We have already seen the actual and potential role of herpesviruses in the causation of human cancer. EBV was among the first definitive human cancer-causing viruses, and the herpes sim- plex group has been suggested but not proven to have a role in the development of cervical cancer in the human. In 1994 Chang et al. demonstrated the presence of a human herpesvirus, now termed HHV-8 or Kaposi sarcoma–associated herpesvirus (KSHV), in all epidemiological forms of Kaposi sarcoma, an angiosarcoma found worldwide but most recently at an extremely high incidence in AIDS patients, which is 7000 times higher than in the non-AIDS population (Emmanoulides et al., 1996). HHV-8 genomes have also been consistently found in primary ef- fusion lymphoma (PEL) and multicentric Castleman disease (MCD). Originally, PEL was con- fused with the form of Burkitt lymphoma seen in western nations, involving primarily
Figure 12.17 Age-specific incidence of cervical, vulvar, anal, and penile cancer in the Danish popula- tion. (After Melbye and Frisch, 1998, with permission of the authors and publisher.)
abdominal lymphoid structures. However, closer investigation revealed clear differences be- tween the two and particularly in the viral genomes involved. The virus has also been found in several benign and malignant endothelial lesions in patients with Kaposi’s sarcoma (Dictor et al., 1996). In addition, in other studies the presence of HHV-8 sequences was seen in premalig- nant Bowen disease (71.4%) and malignant squamous cell carcinoma (50%), as well as in 33.3% of actinic keratoses (Inagi et al., 1996). In addition, McDonagh et al. (1996) reported the pres- ence of HHV-8 sequences in 29% of angiosarcomas in patients, most of whom were not immu- nocompromised. Transmission of HHV-8 in AIDS patients appears to be largely by sexual means. However, in Africa, both horizontal and vertical transmission of HHV-8 is quite common among young children (cf. Schulz, 1999). Although the presence of the virus in Kaposi sarcoma, PEL, and MCD argues very strongly that there is a causative association between infection and the neoplastic transformation, other data are also supportive of this argument. Flore et al. (1998) demonstrated the transformation of primary human endothelial cells by HHV-8 in vitro. In addi- tion, the relationship of the presence of antibodies to HHV-8–associated latent nuclear antigens (see below) in relation to the development of Kaposi sarcoma strongly indicates a direct caus- ative relationship (Figure 12.18).