Epstein–Barr virus and Hodgkin’s disease: further evidence for the three disease hypothesis

Armstrong, A.A.; Alexander, FE; Cartwright, R. A.; Angus, Brian; Krajewski, A. S.; Wright, D. H.; Brown, Ian; Lee, F; Kane, Eleanor; Jarrett, Ruth F.

doi:10.1038/sj.leu.2401097

Cited by 130 publications

(118 citation statements)

References 38 publications

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“…The EBV-positive rate in comparable cases of HD by age in the series of Armstrong et al 18 and this series is given in Table 3. Our series failed to show that the frequency of EBV-associated HD was greatest in age groups 0-14 years and 45+ years, compared with 15-34 years and 35-44 years.…”

Section: Ebv-positive Rate By Age: a Comparison Of Case Seriesmentioning

confidence: 84%

“…[7][8][9] Evidence of an association at the cellular level was provided by the localisation of EBV DNA 10,11 and the latent gene products, including the EBERs, 12 the Epstein-Barr nuclear antigen-1, 13 and the latent membrane proteins-1 14,15 and -2, 16,17 to the malignant Hodgkin and Reed-Sternberg (HRS) cells of HD. The frequency of EBV-associated HD has been shown to vary with age, [18][19][20] sex, 21 histological subtype, 19 country of residence 21 and ethnicity. 21 In a recent study from the UK, the frequency of EBV-associated HD was found to be higher in the age groups 0-14 years and 45+ years when compared to patients in the 15-34 or the 35-44 age groups.…”

Section: Introductionmentioning

confidence: 99%

“…21 In a recent study from the UK, the frequency of EBV-associated HD was found to be higher in the age groups 0-14 years and 45+ years when compared to patients in the 15-34 or the 35-44 age groups. 18 This led the authors to propose a 'three disease' model for HD based on age and EBV status. In this model, HD of childhood (0-14 years) and older adults (45+ years) is commonly EBV-associated and of MC type, whereas young adult HD (15-34 years) is generally not EBVassociated and is usually characterised by NS disease.…”

Section: Introductionmentioning

confidence: 99%

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Variation in the frequency of Epstein–Barr virus-associated Hodgkin's disease with age

et al. 2000

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A number of studies in developed countries have reported variation in the frequency of Epstein-Barr virus (EBV)-associated Hodgkin's disease (HD) with age. A 'three disease' model for HD that incorporates the EBV association, histological subtype of HD and age has recently been proposed. In this model, Hodgkin's disease of childhood and older adults is commonly EBV-associated and of mixed cellularity type, whereas young adult HD is generally not EBV-associated and is usually characterised by nodular sclerosis disease. A case series of HD diagnosed in the West Midlands between 1981 and 1997, inclusive, was used to investigate the applicability of the 'three disease' model. In situ hybridisation for the EBV early RNAs (EBERs) was used to determine the presence of EBV in the malignant Hodgkin/Reed-Sternberg cells. In contrast to the 'three disease' model, nodular sclerosis was the predominant subtype in each of the age groups within the case series. In addition, overall there was little variation in EBV-positive rates across the age ranges examined. However, when females were analysed separately, older women (45؉ years) were significantly more likely to have EBV-positive disease than their younger counterparts (Ͻ45 years). In summary our results do not generally support the 'three disease' model. Leukemia (2000) 14, 748-753.

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Section: Ebv-positive Rate By Age: a Comparison Of Case Seriesmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Variation in the frequency of Epstein–Barr virus-associated Hodgkin's disease with age

et al. 2000

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“…For EBV-positive HL, this inconsistency may result from our limited statistical power due to the low prevalence of this form of HL in women. However, for EBV-negative HL, the null findings are somewhat unexpected, 23 given the prior evidence for infection-related risk factors in HL overall, 4,24-29 which primarily comprises EBV-negative disease in this and most adult populations.…”

Section: Discussionmentioning

confidence: 85%

Exposure to childhood infections and risk of Epstein‐Barr virus–defined Hodgkin's lymphoma in women

Glaser

Keegan

Clarke

et al. 2005

Intl Journal of Cancer

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The role of Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) etiology remains unresolved as EBV is detected in only some HL tumors and few studies have tried to reconcile its presence with factors suggesting viral etiology (e.g., childhood social class, infection history). In a population-based case-control study of San Francisco Bay area women, we analyzed interview data by tumor EBV status. Among 211 young adult cases, EBV-positive HL (11%) was associated with a single vs. shared bedroom at age 11 (OR ¼ 4.0, 95% CI 1.1-14.4); risk was decreased for common childhood infections (OR ¼ 0.3, 95% CI 0.1-1.0), including measles before age 10, but not with prior infectious mononucleosis (IM), which is delayed EBV infection. No study factors affected risk of young adult EBV-negative HL. Among 57 older adult cases, EBV-positive HL (23%) was unrelated to study factors; EBV-negative HL was associated with a single bedroom at age 11 (OR ¼ 3.6, 95% CI 1.5-9.1) and IM in family members (OR ¼ 3.1, 95% CI 1.1-9.0). Thus, delayed exposure to infection may increase risk of EBV-positive HL in young adults, but risk patterns differ in younger and older women for both EBV-positive and -negative HL. Late EBV infection does not appear relevant to risk, suggesting that other pathogens impact HL etiology in affluent female populations. Inconsistency of findings with prior studies may reflect failure of study risk factors to proxy meaningful exposures, risk differences by gender, or selection or misclassification bias. Null findings for EBV-negative HL indicate that etiologic models should be reconsidered for this common form. ' 2005 Wiley-Liss, Inc.Key words: Hodgkin's lymphoma; Epstein-Barr virus; etiology; risk factor; infectious mononucleosis Infections have long been suspected in the etiology of HL, particularly for young adult cases. Initial clues came from its heterogeneous clinical behavior and histologic appearance, which suggest both a chronic infection and a malignancy. 1,2 Subsequently, epidemiologic studies showed that young adult HL cases tended to have childhood characteristics such as early birth order and small family size that are consistent with delayed exposure to other children, suggesting that timing of childhood infections was etiologically important. 3,4 EBV, a ubiquitous herpesvirus, was of early interest as a possible causative infectious agent because HL patients were more likely than controls to report prior IM (the clinical manifestation of primary infection with EBV delayed until adolescence) and to have elevated antibody titers to EBV before as well as after HL diagnosis. 5,6 Involvement by EBV was further supported when molecular studies identified EBV genes and gene products within malignant cells of affected HL tumors and in a form suggesting that infection preceded malignant transformation. 7 Nevertheless, the role of EBV in HL etiology remains unresolved as present methods detect evidence of EBV in the tumor cells of only a proportion of HL patients, and this evidence is least common in young adul...

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“…[3][4][5] Later studies using methods to detect gene products of EBV within tumor cells, considered evidence of etiologic involvement, led to an unexpected conundrum: EBV is not detected in tumors of most young adults with HD. 6,7 This apparent paradox renewed interest in the possibility that elevated anti-EBV antibody titers in young-adult HD patients are markers for another etiologic virus. 5 As reported recently in this journal, Gallagher et al 8 have searched for herpesviruses in HD tumors, using 2 PCR assays shown to detect all known viruses in this family.…”

Section: Dear Sirmentioning

confidence: 99%

Hodgkin's disease etiology and novel viruses: Clues from groups exposed to blood products

Glaser

Clarke

Darrow

2003

Intl Journal of Cancer

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Epstein–Barr virus and Hodgkin’s disease: further evidence for the three disease hypothesis

Cited by 130 publications

References 38 publications

Variation in the frequency of Epstein–Barr virus-associated Hodgkin's disease with age

Variation in the frequency of Epstein–Barr virus-associated Hodgkin's disease with age

Exposure to childhood infections and risk of Epstein‐Barr virus–defined Hodgkin's lymphoma in women

Hodgkin's disease etiology and novel viruses: Clues from groups exposed to blood products

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