THE RELATIONSHIP OF HUMAN PAPILLOMAVIRUS-RELATED CERVICAL TUMORS TO CIGARETTE-SMOKING, ORAL-CONTRACEPTIVE USE, AND PRIOR HERPES-SIMPLEX VIRUS TYPE-2 INFECTION

It has now been established that infection with human papillomavirus ( HPV) is necessary for the development of most cervical cancers. HPV is not sufficient for the development of cancer. Other exposures or host factors are necessary for cancer to occur. As part of an ongoing, pop ulation-based case-control study of invasive cervical cancer, we inves tigated the role of cigarette smoking, oral contraceptive (OC) use, an d herpes simplex virus type 2 (HSV-2) as potential cofactors with HPV in the development of cervical cancer. Residents of three counties in western Washington State who were diagnosed with invasive squamous cel l cervical cancer (It = 314) from January 1986 through December 1992 w ere interviewed about their sexual, reproductive, contraceptive, and c igarette smoking histories. Similar information was obtained from cont rol women identified through random digit dialing (n = 672). The sera from 206 cases and 522 controls were tested for both HPV 16 capsid ant ibodies and HSV-2 antibodies. PCR was used to test paraffin-embedded t umor tissues for the presence of HPV DNA types 6, 16, 18, 31, 33, 35, and 39. Women with cervical cancer were more likely to be current smok ers at diagnosis than population controls [relative risk (RR), 2.5; 95 % confidence interval (CI), 1.8-3.4]. The risk associated with smoking was present to a similar extent among women positive and negative for HPV as measured by HPV 16 capsid antibodies and HPV DNA in the tumor tissue (cases). OC use was only important if first use was at an early age, particularly ages less than or equal to 17 years (RR, 2.3; 95% C I, 1.4-3.8). There was only a slight risk for cervical cancer associat ed with antibodies to HSV-2 (RR, 1.2; 95% CI, 0.9-1.7). However, when we stratified by markers of HPV exposure, we found a significant incre ase in risk associated with HSV-2 among women negative for HPV 16 anti bodies (RR, 2.0; 95% CI, 1.3-3.0), which was strengthened when we conf ined our analysis to cases whose tumors were HPV DNA negative (RR, 3.6 ; 95% CI, 1.6-8.0). There was no indication that cigarette smoking, OC use, or HSV-2 infection influence the ability of HPV infection to cau se invasive cervical cancer. OC use may only be important in the etiol ogy of invasive squamous cell cervical tumors if the use occurs at a c ritical time in the development of a woman's reproductive tract, at ag es less than or equal to 17 years. The majority of risk associated wit h HSV-2 was confined to HPV-negative tumors, indicating a possible sep arate pathway to disease that may account for 5-10% of invasive cervic al cancers.