EBV and HIV-Related Lymphoma
Michele Bibas and Andrea Antinori
Clinical Department, National Institute for Infectious
Diseases “Lazzaro Spallanzani”, IRCCS, Rome, Italy
Bibas, MD, Clinical Department, National Institute for Infectious
Diseases, “Lazzaro Spallanzani, IRCCS, via Portuense 292 – 00149 Rome,
Italy. Phone: +39 06 55170480, Fax. +39 06 55170477. E-mail: email@example.com
Published: December 29, 2009
Received: December 23, 2009
Accepted: December 27, 2009
Medit J Hemat Infect Dis 2009, 1(2): e2009032, DOI
This article is available from: http://www.mjhid.org/article/view/5272
This is an Open Access article
distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited
HIV-associated lymphoproliferative disorders
represent a heterogeneous group of diseases, arising in the presence of
HIV-associated immunodeficiency. The overall prevalence of
lymphoma is significantly higher compared to that of the general
it continues to be relevant even after the wide availability of highly
antiretroviral therapy (HAART) (1). Moreover, they still represent one
most frequent cause of death in HIV-infected patients. Epstein–Barr
(EBV), a γ-Herpesviruses,
is involved in human lymphomagenesis, particularly in HIV
patients. It has been largely implicated in the development of B-cell
lymphoproliferative disorders as Burkitt lymphoma (BL), Hodgkin disease
systemic non Hodgkin lymphoma (NHL), primary central nervous system
(PCNSL), nasopharyngeal carcinoma (NC). Virus-associated lymphomas are
of significant concern for the mortality of long-lived HIV
patients, and therefore, research of advanced strategies for
is an important field in cancer chemotherapy. Detailed understanding of
EBV lifecycle and related cancers at the
molecular level is required for novel strategies of molecular-targeted
chemotherapy The linkage of HIV-related lymphoma with EBV infection of
tumor clone has several pathogenetic, prognostic and possibly
implications which are reviewed herein.
of AIDS related lymphomas:
Categories of HIV-associated
Registry linkage studies in the pre-highly active
therapy (HAART) era found that the incidence of high grade B-cell
non-Hodgkin’s lymphoma (NHL) in HIV-infected individuals was 60-200
times higher than that in HIV-uninfected persons. The introduction of
HAART during the mid-1990s has been associated with a fall in incidence
of opportunistic infections and AIDS-associated malignancies, including
Within the French Hospital Database on HIV Infection (FHDH), the
incidence of systemic NHL has decreased between 1993 and 1994 and
between 1997 and 1998, from 8.6 per 1,000 to 4.3 per 1,000
person-years, respectively ; the incidence in the same cohort was
2.8 per 1,000 person-years in 2006. This is consistent with reports of
decreased incidence of HIV-related NHL in the post HAART era from the
U.K., Australia, California . Nevertheless, the incidence ratio of
NHL still remains relatively high in HIV-infected patients [5,6]. On
the contrary, the incidence of PCNSL has dramatically decreased since
the introduction of HAART . Concerning HD, the relative risk is
increased, ranging from five- to 25-fold compared to that of the
general population [7,8,9].
Approximately 1–6% of HIV infected patients develop lymphoma each year.
In 2006 the World Health Organization estimated 39.5 million people
were living with HIV and that during that year there were 4.3 million
new infections with 65% of these occurring in sub-Saharan Africa. Major
increases were also seen in Eastern Europe and Central Asia, where it
appears that infection rates have risen by more than 50% since 2004.
Many of those with retroviral infection will either have limited access
to HAART or will be unaware of their HIV status. Therefore the
incidence of HIV-associated lymphomas will most likely increase
globally in the years to come [10,11].
The WHO (12) classification of lymphoid neoplasms categorises (Table 1
- Those also occurring in immunocompetent patients, as
Burkitt and Burkitt –like lymphomas, Diffuse large B-cell lymphomas
Centroblasti and Immnunoblastic (including primary CNS Lymphoma),
Extranodal marginal zone lymphoma of Malt Type, Peripheral T-cell
lymphoma, Classical Hodgkin lymphoma (80% of all HIV lymphomas)
- Those occurring more specifically in HIV-positive patients
Effusion Lymphoma4 and Plasmablastic Lymphoma of oral cavity type and
other variants (3%)
- Those also occurring in patients with other forms of
as Polymorphic B-cell lymphoma (PTLD-like) (5% of all HIV
and pathogenesis of lymphomas in HIV-infected
HIV is a lentivirus of the
retrovirus family, and thus integrates into host chromosomal DNA using
intermediate. It has been generally believed that integration of HIV is
random process, and therefore this process is not in itself oncogenic .
Accordingly with this theory is the fact that Southern blot analysis of
lymphomas has failed to detect HIV sequences ,
with rare reports
of clonal integration restricted to T-cell neoplasms .
the neoplastic cells are not themselves infected with HIV in most
vitro evidence suggests that HIV does have transforming properties.
and Astrin showed that HIV infection of B-cell lines derived from
EBV-seropositive individuals led to B-cell immortalisation,
MYC, and activation of EBV . Certain HIV gene
particularly Tat, have been implicated as potentially oncogenic in
as transactivators of cellular genes, such as IL6 and IL10 .
protein can more directly interfere with cell cycle control by
the regulatory protein Rb2/p130 . This role of the
Tat protein has
been proposed as a significant factor in the pathogenesis of
Burkitt lymphoma .
contribution of HIV to lymphoma pathogenesis is believed to be through
mechanisms. The increased risk for lymphoma among HIV-infected
appears related to multiple factors, including duration and degree of
immunosuppression, induction of cytokines leading to B-cell
opportunistic infections with oncogenic herpesviruses such as EBV and
are commonly considered to be the result of diminished immune
against viruses and virus-infected tumor cells. The beneficial effects
on these tumors have therefore been interpreted as the result of
HIV suppression and immune reconstitution.
This is supported by
several findings. For example, EBV load is increased in patients before
development of B-cell lymphoma, whereas specific immune responses
virus are decreased [16,17,18]. The relative risk of
malignancies increases progressively as a function of the progressive
of CD4+ T-cell counts . Nevertheless, the relation between immune
deficiency and tumor development is not straightforward.
In fact, only certain types
of AIDS-associated tumors arise in immunodeficient patients. In
subtypes including Immunoblastic lymphomas and PCNSL, along with
lymphomas, typically develop in patients with very low CD4+ T-cell
the other hand, the incidence of other NHL subtypes such as
Diffuse Large-cell Lymphomas, along with classic Burkitt’s Lymphoma,
disease, cervical cancer and, most notably, Kaposi’s sarcoma, increases
patients who have significantly higher CD4+ T-cell numbers [9,20,21].
The overall risk of tumour
development is very high in HIV-infected individuals, but the relative
in tumor risk with stepwise decreases in CD4+ T-cell counts is only
It has been observed that the risk of tumor development increases
CD4+ T-cell counts decline below a certain threshold, nevertheless,
this threshold, cancer risk becomes less dependent on further CD4+
T-cell loss .
However, evidence indicates
that this hypothetical CD4+ T-cell count threshold can be very high in
individuals. In particular, in HIV-infected homosexual men, the
of Kaposi’s sarcoma increases by more than 1000-fold before a
T-cell decline . So, CD4+ T-cell loss and
deficiency cannot fully explain the increased incidence of certain
in HIV-infected individuals. Indeed, several recent studies show that
activation causes and precedes the development of immune deficiency in
infection [23,24,25]. Sustained and uncontrolled HIV
to continuous antigenic stimulation and to chronic T-cell activation
proliferation, which, in turn, generates a continuous drain of naive
T cells that become activated, proliferate, die by apoptosis or
pool of memory T cells. However, this exhausts the pool of naive T
impairing the capacity to mount antigen-specific immune responses [22-25].
Several other studies also
indicate that immune activation, rather than immune deficiency, is the
factor in the initiation of B-cell lymphomas. In particular,
B-cell lymphomas are described to be preceded by chronic antigen
B-cell stimulation leading to a persistent and generalized
lymphadenopathy that, in turn, promotes
the clonal expansion
of pre-neoplastic antigen-specific B-cell populations [26,27].
Furthermore, an increased
EBV load precedes the development of B-cell lymphoma ,
extracellular Tat increases B-cell proliferation and induces B-cell
in mice [26,27].
role of EBV:
EBV, the percentage of cases within each histotypes with EBV viral
variable, ranging from 60% to 100%. In contrast to other lymphomas, a
frequency of EBV association has been shown in HL (80%-100%) tissues
HIV-infected people and the EBV-transforming protein, EBV-encoded
membrane protein-1 (LMP-1), is expressed in virtually all HIV-HL cases [28,29].
On this basis, HL in HIV-infected persons appears to be an EBV-driven
The spectrum of lymphomas
occurring in HIV-infected patients includes pathologic subtypes
specific association with distinct viruses. BL and DLBCL-IB with
differentiation are often HIV associated and closely linked to EBV
The HIV-associated DLBCL-IB
is distinct from other large cell lymphomas occurring in both
and -seronegative patients because HIV-associated DLBCL-IB lymphomas
plasma cell–related phenotype.
lymphoproliferative disorders, including primary central nervous system
lymphoma, systemic DLBCL IB-plasmacytoid, PEL and its solid variant,
of the oral cavity type, display a phenotype related to plasma cells
linked to EBV infection.
EBV-positive high-grade B cell Lymphomas, Burkitt Lymphoma (BL)
particular position as being the tumor type in which EBV was
and Burkitt-like/atypical Burkitt lymphomas make up the largest
group of HIV-associated non-Hodgkin lymphomas, comprising up to 35–50%
neoplasms in some studies .
Classification of these lymphomas in the HIV
setting follows the same diagnostic criteria as are used in the general
population. That is, a diagnosis of Burkitt or Burkitt-like lymphoma
medium-sized CD10-positive B-cell population with a high proliferative
demonstration of a translocation involving the MYC gene .
Peripheral blood involvement is less common in HIV-infected patients
to HIV-negative patients with Burkitt lymphoma, although it can occur [12,31,32].
Burkitt lymphoma occurring in the HIV setting is characterised by
genetic lesions, with the relative significance of each in the
this lymphoma unknown. In addition to the translocation involving MYC,
mutations in regulatory regions associated with MYC and within the TP53
suppressor gene are common .
In the context of HIV infection, EBV-encoded
RNA (EBER) can be detected by in situ hybridisation in tumor cells in
of Burkitt lymphomas, 50–70% of Burkitt lymphomas with plasmacytoid
differentiation, and 30–50% of Burkitt-like lymphomas.
Similarly to sporadic or epidemic forms of
Burkitt lymphoma, in HIV-associated EBER-positive disease the viral
LMP-1 and EBNA-2 are not expressed (Table 2,
Although not essential in the pathogenesis of
BL, EBV supports tumor development. EBNA-1, a viral protein required
replication and maintenance of the latent viral episomal DNA, is found
in BL cells . The presence of latent EBV in BL
cells has been shown
to promote genetic instability , suggesting a
mechanism by which latent EBV
could contribute to genetic alterations required for the development of
This is in contrast to EBER-positive
immunoblastic DLBCL and PEL, which do show expression of these
viral oncogenes. Thus EBV may not play the same role in oncogenesis in
different types of lymphoma. It is interesting to note that although
lymphoma is common in HIV-infected patients, it is not associated with
forms of immunosuppression.
This may indicate that the oncogenic properties
of HIV itself play a greater role in pathogenesis in this highly
tumour compared with EBV or that there are other mechanisms.
cell cycle proteins has been implicated in the development of Burkitt
Inactivating mutations of the tumour suppressor gene RBL2 (Rb2/p130)
frequently found in endemic Burkitt lymphoma, and are also found in
By contrast, in HIV-associated cases,
abnormal overexpression of wild-type RBL2 is seen. This finding, in
with studies indicating that the function of Rb2/p130 in the control of
G0/G1 transition can be negated by physical interaction with the Tat
HIV-1, may suggest a direct role for HIV proteins acting
MYC activation in the pathogenesis of Burkitt lymphoma .
As in the HIV-negative
setting, the category of HIV associated DLBCL is a clinically and
pathologically heterogeneous group Lymphomas with a predominance of
centroblasts have been termed centroblastic DLBCL, whereas those with
than 90% immunoblasts/plasmablasts have been termed immunoblastic DLBCL.
These two general morphological subtypes show
correlation with certain clinical features and molecular profiles. The
occur with approximate equal frequency in HIVinfected patients, with
relative frequency of centroblastic DLBCL increasing and that of
DLBCL decreasing in recent years due to advances in HIV therapy.
DLBCL occurs in the setting of mild immunosuppression, has a low
EBV positivity (30–40%) without expression of LMP-1, shows a germinal
phenotype (expression of CD10 and BCL6, and lack of expression of CD138
MUM1), and frequently shows rearrangements of the BCL6 gene.
In contrast, immunoblastic DLBCL usually
occurs in the context of severe immunosuppression, has a high frequency
positivity (80–90%) with frequent expression of LMP-1 and EBNA-2, shows
non-germinal centre B-cell/activated B-cell phenotype (lack of
CD10 and BCL6, expression of CD138 and MUM1), and lacks rearrangements
of BCL6  (Table 2,
The transforming EBV protein LMP-1 is
frequently expressed [37,38]. LMP-1 plays a crucial
role in the
transformation of B-lymphocytes by EBV . Thus,
rodent fibroblasts  transgenic mice that express
LMP-1 in B cells
show increased development of B-cell lymphomas 
and LMP-1 deletion
mutants of EBV are compromised in their ability to immortalize human
cells . LMP-1 activates the NFkB as well as the
JNK and p38
pathways [39,40,41], by recruiting cellular TRAF 1-3
and TRADD molecules to 2
short sequence motifs, CTAR-1 and CTAR-2, respectively, in the
domain of the LMP-1 molecule [43,44,45].
In B cells, LMP-1 increases the expression of
the antiapoptotic proteins A20 and bcl-2, the adherence molecule
the cell-cycle regulator p27Kip,71 and many others .
In DLBCL, expression of LMP-1 correlates
inversely with the expression of BCL6, a marker for germinal center B
suggesting that, among DLBCLs, the impact of EBV LMP-1 is likely to be
strongest in tumors representing a post–germinal center plasmacytic
differentiation profile . In addition, knockdown
of LMP-1 in cell
lines derived from AIDS-DLBCL results in apoptosis, indicating that
oncoprotein plays a role in lymphoma pathogenesis .
EBV-associated DLBCLs have t been considered
as EBV-driven lymphoproliferations occurring in the context of a
T-cell immunity against EBV . However, unlike
lymphoproliferative disease in transplant recipients, which includes
oligoclonal, as well as polyclonal B-cell proliferations, DLBCL is
monoclonal. This suggests that, in addition to the effects contributed
LMP-1, additional factors such as genetic damage are likely to
the pathogenesis of AIDS-DLBCL.
Primary CNS Lymphoma:
Accounting for 15% of
HIV-associated lymphomas, PCNSL has a reported incidence of over 1000
greater than in the non-HIV population . This is
most likely a
reflection of the brain as a relatively immuno-privileged site. There has been a decline in its incidence
since HAART introduction , and it would confirm
association of this tumor with severe and prolonged immunosuppression. Clinical presentation results from
neurological deficits related to the site of the tumor, with mental
disturbance and seizures more common than in non-HIV PCNSL. Systemic B
are also common [52,53].
These tumors have a
tendency to occur late in the course of HIV infection and show EBV
virtually 100% of the cases . A few studies have
detection of EBV in the cerebrospinal fluid of HIV-positive patients
with a CNS
lesion infers a diagnosis of lymphoma [54,55,56].
These lymphomas have
been reported to express all EBV latent encoded proteins (latency III) ,
and there are observations consistent with their histogenetic
germinal center-related B cells . Nevertheless,
the exact role of EBV in
the pathogenesis of these disorders remains not completely defined (Table 2,
Most patients have CD4 counts <50/uL and
have multifocal lesions at time of diagnosis. Ocular involvement occurs
to 20% of cases . Full staging at time of
diagnosis is essential to
exclude system NHL involving the brain. MRI brain scan has a higher
yield than CT and is recommended for suspected intracranial masses .
Up to 30% of CNS lesions in HIV patients are found to be PCNSL with
toxoplasmosis and progressive multifocal leukoencephalopathy making up
remaining cases . The most common histology is
Differentiation between PCNSL and
toxoplasmosis can be difficult, as both cause ring enhancing lesions
effect and oedema (although PCNSL lesions are more likely to be
periventricular) and up to 15% false negative rates for toxoplasmosis
Radionuclide scanning has also been
investigated. PCNSL lesions are avid by 201Thallium single
emission CT and  fluorodeoxyglucose-positron
(FDG-PET), however improve specificity should be combined with PCR and
emerging as an alternative to brain biopsy [63,64].
This needs to be
further validated and brain biopsy is still the definitive diagnostic
procedure, but must be weighed against a mortality rate of 2–3% ,
particularly in the post-HAART era during which it seems that EBV-DNA
shows a reduced negative predictive value compared to that of the
In the new trials the use of EBV-DNA
measurement is used as a surrogate to brain biopsy. Response to therapy
also be monitored with EBV-DNA. There is
no standard therapy for PCNSL. Whole-brain radiation (WBRT) achieves CR
to 50% but this is not translated to increased survival, with median
no more than 3 months. Deaths are generally related to opportunistic
due to overwhelming immunosuppression at time of diagnosis. Even though
patients are unable to tolerate the full dose of radiation, the
predictors of outcome are performance status and the ability to deliver
A promising alternative to WBRT was studied
in 15 patients using single-agent MTX intravenously at 3g/m2. The mean
count in these patients was 30/uL. Almost 50% had achieved CR with a
survival of 19 months and a relapse rate of only 14% .
There is a
survival benefit associated with the use of cART after diagnosis ,
and there is evidence that cART may increase the radio-sensitivity of B
within the lymphoma [67,68]. Given the very limited
benefit of current
modalities, patients should be referred to clinical trials.
Since there is universal association of EBV
in HIV-associated PCNSL, therapeutic options which target the virus
explored. In this regard it should be noted that EBV-specific
have been shown to cross the blood brain barrier and induce tumour
the absence of an available study, either first-line WBRT or
high-dose MTX with the option of WBRT consolidation should be
Concomitant HAART therapy to enhance the immune system is critical to
is the most common type of non-AIDS defining tumor. The risk of
in HIV patients is up to 11-18 times above the general population .
It is associated with advanced disease and is more common in the
drug group than in homosexual men. Its hallmark includes aggressive
presentation with systemic B symptoms, widespread non-contiguous
lesions and frequent bone marrow involvement (in up to 50% of cases).
morphological patterns are similar to those seen in patients without
infection, although with a greater proportion of the subtypes (mixed
cellularity, lymphocyte depleted) with less favourable prognosis
the general population . As noted above, the greater proportion of
mixed cellularity and lymphocyte depleted subtypes appears specifically
to severe immunocompromise in HIV, while HIV-infected patients with
immunocompromise are more at risk for the development of the nodular
The composition of the
reactive inflammatory infiltrate in HIV-associated HL is often
a predominance of CD8-positive T lymphocytes over CD4-positive
contrast with the background in HL without HIV infection .
finding may simply reflect the depleted peripheral CD4 counts in this
population. The cytological and phenotypic features of the Hodgkin
Reed–Sternberg (HRS) cells in HIV-associated HL are similar to those in
associated HL. It has been determined that RS cells of all histologic
categories of HIV-HD consistently display the BCL-6(-)/syn-1(+)
thus reflect post-GC B cells .
The HRS cells typically
express CD15 and CD30, express CD20 in a minor subset, and lack
CD45  In the vast majority of HIV associated HL
there is coincident
EBV infection. The latent EBV proteins EBNA-1, LMP-1, and LMP2A are
in the RS cells, the malignant cell population of this tumor . RS
cells are derived from B cells that have passed through the germinal
shown by the presence of somatic mutations in the rearranged Ig
of their immunoglobulin genes  LMP2A interferes
with normal B-cell
development, allows BCR-negative B cells to leave the bone
peripheral lymphoid organs , and induces a
transcriptome pattern in
B cells, which resembles that of HL RS cells .
infection, LMP2A is essential for the survival and continued
germinal center B cells lacking a functional B-cell receptor [76,77].
LMP2A may therefore promote the survival of “crippled” germinal center
and could thus aid their development into RS cells (Table 2,
LMP-1 may also induce an
“HL-like” transcriptional program in germinal center B cells  Among
the cellular genes up-regulated by LMP-1 in HL cells is bmi-1, a
family member known to cause lymphoma in transgenic mice and to
the ATM tumor suppressor . EBNA-1 was shown to
secretion in RS cell lines and to thereby promote the migration of
cells, which could be envisaged to downmodulate EBV-specific T-cell
This association with EBV
is considerably stronger than that seen in HL in the non-HIV infected
population. HIV-associated HL most often presents at an advanced
stage, with B symptoms, frequent extranodal disease, as bone marrow
and an aggressive course . Unusual extranodal
sites, such as the
skin, lung and gastrointestinal tract may be involved .
are essentially never involved by HL that is not associated with HIV.
HIV-HL patients have
reduced CR rates and survival compared with the HIV negative
population. In the
early years post-HAART therapy the incidence of HIV-HL appeared to be
decline however two studies showed that the incidence may actually have
The post-HAART era was also
associated with an improvement in survival which was attributed to
response to antiretroviral therapy and a reduction in HIV-associated
In another study of 47 patients in the post-HAART era, the median
not reached compared with 19 months in the pre-HAART era [86,87].
Optimal therapy for HIV-HL
has not been defined. Treatment regimes used are similar to those used
in HL in
the seronegative population [88,89].
is a distinct clinicopathological entity occurring almost
in HIV-infected patients. This lymphoma subtype comprises less than 5%
HIV-associated NHL. Cases of this type were first described by Knowles
et al in
1989, but its distinctive features were not fully recognised until
after the identification of the Kaposi sarcoma-associated
8 (KSHV/HHV8) in 1994 [91,92], PEL is a distinct
type of B-cell
non-Hodgkin lymphoma (NHL) that presents most frequently in body
lymphomatous effusions without an associated tumor mass.
The tumor cells have large
round to irregular nuclei with prominent nucleoli, and abundant deeply
basophilic and occasionally vacuolated cytoplasm. These are described
immunoblastic/plasmablastic or anaplastic morphological features.
studies have broadened the scope of PEL to include those presenting as
tumour mass with or without an associated effusion [93,94,95].
so-called ‘‘extracavitary’’ or ‘‘solid variant’’ of PEL most commonly
the gastrointestinal tract or soft tissue, but can also involve lymph
Some studies have suggested that the extracavitary variant of PEL has a
slightly better prognosis when compared with cases presenting with
A defining property of PEL
is its consistent association with KSHV infection. Most cases are also
co-infected by EBV. It is believed that KSHV, rather than EBV, is a
force in these tumors, as in PEL, at least 5 KSHV viral genes are
which provide proliferative and antiapoptotic signals. In contrast, EBV
restricted latency pattern of gene expression in PEL, where only EBNA1
EBERs are expressed . However, the viral
oncoprotein LMP-1 is
generally not expressed [94-97] (Table 2,
features of PEL often make it difficult to confirm B-cell lineage, as
neoplasm usually lacks expression of most B-cell associated antigens
CD19, CD20, CD79a and immunoglobulins. The most frequently expressed
include those associated with activation or plasmacytic
as CD30, CD45, EMA, CD71, MUM1, and CD138. Aberrant expression of Tcell
associated antigens CD3 and CD7 has been reported [98-102].
B-cell origin of PELs, can
be demonstrated by the presence of clonal immunoglobulin gene
Evidence points toward a post–germinal center B-cell derivation, as
contain somatic hypermutation of Ig genes as well as frequent somatic
hypermutation of the noncoding region of the BCL6 gene [103,104].
Consistent with this notion is the expression of plasma cell markers
CD138/Syndecan-1. Recently, gene expression analysis of PEL showed
most similar to AIDS immunoblastic lymphoma and multiple myeloma, again
indicating a pre–plasma cell or “plasmablastic” profile .
Again, the exact role of
EBV has been debated; but the fact that both viruses are detected
most of the cases suggests that EBV may act as a cofactor in the
events (because it can immortalize and transform B cells in vitro and
cannot), whereas HHV-8 may be the driving force for the tumor .
With or without therapy, PEL is invariably associated with an adverse
prognosis. There is limited data on the treatment of PEL. The
local tissue despite aggressive therapy leads to shortened survival .
radiotherapy may result in responses but these are seldom durable and
is generally less than 12 months although a small series suggests the
of high-dose MTX may improve outcome  .
Interestingly, a patient
treated with a combination of zidovudine and a-interferon
entered into durable remission after only 5 days .
Study of the primary tumour cells derived from this patient
azidothymidine (AZT) blocked nuclear translocation of NFkB and
pro-apoptotic effect of a-IFN (which induces another death receptor
TRAIL). Further clinical studies of this combinationare under way. In a
system sirolimus showed promising activity which was in part mediated
inhibition of IL-10 signaling . Given the
relative rarity of this
lymphoma, patients should be enrolled in clinical trials where
Concomitant administration of HAART is advised and there are several
remission of PEL with use of HAART alone.
of the oral cavity type:
lymphoma is a distinct type of diffuse large B-cell lymphoma that
often in the oral cavity or jaw of HIV-infected individuals . This
rare lymphoma subtype accounts for 2.6% of HIV-related NHL  The
first description designated this tumour as a lymphoma of the oral
however, subsequent reports have described less frequent involvement of
extraoral sites such as the anal cavity, gastrointestinal tract, lung,
paranasal sinus, skin, spermatic cord, testicle, bone and lymph nodes [112-118].
Regardless of the site of occurrence,
plasmablastic lymphoma shows similar morphological and phenotypic
neoplastic cells are intermediate to large in size, with round nuclear
and occasional multinucleation . Plasmacytic differentiation is usually
apparent, with a cytological spectrum including a minor population of
plasmacytoid cells with condensed chromatin ranging to large cells with
dispersed chromatin, prominent central nucleoli and abundant basophilic
with a paranuclear hof [112,113,114]. The
generally expresses CD45 and plasmacytic markers such as CD138, EMA and
and usually lacks expression of pan-B-cell antigens such as CD20 and
In early reports, slightly more than 50% of cases were EBER positive as
by in situ hybridisation studies  in more
recent series all cases
of plasmablastic lymphoma have been shown to be EBER positive , 73
EBER-positive cases generally lack expression of EBNA2 and LMP-1 [115,116] (Table 2,
Table 3). HHV8
infection is not
implicated in the pathogenesis of plasmablastic lymphoma, with all
negative for LNA1 when tested by immunohistochemistry. While there is
morphological and phenotypic overlap with anaplastic myeloma,
presentation and frequent EBV infection are distinctive features. A potential role for EBV
in the pathogenesis of the disease remains unknown, especially with the
restricted latency expression pattern.
Despite the use of aggressive chemoteraphy and HAART the prognosis
remains poor .
results in a reduction of T-cell immunity similar to that
iatrogenically induced in transplant patients. Is not surprising that
polymorphic lymphoid proliferations resembling post-transplant
lymphoproliferative disorders (PTLD) have been reported in HIV-infected
and children. According to the WHO
classification, they are divided into early lesions (reactive
and mononucleosis-like syndrome), polymorphic lesions, monomorphic
Hodgkin-like lesions . Similarly to PTLD,
these infiltrates are
often associated with EBV infection. By contrast with HIV-associated
these polymorphic infiltrates often show more limited disease
lack oncogene and tumour suppressor gene alterations, and may be
show a minor B-cell clone in a polyclonal background. Regression of
B-cell lymphoma in an HIV-infected patient after anti-retroviral
been reported .
EBV has been linked to most
PTLDs, with a near 100% association in the early-occurring cases
year) and in PTLD-associated Hodgkin lymphoma .
PTLDs constitute approximately 20% of all cases, have a tendency to
occurrence and have an unknown etiology. Type III latency is exhibited
EBV-positive B cells in PTLD, although some studies have reported a
restricted latency pattern . The wide
expression of the latent
EBV-encoded proteins strongly suggests an important role that EBV may
the oncogenic process (Table 2,
The mechanism by which EBV
is thought to contribute to the pathogenesis of PTLD is similar to its
role in Hodgkin lymphoma. Because approximately 50% of PTLD cases are
from GC B cells lacking a functional BCR because of certain crippling
mutations, and because these cells manage to escape apoptosis despite
antigen affinity, it is believed that EBV aids in rescuing these cells
from an imminent
programmed cell death [124,125]. As in Hodgkin
cases, LMP1 and LMP2A
may replace survival signals induced by activated BCR and CD40
also activate the NF-κB signaling pathway, inducing
proliferation of neoplastic cells. The
decreased cytotoxic T-cell surveillance because of immunosuppression in
patients is also believed to greatly facilitate the actions of EBV. The
role that EBV is thought to play in inducing the survival and
transformation of infected GC cells in both PTLD and Hodgkin lymphoma,
addition to the near 100% EBV positivity in PTLD-associated Hodgkin
has led some investigators to speculate a connection between the 2
the possibility that EBV infection and its GC effects may be the
role in the pathogenesis of both entities .
HIV-associated lymphomas represent a
particular setting characterizing specific pathogenetic models
driven by EBV and by immunodeficiency. The impact of combined
therapy has substantially changed the risk and prognosis of lymphoma in
HIV-infected population, as well as the relationship with the natural
of HIV disease. As a consequence of cART, many authors now strongly
that patients with lymphoma and HIV infection should be treated as
with lymphoma of the general population.
In fact, due to the
improvement of morbidity and mortality related with cart exposure, more
aggressive treatment protocols can be taken into consideration, on the
the results in terms of efficacy and tolerability reported in the
population, such as the use of high-dose chemotherapy in combination
transplantation in HIV-NHL which showed response rates similar to those
obtained in HIV- negative patients.
The concurrent use of
antiblastic chemotherapy and cART should be considered a potential
for tumor prognosis and for reducing risk of toxicities associated to
antineoplastic drugs, even though concerns due to drug-drug
be suggested. In perspectives, the molecular and epidemiological
between AIDS-related malignancies and EBV-infection suggests that viral
products would be potential targets for molecular-targeted
understanding of the EBV lifecycle and
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