EM4 - Role of HPV Testing in Cervical Cancer Screening

Chairs: C. Meijer and T. Cox

General Issues

1. Cervical cancer is a rare complication of cervical infection with a high-risk HPV type.
2. A persistent high-risk HPV infection is necessary for the development, maintenance and progression of a cervical cancer precursor lesion (high-grade cervical intraepithelial lesion, CIN3).
3. Women and clinicians should be educated on the mostly benign nature of infection with a high-risk type. This includes the commonness and transient nature of most HPV infections leading to clearance of the virus in most individuals and the relatively small risk of developing invasive cervical cancer.

Primary Screening

1. Primary HPV infection and minor cytologic and histologic lesions with little risk of progression to cervical cancer are very common in women under the age of 30, and cervical cancer is rare before this age. In consideration of these facts and the harmful consequences that occur from overscreening and overtreatment of young women, the ideal age to begin continue to promote earlier screening in order to attempt to interdict the few cancers that occur prior to this age. In any case, an understanding of the natural history of HPV and cervical cancer does not logically support screening for cervical cancer precursors before the age of 25, or prior to 8 years from first intercourse.
2. At present, primary screening for cervical cancer precursors is usually done by cytological examination of cervical smears. Liquid-based cytology and neuronal network screening both decrease the false negative rate without an adverse impact upon specificity. Additionally, liquid-based cytology enhances the clarity of the smear and improves sampling. Neither can redress the basic subjectivity of cytology.
3. HPV testing is objective and highly reproductible. The detection of high-risk HPV in virtually all (99,8%) cervical cancers establishes the rationale for utilization of high-risk HPV testing in cervical cancer screening programs.
4. Countries that presently begin cervical cytology screening before age 30 and screen annually should extend the screening interval to 2 to 3 years until age 30, when the increased sensitivity and negative predictive value of combined cytology and a high-risk HPV test allow for lengthening of the screening interval. HPV testing should not be utilized in the primary screening of women prior to age 30 due to the high incidence of transient HPV detected in women younger than this age.
5. The very high sensitivity of HPV testing for high-grade cancer precursors and the declining level of HPV detection in normal women over the age of 30 establishes testing for HPV as a more effective primary screen for women over this age than currently practiced cervical cytology.
6. The extremely high negative predictive value (99-100%) of the combination of a normal cytologic screen and a negative HPV test should allow safely lengthening intervals up to 8-10 years. Where public policy has established voluntary annual screening as an alternative to organized 3-5 year screening, the combination of normal cytology and a negative HPV test would allow the adoption of sale and cost-effective wider screening intervals even under voluntary screening programs.
7. The specificity of a combined cytology and HPV testing protocol will be enhanced by referral to colposcopy of only women who: 1). have a high-grade cytologic diagnosis regardless of HPV status, 2). are cytologically normal but persistently HPV positive (at 12 months), or 3). have an equivocal or low-grade cytologic diagnosis that persists on repeat and/or is HPV positive.
8. Emerging data in several primary screening trials is documenting that testing for HPV has a very high negative predictive value (99-100%) due to high sensitivity for detection of high-grade cancer precursors (CIN3) in the range of 95-100%. The sensitivity for high-grade disease reported for cervical cytology in the same studies is 40-85%. This invites consideration of utilizing HPV testings as the primary cervical cancer screen, followed by reading of a cytologic specimen only in women found to be positive on the HPV test. Recommendations for this approach await further studies.
9. Testing for persistent HPV infection should take into account the usual clearance time reported for transient HPV infections (7-8 months) when designing management protocols for womem with HPV positive high-risk HPV tests.

Secondary Screening

1. Cervical cancer screening protocols that utilize cervical cytology as the sole primary screen will continue to have equivocal diagnoses (ASCUS or borderline Pap results) for which the meaning will remain unclear. While the majority of women with these cytological readings will be normal, 6-11% will have a high-grade cervical cancer precursor and approximately 1/1000 will have an existing cervical cancer. Medicolegal concerns and the desire to protect all women from cervical cancer have driven immense expenditures in the management of these minor Pap abnormalities, particularly in some countries.
2. The high sensitivity and negative predictive value of HPV testing reported in primary screening has been substantiated in the management of women with equivocal Pap diagnoses as well.
3. Recent studies on the management of ASCUS have documented that the sensitivity for the detection of high-grade percursors and cervical cancer by repeat cytology is 11% to 15% less than that reported in the same studies for HPV testing, while referring approximately the same number to colposcopy.
4. The lack of interlaboratory variability in the performance of the HPV test, in comparison with the known interobserver variability of cytologic diagnoses, further enhances the importance of these findings since repeat cytologic has been optimized in most studies.
5. In consideration of the above, women given the diagnosis of an equivocal Pap result are best managed by performing and HPV test. If the HPV test is positive, colposcopy is indicated, while women with a negatice HPV test can be reassured. At present, standard protocols include a repeat cytological smear in 6 months for ASCUS-HPV negative women. Continued documentation of these very high levels of sensitivity for high-grade precursors and cervical cancer may allow for return to routine screening without further accelerated follow-up.