Risk factors for Hodgkin's lymphoma by EBV status and significance of detection of EBV genomes in serum of patients with EBV-associated Hodgkin's lymphoma

Abstract

Epstein Barr virus (EBV) is associated with around one-third of Hodgkin's lymphoma (HL) cases and this association is believed to be causal. In these EBV-associated cases, there is a clonal EBV infection within tumors, and EBV genomes and gene products are detectable in Hodgkin and Reed-Sternberg (HRS) cells. The proportion of EBV-associated HL in any population varies with age, sex, ethnicity and histologic subtype. Two population-based epidemiologic studies have examined risk factor profiles in HL with cases stratified according to EBV status. For EBV-associated HL cases, there is a small peak in incidence in young adults (15-24 years) and a second larger peak in older adults. By contrast, HL that is not associated with EBV (EBV-negative HL) accounts for the major part of the young adult incidence peak after which the incidence of this disease entity then declines. Prior infectious mononucleosis (IM) is associated with an increased risk of developing HL, and there is a specific, probably causal, association between previous IM and young adult EBV-associated HL. We therefore believe that the small peak in the incidence of EBV-associated HL in young adults is real and related to late infection by EBV. EBV-associated HL in childhood and young adults, therefore, appears to follow primary infection by the virus. At the time of diagnosis, EBV-associated HL patients have an increased frequency of circulating EBV-infected cells compared to patients with EBV-negative HL and normal controls. The EBV is present in memory B cells and most probably reflects increased viral replication at another site, such as the oropharynx. EBV genomes are detectable in the serum and plasma of EBV-associated HL cases. The origin of EBV genomes in serum/plasma differs in different disease states; in HL viral genomes are present as naked DNA and are probably shed from tumors. EBV genome copy number in serum/plasma may provide an indication of tumor burden and may prove to be a useful marker for monitoring HL patients. The etiology of EBV-negative HL remains unknown and, while the involvement of an infectious agent may be suspected, none has yet been identified. Overall, epidemiologic studies support the idea that HL can be divided into two etiologic subgroups on the basis of EBV status and suggest that EBV-associated cases can be further divided into three groups related to age at diagnosis.