ T-­cell
these cases.138 In addition, from a biological standpoint, subsets.143 NK cells may show a loss of activating markers
understanding the effects of primary immunodeficiencies such as NKP30 and increased expression of inhibitory Killer
highlights important immune pathways that control the cell immunoglobulin-­like receptors. Overall, the cumulative
latent and lytic phases of EBV infection. CTL function and changes to innate and adaptive immune cells result in a state
innate immunity by NK cells are particularly important of chronic inflammation known as ‘inflammageing’.143 This
in the increased risk of EBV-­a ssociated diseases in these may lead to impaired immunity to viral pathogens.144
patients.139 IEIs that predispose to severe EBV-­a ssociated A multicentre retrospective review explored the clinical
complications include XLP1 (X-­linked lymphoprolifera- and pathological characteristics of age-­related EBV lym-
tive disorder-­1), mutations that effect TCR signalling (in- phoid proliferations over a 15-­year period.145 These were
cluding MAGT1 and ITK deficiency) and those involving classified as follows: reactive hyperplasia; EBV-­ positive
T-­cell costimulatory molecules of the tumour necrosis su- polymorphic B-­ cell lymphoproliferative disorder sub-
perfamily (including TNFRSF9/4-­1BB mutations). classified into nodal and extra-­nodal subtypes, including
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
428 |    EBV-­A SSOCIATED LYMPHOMAS

EBV-­associated mucocutaneous ulcer; and EBV-­associated skin, subcutaneous tissues, parotid glands, lung and breast),
DLBCL. The median age of the cohort was 75 years. TCR but exclusively nodal sites have been reported. Targeted se-
clonality was frequently observed, suggesting a restricted T-­ quencing suggests EBV-­associated cases are less complex
cell response associated with ageing; however, comparisons than non-­EBV-­associated MZL and may be enriched in IRF
with younger cohorts and more modern TCR sequencing are genetic aberrations, including copy number abnormalities or
needed to be confident of this association. Clinical outcomes mutations.152 T-­cell infiltration is infrequent (in contrast to
were the worst for patients with EBV-­associated DLBCL and EBV-­associated mucocutaneous ulcer), but the TME remains
polymorphic LPD, with 5-­year disease-­free survival of 57% adequately characterised.153 Further studies are required to
and 25% respectively.145 establish the frequency and biology of this rare entity.

DE V E L OPM E N T OF E BV-­A S SO CI AT E D VAC CI N E S

L PDS I N PAT I E N T S W I T H
AU TOI M M U N E DISE A SE S The strong role of EBV-­specific T-­cell immunity and an in-
complete knowledge of how it impacts genetic susceptibil-
Patients with autoimmune disease have an increased risk ity have so far hampered strategies to develop an effective
of developing LPDs, many of which are EBV-­a ssociated. preventative vaccine in EBV-­seronegative individuals (pri-
Factors contributing to this risk include underlying im- mary prevention) or to control latently infected B cells in
mune changes associated with autoimmunity and immu- at-­risk EBV-­seropositive individuals (secondary prevention).
nosuppression used to treat the disease.146 Rheumatoid Initially, vaccine approaches focussed on eliciting protective
arthritis (RA) is one of the most prevalent autoimmune antibody responses. Human Phase II clinical trials of such
diseases, and there is a strong association with an in- approaches demonstrated clinical efficacy in preventing the
creased risk of lymphoma in these patients.144 A recent development of IM but did not prevent EBV infection.154
meta-­a nalysis of LPDs in patients with rheumatoid ar- However, novel vaccine approaches that induce broad hu-
thritis showed 54% of all RA-­a ssociated LPDs were EBV-­ moral and cellular immunity against multiple viral determi-
positive.144 The prevalence of EBV-­a ssociated LPDs was nants are more likely to provide better protection against the
significantly higher in patients with RA compared to con- development of EBV-­associated LPDs. For example, a recent
trol patients without RA and LPD.144 There is a reduced lymph node-­targeting dual humoral/cellular immune ap-
ability to generate EBV-­specific CTLs in patients with proach demonstrated potent and durable immunity in pre-
RA.147 In addition, patients with RA have higher EBV-­ clinical models.155
DNA loads compared to matched controls, independent of Further understanding of the viral and host genetic basis
the presence of disease-­modifying agents.148 of susceptibility to EBV-­associated lymphomas may also
contribute to the development of preventive vaccines. Case
reports of individual cases with a high susceptibility to EBV
E BV-­A S SO CI AT E D E X T R A-­N ODA L infection have shed light on the importance of this interac-
M A RGI NA L Z ON E LY M PHOM A S tion.156 At a population level, polymorphisms in the HLA-­
class I molecule HLA-­A are associated with an increased
Initially, low-­grade B-­cell lymphomas were excluded from risk of developing EBV-­ associated cHL.157 Mechanistic
the category of monomorphic PTLD. Subsequently, follow- studies suggest that the association is due to the impact of
ing reports identifying EBV-­associated extra-­nodal marginal HLA-­class I molecules on the magnitude of CD8+ T-­cell re-
zone lymphoma (MZL) in the post-­transplant setting,149 the sponses to latent EBV-­antigens and that polymorphisms in
revised 2017 4th edition of the WHO tumour classification EBV-­latency genes influence the potency of CD8+ T-­cell re-
included this as an entity (although it is absent from the sponses in EBV-­associated PTLD.38,42 More recently, it has
WHO-­HAEM5 and ICC). Increasingly, there is recognition been shown that variations in CD94/NKG2A–HLA-­E inter-
that it can occur in a variety of other immunocompromised actions on T-­and NK-­cell subsets have functional relevance
settings, including immune suppression for autoimmune in EBV control.158
disorders, prior chemotherapy, primary immunodeficiency
and as part of immunosenescence and age-­ related lym-
phoid proliferations.150,151 In the setting of PTLD, reduced C ONC LUSIONS
immunosuppression may be sufficient to induce tumour
regression, emphasising the role of immunosuppression in As outlined in this review, emerging data has challenged
its pathogenesis. Latency is predominantly type I but oc- our view on the contribution of EBV to lymphomas. It is
casionally type II, and the EBER-­ISH-­staining malignant B hoped that this will lead to new therapeutic approaches.
cells are light chain restricted. Although there is evidence of Irrespective of whether an immune, epigenetic or small
plasmacytic differentiation, the atypical plasmacytoid cells molecule inhibitor or a combination of these or other
are often CD20+ and are negative for the MYD88 L265P mu- approaches are used, a better understanding of EBV-­
tation. They typically occur at extra-­nodal sites (such as the associated LPDs will allow us to more effectively explore
 13652141, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.19255 by CAPES, Wiley Online Library on [07/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BEDNARSKA et al.    | 429

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