The road ahead for cervical cancer prevention and control

Abstract

Since the early 1950s, Papanicolaou ("Pap") cytology screening has dramatically reduced cervical cancer mortality in most high-income settings. Currently, human papillomavirus (hpv) vaccination has the greatest potential to reduce the global burden of cervical cancer and precancerous lesions. However, as the prevalence of precancerous lesions declines, maintaining cytology as the primary screening test in settings with established programs might become less efficient. A reduction in test performance (sensitivity, specificity, and positive predictive value) would lead to an increase in unnecessary colposcopy referrals. Fortunately, hpv dna testing has emerged as a suitable candidate to replace cytology. Compared with the Pap test, hpv testing is less specific but much more sensitive in detecting high-grade precancerous lesions, less prone to human error, and more reproducible across settings. Linkage of hpv vaccination and screening registries could serve the added role of monitoring vaccine efficacy. As a triage test, cytology is expected to perform with sufficient accuracy because most hpv-positive smears would contain relevant abnormalities. This approach and others-for example, hpv testing followed by genotyping-are being evaluated in large population studies and have already been recommended in some settings. Other specific biomarkers that might perform well for screening and triage include hpv E6/E7 messenger rna testing, methylation of host or viral genes, and p16(INK4a) staining. Considering the rapid pace of major discoveries and the anticipated arrival of a nonavalent hpv vaccine (currently in phase iii trials), the evidence base in this field has become an elusive target and will continue to be an obstacle for policymakers.

Keywords: Cervical cancer; human papillomavirus; screening; vaccination.

FIGURE 1

Proposed generic algorithm for opportunistic or organized cervical cancer screening that uses human papilloma virus (hpv) testing as the primary test, followed by triage with Pap cytology or genotyping [hpv 16 and 18 and possibly other high oncogenic risk (hr) hpv types]; modified from Cuzick et al., 2008. The cytologic grade threshold and definition of extended screening interval may vary according to local preferences and be modified as new evidence from screening studies becomes available. asc-us = atypical squamous cells of undetermined significance; bmd = borderline or mild dyskaryosis.

FIGURE 2

Opportunities for prevention at various ages and times along the pathway from exposure, acquisition, and persistence of the human papilloma virus (hpv) to development of preinvasive lesions. The boxes within the large arrow depict the natural history of cervical carcinogenesis. At each step during this process, most cases will regress. In the absence of screening, only a very small fraction would be expected to progress to invasive cervical cancer. Targeted age groups for vaccination (9–26 years, including “catch-up”) and screening (21–65 years) presented here are based on current recommendations in the United States. In Canada, the only difference is that women less than 25 years of age are not advised to initiate screening, according to guidelines from the Canadian Task Force on Preventive Health Care. hr-hpv = high oncogenic risk hpv.