Context

Screening women with limited access to health care is difficult—in both the United States and the third world. We now know that invasive cervical carcinoma is universally associated with persistent human Papillomavirus (HPV) infection, and that only a small subset of viral types place women at high risk for developing cervical intraepithelial neoplasia (CIN) 3 or carcinoma.

In an effort to increase the sensitivity of the initial encounter with the healthcare system among women with limited resources and access, several researchers and agencies are investigating the use of HPV DNA testing in conjunction with standard Papanicolaou (Pap) smears, thin-layer smears, or HPV testing alone as the primary screening method.

Method and Results

This well-designed prospective trial uses a large Planned Parenthood population to compare the sensitivity, specificity, and frequency of referral for colposcopy in patients undergoing thin-layer Pap smear, HPV testing by polymerase chain reaction (PCR), or HPV testing by liquid-based RNA-DNA hybridization capture with signal amplification.

Unfortunately, the demographics of the study population are not necessarily comparable to those of the average practicing Ob/Gyn. Therefore, it may not be appropriate to extrapolate the results universally. The mean age of participants was 25 years; more than 80% of the eligible women were under age 30. The prevalence of HPV DNA, cervical dysplasia, and carcinoma is significantly different in this age group, compared with women over 30 years of age.

Women in the trial were predominantly Caucasian, with an average of 5 sexual partners in the group under 25 years of age and 9 sexual partners in the over-30 group.

As the authors point out, another limitation of the study is the failure of some patients to return for colposcopy when recommended by the protocol. Only 72.7% of women with abnormal Pap test results and 67.9% of women with high-risk HPV DNA returned for colposcopic evaluation. This limited the reliability of the sensitivity and specificity calculations to some extent.

As expected, HPV DNA testing was more sensitive but less specific than cytology in identifying high-grade dysplasia or cervical carcinoma. HPV DNA by signal amplification identifies more intermediate- and low-risk HPV types than the PCR technique. Therefore, this method has a higher sensitivity but lower specificity for detecting high-grade lesions. All the screening strategies Human Papillomavirus were more sensitive for identifying CIN 3 or higher in women younger than 30 years of age. Specificity, however, was significantly greater for women older than 30 years of age.

Who May Be Affected?

All sexually active women.

Persistence of high-risk HPV DNA types—not the initial presence—is a risk factor for cervical carcinoma.

Expert Commentary

Universal cervical cytology screening of sexually active women has greatly decreased the incidence of invasive cervical carcinoma in developed countries. Recently, commercialization of molecular biology techniques and cytology processing improvements have led to new products for cervical carcinoma screening.

In counseling patients, it is important to remember that it is the persistence of high-risk HPV DNA types—not the initial presence—that is a risk factor for cervical carcinoma. Most HPV infections regress spontaneously, with only about 10% of women remaining infected at 5 years. Young, recently sexually active women are likely to test positive for multiple HPV types. If they can be educated to comply with routine screening recommendations, it will not be clinically useful to employ primary screening with HPV DNA testing.

The downside to universal HPV DNA primary screening is that large numbers of women with transient high-risk HPV infections have normal cytology findings and no “disease.” Labeling them as high risk would create a psychological burden on both the patient and the physician.

Until we have well-studied clinical protocols for managing these patients, we should avoid this dilemma by continuing current Pap screening in women who have good access to care and who are willing to participate in screening at appropriate intervals.

Primary HPV DNA screening is appropriate for women who are unwilling or unable to participate in routine screening.

Bottom Line

Screening strategies for cervical cancer are evolving. Techniques appropriate for young, sexually active women with somewhat limited access to care should not be extrapolated to a low-risk, stable, monogamous population.

If women understand the limitations of cytology screening and the need for repeated tests to capture the majority of true abnormal findings, and if they have financial and geographic access to routine care, it makes sense to use a specific but somewhat less sensitive testing strategy, i.e., cytology screening.

For women with minimal access to routine care, it is essential to use the simplest, most sensitive test to minimize false negatives. It is these women in whom primary screening with HPV DNA with or without cytology makes sense.

Suggested Reading

Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003;348:489-901.

Is HPV DNA testing a reliable alternative to the Pap test?