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Molecular Screening For Cervical Cancer: Is it Time to Abandon the Papanicolaou Test?

Carolyn D. Runowicz, MD

Since the introduction of the Papanicolaou (Pap) test more than 60 years ago, there has been a 70% decline in cervical cancer mortality in the United States, largely attributable to the implementation and widespread acceptance of a cervical cytologic screening program. More than half of the women in the United States who develop cervical cancer have never been screened or have not been screened within the past 5 years.1 However, cervical cytology has recognized limitations with an estimated sensitivity of only 51%, resulting in the need for repeat cervical cytology at regular intervals to accommodate for this limitation.2 In the United States, most Pap tests utilize a liquid-based technology as compared with conventional cytology.

Persistent infection with oncogenic (high risk) human papillomavirus (HPV) has been identified as the underlying cause of cervical cancer,3 leading some to believe that it is time to move from cytologic screening to a molecular screen for HPV DNA. HPV DNA testing is highly reproducible, easily monitored, and provides an objective outcome. It is substantially more sensitive than cytology at detecting high-grade cervical intraepithelial neoplasia. However, HPV testing has a lower specificity and is more expensive.4 A lower specificity could result in more downstream testing, such as colposcopy and extirpative procedures, including loop electrocautery excision procedures in patients with only transient infections.

The results of the first screening round of the Canadian Cervical Cancer Screening Trial were recently published.5 The findings from this trial were consistent with previous split-sample and randomized studies, which revealed a higher sensitivity (55% vs 94.6%) for HPV DNA testing as compared with conventional cervical cytology, but a lower specificity. Since this is the first screening round, the authors were not able to address the length of protection afforded by a negative HPV DNA test.

Another recently reported study from a Swedish cervical cancer screening program reported a reduction in the incidence of cervical intraepithelial neoplasia 2/3 at subsequent screening in women who were initially screened with HPV DNA and conventional cytologic screening as compared with conventional cytology only.6 Their results are consistent with other trials utilizing cervical cytology and HPV DNA testing.4 Using both tests (HPV DNA and cytology) substantially raised the initial cost of screening.

Liquid-based cytology reduces the number of false-negative results as compared with conventional cytology for average risk populations of women, although not for high-risk populations. This technology also reduces the proportion of unsatisfactory specimens compared with conventional smears.7 Based on the potential for improved sensitivity of liquid-based cytology as compared with conventional cytology, the gain in sensitivity for HPV DNA testing may be reduced. A randomized trial of HPV testing and liquid-based cytology in a primary cervical screening involving 25000 women called A Randomised Trial of HPV Testing in Primary Cervical Screening (ARTISTIC), should address this issue.8

The current published studies suggest that HPV DNA screening is on the horizon. However, large demonstration projects will be needed to evaluate new paradigms for screening, including triage of positive HPV DNA testing with perhaps repeat testing or possibly followed by cervical cytology. The length of protection afforded by a negative HPV DNA test awaits longer term screening data to determine the optimal screening interval. The possibility of self-collected vaginal samples for HPV DNA could further reduce the cost and increase access to screening if rapid, simple, accurate and affordable HPV DNA tests are developed.9

The ultimate goal of cervical cancer screening is to reduce the incidence and mortality from invasive cervical cancer worldwide with a cost-effective, readily available test. We have not yet reached that goal.

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Carolyn D. Runowicz, MD, is Professor and Director, Carole and Ray Neag Comprehensive Cancer Center, and Northeast Utilities Endowed Chair in Experimental Therapeutics, University of Connecticut School of Medicine, University of Connecticut Health Center, Farmington, CT.

References

1. NCI Consensus Conference: Cervical cancer. NIH Consens Statement. 1996.14(1):1-38.
2. Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Int Med. 2000; 132(10): 810-819.
3. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12-19.
4. Koliopoulos G, Arbyn M, Martin-Hirsch P, et al. Diagnostic accuracy of human papillomavirus testing in primary cervical screening: a systematic review and meta-analysis of non-randomized studies. Gynecol Oncol. 2007;104(1):232-246.
5. Mayrand MH, Duarto-Franco E, Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007; 357(16):1579-1588.
6. Naucler P, Ryd W, Törnberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;357(16): 1589-1597.
7. Noorani HZ, Brown A, Skidmore B, Stuart GCE. Liquid-based cytology and human papillomavirus testing in cervical cancer. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2003. Technology report no 40.
8. Kitchener HC, Almonte M, Wheeler P, et al. HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial. Br J Cancer. 2006;95(1):56-61.
9. Wright TC Jr, Denny L, Kuhn L, Pollack A, Lorincz A. HPV DNA testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer. JAMA. 2000;283(1):81-86.