Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma.

An altered anti-Epstein-Barr virus (EBV) serologic profile preceding diagnosis is associated with an increased risk of Hodgkin lymphoma. It is unknown whether this atypical pattern predicts Hodgkin lymphoma risk further subdivided by determination of EBV in tumor cells. A nested case-control study of 128 incident Hodgkin lymphoma cases and 368 matched controls from active-duty military personnel with archived serum in the US Department of Defense Serum Repository was conducted to determine whether a panel of anti-EBV antibody titers differed in EBV(+) and EBV(-) Hodgkin lymphoma. Among 40 EBV(+) Hodgkin lymphoma cases and matched controls, statistically significant increased risks were associated with elevated anti-EBV VCA IgG antibody titers (relative risk = 3.1; 95% confidence interval [CI], 1.1-8.7), and an anti-EBNA-1/anti-EBNA-2 antibody ratio ≤ 1.0 versus > 1.0 (relative risk = 4.7; 95% CI, 1.6-13.8). In contrast, no significant associations were found among 88 EBV(-) Hodgkin lymphoma cases relative to their matched controls. In case-case analysis, EBV(+) disease was significantly associated with a low anti-EBNA-1/anti-EBNA-2 antibody ratio. This distinctive serologic response to EBV latent antigens, indicative of immune dysfunction in other clinical settings, is associated with an increased risk of developing EBV(+) but not EBV(-) Hodgkin lymphoma.

Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations.

Epstein-Barr virus (EBV) is detected in the tumor cells of some but not all Hodgkin lymphoma (HL) patients, and evidence indicates that EBV-positive and -negative HL are distinct entities. Racial/ethnic variation in EBV-positive HL in international comparisons suggests etiologic roles for environmental and genetic factors, but these studies used clinical series and evaluated EBV presence by differing protocols. Therefore, we evaluated EBV presence in the tumors of a large (n = 1,032), racially and sociodemographically diverse series of California incident classical HL cases with uniform pathology re-review and EBV detection methods. Tumor EBV-positivity was associated with Hispanic and Asian/Pacific Islander (API) but not black race/ethnicity, irrespective of demographic and clinical factors. Complex race-specific associations were observed between EBV-positive HL and age, sex, histology, stage, neighborhood socioeconomic status (SES), and birth place. In Hispanics, EBV-positive HL was associated not only with young and older age, male sex, and mixed cellularity histology, but also with foreign birth and lower SES in females, suggesting immune function responses to correlates of early childhood experience and later environmental exposures, respectively, as well as of pregnancy. For APIs, a lack of association with birth place may reflect the higher SES of API than Hispanic immigrants. In blacks, EBV-positive HL was associated with later-stage disease, consistent with racial/ethnic variation in certain cytokine polymorphisms. The racial/ethnic variation in our findings suggests that EBV-positive HL results from an intricate interplay of early- and later-life environmental, hormonal, and genetic factors leading to depressed immune function and poorly controlled EBV infection.

Body size, physical activity, and risk of Hodgkin's lymphoma in women.

Few studies have examined the associations of body size and physical activity with the development of Hodgkin's lymphoma (HL) in women. In data from a population-based case-control study in women ages 19 to 79 years, we assessed the relation of self-report height, weight, body mass index (BMI), and strenuous physical activity to HL risk in 312 cases with diagnostic re-review and 325 random-digit dialed controls using logistic regression. Analyses were stratified by age group and tumor cell presence of EBV. After adjustment for social class measures, taller childhood and adult height were associated with higher HL risk. In women ages 19 to 44 years, HL risk was elevated for higher, but healthy, BMI values, whereas in women ages 45 to 79 years, associations with BMI were inverse. The odds of developing HL were lower with participation (versus nonparticipation) in strenuous physical activity in the past year [odds ratio (OR), 0.58; 95% confidence interval (95% CI), 0.39-0.87 in women 19-44 years; OR, 0.45; 95% CI, 0.19-1.06 in women 45-79 years] and throughout adult life, and with sports team membership (versus nonmembership) in high school and/or at ages 18 to 22 years. Results were similar in cases (n = 269) with and without tumor-cell EBV compared with controls, although the inverse association with physical activity was somewhat stronger for women with EBV-positive disease. These findings show that in women, body size and strenuous physical activity, both modifiable characteristics, are associated with HL risk in adult life possibly through immunologic, infectious, or genetic mechanisms.

Epstein-Barr virus as a marker of survival after Hodgkin's lymphoma: a population-based study.

PURPOSE: Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) cells has been considered as a prognostic marker for this heterogeneous disease, but studies have yielded mixed findings, likely because of selected patient series and failure to acknowledge an effect of age on outcome. This study assessed survival after HL in a population-based cohort large enough to examine the joint effects of EBV with other factors including age, sex, and histologic subtype. PATIENTS AND METHODS: Included were 922 patients with classical HL diagnosed between mid-1988 and 1997 in the Greater San Francisco Bay Area, with archived biopsy specimens assayed for EBV with immunohistochemistry and in situ hybridization. Vital status was followed through December 30, 2003 (median follow-up time, 97 months). Overall and disease-specific survival were analyzed with the Kaplan-Meier method and Cox proportional hazards regression models. RESULTS: In children less than 15 years old, EBV presence was suggestively associated (P = .07) with favorable survival. In adults aged 15 to 44 years, EBV did not affect HL outcome, although a protective effect was suggested. In older adults (45 to 96 years), EBV presence nearly doubled the risk of overall and HL-specific mortality but only for patients with nodular sclerosis (NS) histologic subtype (hazard ratio for death = 2.5; 95% CI, 1.5 to 4.3). CONCLUSION: In HL, EBV tumor cell presence is associated with better survival in young patients and poorer survival in older patients with NS, independent of other factors. Variation in outcome by age and histology could indicate biologically distinct disease entities. Evidence that EBV is a meaningful prognostic marker may have therapeutic relevance.

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

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 = 4.0, 95% CI 1.1-14.4); risk was decreased for common childhood infections (OR = 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 = 3.6, 95% CI 1.5-9.1) and IM in family members (OR = 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.

Childhood social environment and Hodgkin's lymphoma: new findings from a population-based case-control study.

BACKGROUND: Risk of Hodgkin's lymphoma in young adults has previously been associated with higher childhood socioeconomic status (SES) and other markers of delayed infection with common childhood pathogens, especially the Epstein-Barr virus. This study examines the current role of childhood social environment in the development of Hodgkin's lymphoma. METHODS: A population-based case-control study of 565 Hodgkin's lymphoma cases and 679 controls was conducted in the Boston, MA metropolitan area and the state of Connecticut to investigate the viral etiology of Hodgkin's lymphoma. RESULTS: A novel association was detected between attendance of nursery school or day care and reduced risk of Hodgkin's lymphoma among individuals ages 15 to 54 years. The odds ratio (95% confidence interval) for having attended preschool for at least 1 year was 0.64 (0.45-0.92). Risk of young-adult Hodgkin's lymphoma was also associated with family history of hematopoietic cancer, Jewish ethnicity, and cigarette smoking. Other indicators of childhood SES were not associated with young-adult Hodgkin's lymphoma. Among older adults ages 55 to 79 years, Hodgkin's lymphoma was associated with lower childhood SES but not with preschool attendance. CONCLUSIONS: Early exposure to other children at nursery school and day care seems to decrease the risk of Hodgkin's lymphoma in young adults, most likely by facilitating childhood exposure to common infections and promoting maturation of cellular immunity. This finding supports the delayed infection model of Hodgkin's lymphoma etiology in young adults while introducing a new major determinant of age at infection. Hodgkin's lymphoma seems to have a separate pathogenesis among older adults.

Heterogeneity of risk factors and antibody profiles in epstein-barr virus genome-positive and -negative hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) tumors that contain the Epstein-Barr virus (EBV) genome may differ etiologically from EBV-negative HL tumors. METHODS: A case-case study examining heterogeneity of risk factors between disease subgroups compared personal characteristics and EBV antibodies between 95 EBV-positive and 303 EBV-negative patients with HL. RESULTS: We confirmed previous associations of EBV-positive HL with older age, male sex, and mixed-cellularity (MC) histological subtypes. EBV-positive patients were less educated and more likely to have smoked cigarettes and had more prevalent and higher EBV antibody titers, compared with EBV-negative patients. After adjustment for all independent risk factors, those most strongly associated with EBV-positive HL were histological subtypes (odds ratio [OR] for MC vs. nodular sclerosis histology, 3.2; 95% confidence interval [CI], 1.4-7.2), elevated anti-viral capsid antigen level (OR, 3.1; 95% CI, 1.6-6.0), and less education (OR, 0.7; 95% CI, 0.5-1.0). Cigarette smoking and a low anti-Epstein-Barr nuclear protein (EBNA) 1 : anti-EBNA-2 ratio were also marginally associated with EBV-positive HL. CONCLUSIONS: EBV-positive HL is more common among individuals who have markers of diminished cellular immunity and an abnormal EBV antibody response. EBV appears to participate in the etiology of EBV-positive HL but may not be involved in EBV-negative HL.

Smoking and Hodgkin lymphoma risk in women United States.

OBJECTIVE: Smoking has received little consideration as a risk factor for Hodgkin lymphoma (HL) in women, despite recent significant findings in men and gender differences in HL incidence. We investigated the association of HL with lifetime cigarette smoking and household environmental tobacco smoke (ETS) exposure in women. METHODS: In data from a population-based case-control study in women ages 19-79, we analyzed HL risk associated with self-reported smoking and household ETS exposure in 312 diagnostically re-reviewed cases and 325 random-digit dialing controls using logistic regression. Epstein-Barr virus (EBV) presence was determined in tumors of 269 cases. RESULTS: In 253 cases compared to 254 controls ages 19-44, risks of HL overall, and of nodular sclerosis and EBV-negative HL, were increased 50% with ETS exposure in childhood; for 11 cases of mixed cellularity (MC) HL, current smoking and adult ETS exposure also increased risk; for 24 cases of EBV-positive HL, risk was elevated for current smoking, greater smoking intensity and duration, and ETS exposure. In 59 cases and 71 controls ages 45-79, most smoking characteristics did not appear to affect risk. CONCLUSIONS: Apparent effects of current smoking on risks of MC HL and EBV-positive HL and of household ETS on risk of all HL in young adult females may broaden the evidence implicating tobacco smoke exposures in HL etiology.

Inter- and intra-observer reliability of Epstein-Barr virus detection in Hodgkin lymphoma using histochemical procedures.

EBER in situ hybridization (EBER) and LMP-1 immunohistochemistry (LMP-1) are widely used for identifying Epstein-Barr virus (EBV) within tumor cells of Hodgkin lymphoma (HL), but measurement error has never been formally evaluated. To determine assay reliability, 40 HL tumors with known EBV status were stained for both EBER and LMP-1 by two laboratories and reviewed twice by four hematopathologists. Inter- and intra-observer agreement were good to excellent, with kappas above 0.78 overall and above 0.60 for most subgroup analyses. However, reliability varied by histologic subtype, preparing laboratory, reviewer and EBV status determined on consensus review. For EBER, inter-observer agreement was high for nodular sclerosis HL but somewhat lower for EBV-negative mixed cellularity HL. For LMP-1, agreement was excellent for mixed cellularity HL but somewhat less reliable for EBV-positive nodular sclerosis HL. Agreement was good for EBER and LMP-1 applied to the same specimens but differed by consensus EBV status. The variability in assay interpretation justifies caution in comparing EBV association results across HL studies and underscores the need for interpretation guidelines.

Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors.

PURPOSE: To determine whether therapy with a DNA methyltransferase inhibitor is effective in achieving demethylation and gene re-expression in tumor DNA in patients. METHODS: Biopsy specimens were obtained from patients with Epstein-Barr virus-associated tumors, enrolled on a clinical trial of 5-azacitidine, within 72 hours of the conclusion of the last infusion of the first cycle of therapy, and compared to pretreatment specimens. Methylation-specific polymerase chain reaction, bisulfite genomic sequencing, and immunohistochemistry were used to assess demethylation and gene re-expression. RESULTS: Substantial degrees of demethylation were detected in all latent and lytic Epstein-Barr virus promoters examined. Immunohistochemistry suggested activation of a previously silent viral antigen expression in one instance. CONCLUSION: Pharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients.