Epstein-Barr virus is associated with all histological subtypes of Hodgkin lymphoma in Vietnamese children with special emphasis on the entity of lymphocyte predominance subtype

A role for Epstein Barr virus (EBV) in Hodgkin lymphoma (HL) pathogenesis is supported by the detection of EBV genome in about one-third of HL cases, but is not well defined. We previously reported that an elevated prediagnosis antibody titer against EBV nuclear antigens (EBNA) was the strongest serologic predictor of subsequent HL. For the present analysis, we measured antibody levels against EBNA components EBNA1 and EBNA2 and computed their titer ratio (anti-EBNA1:2) in serum samples from HL cases and healthy siblings. We undertook this analysis to examine whether titer patterns atypical of well-resolved EBV infection, such as an anti-EBNA1:2 ratio ≤ 1.0, simply reflect history of infectious mononucleosis (IM), an HL risk factor, or independently predict HL risk. Participants were selected from a previous population-based case-control study according to their history of IM. We identified 55 EBV-seropositive persons with a history of IM (IM+; 33 HL cases, 22 siblings) and frequency-matched a comparison series of 173 IM history-negative, EBV-seropositive subjects on HL status, gender, age and year of blood draw (IM-; 105 cases, 58 siblings). In multivariate logistic regression models, an anti-EBNA1:2 ratio ≤ 1.0 was significantly more prevalent in HL cases than siblings (odds ratio, 95% confidence interval = 2.43, 1.05-5.65); similar associations were apparent within the IM+ and IM- groups. EBNA antibodies were not significantly associated with IM history in HL cases or siblings. These associations suggest that chronic or more severe EBV infection is a risk factor for HL, independent of IM history.

Primary infection with Epstein-Barr virus (EBV) is asymptomatic in children with immature immune systems but may manifest as infectious mononucleosis, a vigorous immune activation, in adolescents or adults with mature immune systems. Infectious mononucleosis and chronic immune activation are linked to increased risk for EBV-associated lymphoma. Here we show that EBV initiates progressive lytic infection by expression of BZLF-1 and the late lytic genes gp85 and gp350/220 in cord blood mononuclear cells (CBMC) but not in peripheral blood mononuclear cells (PBMC) from EBV-naive adults after EBV infection ex vivo. Lower levels of proinflammatory cytokines in CBMC, used to model a state of minimal immune activation and immature immunity, than in PBMC were associated with lytic EBV infection. Triggering the innate immunity specifically via Toll-like receptor-9 of B cells substantially suppressed BZLF-1 mRNA expression in acute EBV infection ex vivo and in anti-IgG-stimulated chronically latently EBV-infected Akata Burkitt lymphoma cells. This was mediated in part by IL-12 and IFN-gamma. These results identify immune activation as critical factor for the suppression of initiation of lytic EBV infection. We hypothesize that immune activation contributes to EBV-associated lymphomagenesis by suppressing lytic EBV and in turn promotes latent EBV with transformation potential.

Immunologic pathomechanism of Hodgkin's lymphoma

To investigate the Epstein Barr virus(EBV) positive rate in newly diagnosed Hodgkin's lymphoma(HL) and the prognostic significance of EBV status. A total of 120 previously untreated patients with histologically confirmed Hodgkin's lymphoma were enrolled in this study. The EBV infection status was confirmed through examining EBV-RNA(EBER) or EBV latent membrane protein-1, and these patients were divided into EBV positive group and EBV negative group. The correlation of clinical features and EBV infection status was analyzed. For analysis of prognostic significance of EBV infection, the patients were divided into dead and survival groups, and the factors affecting the living conditions were analyzed. Among 120 patients with HL, 36 patients(30.0%) were found with EBV infection. In EBV+ HL group patients were male, aged 6-15 and 61-74, the proportion of patients with mixed cellular sybtype was significantly higher than that in EBV- HL group(P<0.05). The 1 year and 2 year total survival rate of patients in EBV+ group were 88.9% and 83.3%, and significantly lower than 97.6% and 95.2% in EBV- group. Out of the 120 patients with HL, 10 patients died(8.3%). In death group, patients aged 61-74 and did not received radiotherapy, their proportion of EBV+ infection was significantly hyher than that in survival group (P<0.05). Multiriabl analysis showed that the age 61-74 and EBV+ infection were the risk factors for survival coditions of patients (P<0.05). The EBV infection relates with HL, the clinical featuses of HL patients with EBV+ or EBV- are different, the total survival time of patients in EBV+ group is shorter than that of patients in EBV- group, the EBV+ infection is a risk factor for total survival time of patients with HL.

Somatic Mutational Landscape and Transcriptomic Profiles of Lymphoproliferative Disorders with Epstein-Barr Virus Infection in Activated PI3K Delta Syndrome

Malignant lymphomas are among the common tumors that are associated with and may complicate Epstein Barr Virus (EBV) infection. Although the strongest association is with the endemic Burkitt lymphomas (BL), the trend of association with sporadic lymhpomas reveals a consistently increasing prevalence of the virus in Hodgkin’s disease (HD) in recent years compared to the non-Hodgkin type (NHL) which may point to a possible role for the virus in the predisposition and etio-pathogenesis of the disease.evaluate the association of EBV with Hodgkin’s and non-Hodgkin lymphomas in relation to age, sex and HD subtype retrospectively using archival tissue biopsy sections.Method: EBV was detected by In Situ Hybridization (ISH) using EBERs RNA probes in paraffinembedded tissue sections prepared from archival tissue biopsy blocks.&#x0D; (a) EBV was detected in 25 of 40 HD cases (62.5%), 9 of 30 (30%) NHL cases, 4 of 10 (40%) BL cases, and in 5 of 20 (25%) other (non-BL) NHL cases. (b) Among the EBV-positive HD cases, 19 (76%) were of the mixed cellularity (MC) subtype, 1 (4%) of the Nodular Sclerosis (NS) subtype, 1 (4%) of the Lymphocyte Predominance (LP) subtype and 4 (16%) cases were of the Lymphocyte Depletion (LD) subtype. (c) Age distribution of HD cases revealed a bi-modal pattern characterized by an early major peak (67.5% of cases) below 35 years and a minor peak (32.5% of cases) above the age of 40. On the contrary, NHL cases revealed a nearly even age distribution (43.3% versus 56.6%) below and above the age of 40, respectively. (d) No difference was observed in the incidence of HD between males and females where the ratio was close to 1:1. On the other hand, a slight male predominance was seen among NHL cases with a male to female ratio of 2:1.(a) the prevalence rate of EBV infection was high among HD cases and fell within the prevalence rates found in previous similar studies revealing a range of values from 20 to 90%. (b) the higher prevalence of EBV positivity in HD compared to NHL found in this study points to a more substantial role for the virus in the pathogenesis of former compared to the latter disease which also comes in agreement with the greater environmental element compared to the genetic element in the etiology of HD. (c) The unexpected high EBV positivity in the LD subtype of HD may be interpreted as result of the progression of some of the early less aggressive MC-HD cases to the advanced more aggressive LDHD subtype. (d) the bi-modal age distribution of EBV-positive HD cases follows the same pattern of distribution of the disease in general and testifies for the influence of environmental factors in the incidence of the disease.

Primary Epstein-Barr virus hepatitis complicated by ascites with epstein-barr virus reactivation during primary cytomegalovirus infection.

Introduction. Epstein — Barr virus (EBV) plays an important role in the pathogenesis of lymphoid tumors, in particular Hodgkin lymphoma. The frequency of expression of the EBV varies in different histological variants of classical Hodgkin lymphoma and is rarely observed in nodular lymphocyte predominant Hodgkin lymphoma.Aim — to study the pathomorphological features of the histological variants of Hodgkin lymphoma with lymphoid predominance associated with the EBV, as well as the frequency of their diagnosis in the structure of Hodgkin lymphoma.Materials and methods. The retrospective study included 794 patients with a verified diagnosis of Hodgkin lymphoma using histological and immunohistochemical methods on biopsy material for the period 2018–2019 (age range — 18–91 years old; median — 34 years old; men : women — 1.1 : 1). The presence of EBV in biopsies was assessed by immunohistochemical reaction with antibodies to EBV (clone LMP1), or by chromogenic in situ hybridization with probes for EBV-encoded small RNAs.Results. Classical Hodgkin lymphoma was diagnosed in 91 % (725/794) cases, nodular lymphocyte predominant Hodgkin lymphoma — in 9 % (69/794) cases. EBV-positive Hodgkin lymphoma accounted for 11 % (82/725) of all cases of classical Hodgkin lymphoma, (age range — 18–81 years old, median — 45 years old; men : women — 2.5 : 1). All cases of nodular lymphocyte predominant Hodgkin lymphoma were EBV-negative. Lymphocyte-rich classical Hodgkin lymphoma was found in 14 patients (14/725, 2 %), 4 patients showed intermediate morphoimmunohistochemical features with nodular lymphocyte predominant Hodgkin lymphoma, which were statistically significantly different from classical Hodgkin lymphoma by the presence of B-zones in the form of large nodules (p = 0.0157) and expression CD20 by tumor cells (p = 0.0404).Conclusion. Nodular lymphocyte predominant Hodgkin lymphoma is not characterized by a connection with EBV infection, unlike classical variant — lymphocyte-rich classical Hodgkin lymphoma. The obtained data support the concept of the existence of a transient form of Hodgkin lymphoma, which has the features of nodular lymphocyte predominant Hodgkin lymphoma and classical Hodgkin lymphoma, in the pathogenesis of which the Epstein — Barr virus likely plays a role.

Epstein–Barr virus (EBV) is associated with around one-third of Hodgkin's lymphoma (HL) cases and this association is believed to be causal. In these EBV-associated cases, there is a clonal EBV infection within tumors, and EBV genomes and gene products are detectable in Hodgkin and Reed-Sternberg (HRS) cells. The proportion of EBV-associated HL in any population varies with age, sex, ethnicity and histologic subtype. Two population-based epidemiologic studies have examined risk factor profiles in HL with cases stratified according to EBV status. For EBV-associated HL cases, there is a small peak in incidence in young adults (15 – 24 years) and a second larger peak in older adults. By contrast, HL that is not associated with EBV (EBV-negative HL) accounts for the major part of the young adult incidence peak after which the incidence of this disease entity then declines. Prior infectious mononucleosis (IM) is associated with an increased risk of developing HL, and there is a specific, probably causal, association between previous IM and young adult EBV-associated HL. We therefore believe that the small peak in the incidence of EBV-associated HL in young adults is real and related to late infection by EBV. EBV-associated HL in childhood and young adults, therefore, appears to follow primary infection by the virus. At the time of diagnosis, EBV-associated HL patients have an increased frequency of circulating EBV-infected cells compared to patients with EBV-negative HL and normal controls. The EBV is present in memory B cells and most probably reflects increased viral replication at another site, such as the oropharynx. EBV genomes are detectable in the serum and plasma of EBV-associated HL cases. The origin of EBV genomes in serum/plasma differs in different disease states; in HL viral genomes are present as naked DNA and are probably shed from tumors. EBV genome copy number in serum/plasma may provide an indication of tumor burden and may prove to be a useful marker for monitoring HL patients. The etiology of EBV-negative HL remains unknown and, while the involvement of an infectious agent may be suspected, none has yet been identified. Overall, epidemiologic studies support the idea that HL can be divided into two etiologic subgroups on the basis of EBV status and suggest that EBV-associated cases can be further divided into three groups related to age at diagnosis.

BackgroundThe clinicopathological features and Epstein-Barr virus (EBV) infection status of lymphoma in children and adolescents in South China is under-researched. South China is a well-known high-incidence area of EBV-associated nasopharyngeal carcinoma.MethodsA cohort of 662 consecutive children and adolescents’ lymphomas was retrospectively analyzed and Epstein-Barr virus encoded RNAs (EBERs) in situ hybridization was performed to detect the EBV infection.ResultsThe majority (501/662, 75.7%) of lymphomas in children and adolescents was Non-Hodgkin lymphoma (NHL). One hundred sixty one cases (24.3%) were Hodgkin lymphoma (HL). Of the NHL, precursor cell lymphoma, mature B-cell lymphoma and peripheral T/NK-cell lymphoma accounted for 32.0%, 41.1% and 26.9% respectively. The five common subtypes were lymphoblastic lymphoma (32.0%), Burkitt lymphoma (BL) (21.0%), anaplastic large-cell lymphoma (ALCL) (14.2%), diffuse large B-cell lymphoma (DLBCL) (13.8%) and extranodal NK/T-cell lymphoma, nasal type (ENKTCL) (6.2%). EBV infection was detected in 58.9% classical Hodgkin lymphomas (CHLs), 21.4% mature B-cell lymphomas and 52.4% peripheral T/NK-cell lymphomas. Moreover, EBV was associated with high grade NHL including ENKTCL (100.0%), BL (30.5%) and DLBCL (17.6%).ConclusionThe high proportion of peripheral T/NK-cell lymphomas in children and adolescents in South China are presented in this study and compared to western countries due to the high percentage of ENKTCL. ENKTCL is firmly associated with EBV infection, while more than half of HL, a portion of BL and DLBCL are related to EBV infection. This study conclusively demonstrates that EBV infection is more prevalent in children and adolescents with lymphomas in South China compared to western countries.

To study the clinical and morphological features, immunophenotype and in situ detection of Epstein-Barr virus (EBV) infection in infectious mononucleosis (IM) to enhance the knowledge and diagnosis of the disease. Using routine haematoxylin and eosin staining, immunohistochemistry and EBER in situ hyhridization together with clinical data analysis, 15 cases of IM were evaluated for their clinical features, morphology, immunophenotype and EBV infection status. IM was common in children and young adults with a median age of 18 years. It was an acute disease with lymphadenopathy and frequently fever. Most of the patients had a rapid recovery. Every case showed a markedly T zone expansion with a mottling pattern, composing of small to large lymphocytes, plasma cells and histiocytes. The cells also showed a B-cell differentiation profile ranging from activated lymphoblastoid cells, immunoblasts, plasmablasts, plasma-like cells and plasma cells. Many small lymphocytes in the expanded T zone expressed CD3. Some of the activated lymphoblastoid cells and immonoblasts were CD20 and CD30 positive with variable intensity signals. EBER positive (nuclear staining) cells were seen in every case. The number of EBER positive cells ranged from 10 to more than 100 per high power field. These cells included small to large lymphocytes locating mostly in the expanded T zone and a few were in the follicular germinal centers. IM is an EBV related acute sell-recovering lymphoproliferative disease, having distinct clinical, morphological and immunophenotypic characteristics as well as EBV infection. Taking these features into consideration will facilitate the correct diagnosis of IM.

In developed countries and high socioeconomic groups, Hodgkin lymphoma has an initial peak in young adulthood, whereas in undeveloped countries and low socioeconomic groups, it shows an early childhood peak. In developing countries, 90% of children are infected with the Epstein-Barr virus (EBV) by the age of 6 years, but in developed countries, only 30% to 40% are seropositive by that age. Early childhood EBV infection in 75% of Argentine patients was demonstrated. To explore the epidemiology of Hodgkin lymphoma and its relationship with EBV in Argentine patients. The presence of EBV was assessed by Epstein-Barr encoded RNA in situ hybridization and latent membrane protein 1 immunohistochemistry. We studied 92 pediatric and 42 adult Hodgkin lymphoma cases from a public center as well as 39 adult cases from a private center. The mixed cellularity Hodgkin lymphoma had a prevalence of 52% in the pediatric group, while similar frequencies of both nodular sclerosis Hodgkin lymphoma (47%) and mixed cellularity Hodgkin lymphoma (44%) were observed in adults. As for Epstein-Barr encoded RNAs, 55% of the pediatric cases and 31% of the adult cases were positive. Among adult EBV+ cases, 38% were from the public hospital, and 23% were from the private center. EBV was present in 77% of the pediatric mixed cellularity Hodgkin lymphoma cases when compared with the other histologic subtypes of Hodgkin lymphoma. EBV was mainly detected in mixed cellularity cases (39% in the adult group). Our findings strengthen the argument that EBV is involved in the pathogenesis of Hodgkin lymphoma in most children younger than 10 years. Our findings of EBV prevalence, along with both childhood and second-decade peaks as well as comparable frequencies for Hodgkin lymphomas of mixed cellularity and nodular sclerosis, distinguish our population from others in developing countries.

Infectious mononucleosis-related Epstein-Barr virus (EBV) infection has been associated with an increased risk of Hodgkin's lymphoma in young adults. Whether the association is causal remains unclear. We compared the incidence rates of Hodgkin's lymphoma in two population-based Danish cohorts of patients who were tested for infectious mononucleosis: 17,045 with serologic evidence of having had acute EBV infection, and 24,614 with no such evidence. We combined the cohort of patients who had serologically verified infectious mononucleosis with a cohort of 21,510 Swedish patients with infectious mononucleosis (combined total, 38,555). Biopsy specimens of Hodgkin's lymphomas occurring during follow-up in this combined cohort were tested serologically for the presence of EBV. Using this information, we modeled the relative risk of EBV-negative and EBV-positive Hodgkin's lymphoma in different periods after the diagnosis of infectious mononucleosis and estimated the median incubation time for mononucleosis-related EBV-positive Hodgkin's lymphoma. Only serologically confirmed infectious mononucleosis was associated with a persistently increased risk of Hodgkin's lymphoma. Sixteen of 29 tumors (55 percent), obtained from patients with infectious mononucleosis, had evidence of EBV. There was no evidence of an increased risk of EBV-negative Hodgkin's lymphoma after infectious mononucleosis. In contrast, the risk of EBV-positive Hodgkin's lymphoma was significantly increased (relative risk, 4.0; 95 percent confidence interval, 3.4 to 4.5). The estimated median incubation time from mononucleosis to EBV-positive Hodgkin's lymphoma was 4.1 years (95 percent confidence interval, 1.8 to 8.3). A causal association between infectious mononucleosis-related EBV infection and the EBV-positive subgroup of Hodgkin's lymphomas is likely in young adults.

Epstein-Barr virus (EBV) has been implicated in the development of a wide range of lymphoproliferative disorders. In this process, the role of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) has remained to be clarified. A meta-analysis of 20 studies was performed and risk ratios (RRs) with 95% confidence intervals (CIs) were used to evaluate the association between PD-L1/PD-1 expression and the status of EBV infection. The results showed that the expression level of PD-L1 in tumor cells was significantly higher in EBV+ cases with a pooled RR of 2.26 (95% CI, 1.63-3.14; P<0.01), particularly in subtypes of diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma. Similarly, EBV infection increased the expression of PD-L1 in immune cells with a pooled RR of 2.20 (95% CI, 1.55-3.12; P<0.01). In subtypes of DLBCL and post-transplant lymphoproliferative disorder, the expression of PD-L1 in immune cells is increased in EBV+ cases. Regarding the expression level of PD-1 in tumor-infiltrating lymphocytes (TILs), no significance was found between EBV infection and PD-1 expression, with a pooled RR of 1.10 (95% CI, 0.81-1.48; P>0.05). The present meta-analysis demonstrated that in EBV-associated lymphoproliferative disorders, EBV infection was associated with the expression level of PD-L1 in tumor cells and immune cells but was not associated with the expression of PD-1 in TILs.

Hodgkin lymphoma (HL) shows wide geographic variation in histological subtypes and in its association with the Epstein–Barr virus (EBV). HL has three main epidemiological patterns (I, II and III). Type I pattern, which is prevalent in developing countries, shows a relatively high incidence in male children, a low incidence in the third decade and a second peak of high incidence in older age groups. Type III, which is usually seen in developed countries, is characterised by a low rate in children and a pronounced initial peak in young adults. The third pattern (Type II), which is described in many Asian countries, is intermediate and reflects a transition between types I and III. In this pattern there is both a childhood and a third decade peak. The proportion of EBV positive HL is low in industrialised countries, high in non-industrialised countries and intermediate in early-industrialised countries. Reports from the Arabian Gulf and Middle East are few. The aim of this study is to determine the epidemiology of HL in a population of United Arab Emirates (UAE) nationals, an early industrialised country in the Arabian Gulf, and to delineate the extent of its association with EBV. In total, 88 cases of HL were diagnosed in native patients during the period 1988 through 2004 at Tawam hospital. Forty-five paraffin blocks were available for this study. Five-micrometer sections were prepared and stained with hematoxylin and eosin and the immunohistochemical streptavidin–biotin methods for CD45, CD3, CD20, CD15 and CD30. Other sections were examined for the presence of EBV using the immunohistochemical streptavidin–biotin method for the latent membrane protein 1 and in situ hybridisation for EBV encoded RNA to determine the prevalence of EBV in Hodgkin cells and its possible role in the pathogenesis of HL. Nodular sclerosis (NS) subtype was the most common type of HL among UAE nationals followed by mixed cellularity (MC), lymphocytic predominant (LP), unclassified, lymphocytic depletion (LD) and lymphocyte rich (LR) subtypes, respectively. EBV was seen in 17 of 45 (38%) cases of HL and was predominately seen in the MC subtype followed by NS, LD and LR subtypes, respectively. EBV was more frequently expressed in HL in the pediatric age group than the adult age group. These data indicate that the epidemiology of HL in a native population of the UAE is suggestive of a type II epidemiologic pattern in terms of age distribution, and histopathologic subtypes, whereas the frequency of EBV expression is more suggestive of a type III epidemiologic pattern. The significant association between EBV and HL that we have found further strengthens the suggestion that all cases of HL should be assessed for EBV status, because its presence may have a significant impact on prognosis and response to therapy.