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![1245
C H A P T E R 82
VIRUS-ASSOCIATED LYMPHOMA
Jennifer A. Kanakry and Richard F. Ambinder
There are five well-characterized human viruses that are generally
accepted as important in lymphomagenesis (Table 82-1). These
viruses may infect tumor cells (or their progenitors) or may act at a
distance. The genomes of Epstein-Barr virus (EBV), Kaposi sarcoma–
associated herpesvirus (KSHV, also known as human herpesvirus 8
[HHV-8]), and human T-lymphotropic virus-1 (HTLV-1) are present
in tumor cells. The viral genes expressed in tumor cells modulate
cellular metabolism, proliferation, and cell death. In contrast, the
human immunodeficiency virus (HIV) genome is generally not
detected in tumor cells. Whether hepatitis C virus (HCV) genomes
are present in lymphoma cells remains a subject of controversy.
Although viral infection plays a role in the pathogenesis of some
lymphomas, lymphomagenesis is unusual. Only a small subset of
infected people develops lymphoma. Furthermore, although primary
viral infection may be followed by lymphomagenesis within days or
weeks in exceptional circumstances, most lymphomas arise years or
decades after primary infection. Indeed the term adult in adult T-cell
leukemia/lymphoma (ATL) reflects the time lag between HTLV-1
infection in infancy and the evolution to malignancy. Geography and
associated environmental exposures, host genetic factors, and immune
status all modify risk.
Aspects of the biology and epidemiology of each of these viruses
and their relationship with lymphomagenesis are reviewed. In addi-
tion, clinically important and distinctive features of diagnosis and
treatment of the associated lymphomas are presented.
EPSTEIN-BARR VIRUS
Viral Biology
EBV is a gammaherpesvirus transmitted mainly through saliva.1,2
After primary infection, some of the infected cells are driven to pro-
liferate and thereby spread infection throughout the B-cell compart-
ment. Ultimately, in the normal host, there is an immune response
that controls infection and eradicates virus-infected proliferating
cells. Thereafter the viral genome is harbored mainly in resting
memory B lymphocytes that persist for life. These B cells that harbor
virus elude immune surveillance in part because of their very restricted
viral gene expression such that few viral antigens are presented. Occa-
sionally there is activation of viral lytic gene expression (at least in
some instances this occurs in concert with plasma cell differentiation)
leading to production of infectious virions that may infect other B
cells. T cell–mediated immune function keeps such proliferation in
check.3
In vitro EBV immortalizes B cells such that they grow indefinitely
as lymphoblastoid cell lines (LCLs) (Fig. 82-1). LCLs are tumorigenic
in immunodeficient mice. In LCL, viral genomes are present as cir-
cular double-stranded deoxyribonucleic acid (DNA) episomes within
the nucleus. The viral proteins required for immortalization include
Epstein-Barr virus nuclear antigen-1 (EBNA1), a sequence-specific
DNA-binding protein important in the maintenance of the viral
episome; EBNA2, a transcription factor that has many effects similar
to those of activated Notch receptors; and latent membrane protein-1
(LMP1), a constitutively activated member of the tumor necrosis
factor (TNF) receptor superfamily, which most closely resembles
CD40.4
LMP1 activates the nuclear factor kappa-B (NFκB) pathway,
which modulates cell proliferation and apoptosis.5
Several other EBV
proteins are also required for immortalization. Although EBV immor-
talization of B cells in vitro may offer some insights into tumorigen-
esis, some caution is required in using LCL as a tumor model. Most
EBV tumors, including tumors of B-lineage cells, do not express
many of the viral genes required for lymphocyte immortalization.
The only tumors that express the full complement of viral proteins
required for immortalization are those that arise in the most pro-
foundly immunocompromised patients (organ or hematopoietic
transplant recipients, patients with congenital immunodeficiency, or
patients with far advanced acquired immunodeficiency syndrome
[AIDS]). Thus in posttransplantation lymphoproliferative disorder
(PTLD), tumor cells may resemble LCL in expressing many viral
latency genes in association with normal karyotype (and few muta-
tions of the cellular genome). It has been suggested that there is an
inverse relationship between cellular mutations and viral gene expres-
sion in tumors.6
EBV gene expression may directly drive proliferation or inhibit
apoptotic pathways as illustrated by lymphocyte immortalization.
However, viral gene expression may also perturb normal lymphocyte
biology. Thus LMP1 expression upregulates activation induced (cyti-
dine) deaminase expression, which facilitates somatic hypermutation
and immunoglobulin class switching.7
LMP1 expression may also be
important in the conversion of naive B-cells to post-germinal center
memory B-cells. LMP2A allows B-cells that lack normal immuno-
globulin expression to escape regulatory checkpoints and survive.8
Epidemiology of Viral Infection
EBV infection is ubiquitous. The vast majority of adults are infected
worldwide. Primary infection is most often asymptomatic, especially
when it occurs in childhood.9
Primary infection may be associated
with the syndrome of infectious mononucleosis. Symptomatic
primary infection occurs more frequently in older children and in
adults than in younger children. Other possible determinants of
symptomatic primary infection include genetic factors and possibly
the size of the viral inoculum.
Strain differences in EBV are well recognized.10
However, the
importance of these strain differences with regard to lymphomagen-
esis remains poorly understood. There is general agreement that the
Type 1 strain EBV is most common worldwide and in tumors. The
Type 2 strain virus has been identified in some African Burkitt lym-
phoma (BL) and in some AIDS-associated lymphoma. A-strain virus
is more efficient at lymphocyte immortalization in vitro and lym-
phomagenesis in mouse models. The two strains of virus differ mainly
in the EBNA2 gene, but differences are recognized in some other
viral proteins as well.11
Variations in the regulatory regions or coding
regions of a variety of other genes including EBNA1, LMP1, and
ZTA have been recognized and suggested to play a role in
lymphomagenesis.
A simple classification of latent viral gene expression recognizes
three patterns as shown in the Table 82-2.](https://image.slidesharecdn.com/l3-140613130911-phpapp01/85/Linfomas-y-VIH-III-1-320.jpg)
![1245
C H A P T E R 82
VIRUS-ASSOCIATED LYMPHOMA
Jennifer A. Kanakry and Richard F. Ambinder
There are five well-characterized human viruses that are generally
accepted as important in lymphomagenesis (Table 82-1). These
viruses may infect tumor cells (or their progenitors) or may act at a
distance. The genomes of Epstein-Barr virus (EBV), Kaposi sarcoma–
associated herpesvirus (KSHV, also known as human herpesvirus 8
[HHV-8]), and human T-lymphotropic virus-1 (HTLV-1) are present
in tumor cells. The viral genes expressed in tumor cells modulate
cellular metabolism, proliferation, and cell death. In contrast, the
human immunodeficiency virus (HIV) genome is generally not
detected in tumor cells. Whether hepatitis C virus (HCV) genomes
are present in lymphoma cells remains a subject of controversy.
Although viral infection plays a role in the pathogenesis of some
lymphomas, lymphomagenesis is unusual. Only a small subset of
infected people develops lymphoma. Furthermore, although primary
viral infection may be followed by lymphomagenesis within days or
weeks in exceptional circumstances, most lymphomas arise years or
decades after primary infection. Indeed the term adult in adult T-cell
leukemia/lymphoma (ATL) reflects the time lag between HTLV-1
infection in infancy and the evolution to malignancy. Geography and
associated environmental exposures, host genetic factors, and immune
status all modify risk.
Aspects of the biology and epidemiology of each of these viruses
and their relationship with lymphomagenesis are reviewed. In addi-
tion, clinically important and distinctive features of diagnosis and
treatment of the associated lymphomas are presented.
EPSTEIN-BARR VIRUS
Viral Biology
EBV is a gammaherpesvirus transmitted mainly through saliva.1,2
After primary infection, some of the infected cells are driven to pro-
liferate and thereby spread infection throughout the B-cell compart-
ment. Ultimately, in the normal host, there is an immune response
that controls infection and eradicates virus-infected proliferating
cells. Thereafter the viral genome is harbored mainly in resting
memory B lymphocytes that persist for life. These B cells that harbor
virus elude immune surveillance in part because of their very restricted
viral gene expression such that few viral antigens are presented. Occa-
sionally there is activation of viral lytic gene expression (at least in
some instances this occurs in concert with plasma cell differentiation)
leading to production of infectious virions that may infect other B
cells. T cell–mediated immune function keeps such proliferation in
check.3
In vitro EBV immortalizes B cells such that they grow indefinitely
as lymphoblastoid cell lines (LCLs) (Fig. 82-1). LCLs are tumorigenic
in immunodeficient mice. In LCL, viral genomes are present as cir-
cular double-stranded deoxyribonucleic acid (DNA) episomes within
the nucleus. The viral proteins required for immortalization include
Epstein-Barr virus nuclear antigen-1 (EBNA1), a sequence-specific
DNA-binding protein important in the maintenance of the viral
episome; EBNA2, a transcription factor that has many effects similar
to those of activated Notch receptors; and latent membrane protein-1
(LMP1), a constitutively activated member of the tumor necrosis
factor (TNF) receptor superfamily, which most closely resembles
CD40.4
LMP1 activates the nuclear factor kappa-B (NFκB) pathway,
which modulates cell proliferation and apoptosis.5
Several other EBV
proteins are also required for immortalization. Although EBV immor-
talization of B cells in vitro may offer some insights into tumorigen-
esis, some caution is required in using LCL as a tumor model. Most
EBV tumors, including tumors of B-lineage cells, do not express
many of the viral genes required for lymphocyte immortalization.
The only tumors that express the full complement of viral proteins
required for immortalization are those that arise in the most pro-
foundly immunocompromised patients (organ or hematopoietic
transplant recipients, patients with congenital immunodeficiency, or
patients with far advanced acquired immunodeficiency syndrome
[AIDS]). Thus in posttransplantation lymphoproliferative disorder
(PTLD), tumor cells may resemble LCL in expressing many viral
latency genes in association with normal karyotype (and few muta-
tions of the cellular genome). It has been suggested that there is an
inverse relationship between cellular mutations and viral gene expres-
sion in tumors.6
EBV gene expression may directly drive proliferation or inhibit
apoptotic pathways as illustrated by lymphocyte immortalization.
However, viral gene expression may also perturb normal lymphocyte
biology. Thus LMP1 expression upregulates activation induced (cyti-
dine) deaminase expression, which facilitates somatic hypermutation
and immunoglobulin class switching.7
LMP1 expression may also be
important in the conversion of naive B-cells to post-germinal center
memory B-cells. LMP2A allows B-cells that lack normal immuno-
globulin expression to escape regulatory checkpoints and survive.8
Epidemiology of Viral Infection
EBV infection is ubiquitous. The vast majority of adults are infected
worldwide. Primary infection is most often asymptomatic, especially
when it occurs in childhood.9
Primary infection may be associated
with the syndrome of infectious mononucleosis. Symptomatic
primary infection occurs more frequently in older children and in
adults than in younger children. Other possible determinants of
symptomatic primary infection include genetic factors and possibly
the size of the viral inoculum.
Strain differences in EBV are well recognized.10
However, the
importance of these strain differences with regard to lymphomagen-
esis remains poorly understood. There is general agreement that the
Type 1 strain EBV is most common worldwide and in tumors. The
Type 2 strain virus has been identified in some African Burkitt lym-
phoma (BL) and in some AIDS-associated lymphoma. A-strain virus
is more efficient at lymphocyte immortalization in vitro and lym-
phomagenesis in mouse models. The two strains of virus differ mainly
in the EBNA2 gene, but differences are recognized in some other
viral proteins as well.11
Variations in the regulatory regions or coding
regions of a variety of other genes including EBNA1, LMP1, and
ZTA have been recognized and suggested to play a role in
lymphomagenesis.
A simple classification of latent viral gene expression recognizes
three patterns as shown in the Table 82-2.](https://image.slidesharecdn.com/l3-140613130911-phpapp01/75/Linfomas-y-VIH-III-1-2048.jpg)
![Chapter 82 Virus-Associated Lymphoma 1253
whether infection of B cells plays any role in this process. A lym-
phoma cell line that produces infectious HCV has been reported.
Even in the absence of infection of B cells, interaction of the HCV
E2 protein with CD81 on B cells may drive B-cell proliferation or
lower the threshold for other B-cell stimuli to drive proliferation. Ig
signaling may be activated by Ig-virus complexes, and Toll-like recep-
tor 7 signaling may be activated by viral RNA. Finally, it is noted
that E2 binding triggers expression of activation-induced deaminase,
an enzyme that is important in generating somatic hypermutation
and that has also been implicated in mediating mutations thought to
play a role in DLBCL lymphomagenesis.77
Epidemiology of Viral Infection
and Associated Lymphoma
The association between HCV and lymphoma was first recognized
in patients with HCV-associated type II mixed cryoglobulinemia, an
autoimmune extrahepatic manifestation of HCV infection.79
There
followed demonstration of an increased risk for certain subtypes of
B-cell lymphoma (marginal zone lymphoma [MZL], lymphoplasma-
cytic lymphoma and to a lesser extent DLBCL in HCV-infected
patients).80-83
For example, in Taiwan the rate of chronic HCV infec-
tion in patients with NHL was 11%, 10-fold higher than in the
general Taiwanese population.84
Among HCV-infected patients with
lymphoma, nodal and splenic MZL, but not mucosa-associated lym-
phoid tissue (MALT) lymphomas, were increased. The HCV-
lymphoma association is more apparent in some countries than
others, with the association being established most clearly in Italy and
Japan. A multitude of studies in regions or countries where HCV
infection is less prevalent have failed to identify any association with
lymphoma.85-87
Further evidence in support of an etiologic relationship comes
from studies in which successful treatment of HCV was followed by
lymphoma regression.88
The most dramatic illustration comes from
patients with splenic lymphoma with villous lymphocytes treated
with ribavirin and interferon.
Certain HCV genotypes may confer increased risk for NHL, with
genotypes 2a/III and 2b/IV seen more frequently in the HCV-
seropositive patients that develop NHL.
Diagnostic Considerations
In contrast to EBV-, KSHV-, or HTLV-1–associated tumors, there is
no established role for studies demonstrating HCV nucleic acid or
protein in tumor cells. Thus serologic study and measurement of
HCV copy number are the only tools available for inferring an asso-
ciation. We recommend checking HCV serologic characteristics in
all patients with B-cell lymphomas most commonly associated with
chronic HCV infection.89
In addition, screening patients with chronic
HCV for a monoclonal gammopathy and cryoglobulinemia may be
of benefit to identify patients at highest risk for malignant transfor-
mation. Elevated serum γ-globulin levels have been found to be a
predictor of NHL among patients with type II mixed cryoglobuline-
mia.90
In patients who are HCV seropositive, we evaluate HCV RNA
in plasma.
Therapy
In patients with indolent lymphomas and untreated HCV infection,
antiviral treatment may obviate the need for cytotoxic chemotherapy
and should be considered as an initial therapeutic strategy. The
studies showing that antiviral therapy may lead to regression of HCV-
associated lymphomas involved treatment with ribavirin and inter-
feron. In the last year new antiviral agents have become available,
notably protease inhibitors specific for the HCV protease. Likelihood
of response to older therapy is a function of viral genotype, host
genetics (IL28R polymorphisms play a critical role in response to
chemotherapy dose adjustments. Ritonavir inhibits the clearance of
midazolam, phenytoin, and voriconazole and other agents metabo-
lized by the cytochrome P-450 CYP3A4 pathway.
Supportive Care
Although PJP prophylaxis is recommended only when the CD4+
count is less than 200 cells/mm3
for HIV patients not receiving
cytotoxic chemotherapy, prophylaxis is universally recommended for
HIV patients receiving cytotoxic chemotherapy. The following are
also commonly used: fungal prophylaxis with fluconazole; herpes
simplex and varicella prophylaxis with acyclovir, valacyclovir, or fam-
ciclovir; quinolone prophylaxis when neutrophil counts fall below
1000 cells/mm3
; and granulocyte growth factors.
Bone Marrow Transplantation in HIV Patients
Autologous bone marrow transplant has been successful in HIV-
seropositive NHL patients, with these patients having adequate stem
cell mobilization, nonrelapse mortality rates comparable to those for
HIV-negative patients, count recovery within 2 weeks of stem cell
rescue, and maintained control of HIV viral loads and CD4+
counts
after high-dose chemotherapy.73,74
There have also been successful
reduced-intensity allogeneic bone marrow transplants in HIV-
seropositive patients, making the possibilities for treating HIV
patients with NHL even more vast, even in those patients with
chemotherapy-resistant disease (see box on Autologous Bone Marrow
Transplant in an HIV-Seropositive Hodgkin Lymphoma Patient).75
HEPATITIS C VIRUS
Viral Biology and B-Lymphocyte Proliferation
HCV is an enveloped positive-strand RNA virus.76,77
Infection
involves interactions between E2, a viral structural protein with two
hypervariable regions, and a cellular protein CD81 present on hepa-
tocytes and B lymphocytes. A polyprotein is translated from viral
RNA and is cleaved by cellular and viral proteases, including NS3,
to yield proteins required for viral replication. The RNA-dependent
RNA polymerase that replicates the viral genome lacks proofreading
capacity, thus generating genetic heterogeneity among viral progeny.
Viral replication occurs predominantly in the liver, but some evidence
suggests that B cells may also be infected.
Chronic infection can be associated with mixed cryoglobulinemia,
a systemic vasculitis that results from clonal expansion of B cells
producing an IgM autoantibody against IgG, leading to deposition
of immune complexes on endothelial surfaces, resulting in inflamma-
tion.78
Several hypotheses have been advanced with regard to how
HCV might drive B-cell proliferation. There is controversy as to
Autologous Bone Marrow Transplant in an HIV-Seropositive Hodgkin
Lymphoma Patient
A 38-year-old human immunodeficiency virus (HIV)–positive
patient with CD4+
count of 485 cells/mm3
is diagnosed with
classic Hodgkin lymphoma (HL) and treated with doxorubicin
(Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD),
achieving a complete remission. Two years later he presents with
retroperitoneal lymphadenopathy and is found on biopsy to have
relapsed HL. He is treated with salvage chemotherapy with com-
plete response, as well as good performance status and no active
infections. His HIV remains well controlled on antiretroviral
therapy. He is deemed an excellent candidate for high-dose
therapy and undergoes consolidation with autologous bone
marrow transplant.](https://image.slidesharecdn.com/l3-140613130911-phpapp01/85/Linfomas-y-VIH-III-9-320.jpg)
![Part VII Hematologic Malignancies1254
Choi I, Tanosaki R, Uike N, et al: Long-term outcomes after hematopoietic
SCT for adult T-cell leukemia/lymphoma: Results of prospective trials.
Bone Marrow Transplant 46:116, 2011.
Chuang SS, Liao YL, Chang ST, et al: Hepatitis C virus infection is signifi-
cantly associated with malignant lymphoma in Taiwan, particularly with
nodal and splenic marginal zone lymphomas. J Clin Pathol 63:595, 2010.
Engels EA, Pfeiffer RM, Landgren O, et al: Immunologic and virologic
predictors of AIDS-related non-Hodgkin lymphoma in the highly active
antiretroviral therapy era. J Acquir Immune Defic Syndr 54:78, 2010.
Epeldegui M, Hung YP, McQuay A, et al: Infection of human B cells with
Epstein-Barr virus results in the expression of somatic hypermutation-
inducing molecules and in the accrual of oncogene mutations. Mol
Immunol 44:934, 2007.
Evens AM, Roy R, Sterrenberg D, et al: Post-transplantation lymphoprolifera-
tive disorders: Diagnosis, prognosis, and current approaches to therapy.
Curr Oncol Rep 12:383, 2010.
Giordano TP, Henderson L, Landgren O, et al: Risk of non-Hodgkin lym-
phoma and lymphoproliferative precursor diseases in US veterans with
hepatitis C virus. JAMA 297:2010, 2007.
Guech-Ongey M, Simard EP, Anderson WF, et al: AIDS-related Burkitt
lymphoma in the United States: What do age and CD4 lymphocyte pat-
terns tell us about etiology and/or biology? Blood 116:5600, 2010.
Heslop HE, Slobod KS, Pule MA, et al: Long-term outcome of EBV-specific
T-cell infusions to prevent or treat EBV-related lymphoproliferative disease
in transplant recipients. Blood 115:925, 2010.
Hishizawa M, Kanda J, Utsunomiya A, et al: Transplantation of allogeneic
hematopoietic stem cells for adult T-cell leukemia: A nationwide retrospec-
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tions. Blood 117:5019, 2011.
Keegan TH, Glaser SL, Clarke CA, et al: Epstein-Barr virus as a marker of
survival after Hodgkin’s lymphoma: A population-based study. J Clin Oncol
23:7604, 2005.
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a virus-associated malignancy. Hematology Am Soc Hematol Educ Program
2007:277, 2007.
Kitahata MM, Achenbach CJ, Saag MS: Age at cancer diagnosis
among persons with AIDS. Ann Int Med 154:642; author reply 643,
2011.
Levine AM: HIV-associated lymphoma. Blood 115:2986, 2010.
Libra M, Polesel J, Russo AE, et al: Extrahepatic disorders of HCV infection:
A distinct entity of B-cell neoplasia? Int J Oncol 36:1331, 2010.
Matsuoka M, Jeang KT: Human T-cell leukaemia virus type 1 (HTLV-1)
infectivity and cellular transformation. Nat Rev Cancer 7:270, 2007.
Matsuoka M, Jeang KT: Human T-cell leukemia virus type 1 (HTLV-1) and
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Moore PS, Chang Y: KSHV: Forgotten but not gone. Blood 117:6973, 2011.
Ratner L, Harrington W, Feng X, et al: Human T cell leukemia virus reactiva-
tion with progression of adult T-cell leukemia-lymphoma. PLoS One
4:e4420, 2009.
Rudek MA, Flexner C, Ambinder RF: Use of antineoplastic agents in patients
with cancer who have HIV/AIDS. Lancet Oncol 12:905, 2011.
Savoldo B, Goss JA, Hammer MM, et al: Treatment of solid organ transplant
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Sparano JA, Lee JY, Kaplan LD, et al: Rituximab plus concurrent infusional
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protease inhibitors) and other factors. The field is rapidly evolving,
and colleagues with specific expertise in appropriate antiviral
approaches should be consulted.76
Rituximab has posed an interesting dilemma for the treatment of
patients with HCV and lymphoma. It has been reported that HCV
plasma RNA increases following rituximab treatment, and there is
certainly the possibility that elimination of B cells for 3 to 18 months
following treatment may compromise humoral responses to the evo-
lution of HCV quasispecies. However, in studies to date overall
survival is not inferior.91
Similarly, combination chemotherapy is safe
in patients with HCV infection.92
Rituximab is specifically recom-
mended for the treatment of HCV-associated cryoglobulinemia
(although as in the treatment of Waldenström macroglobulinemia, it
must be appreciated that the initial response to rituximab may be an
increase in the IgM paraprotein level, necessitating plasmapheresis).
Aspects of Therapy
With regards to the use of rituximab to treat B-cell lymphomas in
patients with HCV, overall survival is not inferior, although there do
appear to be increased rates of hepatotoxicity and rises in HCV viral
load during therapy. Similarly, combination chemotherapy is safe in
patients with HCV infection, although HCV RNA levels can rise
during treatment. Interestingly, patients with HCV and splenic MZL
have had regression of their tumors with treatment for HCV infection
with interferon-α and ribavirin, an effect not seen in HCV-negative
patients with splenic MZL treated with the same regimen.
FUTURE DIRECTIONS
In this chapter a variety of virus-associated lymphomas and lympho-
proliferative diseases have been reviewed. For most of these lympho-
mas, standard antiviral drugs do not have a role in treatment. There
are, however, several exceptions, and these are worth highlighting.
Antiviral therapy for HCV-associated splenic lymphoma with villous
lymphocytes is accepted as a standard approach and likely has a role
in the treatment of other HCV-associated indolent lymphomas. Simi-
larly, ganciclovir or valganciclovir appears to have a role in the man-
agement of MCD associated with KSHV in HIV patients. And of
course there is an established role for antiretroviral therapy in the
treatment of HIV patients with malignancy. There are virus-targeted
therapies that are broadly accepted as standard, including adoptive
immunotherapy with EBV-specific T cells for PTLD. The use of
targeted T cells also has promise in other settings, including EBV-
associated HL. Other virus-targeted therapies are being developed.
Some involve vaccination; others involve induction of viral genes in
tumor cells, rendering them more susceptible to pharmacologic treat-
ment. Finally, it may ultimately be possible to prevent some kinds of
lymphoma by preventing viral infection or altering the host response
to viral infection.
SUGGESTED READINGS
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consortium trials evaluating rituximab plus CHOP or infusional EPOCH
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gamma-herpesviruses. Blood 113:1213, 2009.](https://image.slidesharecdn.com/l3-140613130911-phpapp01/85/Linfomas-y-VIH-III-10-320.jpg)
![Chapter 82 Virus-Associated Lymphoma 1254.e3
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Linfomas y VIH III
This document discusses viruses associated with lymphoma. It focuses on Epstein-Barr virus (EBV) which is present in tumor cells of some lymphomas. EBV infects B cells and can immortalize them in vitro, expressing genes that drive proliferation. While EBV infection is common, only a small subset develops lymphoma, showing lymphomagenesis requires additional factors. EBV is strongly associated with several lymphoma subtypes, variably associated with others, and rarely associated with some. Post-transplant lymphoproliferative disorder is often EBV-associated due to immunosuppression allowing infected B cells to proliferate.
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Linfomas y VIH III
- 1. 1245 C H AP T E R 82 VIRUS-ASSOCIATED LYMPHOMA Jennifer A. Kanakry and Richard F. Ambinder There are five well-characterized human viruses that are generally accepted as important in lymphomagenesis (Table 82-1). These viruses may infect tumor cells (or their progenitors) or may act at a distance. The genomes of Epstein-Barr virus (EBV), Kaposi sarcoma– associated herpesvirus (KSHV, also known as human herpesvirus 8 [HHV-8]), and human T-lymphotropic virus-1 (HTLV-1) are present in tumor cells. The viral genes expressed in tumor cells modulate cellular metabolism, proliferation, and cell death. In contrast, the human immunodeficiency virus (HIV) genome is generally not detected in tumor cells. Whether hepatitis C virus (HCV) genomes are present in lymphoma cells remains a subject of controversy. Although viral infection plays a role in the pathogenesis of some lymphomas, lymphomagenesis is unusual. Only a small subset of infected people develops lymphoma. Furthermore, although primary viral infection may be followed by lymphomagenesis within days or weeks in exceptional circumstances, most lymphomas arise years or decades after primary infection. Indeed the term adult in adult T-cell leukemia/lymphoma (ATL) reflects the time lag between HTLV-1 infection in infancy and the evolution to malignancy. Geography and associated environmental exposures, host genetic factors, and immune status all modify risk. Aspects of the biology and epidemiology of each of these viruses and their relationship with lymphomagenesis are reviewed. In addi- tion, clinically important and distinctive features of diagnosis and treatment of the associated lymphomas are presented. EPSTEIN-BARR VIRUS Viral Biology EBV is a gammaherpesvirus transmitted mainly through saliva.1,2 After primary infection, some of the infected cells are driven to pro- liferate and thereby spread infection throughout the B-cell compart- ment. Ultimately, in the normal host, there is an immune response that controls infection and eradicates virus-infected proliferating cells. Thereafter the viral genome is harbored mainly in resting memory B lymphocytes that persist for life. These B cells that harbor virus elude immune surveillance in part because of their very restricted viral gene expression such that few viral antigens are presented. Occa- sionally there is activation of viral lytic gene expression (at least in some instances this occurs in concert with plasma cell differentiation) leading to production of infectious virions that may infect other B cells. T cell–mediated immune function keeps such proliferation in check.3 In vitro EBV immortalizes B cells such that they grow indefinitely as lymphoblastoid cell lines (LCLs) (Fig. 82-1). LCLs are tumorigenic in immunodeficient mice. In LCL, viral genomes are present as cir- cular double-stranded deoxyribonucleic acid (DNA) episomes within the nucleus. The viral proteins required for immortalization include Epstein-Barr virus nuclear antigen-1 (EBNA1), a sequence-specific DNA-binding protein important in the maintenance of the viral episome; EBNA2, a transcription factor that has many effects similar to those of activated Notch receptors; and latent membrane protein-1 (LMP1), a constitutively activated member of the tumor necrosis factor (TNF) receptor superfamily, which most closely resembles CD40.4 LMP1 activates the nuclear factor kappa-B (NFκB) pathway, which modulates cell proliferation and apoptosis.5 Several other EBV proteins are also required for immortalization. Although EBV immor- talization of B cells in vitro may offer some insights into tumorigen- esis, some caution is required in using LCL as a tumor model. Most EBV tumors, including tumors of B-lineage cells, do not express many of the viral genes required for lymphocyte immortalization. The only tumors that express the full complement of viral proteins required for immortalization are those that arise in the most pro- foundly immunocompromised patients (organ or hematopoietic transplant recipients, patients with congenital immunodeficiency, or patients with far advanced acquired immunodeficiency syndrome [AIDS]). Thus in posttransplantation lymphoproliferative disorder (PTLD), tumor cells may resemble LCL in expressing many viral latency genes in association with normal karyotype (and few muta- tions of the cellular genome). It has been suggested that there is an inverse relationship between cellular mutations and viral gene expres- sion in tumors.6 EBV gene expression may directly drive proliferation or inhibit apoptotic pathways as illustrated by lymphocyte immortalization. However, viral gene expression may also perturb normal lymphocyte biology. Thus LMP1 expression upregulates activation induced (cyti- dine) deaminase expression, which facilitates somatic hypermutation and immunoglobulin class switching.7 LMP1 expression may also be important in the conversion of naive B-cells to post-germinal center memory B-cells. LMP2A allows B-cells that lack normal immuno- globulin expression to escape regulatory checkpoints and survive.8 Epidemiology of Viral Infection EBV infection is ubiquitous. The vast majority of adults are infected worldwide. Primary infection is most often asymptomatic, especially when it occurs in childhood.9 Primary infection may be associated with the syndrome of infectious mononucleosis. Symptomatic primary infection occurs more frequently in older children and in adults than in younger children. Other possible determinants of symptomatic primary infection include genetic factors and possibly the size of the viral inoculum. Strain differences in EBV are well recognized.10 However, the importance of these strain differences with regard to lymphomagen- esis remains poorly understood. There is general agreement that the Type 1 strain EBV is most common worldwide and in tumors. The Type 2 strain virus has been identified in some African Burkitt lym- phoma (BL) and in some AIDS-associated lymphoma. A-strain virus is more efficient at lymphocyte immortalization in vitro and lym- phomagenesis in mouse models. The two strains of virus differ mainly in the EBNA2 gene, but differences are recognized in some other viral proteins as well.11 Variations in the regulatory regions or coding regions of a variety of other genes including EBNA1, LMP1, and ZTA have been recognized and suggested to play a role in lymphomagenesis. A simple classification of latent viral gene expression recognizes three patterns as shown in the Table 82-2.
- 2. Part VII HematologicMalignancies1246 at very high copy number (perhaps millions of copies per cell) in latently infected cells. The function(s) of these RNAs is disputed, but their use for the detection of virus in a variety of surgical specimens is generally accepted. Viral antigens are detected by immunohistochemistry. In clinical laboratories,immunohistochemistryforLMP1iscommonlyemployed and is sensitive for the detection of EBV in Hodgkin lymphoma (HL). In a variety of other EBV-associated B- andT-cell malignancies, expres- sion is variable. Thus failure to detect LMP1 expression does not exclude the presence of EBV except perhaps in HL. In principle, detec- tion of EBNA1 should be universally applicable, although the low level of antigen expression and the cross-reactivity of available monoclonal antibodies have prevented immunohistochemistry for this antigen from emerging as a standard tool. Association With Particular Types of Lymphoma Some lymphoma types are nearly 100% EBV associated, including endemic BL, extranodal natural killer (NK)/T-cell lymphoma of the nasal type, early PTLD, lymphomatoid granulomatosis, diffuse large B-cell lymphoma (DLBCL) associated with chronic inflammation, EBV-positive DLBCL of older adults, and AIDS primary central nervous system (CNS) lymphoma (PCNSL).13-16 Other lymphoma types are variably EBV associated. These include classic HL, PTLDs occurring many months or years after transplantation, and systemic AIDS-related lymphoma. Some lymphoma types appear never or almost never to be EBV associated, including follicular lymphoma, nodular lymphocyte-predominant HL, and mantle cell lymphoma. Table 82-3 lists the lymphomas that have been associated with EBV, associated cofactors, viral antigen expression, and an estimate of the percentage of tumors within each lymphoma subtype that harbor viral genomes. Posttransplantation Lymphoproliferative Disorder PTLD is a group of lymphoproliferative disorders ranging from poly- clonal lymphoid hyperplasia to lymphomas that arise in patients after solid organ or hematopoietic stem cell transplantation (HSCT).17 PTLD, especially in the first few months after transplantation, is highly associated with EBV (Fig. 82-2, A, B). EBV gene expression in PTLD corresponds to latencies 2 and 3.18 Broad expression of viral proteins is seen only in immunosuppressed hosts, perhaps reflecting that many of these proteins are commonly targeted by cytotoxic T cells. B cells that harbor EBV are able to proliferate in the setting of posttransplantation immunosuppression at least in part due to decreased T-cell surveillance.19 HSCT patients that receive grafts that have been T-cell depleted develop EBV-associated PTLD at very high rates. Treatment of rejection in solid organ transplant recipients with agents such as the monoclonal antibody OKT3, which targets CD3+ cells, is associated with markedly increased risk for PTLD.20 Treat- ment strategies such as the use of rituximab and infusion of EBV- specific cytotoxic T cells have been quite effective in treating or preventing PTLD (see box on Epstein-Barr Virus-Associated Positive Posttransplant Lymphoproliferative Disorder). Figure 82-1 EPSTEIN-BARR VIRUS (EBV)–IMMORTALIZED B CELL. Normal B cells are readily immortalized in vitro with EBV. These cells express EBV nuclear and membrane proteins. The nuclear proteins include a protein expressed in all EBV-associated tumors, Epstein-Barr virus nuclear antigen 1 (EBNA1). This protein is required for episomal maintenance. Other viral nuclear proteins expressed are transcription factors. These include EBNA-LP, EBNA2, EBNA3A, EBNA3B, and EBNA3C. Two membrane proteins are expressed: latent membrane protein 1 (LMP1), which activates NFκB path- ways, and LMP2A, which mimics B-cell receptor (immunoglobulin) signaling. LMP2 LMP1 NF-κB Cell survival B-cell receptor EBNA1 Transcription factors: EBNA-LP EBNA2 EBNA3A, EBNA3B, EBNA3C Table 82-1 Viruses and Lymphomagenesis Virus Viral Genome in Tumor Cell Lymphoma Type EBV Episomal B, T, NK KSHV Episomal B HTLV-1 Integrated T HIV-1 Absent B HCV Uncertain B EBV, Epstein-Barr virus; HCV, hepatitis C virus; HIV-1, human immunodeficiency virus type 1; HTLV-1, human T-lymphotropic virus-1; KSHV, Kaposi sarcoma–associated herpesvirus; NK, natural killer. Table 82-2 Patterns of Epstein-Barr Virus Gene Expression in Latency Latency EBNA1 EBNA2, EBNA3A, EBNA3B, EBNA3C LMP1 LMP2A I + II + + + III + + + + EBNA1, Epstein-Barr virus nuclear antigen 1; EBV, Epstein-Barr virus; LMP1, latent membrane protein 1. Epstein-Barr Virus Detection in Clinical Specimens The sensitivity of polymerase chain reaction (PCR) makes detection of viral DNA straightforward, but the ubiquity of EBV infection, and the persistence of B cells that harbor EBV in all seropositive individu- als, means that EBV DNA is readily detected in many specimens that include normal lymphocytes. Thus diagnosis of the EBV association in general requires viral detection specifically in tumor cells. Tech- niques for viral DNA detection by fluorescence in situ hybridization or related techniques, although greatly improved in recent years, remain the purview of research laboratories and are generally not readily applicable to clinical specimens. This reflects the relatively low copy number of the viral genome in tumor cells, typically 1 to 200 copies per cell. In contrast, in situ hybridization for the Epstein-Barr encoded ribonucleic acids (RNAs) has emerged as a laboratory stan- dard.12 These RNAs are polymerase 3 transcripts that are expressed
- 3. Chapter 82 Virus-AssociatedLymphoma 1247 Hodgkin Lymphoma Approximately 30% of HL tumors in the United States and Europe are EBV associated (Fig. 82-2, C, D).21,22 Epidemiologic studies in Denmark and Sweden suggest that individuals with a history of symptomatic infectious mononucleosis are at increased risk for EBV- associated HL, but not for EBV-negative HL or other lymphomas.23 The period of risk peaks at about 2 years but continues to be elevated for at least 10 years after symptomatic mononucleosis. Figure 82-2 EXAMPLES OF EPSTEIN-BARR VIRUS (EBV)–RELATED LYMPHOMAS. Posttransplantation lym- phoproliferative disorder (PTLD), polymorphic type, EBV+ occurring in the gastrointestinal tract of a 15-month-old girl following an orthotopic liver transplant (A and B). There was a mildly atypical lymphocytic infiltrate in the duodenal mucosa composed of small lymphocytes, plasma cells, and occasional large cells (A). The infiltrate was EBV+ as dem- onstrated by in situ hybridization for Epstein-Barr–encoded RNA (EBER) (B). Hodgkin lymphoma, nodular sclerosing type, EBV+ (C and D). The hematoxylin-eosin section shows a portion of a lymph node from a cervical lymph node biopsy of an 8-year-old girl. There are bands of sclerosis forming a cellular nodule, and within the nodule there is a mixed inflammatory infiltrate and scattered large cells with contracted cytoplasm consistent with lacunar cells (C). The immunophenotype of these cells was that of classic Hodgkin lymphoma, and the cells were EBER+ (D). EBV is seen more frequently in mixed cellularity Hodgkin lymphoma but can be seen in 10% to 40% of cases of nodular sclerosing type. It is even more frequent in cases associated with human immunodeficiency virus (HIV; see text) and in resource- poor regions. Burkitt lymphoma, sporadic type, EBV+ (E and F). A section of the cervical lymph node biopsy of a 9-year-old girl with a rapidly enlarging neck mass is shown. The section illustrates the classic morphologic features of Burkitt lymphoma with a “starry sky” appearance, sheets of intermediate-sized cells with multiple small nucleoli and high mitotic rate. The cells were virtually all EBER+ (F). EBV can be seen in about 20% to 30% of cases of sporadic Burkitt lymphoma and is essentially always positive in endemic cases. F A C E B D F A E Table 82-3 Epstein-Barr Virus-Associated Lymphoma Type Cofactors Viral Gene Expression Approximate % EBV Associated Comment PTLD Immunosuppression, allograft Latency II or III 50-95 Early days/months after transplantation are more commonly associated with EBV Sporadic BL Latency I 20 in the United States Higher in Latin America Endemic BL Malaria Latency I >95 AIDS BL HIV Latency I 30 HL Latency II 30 in the United States Higher % in mixed cellularity, in males, in Hispanics AIDS PCNSL HIV Latency II or III >95 Nasal-type NK cell More common in Asia Latency II >95 AIDS PEL HIV and KSHV Latency I >75 AIDS, Acquired immunodeficiency syndrome; BL, Burkitt lymphoma; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HL, Hodgkin lymphoma; KSHV, Kaposi sarcoma–associated herpesvirus; NK, natural killer; PCNSL, primary central nervous system lymphoma; PEL, primary effusion lymphoma; PTLD, posttransplantation lymphoproliferative disorder. Higher EBV associations are seen in Latin America, Africa, and parts of Asia. Factors associated with EBV tumor positivity include mixed cellularity and lymphocyte-depleted classic HL histo- logic subtypes, male gender, low socioeconomic background, history of symptomatic infectious mononucleosis, and Hispanic ethnic- ity.21,24,25 Organ and hematopoietic stem cell transplant recipients and HIV-positive patients are more likely to develop HL than the general population, and approximately 90% of the tumors are EBV associated.26
- 4. Part VII HematologicMalignancies1248 Figure 82-3 EXAMPLES OF KSHV- AND HTLV-1-ASSOCIATED LYMPHOPROLIFERATIVE DISEASE. Primary effusion lymphoma (A and B). A, The pleural tap had a high cell count, and the cytospin preparation revealed a markedly pleomorphic cell population with large and giant cells with deep-blue cytoplasm. B, A cell block was pre- pared (top) so that in situ hybridization studies could be performed. These studies showed the cells to be KSHV+ by immunohistochemistry for latency associated nuclear antigen-1 (LANA-1) (bottom) and EBV+ by EBER in situ hybrid- ization (not shown). C, Adult T-cell leukemia/lymphoma in a patient who was HTLV-1+. The peripheral smear showed the classic “flower” cells. EBER, Epstein-Barr–encoded RNA; HTLV-1, human T-lymphotropic virus-1; KSHV, Kaposi sarcoma–associated herpesvirus. (A and B courtesy Dr. Elizabeth Hyjek, University of Chicago.) A B C Epstein-Barr Virus-Associated Positive Posttransplant Lymphoproliferative Disorder A 55-year-old renal transplant patient presents with acute renal failure 5 months after transplant. She is found on imaging to have an obstructing mass in the transplanted kidney. She under- goes kidney biopsy, and Epstein-Barr virus (EBV)–positive post- transplant lymphoproliferative disorder (PTLD) involving the transplanted organ is diagnosed. Treatment options include ritux- imab; decreasing immunosuppression (acknowledging the associ- ated risk for organ rejection); changing immunosuppressive agents—switching a calcineurin inhibitor for a mammalian target of rapamycin (mTOR) inhibitor; combination chemotherapy; or, in the case of renal transplant, removal of the transplanted organ and withdrawal of immunosuppression. The EBV gene expression pattern in HL is latency II even when HL occurs in immunocompromised populations.27 LMP1 and LMP2A may mimic signaling of B-cell receptors and thus protect B cells lacking functional immunoglobulin expression from apoptotic signaling. Approximately 20% of HL lack productive immunoglobu- lin gene rearrangements. These tumors appear to be exclusively EBV associated. The EBV association of HL appears not to have prognostic import in young adult patients but is associated with poorer survival in older patients in several reports.22 Treatment strategies involving adoptive therapy with EBV-specific T cells expanded in vitro are under study.28 Burkitt Lymphoma Endemic BL is nearly 100% associated with EBV, whereas sporadic and HIV-associated BL are much more variably EBV associated (see Table 82-3 and Fig. 82-2, E, F).29 Viral expression is latency I (i.e., EBNA1 is the only viral protein consistently expressed). The defining feature of BL is a translocation between c-Myc on chromosome 8 and one of the immunoglobulin genes on chromosomes 2, 14, or 22. It has been generally presumed that falciparum malaria is a cofactor in endemic BL, and the distribution of BL in Africa corresponds to the distribution of holoendemic malaria. However, little is understood of the pathogenesis or interaction between these infectious cofactors. The characteristic presentation of BL is different in the endemic versus sporadic settings, but there is no evidence to link these presentations specifically with the virus. The virus-tumor association does not guide diagnosis, therapy, or estimation of prognosis at present. Diffuse Large B-cell Lymphoma Associated With Chronic Inflammation EBV-associated lymphomas sometimes arise in the setting of long- standing chronic inflammation.15 This was first described in Japanese patients with a remote history of pulmonary tuberculosis treated with thoracoplasty with resulting chronic pyothorax, although many more cases have since been reported. These patients developed EBV- associated DLBCL of the pleural lining and associated lung tissue decades after thoracoplasty. Similar cases of aggressive, EBV-associated B-cell lymphomas have been reported to arise in patients at the sites of chronic inflammation associated with various implants, surgical mesh, or in the lung after chronic empyema. KAPOSI SARCOMA–ASSOCIATED HERPESVIRUS Virus and Tumor Epidemiology KSHV (HHV-8) is a gammaherpesvirus that, unlike EBV, has a low prevalence worldwide.30 The virus is endemic in certain areas, such as in sub-Saharan Africa and the Middle East, and has an intermedi- ate prevalence in Mediterranean countries. Transmission is believed to be predominately through saliva. Similar to EBV, KSHV latently infects B cells; viral genes that promote cell survival are implicated in lymphomagenesis. KSHV was discovered in Kaposi sarcoma but is also present in two lymphoproliferative diseases: primary effusion lymphoma (PEL) (Fig. 82-3, A, B) and multicentric Castleman disease (MCD).16,31 PEL occurs almost exclusively in HIV-positive patients, particularly in men who have sex with men, and typically when CD4 counts are less than 100/mm3 . PELs are usually dually infected with KSHV and EBV, but KSHV is always present. KSHV-associated MCD, although much more common in HIV-infected populations, also occurs in the general population. MCD is a KSHV-associated, immunoglobulin M (IgM) λ– producing nonclonal lymphoproliferative disorder typically involving the mantle zone of lymph nodes and the spleen. The KSHV-positive cells in MCD are always EBV negative. These cells express a broad range of KSHV lytic antigens, and high KSHV copy numbers are reported in plasma. Evolution into or coassociation with an aggressive lymphoma, often of plasmablastic phenotype, is not uncommon.
- 5. Chapter 82 Virus-AssociatedLymphoma 1249 HUMAN T-LYMPHOTROPIC VIRUS-1 Viral Biology HTLV-1 is a retrovirus with a single-stranded RNA genome.37,38 Fol- lowing infection there is reverse transcription and integration of proviral DNA into the host genome. HTLV-1 infects a variety of cell types but persists in CD4+ T lymphocytes. Viral infection within the host is spread from cell to cell through direct cell-to-cell contact. As with EBV, the proliferation of HTLV-1–infected lymphocytes plays a central role in ensuring viral persistence. The HTLV-1 protein Tax plays a central role in T-lymphocyte immortalization and transformation (Fig. 82-4).37,39 Tax affects NFκB and the serine/threonine kinase AKT pathways with diverse prolifera- tive and antiapoptotic effects. As with some of the immunodominant EBV antigens expressed in proliferating lymphocytes, Tax expression is targeted by cytotoxic T cells. Another viral protein, Hbz, suppresses Tax expression, allowing transformed T cells to elude immune sur- veillance.40 Tax interferes with various DNA repair pathways and induces reactive oxygen species, facilitating the development of aneu- ploidy.37,39 Tax leads to functional inactivation of p53 and may inter- fere with the spindle assembly checkpoint that normally operates in mitosis to preserve euploidy. Epidemiology of Viral Infection and Adult T-Cell Leukemia/Lymphoma HTLV-1 is endemic in particular regions of Japan, Africa, South America, and some Caribbean islands.40,41 As assessed by seropreva- lence, rates up to 37% are found on the southwestern Japanese islands of Shikoku, Kyushu, and Okinawa, whereas most other areas of Japan have an intermediate prevalence of 1% to 5%. In the United States Within the HIV population, nearly all cases of MCD are KSHV associated; this viral association is not as strong among HIV-negative MCD patients. High expression of viral interleukin-6 (vIL-6) is thought to contribute to the systemic inflammation seen in this disorder.32 The KSHV-associated lymphomas that arise in association with MCD are not nodal equivalents of PEL; rather these plasma- blastic lymphomas are uniformly EBV negative and express IgM λ.16 Diagnostic and Therapeutic Considerations The requisite finding in PEL is a lymphomatous effusion, which can be pleural, pericardial, or peritoneal, without associated lymphade- nopathy or masses, arising in the setting of immunocompromise. Often, patients with HIV/AIDS will present with PEL in addition to other KSHV-associated diseases, such as Kaposi sarcoma and MCD, so thorough evaluation and staging should be undertaken at diagnosis. On cytologic examination, the PEL tumor cells are large with prominent nucleoli. The effusion cells are clonal B cells with CD45 positivity but typically lack other specific B-cell lineage markers, although CD30 and CD38 positivity can be seen. BCL6 mutations are frequently detected. Tumor cells always harbor KSHV as demonstrated by staining for KSHV-associated latency-associated nuclear antigen-1 (LANA-1). In MCD there is characteristically λ light chain restriction.33 This does not reflect clonality as assessed by study of Ig DNA rearrangements. Rather it reflects a tendency for the virus to selectively infect cells expressing λ or to selectively drive such cells to proliferate. Treatment of PEL is most commonly combination chemotherapy. Outcomes remain quite poor. Treatment of MCD with targeted therapies has been more successful, including the use of rituximab and IL-6 inhibition.34,35 Antivirals such as ganciclovir and valganci- clovir have shown clinical activity in MCD, because viral lytic replica- tion is a feature of this disease.36 Figure 82-4 HTLV-1 AND THE EVOLUTION OF ADULT T-CELL LEUKEMIA/LYMPHOMA. Following HTLV-1 infection, many cells undergo apoptosis, but some infected CD4+ T cells are driven to proliferate by the effects of Tax on the nuclear factor kappa-B (NFκB) pathway and on the AKT pathway. Tax is also suggested to result in inactivation of p53, aneuploidy, and deoxyribonucleic acid (DNA) damage. Over many decades malignancy evolves. HTLV-1, Human T-lymphotropic virus-1. HTLV-1 infection Tax activates AKT and NF-κB, inactivates p53 Apoptosis Tax Tax Tax Tax Viral control by cytotoxic T lymphocytes CTL Proliferation Tax induces aneuploidy and DNA damage 30-40 years Cellular transformation to ATL
- 6. Part VII HematologicMalignancies1250 infection may lead to cell death or establishment of latency in resting cells. HIV infection is spread either through new rounds of virion production with cellular infection or cell-cell fusion. There is no evidence to suggest that infected cells are driven to proliferate. This is in contrast to HTLV-1 and EBV, where proliferation of infected cells appears to play a key role in establishing the long-term viral reservoir and perhaps in mediating lymphomagenesis. The lympho- mas that are increased in HIV-infected patients (Table 82-4) are of B-cell lineage, and there is no substantial evidence that HIV infection of B cells is important in the pathogenesis of these lymphomas. Rather it appears that the HIV infection compromises cellular immu- nity, decreasing immune surveillance of EBV- and KSHV-infected B cells. In addition, HIV infection stimulates proliferation of B lym- phocytes and perhaps genetic aberrations in the proliferating cells.51 Many possible mechanisms have been invoked, including (1) direct stimulation of B cells by HIV antigens or antigens associated with opportunistic infection; (2) stimulation of B cells by cellular proteins (CD40 ligand) incorporated into the HIV virion leading to expres- sion of activation-induced deaminase, an enzyme that mediates double-strand DNA breaks; and (3) dysregulation of B cells as a consequence of T-cell dysfunction.16,51,52 There is also some evidence that host biology may contribute to lymphomagenesis. In particular, there are a variety of genetic poly- morphisms that influence susceptibility to HIV-1 infection, such as CCR5-Δ32.53,54 Individuals who are homozygous for this polymor- phism are much less likely to be infected by HIV than others. Some evidence has emerged to suggest that in heterozygotes who are infected, HIV progression is slowed and there is less likelihood of lymphomagenesis. Many of these lymphomas are associated with EBV, KSHV, or both (see Table 82-4). Epidemiology Lymphoma is increased in all HIV risk groups, in contrast to Kaposi sarcoma, which is rarely seen in injection drug users (or in hemo- philiacs in an earlier era).55 There is a well-established relationship between CD4+ cells per cubic millimeter overall and the risk for lymphoma, but the relationship is complex and differs among lym- phomas (see Table 82-4). The incidence of non-Hodgkin lymphoma (NHL) in the HIV population, particularly PCNSL (Fig. 82-5, A to C), has decreased with the widespread use of highly active antiretroviral therapy (HAART), although HIV patients on HAART still carry an increased risk for lymphoma compared to the HIV-negative population.55 In the HAART era, HIV patients on average have higher CD4+ counts (often greater than 100 cells/mm3 ) when diagnosed with lymphoma as compared to the pre-HAART era. Among HIV patients with very low CD4+ counts,56 NHLs are still seen at rates similar to the pre- HAART era. Patients with HIV are now living much longer because of effective antiretroviral regimens and decreased rates of opportunis- the incidence in blood donors is 0.025%. It has been estimated that about 20 million individuals are infected worldwide. The major mode of transmission in endemic areas is from mother to child in breast milk, although infection is also transmitted through sexual intercourse, transfusion of cellular blood products, and the sharing of needles and syringes. Evidence has been presented that HTLV-1 infection persists in association with certain human leukocyte antigen (HLA) types and may be more readily transmitted from mother to child when these HLA types are shared. ATL is more common in men than in women and typically pres- ents in the fourth or fifth decade of life. Perhaps as a function of the long latency period, cases of ATL following blood transfusion or needle sharing are vanishingly rare. The lifetime risk for ATL has been estimated to be in excess of 6% in men who are HTLV-1 carriers in an endemic region of Japan, although in other settings the risk may be much lower.42 As with EBV, the subset of the infected population that develops lymphoma is quite small. Adult T-Cell Leukemia/Lymphoma Diagnostic Considerations There is a spectrum of HTLV-1–associated leukemia/lymphoma.38 Twenty percent of ATL cases present with a lymphomatous subtype dominated by lymphadenopathy and hepatosplenomegaly. Cutane- ous infiltration, lytic bone lesions, malignant effusions, and involve- ment of the CNS and other extranodal sites are not uncommon.40 Hypercalcemia is common, particularly in leukemic forms. Presenta- tions reflecting immune dysfunction such as strongyloidiasis with dissemination, Pneumocystis jiroveci pneumonia (PJP), mycobacte- rium, or cryptococcal infection are common. In the leukemic subtype of ATL, the classic findings on peripheral blood smear are lympho- cytes with flower-shaped nuclei (Fig. 82-3, C). Histologically ATL shows lymph node effacement by large, atypi- cal T cells usually expressing CD4+ , CD25+ , and CD52+ , with vari- able CD30 and CD15 expression. Aneuploidy is consistent, although characteristic cytogenetic abnormalities have not been identified. Serologic analysis confirms the presence of HTLV-1 infection.38 Therapies Specific to HTLV-1 ATL ATL is an aggressive lymphoma with poor responses to chemother- apy, high relapse rates, and low overall survival. More indolent chronic and smoldering forms are also recognized. Combination chemotherapy regimens used in the treatment of other lymphomas or leukemias are commonly used, but no standard regimen has emerged.38,43 Several antivirals used in the treatment of HIV infection have activity against HTLV-1. Among them are zidovudine and lami- vudine. The combination of interferon and zidovudine has yielded promising results, particularly in the leukemic subtype.38 Proteasome and histone deacetylase (HDAC) inhibitors have attracted interest. Given high CD25 and CD52 expression in ATL, the efficacy of monoclonal antibodies aimed against these two receptors has been investigated. Thus far alemtuzumab, an anti-CD52 monoclonal anti- body, may have some activity in ATL based on small phase II studies and case reports.44,45 Arsenic trioxide combined with interferon-α has been shown to induce remissions in relapsed, refractory patients with ATL, although durable responses were limited. In a trial of 20 ATL patients, all-trans retinoic acid was used with 40% achieving remis- sion. Allogeneic hematopoietic transplantation has been increasingly recognized as an effective therapy for ATL.46,47 HIV-ASSOCIATED LYMPHOMAS Viral Biology and Pathogenesis HIV-1 is a retrovirus that infects CD4+ T cells and monocytes.48,49 It appears to establish a lifelong reservoir in CD4+ T cells.50 Viral Table 82-4 HIV-Associated Lymphoma Lymphoma CD4 Association (cells/mm3 ) EBV Association (%) Other Cofactors PCNSL <50 >95 DLBCL Variable 40 BL >100 30 HL >100 90 PEL <100 >75 KSHV BL, Burkitt lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein- Barr virus; HIV, human immunodeficiency virus; HL, Hodgkin lymphoma; KSHV, Kaposi sarcoma–associated herpesvirus; PCNSL, primary central nervous system lymphoma; PEL, primary effusion lymphoma.
- 7. Chapter 82 Virus-AssociatedLymphoma 1251 Diagnostic Considerations Specific to Lymphoma in Patients With HIV Lymphomas in HIV-infected patients are more likely to present with B symptoms such as fever and night sweats, and advanced stage, including bone marrow, extranodal, and CNS involvement. Thus the approach to diagnosis is somewhat different than the approach in the HIV-negative patient. Unexplained fever and sweats in an HIV-seropositive patient, even in the absence of lymphadenopathy, are sufficient to warrant consid- eration of HL. Patterns of disease involvement also differ in HIV- infected patients. Contiguous spread so characteristic of classic HL in other settings is less common in HIV HL. Bone marrow–only presentations of HL are not uncommon (Fig. 82-5, D to G), and the possibility of HL should be in the differential diagnosis even in the absence of lymphadenopathy. Patients with HIV-associated NHL have higher rates of extranodal involvement, including bone marrow and CNS disease, as well as higher stage disease and more aggressive tumors on average.72 There- fore it is recommended that all HIV-seropositive patients with aggres- sive NHL undergo a diagnostic lumbar puncture. The routine use of CNS intrathecal chemotherapy prophylaxis in all HIV-seropositive NHL patients is controversial but reasonable and typically done in particularly high-risk patients, such as those with BL, marrow or testicular involvement, or extranodal disease. Imaging is often more difficult to interpret in HIV patients than in other settings. Lymphadenopathy associated with HIV infection or opportunistic infection is common, and the presumption that enlarged lymph nodes reflect the presence of lymphoma in patients with known lymphoma or history of lymphoma is not as safe as in tic infection. As a result, malignancy has emerged as the major cause of mortality in HIV populations with access to antiretroviral therapy.57,58 With the widespread use of HAART, the incidence of HL in HIV- seropositive patients has not declined; patients with CD4+ counts between 150 and 199 cells/mm3 actually have higher risk for HIV-associated HL than patients with CD4+ counts of less than 50 cells/mm3 .59 HIV Hodgkin Lymphoma A 42-year-old human immunodeficiency virus (HIV)–positive patient, on highly active antiretroviral therapy (HAART) with a CD4 count of 324 cells/mm3 and undetectable viral load, pres- ents with fever, weight loss, and a palpable axillary lymph node. Hodgkin lymphoma (HL) is diagnosed on excisional biopsy, and Epstein-Barr virus (EBV) positivity is demonstrated by Epstein- Barr–encoded RNA (EBER) in the Reed-Sternberg tumor cells. Although he lacks additional lymphadenopathy, a bone marrow biopsy is performed, and it shows involvement by HL. He has stage IVB disease. Pneumocystis jiroveci pneumonia prophylaxis is started despite adequate CD4 count in anticipation of chemo- therapy. His HAART regimen is reviewed for potential antiviral- chemotherapy drug interactions. He receives six cycles of full-dose, first-line chemotherapy and achieves a complete remission. Figure 82-5 EXAMPLES OF HUMAN IMMUNODEFICIENCY VIRUS (HIV)–RELATED LYMPHOMAS. Primary central nervous system (CNS) lymphoma in HIV+ patients (A to C). Gross appearance (coronal section) of the brain from an autopsy of a 24-year-old HIV+ female patient with temporo- parietal mass due to a primary CNS lymphoma (A). The patient died from uncal and cingulate herniation. Biopsy section from another patient showing a perivascular infiltrate of large lymphoma cells. This is the typical pattern of involvement by CNS lymphoma (B). The cells were shown to be CD20+ B cells and were EBER+ (C). A diagnosis can be made without biopsy when magnetic resonance imaging studies show characteristic features and EBV is demonstrated in the cerebrospinal fluid by polymerase chain reaction (see box on AIDS Primary Central Nervous System Lymphoma). Hodgkin lymphoma extensively involving the bone marrow in an HIV+ patient with stage IVB disease (D to G). The bone marrow biopsy was entirely replaced with Hodgkin lymphoma associated with dense sclerosis (D). An EBER study shows scattered positive cells throughout the marrow (E), corresponding to the Hodgkin and Reed-Sternberg cells (F), which were CD30+ as illustrated (G). Hodgkin lymphoma infrequently involves the bone marrow in HIV-negative cases but some HIV+ patients can first present with extensive bone marrow disease (see box on HIV Hodgkin Lymphoma). (A courtesy Dr. Peter Pytel, University of Chicago.) A B CC E G D F
- 8. Part VII HematologicMalignancies1252 comparable outcomes regardless of HIV status.71 In this study all HIV-seropositive patients were required to be on HAART to enroll, and the majority had CD4+ counts of greater than 200 cells/mm3 . Granulocyte colony-stimulating factor support was used throughout chemotherapy cycles, as well as PJP and other antimicrobial prophy- laxis. Differences in induction-related mortality, duration of neutro- penia, progression-free survival, or overall survival were not detected, although HIV-seropositive patients did have significantly more severe mucositis and infectious complications. Dose Most would agree that dose reduction is appropriate in patients with low CD4+ count (<100 cells/mm3 ), history of ongoing opportunistic infection, performance status below 75%, or compromised organ function. Some regimens begin with a 50% dose reduction in cyclo- phosphamide dose for CD4+ count of less than 100 cells/mm3 with a built-in dose escalation for the next cycle if well tolerated.64,68 Chemotherapy regimens of varying intensity depending on CD4+ count, performance status, and International Prognostic Index score have been studied, including a comparison of low-dose CHOP to standard-dose CHOP, with no differences found in overall survival based on the intensity of the chemotherapy regimen.66 In patients with very low CD4+ counts, low-dose chemotherapy is a reasonable treatment option, while maintaining the possibility of long-term disease-free survival in some. Antiretroviral Therapy A few key special issues in considering concurrent antiretroviral and lymphoma therapy include concerns about shared toxicities, drug-drug interactions, and risk for inability to comply with consis- tent antiretroviral dosing. Zidovudine is myelosuppressive and can exacerbate pancytopenia associated with lymphoma therapy. If patients are already on a zidovudine-containing regimen, it is generally possible to substitute an alternative regimen before the initiation of lymphoma therapy. Many antiretroviral agents alter the metabolism of drugs used in lymphoma treatment. This has been a particular concern when infusional chemotherapy regimens are used, and some investigators have chosen to stop chemotherapy before initiation of such regimens.64 However, in trials involving infusional chemotherapy that allowed patients already on a stable antiretroviral regimen to remain on that regimen during lymphoma treatment, major problems were not noted.68 Nausea and vomiting associated with chemotherapy regimens may interfere with regular antiviral dosing. Intermittent antiretroviral therapy raises concerns about the development of a resistant strain of HIV. Because of the concern that initiation of anti- retroviral therapy with cytotoxic chemotherapy might result in such resistance, many recommend delaying initiation of antiretroviral therapy until an appropriate regimen to control nausea and vomiting is established. Stopping antiretroviral therapy also carries with it some risks. When antiretroviral therapy includes drugs with different half- lives, stopping treatment may result in the longest-lived agent being present in the absence of other antiretroviral agents. This is particu- larly an issue for long-lived nonnucleoside reverse transcriptase inhibi- tors. Even a single dose of such agents in the absence of other antiretroviral agents may lead to resistance to that class of agents.Thus when an interruption of antiretroviral therapy is planned, specific strategies have been advocated, including a “staggered stop” or a change to a regimen with components that have similar half-lives.62 For patients already on antiretroviral treatment at the time of lymphoma diagnosis, the particulars of the regimen should be con- sidered during the pretreatment evaluation. Atazanavir and indinavir are associated with hyperbilirubinemia as a result of UGT1A1 inhibi- tion.62 This is an unconjugated hyperbilirubinemia similar to that occurring with Gilbert syndrome. Elevated total bilirubin in such patients is not indicative of hepatic involvement or other serious hepatic dysfunction and should not guide decisions about other settings. Positron emission tomography–computerized tomog- raphy (PET-CT), although useful, must also be interpreted with caution insofar as HIV infection itself, opportunistic infection, and immune reconstitution following the initiation of antiretroviral therapy are all associated with signal on metabolic imaging with fluorodeoxyglucose. CD4+ counts can help to guide evaluation insofar as CD4+ counts of greater than 300 cells/mm3 are typically associated with BL or HL,60 whereas these diagnoses would be unlikely in patients with very low CD4+ counts of less than 50 cells/mm3 (see box on AIDS Primary Central Nervous System Lymphoma).61 Treatment Aggressive chemotherapy for HIV-associated lymphoma was initially associated with morbidity and mortality related to immunocompro- mise. A phase III randomized study identified a reduced-dose regimen as preferable to standard dose.63 Lower doses were not associated with higher lymphoma cure rates but were associated with less chemotherapy-related morbidity and mortality. However, with the evolution of supportive care, including PJP prophylaxis and neutro- phil growth factors, tolerance of chemotherapy improved. With effec- tive antiretroviral therapy, long-term outcomes improved as well.64,65 And with full-dose therapies, some evidence emerged to suggest that stage-for-stage outcomes might be as good or better in patients with HIV-associated lymphoma compared to those without HIV.66 At the outset of therapy a series of questions must be addressed. Regimen Rituximab, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (R-CHOP); and rituximab, infusional etoposide, predni- sone, vincristine, cyclophosphamide, and hydroxydaunomycin (R-EPOCH) have emerged as standard regimens.67,68 As in the treat- ment of DLBCL in patients without HIV infection, the value of infusional chemotherapy remains controversial. A recent pooled ret- rospective analysis favored the infusional regimen.69 However, insofar as the trials were conducted sequentially (R-CHOP between 1998 and 2002, and R-EPOCH between 2002 and 2006), it is difficult to exclude other factors such as the availability of better antiretroviral agents, improvements in supportive care, or changes in the popula- tion studied. However, there is general agreement that rituximab improves outcome, at least in patients with CD4+ counts of greater than 50 cells/mm3 . BL typically requires more intensive treatment regimens than those used for DLBCL.70 Thus there has been concern about using these regimens in the HIV-seropositive population. A small retrospec- tive study of cyclophosphamide, vincristine (Oncovin), doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytara- bine (IVAC) for BL that included 14 patients with HIV showed HIV-seropositive patients to have similar progression-free survival, overall survival, and complete response rates as compared to the HIV- negative BL patients. In a prospective Spanish study, HIV-seropositive and HIV-seronegative BL patients were treated with six cycles of intensive chemotherapy and rituximab and were found to have AIDS Primary Central Nervous System Lymphoma In acquired immunodeficiency syndrome (AIDS) primary central nervous system lymphoma (PCNSL), Epstein-Barr virus (EBV) polymerase chain reaction of the cerebrospinal fluid is positive approximately 90% of the time and rarely positive in patients with AIDS but without PCNSL. When EBV is detected in the cerebrospinal fluid of an AIDS patient, coupled with characteris- tic magnetic resonance imaging findings, this is sufficient to diagnose AIDS PCNSL without a confirmatory brain biopsy.
- 9. Chapter 82 Virus-AssociatedLymphoma 1253 whether infection of B cells plays any role in this process. A lym- phoma cell line that produces infectious HCV has been reported. Even in the absence of infection of B cells, interaction of the HCV E2 protein with CD81 on B cells may drive B-cell proliferation or lower the threshold for other B-cell stimuli to drive proliferation. Ig signaling may be activated by Ig-virus complexes, and Toll-like recep- tor 7 signaling may be activated by viral RNA. Finally, it is noted that E2 binding triggers expression of activation-induced deaminase, an enzyme that is important in generating somatic hypermutation and that has also been implicated in mediating mutations thought to play a role in DLBCL lymphomagenesis.77 Epidemiology of Viral Infection and Associated Lymphoma The association between HCV and lymphoma was first recognized in patients with HCV-associated type II mixed cryoglobulinemia, an autoimmune extrahepatic manifestation of HCV infection.79 There followed demonstration of an increased risk for certain subtypes of B-cell lymphoma (marginal zone lymphoma [MZL], lymphoplasma- cytic lymphoma and to a lesser extent DLBCL in HCV-infected patients).80-83 For example, in Taiwan the rate of chronic HCV infec- tion in patients with NHL was 11%, 10-fold higher than in the general Taiwanese population.84 Among HCV-infected patients with lymphoma, nodal and splenic MZL, but not mucosa-associated lym- phoid tissue (MALT) lymphomas, were increased. The HCV- lymphoma association is more apparent in some countries than others, with the association being established most clearly in Italy and Japan. A multitude of studies in regions or countries where HCV infection is less prevalent have failed to identify any association with lymphoma.85-87 Further evidence in support of an etiologic relationship comes from studies in which successful treatment of HCV was followed by lymphoma regression.88 The most dramatic illustration comes from patients with splenic lymphoma with villous lymphocytes treated with ribavirin and interferon. Certain HCV genotypes may confer increased risk for NHL, with genotypes 2a/III and 2b/IV seen more frequently in the HCV- seropositive patients that develop NHL. Diagnostic Considerations In contrast to EBV-, KSHV-, or HTLV-1–associated tumors, there is no established role for studies demonstrating HCV nucleic acid or protein in tumor cells. Thus serologic study and measurement of HCV copy number are the only tools available for inferring an asso- ciation. We recommend checking HCV serologic characteristics in all patients with B-cell lymphomas most commonly associated with chronic HCV infection.89 In addition, screening patients with chronic HCV for a monoclonal gammopathy and cryoglobulinemia may be of benefit to identify patients at highest risk for malignant transfor- mation. Elevated serum γ-globulin levels have been found to be a predictor of NHL among patients with type II mixed cryoglobuline- mia.90 In patients who are HCV seropositive, we evaluate HCV RNA in plasma. Therapy In patients with indolent lymphomas and untreated HCV infection, antiviral treatment may obviate the need for cytotoxic chemotherapy and should be considered as an initial therapeutic strategy. The studies showing that antiviral therapy may lead to regression of HCV- associated lymphomas involved treatment with ribavirin and inter- feron. In the last year new antiviral agents have become available, notably protease inhibitors specific for the HCV protease. Likelihood of response to older therapy is a function of viral genotype, host genetics (IL28R polymorphisms play a critical role in response to chemotherapy dose adjustments. Ritonavir inhibits the clearance of midazolam, phenytoin, and voriconazole and other agents metabo- lized by the cytochrome P-450 CYP3A4 pathway. Supportive Care Although PJP prophylaxis is recommended only when the CD4+ count is less than 200 cells/mm3 for HIV patients not receiving cytotoxic chemotherapy, prophylaxis is universally recommended for HIV patients receiving cytotoxic chemotherapy. The following are also commonly used: fungal prophylaxis with fluconazole; herpes simplex and varicella prophylaxis with acyclovir, valacyclovir, or fam- ciclovir; quinolone prophylaxis when neutrophil counts fall below 1000 cells/mm3 ; and granulocyte growth factors. Bone Marrow Transplantation in HIV Patients Autologous bone marrow transplant has been successful in HIV- seropositive NHL patients, with these patients having adequate stem cell mobilization, nonrelapse mortality rates comparable to those for HIV-negative patients, count recovery within 2 weeks of stem cell rescue, and maintained control of HIV viral loads and CD4+ counts after high-dose chemotherapy.73,74 There have also been successful reduced-intensity allogeneic bone marrow transplants in HIV- seropositive patients, making the possibilities for treating HIV patients with NHL even more vast, even in those patients with chemotherapy-resistant disease (see box on Autologous Bone Marrow Transplant in an HIV-Seropositive Hodgkin Lymphoma Patient).75 HEPATITIS C VIRUS Viral Biology and B-Lymphocyte Proliferation HCV is an enveloped positive-strand RNA virus.76,77 Infection involves interactions between E2, a viral structural protein with two hypervariable regions, and a cellular protein CD81 present on hepa- tocytes and B lymphocytes. A polyprotein is translated from viral RNA and is cleaved by cellular and viral proteases, including NS3, to yield proteins required for viral replication. The RNA-dependent RNA polymerase that replicates the viral genome lacks proofreading capacity, thus generating genetic heterogeneity among viral progeny. Viral replication occurs predominantly in the liver, but some evidence suggests that B cells may also be infected. Chronic infection can be associated with mixed cryoglobulinemia, a systemic vasculitis that results from clonal expansion of B cells producing an IgM autoantibody against IgG, leading to deposition of immune complexes on endothelial surfaces, resulting in inflamma- tion.78 Several hypotheses have been advanced with regard to how HCV might drive B-cell proliferation. There is controversy as to Autologous Bone Marrow Transplant in an HIV-Seropositive Hodgkin Lymphoma Patient A 38-year-old human immunodeficiency virus (HIV)–positive patient with CD4+ count of 485 cells/mm3 is diagnosed with classic Hodgkin lymphoma (HL) and treated with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), achieving a complete remission. Two years later he presents with retroperitoneal lymphadenopathy and is found on biopsy to have relapsed HL. He is treated with salvage chemotherapy with com- plete response, as well as good performance status and no active infections. His HIV remains well controlled on antiretroviral therapy. He is deemed an excellent candidate for high-dose therapy and undergoes consolidation with autologous bone marrow transplant.
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Matsuoka M, Jeang KT: Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer 7:270, 2007. Matsuoka M, Jeang KT: Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: Viral infectivity, Tax, HBZ and therapy. Onco- gene 30:1379, 2011. Moore PS, Chang Y: KSHV: Forgotten but not gone. Blood 117:6973, 2011. Ratner L, Harrington W, Feng X, et al: Human T cell leukemia virus reactiva- tion with progression of adult T-cell leukemia-lymphoma. PLoS One 4:e4420, 2009. Rudek MA, Flexner C, Ambinder RF: Use of antineoplastic agents in patients with cancer who have HIV/AIDS. Lancet Oncol 12:905, 2011. Savoldo B, Goss JA, Hammer MM, et al: Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lympho- cytes (CTLs). Blood 108:2942, 2006. Sparano JA, Lee JY, Kaplan LD, et al: Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non- Hodgkin lymphoma. Blood 115:3008, 2010. Uldrick TS, Polizzotto MN, Aleman K, et al: High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Cas- tleman disease: A pilot study of virus-activated cytotoxic therapy. Blood 117:6977, 2011. Vereide DT, Sugden B: Lymphomas differ in their dependence on Epstein- Barr virus. Blood 117:1977, 2011. For complete list of references log on to www.expertconsult.com. protease inhibitors) and other factors. The field is rapidly evolving, and colleagues with specific expertise in appropriate antiviral approaches should be consulted.76 Rituximab has posed an interesting dilemma for the treatment of patients with HCV and lymphoma. It has been reported that HCV plasma RNA increases following rituximab treatment, and there is certainly the possibility that elimination of B cells for 3 to 18 months following treatment may compromise humoral responses to the evo- lution of HCV quasispecies. However, in studies to date overall survival is not inferior.91 Similarly, combination chemotherapy is safe in patients with HCV infection.92 Rituximab is specifically recom- mended for the treatment of HCV-associated cryoglobulinemia (although as in the treatment of Waldenström macroglobulinemia, it must be appreciated that the initial response to rituximab may be an increase in the IgM paraprotein level, necessitating plasmapheresis). Aspects of Therapy With regards to the use of rituximab to treat B-cell lymphomas in patients with HCV, overall survival is not inferior, although there do appear to be increased rates of hepatotoxicity and rises in HCV viral load during therapy. Similarly, combination chemotherapy is safe in patients with HCV infection, although HCV RNA levels can rise during treatment. Interestingly, patients with HCV and splenic MZL have had regression of their tumors with treatment for HCV infection with interferon-α and ribavirin, an effect not seen in HCV-negative patients with splenic MZL treated with the same regimen. FUTURE DIRECTIONS In this chapter a variety of virus-associated lymphomas and lympho- proliferative diseases have been reviewed. For most of these lympho- mas, standard antiviral drugs do not have a role in treatment. There are, however, several exceptions, and these are worth highlighting. Antiviral therapy for HCV-associated splenic lymphoma with villous lymphocytes is accepted as a standard approach and likely has a role in the treatment of other HCV-associated indolent lymphomas. Simi- larly, ganciclovir or valganciclovir appears to have a role in the man- agement of MCD associated with KSHV in HIV patients. And of course there is an established role for antiretroviral therapy in the treatment of HIV patients with malignancy. There are virus-targeted therapies that are broadly accepted as standard, including adoptive immunotherapy with EBV-specific T cells for PTLD. The use of targeted T cells also has promise in other settings, including EBV- associated HL. Other virus-targeted therapies are being developed. Some involve vaccination; others involve induction of viral genes in tumor cells, rendering them more susceptible to pharmacologic treat- ment. Finally, it may ultimately be possible to prevent some kinds of lymphoma by preventing viral infection or altering the host response to viral infection. SUGGESTED READINGS Balsalobre P, Diez-Martin JL, Re A, et al: Autologous stem-cell transplanta- tion in patients with HIV-related lymphoma. J Clin Oncol 27:2192, 2009. Barta SK, Lee JY, Kaplan LD, et al: Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Cancer doi: 10.1002/cncr.26723. [Epub ahead of print], 2011. Bazarbachi A, Suarez F, Fields P, et al: How I treat adult T-cell leukemia/ lymphoma. Blood 118:1736, 2011. Bower M, Newsom-Davis T, Naresh K, et al: Clinical features and outcome in HIV-associated multicentric Castleman’s disease. J Clin Oncol 29:2481, 2011. Carbone A, Cesarman E, Spina M, et al: HIV-associated lymphomas and gamma-herpesviruses. Blood 113:1213, 2009.
- 11. Chapter 82 Virus-AssociatedLymphoma 1254.e1 Key Words Adult T-cell leukemia/lymphoma Burkitt lymphoma Epstein-Barr virus Hepatitis C virus Hodgkin lymphoma Human T-lymphotropic virus-1 Human immunodeficiency virus type 1 Kaposi sarcoma–associated herpesvirus (human herpesvirus 8) Marginal zone lymphoma Natural killer/T-cell lymphoma Posttransplant lymphoma Splenic lymphoma
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