Advances in Anatomic Pathology:
Epstein-Barr Virus in Lymphoproliferative Processes: An Update for the Diagnostic Pathologist
Ng, Siok-Bian MBBS*; Khoury, Joseph D. MD†
*Department of Pathology, National University of Singapore and National University Hospital, Singapore
†Department of Pathology, Nevada Cancer Institute, Las Vegas, NV
Joseph D. Khoury is also Associate Director and Medical Director of Hematopathology at Quest Diagnostics, Las Vegas, NV.
Siok-Bian Ng and Joseph D. Khoury have no financial conflicts of interests to declare.
Reprints: Joseph D. Khoury, MD, Department of Pathology, Nevada Cancer Institute, 1 Breakthrough Way, Las Vegas, NV 89135 (e-mail: firstname.lastname@example.org).
The Epstein-Barr virus is an orally transmitted herpesvirus that is widespread in human populations and exhibits marked B-cell tropism. It is associated with more human neoplasms than any other known virus, and its role in the pathogenesis of such neoplasms has been the subject of intense investigation. This review presents an overview and update of the biology of Epstein-Barr virus and the diagnostic features of lymphoproliferative disorders associated with this intriguing human pathogen.
Epstein-Barr virus (EBV) (also called human herpesvirus 4, HHV-4) is a ubiquitous DNA virus belonging to the γ subfamily of herpesviruses, which includes 2 genera: γ-1 herpesviruses and γ-2 herpesviruses. EBV has been assigned to the γ-1 herpesvirus genus, also known as lymphocryptoviridae. It is the only lymphocryptoviridae that infects humans and the first human virus to be directly implicated in the oncogenesis of both lymphoid and epithelial tumors.
EBV was discovered in cultured Burkitt lymphoma cells by Michael Epstein, Yvonne Barr, and Bert Achong in 1964.1 Subsequent population studies demonstrated the prevalence of EBV infections in virtually all human populations, affecting more than 90% of individuals during the first 2 decades of life throughout the world.2 In developing countries, primary EBV infection occurs during the first few years of life and is often asymptomatic. In more developed countries, there is a tendency toward delayed primary infection, with a proportion of late infections in adolescence and adulthood manifesting clinically as a self-limited infection referred to as infectious mononucleosis (IM).3
EBV has been associated with several hematopoietic, epithelial, and mesenchymal neoplasms in both immunocompetent and immunocompromised individuals.4–8 (Table 1) Several recent reviews have elegantly addressed EBV-associated epithelial and mesenchymal neoplasms.9 This review discusses the histopathologic and clinical features of EBV-associated lymphoproliferative disorders and highlights recent advances elucidating the role of EBV in their pathogenesis. Whereas some nomenclature of EBV-associated lymphoproliferative disorders has evolved over time, the terms employed in this review are based on the recent revision (4th edition) of the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues.10
STRUCTURE AND VIROLOGIC FEATURES OF THE EPSTEIN-BARR VIRUS
EBV contains a 172-kb linear DNA genome whose structure has been well-characterized. Upon infection of a host cell, the linear EBV genome is transformed into a circular episomal DNA structure. The EBV genome is composed of short and long unique sequence domains (US and UL, respectively), and repetitive sections referred to as internal repeats 1 and terminal repeats (TR).11 The heterogeneity of TR in episomal EBV DNA has been exploited to determine clonal infection events, as the number of episomal TR remains unaltered during replication of the virus in a latently infected host cell.12
The EBV genome is encased within a nucleocapsid, which in turn is surrounded by a viral envelope. EBV exhibits marked tropism for B cells. This preferential binding to B cells is mediated by interaction of the major viral envelope, glycoprotein gp350, with the C3d complement receptor, CD21, on the surface of B cells.13,14 Subsequently, a second envelope glycoprotein, gp42, part of a trimolecular complex that includes the gp85/gp25 fusion proteins, binds to human leukocyte antigen (HLA) class II molecules.15–17 The latter interaction initiates a cascade of catalytic events leading to virus-cell membrane fusion and allowing viral entry. In cultured B cells, EBV infection leads to the proliferation and outgrowth of EBV-positive B lymphoblastoid cell lines.
However, EBV is not exclusively B lymphotropic. Indeed, infection of the oropharyngeal squamous epithelium seems to be an integral part of the natural EBV-host interaction, and replication at such sites could explain the elevated levels of infectious virus seen in the throat washings of IM patients.11 Interestingly, exposing epithelial cells to cell-free virus preparations in vitro gives very low rates of infection, but when epithelial monolayers are cocultured with EBV-positive B-cell lines, infection rates increase significantly.18 And, although both thymocytes and mature T cells express low levels of CD21, EBV infection of T cells seems to be a rare event.19,20
LATENT AND LYTIC PHASES OF EPSTEIN-BARR VIRUS INFECTION
As is characteristic of all herpesviridae, EBV is capable of executing several distinct programs of gene expression, which are broadly categorized into lytic phase or latent phase genes. The EBV genome encodes about 100 viral proteins that include transcription activators, DNA replication factors, and structural proteins. The expression of EBV-encoded proteins varies depending on the type, differentiation, and activation status of the target cell. Most of the EBV viral proteins are expressed during lytic viral replication. BZLF1 and BRLF1 are 2 potent transactivators of lytic cycle genes, and they play a key role in ushering the switch from latency to lytic cycle.21
Latently infected virus-carrying B cells in healthy individuals are found in the resting, memory compartment. The viral genome maintained as a circular episome during latency is replicated by the host's cellular DNA polymerase and dispensed equally to progeny cells during the process of cellular division. Only a highly restricted number of genes is expressed during latent infection (Fig. 1), and these include 6 nuclear antigens [EBV nuclear antigen 1 (EBNA1), EBNA2, EBNA3A, EBNA3B, EBNA3C, and EBNA leader protein], 3 latent membrane proteins (LMPs—LMP1, LMP2A, and LMP2B), 2 small, nontranslated (nonencoding) RNA molecules [EBV-encoded small RNAs (EBER1 and EBER2)], and transcripts from the BamHI A region (BARTs).21,22 Genetic studies with recombinant EBV demonstrate that EBNA2, EBNA3A, EBNA3C, and LMP1 are essential for B-cell immortalization in vitro. By selectively limiting the expression of viral genes during latency, EBV decreases the number of viral proteins that would normally allow the recognition of infected cells by cytotoxic T cells.
The EBNA1 protein is a phosphoprotein capable of binding to viral DNA and maintaining the EBV genome in the host cell as a circular episome. It is required for the replication and maintenance of the viral genome and plays a central role in sustaining latent infection and cell immortalization.21,23 EBNA2 up-regulates the expression of viral and cellular genes that contribute to B-cell growth and transformation, including those encoding LMP1, LMP2, CD21, and CD23.21 The C-MYC oncogene seems to be another important target of EBNA2, and this may impact subsequent EBV-induced B-cell proliferation.24 The 3 members of the EBNA3 family (EBNA3A, EBNA3B, and EBNA3C) are transcriptional regulators; EBNA3A and EBNA3C are crucial for B-cell transformation in vitro, whereas EBNA3B seems to be nonessential.25 Although not absolutely needed for B-cell transformation in vitro, EBNA leader protein interacts with EBNA2 to inactivate the tumor suppressor genes p53 and Rb.22,26
LMP1 is the major EBV oncoprotein and is vital for EBV-induced B-cell proliferation in vitro.27 Functionally, LMP1 acts by mimicking CD40 and inducing cellular signaling responses that are critical for B-cell transformation.28 The oncogenic potential of LMP1 is ultimately linked to its ability to recruit an array of cellular genes, which result in constitutive activation of nuclear factor-κB (NF-κB) and up-regulation of cellular adhesion molecules, cytokine production, and B-cell proliferation.22,27,29,30
LMP2 prevents reactivation of EBV from latently infected cells and favors the maintenance of EBV latency in the bone marrow.22,27,30 LMP2 is a hydrophobic membrane protein that exists as 2 alternative forms, LMP2A and LMP2B.31 These forms are transcribed across the fused TRs of the EBV episome from promoters 3 kb apart, which generate mRNAs with 8 common exons and a 5′ exon unique to each type.32 Functional investigations of LMP2A and LMP2B indicate that they are dispensable for B-cell transformation in vitro.33–35
Type III Latency Program—the Growth Program
In this pattern of EBV latency, also referred to as the “growth program”, the full set of EBV-encoded proteins is detected in lymphoblastoid cell line.36 In these cells, the spliced products of a large mRNA transcript are translated into EBNA1 to EBNA6. In addition, the virus encodes LMP1, LMP2A, and LMP2B. The growth program is expressed only in B lymphocytes. LMP1 has a strong impact on the phenotype of B cells, inducing activation markers and costimulatory molecules, which augment their immunogenicity vis-a-vis cytotoxic T cells. For that reason, cells expressing the growth program can exist only during the acute phase of primary infection, before the EBV-specific T-cell response develops, and in some immunocompromised patients.37
Type I Latency Program
This pattern of EBV latency is characterized by the expression of only 1 nuclear protein, EBNA1. The type I latency pattern is expressed in healthy carriers, and this limited repertoire of gene expression prevents frequent viral replication and proliferation, which may kill the host cell. The eventual result of EBV infection in an immunocompetent host leads to a virus-specific, HLA-restricted cytotoxic CD8-positive T-cell response that predominantly targets epitopes on the EBNA3A/B/C subset of latent infection proteins.38 EBNA1 is not a target for this cytotoxic T-cell response, allowing EBV-infected cells exhibiting type 1 latency to evade immune surveillance.
Cytotoxic T cells do not recognize EBNA1 because of a long glycine-alanine repeat creating an inhibitory signal that interferes with antigen processing and major histocompatibility complex class I-restricted presentation.39
Type II Latency Program
The type II latency program has recently been divided into type IIa and type IIb latencies. Although both latencies share several common features, they are set apart by the lack of expression of two pivotal proteins needed for cellular transformation: EBNA2 is absent in type IIa latency, and LMP1 is absent in type IIb latency.
Type IIa Latency Program
In this latency pattern, the EBV gene expression program is limited to EBNA1, LMP1, and LMP2. It was initially identified in nasopharyngeal carcinoma (NPC).40 Subsequently, type IIa latency was identified in EBV-positive Hodgkin lymphoma (HL) as well as in EBV-positive mature T/natural killer (NK) cell lymphomas.41,42 As EBNA2 is necessary for induction of proliferation of EBV-infected B cells, B cells with type IIa latency are generally not induced to proliferate.43
Type IIb Latency Program
The type IIb latency program is characterized by expression of all EBNA proteins and the lack of LMP1 expression. This pattern was first detected in B-chronic lymphocytic leukemia cells infected with EBV in vitro.44–47 The lack of LMP1 expression in the EBNA2-positive B-chronic lymphocytic leukemia cells is noteworthy because normally EBNA2 is responsible for activation of the LMP1 promoter in B cells.48,49
EPSTEIN-BARR VIRUS INFECTION AND THE HOST RESPONSE
The main route of virus entry is the upper aerodigestive tract. EBV-infected B cells are constantly identified in normal nasopharyngeal mucosa and tonsils.50–52 Thereafter, as part of the normal migration and recirculation of lymphocytes, these EBV-infected B cells spread the virus to lymph nodes, peripheral blood, and other mucosal sites.53 Scattered EBV-positive lymphoid cells have been detected in normal gastric mucosa and other mucosa-associated lymphoid tissue sites in healthy individuals.52,54 EBV persists in the infected host in a latent, lifelong nonlethal carrier state (see above). Such a carrier state is punctuated by periodic reactivation from latency to lytic phase leading to low-level shedding of infectious virions from mucosal surfaces throughout the life of the host.55 Intriguingly, lymphomas and carcinomas associated with EBV, such as nasal NK/T-cell lymphoma and undifferentiated nasopharyngeal carcinoma, often occur around the upper aerodigestive tract.
Infection by EBV elicits both humoral and cell-mediated host immune responses. The humoral response, which includes production of antibodies against viral structural proteins—the EBV capsid antigen (VCA-IgG) and early antigen (EA-IgG) —does not seem to play a major role in the control of an established EBV infection.
In the immunocompetent host, latent EBV infection is subdued primarily by a population of virus-specific CD8-positive cytotoxic T cells that recognize epitopes derived from EBNA proteins 2, 3A, 3B, and 3C.56,57 These activated T cells are the characteristic atypical lymphocytes seen in peripheral blood smears of IM patients. Peripheral lymphocytosis, lymphadenopathy, and splenomegaly are a manifestation of such a T-cell proliferation (rather than a proliferation of EBV-infected B cells). These activated cytotoxic T cells are believed to also contribute to the symptoms associated with IM through secretion of cytokines such as interferon (IFN)-γ and interleukin-2.57
The persistence and oncogenic potential of EBV can be attributed to several factors, including: (1) capability of the virus to maintain its viral genome in the cell without endangering the life of the host, (2) strategies which permit evasion of the host immune system, and (3) ability to activate cellular growth control pathways.22,58
EBV encodes several proteins that bear sequence and functional homology to diverse human proteins. These proteins are thought to play a role in the interference of the normal control of EBV-infected cells. BCRF1 is a homolog of human interleukin-10 and enhances viral persistence by inhibiting the synthesis of IFN-γ.59 BARF1 shows homology to colony-stimulating factor 1 and acts as a decoy receptor to block the action of the cytokine, resulting in the inhibition of the expression of IFN-α.60 The EBV protein (BHFR1 homolog of human bcl-2 protein) and LMP1 inhibit apoptosis and prevents the infected B cells from undergoing programmed cell death.61
Immunocompromised patients are at high risk of developing early onset EBV-induced B-cell tumors because of the absence of effective T-cell surveillance, allowing unrestricted expression of EBV genes and autonomous growth of infected cells (type III latency pattern). In immunocompetent hosts, EBV-associated lymphoid malignancies show more restricted forms of latent gene expression, reflecting a more complex pathogenesis that involves additional cofactors, and occur years after the primary infection. The majority of these late onset tumors are non-B cell in origin and probably initiate from a clone of EBV-infected cells, which achieve ultimate oncogenesis after accruing supplementary cellular changes and growth promoting signals from the microenvironment, secondary to additional events such as specific failure of the immune system, secondary genetic aberrations, and stimulation of B-cell proliferation by other infections.22,58
ACUTE SELF-LIMITED PRIMARY EPSTEIN-BARR VIRUS INFECTION AND INFECTIOUS MONONUCLEOSIS
During childhood, primary EBV infection is usually either asymptomatic or indistinguishable from other acute viral illnesses. In some patients, it manifests with enlarged painless lymph nodes and proliferation of oropharyngeal lymphoid tissue. Oropharyngeal infection results in an initial localized lytic infection that is followed by infection of circulating B cells. The appearance of the heterophile antibodies in the serum, which is one of the critical diagnostic markers, is the result of B-cell activation. Heterophile antibodies are composed of an early IgG and IgM antibody response to VCAs coupled with a more delayed seroconversion to antibodies against EBNA proteins.
In adolescents and young adults, EBV infection frequently results in IM, a self-limiting lymphoproliferative disease characterized by sore throat, fever, lymphadenopathy, and splenomegaly. In patients with full blown IM, between 0.1% and 1% of peripheral blood B cells can contain EBV virions.62 These EBV-infected B cells from IM patients express the latency type III pattern. Interestingly, HLA class I polymorphisms appear to predispose some patients to the development of IM upon primary EBV infection, suggesting that genetic variation in T-cell responses can influence the nature of primary EBV infection and the level of viral persistence.63
From a histologic standpoint, lymph node tissue and extranodal lymphoid tissue during IM exhibit reactive secondary follicles with notable expansion of B-cell immunoblasts in paracortical areas (Fig. 2). Large mononuclear or binuclear immunoblasts, occasionally resembling Reed-Sternberg cells, are also seen frequently. In addition to expressing B-cell markers, these immunoblasts are generally positive for CD30. Differentiating such a florid reactive immunoblastic proliferation from lymphoma may sometimes be difficult on the basis of morphologic and immunophenotypic findings alone and requires careful correlation with clinical features.
EPSTEIN-BARR VIRUS-ASSOCIATED LYMPHOPROLIFERATIVE DISEASES OF UNCERTAIN MALIGNANT POTENTIAL
Chronic Active Epstein-Barr Virus Infection
The term chronic active EBV (CAEBV) infection was coined to describe an uncommon IM-like illness persisting for at least 6 months resulting from an abnormal immune response to EBV. By definition, the disease arises in patients without immunodeficiency or autoimmune diseases. It was first described by Virelizier and colleagues64 in 1978 as an atypical illness associated with serologic evidence of persistent EBV infection.
Along one end of the spectrum of CAEBV, common in Western populations, the disease pursues a generally innocuous course, with only rare progression to an EBV-positive T-cell lymphoproliferative disorder.5,65,66 On the other end of the spectrum of CAEBV, common in Asian populations, the disease pursues an aggressive clinical course associated with high mortality and morbidity, characterized by high-grade fever, hepatosplenomegaly, extensive lymphadenopathy, and pancytopenia.67–69 The severe form of CAEBV is associated with high levels of EBV viremia and an abnormal humoral response pattern. Additionally, a significant proportion of patients with severe CAEBV develop life-threatening complications that include hemophagocytic syndrome, liver failure, central nervous system (CNS) involvement, and myocarditis.
Accumulating evidence indicates that the central pathogenetic feature of severe CAEBV is a clonal expansion of cytotoxic T and/or NK cells (rather than B cells). Such clonal expansions have been associated with chromosomal aberrations,70 clonal EBV genome,71 and frequent development of overt T-cell lymphoma.68,72 The latter (discussed below) generally include hydroa vacciniforme-like lymphoma and systemic EBV-positive T-cell lymphoproliferative disease of childhood. Thus, severe CAEBV has been increasingly regarded as an EBV-associated T/NK lymphoproliferative disorder rather than merely an aberrant immunologic response to EBV infection.68,72,73 In fact, according to the revised 2008 WHO classification, severe CAEBV with monoclonal EBV-associated T-cell proliferation is best regarded as part of the spectrum of systemic EBV-positive T-cell lymphoproliferative disease of childhood (see below) and should not be referred to as CAEBV.74
EPSTEIN-BARR VIRUS-ASSOCIATED LYMPHOPROLIFERATIVE NEOPLASMS ARISING IN THE IMMUNOCOMPETENT HOST
Neoplasms of B-cell Derivation
Three clinical variants of Burkitt lymphoma are recognized, based on clinical features, biology, and association with EBV: endemic, sporadic, and immunodeficiency-associated. Endemic Burkitt lymphoma occurs frequently in the equatorial regions of Africa and Papua, New Guinea, where the incidence is 50 to 100 cases per 1,000,000 individuals. Virtually all cases of endemic Burkitt lymphoma are associated with the presence of EBV in tumor cells. In contrast, sporadic Burkitt lymphoma arises mainly in young adults and children in a patternless geographic distribution. Its incidence is lower than that of endemic Burkitt lymphoma, with 2 to 3 cases per 1,000,000 individuals. The association between sporadic Burkitt lymphoma and EBV is low (15% to 30% of cases).
Histologically, Burkitt lymphoma is a diffuse, monomorphic infiltrate of intermediate-sized neoplastic cells with round nuclei, clumped chromatin, and several distinct peripheral nucleolar regions. The neoplastic cells are characterized by a basophilic cytoplasm that often contains variable numbers of clear vacuoles. One of the characteristic features of Burkitt lymphoma is the markedly elevated cell turnover rate manifesting as numerous mitotic figures and apoptotic bodies with scattered macrophages engorged with phagocytosed cellular debris (Fig. 3). The neoplastic cells in Burkitt lymphoma express membrane IgM with light chain restriction, PAX5, CD19, CD20, CD22, CD10, BCL6, CD38, CD77, and CD43. They are generally negative for TdT and BCL2. A hallmark of Burkitt lymphoma is the expression of the proliferation marker Ki67 by virtually 100% of the neoplastic cells.
Burkitt lymphoma is currently defined by its histologic features, immunophenotype, and the presence of translocations involving the c-MYC oncogene at chromosome 8q24 leading to deregulated overexpression of the c-MYC oncoprotein.75 The most common translocation, t(8;14)(q24;q32), is seen in 80% of the cases and leads to juxtaposition of C-MYC and the immunoglobulin heavy chain gene (IgH) on chromosome 14q32. A smaller subset of Burkitt lymphoma cases harbors translocations involving C-MYC and the κ light chain gene at chromosome 2p11 (15% of cases) or λ light chain gene (5% of cases) at chromosome 22q11. Interestingly, the breakpoints at which these translocations occur are different in endemic Burkitt lymphoma on one hand and sporadic and immunodeficiency-associated Burkitt lymphoma on the other. In endemic Burkitt lymphoma, the breakpoints on chromosome 8 occur in the noncoding regions 5′ to C-MYC exon 1, whereas the breakpoints on chromosome 14 occur primarily in the IgH joining regions at sites that are possible targets for somatic hypermutation. In sporadic and immunodeficiency-associated Burkitt lymphoma, the breakpoints on chromosome 8 occur between C-MYC exons 1 and 2, whereas the breakpoints on chromosome 14 occur primarily within the IgH switch region.
Classic Hodgkin lymphoma
The hallmark of classic Hodgkin lymphoma (cHL) is a neoplastic proliferation of altered B cells in association with a prominent reactive inflammatory infiltrate that is occasionally accompanied by fibrosis. The neoplastic B cells in cHL are referred to as Hodgkin cells, Reed-Sternberg cells, or Hodgkin-Reed-Sternberg (HRS) cells (Fig. 4). Four histologic variants of cHL are recognized: nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted. A related, but pathogenetically distinct variant of HL, nodular lymphocyte-predominant HL, is distinguished from cHL and is not associated with EBV.
EBV infection is associated with approximately 40% of cHL cases, most commonly in mixed cellularity cHL. The identification of EBV in some cases of cHL has been long recognized. In cHL, EBV usually expresses type IIa latency infection pattern. In a recent study, LMP1 was found to be capable of reprogramming germinal center B cells toward a HRS-like phenotype.76 cHL associated with EBV has been found to selectively down-regulate certain micro-RNA molecules, miR-96, miR-128a, and miR-128b.77
Polymorphisms in the HLA region could explain ethnic variation in the incidence of HL. The association of EBV-positive cHL with HLA class I suggests that this polymorphism might affect the proper presentation of EBV antigens to cytotoxic T lymphocytes.78 It has also been demonstrated that individuals carrying the HLA-A*02 allele have a reduced risk of developing EBV-positive cHL, whereas individuals carrying the HLA-A*01 allele have an increased risk. It is known that HLA-A*02 can present EBV-derived peptides and can evoke an effective immune response, which may explain the protective phenotype.79
Expression of LMP1 in HRS cells has been associated with a favorable prognosis in patients with cHL, but this effect may be restricted to young adults and those with early stage disease.80 Additionally, patients with EBV-associated cHL showed a significantly longer mean time to first relapse compared with EBV-negative cases, albeit overall survival did not correlate with EBV association.81
Impairment of B-cell differentiation has been proposed as a decisive event in cHL lymphomagenesis.82 During normal B-cell maturation, cells that have rearranged their IgH gene undergo further mutations referred to as ”somatic hypermutations.” Somatic hypermutations contribute to the creation of immunoglobulins with enhanced affinity to prevalent antigens. B cells with a defective immunoglobulin or whose immunoglobulin-antigen affinity is weak normally undergo apoptosis. The neoplastic cells of cHL are postulated to derive from germinal center B cells that harbor crippling mutations in their immunoglobulin genes.83–85 EBV infection seems to provide an alternative mechanism for rescuing such abnormal germinal center B cells from apoptosis. One of the main pathogenetic features of HRS cells is the presence of constitutively elevated levels of NF-κB, which is a key factor in rescuing normal germinal center B cells from apoptosis.86 One mechanism by which NF-κB could be activated in HRS cells is through the action of LMP1, a potent activator of NF-κB.87 In addition, LMP2A is also capable of signaling effectively through the Ig receptor.88 The discovery of HRS cells with mutations in IκB presents an alternative non–EBV-mediated mechanism whereby abnormal, constitutive NF-κB activation may contribute to the development of cHL.89,90 Other nonviral mechanisms that might play a role in maintaining a constitutively activated NF-κB state include amplification of the REL gene (encodes an NF-κB family member)91 or signals acting on surface receptors such as CD30.92
Lymphomatoid granulomatosis (LyG) is an angiocentric and angiodestructive extranodal B-cell lymphoproliferative disorder in which neoplastic EBV-positive B cells are associated with a florid reactive background T-cell infiltrate.93 Although LyG most commonly involves the lungs, it can affect virtually any anatomic site, including brain, kidneys, liver, and skin.94 The neoplastic cells in LyG were initially thought to be of T-cell lineage until it was demonstrated that EBV was present within B cells that had clonal immunoglobulin heavy chain gene rearrangements.95–98
The morphologic spectrum of LyG is variable. On one end are polymorphous infiltrates of small lymphocytes, plasma cells, and histiocytes containing scattered atypical cells with immunoblastic or HRS-like features. On the other end of the spectrum are tumors that are virtually indistinguishable from diffuse large B-cell lymphoma (DLBCL). Lymphocytic vasculitis, vascular damage, and necrosis are also seen in most cases to variable degrees. A 3-tier grading system has been developed for LyG, based primarily on the number of EBV-positive B cells per high-power microscopic field (Table 2).93,99 Only limited information on the latency pattern of EBV infection is available from a small series that demonstrated type III latency (LMP1 and EBNA2 expression) in 2 of the 3 EBV-positive LyG cases.100 The neoplastic EBV-positive cells are usually positive for CD20 and may express CD30. CD15 expression is generally absent.
The prognosis of patients with LyG is variable, ranging from spontaneous regression to aggressive disease course with a median survival of less than 2 years despite intensive chemotherapy.94,99
Diffuse Large B-cell Lymphoma Associated With Chronic Inflammation (Pyothorax-associated Lymphoma)
DLBCL associated with chronic inflammation occurs in the setting of protracted chronic inflammation and shows an association with EBV.101 The prototype example of this category of DLBCL is pyothorax-associated lymphoma (PAL). PAL is a clinically distinct type of B-cell lymphoma arising in the pleural cavity of patients with chronic pyothorax.102,103 The tumor typically exhibits immunoblastic morphology and presents as a pleural mass. The majority of patients are male and have a longstanding history (median 37 y) of pyothorax resulting from tuberculous pleuritis or artificial pneumothorax for treatment of pulmonary tuberculosis.104 The majority of PAL cases (70% to 100%) are associated with EBV and show type III latency pattern that includes EBER, EBNA2, and LMP1 expression.104–106 The precise role of EBV in the pathogenesis of PAL remains unknown.
Although partially responsive to chemotherapy, patients with PAL have an overall poor prognosis.104 The 5-year overall survival ranges from 20% to 35%.107
Epstein-Barr Virus-positive Diffuse Large B-cell Lymphoma of the Elderly (Age-related or Senile Epstein-Barr Virus-associated B-cell Lymphoproliferative Disorders)
A series of immunocompetent elderly patients with EBV-positive B-cell lymphoproliferative disorders (B-LPD) and/or large cell lymphomas was identified by Oyama and colleagues.108 It is postulated that senescence of the immune system that is part of the normal aging process predisposes patients to the development of this B-LPD. EBV-positive DLBCL of the elderly is currently defined by the WHO as an EBV-positive clonal B-cell lymphoid proliferation that occurs in patients without any known immunodeficiency or prior lymphoma and more than 50 years old.109 The median age is 71 years with a range of 45 to 92 years.110 Patients often present with lymphadenopathy, and extranodal sites are commonly involved. The disease shows a wide morphologic spectrum, similar to posttransplant lymphoproliferative disorder, and has been subdivided into 2 subtypes: polymorphous and monomorphous (large cell lymphoma).108 The presence of necrosis and angiodestructive growth pattern are characteristic morphologic features. Some cases contain large cells that resemble HRS cells. The clonal EBV-positive B cells may express CD30 but not CD15. By definition, all cases are EBV positive and most show a type III latency pattern that includes LMP1 and EBNA2 expression.110
EBV-positive DLBCL of the elderly has a significantly inferior survival and chemoresponsiveness compared with EBV-negative DLBCL. The clinical course is aggressive, with a median survival of 2 years.111
Neoplasms of T/Natural Killer-cell Derivation
Extranodal Natural Killer/T-cell Lymphoma, Nasal-type
Extranodal natural killer/T-cell lymphoma, nasal-type (NKTCL-NT) is a distinct clinicopathologic entity most commonly affecting Asian and Central and South American adults and is highly associated with EBV.112 The tumor characteristically arises in the nasal cavity or surrounding structures and presents as a destructive midline facial lesion. Identical “nasal-type” tumors are seen in other anatomic sites, including skin, upper aerodigestive tract, testis, soft tissue, gastrointestinal tract, and spleen.113,114 Hemophagocytic syndrome is often a late clinical complication and is associated with a rapidly fatal course.115
Morphologically, NKTCL-NT exhibits a broad cytologic spectrum ranging from small to large and anaplastic cells, accompanied by a prominent non-neoplastic inflammatory background (Fig. 5). Angiocentric and angiodestructive growth pattern with geographic necrosis and ulceration are other distinctive features. Like normal NK cells, the cells of NKTCL-NT are CD2+, CD56+, surface CD3−, cytoplasmic CD3+, CD8−/+, CD4−, and they express cytotoxic granule proteins [granzyme B, T-cell–restricted intracellular antigen (TIA) and perforin]. CD43, CD45RO, FAS (CD95), and FAS ligand are commonly positive and occasional cases express CD7 or CD30.112
EBV is detected in the neoplastic cells of NKTCL-NT in a clonal episomal form, supporting the role of the virus in tumor pathogenesis.116 Like other EBV-positive T-cell lymphomas, an intriguing finding is the frequent detection of the virus in only a fraction (5% to 50%) of the tumor cells, implying that EBV infection occurs subsequent to tumor initiation.117 EBV expresses latency type II pattern that includes LMP1 and EBNA1, in addition to EBER.118
NKTCL-NT typically does not demonstrate rearrangement of T-cell receptor (TCR) or immunoglobulin genes. However, a minority of cases with identical clinical features exhibits clonal TCR gene rearrangement.119,120 Various cytogenetic aberrations have been reported, of which deletions at chromosome 6q are most frequent but it remains unclear if this is a primary event or progression-related event.121,122
The clinical course is usually aggressive, but long-term survival may be achieved after treatment regimens that include chemotherapy and radiotherapy.123 Factors reported to be useful in predicting prognosis include the stage, bone or skin invasion,112 International Prognostic Index,119 CD94 expression,124 Ki-67 expression,125 and EBV viral load.126,127
The current diagnosis of NKTCL-NT according to the WHO classification requires both EBV positivity and cytotoxic granule protein expression.112 Immunophenotypic deviations, such as CD8 expression, lack of CD56 expression, and molecular evidence of T-cell origin are compatible with a diagnosis of NKTCL-NT, provided the clinical, morphologic, and other features are otherwise typical. Rarely, NKTCL-NT can present as a primary nodal disease. Small cell variant of the tumor and those with a rich inflammatory background may mimic a reactive process and pose a diagnostic challenge. Infiltration of nasal septum bone is considered highly suggestive of malignancy, as this feature is rarely encountered in inflammatory conditions.114 Other clues to suggest a neoplastic process include a dense expansile infiltrate with distortion or destruction of mucosal glands, necrosis and angioinvasion, cells with clear cytoplasm, and frequent mitoses.128
Aggressive Natural Killer-cell Leukemia
Aggressive NK-cell leukemia (ANKL) is a clinically aggressive, systemic proliferation of neoplastic NK cells.129 The disease arises most commonly in teenagers and young adults, with a predilection to Asians. Patients typically present with severe constitutional symptoms that include prostration, fever, hepatosplenomegaly, lymphadenopathy, and a leukemic blood picture, sometimes accompanied by hemophagocytic syndrome. Occasional cases manifest with generalized lymphadenopathy with little or no involvement of the peripheral blood, hence the choice of the term “leukemia/lymphoma” for this entity.130,131
The neoplastic cells in circulation resemble large granular lymphocytes and can have prominent nucleoli. Bone marrow involvement by ANKL ranges from patchy to diffuse. Tissue involvement is characterized by a monotonous destructive infiltrate of medium sized cells with condensed chromatin and small nucleoli; necrosis is common. The neoplastic cells are CD2+, surface CD3−, CD56+, CD57−, TIA1+, and granzyme B+. Most cases harbor EBV in a clonal episomal form. The TCR genes are in a germline configuration.
The disease shares many features with NKTCL-NT, including a strong association with EBV, prevalence among Asians and a similar immunophenotype. Despite the similarities, there are several features that distinguish ANKL from NKTCL-NT (Table 3).132,133 Occasional cases of NKTCL-NT may involve the bone marrow in late stages and some have been found to progress to an aggressive, systemic disease that is indistinguishable from ANKL.134 These observations have led to the suggestion that ANKL might represent the leukemic form or terminal stage of NKTCL-NT. Molecular genetic studies of ANKL and NKTCL-NT have demonstrated a difference in expression profiles but no conclusive data regarding the nature of their pathogenetic origins.135–137
Epstein-Barr Virus-positive T-cell Lymphoproliferative Disorders of Childhood
This category of EBV-associated T-cell LPD (T-LPD) arising in children consists of 2 main entities: hydroa vacciniforme-like lymphoma (HVL) and systemic EBV-positive T-LPD of childhood. These disorders occur with increased frequency in Asian populations and in Native Americans from Central and South America and Mexico.74
A clinicopathologic classification system was recently proposed by the CAEBV Study Group to categorize EBV-associated T/NK-cell lymphoproliferative disorders in children and young adults. The proposed categories—referred to as A1, A2, A3, and B—are based on: (1) morphologic features (polymorphic vs. monomorphic LPD); (2) clonal status of the EBV-infected cells; and, (3) clinical course.138 Under this proposed scheme, systemic EBV-positive T-LPD of childhood is regarded as a category B disorder, given its monomorphic histology, clonal nature, and fulminant clinical course. HVL and other EBV-positive T/NK-LPD of childhood are categorized on the basis of their respective features.
Hydroa Vacciniforme-like Lymphoma
HVL is an EBV-associated cutaneous cytotoxic T-cell lymphoproliferative disorder affecting children from Asia, and Central and South America. Clinically, patients present with a papulovesicular eruption in sun-exposed skin, associated with ulceration.73,139 Systemic symptoms and hemophagocytic syndrome may be present. Marked hypersensitivity to mosquito bites is a characteristic feature that often precipitates the disease. The clinical course for patients with HVL is variable, with some patients exhibiting skin lesions for over a decade. On the other hand, documentation of systemic involvement is associated with a more aggressive course.74
The disease displays significant overlap with NKTCL-NT, and may be considered as a variant of the latter.72,132 In addition to a similar morphology and immunophenotype, including expression of CD56,140 EBV infection in HVL also demonstrates a type II latency gene expression, akin to NKTCL-NT and most of the EBV-associated T-cell and NK-cell malignancies.72 A relationship between HVL and some cases of CAEBV has been demonstrated.141
Systemic Epstein-Barr Virus-positive T-cell Lymphoproliferative Disease of Childhood
This is a life-threatening systemic EBV-positive T-LPD characterized by fever, hepatosplenomegaly, liver failure, pancytopenia, and hemophagocytosis.66 The disease arises in children after primary EBV infection or in patients with antecedent CAEBV. The clinical course is fulminant, with the majority of cases progressing toward multiorgan failure, sepsis, and death.66,142,143 An abnormal EBV serology with low or absent anti-VCA IgM is common.
Several clinical disorders reported in the past showing overlapping features with systemic EBV-positive T-LPD of childhood, are now incorporated under this term according to the revised 2008 WHO classification. They include EBV-associated hemophagocytic syndrome, fatal IM, viral-associated hemophagocytic syndrome, severe CAEBV, EBV-associated T/NK-cell LPD, and fulminant EBV-associated T-cell lymphoproliferative disorder after acute/chronic EBV infection.66,73,74,144–146
Histologically, the infiltrate of EBV-positive T cells consists of small cells with no or mild cytologic atypia, resulting in under-recognition and a delay in establishing the diagnosis. The liver and spleen are generally notable for sinusoidal infiltration by T cells and hemophagocytosis. Lymph nodes show deceptively preserved architecture that includes open sinuses that occasionally contain histiocytes exhibiting erythrophagocytosis. The latter is also noted on bone marrow biopsies.
The T-cell proliferation is monoclonal and typically expresses CD2, CD3, granzyme B, TIA1, and EBER (Fig. 6). CD56 expression is often absent. Notably, systemic EBV-positive T-LPD of childhood arising after primary EBV infection are CD8+,66,147,148 whereas cases arising in the setting of severe CAEBV are CD4+.5,65,66 Rare cases show co-expression of CD4 and CD8.66
The differential diagnosis of systemic EBV-positive T-LPD of childhood includes primarily NKTCL-NT, ANKL, and fulminant IM. The distinctive clinical presentation, immunophenotype, and the identification of clonal TCR gene rearrangement distinguish this disorder from NKTCL-NT.114,149 ANKL and systemic EBV-positive T-LPD of childhood share many clinicopathologic features, but unlike the latter, ANKL is not preceded by primary EBV infection or CAEBV, and the TCR gene is in the germline configuration.74 Although fulminant IM may be difficult to differentiate from systemic EBV-positive T-LPD of childhood due to overlapping clinical and morphologic features, the former is characterized by a polyclonal EBV-positive B-cell proliferation with a predominance of immunoblasts and plasma cells.66
Angioimmunoblastic T-cell Lymphoma
Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma often associated with systemic symptoms, hypergammaglobulinemia, hemolytic anemia, and circulating immune complexes. Histologically, AITL is characterized by a polymorphous lymphoid infiltrate with prominent admixture of eosinophils, lymphoid cells with clear cytoplasm, and arborizing high endothelial venules. Proliferation of extrafollicular follicular dendritic cells and expression of follicular helper T-cell markers, such as CD10, bcl-6, PD-1 and CXCL13, are other distinctive features.150,151 Approximately 20% of AITL are associated with proliferations of large B cells and about 70% of the B-cell proliferations associated with AITL or peripheral T-cell lymphoma, unspecified (PTCL-US), are positive for EBER.150 B-cell lymphomas arising in this setting show latency types II and III pattern.152 EBV-positive cells resembling Reed-Sternberg cells, with expression of CD30 and CD15, have also been reported in AITL and PTCL-US.153
EPSTEIN-BARR VIRUS-ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS IN THE IMMUNOCOMPROMISED HOST
Posttransplantation Lymphoproliferative Disorders
Posttransplantation lymphoproliferative disorders (PTLD) comprise a heterogeneous group of lymphoid proliferations, most commonly of B-cell lineage, arising after organ transplantation. The spectrum of PTLD ranges from reactive appearing, spontaneously regressing, polytypic lymphoplasmacytoid B-cell expansions that resemble inflammatory reactions to lethal clonal B cell proliferations that are indistinguishable from non-HLs. PTLD arises generally from donor-derived B cells that have been infected by EBV.154 EBV-positive B cells in these disorders demonstrate most frequently the latency type III pattern of EBV gene expression. Without sufficient cytotoxic T-cell function, there is uninhibited growth of EBV-infected B cells. Initially, this expanded EBV-infected B-cell pool comprised a polyclonal proliferation. Subsequent genetic aberrations eventually lead to virus-independent cell growth. Such genetic aberrations have been shown to involve genes encoding p53,155 c-MYC,156 or BCL-6.157 Proliferations associated with such genetic defects are usually more aggressive, exhibit a more restricted pattern of EBV latent gene expression, and are unresponsive to reductions in immunosuppression.
According to the WHO classification, PTLD has been divided into 4 main categories: (a) reactive, plasmacytic hyperplasia, or IM-like lymphoid hyperplasia; (b) polymorphic PTLD; (c) monomorphic PTLD; (d) cHL-type PTLD. These tumors are generally extranodal and frequently involve the transplanted organ or gastrointestinal tract. PTLD arise in patients after either solid organ or bone marrow transplantation, and their incidence is related directly to the severity and duration of immunosuppressive therapy. Because immunosuppressive regimens are often more intensive and prolonged after solid organ transplantation, the incidence of PTLDs in this patient group is relatively higher.
Epstein-Barr Virus-associated Lymphomas Arising in Patients With Human Immunodeficiency Virus Infection/Acquired Immunodeficiency Syndrome
Lymphoid neoplasms are the second most common malignancies (after Kaposi sarcoma) in patients with AIDS. It should be noted that antiretroviral therapy for patients with HIV infection has altered the natural course of the disease and lead to a reduction in the incidence of lymphomas in HIV-positive patients. Lymphomas arising in the setting of HIV/AIDS are a heterogeneous group. Some of these lymphomas are seen almost uniquely in the setting of HIV/AIDS, and these include primary effusion lymphoma and plasmablastic lymphoma. Other lymphomas that commonly affect HIV/AIDS patients are similar to those seen in immunocompetent (HIV negative) patients, and these include cHL, Burkitt lymphoma, and DLBCL (primarily involving the CNS). The frequency of EBV association with lymphomas arising in patients with HIV/AIDS is variable. In this setting, EBV is associated with virtually all cases of primary CNS lymphoma and cHL, 80% of DLBCL with immunoblastic features, 70% of primary effusion lymphoma, 60% of plasmablastic lymphoma, and nearly 40% of Burkitt lymphoma.158 The precise role that EBV plays in the pathogenesis of HIV/AIDS-related lymphomas remains largely unclear and seems complex. EBV infection and immunosuppression may increase the pool of B cells at risk for c-MYC translocations and may not be the primary mechanism for driving malignant proliferation.
Primary CNS lymphoma is an aggressive high-grade large B-cell lymphoma that most commonly involves the brain. Its incidence is highest in patients with HIV/AIDS, usually in the latter stage of the disease. The EBV type III latency pattern is expressed in these tumors.159 Plasmablastic lymphoma is an aggressive high-grade lymphoma that arises in the oral cavity. It is regarded as a subtype of DLBCL. Although it is most often seen in the setting of HIV/AIDS, it has also been reported in immunocompetent individuals and outside the oral cavity.160,161 Interestingly, only EBER expression is identified in cases associated with EBV, a feature reminiscent of latency gene expression patterns in B cells with plasmacytoid differentiation.162
Lymphoproliferative Disorders Associated With HHV8 and Epstein-Barr Virus
Primary effusion lymphoma is a distinctive type of large B-cell lymphoma that involves pleural cavities and arises primarily in patients with HIV/AIDS. The disease shows a consistent association with HHV8 and variable association with EBV.163 Cases with EBV exhibit a latency type II pattern, with expression of EBNA1, LMP1, LMP2A, and EBER.164 The neoplastic cells express CD138 and CD45 but lack expression of pan B-cell markers; albeit, at the molecular level there is unequivocal immunoglobulin gene rearrangements and somatic hypermutations indicative of postgerminal center B-cell origin.165
Another entity showing an association between HHV8 and EBV—and not HIV—was recently described by Du and colleagues,166 who suggested the term HHV8-associated germinotropic lymphoproliferative disorder. Histologically, the disease is characterized by confluent aggregates of plasmablastic cells that preferentially involve germinal centers of lymphoid follicles and are positive for HHV8 and EBV. In addition to having plasmablastic cytomorphology, the neoplastic cells have abundant monotypic cytoplasmic immunoglobulin. They are negative for CD20, CD79a, CD138, BCL6, and CD10. Molecular analysis demonstrates a polyclonal or oligoclonal pattern of immunoglobulin gene rearrangement. According to the new 2008 WHO classification, this entity seems to be distinct from “large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease,” which is a monoclonal plasmablastic neoplasm arising in patients with HIV infection.167
PRACTICAL COMMENTS ON THE DIAGNOSTIC APPROACH TO EPSTEIN-BARR VIRUS-ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS
EBV-associated lymphoproliferative disorders encompass a wide spectrum of clinical entities, some of which show significant clinical and histologic overlap. The following is a proposed helpful systematic approach to lymphoproliferative disorders:
(1) Adequate and thorough clinical history, including age, clinical presentation, and sites of involvement. This is especially important for EBV-associated T-cell and NK-cell proliferations because of their morphologic diversity and overlapping immunophenotype. In some of these instances, the clinical syndrome/presentation may be the most important element in establishing the correct diagnosis.149
(2) Immunophenotyping. Using immunohistochemistry and/or flow cytometric analysis to characterize the constituents of the lymphoid proliferation.
(3) Demonstration of EBV infection. The designation of an EBV-associated lymphoproliferative process requires unequivocal demonstration of the presence of the EBV viral genome or gene products within a given cell population. Detection of the EBER using in situ hybridization has become the standard method to identify EBV infection in paraffin-embedded tissue sections. Immunohistochemical analysis for EBV-LMP1 is specific but less sensitive.114 Assessment for EBV infection should always be applied in the clinical setting of immunosuppression, transplantation, elderly patients, children with hemophagocytic syndrome, and in any lymphoproliferative entity in patients of Asian or South American descent. There should also be a high index of suspicion for EBV-related proliferations in the presence of hemophagocytosis or prominent angiocentricity and angiodestruction, particularly in extranodal lymphoid proliferations.
(4) Clonality studies. In select cases, assessment of IgH or TCR gene rearrangement status is essential to confirm clonality. This can be achieved using polymerase chain reaction-based studies on frozen or paraffin-embedded tissue. Alternatively, flow cytometric assessment of TCR Vβ chain and killer cell immunoglobulin receptors expression patterns may also be useful in T-cell or NK-cell proliferations, respectively.168
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