Affiliation of authors: S. E. Hawes (Department of Epidemiology), N. B. Kiviat (Department of Pathology), University of Washington, Seattle.
Correspondence to: Stephen E. Hawes, Ph.D., Department of Epidemiology, Box 359933, University of Washington, Seattle, WA 98195 (e-mail: hawes{at}u.washington.edu).
It is well established that infection with high-risk types of human papillomavirus (HPV) is central to the pathogenesis of invasive cervical cancer. However, many women are infected with high-risk types of HPV, but only a subset of infected women will ever develop cervical cancer, suggesting that other cofactors must be present for the development of malignancy. Prior to the discovery of HPV, both Chlamydia and herpes simplex virus-2 (HSV-2) were postulated to be the sexually-transmitted infections that are important for the development of invasive cervical cancer; however, it is now thought that these associations were likely confounded by the inability to account for the contribution of HPV infection to the risk of invasive cervical cancer. In this issue of the Journal, Smith and colleagues (1) present a well-designed casecontrol study demonstrating that, among women infected with high-risk types of HPV, serologic evidence of past HSV-2 infection is associated with an approximately twofold increased risk of invasive cervical cancer. This study is the latest of a series of studies that have used sensitive and specific polymerase chain reaction-based methods to detect HPV and other agents that cause genital infections and that, after appropriate adjustment for detection, type, persistence, and level of HPV, have found an association between the risk of cervical cancer and sexually transmitted infections (24).
Previous studies that have reported an association between HSV-2 and cervical cancer, after taking HPV infection into account, include a study in Thailand (5), which found that HSV-2 seropositivity was only weakly associated with invasive cervical cancer (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 1.0 to 2.0), and a study in Norway (6), which found that HSV-2 seropositivity was associated with an 11-fold increased risk of high-grade cervical neoplasia in HPV type-16 (HPV-16)-positive subjects. Other infectious agents, including Chlamydia trachomatis (24) and Neisseria gonorrhoeae (7), have also been associated with an increased risk for carcinoma in situ or invasive cervical cancer after accounting for infection with high-risk types of HPV. In a cohort study of the development of high-grade neoplasia, Koutsky et al. (8) found that antibodies to C. trachomatis and N. gonorrhoeae, but not antibodies to HSV-2, were associated with the development of high-grade cervical neoplasia, after adjustment for detection of HPV infections. Two casecontrol studies (9,10) also reported that an increased risk of cervical neoplasia or cancer was associated with the detection of C. trachomatis and N. gonorrhoeae and/or with HSV-2 seropositivity, but only among women without detectable HPV DNA, suggesting an independent role for those infections in the etiology of invasive cervical cancer. Several groups have also reported an association between measures of cervical inflammation and high-grade cervical neoplasia (11) or invasive cervical cancer (12). Interestingly, Schwebke and Zajackowski (13) reported that cervical inflammation, but not the diagnosis of a specific sexually transmitted disease, was associated with squamous intraepithelial lesions within the cervix.
It is possible that the importance of various infections in the etiology of invasive cervical cancer might vary depending on the prevalence of these infectious agents in the population. Although Smith et al. (1) report that there was no statistically significant heterogeneity in the findings across the seven study sites, the ORs for the association between the risk of invasive cervical cancer and HSV-2 seropositivity among HPV DNA-positive women varied from 1.1 (for women in Colombia) to nearly 10 (for women in the Philippines). Similarly, rates of HSV-2 seropositivity in the control subjects across the seven study sites varied from less than 10% (for those in the Philippines and Spain) to nearly 57% (for those in Colombia). The risk of developing invasive cervical cancer that might be attributed to HSV-2 infection may vary according to differences in the prevalence of other unmeasured cofactors.
The specific role of HSV-2 or other infectious agents in the pathogenesis of cervical cancer is unclear. Results of several in vitro studies in transfected cell lines suggest that, under certain conditions, HSV-2 might interact directly with HPV to increase the risk of cervical cancer (14,15). However, it is more likely that the increased cancer risk associated with HSV-2 and other infectious agents is, at least in part, the result of the inflammatory response. C. trachomatis and HSV-2 infections are associated with an intense, and often chronic, inflammatory response, as well as micro-ulceration of the endocervical/cervical epithelium and increases in epithelial cell repair and proliferation (16). Chronic inflammation has been shown to be an important risk factor for a variety of epithelial cancers, including those of the esophagus, stomach, pancreas, liver, biliary tract, colon, vulva, and bladder (1719). The inflammatory response is associated with the generation of free radicals, which are thought to play important roles in both the initiation and the progression of cancers. These substances directly damage DNA and DNA repair proteins and inhibit apoptosis, allowing the development of genetic instability. Inflammatory cells produce cytokines, chemokines, and growth and angiogenic factors, all of which may promote tumor growth.
The study by Smith et al. (1) provides important additional support for the role of ulcerative infection in the development of invasive cervical cancer. At present, relatively little is known about when, during the pathogenesis of HPV-associated invasive cervical cancer, other sexually transmitted infections might increase the risk for carcinoma in situ and invasive cervical cancer. However, a study by Thomas et al. (5) found that the association between HSV-2 seropositivity and carcinoma in situ was not statistically significantly different than that between HSV-2 seropositivity and invasive cervical cancer, suggesting that HSV-2 might play a role in the pathogenesis of cancer prior to the development of carcinoma in situ. Interestingly, we found that HPV-infected commercial sex workers in Senegal, West Africa, who were routinely screened and treated for cervical infections were only half as likely to develop high-grade cervical lesions as were unscreened and untreated (for cervical infections) HPV-infected women who were not commercial sex workers (Hawes SE, Critchlow CW, Sow PS, NDoye I, Coll-Seck AM, Kiviat NB: unpublished data). Further studies of the natural history of HPV infection in relation to infection with other cervical pathogens may provide insights into the mechanisms by which ulcerative sexually transmitted infections and inflammation contribute to the development of the malignant phenotype and may suggest novel approaches to the prevention of cervical neoplasia.
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