Features

Current Issues in Cervical Cancer Screening

Debbie Saslow, PhD

Although the advent of human papillomavirus vaccination promises an unprecedented reduction in cervical cancer rates, no one anticipates a day when cervical cancer screening can be eliminated. Indeed, while ensuring that young women are vaccinated in a timely manner, it is essential that health care professionals emphasize continued screening in accordance with the latest guidelines.

Between 2002 and 2003, the 3 major national organizations that develop cervical cancer screening guidelines—the American Cancer Society (ACS), the United States Preventive Services Task Force (USPSTF), and ACOG—all released updated recommendations for the prevention and early detection of cervical cancer and its precursors.1-3 The recommendations encompassed when to start and stop screening, length of screening interval, and incorporation of new technologies. Since that time, new information has become available (particularly with regard to newer screening technologies), and vaccines have been introduced to prevent human papillomavirus (HPV) infection. The focus of cervical cancer prevention and early detection efforts is now on reaching rarely screened and never-screened women, decreasing excess screening, and vaccinating adolescent girls.

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INITIATING SCREENING

One of the biggest changes in the updated guidelines is the recommended age at which to start screening. Historically, Papanicolaou (Pap) testing was initiated at the onset of sexual activity, or by age 18.4 This recommendation predated the discovery of HPV as the causative agent for cervical cancer and the improved understanding of the natural history of HPV.5

Research has demonstrated that HPV infections are generally transient, and that there is little risk of missing an important cervical lesion within 3 to 5 years of initial HPV exposure. Thus, cervical cytology screening in adolescent girls is unlikely to add appreciable benefits within the first 3 years following the onset of vaginal intercourse. In addition, cervical cancer is extremely rare prior to age 21.6 Furthermore, screening within 3 years of the onset of sexual activity often results in overdiagnosis of cervical lesions that will regress spontaneously, leading to inappropriate intervention that may result in more harm than good. Transient HPV infections are particularly common in young women, who may experience serious obstetric consequences from unnecessary treatment or removal of low-grade cervical changes that are likely to regress without intervention.7 The recommendation for when to begin screening was therefore changed to approximately 3 years after the onset of vaginal intercourse, or by age 21 years. The upper age limit of when to begin screening (ie, age 21) was included because some health care professionals do not ask patients about their sexual history, and because some adolescent girls may be unable or unwilling to disclose this information.1

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SCREENING INTERVAL

For at least the last 2 decades, screening was recommended at an interval of up to 3 years following 3 consecutive normal Pap results.4 The difference in absolute risk of an important lesion progressing to invasive disease is small when comparing 1-, 2-, and 3-year screening intervals with conventional cervical cytology. In 1 large prospective cohort study, the increase in the age-adjusted incidence rate of high-grade lesions, carcinoma-in-situ, or invasive carcinoma was 4 cases per 10,000 women for a 2-year interval and 8 cases per 10,000 women for a 3-year interval.8 However, most women expect annual Pap testing, and most gynecologists recommend annual screening. Approximately 66% of women report having been screened within the previous year.9 Although such frequent screening does increase the sensitivity of cervical screening (ie, the ability to detect cellular abnormalities), it also increases cost and potential harm, including the consequences of false-positive results, such as anxiety and overtreatment.

Current guidelines recommend that after initiation of screening, testing should be performed every 1 to 3 years with conventional or liquid-based Pap tests. At or after age 30, women who have had 3 consecutive normal test results may get screened every 2 to 3 years.1-3 Women who are exposed to diethylstilbestrol (DES) in utero, are immunocompromised, or infected with human immunodeficiency virus (HIV) are at higher risk of cervical cancer, and should be screened annually.1

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POST-HYSTERECTOMY SCREENING

Screening for cervical cancer in women who have had their cervix removed for benign pathology is neither recommended nor beneficial. Nevertheless, approximately 10 million women who have undergone hysterectomy are screened every year, and screening rates are comparable between women who have undergone hysterectomy and women who have an intact cervix.9-11 The ACS, USPSTF, and ACOG all recommend that screening be discontinued following complete hysterectomy. For women with a history of cervical intraepithelial neoplasia (CIN) 2 or 3, screening should continue until at least 3 consecutive normal/negative cytology results are attained within a 10-year period.1,3 Women who have undergone hysterectomy without removal of the cervix should continue cervical cancer screening at least until age 65 or 70. Women who were exposed to DES in utero and those with a history of cervical cancer should continue screening post-hysterectomy for as long as they are in reasonably good health, regardless of age.1

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SCREENING CUTOFF

The incidence of cervical cancer in older women is almost entirely confined to the unscreened and underscreened. The risk of cervical cancer is very low among older women who have been screened regularly.8,12 Furthermore, it may be difficult to obtain a satisfactory cell sample from older women, and such screening is associated with potential harm (eg, false-positive results, invasive procedures, anxiety).13 While guidelines encourage screening of older women who have not been screened regularly, women aged 65 to 70 years of age and older who have had 3 or more normal Pap results and no abnormal Pap findings in the last 10 years may choose to stop cervical cancer screening.1,2 Women with a history of cervical cancer, who have been exposed to DES in utero, or who have conditions that may compromise their immune systems (eg, HIV) should continue regular screenings. Women with severe comorbid or life-threatening illnesses may forego cervical cancer screening regardless of age.1

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SCREENING TECHNOLOGIES

Liquid-based Pap tests account for approximately 80% of Pap screening performed in the United States.14,15 Initial studies suggested that liquid-based cytology offered greater sensitivity than conventional smears, with only slightly decreased specificity. However, more recent studies suggest that the accuracy of liquid-based cytology is similar to that of conventional cytology.16 Nevertheless, liquid-based Pap tests appear to have a decreased likelihood of sampling errors, as well as a lower rate of unsatisfactory specimens.16,17 Another advantage of liquid cytology is the ability to use residual liquid for reflex HPV testing when cytology results indicate atypical squamous cells of undetermined significance (ASC-US).

Human papillomavirus testing was recommended for the triage of ASC-US results in 2002,18 and as an adjunct to primary screening with cytology for women aged 30 and older shortly thereafter.1,3 Human papillomavirus tests have a very high sensitivity for detecting advanced precancerous lesions. A normal Pap test result combined with a negative HPV test result provides close to 100% assurance that cervical cancer is not present and will likely not occur in the next several years. A positive HPV test result, even in the presence of normal Pap findings, indicates an increased risk for either missed disease or for the subsequent development of precancerous lesions or cancer. Because virtually all disease occurs in women who have a persistent HPV infection whereas most infections are transient, it is important to repeat any positive HPV tests in 6 to 12 months.19,20 However, because of the high sensitivity of HPV tests, screening should be repeated no more frequently than every 3 years if both cytology and HPV test results are negative.1,20

Anxiety over a positive Pap or HPV test result can be greatly decreased at the time of screening by emphasizing that:

• The Pap test is primarily to detect cells that may lead to cancer if not identified early and treated
• Only rarely does an abnormal Pap test result reflect the presence of cancer that has already developed
• A positive HPV test with a normal Pap result only identifies a need for increased surveillance.

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POSTVACCINATION SCREENING

The introduction of HPV vaccines provides an unparalleled opportunity to dramatically reduce the burden of cervical cancer, both in this country and internationally. However, a concern about these vaccines is that women and their health care professionals will become complacent about cervical screening. It remains critical to continue screening according to current early-detection guidelines.21 If the availability of HPV vaccines leads to declining participation in screening, then cervical cancers will develop that may otherwise have been prevented. For the foreseeable future, women will continue to require screening to prevent cancers that occur from the other carcinogenic HPV types not covered by the present vaccines. Screening must also continue to protect women who are not vaccinated and those infected prevaccination. These realities caution against reducing cervical cancer screening efforts, as premature relaxation of control measures already in place could potentially lead to a resurgence of cervical cancer rates. The ACS and other organizations will develop new screening guidelines for vaccinated women once data are available to support a change.

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CONCLUSION

Cervical cancer screening represents one of the greatest success stories for cancer prevention and early detection since the introduction of the Pap test in the 1950s. Health care professionals need to focus their efforts on increased screening for the women most at risk—ie, the rarely screened and never-screened—and decreased overscreening and overtreatment of the well screened population. Efforts must also be directed toward improving follow-up for women with abnormal test results as well as increasing vaccination and subsequent screening rates in adolescent girls.

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Debbie Saslow, PhD, is Director of Breast and Gynecologic Cancer, American Cancer Society, Atlanta, GA.

References

1. Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. 2002;52(6):342-362.
2. Screening for cervical cancer: recommendations and rationale. Am Fam Physician. 2003;67(8): 1759-1766.
3. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin: clinical management guidelines for obstetrician-gynecologists. Number 45, August 2003. Cervical cytology screening (replaces committee opinion 152, March 1995). Obstet Gynecol. 2003;102(2):417-427.
4. Fink DJ. Change in American Cancer Society Checkup Guidelines for detection of cervical cancer. CA Cancer J Clin. 1988;38(2):127-128.
5. 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.
6. Ries LAG, Melbert D, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2004. Bethesda, MD: National Cancer Institute; 2007. http://seer.cancer.gov/csr/1975_2004/. Accessed May 25, 2008.
7. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006;367(9509):489-498.
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11. Saraiya M, Lee NC, Blackman D, Smith MJ, Morrow B, McKenna MA. Self-reported Papanicolaou smears and hysterectomies among women in the United States. Obstet Gynecol. 2001;98(2):269-278.
12. Sigurdsson K. Trends in cervical intra-epithelial neoplasia in Iceland through 1995: evaluation of targeted age groups and screening intervals. Acta Obstet Gynecol Scand. 1999;78(6):486-492.
13. Sawaya GF, Grady D, Kerlikowske K, et al. The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/progestin Replacement Study (HERS). Ann Intern Med. 2000;133(12):942-950.
14. Noller KL, Bettes B, Zinberg S, Schulkin J. Cervical cytology screening practices among obstetrician-gynecologists. Obstet Gynecol. 2003;102(2): 259-265.
15. Saint M, Gildengorin G, Sawaya GF. Current cervical neoplasia screening practices of obstetrician/gynecologists in the US. Am J Obstet Gynecol. 2005;192(2):414-421.
16. Ronco G, Cuzick J, Pierotti P, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ. 2007;335(7609):28.
17. Davey E, Barratt A, Irwig L, et al. Effect of study design and quality on unsatisfactory rates, cytology classifications, and accuracy in liquid-based versus conventional cervical cytology: a systematic review. Lancet. 2006;367(9505):122-132.
18. Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287(16):2120-2129.
19. Wright TC Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004; 103(2):304-309.
20. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol. 2007;197(4): 340-345.
21. Saslow D, Castle PE, Cox JT, et al. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. 2007;57(1):7-28.

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