A population-based cohort study on early-stage Hodgkin lymphoma treated with radiotherapy alone: with special reference to older patients.

BACKGROUND: Combined modality treatment has reduced the risk of relapse among younger early-stage Hodgkin lymphoma (HL) patients. Older HL patients may not tolerate chemotherapy and their prognosis is less favorable. We conducted a population-based study to evaluate long-term follow-up outcome in older early-stage HL patients initially treated with radiotherapy (RT) alone. PATIENTS AND METHODS: We included 308 consecutive patients (22% were >or=60 years) diagnosed 1972-1999 (median follow-up 20 years; range 1-28). Using Cox regression models we defined risk of relapse and survival in relation to clinical factors. RESULTS: 272/308 (88%) patients obtained complete remission following first-line RT alone. Among these, 42% relapsed within a median of 21 months. The relapse rate was independent of gender and age at diagnosis (median age 32 years, range 14-85); however, lymphocyte-predominant HL was associated with borderline (P=0.049) 56% decreased risk of relapse. Among patients<60 years and >or=60 years, we observed 29 (median latency 10 years, range 2-25) and 11 (median latency 3 years, range 1-10) second tumors, respectively. CONCLUSIONS: Older age (>or=60 years) was not associated with an increased risk of relapse following RT alone. Given the risks of iatrogenic morbidity/mortality of chemotherapy in older patients, RT alone could be an alternative first-line therapy in early-stage older HL patients.

Does place of birth influence endogenous hormone levels in Asian-American women?

In 1983-87, we conducted a population-based case-control study of breast cancer in Asian women living in California and Hawaii, in which migration history (a composite of the subject's place of birth, usual residence in Asia (urban/rural), length of time living in the West, and grandparents' place of birth) was associated with a six-fold risk gradient that paralleled the historical differences in incidence rates between the US and Asian countries. This provided the opportunity to determine whether endogenous hormones vary with migration history in Asian-American women. Plasma obtained from 316 premenopausal and 177 naturally premenopausal study controls was measured for levels of estrone (E1), estradiol (E2), estrone sulphate (E1S), androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), progesterone (PROG) and sex hormone-binding globulin (SHBG). Levels of the oestrogens and sex hormone-binding globulin did not differ significantly between Asian- and Western-born women, although among premenopausal women, those least westernised had the lowest levels of E1, E2, and E1S. Androgen levels, particularly DHEA, were lower in women born in the West. Among premenopausal women, age-adjusted geometric mean levels of DHEA were 16.5 and 13.8 nmol l(-1) in Asian- and Western-born women respectively; in postmenopausal women these values were 11.8 and 9.2 nmol l(-1), (P<0.001) respectively. Among postmenopausal women, androgens tended to be highest among the least westernised women and declined as the degree of westernisation increased. Our findings suggest that aspects of hormone metabolism play a role in population differences in breast cancer incidence.

Elevated serum homocysteine levels and increased risk of invasive cervical cancer in US women.

OBJECTIVES: To explore the relationship between serum homocysteine, a sensitive biomarker for folate inadequacy and problems in one-carbon metabolism, and invasive cervical cancer. METHODS: A large case-control study was conducted in five US areas with up to two community controls, obtained by random-digit dialing, individually matched to each case. Cervical cancer risk factors were assessed through at-home interview. Blood was drawn at least 6 months after completion of cancer treatment from 51% and 68% of interviewed cases and controls. Serum homocysteine was measured by high-performance liquid chromatography, and exposure to human papillomavirus (HPV) type 16, the most prevalent oncogenic type, was assessed using an enzyme-linked immunosorbent assay. Cases with advanced cancer and/or receiving chemotherapy were excluded, leaving 183 cases and 540 controls. RESULTS: Invasive cervical cancer risk was substantially elevated for women in the upper three homocysteine quartiles (> 6.31 micromol/L); multivariate-adjusted odds ratios ranged from 2.4 to 3.2 (all 95% CIs excluded 1.0). A trend was apparent and significant (p = 0.01). When cases were compared with HPV-16 seropositive controls only, odds ratios were comparable. CONCLUSIONS: Serum homocysteine was strongly and significantly predictive of invasive cervical cancer risk. This association could reflect folate, B12 and/or B6 inadequacy, or genetic polymorphisms affecting one-carbon metabolism.

Insulin-like growth factors and prostate cancer: a population-based case-control study in China.

Insulin-like growth factors (IGFs) have potent mitogenic and antiapoptotic effects on prostate epithelial cells. Through modulation of IGF bioactivity and other mechanisms, IGF-binding proteins (IGFBPs) also have growth-regulatory effects on prostate cells. Recently, IGF-I and IGFBP-3 have been implicated in prostate cancer risk among Western populations. To assess whether IGF-I, IGF-II, IGFBP-1, or IGFBP-3 are also associated with prostate cancer in a low-risk population, we measured plasma levels of these factors among 128 newly diagnosed prostate cancer cases and 306 randomly selected population controls in Shanghai, China. Relative to the lowest quartile of IGF-I levels, men in the highest quartile had a 2.6-fold higher prostate cancer risk, with a significant trend [odds ratio (OR) = 2.63; 95% confidence interval (95% CI) = 1.19-5.79; P(trend) = 0.01]. In contrast, men in the highest quartile of IGFBP-3 levels had a 46% decreased risk relative to the lowest quartile (OR = 0.54; 95% CI = 0.26-1.15; P(trend) = 0.08). A similar but less distinct result was observed for IGFBP-1 (OR = 0.60; 95% CI = 0.31-1.17; P(trend) = 0.25). Men in the highest quartile for the IGF-I:IGFBP-3 molar ratio (an indirect measure of free IGF-I) had a 2.5-fold higher risk compared with the lowest quartile (OR = 2.51; 95% CI = 1.32-4.75, P(trend) < 0.001). These associations were more pronounced after adjustment for serum 5alpha-androstane-3alpha,17beta-diol glucuronide and sex hormone-binding globulin levels. There was no significant association with IGF-II levels. Our findings in a low-risk population provide evidence that IGF-I, IGFBP-3, and IGFBP-1 are determinants of prostate cancer and indicate that additional studies are needed to evaluate their effects on ethnic and geographic incidence differentials and to elucidate carcinogenic mechanisms.

Retinoblastoma incidence and sunlight exposure.

To evaluate positive findings from an earlier report, we studied the relation between retinoblastoma incidence and ultraviolet (UV-B) radiation levels in the Surveillance, Epidemiology, and End Results (SEER) programme areas of the USA using weighted regression, as well as in international data after adjusting for race, economic development, and climate. The association was not statistically significant within the USA (P > 0.20). At an international level, the relation was significant overall and after adjusting for economic development, but it was not significant after adjusting for race and tropical climate, suggesting that environmental factors other than UV-B may be responsible for the geographic patterns of retinoblastoma.

Reproducibility studies and interlaboratory concordance for androgen assays in female plasma.

We conducted studies to determine the magnitude and sources of variability in androgen assay results and to identify laboratories capable of performing such assays for large epidemiological studies. We studied androstanediol (ADIOL), androstanediol glucuronide (ADIOL G), androstenedione (ADION), androsterone glucuronide (ANDRO G), androsterone sulfate (ANDRO S), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA S), dihydrotestosterone (DHT), and testosterone (TESTO). A single sample of plasma was obtained from five postmenopausal women, five premenopausal women in the midfollicular phase of the menstrual cycle, and five women in the midluteal phase, divided into aliquots, and stored at -70 degrees. Four sets of two coded aliquots from each woman were then sent to participating labs for analysis at monthly intervals over 4 months. Using the logarithm of assay measurements, we estimated the components of variance and three measures of reproducibility. The usual coefficient of variation is a function of the components that are under the control of the laboratory. The intraclass correlation between measurements for a given individual is the proportion of the total variability that is associated with individuals. The minimum detectable relative difference is important to evaluate study feasibility. Results suggest that a single sample of ADIOL G, DHEA, DHEA S, and ANDRO G (with two lab replicates per sample) can be used to discriminate reliably among women in a given menstrual phase or menopausal status. The results for DHT, TESTO, ADION, and ANDRO S are more problematic and suggest that the present measurement techniques should be used with care, especially with midluteal phase women. The results for ADIOL suggest that this assay is not yet ready for use in epidemiological studies.

Cancer surveillance series: changing patterns of cutaneous malignant melanoma mortality rates among whites in the United States.

BACKGROUND: Mortality from melanoma among whites is still increasing in the United States. In this study, we describe the changing patterns of melanoma mortality rates among whites by demographic factors and geography and further assess the relationship between the geographic patterns and the UV radiation (UV-B) level. METHODS: Age-adjusted incidence and mortality rates were computed by use of the 1970 U.S. population standard. Annual percent changes of mortality were estimated by fitting regression lines to the logarithm of rates. The relationships between melanoma mortality rates and UV-B level over time were assessed by weighted regressions. All statistical tests were two-sided. RESULTS: From 1950-1954 through 1990-1994, melanoma mortality rates increased by 191% and 84% among males and females, respectively. Mortality rates peaked in the 1930 through 1950 birth cohorts for females and in the 1935 through 1950 birth cohorts for males. In the 1950 through 1969 study period, melanoma mortality rates showed a strong North-South gradient, but the gradient weakened in recent periods. The absolute change in mortality for a 10% increase in UV-B among females decreased from 0.08 additional deaths per 100 000 person-years in 1950-1959 to 0.01 additional deaths in 1990-1995. In contrast, the absolute change in mortality among males showed little change over time; additional deaths increased from 0.11 to 0.12 per 100 000 person-years. CONCLUSIONS: Melanoma mortality in the United States reflects the complex interplay of UV radiation levels in each geographic region, the sun-protection behaviors of each generation of males and females in childhood and adulthood, the geographic mobility of the population, and the risk awareness and early detection.

Analysis of a two-stage case-control study with cluster sampling of controls: application to nonmelanoma skin cancer.

We present a pseudolikelihood approach for analyzing a two-stage population-based case-control study with cluster sampling of controls. These methods were developed to analyze data from a study of nonmelanoma skin cancer (NMSC). This study was designed to evaluate the role of ultraviolet radiation (UVB) on NMSC risk while adjusting for age group, which is known for all subjects, and for other individual-level factors, such as susceptibility to sunburn, which are known only for participants in the case-control study. The methods presented yield estimates of relative and absolute risk, with standard errors, while accounting naturally for the two-stage sampling of the cohort and cluster sampling of controls.

A new ELISA kit for measuring urinary 2-hydroxyestrone, 16alpha-hydroxyestrone, and their ratio: reproducibility, validity, and assay performance after freeze-thaw cycling and preservation by boric acid.

There is considerable controversy regarding the role of estrogen metabolites in breast cancer risk, fueled in part by the development of a rapid ELISA that is suitable for large scale investigations. An earlier version of the ELISA could detect values of the 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1) metabolites as low as 2 ng/ml and produce consistent results in premenopausal urines. However, reproducibility was problematic in postmenopausal urines where concentrations of these compounds are much lower. In response to our concern, a new ELISA was developed with a sensitivity of 0.625 ng/ml, which we evaluated using the same pre- and postmenopausal urine samples analyzed in the earlier ELISA. In this report, we present findings on the new kit with regard to reproducibility of the 2-OHE1 and 16alpha-OHE1 measurements, comparability of results with gas chromatography-mass spectroscopy values, and with regard to the stability of the metabolites after repeated freeze-thaw cycles and after preservation by boric acid. For the most part, we found the new ELISA to be reproducible, with assay coefficients of variation ranging from 10 to 20%, and intraclass correlation coefficients (ICCs) ranging from 80 to 95% in both the pre- and postmenopausal urines. ELISA results for 16alpha-OHE1 differed from 1 day (i.e., batch) to the next, and the absolute values of the metabolites obtained by the ELISA were consistently lower than but well correlated with those obtained by gas chromatography-mass spectroscopy. Values of the 2-OHE1:16alpha-OHE1 ratio also differed between the methods, but because the range of values was not large, the magnitude of these differences was not as great. For the ratio, the correlation between methods was excellent, and the ICCs were high for both groups of women. After preservation by boric acid, values of the ratio varied according to acid concentration but not in a linear fashion. Ratio values were similar in urine samples exposed to four different freeze-thaw cycle treatments, although values for all treatments were consistently lower in one batch. Because batch-to-batch variability was not negligible, it is advisable that matched cases and controls be analyzed in the same batch. Provided this is done, the relatively low assay coefficient of variation and high ICC demonstrate that the new ELISA kit can reliably measure the 2-OHE1:16alpha-OHE1 ratio and detect small case-control differences in large population-based studies, where rapid and relatively easy laboratory methods are critical.

Reproducibility and validity of radioimmunoassays for urinary hormones and metabolites in pre- and postmenopausal women.

The reproducibility of RIAs of circulating sex hormones has been evaluated as part of recent epidemiological investigations, but none seem to have addressed the reproducibility or validity of RIAs for urinary hormones or their metabolites. As part of a case-control study of breast cancer in Asian-American women, 12-h overnight urine samples were obtained, and a methodological study was conducted to identify laboratories capable of assaying urinary hormones. For the reproducibility component of this study, two laboratories with extensive experience in hormone assays measured urinary estrone, estradiol, estriol, pregnanediol glucuronide, and estrone glucuronide using samples from 15 women (5 midfollicular, 5 midluteal, and 5 postmenopausal). Variance estimates from these measurements were used to calculate the laboratory variability (coefficient of variation) and to assess the magnitude of the biological variability among the women in relation to the total variability (intraclass correlation coefficient). For the validity component, urinary estrone, estradiol, and estriol levels were measured in the same samples by gas chromatography-mass spectroscopy in the laboratory of Dr. Herman Adlercreutz (University of Helsinki, Helsinki, Finland). We found that the degree of assay reproducibility differed between the laboratories, but that laboratory variability was usually low compared with the range of hormone values among women, particularly for the estrogens. Values for estrone and estradiol were well correlated among all of the laboratories. For estriol, the RIAs tended to overestimate levels compared with gas chromatography-mass spectroscopy. In one laboratory, assays for pregnanediol glucuronide and estrone glucuronide were consistently reproduced; in the other, the reproducibility of the RIA for pregnanediol glucuronide was problematic, and estrone glucuronide was not measured. Despite some limitations, urinary hormones and their metabolites can be reliably measured by current RIAs in large investigations attempting to link hormone level to disease risk and may be particularly advantageous for studies of postmenopausal women, where serum concentrations of estrone and estradiol are low and assay measurements are not as dependable.

Cancer and a fatiguing illness in Northern Nevada--a causal hypothesis.

PURPOSE: We investigated the possibility that chronic fatigue syndrome (CFS) predisposes to cancer by comparing the cancer pattern in an area in northern Nevada, where an outbreak of a fatiguing illness, which included cases of CFS, was reported, to an area in southern Nevada, where no such illness was reported. METHODS: Data from the computerized Nevada Cancer Registry were utilized to compare incidence rates of four malignancies--brain cancer, non-Hodgkin lymphoma (NHL), lung cancer, and breast cancer--in Washoe and Lyon Counties, where an unexplained fatiguing illness was reported during 1984-86, with comparably sized Clark County, where no such illness was reported. RESULTS: Higher incidences of NHL and primary brain tumors were noted in the two northern Nevada counties (Washoe and Lyon) in 1986 and 1987 respectively, compared to the southern Nevada (Clark) county. Similar patterns were not seen for breast or lung cancer. CONCLUSIONS: This study provides a model for investigating the possible predisposition of CFS patients to develop cancer using other cohorts, but it is currently premature to accept such a link at this time.

Pathways Linking Treatment Intensity and Psychosocial Outcomes among Adult Survivors of Childhood Leukemia.

To determine the pathways between treatment intensity (age at diagnosis, dosage of chemotherapy [intrathecal methotrexate; IT-MTX] and cranial radiation [CRT]) and various psychosocial outcomes, review of medical records and structured interviews were carried out in 510 adult survivors of childhood leukemia. Structural equation modeling revealed that higher treatment intensity during childhood (indicated by treatment with high-dose CRT, low-dose IT-MTX, and adjusted by younger age at diagnosis) predicted more health- compromising behaviors as adults through lower educational achievement. Additionally, higher childhood treatment intensity predicted current negative mood both directly and via changes in perceived limitations. The present study's findings suggest that higher treatment intensity during childhood may serve as a risk factor for adult survivors' health-compromising behaviors through neuropsychological deficits that arise from cancer treatment.

Menarche in a cohort of 188 long-term survivors of acute lymphoblastic leukemia.

OBJECTIVE: As more children survive acute lymphoblastic leukemia (ALL), questions are raised regarding how the disease and its therapy affect their pubertal development. STUDY DESIGN: The National Institute of Child Health and Human Development-National Cancer Institute-Children's Cancer Group Leukemia Follow-Up Study used a historical cohort design to investigate menarche in 188 ALL survivors who were premanarchal at diagnosis, aged at least 18 years, at least 2 years after diagnosis, alive, and in remission. Female siblings of ALL survivors (n = 218) served as control subjects. RESULTS: Menarche occurred within the normal age range in 92% of survivors and 96% of the control subjects (p = 0.09). Early menarche occurred in four survivors (2%) and three control subjects (1%). Delayed, absent, or medically induced menarche was reported by 12 survivors (6%) and six control subjects (3%). Compared with the control subjects, survivors of ALL who received 1800 cGy cranial radiation before the age of 8 years had significantly earlier menarche, relative hazard (RH) of 2.2 (95% confidence interval: 1.4, 3.4 [p = 0.0003]). Survivors receiving 2400 cGy of craniospinal radiation with or without abdominal radiation had significantly later menarche than the control subjects, RH 0.4 (95% confidence interval: 0.3, 0.7 [p = 0.0002]). CONCLUSIONS: In this large cohort of ALL survivors, the risk of disordered menarche was low. However, younger subjects receiving 1800 cGy cranial radiation and those receiving 2400 cGy below the diaphragm required careful monitoring.

Late effects of therapy in survivors of Ewing's sarcoma family tumors.

PURPOSE: This late effects study was designed to determine if survivors of Ewing's sarcoma family tumors (ESFT) had adverse outcomes in employment, marital status, fertility, and functional status when compared to sibling controls. SUBJECTS AND METHODS: Eighty-nine survivors (case subjects) of ESFT treated at the National Cancer Institute between 1965 and 1992 and 97 sibling controls completed a questionnaire probing aspects of quality of life. The answers from case subjects were compared to pooled and matched sibling controls for all key variables. Odds ratios (OR) and p values from pooled analyses are presented. RESULTS: Although case subjects and controls did not differ in educational achievement, case subjects were less likely to be employed full-time (OR 0.4, p < 0.01), to be married (OR 0.2, p < 0.01), and to have children (OR 0.3, p < 0.01). Their most common treatment-related difficulties included permanent hair and skin changes (43%), lung problems (18%), neurologic problems (14%), visual difficulties (10%), second malignancy (7%), and amputation (5%). Functional status, measured by Karnofsky performance scale, was also adversely affected in case subjects. Case subjects did not differ from sibling controls in health care insurance status or in utilization of health services. CONCLUSIONS: Important aspects of life such as employment, marital status, fertility, and functional status are affected in survivors of ESFT. More studies are needed to better define the health status of adult survivors of pediatric cancer and the impact of cancer in adolescence on psychosocial development.

Quantifying estrogen metabolism: an evaluation of the reproducibility and validity of enzyme immunoassays for 2-hydroxyestrone and 16alpha-hydroxyestrone in urine.

Rapid and simple enzyme immunoassays (EIAs) were recently developed to measure 2-hydroxyestrone and 16alpha-hydroxyestrone in unextracted urine. The balance between these competing estrogen metabolism pathways may serve as a biomarker of breast cancer risk. Before testing these assays in epidemiologic studies, we evaluated their reproducibility, and validity relative to gas chromatography-mass spectroscopy (GC-MS). Overnight 12-hr urine collections from five midfollicular premenopausal women, five midluteal premenopausal women, and five postmenopausal women were aliquoted and stored at -70 degrees C. Two aliquots from each woman were assayed with the EIAs in a random, blinded order, monthly over 4 months and 1 year later. Reproducibility over 4 months was good for both metabolites in premenopausal women (coefficient of variation = 8-14%) and satisfactory in postmenopausal women (approximately 19%). Reproducibility over 12 months remained good in premenopausal women, but was poor in postmenopausal women, with mean readings increasing 50 to 100%. Wide variation in estrogen metabolite levels enabled a single EIA measurement to characterize individual differences among premenopausal women in midfollicular (intraclass correlation coefficient = 98-99%) and midluteal phase (85-91%). A narrower range in metabolite levels among postmenopausal women reduced discrimination (78-82%). The correlation between EIA and GC-MS measurement was excellent for both metabolites (r>0.9), except for 2-hydroxyestrone in postmenopausal women (r=0.6). Analysis of absolute agreement suggested that both EIAs were less sensitive than GC-MS, and each detected nonspecific background. The low concentration of estrogen metabolites in urine from postmenopausal women may explain the problems with reproducibility and validity in this menstrual group. Accordingly, more sensitive EIAs have been developed and are now being evaluated.

Risk of secondary leukemia after treatment with etoposide (VP-16) for Langerhans' cell histiocytosis in Italian and Austrian-German populations.

To estimate the risk of secondary leukemias after treatment with etoposide (VP-16), we evaluated subjects treated for Langerhans' cell histiocytosis (LCH) according to cooperative protocols in Italy or in Austria, Germany, Holland and Switzerland (AGDS). For each subject, information was collected on the cumulative dosages of chemotherapy and radiotherapy received, vital status and occurrence of secondary leukemia. The expected number of leukemias was estimated using age-specific incidence rates from the cancer registries in Italy and Germany. Standardized incidence ratios (SIR) were used to measure the risk of secondary leukemia among LCH patients. Five leukemias occurred among the 241 Italian study patients (SIR 520), whereas no cases were reported among the 363 AGDS patients. Interestingly, and in contrast to previous descriptions of epipodophyllotoxin-related leukemias which are mostly FAB M4 or M5, these leukemias showed typical FAB M3 features, and received a dose of VP-16 > 4,000 mg/m2. Among the AGDS cohort, very few subjects were exposed to high doses of VP-16. The risk of secondary acute non-lymphoblastic leukemia (s-ANLL) among the Italian subjects exposed to VP-16 was more than 1,000 times greater than expected. The study suggests that high doses of VP-16 appear to increase the risk of s-ANLL in LCH patients. The fact that all the leukemias described in the Italian LCH cohort were promyelocytic, and evidence of a higher incidence of promyelocytic leukemias among Italians and Latinos, suggest that high doses of etoposide in subjects of Latino origin may lead to aberrations on chromosomes 15 and 17.

Epidemiology of squamous cell conjunctival cancer.

The etiology of squamous cell carcinoma of the conjunctiva (SCCC) is not well known. A possible role of UVB radiation is suggested by an excess of SCCC in tropical countries and by the association between squamous cell skin cancer and exposure to UVB. Human papillomavirus type 16 also may be involved, given that it has been detected in benign and malignant conjunctival lesions and is the primary etiological agent involved in carcinoma of the anogenital tract. To examine the relationship between UVB exposure and SCCC, population-based age-adjusted incidence rates of SCCC and of conjunctival melanoma and squamous cell cancer of the eyelid were plotted against the UVB insolation of each registry site. Incidence data were examined further for patterns of second primary cancers among people with SCCC. SCCC was rare in the United States, with an incidence rate of 0.03 per 100,000 persons, although the rate was approximately 5-fold higher among males and whites. Regression analysis suggested a link between UVB exposure and SCCC rates (beta = 2.25; r = 0.58) that was as strong as that for squamous cell carcinoma of the eyelid (beta = 2.73; r = 0.62) and much stronger than for conjunctival melanoma (beta = 0.28; r = 0.02). Risk of a second malignancy after SCCC was not increased overall (20 observed and 14.1 expected), although a significant excess of salivary gland cancer (4 observed and 0.03 expected) and a borderline excess of lung cancer (6 observed and 2.4 expected) were noted. These observations suggest that UV radiation likely contributes to SCCC development. Additional research is needed to define the other exposures and host susceptibility that likely interact with UV-related genetic damage in the multifactorial development of this rare neoplasm.

Epstein-Barr virus and familial Hodgkin's disease.

Several studies suggest that the Epstein-Barr virus (EBV) is etiologically linked to Hodgkin's disease (HD). This study was undertaken to examine the role of EBV in familial HD (FHD). Among 60 FHD patients from 27 families with two or more cases per family, we tested available paraffinized tumor tissues from 46 cases by in situ hybridization for EBV-encoded RNA (EBER1) expression. Thirteen of 46 FHD patients (28%) had EBER1 expressed in the Reed-Sternberg cells. Concordance rate of EBV positivity was evaluated among 34 first-degree related pairs from 17 families for which both cases had available paraffinized tumor tissues. Only two of 17 pairs were concordant for EBER1 positivity. There was no excess of positive concordance (P = .18). Serologically, FHD patients had higher geometric mean antibody titers (GMTs) to the viral capsid antigen (VCA) and early antigen D (EA-D). There was no difference in seroprevalence between patients and control groups, nor was there concordance in elevated serology among 15 pairs of first-degree related FHD cases. Young adult unaffected family members (UFM) may not react to EBV in the same way as the general population as evidenced by the lower titer of VCA, although not statistically significant, and significantly lower titers of EA-D, compared with age-matched controls. While EBV might have some role in a subset of HD, lack of concordance of EBER1 expression and EBV serology among the FHD cases in the same family suggest that EBV does not play an important role in FHD.