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.

C-Kit (CD117) expression in AIDS-related, classic, and African endemic Kaposi sarcoma.

Kaposi sarcoma (KS) is a multicentric vascular neoplasm characterized histologically by the progressive proliferation of spindle-shaped tumor cells in all epidemiologic (AIDS-related, classic, endemic, and iatrogenic) forms. Human herpesvirus 8 (HHV8) is associated with all epidemiologic forms of KS and has been shown in vitro to induce the tyrosine receptor kinase c-kit in HHV8-infected cells. To date, c-kit immunoreactivity has not been systematically studied in KS lesions. Therefore, the aim of this study was to evaluate c-kit expression by immunohistochemistry in different proliferative stages and epidemiologic forms of KS. Archival cases of formalin-fixed, paraffin-embedded KS lesions, including 9 classic, 11 AIDS-related, and 15 African (endemic) forms at various histologic stages (5 patch, 8 plaque, 22 nodular), biopsied from different sites, were stained using immunohistochemistry with antibodies to HHV8 (LNA-1) and c-kit (CD117). C-kit immunoreactivity of lesional cells was demonstrated in 15 (43%) cases overall. A total of five (56%) classic, five (45%) AIDS-related, and five (33%) endemic KS cases were positive for c-kit. There was no difference in the intensity of c-kit staining between the different epidemiologic groups and histologic stages of KS. HHV8 (LNA-1) immunoreactivity was present in all (100%) classic, 10 (91%) AIDS-related, and 9 (60%) endemic cases. LNA-1 staining was demonstrated in 13 (93%) of the c-kit-positive and 15 (75%) of the c-kit-negative KS lesions. These findings indicate that c-kit expression in lesional cells can be detected by immunohistochemistry in different epidemiologic forms and histologic stages of KS. Furthermore, the expression of c-kit does not correspond with the presence of HHV8 (LNA-1) immunoreactivity in KS lesions.

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.

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.

Expert review of non-Hodgkin's lymphomas in a population-based cancer registry: reliability of diagnosis and subtype classifications.

Incidence rates of non-Hodgkin's lymphomas (NHLs) have nearly doubled in recent decades. Understanding the reasons behind these trends will require detailed surveillance and epidemiological study of NHL subtypes in large populations, using cancer registry or other multicenter data. However, little is known regarding the reliability of NHL diagnosis and subtype classification in such data, despite implications for the accuracy of incidence statistics and studies. Expert pathological re-review was completed for 1526 NHL patients who were reported to the Greater Bay Area Cancer Registry and who participated in a large population-based case-control study. Agreement of registry diagnosis with expert diagnosis and with International Classification of Diseases for Oncology-2 (Working Formulation) subtype classifications was measured with positive predictive values and kappa statistics. Agreement of registry and expert diagnoses was high (98%). Thirty patients were found on review not to have NHL; most of these had leukemia. For subtypes, agreement of registry and expert classification was more moderate (59%). Agreement varied substantially by subtype from 5% to 100% and was 77% for the most common subtype, diffuse large cell lymphoma. Seventy-seven percent of 128 registry-unclassified lymphomas were assigned a subtype on re-review. Our analyses suggest excellent diagnostic reliability but poorer subtype reliability of NHL in cancer registry data information that is critical to the interpretation of lymphoma time trends. Thus, overall NHL incidence and survival statistics from the early 1990s are probably accurate, but subtype-specific statistics could be substantially biased, especially because of high (15-20%) proportions of unclassified lymphomas.

Human herpesvirus-8 latent nuclear antigen-1 expression in endemic Kaposi sarcoma: an immunohistochemical study of 16 cases.

Human herpesvirus-8 (HHV-8) infection is considered the initiating factor in all forms of Kaposi sarcoma (KS). Latent nuclear antigen (LNA-1) is constitutively expressed in all HHV-8-infected cells. An antibody to LNA-1 has recently become commercially available. The current study addresses the role of immunohistochemistry in the diagnosis of KS, particularly the endemic form. Seven recent cases of KS, 1 atypical vascular lesion in a patient subsequently diagnosed with KS, and 16 endemic cases collected in South Africa in the early 1960s were stained with an antibody to LNA-1. Nine benign vascular lesions and three angiosarcomas were also stained. All 7 recent cases expressed the antigen as did the atypical vascular lesion. Of particular interest was the finding that 10 of the 16 endemic cases were positive. None of the other vascular lesions showed staining. A subset of the endemic lesions was stained for CD31, an antigen universally expressed in KS. CD31 staining was reduced compared with a positive control suggesting that the current study may underestimate the sensitivity of LNA-1 immunohistochemistry in endemic KS because of poor antigen preservation in the archival tissue. Our results confirm the utility of LNA-1 immunohistochemistry as an aid in the diagnosis of KS.

Reproductive factors in Hodgkin's disease in women.

Reproductive factors have been suggested to have an impact on the development of Hodgkin's disease (HD) in women. In the San Francisco Bay Area, the authors conducted a population-based case-control study addressing the effects of reproductive experience and hormone use on HD risk. Cases were 370 women with HD diagnosed at ages 19-79 years between July 1988 and December 1994. Controls were 450 community women found through random digit dialing. Among the 312 cases and 325 controls interviewed, HD risk was related to parity versus nulliparity but only among never nursers (odds ratio (OR)=2.2, 95% confidence interval (CI): 1.0, 5.0). Risk was marginally related to having uterine fibroids (OR=0.6, 95% CI: 0.5, 1.0) and long-term versus short-term hormone use (OR=0.7, 95% CI: 0.4, 1.0) and was significantly related to recurrent miscarriage (OR=2.8, 95% CI: 1.1, 7.4). Among women aged 35-54 years, for whom the sex difference in incidence is largest, nursing decreased risk; among never nursers, a parity of 1 lowered risk and higher parity increased risk; long-term hormone use lowered risk; and recurrent miscarriage increased risk. Among women under age 35 years, endometriosis lowered HD risk; the lack of significant findings for most other variables may reflect selection bias in controls. Among older women, no significant associations were observed, although hormone use appeared to be protective. These data suggest that steroid hormones may affect HD development.

Population-based patterns of human immunodeficiency virus-related Hodgkin lymphoma in the Greater San Francisco Bay Area, 1988-1998.

BACKGROUND: Epidemiologic characteristics of human immunodeficiency virus (HIV)-related Hodgkin lymphoma (HL) have not been examined in the Greater San Francisco Bay Area, a center of the HIV/acquired immunodeficiency syndrome (AIDS) epidemic, for a decade, despite changes in AIDS-associated diseases after the availability of highly active antiretroviral therapies (HAART). METHODS: With population-based cancer registry data for 1988-1998, the authors examined risk factors, Epstein-Barr virus (EBV) association, incidence rates, and survival probabilities for 1752 patients with HL who were classified as HIV-positive or HIV-negative by a cancer registry-based method. RESULTS: One hundred twenty-eight patients with HL (7%) were classified with HIV/AIDS; 95% were male. Among males, multivariate analysis (n=514 patients) found that HIV-related HL was associated strongly at diagnosis with ages 30-49 years, San Francisco residence, late-stage disease, lymphocyte depletion and unspecified histologic subtypes, and tumor cell EBV but not with other clinical features or mixed cellularity histology. Survival among patients with HIV-related HL, although it was poor, did not differ by race/ethnicity but was worse for patients with the nonnodular sclerosis histologic subtypes. Patients who were HIV-positive with HAART era (1996-1998) diagnoses were slightly older, were less likely to live in San Francisco, and were much more likely to be Hispanic compared with HIV-positive patients who were diagnosed before the HAART era; they had somewhat less aggressive disease and better survival. Incidence rates were higher for patients with HL overall compared with patients who had HIV-unrelated HL by 11% for white patients, 22% for black patients, and by 14% for Hispanic patients; excesses were greater in young adults. CONCLUSIONS: Among males in the San Francisco Bay Area, HIV-related HL had distinctive demographic features, more aggressive clinical characteristics, stronger EBV association, and poorer survival and contributed to elevated regional HL incidence rates, particularly in young adults. Patients with HIV-related HL who were diagnosed after HAART was introduced appeared to have less aggressive disease and better survival.

Lack of human herpesvirus 8 and Epstein-Barr virus in Kikuchi's histiocytic necrotizing lymphadenitis.

Kikuchi's histiocytic necrotizing lymphadenitis is a self-limited disorder that typically involves the cervical lymph nodes of young women. Although a viral etiology has been postulated, a definitive viral agent has not been identified. Recent reports have suggested that human herpesvirus 8 (HHV 8) or Epstein-Barr virus (EBV) may play an etiologic role. We investigated the presence of HHV 8 and EBV in archival tissue from 34 cases of Kikuchi's histiocytic necrotizing lymphadenitis. We examined 29 cases for HHV 8 using a nested polymerase chain reaction (PCR) on paraffin-embedded or frozen tissue, and 24 cases for EBV RNA using in situ hybridization (ISH) for EBER1. Controls included reactive lymph nodes from 8 adult women presenting with cervical or axillary lymphadenopathy. The study patients included 7 men and 27 women with a mean age of 28 years. All patients were previously healthy without evidence of immunocompromise and presented with cervical, axillary, or inguinal lymphadenopathy. Two cases exhibited EBV RNA by ISH; this was confirmed by PCR for EBV DNA. HHV 8 DNA was not amplified by nested PCR in any of the cases of Kikuchi's histiocytic necrotizing lymphadenitis or reactive lymph nodes; control PCR demonstrated the presence of amplifiable DNA in all cases. These findings suggest that HHV 8 and EBV do not play causative roles in Kikuchi's histiocytic necrotizing lymphadenitis.

Social class and risk of Hodgkin's disease in young-adult women in 1988-94.

Hodgkin's disease (HD) risk in young adults has been associated with higher childhood social class. Although recent decades have witnessed increases in both young-adult HD incidence rates and the socioeconomic affluence reported to influence risk, social class risk factors have not been reexamined. For 204 cases and 254 controls aged 19-44 years from a population-based case-control study of HD diagnosed in 1988-94 in San Francisco area females, we evaluated social class predictors of HD overall and for subgroups defined by age and by ethnicity. HD was associated weakly with a few childhood social class markers but more strongly with combinations of these variables. Risk was higher for women with family-owned than rented childhood homes; for US-born women with single vs. shared bedrooms at age 11; and for women with 2+ births who were from smaller than larger childhood households. These patterns differed by age, with risk appearing to increase over the young-adult years for some factors and to decrease for others. In whites, risk was additionally associated with having a single childhood bedroom in larger households, and with tall adult height in women from smaller childhood households. In nonwhites, risk was higher for single bedrooms at age 11 in smaller childhood households, taller height and higher maternal education. Most study findings support the hypothesis that HD development in young adults follows protection from early exposure to other children. Variation in risk by age suggests differing etiologies across young adulthood, or the importance of birth cohort-appropriate social-class measures. Negative findings for previously reported risk factors may reflect their insufficient heterogeneity of exposure or their failure to measure cohort-relevant exposures in this population.