Chapter 5: Updating the natural history of HPV and anogenital cancer.

The major steps in cervical carcinogenesis include infection of the metaplastic epithelium of the cervical transformation zone with one or more of the 12-18 carcinogenic types of human papillomavirus (HPV) infection, viral persistence, clonal progression of the persistently-infected epithelium to cervical precancer, and invasion. Although these fundamental steps are established, several new epidemiologic studies have shed light on the factors that influence each of these transitions. The importance of the transformation zone in cervical cancer has been extended to other HPV-induced cancers such as anal or tonsillar cancers. Natural history studies show that HPV with normal cervical cytology and cervical intraepithelial neoplasia (CIN) grade 1 behave similarly, with the majority of both showing regression. Although these studies have demonstrated the importance of HPV persistence in the development of precancer CIN-3, the timing from infection to evidence of CIN-3 varies from 1 to 10 years. Whether equivalent lesions diagnosed later differ in their natural history remains unknown. Several factors have been implicated in enhancing persistence and/or progression. However, none are consistently associated with both except age: young women are less likely to show persistence and older women with persistence are more likely to be at risk of invasive cancer. Recent studies have also underscored the importance of the host immune response in clearance of established infections. Finally, data on non-cervical HPV infections, such as penile infections are limited to date compared to cervical infections. Several ongoing cohort studies should give us further insight into male infections in the near future.