Symposium

Human papillomavirus and cervical cancer screening

Cervical cancer is now a disease that can—at least theoretically—be prevented by screening the population at risk, detecting cervical cancer precursors, and appropriately treating those precursors and preventing the development of invasive cancer. In earlier symposia and articles in Contemporary OB/GYN ["Cervical neoplasia: past, present, and future," May 1998, Special 25th Anniversary Issue; "HPV DNA testing comes of age," July 1995, among others], we've highlighted the technology of HPV DNA and how the new commercially available tests allow us to detect high-grade lesions and invasive cancers with a high degree of probability and low-grade lesions with a reasonable degree of probability.

The continued advance of technology makes this an especially exciting time to update the topic, which we have done by bringing together a distinguished panel at the 18th annual Human Papillomavirus (HPV) Meeting in Barcelona, Spain. At this juncture, all the basic work that has been applied to the understanding of HPV and its role in human disease is finally culminating in some really practical potential applications for screening. Our experts grapple with such topics as: How do we apply this in primary screening? Given the high false-negative rate of cytology, will the Pap smear give way to HPV DNA? What will be its role in evaluating the gray area of ASCUS Pap smears? Can we use high-risk HPV testing for triage?

—Ralph M. Richart, MDModerator

Richart: Dr. Kjaer, please briefly outline the evidence that HPV is the cause of human cervical cancer.

Kjaer: Evidence comes from both the epidemiologic and laboratory fields. HPV has been found in more than 95% of cervical cancers worldwide.^1,2 Furthermore, when women who are infected with the so-called high-risk HPV types are compared with HPV-negative women in case­control studies, they have been found to have a substantially increased risk for high-grade cervical lesions.^3-5 Most recently, data from prospective cohort studies have also shown that HPV both precedes and predicts the development of high-grade squamous intraepithelial lesions (HSIL), and that especially persistent HPV infection is a key factor.^6,7

Richart: And the evidence doesn't stop there, does it?

Meijer: Indeed not. A third argument is the good histologic and cytologic evidence that high-risk HPV types can be demonstrated only in the tumor cells or the neoplastic cells but not in the reactive cells.

Cuzick: And finally there is good evidence that the virus has a direct role in the carcinogenetic processes leading up to cancer. The virus makes oncogenic proteins—called E6 and E7—that bind with the cell-regulatory proteins p53 and pRB respectively, thereby unblocking the cell cycle, which essentially leads to genetic instability. This later gives rise to additional genetic changes that lead to cervical cancer by preventing apoptosis of cells with DNA mutations. This process has been shown to be specific to the high-risk HPV types and does not occur, for example, with HPV 6 and 11. These two types are associated with benign warts, but have no role in cancer.