Expression of Epstein–Barr virus in Hodgkin lymphoma in a population of United Arab Emirates nationals

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.

Immunologic pathomechanism of Hodgkin's lymphoma

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

Introduction: Hodgkin lymphomas are B-cell lymphoid neoplasms histologically characterized by a mixed inflammatory cellular component and few Hodgkin/Reed-Sternberg neoplastic cells. Classical Hodgkin Lymphoma (CHL) represents 10% of all lymphoma cases and 85% of all Hodgkin Lymphomas. According to the current World Health Organization classification, CHL is divided into 4 types: Nodular Sclerosing (NS), Mixed Cellularity (MC), Lymphocyte-Rich (LR), and Lymphocyte-Depleted (LD). Objetive: We reviewed all cases of Classical Hodgkin Lymphoma in the Pathological Anatomy Department at Edgardo Rebagliati Martins National Hospital during 2015 to 2019, in order to determine the most frequent type, the incidence according to age and gender, phenotypical characteristics and relation to Epstein Barr Virus (EBV). Materials and Methods:  We performed a retrospective descriptive case study of Classical Hodgkin Lymphoma and its 4 clinical-pathological types in the Pathological Anatomy Department at Edgardo Rebagliati Martins National Hospital during 2015 to 2019. 72 patients were identified with Classical Hodgkin Lymphoma diagnosis, of which only 64 were selected for the study. The exclusion criteria were the absence of confirmatory immunohistochemical tests and relapse cases. Results: The most frequent type observed was Nodular Sclerosing with 34 cases (53.12%) and the least frequent type was Lymphocyte-Rich with 2 cases (3.12%). Likewise, a predominance in the male gender was observed, with 42 cases, 20 of which were Nodular Sclerosing and 14 not classified, as the most frequent types, and a greater incidence among those 41 to 50 years of age, without detection of the bimodal peak referenced in international literature. The most frequent immunohistochemical profile of Hodgkin/ Reed- Sternberg was CD15 and CD30 positive, with CD45 negative. EBV was present in 36% of cases and is more frequent in the Mixed Cellularity and Lymphocyte-Depleted types. Conclusions: Classical Hodgkin Lymphoma is a group of lymphoid neoplasms with clinical, histological, and phenotypically defined characteristics. It is more frequent in men between 41 and 50 years of age. A complete clinical information and a good biopsy, preferably excisional, is required for an adequate diagnosis. The Nodular Sclerosing type is the most frequent and the Lymphocyte-Rich is the least frequent type. Hodgkin/ Reed- Sternberg cells are usually CD-15 and CD-30 positive and CD-45 negative. The Pax-5 mild positivity allows it to be differentiated from B-cell Non-Hodgkin Lymphomas. EBV is most frequent in Mixed Cellularity and Lymphocyte-Depleted types.

The Epstein-Barr virus (EBV) has been implicated as a contributing factor in the development of Hodgkin's disease. Western cases of Hodgkin's disease have shown the presence of EBV in Hodgkin and Reed-Sternberg cells in approximately 50%. We studied a total of 100 consecutive cases of Hodgkin's disease from Malaysia, with the aim to elucidate its association with EBV in a multi-ethnic Asian population. Of 34 patients (34%) less than 15 years of age (childhood), 25 had classical Hodgkin's disease (eight nodular sclerosis, 16 mixed cellularity, one lymphocyte depleted) and nine had lymphocyte predominance Hodgkin's disease. Of the 66 from patients aged 15 years and above, 33 had nodular sclerosis, 24 mixed cellularity, two lymphocyte depleted, one unclassifiable and six lymphocyte predominance Hodgkin's disease. The ethnic distribution of classical Hodgkin's disease was: Malay 23, Chinese 32 and Indian 30 (Malay:Chinese:Indian = 1:1.4:1.3), and the ethnic distribution in the 15 cases of lymphocyte predominance Hodgkin's disease was: Malay four, Chinese 10 and Indian one. Taking into account the ethnic distribution of the general population and of hospital admissions, there appears to be a significant predilection of classical Hodgkin's disease cases in ethnic Indian compared to non-Indian patients (chi-squared test, 0.025 > P > 0.01). Eighty-one cases were tested for the presence of EBV by in situ hybridization for EBV encoded RNA, and 57 cases by immunostaining for EBV latent membrane protein 1. In the younger age group, all except one of the 15 cases (nine mixed cellularity, six nodular sclerosis) showed the presence of EBV (93%). In the older age group, EBV was detected (52%) in the following proportion: 6/27 nodular sclerosis, 19/22 mixed cellularity, 1/2 lymphocyte depleted, 1/1 unclassifiable. None of the 14 cases of lymphocyte predominance Hodgkin's disease showed the presence of EBV in the Hodgkin and Reed-Sternberg cells. The findings suggest a strong association of EBV with Hodgkin's disease in Malaysians (41/67, 61%), in particular childhood cases (93%). In adults, the association with EBV is significantly higher in the mixed cellularity subtype (86%) compared with the nodular sclerosis subtype (22%).

There is no published data regarding adult acute leukemia (AL) in the United Arab Emirates (UAE). Our objectives were to determine the distribution and incidence of adult AL in UAE (nationals and non-nationals). This epidemiological survey recovered 263 adult patients with AL diagnosed between January 2000 and December 2006 with a median age of 34 years. Twenty-four percent were UAE nationals and 63% were males. Acute lymphoblastic leukemia (ALL) was more frequently diagnosed (32%) than in western countries. This clearly reflects the population structure of the UAE which consists of predominantly young males. There is a tendency for lower crude and age-specific incidence rates of AL, acute myeloid leukemia (AML) and ALL in the UAE when compared with those in western countries. We found a statistically significant higher incidence of AML among national females than in national males (p = 0.04). This is reflected in a significantly higher incidence of AL (p = 0.02) and AML (p = 0.02) among the females when compared with the males in the total population of the UAE. This result contradicts the generally known finding that AML and ALL are more common in males. The implication of cumulative risk factors to which females could be exposed, such as vitamin D deficiency as a result of sunlight deprivation and direct exposure to benzene and color enhancement chemicals in henna, could not be excluded and warrant further investigation.

Historical review of lymphomas.

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.
 (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 refractory Hodgkin lymphoma: Limited options and poor survival—but not always

The economic growth has paralleled the rise of diabetes and its complications in multiethnic population of United Arab Emirates (UAE). Previous studies have shown that characteristics of diabetes is variable across different ethnicities. The objective of this study was to compare diabetes prevalence and risk factors between UAE nationals and different expatriate’s ethnic groups in UAE using data from UAE National Diabetes and Lifestyle Study (UAEDIAB). The UAE nationals made one-fourth (n = 797, 25%) of total cohort and the remaining 75% belonged to immigrants. Across different ethnicities, adjusted prevalence of prediabetes ranged from 8% to 17%, while adjusted prevalence of newly diagnosed diabetes ranged from 3% to 13%. UAE nationals, Arabs non-nationals and Asians had the highest number of pre-diabetic as well as newly diagnosed diabetic patients. Adjusted prevalence of diabetes was highest in UAE nationals (male 21% and female 23%) as well as Asian non-Arabs (male 23% and female 20%), where 40% of both groups fell under the range of either prediabetes or diabetes conditions. Multivariate factors of diabetes versus non-diabetes included older age, ethnicities of Asian non-Arabs and local UAE nationals, family history of diabetes, obesity, snoring, decreased level of high density lipoprotein, elevated levels of triglycerides and blood pressure. In conclusion, diabetes prevalence and risk factors vary across the different ethnic groups in UAE, and hence interventions towards identification and prevention of diabetes should not treat all patients alike.

The etiology and pathogenesis of Hodgkin lymphoma (HL) are not yet known. There are implications of genes involved in programmed cell death (apoptosis), and there have been repeated suggestions of an association with Epstein-Barr virus (EBV). The aim of this study was to investigate the protein expression patterns of key cell cycle-related genes, together with evidence of apoptosis and EBV status, in relation to clinical stage in HLs. A double immunohistochemical and in situ hybridization technique was used to detect the expression of bcl-2, p53, retinoblastoma (Rb), p21, Ki67 (MIB 1), and topoisomerase IIalpha (TopoIIalpha), together with latent membrane protein-1 and EBER for EBV status and TdT-mediated dUTP-FITC nick end-labeling (TUNEL) as a measure of apoptosis, on tissue microarray sections of 62 cases of classic HL (35 NS, 17 MC, 8 LR, and 2 LD). A panel of phenotypic markers was used to facilitate recognition of Hodgkin and Reed-Sternberg (H-RS) cells: CD3, CD20, CD30, CD15, and EMA. The H-RS cells of 62 classic Hodgkin lymphomas were bcl-2-positive in 35 cases (56.45%), p53-positive in 14 (22.58%), and positive for both EBV latent membrane protein-1 and EBER in 37 (59.68%); there was complete concordance of results for EBV by both procedures. No correlation was found between expression of bcl-2, p53, or EBV markers in H-RS cells and clinical stage (P > 0.05). Expression of Rb, Ki67, p21, and TopoIIalpha did, however, show significant differences with clinical stage. Expression of Rb and p21 in CD30-positive H-RS cells decreased with more advanced stage (P < 0.001). In contrast, Ki67 and ToPoIIalpha expression increased with later stage (P < 0.01). No correlation was found between expression of any of these markers in H-RS cells and the subtypes of nodular sclerosis HL, mixed cellularity HL, and LRHL (P > 0.05). TUNEL was found in the nonneoplastic cellular background in all cases and in H-RS cells in only 10 of 62 cases (16.12%) (8 nodular sclerosis HL, 1 mixed cellularity HL, and 1 LRHL). There was a significant correlation between high expression of bcl-2 and a low score by TUNEL (P < 0.05). These data are consistent with the notion that overexpression of bcl-2 may be linked to blockage of apoptosis-mediated death of H-RS cells in classic HL. Abnormal expression of p53-related protein may not play a major role in HL, because it is present in H-RS cells in only a minority of cases. Increased expression of Ki67 and TopoIIalpha by H-RS cells is significantly associated with advanced stage and may indicate aggressive disease. Adverse clinical outcome in HL also is associated with loss of Rb and p21 protein expression, consistent with the possible roles of Rb and p21 in inhibition of the growth of H-RS cells. Within the limitations of the methods used, almost two thirds of cases of HL provide evidence of an association with EBV. The tissue microarray technique is valuable not only for examination of large numbers of cases of a disease by a complex panel of markers but also potentially as a control for staining quality in immunohistochemistry and in situ hybridization.

High prevalence of a 30-base pair deletion in the Epstein-Barr virus (EBV) latent membrane protein 1 gene and of strain type B EBV in Mexican classical Hodgkin's disease and reactive lymphoid tissue

Hodgkin's and Reed/Sternberg (HRS) cells, the tumour cells in classical Hodgkin's lymphoma (HL), represent transformed B cells in nearly all cases. The detection of destructive somatic mutations in the rearranged immunoglobulin (Ig) genes of HRS cells in classical HL indicated that they originate from preapoptotic germinal centre (GC) B cells that lost the capacity to express a high-affinity B-cell receptor (BCR). Several aberrantly activated signalling pathways and transcription factors have been identified that contribute to the rescue of HRS cells from apoptosis. Among the deregulated signalling pathways, activation of multiple receptor tyrosine kinases in HRS cells appears to be a specific feature of HL. In about 40% of cases of classical HL the HRS cells are infected by Epstein-Barr virus (EBV), indicating an important role of EBV in HL pathogenesis. Interestingly, nearly all cases of HL with destructive Ig gene mutations eliminating BCR expression (e.g. nonsense mutations) are EBV-positive, suggesting that EBV-encoded genes have a particular function to prevent apoptosis of HRS-cell precursors that acquired such crippling mutations. This idea is further supported by the recent demonstration that isolated human GC B cells harbouring crippled Ig genes can be rescued by EBV from cell death, giving rise to lymphoblastoid cell lines. The molecular analysis of composite Hodgkin's and non-Hodgkin's lymphomas indicated that many cases develop from a common GC B-cell precursor in a multistep transformation process with both shared and distinct oncogenic events.

Current and potential use of pathological targets in the treatment of Hodgkin lymphoma.

Background: Epstein-Barr virus (EBV) is a ubiquitous virus belonging to γ-Herpesvirus subfamily, infecting B cells, T cells, Natural killer (NK) cells &amp; causes both benign and malignant diseases. It has been detected in large subset of Hodgkin lymphoma (HL) cases around the world, especially in countries with poor socioeconomic conditions and among younger age. Limited studies are available reflecting the Indian scenario of HL and EBV association. EBV positivity in Indian HL varies from 28-97% Majority of these studies employed Immunohistochemistry (IHC) for LMP1, a few performed In Situ Hybridisation (ISH) for EBER.&#x0D; Objective: To study the association of EBV in classical HL by immunohistochemical expression of latent membrane protein 1 (LMP1) antigen in North Indian population and to correlate it with different demographic variables &amp; subtypes of HL.&#x0D; Materials and Methods: Observational study including 26 untreated HL cases diagnosed on lymph node excision biopsy. IHC was performed for EBV LMP1, CD15, CD30, CD45, CD3, CD20.&#x0D; Results: Patients ranged in age from 5-55years (median 18yrs), with M:F ratio of 3.3:1. Palpable lymphadenopathy was found in all cases followed by pallor (64%), B symptoms (50%), nodal pain (30.8%) &amp; bulky disease (19.2%). Maximum number of patients were in Stage I (65.4%) followed by stage II&amp;III (15.4% each) &amp; stage IV (3.8%). Mixed cellularity HL comprised 77%, lymphocyte depleted 11.5%, nodular sclerosis 7.7% &amp; lymphocyte rich 3.8%. IHC for EBV LMP1 was positive in 73.1% cases. Mixed cellularity HL showed an association in 70% cases.&#x0D; Conclusions: HL in India is a disease of young males, with mixed cellularity as the commonest subtype, highly associated with EBV and presentation at an early stage.