The Possible Relationship Of Epsteinbarr Virus To Hodgkins Lymphoma

A Danish population-based study published in 1974 described over 17,000 people with a history of a positive Epstein-Barr (EBV) test, to determine if these patients were at risk for the development of subsequent malignancies. A significantly higher-than-expected incidence of HL in this patient population was discovered.23

Since this observation, many investigators have employed increasingly sophisticated techniques attempting to determine not just a link but also a causal association between EBV and the development of HL. Between 19 and 40% of diagnosed cases of HL are generally reported to have detectable EBV viral genomes in Reed-Sternberg cells.24 Other investigators have noted the following: pediatric cases of HL seem to have a higher proportion of EBV-associated HL than do those of adults; there is a higher incidence of mixed cellular-ity histologic subtype associated with EBV than of other HL histologic subtypes; and the association of EBV in HL may be stronger in less developed countries and in populations with lower socioeconomic status.25-30

A recent update of a vast population-based registry study from Denmark and Sweden involving over 38,000 infectious mononucleosis patients confirmed that only HL and skin cancers occurred in statistically significant increased numbers; no other cancer was associated with infectious mononucleosis/EBV.31 The conclusion was that the increased risk of HL appears to be a specific phenomenon.

However, many questions remain. The most obvious question is why are some cases of HL EBV positive and other cases EBV negative? Additionally, whether or not the presence of EBV viral genome Reed-Sternberg cells is a proof of causality is a very open question; most of the US population has been exposed to EBV, and one recent study found that the vast majority of small EBV-positive CD30~ cells carried somatically mutated V-region genes, indicating that in lymph nodes of patients with HL, as in the peripheral blood of healthy individuals, EBV persists in memory B cells.32 One might argue that EBV-negative HL is associated with other viruses; however, there is no significant evidence that this is the case.33 Another theory suggests that EBV may be involved in all HL cases but may be undetectable only in some; EBV might infect the cell, transform it, and then it is eliminated (the hit-and-run theory), though this theory has been difficult to substantiate.

A large Danish and Swedish registry study comparing EBV-positive and EBV-negative HL has recently been published.34 Over 17,000 patients with serologic evidence of EBV infection were compared to a cohort of over 24,000 individuals without known EBV infection. Tumor specimens from patients developing HL were tested for the presence of EBV. Fifty-five percent of tumor specimens obtained from patients with infectious mononucleosis had evidence of EBV. There was no evidence of an increased risk of EBV-negative Hodgkin's lymphoma after infectious mononucleosis. In contrast, the risk of EBV-positive Hodgkin's lymphoma was significantly increased. The estimated median incubation time from mononucleosis to EBV-positive Hodgkin's lymphoma was 4.1 years. The risk of Hodgkin's lymphoma in the seropositive cohorts remains increased for two decades. The authors concluded that a causal association between infectious-mononucleosis-related EBV infection and the development of EBV-positive Hodgkin's lymphoma was likely. The authors also emphasized that in absolute terms, the risk of Hodgkin's lymphoma after infectious mononucleosis is only approximately 1/1000 persons; thus, other cofactors to explain the ultimately etiology of EBV-positive and EBV negative HL remain to be elucidated.

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