Risk Factors For Hodgkin Lymphoma Research Articles

Reduction of the Vertebral Bone Mineral Density in Patients with Hodgkin Lymphoma Correlates with Their Age and the Treatment Regimen They Received.

Simple SummaryHodgkin lymphoma (HL) is considered a largely curable disease (~80%). The young patient age at diagnosis and their long life expectancy make quality-of-life issues, including osteopenia, exceedingly important. This study aimed to assess treatment-related bone mineral density (BMD) changes that are overlooked in this young population. BMD was measured using PET/CT scans. Among 213 patients (median age 29 years), post-treatment BMD reduction of >15% was significantly more common in those aged ≥30 years and was also associated with a cumulative dose of steroids used. At 6 months post-therapy, BMD recovery was observed in ABVD (adriamycin/bleomycin/vinblastine/dacarbazine) treated patients, while individuals receiving EB (bleomycin/etoposide/adriamycin/cyclophosphamide/oncovin/procarbazine/prednisone) regimens demonstrated persistent BMD loss and higher rates of osteopenia. Our findings suggest that steroid use should be minimized and highly gonadotoxic drugs like procarbazine should be substituted with less toxic ones, due to their deleterious effect on BMD. Adequate vitamin D levels should be maintained.Nowadays, Hodgkin lymphoma (HL) has become highly curable. The young age at diagnosis and long life expectancy emphasize the importance of preventing long-term treatment side effects, including bone mineral density (BMD) loss, in these patients. We aimed to evaluate the effects of first-line therapeutic modalities on BMD dynamics in HL patients, intending to identify individuals at risk for osteopenia. Demographics, HL risk factors, treatment, including cumulative steroid doses, and BMD of 213 newly-diagnosed HL patients (median age 29 years), treated at Rambam between 2008–2016, were analyzed. The main chemotherapy regimens applied were: ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP (EB; bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin, procarbazine, prednisone). BMD was measured using PET/CT scans. BMD loss >15% was revealed in 48% of patients at therapy completion, with osteopenia prevalence of 4% and 14% at baseline and post-therapy, respectively. Cumulative hydrocortisone equivalent doses >3400 mg/m2 correlated with significant BMD reduction. Multivariate analysis at 6 months post-therapy identified age ≥30 years and EB-regimens as significant risk factors for BMD decrease >15%. Therapy-related BMD loss is common in HL patients. Its persistence is associated with age ≥30 years and EB treatment. Reduction of cumulative steroid doses and switch to non-gonadotoxic drugs should be considered.

The Role of Lymphomas in Subsequent Primary Cancers in People with HIV/AIDS: An Australian National Population-Based Data Linkage Study

Background Despite combination antiretroviral therapy (cART), the incidence of lymphomas remains elevated in persons with HIV/AIDS (PWHA). While the risk of subsequent primary cancers (SPCs) in the general population is well understood, these data are lacking for PWHA. Underlying aetiologic factors in PWHA, including oncogenic viruses and immunodeficiency, may have a differential impact on SPCs. We conducted a nationwide data linkage study in order to examine the role of lymphoma in SPCs in PWHA in two ways. First, we determined the incidence of and risk factors for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) (including chronic lymphocytic leukaemia) in PWHA previously diagnosed with an initial cancer of any type. Second, we assessed the incidence and features of SPCs of any type in PWHA after a primary HL or NHL. Methods Since 1982 Australia has had compulsory disease notification of all new HIV infections and all invasive cancers. We conducted a probabilistic data linkage study between the Australian National HIV Registry, the Australian Cancer Database and National Death Index to identify PWHA diagnosed with an initial cancer, followed by at least one SPC between 1982 and 2012. Follow up commenced from 90 days post the date of first cancer diagnosis at or following HIV diagnosis, and ended on 31 December 2012 or death, whichever came earlier. A SPC was defined as a cancer of diverse site and histology to the first cancer and diagnosed more than 90 days later (in order to mitigate ascertainment bias). The incidence of SPC was compared using Poisson regression. Risk factors considered included: age, sex, HIV exposure modality (such as male-to-male, intravenous drug, etc.) and CD4+ cell count at HIV diagnosis (<50, 50-199, 200-499, >500 cells/µL). Incidence was also compared across various eras corresponding to HIV treatment advances: 1982-1995 (pre-cART); 1996-1999 (early-cART); 2000-2004 (availability of protease inhibitors for HIV); and, 2005-2012 (availability of fusion inhibitors for HIV and rituximab for CD20-positive lymphomas). Results Out of 28,696 PWHA, 3,548 were identified with a first cancer. Among them, 229 SPCs were identified over 27,398 person-years (PY) of follow-up. The crude incidence of SPCs was 8.36 per 1000 PY (95% CI 7.34-9.51). Of 229 SPCs, 88 were lymphomas, comprising 42 diffuse large B cell, 4 Burkitt, 3 T cell, 2 primary effusion, 3 low grade lymphomas and 5 HLs; 29 NHLs were not sub-classified in the Database. The majority of first cancers in the group with SPCs were Kaposi sarcoma (KS) (55%). The incidence of lymphoma as an SPC decreased from 8.10 to 0.79 per 1000 PY from 1982-1995 to 2005-2012 (p=0.003). Median time from first cancer diagnosis to the diagnosis of a lymphoma SPC was 2.0 years (interquartile range (IQR): 0.8-4.0). Median age at diagnosis of a lymphoma SPC was 39 years (IQR: 34-49). The risk of a lymphoma SPC decreased with older age, from 10.68 per 1000 PY in those under 35 to 1.28 per 1000 PY in those above 55 (p=0.003). CD4 count at HIV diagnosis and HIV exposure modality were not associated with the risk of a lymphoma SPC. The incidence of a SPC after lymphoma as a first cancer (n=39) was 5.60 per 1000 PY, versus 9.30 per 1000 PY when the first cancer was not lymphoma (n=190, p=0.004). KS was the most common SPC after an initial lymphoma (49% of cases). Only two myeloid SPCs occurred. Median time to diagnosis of SPC after an initial lymphoma was 2.6 years (IQR: 1.1-6.7). Risk of a SPC after a first lymphoma increased significantly from 4.12 per 1000 person-years in those diagnosed with HIV in the 1982-1995 pre-cART era, to 33.15 per 1000 person-years in patients diagnosed with HIV between 2009-2012 (p=0.005). Conclusion The incidence and spectrum of SPC in PWHA is increasingly important as overall and cancer-specific survival of these patients continues to improve. The incidence of lymphomas as SPC in PWHA has decreased over time, which may be a function of improved HIV treatment and reduced susceptibility to immunosuppression-related lymphoma. However, PWHA diagnosed with lymphoma as a first cancer are experiencing increasing incidence of SPCs, occurring after relatively short intervals. Longer survival is likely contributing to this effect. Importantly, therapy-related cancers do not appear prominent, suggesting HIV-specific factors may play a role. These findings emphasise the importance of SPC surveillance tailored to this special population. Disclosures Di Ciaccio: Janssen: Honoraria.

Allergic disease, corticosteroid use, and risk of Hodgkin lymphoma: A United Kingdom nationwide case-control study

BackgroundImmunodeficiency syndromes (acquired/congenital/iatrogenic) are known to increase Hodgkin lymphoma (HL) risk, but the effects of allergic immune dysregulation and corticosteroids are poorly understood.ObjectiveWe sought to assess the risk of HL associated with allergic disease (asthma, eczema, and allergic rhinitis) and corticosteroid use.MethodsWe conducted a case-control study using the United Kingdom Clinical Practice Research Datalink (CPRD) linked to hospital data. Multivariable logistic regression investigated associations between allergic diseases and HL after adjusting for established risk factors. Potential confounding or effect modification by steroid treatment were examined.ResultsOne thousand two hundred thirty-six patients with HL were matched to 7416 control subjects. Immunosuppression was associated with 6-fold greater odds of HL (adjusted odds ratio [aOR], 6.18; 95% CI, 3.04-12.57), with minimal change after adjusting for steroids. Any prior allergic disease or eczema alone was associated with 1.4-fold increased odds of HL (aOR, 1.41 [95% CI, 1.24-1.60] and 1.41 [95% CI, 1.20-1.65], respectively). These associations decreased but remained significant after adjustment for steroids (aOR, 1.25 [95% CI, 1.09-1.43] and 1.27 [95% CI, 1.08-1.49], respectively). There was no effect modification by steroid use. Previous steroid treatment was associated with 1.4-fold greater HL odds (aOR, 1.38; 95% CI, 1.20-1.59).ConclusionsIn addition to established risk factors (immunosuppression and infectious mononucleosis), allergic disease and eczema are risk factors for HL. This association is only partially explained by steroids, which are associated with increased HL risk. These findings add to the growing evidence that immune system malfunction after allergic disease or immunosuppression is central to HL development.

Incidence and survival of Hodgkin lymphoma patients in Girona (Spain) over three decades: a population-based study.

Hodgkin lymphoma (HL) is characterized by heterogeneous histologic findings, clinical presentation and outcomes. Using the Girona population-based cancer registry data we sought to explore the incidence of HL over three decades in Girona Province (Spain) and examine the relationship between clinical features at diagnosis and survival. From 1985 to 2013, 459 cases were recorded. Patients were stratified by sex, age group, stage at diagnosis, histological subtypes and the presence of B-symptoms. The crude incidence rate (CR) was 2.7 and the corresponding European age-adjusted rate was 2.6, being higher in men than in women (sex ratio=1.6). Incidence remained constant throughout the period of study. Nodular sclerosis was the most frequent histology and showed an increasing incidence over time [estimated annual percentage change=+2.4, 95% confidence interval (CI): 0.8-4.0]. The 5-year observed survival and relative survival of patients diagnosed with HL were 73.1% (95% CI: 69.0-77.5) and 74.6% (95% CI: 70.0-79.4), respectively. No statistical differences in observed survival were observed across the three decades of study (P=0.455). Clinical parameters negatively influencing 5-year relative survival in the multivariate analysis were as follows: age at diagnosis at least 65 years; clinical stage IV; and presence of B-symptoms. These current patterns of presentation and outcomes of HL help delineate key populations in order to explore risk factors for HL and strategies to improve treatment outcomes.

Latent membrane protein 1 (LMP1) expression in Hodgkin lymphoma and its correlation with clinical and histologic parameters

BackgroundHodgkin lymphoma is one of the most prevalent lymphoproliferative disorders in Pakistan; however, no risk factors for this disease have yet to be established in our population. Epstein–Barr virus (EBV) is a well-known risk factor for Hodgkin lymphoma in endemic regions of the world; however, frequency of its association in our population has not been widely studied. Latent membrane protein 1 (LMP1) expression by immunohistochemistry (IHC) is a surrogate marker of EBV in Hodgkin lymphoma. Therefore, we aimed to evaluate the frequency of expression of LMP1 in cases of Hodgkin lymphoma at our institute and its correlation with other clinical and histologic parameters.MethodsThe study included 66 cases of Hodgkin lymphoma diagnosed at Liaquat National Hospital over a duration of 2 years from January 2014 to December 2015. The slides and blocks of all cases were retrieved, and representative blocks were selected for LMP1 by IHC. LMP1 expression of >10% of cells was considered as positive expression and correlated with histologic subtypes and clinical parameters like age, gender, and site of involvement.ResultsThe mean age of patients was 35.11 (+20.22). LMP1 expression was found in 68.1% (45/66) of cases of Hodgkin lymphoma. Mean age of the patients with LMP1 expression was 32.04 (+21.02). LMP1 expression was found in 40% cases of lymphocyte-rich, 66.7% of lymphocyte-depleted, 73.9% of mixed cellularity, 66.7% of nodular sclerosis, and 73.7% of classic Hodgkin lymphoma, NOS. No significant correlation of LMP1 expression with any clinical or histological parameter could be established in our studied patient population.ConclusionsA high frequency of expression of LMP1 is seen in cases of Hodgkin lymphoma at our setup comparable to endemic regions of the world; therefore, preventive and treatment protocols should be designed accordingly.

Relationship between ambient ultraviolet radiation and Hodgkin lymphoma subtypes in the United States.

Background:There are few modifiable risk factors for Hodgkin lymphoma (HL), the most common cancer among young adults in Western populations. Some studies have found a reduced risk with exposure to ultraviolet radiation (UVR), but findings have been inconsistent and limited to HL as a group or the most common subtypes.Methods:We evaluated UVR and incidence of HL subtypes using data from 15 population-based cancer registries in the United States from 2001 to 2010 (n=20 021). Ground-based ambient UVR estimates were linked to county of diagnosis. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quintiles using Poisson regression models adjusted for age, sex, race/ethnicity, diagnosis year, and registry.Results:Hodgkin lymphoma incidence was lower in the highest UVR quintile for nodular sclerosis (IRR=0.84, 95% CI=0.75–0.96, P-trend<0.01), mixed cellularity/lymphocyte-depleted (IRR=0.66, 95% CI=0.51–0.86, P-trend=0.11), lymphocyte-rich (IRR=0.71, 95% CI=0.57–0.88, P-trend<0.01), and nodular lymphocyte predominant HL (IRR=0.74, 95% CI=0.56–0.97, P-trend<0.01), but ‘not otherwise specified' HL (IRR=1.19, 95% CI=0.96–1.47, P-trend=0.11).Conclusions:This is the largest study of UVR and HL subtypes covering a wide range of UVR levels; however, we lack information on personal UVR and other individual risk factors. These findings support an inverse association between UVR and HL.

Candidate gene association studies and risk of Hodgkin lymphoma: a systematic review and meta-analysis.

To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to Hodgkin lymphoma (HL), we conducted a systematic review and meta-analysis of published case-control studies. Of the variants examined more than once in candidate gene association studies, we identified 21 studies that reported on 12 polymorphic variants in 10 genes. Data were also extracted from a published genome wide association study to allow analysis of an additional 47 variants in a further 30 genes. Promising associations were seen in nine of the variants (p < 0.05). Given that the estimated false positive report probabilities (FPRPs) for all associations are high (i.e. FPRP > 0.2), these findings should be interpreted with caution. While studies of candidate polymorphisms may be an attractive means of identifying risk factors for HL, future studies should employ sample sizes adequately powered to identify variants having only modest effects on HL risk. Furthermore, because of aetiological heterogeneity within HL, stratification of genotyping according to age, tumour Epstein-Barr virus status and histology is essential. Copyright © 2015 John Wiley & Sons, Ltd.

Variants in PVT1 are Associated with Susceptibility for Hodgkin Lymphoma in Children and Adolescents: A Children’s Oncology Group Study

Few studies have investigated the etiology of pediatric and adolescent Hodgkin lymphoma (HL), the 8th most common cancer in U.S. children aged <15 years. In economically developed countries, HL in children has distinct demographic and clinical characteristics and risk factor profile from HL in older adolescents and young adults (15-39 years), implying a unique etiology. Established HL risk factors include congenital and acquired immunodeficiency, Epstein-Barr virus (EBV) infection, and family history of hematological cancer. The latter strongly supports a genetic component to HL etiology, although few susceptibility variants have been consistently identified. Linkage studies and genome-wide association studies (GWAS) in adult HL have implicated the major histocompatibility (MHC) region in susceptibility; however, these associations are thought to be insufficient to fully explain the strong familial clustering observed. Single nucleotide variants (SNVs) in PVT1, REL, GATA3, and EOMES have also been identified via GWAS. We hypothesized that these same SNVs would also be associated with risk for pediatric/adolescent HL.HL cases (n=160) diagnosed in 1989-2003 at 3-17 years of age were enrolled through North American Children’s Oncology Group institutions and genotyped via the Illumina HumanCoreExome array. These data were merged with a convenience control sample of unrelated parents of pediatric/adolescent germ cell tumor cases genotyped using the same array. Genotype clusters were called together and manually reviewed for all SNVs of interest using GenomeStudio. Race/ethnicity was jointly determined by principal components analysis (PCA) using the EIGENSOFT package and HapMap2 and 1000 Genomes Project samples as anchors. Primary analyses were restricted to Hispanic and non-Hispanic white individuals (128 cases and 746 controls). Case genotypes were compared to controls for 18 SNVs previously identified in adult HL GWAS via unconditional logistic regression using an additive model and adjusting for sex and the first two principal components for race/ethnicity, resulting in odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the risk per additional copy of the variant allele. A second control sample pulled from three Minnesota Center for Twin and Family Research studies was also used for comparison. Different arrays were used (Illumina 660W-Quad, HumanExome12 v1.0), so separate PCAs were performed to select only non-Hispanic white case and control samples (95 cases and 3,124 unrelated controls). These analyses were also performed using an additive logistic regression model adjusted only for sex.The primary analyses revealed significant associations (Bonferroni alpha<0.003) with SNVs in/near PVT1 on chromosome 8 (rs2608053: OR=0.56, 95% CI: 0.41-0.75, P=0.0001; rs2019960: OR=1.49, 95% CI: 1.10-1.99, P=0.008). Comparable ORs were observed for the 3-9 and 10-17 year age groups examined separately. Restricting to non-Hispanic white individuals produced similar results (twin studies controls: rs2608053: OR=0.59, 95% CI: 0.44-0.80, P=0.0007; rs2019960: OR=1.71, 95% CI: 1.26-2.33, P=0.0007), indicating the observation is not attributable to population stratification. PVT1, a non-protein coding oncogene adjacent to and interacting with MYC, is a compelling candidate for further exploration, given that its transcripts are important in the generation of murine T-lineage lymphomas. Additionally, reciprocal translocations involving PVT1 are observed in variant Burkitt lymphoma.SNVs in the MHC region, including rs6903608, rs204999, and rs2248462, trended toward significance (P<0.05), suggesting that MHC variants are likely associated with pediatric/adolescent HL risk. Unfortunately, we lacked sufficient statistical power to achieve significance for any single marker examined in this region. Importantly, rs204999 has been specifically associated with EBV EBNA-1 antibody levels, supporting a role for MHC variants to impact lymphocyte responses to EBV infection.We found that some of the SNVs identified in adult HL GWAS are also associated with pediatric/adolescent HL. Additional strategies are needed to identify etiologically relevant variants to uncover the “missing heritability” of this unique malignancy and to understand the significance of MHC variants in imparting susceptibility. DisclosuresNo relevant conflicts of interest to declare.

Different time trends by gender for the incidence of Hodgkin's lymphoma among young adults in the USA: a birth cohort phenomenon.

Hodgkin's lymphoma (HL) is one of the most common cancers among young adults. We investigated the time trends for HL among the 20-44 age group in the USA by gender to identify the potential factors accounting for the incidence trends. Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program for 1973-2010, we conducted age-period-cohort modeling to evaluate birth cohort patterns on incidence trends of HL over time. For all races combined, the age-adjusted incidence patterns were similar to that of whites. The birth cohort patterns for whites and all races were similar, but the patterns differed according to gender. Specifically, except for the 1970-1975 birth cohort, all other birth cohorts showed an increasing birth cohort trend for females. Conversely, there was a decreasing cohort trend in males beginning in the 1960 birth cohort regardless of the assumptions of the period effect. The established risk factors for HL can seemingly not explain the gender disparities of the cohort pattern, which necessitates further analytical epidemiological studies to explore the risk factors for this disease with respect to potential differences by gender and by histological subtype.

Perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood.

The incidence of Hodgkin lymphoma has increased among adolescents and young adults in recent decades, but the relevant risk factors in early life are still unknown. A national cohort study was conducted of 3,571,574 individuals born in Sweden in 1973-2008 and followed up for Hodgkin lymphoma incidence through 2009, to examine perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood (ages 0-37 years). There were 943 Hodgkin lymphoma cases identified in 66.3 million person-years of follow-up. High fetal growth was associated with an increased risk of Hodgkin lymphoma after adjustment for gestational age at birth and other potential confounders (P(trend) = 0.005). Family history of Hodgkin lymphoma in a sibling or parent also was strongly associated with an increased risk, with adjusted hazard ratios = 8.83 (95% confidence interval: 3.67, 21.30) and 7.19 (95% confidence interval: 3.58, 14.44), respectively. No association was found between gestational age at birth, birth order, twinning, parental age, or parental education and Hodgkin lymphoma. These findings did not vary by age at Hodgkin lymphoma diagnosis. Similar associations were found for nodular sclerosis and mixed cellularity subtypes. These findings suggest that perinatal factors including possible growth factor pathways may contribute to the risk of Hodgkin lymphoma in childhood through young adulthood.

Antibody titers against EBNA1 and EBNA2 in relation to Hodgkin lymphoma and history of infectious mononucleosis

A role for Epstein Barr virus (EBV) in Hodgkin lymphoma (HL) pathogenesis is supported by the detection of EBV genome in about one-third of HL cases, but is not well defined. We previously reported that an elevated prediagnosis antibody titer against EBV nuclear antigens (EBNA) was the strongest serologic predictor of subsequent HL. For the present analysis, we measured antibody levels against EBNA components EBNA1 and EBNA2 and computed their titer ratio (anti-EBNA1:2) in serum samples from HL cases and healthy siblings. We undertook this analysis to examine whether titer patterns atypical of well-resolved EBV infection, such as an anti-EBNA1:2 ratio ≤ 1.0, simply reflect history of infectious mononucleosis (IM), an HL risk factor, or independently predict HL risk. Participants were selected from a previous population-based case-control study according to their history of IM. We identified 55 EBV-seropositive persons with a history of IM (IM+; 33 HL cases, 22 siblings) and frequency-matched a comparison series of 173 IM history-negative, EBV-seropositive subjects on HL status, gender, age and year of blood draw (IM-; 105 cases, 58 siblings). In multivariate logistic regression models, an anti-EBNA1:2 ratio ≤ 1.0 was significantly more prevalent in HL cases than siblings (odds ratio, 95% confidence interval = 2.43, 1.05-5.65); similar associations were apparent within the IM+ and IM- groups. EBNA antibodies were not significantly associated with IM history in HL cases or siblings. These associations suggest that chronic or more severe EBV infection is a risk factor for HL, independent of IM history.

Predictors of histology, tissue eosinophilia and mast cell infiltration in Hodgkin’s Lymphoma - a population-based study

Classical Hodgkin's lymphoma (HL) lesions comprise few tumour cells, surrounded by numerous inflammatory cells. Like in other malignancies, the microenvironment is presumed to be clinically important in HL; however, microenvironment predictors remain poorly characterised. The aim of this study was to investigate how selected patient characteristics and genetic factors affect HL phenotype, in particular tissue eosinophilia, mast cell counts and HL histological subtype. In a population-based study, patients with HL were interviewed about potential HL risk factors. Available tumours, n=448, were classified histologically; the number of eosinophils and mast cells were estimated, and eosinophil cationic protein (ECP) and eosinophil protein-x (EPX) gene polymorphisms were determined. Associations were assessed in regression models. Self-reported history of asthma was predictive of having tumour eosinophilia [≥200 eosinophils/10 high power fields, univariate odds ratio (OR)=2.22, 95% CI 1.06-4.64, P=0.03]. High numbers of eosinophils were predominantly seen in patients carrying the genotype ECP434GG [multivariate relative levels (RLs)=1.84, 95% CI 1.02-3.30, P=0.04]. Lower number of eosinophils was seen in Epstein-Barr virus (EBV)-positive tumours (univariate RL=0.52, 95% CI 0.3-0.9, P=0.02) and in older patients (univariate RL=0.85, 95% CI 0.73-0.99, P=0.03). Well-known factors such as young age, female sex and EBV-negative status predicted nodular sclerosis histology. The number of eosinophils in HL tumours is influenced by patient traits such as asthma, ECP genotype and EBV status. EBV status was predictive of histology.

Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma

AbstractA strong clustering of Hodgkin lymphoma in certain families has been long acknowledged. However, the genetic factors in the background of familial Hodgkin lymphoma are largely unknown. We have studied a family of 4 cousins with a rare subtype of the disease, nodular lymphocyte predominant Hodgkin lymphoma. We applied exome sequencing together with genome-wide linkage analysis to this family and identified a truncating germline mutation in nuclear protein, ataxia-telangiectasia locus (NPAT) gene, which segregated in the family. We also studied a large number of samples from other patients with Hodgkin lymphoma, and a germline variation leading to the deletion of serine 724 was found in several cases suggesting an elevated risk for the disease (odds ratio = 4.11; P = .018). NPAT is thus far the first gene implicated in nodular lymphocyte predominant Hodgkin lymphoma predisposition.

Incidence Patterns and Outcomes for Hodgkin Lymphoma Patients in the United States

Hodgkin lymphoma (HL) demonstrates heterogenous histologic findings, clinical presentation, and outcomes. Using the United States Surveillance, Epidemiology, and End Results (SEER) data we examined relationships between patient characteristics, clinical features at diagnosis, and survival in HL patients. From 2000 to 2007, 16,710 cases were recorded in 17 SEER registries. Blacks and Asians had low incidence (black/white incidence rate ratio (IRR) 0.86, P < .01; Asian/white IRR 0.43, P < .01). The bimodal pattern of incidence was less prominent for black males. Asians and Blacks presented at a mean age of 38 years compared to 42 years for Whites (P < .001). Race was a predictor for survival with HR of 1.19 (95% CI 1.11–1.28) for Blacks. Age was the most important predictor of survival (HR for patients ≥45 years 5.08, 95% CI 4.86–5.31). These current patterns for presentation and outcomes of HL help to delineate key populations in order to explore risk factors for HL and strategies to improve treatment outcomes.

Clinical, Molecular, and Environmental Risk Factors for Hodgkin Lymphoma

Epidemiological studies suggest unique occurrence patterns of Hodgkin lymphoma (HL) worldwide. In most Western countries there is a clear bimodal age distribution with an early peak in young adults followed by a second peak in older adults, particularly among males. In the Middle East and Asia, HL is more common in early childhood. There also are marked racial differences in the presentations of HL and HL subtypes, and particular single nucleotide polymorphisms (SNPs) have been identified as etiological factors suggesting that gene-gene and gene-environment interactions are involved. Personal health choices such as exercise and smoking may modify an individual's chances of developing HL. Numerous studies highlight the impact that exposure to Epstein-Barr virus and other environmental factors have on HL risk. Understanding the relative importance of each of these findings and their links to HL development and survival will help clinical researchers expand curative therapies and create preventative strategies for HL.

Hodgkin Lymphoma Among US Solid Organ Transplant Recipients

To assess the risk and identify risk factors of Hodgkin lymphoma (HL) in solid organ transplant recipients. Prior research has been limited by the rarity of HL and the requirement for extended follow-up after transplantation. Using data from the Scientific Registry of Transplant Recipients (SRTR), we conducted a retrospective cohort study of US solid organ transplant recipients (1997-2007). We estimated hazard ratios (HRs) for HL risk factors using proportional hazards regression. Standardized incidence ratios (SIRs) compared HL risk in the transplant cohort with the general population. The cohort included 283,190 transplant recipients (average follow-up: 3.7 years after transplantation). Based on 73 cases, HL risk factors included male gender (HR: 2.1, 95% CI: 1.2-3.7), young age (4.0, 2.3-6.8), and Epstein-Barr virus (EBV) seronegativity at the time of transplantation (3.1, 1.2-8.1). Among tumors with EBV status information, 79% were EBV positive, including all tumors in recipients who were initially seronegative. Overall, HL risk was higher than in the general population (SIR: 2.2) and increased monotonically over time after transplantation (SIR: 4.1 at 8-10 years posttransplant). Excess HL risk was especially high after heart and/or lung transplantation (SIR: 3.2). HL is a late complication of solid organ transplantation. The high HL risk in recipients who were young or EBV seronegative at the time of transplant and the fact that most HL tumors were EBV positive highlight the role of primary EBV infection and poor immune control of this virus. The occurrence of HL may rise with improved long-term survival in transplant recipients.

Tonsillitis, tonsillectomy and Hodgkin's lymphoma

It has been debated whether the reported increased risk of Hodgkin's lymphoma (HL) after tonsillectomy could be due to some underlying factor rather than the surgery itself. We studied whether not only tonsillectomy but also tonsillitis was associated with HL. This nationwide cohort study included all Danish residents during 1977-2001. Information on a diagnosis of tonsillitis, tonsillectomy, or HL was obtained from national registries. During 124 million person-years we observed 2,988 HL patients of whom 58 were tonsillectomized (most with preceding tonsillitis) and 14 were diagnosed with only tonsillitis at more than 1 year before HL diagnosis. Tonsillectomy was associated with a significantly increased HL risk in persons under 15 years of age as follows: 1-4 years after tonsillectomy, relative risk (RR) = 3.9 [95% CI: 1.4-11; n = 4]; >5 years after tonsillectomy, RR = 3.5 [1.4-8.5; n = 5]. No young cases of HL occurred among persons diagnosed with only tonsillitis. In contrast, 1-4 years after a hospital diagnosis of tonsillitis without subsequent tonsillectomy we found an increased HL risk in persons aged 15 years or above as follows: 15-34 years of age at HL diagnosis, RR = 3.5 [1.6-7.7; n = 6]; 35+ years, RR = 5.9 [2.2-16; n = 4]. Age at tonsillitis or tonsillectomy did not modify HL risk within the 3 age strata. An increased HL risk was found both after tonsillectomy and after an isolated diagnosis of tonsillitis. These results suggest that tonsillitis is a risk factor for HL and not that, as previously reported, only the surgical removal of tonsils is a risk factor.

Aspirin and Other Nonsteroidal Anti-inflammatory Drugs in Relation to Hodgkin Lymphoma Risk in Northern Denmark

There are few known modifiable risk factors for Hodgkin lymphoma, but the recent finding of an inverse association between routine regular-strength aspirin use and Hodgkin lymphoma risk suggests that aspirin may protect against Hodgkin lymphoma development. To further investigate this association using prospectively collected data, we conducted a population-based case-control study in northern Denmark. A total of 478 incident Hodgkin lymphoma cases were identified in nationwide health-care databases from 1991 to 2008. Ten population controls were matched to each case on age, sex, and county using risk-set sampling. Use of aspirin, selective cyclooxygenase-2 inhibitors, and other nonsteroidal anti-inflammatory drugs (NSAIDs) from 1989 to 2007 was ascertained by linkage to a population-based prescription database. Conditional logistic regression was used to estimate odds ratios for associations between medication use and risk of Hodgkin lymphoma. The odds ratio (95% confidence interval) for ever use (>2 prescriptions) compared with never/rare use (< or =2 prescriptions) of low-dose aspirin was 0.7 (0.5-1.2). The association with low-dose aspirin use did not vary appreciably by recentness, duration, or intensity of use. Recent use (>2 prescriptions in the 1-2 years before the index date), short-term use (<7 years), and medium/high-intensity use (> or =25% of duration of use covered by prescription) of selective cyclooxygenase-2 inhibitors or other NSAIDs was associated with increased Hodgkin lymphoma risk possibly due to prodromal symptoms among cases. In conclusion, our results provide some evidence of a protective effect of low-dose aspirin, but not other NSAIDs, against Hodgkin lymphoma development.

HIV-Related Hodgkin Lymphoma in the Era of Highly Active Antiretroviral Therapy: Incidence and Survival in a Prospective European Multi-Cohort Study On Behalf of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) Study Group.

Abstract 895 Introduction:HIV-infected patients are at increased risk to develop Hodgkin Lymphoma (HL). We examined the incidence and risk factors for HL, and the prognosis of patients with HIV-related HL in the era of highly active antiretroviral therapy (HAART) in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Patients and Methods:40,168 adult HIV-1 infected patients who started HAART in one of 16 prospective cohort studies in Europe were included in the present analysis. Incidence rates per 100,000 person-years, Kaplan-Meier estimates of cumulative incidence and survival, and adjusted hazard ratios (HRs) from Weibull random-effects models, with 95% confidence intervals (CIs), were calculated. Results:During 159,133 person-years of follow-up, 78 patients were diagnosed with HL. The crude incidence rate of HL was 50.4 per 100,000 person-years for patients who developed HL before starting HAART (17 cases) and 48.7 per 100,000 person-years in patients who were already on HAART (61 cases). Age, gender, CDC clinical stage, CD4 cell counts and HIV-1 RNA viral load at baseline (start of observation) were not significantly associated with the risk of HL. At HL diagnosis median age was 38.9 years (inter quartile range (IQR) 35.3 - 45.9 years) and the median CD4 cell count was 158 cells/μL (IQR 54 – 281 cells/μL). During a median follow-up of 18 months (IQR 4.8 - 34.8 months) 12 of 78 patients with HL died (15%), six of them during the first 6 months after diagnosis. Survival was 88% (95% CI 77% - 94%) at one year and 81% (95% CI 68% - 89%) at two years. Restricting the analysis to patients aged 16-44 years, one year survival in our population (86%, 95% CI 73% - 93%) was less compared to a European population of male Hodgkin patients of similar age (97.7%) [1]. The figure shows Kaplan-Meier plots of cumulative incidence (upper panel) and survival (lower panel). Conclusions:HL incidence rates were similar in HAART treated and untreated patients. In contrast to HIV-related Non-Hodgkin's Lymphoma no clear association with baseline CD4 cell count was observed. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Changing patterns in the frequency of Hodgkin lymphoma subtypes and Epstein–Barr virus association in Taiwan

Epstein-Barr virus (EBV) infection is a risk factor for Hodgkin lymphoma (HL). To test whether the frequency of HL subtypes and their association with EBV has shifted with rising socioeconomic status in Taiwan, we compared the pathological features and EBV status, detected by in situ hybridization, of HL diagnosed between 1996 and 2007 (99 cases) and 1982 and 1995 (74 cases). The male-to-female ratio was 121:52 (2.3:1) and the mean age at presentation was 41.5 years. The overall EBV positivity rate was 50% (86/173 cases). Comparing the distribution of HL cases diagnosed at two different time periods, we found an increased frequency of the nodular sclerosis (NS) subtype (53 vs 68%, P = 0.045), a decreased frequency of the mixed cellularity subtype (35 vs 13%, P < 0.001), a reduced male-to-female ratio (2.9:1 compared to 1.4:1) and mean age (42.4 vs 36.6 years) in the NS subtype, and a significant decrease in EBV positivity rates among the NS and lymphocyte-depletion subtypes (61 vs 39%, P = 0.03). These data indicate shifts in the frequency of histological subtype and EBV association for HL in Taiwan over the last decade, with a trend closer to that seen in Western countries and Japan.