Virus de Epstein-Barr: más que una mononucleosis infecciosa / Epstein-Barr virus: more than infectious mononucleosis

El virus de Epstein-Barr (VEB) fue el primer virus asociado a neoplasias en humanos. Infecta el 95 % de la población mundial, y aunque usualmente es asintomático, puede causar mononucleosis infecciosa y se relaciona con más de 200.000 casos de neoplasias al año. De igual forma, se asocia con esclerosis múltiple y otras enfermedades autoinmunes. A pesar de ser catalogado como un virus oncogénico, solo un pequeño porcentaje de los individuos infectados desarrollan neoplasias asociadas a VEB. Su persistencia involucra la capacidad de alternar entre una serie de programas de latencia, y de reactivarse cuando tiene la necesidad de colonizar nuevas células B de memoria, con el fin de sostener una infección de por vida y poder transmitirse a nuevos hospederos. En esta revisión se presentan las generalidades del VEB, además de su asociación con varios tipos de neoplasias, como son el carcinoma nasofaríngeo, el carcinoma gástrico, el linfoma de Hodgkin y el linfoma de Burkitt, y la esclerosis múltiple. Adicionalmente, se describen los mecanismos fisiopatológicos de las diferentes entidades, algunos de ellos no completamente dilucidados

Epstein-Barr virus (EBV) was the first virus associated with human cancer. It infects 95% of the world's population, and although it is usually asymptomatic, it causes infectious mononucleosis. It is related to more than 200,000 cases of cancer per year, and is also associated with multiple sclerosis and other autoimmune diseases. Despite being classified as an oncogenic virus, only a small percentage of infected individuals develop EBV-associated cancer. Its persistence involves the ability to alternate between a series of latency programs, and the ability to reactivate itself when it needs to colonize new memory B cells, in order to sustain a lifelong infection and be able to transmit to new hosts. In this review, the general characteristics of EBV are presented, in addition to its association with various types of cancers, such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma, and multiple sclerosis. Additionally, the pathophysiological mechanisms of the different entities are described, some of them not completely elucidated yet

Immunodeficiency-associated Burkitt's lymphoma in pediatric patients: a clinical case report

Burkitt's lymphoma, a form of non-hodgkin lymphoma, is a neoplastic monoclonal proliferation of lymphoid cells in areas of the immune system. it can occur in HIV-positive patients, as AIDS is related to the development of non- hodgkin lymphoma. burkitt's lymphoma is a rare subtype, highly prevalent in patients with AIDS. incisional biopsy, in situ hybridization and computerized axial tomography are the appropriate tests to determine the characterize of the lesions. the case of a 4-year-old HIV-positive patient, who developed burkitt's lymphoma of the oral cavity, is reported in this paper. the aim of this case report is to describe the course of the pathology, taking into account its clinical imaging characteristics and treatment.

Linfoma de Burkitt en un escolar con infección perinatal por VIH lentamente progresiva / Burkitt's lymphoma in a school boy with slow progression perinatally acquired HIV

Resumen Las manifestaciones clínicas en los niños con infección por el virus de la inmunodeficiencia humana (VIH) de transmisión perinatal, pueden ser de inicio precoz o tardío. El linfoma asociado a VIH es una manifestación tardía que se asocia a estadios avanzados de inmunosupresión. Se presenta el caso de un escolar de 9 años con diagnóstico de novo de infección por VIH que debutó con un linfoma de Burkitt. En niños, la frecuencia de esta asociación es de 1-2% con pocos casos reportados en la literatura médica.

Children with perinatal human immunodeficiency virus (HIV) infection can present early or late clinical disease. HIV-associated lymphoma is a later manifestation that is associated with advanced immunosuppression (acquired immunodeficiency syndrome -AIDS). This is a case of a 9-year-old boy with recent diagnosis of HIV with Burkitt's lymphoma as first clinical manifestation. In children, the frequency of this association is very low and there are few cases reported.

[Burkitt's lymphoma in a school boy with slow progression perinatally acquired HIV]. / Linfoma de Burkitt en un escolar con infección perinatal por VIH lentamente progresiva.

Children with perinatal human immunodeficiency virus (HIV) infection can present early or late clinical disease. HIV-associated lymphoma is a later manifestation that is associated with advanced immunosuppression (acquired immunodeficiency syndrome -AIDS). This is a case of a 9-year-old boy with recent diagnosis of HIV with Burkitt's lymphoma as first clinical manifestation. In children, the frequency of this association is very low and there are few cases reported.

Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations.

Epstein Barr virus (EBV) sequence variation is thought to contribute to Burkitt lymphoma (BL), but lack of data from primary BL tumors hampers efforts to test this hypothesis. We directly sequenced EBV from 12 BL biopsies from Ghana, Brazil, and Argentina, aligned the obtained reads to the wild-type (WT) EBV reference sequence, and compared them with 100 published EBV genomes from normal and diseased people from around the world. The 12 BL EBVs were Type 1. Eleven clustered close to each other and to EBV from Raji BL cell line, but away from 12 EBVs reported from other BL-derived cell lines and away from EBV from NPC and healthy people from Asia. We discovered 23 shared novel nucleotide-base changes in the latent membrane protein (LMP)-1 promoter and gene (associated with 9 novel amino acid changes in the LMP-1 protein) of the 11 BL EBVs. Alignment of this region for the 112 EBV genomes revealed four distinct patterns, tentatively termed patterns A to D. The distribution of BL EBVs was 48%, 8%, 24% and 20% for patterns A to D, respectively; the NPC EBV's were Pattern B, and EBV-WT was pattern D. Further work is needed to investigate the association between EBV LMP-1 patterns with BL.

Epstein-Barr virus (EBV) association and latency profile in pediatric Burkitt's lymphoma: experience of a single institution in Argentina.

The aim of this study is to characterize EBV expression and latency pattern in pediatric Burkitt's lymphoma in a single institution in Argentina. EBV-encoded RNA or protein was analyzed in 27 patients. EBERs was expressed in 37% of patients (29% of immunocompetent and 100% of immunosuppressed patients). EBV-positive cases were observed exclusively in patients younger than 5 years old. EBV association with immunocompetent patients exhibits the sporadic pattern in region under study, while its presence in patients infected with HIV was higher than described previously. EBV latency I profile was present in most of the patients, except for two immunosuppressed patients who displayed LMP1 expression.

Relationship of Epstein-Barr virus and interleukin 10 promoter polymorphisms with the risk and clinical outcome of childhood Burkitt lymphoma.

Epstein-Barr virus (EBV) is an important environmental factor associated to the development of Burkitt lymphoma (BL) in endemic and intermediate risk regions. However, little is known about the contribution of genetic constitution to the development and clinical response of the disease. The aim of this work was to investigate the role of EBV and Interleukin 10 (IL10) single nucleotide polymorphisms (-1082A/G, -819C/T, -592C/A) and microsatellites (IL10.R and IL10.G) in susceptibility and clinical outcome in pediatric BL patients, in a region with intermediate EBV association frequency. The frequencies of IL10 promoter Single nucleotide polymorphisms -1082A/G, -819C/T, -592C/A, and IL10.R and IL10.G microsatellites were compared in 62 pediatric patients and 216 healthy donors. IL10 -1082GG and GCC/GCC genotypes were more frequent in patients than in controls, and associated to a higher risk of BL development (GG genotype OR 2.62, 95% CI, 1.25-5.51; P = 0.008; Pc = 0.024). EBV was detected in tumor samples by EBER-ISH in 54.1% of cases. EBV+ patients exhibited a better event free survival (EFS) (P = 0.019) than EBV- patients. Carriers of IL10 R3-GCC had worse EFS (P = 0.028). Our results suggest a risk effect and an independent prognostic value of IL10 polymorphisms and EBV in childhood BL patients.

Distinctive Epstein-Barr virus variants associated with benign and malignant pediatric pathologies: LMP1 sequence characterization and linkage with other viral gene polymorphisms.

The ubiquitous Epstein-Barr virus (EBV) is related to the development of lymphoma and is also the etiological agent for infectious mononucleosis (IM). Sequence variations in the gene encoding LMP1 have been deeply studied in different pathologies and geographic regions. Controversial results propose the existence of tumor-related variants, while others argued in favor of a geographical distribution of these variants. Reports assessing EBV variants in IM were performed in adult patients who displayed multiple variant infections. In the present study, LMP1 variants in 15 pediatric patients with IM and 20 pediatric patients with EBV-associated lymphomas from Argentina were analyzed as representatives of benign and malignant infections in children, respectively. A 3-month follow-up study of LMP1 variants in peripheral blood cells and in oral secretions of patients with IM was performed. Moreover, an integrated linkage analysis was performed with variants of EBNA1 and the promoter region of BZLF1. Similar sequence polymorphisms were detected in both pathological conditions, IM and lymphoma, but these differ from those previously described in healthy donors from Argentina and Brazil. The results suggest that certain LMP1 polymorphisms, namely, the 30-bp deletion and high copy number of the 33-bp repeats, are associated with EBV-related pathologies, either benign or malignant, instead of just being tumor related. Additionally, this is the first study to describe the Alaskan variant in EBV-related lymphomas that previously was restricted to nasopharyngeal carcinomas from North America.

Burkitt lymphoma in Brazil is characterized by geographically distinct clinicopathologic features.

Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin lymphoma with a consistent MYC translocation. Epstein-Barr virus (EBV) has been associated with BL at different frequencies, depending on the clinical variant and geographic regions. This is a large-scale study of BL in Brazil, including 234 patients from 5 geographic regions that are widely disparate socioeconomically, including pediatric (61.1%) and adult (37.6%) populations. EBV was present in 52.6% of all BL cases, varying from 29% (12/42) in the South to 76% (13/17) in the North. Most of the cases were EBV type A. The frequency was higher in the pediatric group, and EBV association within this age range predominated in all regions except the South. Expression of p53 protein was observed in 16.2%, and only rare cases showed p63 expression. BL in Brazil is regionally distinct and has a low incidence of p53 overexpression and a higher-than-expected association with EBV in sporadic cases.

Viral studies in burkitt lymphoma: association with Epstein-Barr virus but not HHV-8.

Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin lymphoma, composed of a monomorphic population of medium-sized B cells with a high proliferation rate and a consistent MYC translocation. Epstein-Barr virus (EBV) has been associated with BL with different frequencies depending on the clinical variant. Kaposi sarcoma-associated herpesvirus, or human herpesvirus 8 (HHV-8), infects a wide range of normal cells, having a well-established role in the pathogenesis of various neoplasms, including Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease (MCD) and MCD-associated plasmablastic lymphoma. In secondary immunodeficiencies, such as HIV-1 infection and organ transplantation, HHV-8 is considered an opportunistic pathogen linked to the development of lymphomas in patients with AIDS and HIV + patients. We studied the association of EBV and HHV-8 by immunohistochemical analysis, in situ hybridization, and polymerase chain reaction in a large number of well-characterized BLs. EBV was present in 45.0% of all BL cases with higher incidence in the pediatric group; most cases were EBV type A. We found no association of BL with HHV-8 in EBV + BL or in EBV-cases, including the HIV + BL group.

Detection of Epstein-Barr virus in children and adolescents with Burkitt's lymphoma by in situ hybridization using tissue microarrays.

In this retrospective study, we evaluated 53 patients diagnosed with Burkitt's lymphoma (BL). Patients were admitted to the Pediatric Department of Santa Casa de São Paulo, Brazil from August 1988 to September 2006. The male gender was found more frequently in the proportion of three males to one female. At the time of the diagnosis, the mean age was 6 years. The most frequent clinical presentation was abdominal (extra nodal) in 42 (79.2%) cases. The patients were treated with chemotherapy using two different treatment methods, 30 cases until September 1994 with BGLTI -87 and the other 23 until September of 2006 with BGLTI -96. According to Murphy's classification, 90.2% of the patients were diagnosed as stages III and VI showing an advanced disease at time of diagnosis. Using Tissue Microarrays (TMA); we searched for the expression of the Epstein-Barr virus (EBV) RNA in 50 patients. The presence of EBV using in situ hybridization was found in 33/50 (66%) and there was no association between the presence of the virus in the tumor cells or patient age, as well as the survival rate. There was 74.5% global survival rate until September, 2005 of 12 years and 8 months. The disease free survival rate was 86.5%. The frequency of the EBV association with this neoplasia in Brazil is intermediate between the endemic and sporadic forms of disease.

Clinical and demographic characteristics of Epstein-Barr virus-associated childhood Burkitt's lymphoma in Southeastern Brazil: epidemiological insights from an intermediate risk region.

We studied a group of 54 children with Burkitt's lymphoma from Southeastern Brazil, where epidemiological status of Burkitt's lymphoma is poorly understood. Epstein-Barr virus association showed an intermediate frequency (~60%) between endemic and sporadic subtypes. Median age was five years. Epstein-Barr virus infection was significantly associated to low age (Epstein-Barr virus(+) four years vs. Epstein-Barr virus(-) eight years). Sex ratio (M:F) was 2:1, with a significantly higher number of males in old age classes. Young age at diagnosis and excess of males at older ages, as well as a causal relationship between low age, epstein-barr virus and Burkitt's lymphoma risk, may characterize Burkitt's lymphoma in Brazil.

Zidovudine: a targeted therapy for endemic Burkitt's lymphoma.

BACKGROUND: Although cyclophosphamide based regimens can produce remission rates approaching 60 to 80% in endemic Burkitts lymphoma, relapses and refractory disease are fairly common in developing countries, due to advanced stage disease and cost-constraints in the implementation of optimal chemotherapeutic protocols. OBJECTIVE: To evaluate an affordable, tolerable and targeted approach to chemotherapy for endemic Burkitt's lymphoma as would be desirable in resource poor settings such as Africa. METHOD: We present data and review pertinent literature that indicates that the antiviral agent Zidovudine specifically targets this tumour through a unique and novel mechanism. DATA SOURCE: Our original studies, publications original and review articles searched in Pubmed indexed for Medline. DATA EXTRACTION: A systematic review to identify studies relating to Zidovudine, EBV+ and Burkitt's lymphoma, indicating antiviral agents zidovudine targeting BL in a unique and novel mechanisms. DATA SYNTHESIS: Our data and a qualitative assessment of the relevant literature was undertaken, given the heterogenicity of the study types making it inappropriate to pool results across studies. CONCLUSION: Our data suggests that the incorporation of Zidovudine into Burkitt's regimens may enhance tumour kill and abbreviate the duration of treatment necessary for this disease. Furthermore, the addition of the widely available and inexpensive agent hydroxyurea, markedly potentiates the tumorcidal activity of Zidovudine in Epstein Barr virus positive Burkitt's lymphomas. We recommend that further clinical studies in patients afflicted with this disease are needed to clearly define this potential use of Zidovudine.

Geographic variation in Epstein-Barr virus-associated Burkitt's lymphoma in children from Brazil.

In developing countries, BL has a strong association with EBV infection during childhood. In South America, the data have shown an EBV association intermediate between that reported in the United States (30%) and that in equatorial Africa (95%). Early age at EBV infection and lower socioeconomic status have been related to increased EBV-associated BL in developing countries. In Brazil, there are not enough data on childhood BL related to EBV infection. Our aim was to evaluate the clinicopathologic features and EBV association of 44 children with NHL from the state of Rio de Janeiro, situated in the southeast of Brazil. EBV was detected using RNA in situ hybridization in 36 biopsy specimens. DNA from fresh tumor samples and from paraffin-embedded tissues of patients were analyzed by PCR, in which the first reaction included primers for an EBNA-2 common region while the nested reaction amplified the region discriminating between EBV types 1 and 2 in separate reactions. EBV was detected in 21 of 29 BLs (72%), and type 1 virus infected the majority of EBV-positive BLs (18/21). There was a trend for younger age in children with EBV-positive BL compared to EBV-negative BL (median age 4 compared to 6 years, respectively; p = 0.056). Our study confirmed that in the southeast of Brazil BL had an intermediate association with EBV. A higher rate of EBV-associated BL was described in the northeast of Brazil. These differences are probably related to regional socioeconomic status. In conclusion, our study suggests that early infection with EBV in the background of a low socioeconomic condition associated with other environmental factors could contribute to BL in Brazil.

Burkitt's lymphoma of the scapula.

Burkitt's lymphoma may involve the maxilla or mandible, but to date, there has been no reference in the literature to scapular involvement by this tumor. This article describes the case of a 9-year-old child who presented with a huge tumor involving the right shoulder with osteolytic and sclerotic lesions in the scapula. The histopathological findings were suggestive of Burkitt's lymphoma, and the immunohistochemical findings discard a lymphoblastic lymphoma or plasmablastic lymphoma. In addition, in situ hybridization for Epstein-Barr virus encoded small nuclear RNA (EBER) was positive. Although the child also presented a cervical lymphadenopathy, the fact that Burkitt's lymphoma is generally extranodal, the marked swelling of the shoulder, and the extensive involvement of the bone strongly argue that this tumor had its origin in the scapula. This case demonstrates the importance of including Burkitt's lymphoma in the differential diagnosis of lymphoma involving bones in children.

Association of Burkitt's lymphoma with the Epstein-Barr virus in two developing countries.

The clinical presentation of Burkitt's lymphoma (BL) and it's association with the Epstein-Barr virus (EBV) varies in different geographic areas, BL in developing countries being "intermediate" between the sporadic and endemic types, both in it's clinical presentation and it's association with EBV, which varies from 25-80%. In this study we have analysed the clinical features, EBV association, subtype and prevalence of the deleted variant of the Latent Membrane Protein-1 (LMP-1) of EBV in forty-two cases from two developing countries- India (n = 25) and Argentina (n = 17). In both countries the abdomen was the site most commonly involved while jaw involvement was rare. EBV was detected by in-situ hybridization using the EBER-1 RNA probe. 47% of cases from Argentina and 80% of cases from India were EBER positive. EBV typing using EBNA-3C primers showed a predominance of Type A in both countries (India-13/16 and Argentina-(7/8)). The 30bp deletion of the LMP-1 gene was detected in all evaluated cases from Argentina while the wild type of the gene was seen in all the evaluable Indian cases. Our study highlights the similarities and differences in the clinical presentation and EBV association of BL in two developing countries and also indicates that the subtype of EBV and prevalence of the LMP-1 deletion may reflect the predominant subtype in a particular population.

Analysis of Epstein-Barr virus (EBV) nuclear antigen 1 subtypes in EBV-associated lymphomas from Brazil and the United Kingdom.

EBNA-1 is the only viral protein consistently expressed in all cells latently infected by Epstein-Barr virus (EBV). There is a high frequency of sequence variation within functionally important domains of EBNA-1, with five subtypes identified. Individuals may be infected with multiple EBV strains (classified according to EBNA-1 subtype), but Burkitt's lymphoma (BL) tumours carry a single subtype and exhibit some subtype preference. Subtype variation has also been related to geographical location. In the present study EBNA-1 polymorphisms were examined in a series of haematological malignancies from two distinct geographical regions, Brazil and the United Kingdom. Nucleotide sequence analysis of the carboxy-terminal region of EBNA-1 in 34 cases revealed six distinct sequences, some of which are novel. A new subtype, named V-Ala, was identified. EBNA-1 subtype in tumours differed markedly according to geographical location. In contrast to previous studies, we found evidence of EBNA-1 sequence variation within individual BL tumour samples.

Expression of Epstein-Barr virus-gene products in Burkitt's lymphoma in Northeast Brazil.

The Epstein-Barr Virus (EBV) is consistently found in tumor cells of Burkitt's lymphoma (BL) endemic in central Africa and malaria is considered a pathogenic cofactor. In contrast, fewer than 20% of BL cases occurring in Western countries are EBV-associated. We have investigated 54 BL cases from Bahia, a tropical region of Northeast Brazil, for expression of EBV gene products by in situ hybridization and immunohistology and performed typing of the EBV by polymerase chain reaction. Ten pediatric BL cases from Germany served as controls. New cases of malaria were not observed in the period and area of our study. Small nuclear EBV encoded transcripts, EBER, were found in tumor cells of 47 of 54 Brazilian cases (87%) but in only 2 of 10 German cases (20%). Type I latency of the EBV infection with absence of EBV-encoded proteins LMP1 and EBNA2 was found in 45 of 47 of the EBER-positive Brazilian cases. In two cases, occasional LMP1-containing tumor cells were found in the neighborhood of small Schistosoma mansoni granulomas and scars. BHLF1 transcripts associated with lytic EBV infection could be detected in few cells in 3 of the 40 EBER-positive Brazilian cases investigated. EBV type A was found in the majority of Brazilian BL cases (20 of 30 A-type, 7 of 30 B-type, and 3 of 30 not amplifiable). Our results indicate that the association of Bahian BL with EBV, but not the regional prevalence of malaria, is similar to endemic African BL. In two cases, type II latency was found in association with schistosomiasis, suggesting a role of this parasitosis in the induction of an EBV expression pattern that is unusual for BL. Because chronic schistosomiasis is associated with elevated Th2 cytokine expression resulting in reduced cell-mediated cytotoxicity, it seems possible that altered local immunity is responsible for this peculiar phenotype.

Burkitt's lymphoma in Brazil: strong association with Epstein-Barr virus.

The incidence of Burkitt's lymphoma (BL) in Brazil is intermediate between the endemic form of equatorial Africa and the sporadic form in the United States. To characterize these lymphomas, we evaluated the clinical, morphologic, and immunohistochemical features of 24 Brazilian cases of BL. We also analyzed the cases for the presence of Epstein-Barr virus (EBV)-RNA using a highly sensitive and specific method of in situ hybridization. Most cases presented with involvement of intraabdominal organs, similar to the sporadic form of BL. EBV-RNA was detected in 17 of 24 cases (71%) in all or virtually all the tumor cells. This prevalence of EBV-positivity in our cases is intermediate between the endemic form of BL in equatorial Africa (100%) and the sporadic form in the United States (30%). These findings suggest that EBV plays an important role in the pathogenesis of BL in Brazil. This intermediate incidence of EBV infection may explain in part the differences of incidence of BL in different geographic regions.