Re: Jarrett. Viruses and lymphoma/leukaemia. J Pathol 2006;208:176–186

I read with interest the paper entitled “Viruses and lymphoma/leukaemia” [1], in which the author reviewed data on RNA-containing viruses (hepatitis C virus [HCV], human T cell leukaemia virus type I, and human immunodeficiency virus [HIV]) and DNAcontaining viruses (Epstein-Barr virus [EBV], human herpesvirus 8 [HHV8], and Simian virus 40 [SV40]) and their link to human lymphomas and leukaemia. However, before causal conclusions are made [1], it is necessary to examine the known tenets of viral carcinogenesis (Table 1) to evaluate the potential contribution of these biological agents in haematological malignancies [2–5]. The dynamics of an infectious disease impose an element of variability that makes establishing associations with cancer more difficult. Viruses associated with human lymphomas and leukaemia [1,4] tend to establish persistent infections, as compared with most common viral diseases. The host exerts pressure on a chronic virus infection and, in defence, viruses contain genes that modulate such host responses. EBV and HHV8 have a plethora of such viral defence mechanisms as their genomes contain a number of cellular regulatory gene homologues [3]. In addition, recent data suggest that SV40 generates effectors that trigger less cytokine production by cytotoxic T-cells and enhance the probability of successful infection [6]. The classic example of virus strains differing in oncogenic capacity is the human papillomavirus group; of the more than 75 types described, only a few are associated with the development of cervical carcinoma [7]. There is no evidence of such pronounced diversity among strains of viruses associated with haematological malignancies. However, HCV isolates show extensive genetic heterogeneity [8] and there are suggestions of strain variation in the EBV oncogene, latent membrane protein 1 [9]. In addition, studies indicate that strain distinction may represent another factor that influences the dynamics of infection by SV40, including the development of malignancies [10], and viruses identified in some human lymphomas are different from known strains [11,12]. Therefore, the possibility exists that unrecognized viral strain differences may be responsible for the relatively infrequent rate of lymphomas occurring among subjects infected with a specific oncogenic virus. Viruses are not complete carcinogens, and the known viruses associated with human haematological malignancies display different roles in transformation. The obvious diversity among these viruses illustrates that the tenets of viral carcinogenesis are applicable across taxonomic boundaries (Table 1). However, because of the heterogeneity among the viruses with respect to basic characteristics and pathogenesis, not all premises apply to all virus cancer systems [2–5]. Thus, the validity of some studies cited by Jarrett [1] depends on existing knowledge of the biological properties of each virus and the identification of the population infected with them [2,3,13]. This is important when evaluating the growing data on HCV and SV40 and their association with some human lymphomas. Data suggesting an association between HCV and lymphomas are based on epidemiological studies [1]. However, unlike EBV in lymphoproliferative disorders, HCV is not detected in lymphomas [14]. Perhaps more analogous are the EBV-negative B-cell lymphomas in patients with AIDS, which are thought to result from immunological stimulation by infection with HIV. In contrast, SV40 markers in B-cell neoplasms from adult immunocompetent and immunocompromised patients have been reported in independent studies in the United States [11,12,15–20], Italy [21], Japan [22], and Costa Rica [23] as well as from children with haematological malignancies in Germany [24]. Importantly, the expression of the viral oncoprotein, large tumour antigen [19–21, 23], the detection of SV40 DNA in many malignant Bcells by in situ hybridization [22], and the specific methylation of promoter genes in SV40-positive nonHodgkin’s lymphoma (NHL) [18] support the possibility that the virus may be functionally significant in some human lymphomas. However, a report from Japan found a low frequency of SV40 sequences in NHL [25], and some studies in Europe failed to detect virus sequences in some lymphomas [26–29]. These differences among studies may occur because of variations in sample processing or assays [30,31], and the inclusion of many T-cell neoplasms and EBV-positive lymphomas in surveys [25–27]. The latter factor may decrease the probability of detecting SV40 because the virus has rarely been found in T-cell neoplasms, SV40 and EBV are seldom found together in a given tumour [11,12,17], and data indicate that a germinal centre B-cell like profile is associated with SV40 [20,23]. Together, these observations are consistent with animal studies showing that B-cell neoplasms are induced by SV40 [32], and with the recognition of the Institute of Medicine of the National Academies that ‘the present biological evidence indicates that SV40 infections could lead to cancer in humans under natural conditions’ [4].