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C H A P T E R 83

VIRUS-ASSOCIATED LYMPHOMA

Jennifer A. Kanakry and Richard F. Ambinder

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There are five well-characterized human viruses that are generally which modulates cell proliferation and apoptosis. Several other EBV
accepted as important in lymphomagenesis (Table 83.1). These proteins are also required for immortalization. Although EBV
viruses may infect tumor cells (or their progenitors) or may act at a immortalization of B cells in vitro may offer some insights into
distance. The genomes of Epstein-Barr virus (EBV), Kaposi sarcoma– tumorigenesis, some caution is required in using LCL as a tumor
associated herpesvirus (KSHV, also known as human herpesvirus 8 model. Most EBV tumors, including tumors of B-lineage cells, do
[HHV-8]), and human T-lymphotropic virus-1 (HTLV-1) are present not express many of the viral genes required for lymphocyte immor-
in tumor cells. The viral genes expressed in tumor cells modulate talization. The only tumors that express the full complement of viral
cellular metabolism, proliferation, and cell death. By contrast, the proteins required for immortalization are those that arise in the most
human immunodeficiency virus (HIV) genome is generally not profoundly immunocompromised patients (organ or hematopoietic
detected in tumor cells. Whether hepatitis C virus (HCV) genomes transplant recipients, patients with congenital immunodeficiency, or
are present in lymphoma cells remains a subject of controversy. patients with far-advanced acquired immunodeficiency syndrome
Although viral infection plays a role in the pathogenesis of some [AIDS]). Thus in posttransplant lymphoproliferative disorder
lymphomas, lymphomagenesis is unusual. Only a small subset of (PTLD), tumor cells may resemble LCL in expressing many viral
infected people develops lymphoma. Furthermore, although primary latency genes in association with normal karyotype (and few muta-
viral infection may be followed by lymphomagenesis within days or tions of the cellular genome). It has been suggested that there is an
weeks in exceptional circumstances, most lymphomas arise years or inverse relationship between cellular mutations and viral gene expres-
decades after primary infection, speaking to the role of cofactors in sion in tumors. 6
the development of malignancy. Indeed the term adult in adult T-cell EBV gene expression may directly drive proliferation or inhibit
leukemia/lymphoma (ATL) reflects the time lag between HTLV-1 apoptotic pathways, as illustrated by lymphocyte immortalization.
infection in infancy and the evolution to malignancy. Geography and However, viral gene expression may also perturb normal lymphocyte
associated environmental exposures, host genetic factors, and immune biology. Thus LMP1 expression upregulates activation induced (cyti-
status all modify risk. dine) deaminase expression, which facilitates somatic hypermutation
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Aspects of the biology and epidemiology of each of these viruses and immunoglobulin class switching. LMP1 expression may also be
and their relationship with lymphomagenesis are reviewed in this important in the conversion of naïve B cells to postgerminal center
chapter. In addition, clinically important and distinctive features of memory B cells. LMP2A allows B cells that lack normal immuno-
diagnosis and treatment of the associated lymphomas are presented. globulin expression to escape regulatory checkpoints and survive. 8

EPSTEIN-BARR VIRUS Epidemiology of Viral Infection

Viral Biology EBV infection is ubiquitous. The vast majority of adults are infected
worldwide. Primary infection is most often asymptomatic, especially
1,2
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EBV is a gammaherpesvirus transmitted mainly through saliva. when it occurs in childhood. Primary infection may be associated
After primary infection, some of the infected cells are driven to with the syndrome of infectious mononucleosis. Symptomatic
proliferate and thereby spread infection throughout the B-cell com- primary infection occurs more frequently in older children and in
partment. Ultimately, in the normal host, there is an immune adults than in younger children. Other possible determinants of
response that controls infection and eradicates virus-infected prolif- symptomatic primary infection include genetic factors and possibly
erating cells. Thereafter the viral genome is harbored mainly in resting the size of the viral inoculum.
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memory B lymphocytes that persist for life. These B cells that harbor Strain differences in EBV are well recognized. However, the
virus elude immune surveillance in part because of their very restricted importance of these strain differences with regard to lymphomagen-
viral gene expression, such that few viral antigens are presented. esis remains poorly understood. There is general agreement that the
Occasionally there is activation of viral lytic gene expression (occur- type 1 strain EBV is most common worldwide and in tumors. The
ring at least in some instances in concert with plasma cell differentia- type 2 strain virus has been identified in some African Burkitt lym-
tion), leading to production of infectious virions that may infect phoma (BL) and in some AIDS-associated lymphoma. The type 1
other B cells. T cell–mediated immune function keeps such prolifera- strain virus is more efficient at lymphocyte immortalization in vitro
tion in check. 3 and lymphomagenesis in mouse models. The two strains of virus
In vitro, EBV immortalizes B cells such that they grow indefinitely differ mainly in the EBNA2 gene, but differences are recognized in
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as lymphoblastoid cell lines (LCLs) (Fig. 83.1). LCLs are tumorigenic some other viral proteins as well. Variations in the regulatory regions
in immunodeficient mice. In LCLs, viral genomes are present as or coding regions of a variety of other genes, including EBNA1,
circular, double-stranded deoxyribonucleic acid (DNA) episomes LMP1, and ZTA, have been recognized and suggested to play a role
within the nucleus. The viral proteins required for immortalization in lymphomagenesis. A simple classification of latent viral gene
include Epstein-Barr virus nuclear antigen-1 (EBNA1), a sequence- expression recognizes three patterns, as shown in Table 83.2.
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 Epstein-Barr Virus Detection in Clinical Specimens
protein-1 (LMP1), a constitutively activated member of the tumor
necrosis factor receptor superfamily, which most closely resembles The sensitivity of polymerase chain reaction (PCR) makes detection
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CD40. LMP1 activates the nuclear factor-κB (NFκB) pathway, of viral DNA straightforward, but the ubiquity of EBV infection, as
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