Primary Screening for Cervical Cancer: Incorporating New Guidelines and Technologies into Clinical Practice

Article Outline

• Abstract
• Introduction
• Cervical Cancer Screening
  • Pap Test
  • HPV DNA Testing
• Primary Cervical Cancer Screening Guidelines
• Understanding the New ACOG Guidelines
  • Initiate Screening at Age 21
  • Extended Screening Interval
  • Women Vaccinated Against HPV-16 and HPV-18 Infection Should Continue Routine Screening
  • When to Stop Screening
  • Women Who Have Risk Factors Should Have More Frequent Screening
• Conclusions
• References
• Copyright

Abstract 

Cervical cancer screening has been a remarkable success story in the United States. The annual Papanicolaou (Pap) test is ingrained in the U.S. healthcare system, yet recent evidence suggests that many women do not need yearly screening. The American College of Obstetricians and Gynecologists' (ACOG) newest guidelines, published in December 2009, challenge traditional cervical cancer screening modes and intervals with level-A recommendations for starting later and screening low-risk women less frequently. The aim of this article is to provide an evidence-based approach to incorporation of the new cervical cancer screening guidelines into clinical practice by reviewing the goals of screening, epidemiology of human papillomavirus and cervical cancer, costs of overscreening, and rationale for the specific recommendations.

Keywords:  cancer screening , cervical cancer , cervical cytology , clinical practice guidelines , human papillomavirus , women's health

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Introduction 

Read the following clinical vignettes and consider whether you would perform any cervical cancer screening and, if so, what screening would you perform, a Papanicolaou (Pap) test or a test for human papillomavirus (HPV) infection or both?

For over 50 years, the annual Pap test has been a yearly ritual for most women. Both patients and providers look at the Pap as the focal point of the annual well-woman examination, the test that motivates women to return year after year. National clinical practice guidelines suggest that lengthening the screening interval between Pap tests, adding a test for human papillomavirus, and stopping testing altogether may be appropriate for some women.¹, ³ These clinical practice guidelines from the American Cancer Society (ACS) and the U.S. Preventative Services Task Force (USPSTF) were revised in 2002 and 2003, and most recently, the American College of Obstetricians and Gynecologists (ACOG) in 2009 revised the guidelines to reflect new evidence regarding the natural course of cervical cancer, the role of HPVinfection in the development of cervical cancer, and new technologies available to screen for cervical cancer. Despite years of exposure to these guidelines, there seem to be wide variations in cervical cancer screening practices, even among obstetrician-gynecologists who state that the guidelines are influential.⁴

Studies show that clinicians are overwhelmingly overtesting.⁴, ⁵, ⁶ Recent research sponsored by the National Cancer Institute, Centers for Disease Control and Prevention (CDC), and the Agency for Healthcare Research and Quality found that on average, only 22% of internists, family practice physicians, and obstetrician-gynecologists responded correctly to standardized cervical cancer screening vignettes.⁴ Midwives fared about the same in a survey using similar clinical scenarios.⁶ There seems to be confusion among providers over when to start and stop screening, how often to screen, and what screening tests are appropriate for women based on age and risk factors. The revised guidelines address these concerns. Moreover, recent evidence supports the changes that were made to prior guidelines, such as increased screening intervals for low-risk women with negative Pap test results, HPV testing for women over 30⁷, ⁸, ⁹, ¹⁰, ¹¹, and delaying initial screening until age 21.¹²

Providers may overscreen because of concerns over lost revenue, fear of missing a cancer, insurance coverage, or patient request.⁵ A survey of women aged 65 and over revealed that the majority thought Pap tests should be continued lifelong, regardless of their risk for cervical cancer.¹³ Consideration of existing evidence is important, since approximately nine to ten million unnecessary Pap tests are performed in women who have had hysterectomies, who do not have a cervix.¹⁴ The funds expended for these unwarranted tests could certainly be diverted to more important uses.

Cervical cancer screening should no longer be the sole focus of the annual well-woman examination. Incorporating new evidence-based cervical cancer screening guidelines into primary screening for cervical cancer requires a paradigm shift: a move from the annual “Pap test” to a more comprehensive, evidence-based approach to cervical cancer screening that may or may not include HPV testing (depending on the patient's characteristics and history) and extended screening intervals.

In order to accomplish this feat, providers need to understand and correctly incorporate the current cervical cancer screening guidelines into practice. The aim of this article is to help clinicians interpret the current guidelines and incorporate them into practice by reviewing the purpose of cervical cancer screening, the harm of overtesting, the natural course of cervical cancer and HPV infection, the efficacy of cytology and HPV DNA testing, the growing body of evidence regarding HPV DNA testing, and the safety of extended screening intervals that has emerged in recent years.

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Cervical Cancer Screening 

Pap Test 

Cervical cancer screening has been a great success in the United States since the introduction of the Pap test.¹ Between 1955 and 1992, deaths from cervical cancer decreased by 74%.¹⁵ In the United States, the age-adjusted incidence rate in 2008 was 8.4 cases per 100,000 women, and the lifetime risk of developing cervical cancer is 0.69%. The median age at diagnosis is 48 years, and the median age of death from cervical cancer is 57 years of age.¹⁶ Five-year survival rates are near 100% for preinvasive lesions and approximately 92% for early-stage invasive lesions.¹

The goal of cervical cancer screening is to identify preinvasive lesions and early-stage invasive lesions, as treatment of these lesions may halt progression of the disease.¹, ³ Cervical cancer screening is a success because squamous cell cervical cancer follows a predictable course from initial exposure to the primary cause, HPV infection, to premalignant cellular changes to cancer, which takes an average of 9 to 15 years.¹⁷ Thus, routine screening has a good chance of detecting most premalignant cellular changes, that is, lesions at a level of CIN2 or higher.

In 2000, approximately 83% of U.S. women with an intact cervix reported screening for cervical cancer within the previous 3 years.¹⁴ However, of the women diagnosed with cervical cancer, approximately 50% have never had a Pap test, and 10% have not had a Pap test in the preceding 5 years.¹⁸ Improved testing that allows for longer screening intervals could remove some barriers to screening in terms of cost and convenience, thereby allowing more women to be screened.

The cervical cytology test is far from perfect. Even with annual screening, some cancers may slip through the cracks. Sensitivity of conventional cytology ranges from 30% to 87%,¹⁹ and 70% to 80% for liquid based cytology.¹⁷ This translates to a large number of false-negative results and the need for frequent screening. Human errors in sampling and interpretation contribute to the low sensitivity of cytology testing. Specificity is higher, ranging from 86% to 100%.¹⁹ The Pap test detects cellular changes, including the effect of HPV infection. Testing for HPV DNA, a newer cervical cancer screening technology, focuses on detection of the cause of cervical cancer.

HPV DNA Testing 

Of the nearly 100 types of HPV that have been identified, between 15 and 20 types are considered “high-risk types” for cervical cancer. HPV types 16 and 18 account for about 70% of all cervical cancers¹⁷ and are rarely found in normal cytology tests.²⁰ HPV is detected in 99% of cervical cancers,²¹ yet most HPV infections clear within 1 to 2 years and do not progress to cervical cancer.²², ²³ HPV is common among U.S. women, with an overall prevalence of 26.8% among women aged 14 to 59 years.²⁰ Prevalence peaks in women under age 30 and declines with age.²⁰, ²⁴, ²⁵ While HPV infection prevalence declines with age, cervical cancer incidence peaks in the third and fourth decade,¹⁶ implying that it is the persistent infections occurring in women over age 30 years that are of most concern.

Testing for HPV DNA was approved by the U.S. Food and Drug Administration (FDA) in 2000 for the triage of ASC-US by cytology reading and in 2003 for the primary screening of cervical cancer for women aged 30 years and older as an adjunct to cytology.¹⁷ HPV DNA testing was approved on the basis of its superior sensitivity for high-grade lesions over that of cytology alone and its negative predictive values for combined testing approaching 100%.⁹ Two HPV DNA tests are FDA approved: Hybrid Capture 2HPV (HC-2; Digene, Gaithersburg, MD) test and Cervista HPV High Risk (Hologic, Bedford, MA). The HC-2 test for 13 high-risk types of HPV (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68).²⁶ It is not a virus type-specific test, meaning a positive result indicates that a person has tested positive for one or more of the 13 high-risk types identified in the HC-2. Cervista HPV HR was approved in March 2009. It adds HPV type 66 to the high-risk HPV type panel of the HC-2. An additional test, Cervista HPV types 16/18, allows further risk stratification for those who test HPV DNA positive with the primary screen.²⁷

Although HPV DNA testing is more sensitive than cytology, it is less specific. That is, it is associated with more false-positive results. Mayrand et al.²⁸ found specificity for CIN2 or CIN3 to be significantly lower for HPV testing (94.6%) versus cytology (96.8%); combined testing further lowered specificity to 92.5%.²⁸ A false-positive HPV test does not mean that a patient does not have HPV infection. Rather, it means that the patient has a positive HPV test result but does not have severe dysplasia. Consequently, it is important to remember that the purpose of cervical cancer screening is to detect preinvasive lesions and that HPV clears without treatment in most women (Fig. 1).

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• Figure 1. 

  HPV risk: prevalence and cervical cancer incidence by age.

From Qiagen Corp; with permission.

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Primary Cervical Cancer Screening Guidelines 

Up until recently, the three major sets of guidelines were relatively consistent. ACOG (2003),¹⁸ ACS,²⁹ and USPSTF² agreed on starting screening within 3 years of first vaginal intercourse or no later than age 21. The 2009 ACOG guidelines now recommend waiting until age 21 to initiate screening.¹² For women under age 30, the ACS recommends an annual Pap smear if the provider is using conventional cytology and every 2 years for liquid-based cytology. For women aged 30 and older, the interval can be extended to every 2 to 3 years if three prior Pap test results are negative.²⁹ ACOG has now extended screening intervals for all ages: cytology every 2 years for women ages 21 to 29 and every 3 years for women aged 30 and older who have had multiple negative screens.¹² Primary screening with cytology and HPV DNA testing for women aged 30 and older is an option per ACS and ACOG and is now a level “A” recommendation for ACOG. The USPSTF found insufficient evidence for or against adjunctive HPV DNA testing.² As a result, the USPSTF recommends cytology testing at least every 3 years for women up to age 65. Cervical cancer screening should cease after hysterectomy with removal of the cervix for benign causes.¹, ², ³ Organizations disagree on an upper age limit for screening. The ACS recommends stopping screening at age 70 for low-risk women, the USPSTF recommends stopping at age 65, and ACOG does not recommend a screening age cutoff.

To place these guidelines into perspective, it may be helpful to make a comparison between cervical cancer screening in the U.S. versus that in other industrialized nations. In the United Kingdom and other European countries with national health programs, women are invited to undergo screening every 3 to 5 years. The age to start screening varies from 25 in the U.K. to 30 in The Netherlands. Revised National Health System guidelines in the U.K. raised the age for the first screen from 21 to 25 but shortened the interval for women ages 25 to 49 from every 5 years to every 3 years.³⁰ In a national health system, fewer screening visits are desired as they require fewer resources. In fact, many of the studies of efficacy and screening intervals come from Europe where cost-effectiveness and reduction of cervical cancer are more closely evaluated for risk and benefit. The incidence of cervical cancer in 2006 was 8.2 cases per 100,000 population in the U.S.,¹⁶ 8.5 cases per 100,000 population in the U.K.,³¹ and 11.1 cases per 100,000 population in The Netherlands.³² Mortality rates in the U.K and the U.S. are comparable at 2.4 deaths per 100,000 population³¹ and 2.5 deaths per 100,000 population,¹⁶ respectively.

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Understanding the New ACOG Guidelines 

Initiate Screening at Age 21 

Cervical cancer is extremely rare in women younger than 21. In 2006, only 0.2% of U.S. cervical cancer cases occurred in women under age 20.¹⁶ HPV infection is common in this population, though most infections clear without treatment in 1 to 2 years.²³ ACOG favors conservative management of women under the age of 21 who are found to have lesions of less than CIN grade 3.³³ It follows logically then to delay screening until age 21 if treatment would not otherwise be pursued. In the case of these young women, the potential for harm from positive screening, that is, additional screening, colposcopy and biopsy, excisional treatments, and emotional burden, far outweighs any benefit, since most of these mild-to-moderate lesions will clear without treatment. Considering that the usual course of cervical cancer progression is 10 or more years and that the objective of cervical cancer screening is to detect preinvasive lesions, it seems reasonable to delay testing until after age 21.

Extended Screening Interval 

Extended screening intervals appear to be safe and cost-effective for low-risk women.

Cytology is recommended every 2 years for women ages 21 to 29. Women ages 21 to 29 should have a Pap test every 2 years. Studies have demonstrated less protection in this age group from negative cytology results than in women over age 30,³⁴ so triennial screening is not appropriate in these younger women.

Cytology is recommended every 3 years for ages 30+ if there have been multiple prior negative screens. Studies show that cytology testing every 3 years is safe and cost-effective for low-risk women ages 30 and older who have had three consecutive negative Pap test results.¹² For women ages 30 to 64, the risk of cervical cancer is calculated to be only 8 cervical cancers per 100,000 women at 3-year screening intervals compared to 4 cancers per 100,000 women at yearly intervals.³⁵ The risk in well-screened populations is quite low. The ACOG guidelines stress the importance of taking a careful history of patients' prior cervical cancer screening. If the history is unknown or the patient is unsure of the results or dates of prior screens, then more frequent screening may be appropriate.¹²

Cotesting for cytology and HPV DNA is appropriate in women ages 30 and older. Cotesting for HPV DNA plus cytology is a level-A recommendation for women ages 30 and over.¹² For low-risk women, if both tests show negative results, screening should be repeated “no sooner than 3 years subsequently.”¹² HPV DNA testing has been shown to have higher specificity for women from the ages of 30 to 35.³⁶, ³⁷ HPV DNA, prevalent in women under 30, declines with age. Yet it is after age 30 that a positive screen becomes relevant, as persistent HPV infection manifests as the rate of cervical cancer begins to increase.

Women whose dual-test results are negative (negative cytology and negative HPV DNA results) can be reassured that their risk for cervical cancer is extremely low and that protection lasts several years. The recommended 3-year screening interval for combined testing was initially supported by 10-year cohort analysis by Sherman et al.⁹ (n = 20,810), which showed there was a low risk (0.16%) of CIN3 or cervical cancer in the 45 months following dual-negative baseline testing results. More recent studies support the safety of extending screening intervals up to 6 years for programs that implement HPV DNA testing.⁷, ⁸, ¹⁰, ¹¹ Khan et al.³⁸ reported a 10-year 0.5% cumulative incidence rate for HC-2-negative women over age 30 who had negative baseline cytology results. In The Netherlands, the Population Based Screening Study Amsterdam (POBASCAM) trial,¹⁰ found that combined testing led to earlier detection of histologically confirmed CIN3 and higher lesions, 70% more at baseline, and 55% fewer CIN3 at 5-year follow-up testing.

Primary screening with HPV DNA testing is not recommended in women under age 30. Due to the high rate of HPV prevalence in this age group, the risk of a false-positive screen is unacceptably high. The CDC recommends against screening for HPV as part of an STI evaluation.³⁹ In women ages 21 to 29, HPV DNA testing should be used only to triage Pap readings determined to be ASC-US.¹²

Women Vaccinated Against HPV-16 and HPV-18 Infection Should Continue Routine Screening 

Although HPV-16 and HPV-18 infections account for most cases of cervical cancer, some 30% of cervical cancers are caused by other strains.¹⁷ Women who have been vaccinated against HPV-16 and HPV-18 should continue screening per the guidelines for their age group and cytology history.¹²

When to Stop Screening 

ACOG recommends that women who have had a hysterectomy with removal of the cervix for benign conditions, such as uterine fibroids, and who have no history of high-grade CIN, should discontinue routine cervical cancer screening.

ACOG has not established an absolute upper age for screening but offers a level-B recommendation for considering discontinuation of screening in women between 65 and 70 years of age who have had three consecutive normal smears and no abnormal test results in the past 10 years.

Women Who Have Risk Factors Should Have More Frequent Screening 

ACOG recommends that women who have human immunodeficiency virus (HIV) infection, who are otherwise immunocompromised, who were exposed to diethylstilbestrol (DES) in utero, and who have previously been treated for CIN2, CIN3, or cancer should have more frequent screening. Immunocompromised women with HPV infection may progress to cervical cancer more quickly than healthy women, so more frequent screening is appropriate in this population. DES daughters are at higher risk for clear cell adenocarcinoma of the cervix and vagina, a rare cancer that occurs more in young women under the age of 30. The FDA removed DES from the U.S. market in 1971.⁴⁰ Women who have had severe dysplasia or cancer continue to be at risk and should continue to have annual screening after the immediate posttreatment period for at least 20 years.¹² Clinicians should refer to ACOG and American Society for Colposcopy and Cervical Pathology for guidelines on the management of high-risk patients and patients with abnormal screening (Table 1).

Table 1. Primary Cervical Cancer Screening Guidelines

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Conclusions 

Screening for disease is the foundation of well-patient examination. When performing a screening test, the clinician should be informed as to the intended population to be screened and the purpose, cost, and implications of testing. Just what does it mean if the test result is positive or negative? What steps come next if the test result is positive or negative? When the test result comes back positive, will it survive the “so what” question? If the answer is no, would you still order the test?

Cytology-based cervical cancer screening programs have been highly successful. The addition of HPV DNA testing promises to further improve the efficacy of screening. It is vital that clinicians understand the benefits, limitations, and harms of testing. False-positives can be reduced by adhering to the guidelines for age-related testing and the recommended longer screening intervals. Patients must be well informed regarding the role of HPV infection testing in cervical cancer screening. New technologies are rapidly evolving, challenging older screening techniques, and changing the way clinicians practice. Proper implementation of cervical cancer screening guidelines will prepare clinicians for a paradigm shift away from the yearly Pap test to a more comprehensive view of cervical cancer screening and women's health care.

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