Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Low Genit Tract Dis. Author manuscript; available in PMC 2014 February 6.
Published in final edited form as:
PMCID: PMC3915715

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer


An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from six working groups, and a recent symposium co-sponsored by the ACS, American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP), which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (e.g., management of screen positives and screening interval for screen negatives) of women after screening, age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.


Cervical cancer screening has successfully decreased cervical cancer incidence and mortality. The ACS Guideline for the Early Detection of Cervical Cancer was last reviewed and updated in 2002; for the first time, those recommendations incorporated human papillomavirus (HPV) DNA testing.1 Since that time, numerous studies have been published that support changes to recommended age-appropriate screening as well as the management of abnormal screening results, as summarized in Table 1.2

Table 1
Summary of Recommendations


High-quality screening with cytology (Pap testing) has markedly reduced mortality from squamous cell cervical cancer, which comprises 80-90% of cervical cancers.3-5 Since the introduction of cervical cytology in United States in the mid-20th century, cervical cancer, once the most frequent cause of cancer deaths in women, now ranks 14th for cancer deaths.6 This reduction in mortality through screening is due to 1) an increase in detection of invasive cancer at early stages, where the five-year survival rate is approximately 91 percent7 and 2) detection and treatment of pre-invasive lesions, which reduces the overall incidence of invasive cancer. In 2012, an estimated 12,170 cases of invasive cervical cancer will be diagnosed, and an estimated 4,220 women will die.6

It is now understood that persistent cervical infection with high-risk human papillomavirus (HPV) genotypes (“types”) is necessary for the development of cervical cancer and its immediate precursor lesion (“precancer”), cervical intraepithelial neoplasia (CIN) grade 3 (CIN3). Epidemiologic case series have shown that nearly 100% of cervical cancer cases test positive for HPV.8 HPV16 is the most carcinogenic HPV genotype and accounts for approximately 55%-60% of all cervical cancers.8-10 HPV18 is the next most carcinogenic HPV genotype, and accounts for 10-15% of cervical cancers.8-10 Approximately ten other HPV genotypes cause the remaining 25-35% of cervical cancers. HPV causes all common and most rare histologic types of cervical cancer. HPV18 causes a greater proportion of glandular cancers, adenocarcinoma and adenosquamous carcinoma, than squamous cell carcinoma (approximately 32% vs. 8%, respectively.9 The establishment of the causal link between HPV and cervical cancer, along with an understanding of the epidemiology and natural history of HPV infection, has led to a new model for cervical carcinogenesis: HPV acquisition, HPV persistence (versus clearance), progression to precancer, and invasion,11,12 which helps guide age-appropriate interventions to prevent cervical cancer.

Genital HPV is acquired through sexual and genital skin-to-skin contact. In most populations, prevalence peaks within a few years after the median age of sexual debut, which in the U.S. is 17 years.13 Most (~90%) HPV infections are transient, becoming undetectable within one to two years.14,15 Women whose infections persist are at significant risk of developing precancerous lesions. One-year16 and two-year HPV persistence,17 especially by HPV16, strongly predict CIN3 or more severe diagnoses (CIN3+) in the subsequent years (e.g., 20-30% risk of CIN3+ over 5 years for one-year or two-year persistent HPV16). Untreated CIN3 has a 30% probability of becoming invasive cancer over a 30-year period, although only about 1% of properly treated CIN3 will become invasive.18

The fundamental goal of cervical cancer screening is to prevent morbidity and mortality from cervical cancer. The optimal screening strategy should identify those cervical cancer precursors likely to progress to invasive cancers (maximizing the benefits of screening) and avoid detection and unnecessary treatment of transient HPV infection and its associated benign lesions that are not destined to become cancerous (minimizing the potential harms associated with screening). Cytology (Pap test) screening has been very successful in lowering cancer incidence and mortality in countries where good quality screening is available, yet false-positive results are common, since most abnormal (atypical squamous cells of undetermined significance or more severe) cytology is not associated with concurrent CIN3 or cancer, and therefore still a concern.19, 20 Increased understanding of the association between HPV and cervical cancer risk has led to the development of molecular tests for HPV* that offer increased sensitivity albeit lower specificity compared to cytology. HPV tests may better forecast which women will develop CIN3+ over the next 5-15 years than cytology.21-23 Incorporation of HPV testing into cervical cancer screening strategies has the potential to allow both increased disease detection (improving benefits) and increased length of screening intervals (decreasing harms such as psychosocial impact of screening positive, additional clinical visits and procedures, and treatment of lesions destined to resolve). In the development of this evidence-based review and guideline update, we considered the tradeoffs of benefits and harms of screening while considering different screening modalities and ages.

Of note, approximately half of the cervical cancers diagnosed in the United States are in women never screened, and an additional 10 percent of cancers occur among women not screened within the past five years.24-26 The current opportunistic approach to cervical cancer screening in the U.S. fails to reach sub-populations of women mainly living in low-resource, medically underserved regions, and thus invasive cervical cancer is one among a complex of diseases strongly linked to socioeconomic, geographic, and/or racial disparities. Annual rates of cervical cancer incidence and mortality in these populations are several-fold higher than in the rates in the general U.S. population and are similar to the rates observed in some lower-income countries.24-26

Technologic improvements in screening are unlikely to have a substantial impact on mortality if they do not reach this population.27 While this new ACS-ASCCP-ASCP screening guideline includes a review of molecular screening tests and strategies, perhaps the largest immediate gain in reducing burden of cervical cancer incidence and mortality could be attained by increasing access to screening (regardless of the test used) among women who are currently unscreened or screened infrequently. Incorporation of HPV testing may offer advantages over what is already a successful screening strategy if utilized, i.e., cytology. For example, HPV testing provides longer-term safety following a negative test than cytology, a useful characteristic for the infrequently screened.


Guideline Development and Organization

From 2009 to 2011, the ACS, ASCCP, and ASCP worked collaboratively to convene an expert panel to develop new screening recommendations based on a systematic review of the available evidence. The process was overseen by a Steering Committee composed of representatives from the sponsoring organizations, other stakeholder organizations and agencies, and experts representing multiple disciplines (see page 52 for names of all committee members). An independent Evidence Evaluation Committee (the “Data Group”) composed of experts in literature reviews, evidence evaluation, and data analysis had primary responsibility for overall development and implementation of the guidelines process, and for providing feedback and guidance to the Working Groups. The six topic areas to be addressed by the recommendations were identified by the Steering Committee. A Working Group consisting of experts on a particular topic and representing different disciplines was assigned to each area, with each Working Group having a member of the Data Group serving as a liaison. Each group met regularly via teleconference, including web-based conferences for all participants to review specific methodologic issues.

The six working groups addressed the following topic areas:

  1. Optimal cytology screening intervals
  2. Screening strategies for women 30 years and older
  3. Management of discordant combinations of cytology and HPV results (e.g., HPV positive, cytology negative and HPV negative, atypical squamous cells of undetermined significance (ASC-US) results)
  4. Exiting women from screening
  5. Impact of HPV vaccination on future screening practices
  6. Potential utility of molecular screening (Specifically, HPV testing for primary screening was assessed as a potential future strategy.)

The working groups were instructed to propose evidence-based cervical cancer prevention strategies that best serve women, specifically balancing benefits and harms of screening and, in some cases, management of screening results. They were specifically directed not to consider financial cost in making their recommendations.

Conflict of Interest

In planning this workshop, the Steering Committee critically examined some of the issues involved in defining conflict-of-interest (COI) and recognized that all interests – whether directly financial or more indirect such as an affiliation with a company, the success of one's clinical practice, or the prominence of a professional specialty – represent potential conflicts. Steering Committee members, Working Group and Data Group co-chairs, and members of the Writing Committee were required to not have any financial ties to companies that market or sell screening tests or devices (e.g., methods to visualize the cervix such as colposcopes). All participating individuals were required to disclose all real or potential conflicts of interest. Employees or representatives of industry and insurance companies were not invited to participate in the development of these guidelines due to their significant, direct financial interests in the outcome of these guidelines. The complete COI policy can be found in the online supplement.

Risk-based strategies

The six Working Groups independently considered a series of screening and management questions. We recognized that different groups of experts could evaluate the same data for related questions and reach different conclusions because of differences in weighing benefits and harms of screening. Therefore we harmonized the main outcomes for benefits and harms across Working Groups as defined below.

Benefit Outcomes

Ideally, the screening test(s) should efficiently and accurately identify women with precancer who are at significant risk of developing cancer, so that appropriate intervention will prevent progression to invasive cancer. We used detection of CIN3 as the measure of a screening test's sensitivity for precancer because a substantial proportion of women with CIN3 would develop invasive cervical cancer if left untreated.18 Also, given the natural history of cervical carcinogenesis and the relative rarity of cervical cancer in screened populations, it is the most feasible directly measurable outcome in controlled clinical studies. By contrast, CIN2 is an equivocal diagnosis that includes some precancer lesions (CIN3) but also some lesions (e.g., CIN1) that would regress on their own.28-30 Although CIN2 is the widely accepted threshold for treatment2 -- to provide an additional margin of safety -- we posited that CIN2 should not be the primary target of cervical cancer screening.

Ideally, the screening interval for a particular testing modality should be chosen such that development of invasive cancer is highly unlikely before the next screen. Because few studies have sufficient numbers of cancer cases to assess cancer risk directly, we considered the absolute risk of CIN3, including the rare cases of cancer (CIN3+) between or at the next visit as our best measure of incident cervical cancer risk. When available and appropriate, we also noted the risk of invasive cancer, especially in relationship to screening intervals, following a negative screening test.

Thus, for these guidelines, we judged that a screening test or modality provided greater benefit if MORE CIN3 was detected immediately by the screening test, and risk of CIN3+ was reduced in the interval before the next screening test.

Harm Outcomes

Most episodes of HPV infection and many CIN1 and CIN2 cases are transient and will not develop into CIN3 or cancer.28-30 The potential harms associated with detecting these transient lesions include the anxiety associated with a “positive” cancer screening test, potential stigmatization from the diagnosis of a sexually transmitted infection, discomfort from additional diagnostic and treatment procedures, bleeding from treatment, and, longer term, an increased risk of pregnancy complications such as preterm delivery due to treatment31. Having a positive test at any point in one's life may contribute to a perception of an increased risk of cancer, and a subsequent desire for more testing, further increasing the likelihood of another positive test.32 Although any false positive test has the potential for inducing anxiety or other psychological distress, quality-of-life instruments are rarely included in controlled clinical trials of screening. Because of this, we used the number of colposcopies, both alone and relative to CIN3+ and cancer detected, as the primary measure of harm, since colposcopies themselves are associated with physical discomfort, and are a necessary pre-requisite to more invasive treatments with greater short- and long-term risks of harms. Since the number of subjects undergoing colposcopy is usually reported in controlled studies, and more screening leads to more screen positives and therefore more colposcopy, it provides a surrogate for potential harm of screening analogous to the use of the detection of CIN3 as a surrogate for cervical cancer for potential benefits of screening.

Our basic tenets regarding risk and risk-based interventions were as follows:

  1. Preventing all cervical cancer is unrealistic. No screening test has perfect sensitivity, and therefore there will always be a residual cancer risk following any round of screening. More rapidly progressive cervical cancers, such as those occurring in women in their teens and early twenties, may not be preventable through feasible screening strategies.33
  2. Reasonable risk is determined by the strategy of cytology alone as a benchmark. Cytology alone at 2 to 3 year intervals is consistently included in current guidelines of major professional societies1,2,34 and is generally accepted as the standard of care in the United States. Screening strategies that achieve equivalent or better reduction in cervical cancer incidence and mortality– without an undue increase in harms – compared to cytology would be acceptable options for consideration. The optimal balance of benefit and harm should be chosen so that equipoise is achieved between screening too frequently and finding mostly benign HPV infections or correlates of HPV infection (e.g., low-grade squamous intraepithelial lesions [LSIL]), or too infrequently and thereby exceeding the reasonable interval cancer risk threshold.
  3. Women at similar cancer risk should be managed alike. Independently of how the risk is measured (i.e., screening modality), women with similar cancer risk share the same tradeoffs of benefits and harms from routine screening, increased surveillance, referral to colposcopy, or treatment. It is therefore rational to provide the same care for similar women at similar cancer risk.

We recognize that the women at different ages may have different tradeoffs in benefits and harms from screening. These differences are addressed through the development of age-specific screening recommendations.

Considerations Regarding Cytology

Based on good evidence showing similar sensitivity and specificity of conventional and liquid-based cytology for CIN grade 2 or more severe diagnoses (CIN2+),35,36 we included studies that used either cytology method. We found no data to suggest a need to analyze data from studies using liquid-based cytology separately from those using conventional cytology.

Considerations Regarding HPV Testing

The hallmarks of HPV testing are greater sensitivity but lower specificity for CIN3+ and CIN2+37-43 and better reproducibility than cytology.44-46 Benchmarks for clinical performance of HPV testing are described in detail elsewhere.47,48 Our general assumptions are that the sensitivity of HPV testing for CIN3+ and CIN2+ should be ≥90% and the percent of women in the general population who test (screen) positive, as a measure of false positives, should be less than or equal to established thresholds from well-validated HPV DNA tests.47,48

Several U.S. Food And Drug Administration (FDA)-approved HPV tests are commercially available, though none is yet approved for primary, stand-alone screening. The performance characteristics vary among these HPV tests, and comparability cannot be assumed. For use in the U.S., HPV tests should both be FDA approved (for validity) and meet specific criteria for clinical performance as described above.47,48 Other well-validated tests (e.g., GP5+/6+ EIA) are commercially available in Europe, and data using these tests were included in our review,39,40 but these are not FDA-approved. HPV tests not meeting these standards of performance (including FDA-approved tests) should not be used. In particular, excessive analytic sensitivity is a significant concern, as it will be unlikely to improve already very high clinical sensitivity for CIN3+ but may increase harms due to poorer specificity.49 The updated guidelines for cervical cancer screening described here were developed based on HPV tests that have performance characteristics similar to those of the HPV tests used in the supporting evidence. The guidelines cannot be expected to perform as designed (i.e., to balance benefits and harms) when using HPV tests with different performance characteristics.

Laboratory-developed tests (LDTs), which are currently exempt from the FDA regulatory oversight, rarely have undergone the necessary evaluation using clinical endpoints of CIN3+ and CIN2+ in properly designed studies. Therefore, we recommend against the use of LDTs for cervical cancer screening.

HPV tests should be used in accordance with their package labeling. Professional medical organizations with clinical expertise in gynecological cancer may recommend off-label applications of FDA-approved tests (e.g., HPV testing for post-treatment follow-up as recommended by the ASCCP).2 Laboratory standard operating procedures and robust quality assurance programs should accompany the use of any HPV test. Inter-laboratory or proficiency testing to ensure quality results across laboratories should be established.50 While well validated in the research setting, additional studies of inter-laboratory comparability of HPV testing in the clinical laboratory setting would be helpful.

Evidence Review

We utilized the Grading Recommendations Assessment, Development, and Evaluation (GRADE) system51-56 to provide a framework for the guidelines development process. An initial literature search for terms relevant to all the Working Groups was performed, and abstracts were reviewed by Data Group members. Papers meeting initial inclusion criteria were retrieved and distributed to each Working Group as appropriate. The search included articles from 1995 through July 5, 2011. (See online supplement, Figure 1 and Figure 2 for details.)

Each Working Group took the initially defined areas and formulated specific questions using the GRADE framework.51-56 From an initial list of potential outcomes identified by the Data Group, each Working Group defined 3-4 outcomes as “Critical,” 3-4 as “Important,” and 3-4 as “Useful” (see online supplement for list of outcomes). Members of the Working Groups then reviewed each article to determine if data were available on critical or important outcomes. We did not perform formal data synthesis or meta-analysis to create single summary estimates for each outcome/intervention pair. Instead, summary data from each included article, along with a quality grade of “high, moderate, low, or very low” were presented to the group, with a subsequent quality grade for the entire body of evidence for a given outcome/intervention pair.

The GRADE system does not specifically address modeling studies, which were frequently the only evidence available for comparing alternatives, particularly different screening intervals. Because modeling integrates evidence from a wide range of sources of varying quality, we considered individual modeling studies as “low” quality evidence, but, if the individual studies followed best practices for model-based analyses, and the results were consistent across studies done by different groups using different methods, the rating of the overall body of evidence based on modeling could be graded as of “moderate” quality.

Strength of Recommendation

Based on the initial grading of evidence, each Working Group formulated an initial summary recommendation, graded as “Strong” or “Weak,” based on the overall quality of the evidence for outcomes considered “Critical,” as well as additional criteria such as variation in patient preferences (if data were available) and feasibility of obtaining additional evidence. A “strong” recommendation means that the group felt confident that further research would be unlikely to change the recommendation, based on the overall quality of the available evidence, the prospect of obtaining better evidence, and the balance between benefits and harms. A “weak” recommendation means that there is substantial uncertainty surrounding the balance of benefits and harms, and further research is needed to increase confidence in the results, or that benefits and harms are closely balanced, with decisions based largely on individual preferences and values.* Members of the Steering Committee and Data Group, as well as the other Working Groups, reviewed these recommendations and corresponding rationale and provided feedback. After revision, the draft recommendations and rationale were posted on the ASCCP website for public comment from October 19, 2011 to November 9, 2011. The public comments were distributed to each Working Group, and revisions were made to address or clarify issues raised. However, each Working Group had the ultimate authority and responsibility for the (revised) draft recommendations presented at the symposium for consideration.

Consensus Conference

A symposium was held November 17-18, 2011 to discuss, revise as necessary and vote on the final recommendations. In addition to the members of the Steering Committee, Data Group and Working Groups, representatives from other stakeholder organizations were invited (see online supplement for list). Each Working Group presented their evaluation of the evidence and draft recommendations. After the presentation, there was an open discussion, followed by voting on the recommendations, including both the wording of the recommendation and the strength of the recommendation. A two-thirds majority was required for a recommendation to be accepted—if this threshold was not achieved, the recommendation was revised by the Working Group and brought back to the plenary participants for voting.*

Special Populations

These guidelines were developed to address cervical cancer screening in the general population. These guidelines do not address special, high-risk populations who may need more intensive or alternative screening. These special populations include women 1) with a history of cervical cancer, 2) who were exposed in utero to diethylstilbestrol (DES), and 3) who are immune-compromised (e.g., infection with human immunodeficiency virus).57


The following recommendations are based on review and assessment of the published peer-reviewed literature available at the time of the symposium. It is anticipated that they will be reviewed on an ongoing basis and revised as new evidence becomes available about the impact of alternative strategies on the balance of benefits and harms associated with cervical cancer screening.

Age to Begin Screening

The question of when to begin screening was addressed at the 2009 Practice Improvement in Cervical Screening and Management (PICSM) Symposium on Management of Cervical Abnormalities in Adolescents and Young Women33 and was not part of the current review. The following recommendation has been previously endorsed by the several organizations that participated in that meeting.


Cervical cancer screening should begin at age 21 years. Women under the age of 21 should not be screened regardless of the age of sexual initiation or other risk factors.

Rationale and Evidence

Cervical cancer is rare in adolescents and young women58 and may not be prevented by cytology screening.59 The incidence of cervical cancer in this age group has not changed with increased screening.58 Screening adolescents leads to unnecessary evaluation and potentially to treatment of pre-invasive cervical lesions that have a high probability of regressing spontaneously. This overtreatment, and subsequent increased risk of reproductive problems, represents a net harm.33 Adolescent cervical cancer prevention programs should focus on universal HPV vaccination, which is safe, highly efficacious, and when used in adolescents before becoming sexually active, highly effective and cost-effective.60,61 Even without cervical cancer screening, it is critical that adolescents continue to have access to appropriate health care, including assessment of health risks, family planning and contraception, and prevention counseling, screening and treatment of sexually transmitted infections.33

Screening Periodicity

Over time, growing evidence and the improved understanding of the natural history of cervical cancer have led to growing recognition that earlier recommendations for annual screening were excessive and led to an increased rate of harms. Today, there is little evidence to support annual screening of women at any age by any screening test, method, or modality. Annual screening leads to a very small increment in cancers prevented, at the cost of a very large excess of unnecessary procedures and treatments62,63 due to the high prevalence of transient, benign HPV infections and associated lesions, most of which will regress within a year or two or, of those that do not, are many years on average from causing cancer. Women at any age should NOT be screened annually by any screening method; rather, recommended screening intervals for women at average risk are based on age and clinical history.

Women Ages 21-29


For women 21-29 years of age, screening with cytology alone every 3 years is recommended. For women 21-29 years of age with 2 or more consecutive negative cytology results, there is insufficient evidence to support a longer screening interval (i.e. >3 years).

HPV testing should not be used to screen women in this age group, either as a stand-alone test or as a cotest with cytology.


For women under 30 years of age, there are few studies specifically addressing the optimal interval for cytology-based screening. Those studies meeting selection criteria were mainly modeling studies. While affording slightly greater cancer risk reduction, annual screening results in twice the number of colposcopies compared to screening every 3 years.63 Only one study modeled the trade-offs between cancers detected and colposcopies for screening every 2 years versus every 3 years in this age group.62 The results for both intervals conducted over a 10-year interval were similar for reducing the lifetime cancer burden. Combining these results with findings of other studies64,65 that showed no significant difference in cancer reduction between a 2- and 3-year screening interval, we determined that screening every 3 years provided the best balance of benefits and harms of screening in this age group.

Because of the high prevalence of HPV in women under the age of 30,25,66,67 HPV testing should not be used to screen women in this age group due to the potential harms as described above.


Table 2(62,63,68-70) shows patient outcomes, number of studies and quality of the evidence. In the absence of screening, modeling predicts a lifetime risk of cervical cancer in the U.S. of approximately 31-33 incident cancers per 1000 women.63,70 In addition, these studies predict a lifetime risk of cancer associated with screening every 3 years of approximately 5 to 8 incident cancers per 1000 women.62,63,68-70 Screening every 2 years is associated with a lifetime cancer risk ranging from 4 to 6 incident cancers per 1000 women;63,69 screening annually is associated with a lifetime risk of about 3 per 1000 women.63,69 Early stage cervical cancer has a very high 5-year survival rate of 90%. The predicted lifetime risks of death due to cervical cancer associated with screening every 3 years, every 2 years and annually are even lower: 0.05, 0.05, and 0.03 per 1000 women, respectively.

Table 2
Evidence for Screening Women aged 21-29

With respect to harm, screening every 3 years is associated with a lifetime prediction of about 760 colposcopies per 1000 women, screening every 2 years with about 1080 per 1000 women (a 40% increase vs. screening every 3 years), and screening every year is predicted to double the total number of lifetime colposcopies to close to 2000 per 1000 women, or nearly three times the rate expected from screening every 3 years.

A modeling study that examined outcomes for women 20 years of age screened over a subsequent 10-year time period,62 predicted that there would be a doubling of the colposcopies (using ASC-US as the threshold for referral) per 1000 women with annual screening compared with screening every 3 years. These results are similar to those reported by Kulasingam63 who examined outcomes associated with screening every 2 years. Compared to screening every 3 years, screening every 2 years (starting screening at any age between 15 and 25) was associated with little additional patient benefit in terms of reduced lifetime risk of cancer modeled over a slightly shorter time period than reported by Stout (9 versus 10 years).62

There is insufficient high quality evidence from RCTs to increase screening interval based on prior negative cytology results for any age group. Miller71 calculated the risk of invasive cervical cancer associated with different intervals since the last negative cytology test. The odds ratio comparing a 3-year vs. 2-year interval was 1.20 (95% confidence interval (0.65, 2.21). Adjusting for a history of an abnormal cytology or prior consecutive negative cytology tests did not substantially change the results. The authors also reported an incremental rise in cancer risk (≥3.16) over time as the interval from the last negative cytology test moved beyond three years72 and did not find a significantly reduced risk of CIN3+ associated with increasing numbers of prior negative cytology tests after controlling for time since last normal cytology test.

Women ages 30-65


Women ages 30-65 years should be screened with cytology and HPV testing (“cotesting”) every 5 years (preferred) or cytology alone every 3 years (acceptable). There is insufficient evidence to change screening intervals in this age group following a history of negative screens.


Cytology Only

For women 30-65 years of age, even with a history of negative cytology tests, the limited available evidence does not support a longer screening interval than 3 years. Studies of screening intervals in women with a history of negative cytology results report an increased risk of cancer after 3 years even after controlling for prior number of negative cytology tests.71 Furthermore, the only modeling study that examined the screening interval among US women with a history of prior normal cytology results compared screening every year to screening every 3 years.73 A longer interval was not examined in this review, although some countries (e.g., The Netherlands) use a 5-year interval. Modeling studies have shown a stepwise increase in cancer risk with increasing interval from 1 year to 3 years to 5 years.62,63 As such, we concluded that a 3-year interval for cytology provides an appropriate balance of benefits and harms and that there was insufficient evidence to support a longer interval than every 3 years utilizing cytology alone in women aged 30 years or older, even with a screening history of consecutive negative cytology tests.

HPV and cytology (cotesting)

In the majority of studies reviewed, the addition of HPV testing to cytology resulted in an increased detection of prevalent CIN3 with a concomitant decrease in CIN3+ or cancer detected in subsequent rounds of screening.39-41 This increase in diagnostic lead-time with cotesting translates into lower risk following a negative screen, permitting a longer interval between screens with incident cancer rates similar to or lower than screening with cytology alone at shorter intervals. If the incident cervical cancer rates associated with cytology at 3-year intervals are acceptable, cotesting at 5-year intervals provides similar or lower cancer risk.22,74

The addition of HPV testing to cytology also enhances the identification of women with adenocarcinoma of the cervix and its precursors.42,74 Compared to squamous cell cancers, cytology has been relatively ineffective in decreasing the incidence of invasive adenocarcinoma of the cervix.75,76 A strategy of cotesting may become increasingly important based on evidence of increasing incidence of adenocarcinoma, which has been observed in several European countries76 and the U.S.77 that have exclusively or primarily used cytology-only screening.

Cotesting at a 3-year interval, as recommended in interim guidelines from 2002 and 2004,1,78 resulted in a significantly smaller diagnostic yield of CIN3+ in the second round of cotesting following a prior negative cotest,74 supporting the recommendation to use a longer interval between cotests. Modeling studies have shown that cotesting in 40-year-old women at a 3-year versus a 5-year interval over a 10-year period only slightly decreases lifetime cervical cancer risk (0.39% vs. 0.61%, respectively) while significantly increasing the number of colposcopic evaluations.62 In the same modeling study, the lifetime cancer risk estimates for 40-year-old women undergoing 3-year cytology versus 5-year cotesting over a 10-year period were comparable (0.69% vs. 0.61%, respectively). Cotesting more frequently than at 3-year intervals, and especially annual screening, is predicted to further exacerbate the harms of increases in colposcopic referrals and treatments.62 Unfortunately, there is evidence that cotesting is being used at shorter intervals than 3 years.79 The lack of greater benefits and the increase in potential harms associated with screening more frequently support a recommendation of cotesting every 5 years.


Table 3 (39-41) shows patient outcomes, number of studies and quality of the evidence.

Table 3
Evidence for cotesting with HPV and cytology vs cytology alone

Increased Sensitivity of Cotesting

Compared with cytology, HPV testing is more sensitive but less specific for identifying women with prevalent CIN3+.80 In a meta-analysis,80 the sensitivity of HPV testing for CIN3+ was 37% greater than that of cytology using a positive cut point of LSIL (i.e., LSIL or more severe cytologic abnormalities were considered screen positive), while the specificity of HPV testing was 7% lower. The sensitivity of HPV tests for CIN3+ was 28% greater than that of cytology at a positive cutpoint of ASC-US, while the specificity of HPV tests and cytology were the same.

When compared with women with negative cytology, those with negative HPV tests have a lower subsequent risk of CIN3+22,74 and, more importantly, cancer.41 Results from FDA-approved or well-validated HPV tests are also more reproducible (intra-assay reliability) than cytology.45,46,81

There are four RCTs39-41,82 in which two rounds of screening are reported comparing cotesting with cytology and HPV testing to cytology alone; three of those trials provided adequate evaluation of HPV-positive, cytology-negative results. Each of the trials had a complex protocol and each differed in the way that HPV-positive women were evaluated. ARTISTIC (a randomized trial of HPV testing in primary cervical screening) differed from the other three in that the lower age limit of eligible women was 20 years, while for the other three trials, it was 32 years, 29 years, and 35 years.39-41 The ARTISTIC trial82 also differed in that women in ARTISTIC who tested HPV positive, cytology negative were referred to one-year follow-up, similar to the interim guidelines in the U.S.,1,78 rather than being immediately referred to colposcopy as was done in the other trials.41 As the added benefit of HPV testing is only realized with thorough follow-up of and disease ascertainment in women with HPV-positive, cytology-negative results, it is not surprising that ARTISTIC did not show a benefit to cotesting versus cytology alone, with only half of the HPV-positive, cytology-negative women returning in a year. Saseini83 pointed out that if all of the HPV-positive, cytology-negative women had been evaluated and disease rates in those who were lost to follow-up had been comparable to those found among the women evaluated, ARTISTIC would have demonstrated increased sensitivity with the addition of HPV testing to cytology, as observed in other studies, compared to cytology alone.83 The other three trials39-41 were powered to detect differences in the rate of CIN3+ in the second round of screening, but not powered to detect differences in the rate of cancer in the second round of screening. Their protocols and results are described in detail in the online supplement.

In each of the three trials considered,39-41 the cotesting arm detected a greater proportion of CIN3+ in the first round of screening compared to cytology alone. The difference in the incidence of cancer in the second round of screening was not stated in Naucler et al.,39 showed a trend towards declining incidence (not statistically significant) in Bulkmans et al. (0.08% vs. 0.02%),40 and showed a statistically significant decrease in Ronco et al. (0.03% vs. 0%, p=0.004).41 The number of colposcopy referrals in the three studies was not clearly stated, so the increased number of colposcopies must be inferred based on modeling.

Based on the significant increase in sensitivity in detection of CIN3+ at the first round of screening and the reduction in invasive cancer in the second round of screening in Ronco et al,41 we concluded that the addition of HPV testing to cytology is beneficial. The main harms associated with adding HPV testing-- the increased referral to colposcopy and diagnosis of CIN2, some of which would regress without intervention-- can be mitigated by extending the screening interval to 5 years (as discussed below) and thereby reducing the detection of transient HPV infections and related lesions that would trigger clinical follow-up in low-risk women.62

While cotesting is preferred to cytology alone based on risks and harms assessment, such a strategy might not be feasible in all clinical settings in the U.S. due to a lack of payment for cotesting or due to local policies. With regards to the primary goal of cervical cancer screening, which is prevention of cervical cancer, a cytology-based screening strategy in women over 30 has been and continues to be an acceptable option. As mentioned previously in this document, a more frequent, cytology-only strategy does lead to more colposcopy and other harms including the potential need for prescribing shorter screening intervals due to equivocal cytology results that have minimal cancer risk.

Rationale for and Safety of Interval Extension

Cotesting has increased sensitivity for detecting CIN3+ compared to cytology. Consequently, women screened with cotesting also have a lower subsequent risk of CIN3+ and invasive cancer, permitting a lengthening of screening intervals. Seven observational studies involving 24,295 women were pooled to examine the long-term predictive values of HPV testing and cytology.22 The 6-year risk of CIN3+ following a negative HPV test was 0.27%, compared to 0.28% among cotest negatives. By comparison, the 6-year risk of CIN3+ following a negative cytology alone was significantly greater at 0.97%. The authors also noted that the risk of CIN3+ at a 3-year screening interval, the most commonly used screening interval in Europe, after negative cytology was 0.51%. In a retrospective observational study of 330,000 women aged 30 years and older undergoing cotesting in routine clinical practice,74 the 3-year risk of CIN3+ following negative cytology alone (regardless of the HPV result) was 0.17%; the 5-year risk of CIN3+ following a negative HPV test alone (regardless of the cytology result) was 0.17%; and the 5-year risk of CIN3+ following a negative cotest was 0.16%, essentially comparable results across each testing strategy. Likewise, the risks of cancer also were comparable (0.018%, 0.019%, and 0.016%, respectively).

In the same analysis,74 women who were cotest negative at the initial screening and HPV and/or cytology positive 3 years later were at a lower risk of CIN3+ or cancer than women with a positive HPV and/or cytology result at the initial screen. This lower risk associated with previously normal findings presumably is due to the prolonged period of HPV carriage (chronic infections) required for invasive cancer to develop. Taken together, these reports indicate that healthcare providers can rely on the negative predictive value of the HPV test to assure women who cotest negative that they are at very low risk for CIN3 and cancer for at least 5 years after negative cotesting.

Risks Associated with Screening at Different Intervals

Modeling from several sources indicates that there is a dramatic increase in colposcopy rate with minimal change in invasive cancer incidence as screening intervals decrease below 3 years, regardless of the modality employed.63,84,85 Despite differing assumptions, all three analyses indicated that the number of colposcopies more than tripled with annual cytology starting at age 21, in comparison to annual cytology for ages 21-29 and cotesting at 5-year intervals starting at age 30. The models also agreed that cotesting of women aged 30 and older at 5 years intervals involves fewer colposcopies with similar or slightly lower cancer risk compared with 3-year cytology alone.

Detection of Adenocarcinoma of the Cervix and Its Precursors

Case control studies in Australia and Italy demonstrated that cytologic screening provides only modest protection against adenocarcinoma.86,87 More recently, the International Collaboration of Epidemiological Studies of Cervical Cancer Group pooled screening data from 12 studies involving 1,374 women with adenocarcinoma and concluded that risk reduction of a preceding cytology test was greater for squamous cell carcinoma than for adenocarcinoma.88

In Castellsague et al,.89 HPV was detected in 93% of 167 adenocarcinomas cancers of the cervix (including 55 adenosquamous carcinomas). A case control study with these cases and 1881 controls was also reported. Testing HPV positive (vs. negative) was strongly associated (odds ratio = 81.3) with a diagnosis of cervical adenocarcinoma.89 From Katki et al.74 63% of the adenocarcinomas diagnosed over a 5-year period followed an HPV-positive, cytology-negative cotest.

Management of Women with HPV Positive, Cytology Negative Cotests


Women cotesting HPV positive, cytology negative should be followed with either (as noted in the interim ASCCP guidelines:78 (1) repeat cotesting in 12 months (Option 1), or (2) immediate HPV genotype-specific testing for HPV16 alone or for HPV16 and HPV18 (Option 2). If cotesting is repeated at 12 months, women testing positive on either test* should be referred to colposcopy; women testing negative on both tests** should return to routine screening. If immediate HPV genotype-specific testing is used, women testing HPV16 positive or HPV16 and/or HPV18 positive should be referred directly to colposcopy; women testing HPV16 negative or HPV16 and HPV18 negative should be cotested in 12 months, with management of results as described in option 1.

Women cotesting HPV positive, cytology negative should not be referred directly to colposcopy. Furthermore, they should not be tested for individual HPV genotypes other than HPV16 and HPV18. The use of HPV genotype-specific testing for HPV16 or HPV16 and HPV18 is recommended only for the management of HPV-positive, cytology-negative women. Currently, there is insufficient evidence to support the use of non-HPV biomarkers.


There are no RCTs that directly compare different management strategies for women cotesting HPV positive, cytology negative. Consistent, high-quality evidence from prospective observational studies indicates that the short-term risk of CIN3 in this population is far below the risk threshold of HPV positive ASCUS and LSIL used for referral to colposcopy (i.e., 2-year risk of 8-10% in the ASCUS/LSIL Triage Study).20,90 For this reason, immediate colposcopy for all HPV-positive women (including HPV-positive, cytology-negative women) was strongly dismissed by the consensus conference participants as a potential management strategy. Repeat cotesting at 12 months is the current recommended management2 for women testing HPV positive, cytology negative. This is supported by evidence from cohort studies showing the majority of transient infections clear by 12 months,15,91 returning the majority of women to routine screening without excessive risk.

Where available, HPV genotype-specific testing for HPV16 or HPV16/HPV18 may be performed following HPV-positive, cytology-negative results. Large cohort studies17,92 and one industry-sponsored trial93 have shown that HPV16-positive or HPV16- and HPV18-positive results are associated with clinically relevant short-term risk of CIN3 or cancer in HPV-positive, cytology-negative women, supporting immediate referral to colposcopy. In all studies, HPV16 conferred much higher absolute risk than any other carcinogenic type and was most commonly followed by HPV18. Other types such as HPV31 and HPV58 were associated with short-term risks similar to those of HPV18 in some populations.17,94 However, large international case series studies of type attribution to cervical cancers have demonstrated that the etiologic fraction of HPV18 is much higher than that of any other type (except for HPV16),9,10,95,96 and the etiologic fraction is even higher in adenocarcinomas. Thus, including HPV18 in genotype-specific assays appears warranted.

Aside from management of HPV-positive, cytology-negative women, no other clinical indications have sufficient evidence to recommend HPV genotype-specific testing for HPV16 or HPV16 and HPV18. Further studies are likely to further refine the risk estimates of specific test result combinations. There is also a lack of evidence to support the use of other molecular markers in HPV-positive, cytology-negative women. However, studies are ongoing, with results anticipated within 2-3 years.


Table 4(74,93,97-105) shows patient outcomes, number of studies and quality of the evidence. The prevalence of HPV-positive, cytology-negative screening results was reported in nine studies (online supplement, Working Group 3a report Table 1)74,93,97-102,106,107 and ranged from 3.4% to 8.2% in women age 30 years and older. In a screening population of women age 30 years and older,74 the proportion of HPV-positive, cytology-negative results (3.7%) was more than twice that of HPV-positive, cytology-positive results (1.4%), implying a significant increase in referral to colposcopy if HPV-positive, cytology-negative women were referred for immediate colposcopy.

Table 4
Evidence for managing women aged 30-65 with HPV positive, cytology negative or HPV negative, ASCUS cytology results

Cumulative risks of CIN2 or CIN3 among HPV-positive, cytology-negative women have been reported from 11 prospective studies with heterogeneous populations, varying disease ascertainment, and length of follow-up ranging from 1-16 years (online supplement, Working Group 3a report Table 2). The estimated 12-month risk of CIN3+ following an HPV-positive, cytology-negative cotest, relevant for management decisions, ranged from 0.8%74 to 4.1% .93 The estimated 12-month risk of cancer was 0.08%.74

For HPV16 or HPV16 and HPV18 genotype-specific testing in HPV-positive, cytology-negative women, risk of CIN3 reaches 10% over 1-4 years for HPV16 positivity and over 2-5 years for HPV18 positivity.17,92 One industry-sponsored trial reported risk of prevalent disease (within 12 weeks) for HPV16- and HPV18-positive results as 11.4% for CIN2+ and 9.8% for CIN3+, and for HPV16-positive results as 13.6% for CIN2+ and 11.7% for CIN3+.93 The short-term risks associated with non-16/18 oncogenic HPV genotypes were considerably lower. 17,92, 93 While these risk estimates for non-16/18 oncogenic HPV genotypes do not warrant immediate colposcopy, they are elevated compared to those for women cotesting negative; therefore, a reasonable approach for women who test HPV16 or HPV16 and HPV18 negative following an initial HPV-positive, cytology-negative result is to follow with repeat cotesting at 12 months to identify women who are likely to have persistent HPV infection and are at an elevated risk of CIN3+ over many years.92,100

The potential utility of p16INK4A immunocytochemistry for managing HPV-positive women has been demonstrated in an Italian screening trial,108 but this study did not directly evaluate women testing HPV positive, cytology negative. As more data from HPV-positive, cytology-negative populations become available for other biomarkers, revisions to recommendations may be warranted.

Management of women with HPV-negative, ASC-US cytology results


Women with ASC-US cytology and a negative HPV test result should continue with routine screening as per age-specific guidelines.


The cytologic interpretation of ASC-US represents a category of morphologic uncertainty. The definition of ASC-US is “some, but not all” of the features of a LSIL and as such, the differential diagnosis includes both poorly sampled and poorly represented LSIL and the many morphologic mimics of LSIL. An ASC-US interpretation does not represent a specific diagnosis. Because of its morphologically equivocal nature, the inter- and intra-observer reproducibility of an ASC-US interpretation is less than that for the reliable, unequivocal diagnostic categories of LSIL and high-grade squamous intraepithelial lesion (HSIL).81 The current ASCCP recommendation2 of HPV testing for the management of ASC-US cytology tests allows for the use of this more objective test to stratify the risk for the development of cervical cancer precursor lesions. The introduction of HPV testing for management of ASC-US and cotesting for primary screening over the last decade has led to an increased number of women being identified with HPV-negative, ASC-US-cytology results. The key question to provide rationale for this recommendation is as follows: Does the risk of precancerous lesions in women with HPV-negative, ASC-US-cytology results warrant increased surveillance in comparison to that of women who are negative for intraepithelial lesion or malignancy (NILM) and HPV negative?

Data from published studies have shown that the risk of precancerous lesions following an HPV-negative, ASC-US cytology result is very low, and not different from a negative cotest. Because of the very low cervical cancer risk observed in the ASC-US/HPV-negative population, continued routine screening is recommended for this group: 3-year interval for cytology screening of women ages 21-29 or 30-65 years old, and 5-year interval for cotesting of women ages 30-65 years old.

Women with abnormal cytology more severe than ASC-US (LSIL or more severe) should be referred to colposcopy regardless of their HPV status.2 The risks of CIN3+ and cancer following HPV-negative, LSIL+ cytology results are too great to warrant a return to routine screening.19


Table 4 shows patient outcomes, number of studies and quality of the evidence. The risk of CIN3+ following HPV-negative, ASC-US cytology results is very low. In the largest study, the risk of CIN3 at enrollment in ASC-US /HPV-negative women was 0.28%.103 In a longitudinal follow-up study, the risk of CIN3+ in this population at 5 years was 0.54%.74 Analyses from the ASCUS LSIL Triage Study showed that the 2-year cumulative risk of CIN3+ in ASC-US/HPV-negative was less than 2% (1.4% to 1.9% depending on the HPV testing method used).43,104 For comparison, two studies showed follow-up data on cotest-negative women 30 years and older. In these studies, the risks of CIN3+ ranged from 0.3% (prevalent)93 to 0.16% with 5 years follow-up.74

Overall, the absolute risk of a true precancerous lesion in the HPV-negative, ASC-US cytology population is very low (less than 2% overall, and less than 1% when based on the most robust studies). This level of risk does not warrant more frequent screening.

Screening with HPV Testing Alone


In most clinical settings, women ages 30-65 years should not be screened with HPV testing alone as an alternative to cotesting at 5-year intervals or cytology alone at 3-year intervals.


Primary HPV testing has been prospectively assessed as a replacement for current acceptable modalities of cervical cancer screening. RCTs of HPV testing alone have demonstrated that when compared to standard cytologic screening, HPV testing has increased sensitivity for detection of CIN3+ and CIN2+ after a single screening round. Greater sensitivity also means greater negative predictive value over a longer time period, because the absence of positive HPV findings is an indication of low risk of developing CIN3+. RCTs have been less successful at defining the specificity of HPV testing, and so the potential harms of primary HPV testing are poorly quantified.

Although primary HPV-based screening approaches appear promising, the lack of a well-defined and evaluated management strategy for positive tests precludes their practical implementation in the majority of clinical settings in the U.S. at this time. There are no data to estimate how the clinical performance of cytology (as a follow-up test) would be affected by a priori knowledge of positive HPV status. The lack of an internal standard for specimen adequacy for some HPV assays may provide false reassurance among a small number of women whose negative screening results may be a function of specimen inadequacy rather than true absence of disease. Such an event is less common with cytology since specimen adequacy assessment is a routine component of the evaluation and inadequacy prompts intervention and follow-up on the part of the clinician and patient. Thus, the inclusion of cytology with HPV testing, i.e. cotesting, provides some additional reassurance against testing errors due to specimen inadequacy, although the benefits in terms of sensitivity and negative predictive values are only incremental. Implications, such as cost effectiveness of and adherence to implementing such a major change in the current US opportunistic screening setting, require further evaluation and planning.


HPV in Primary Screening

Table 5( 38,74,109,110) shows patient outcomes, number of studies and quality of the evidence. HPV testing for primary screening appears promising in women aged 30 years and older, as this group may be at greatest risk for developing CIN3+. In single round screening studies, HPV testing is more sensitive for detection of CIN2+ and CIN3+ than cytology alone and is almost as sensitive as cotesting (2-5% additional CIN3+ are detected among women with HPV-negative, cytology-positive results, primarily those with LSIL or more severe cytology).74,80,105 And a negative HPV test provided greater reassurance against CIN3+ in the subsequent 5-7 years than cytology alone and is nearly as reassuring as a negative cotest. Therefore an acceptable screening interval for use of HPV testing alone should be comparable to that of cotesting.

Table 5
Evidence for screening with HPV alone compared to cytology

However, the published studies of HPV primary screening are limited by a lack of long-term follow-up, with only one reporting the second round of screening.41 In that study, referral of all HPV-positive women to colposcopy led to a reduction in cancers in the second round of screening 4 years later compared to cytology screening. But more data are needed regarding the long-term impact of using HPV primary testing for cervical cancer screening.

HPV testing for primary screening is less specific than cytology alone and may identify clinically insignificant disease destined to spontaneously regress.41 Thus, a strategy of immediate colposcopy of all HPV-positive women can be associated with significant harms, due to unnecessary diagnostic procedures or treatment, which may outweigh the benefits of the increased sensitivity. For this reason primary screening using HPV testing alone requires yet-to-be-defined appropriate tests for assessing a positive HPV result.

Currently, there are no published large-scale or population-based studies evaluating management strategies of HPV-positive women in an HPV primary screening setting. A recent systematic review of the available published evidence concluded that HPV testing is very promising for primary screening of women aged 30 years and older, particularly when coupled with cytology testing (for follow-up) of HPV positive results, which may reduce the increase in false positives (and their related harms) that would result from HPV testing alone.111 There are no direct data to estimate the performance of cytology in a triage (follow-up) setting, although a simulation analysis using data from a RCT found an improved positive predictive value using HPV testing followed by cytology compared to other combinations of cytology and/or HPV testing.38 Specifically, it is unclear whether the interpretation of cytology in a real-world setting is affected by a priori knowledge of HPV positivity and what impact this may have in a general population screening setting. In addition, as discussed in the Management of Women with HPV Positive, Cytology Negative Cotests section, rational clinical follow-up of HPV-positive, cytology-negative women is critical to realizing the (sensitivity) benefits of using HPV testing (although the HPV-negative patients would still benefit from the added safety). Assessment of the full impact of a primary screening strategy using HPV with or without cytology follow-up may be possible only after implementation in selected clinical settings in a Western or high-resource setting and/or using modeling analyses.111

Other strategies have aimed to improve specificity and reduce harm by interposing secondary testing for management decisions between a positive HPV test and colposcopy. Potential secondary biomarkers included HPV genotyping (for HPV16 or HPV16 /18),92,100 HPV mRNA testing,112 and/or detection of other non-HPV biomarkers (e.g. p16INK4A).108 Although promising, there are limited data regarding the test performance of these markers. Specifically, the cross-sectional and archival nature of most available molecular marker studies as well as the heterogeneity of clinical endpoints examined (CIN2+ vs. CIN3+) limits the current usefulness of these data. Finally, there are no direct comparisons of these various triage strategies and the specificity of such an approach, and the consequential potential harms (or benefits) have not yet been well defined.

Women Over Age 65


Women over 65 years of age with evidence of adequate negative prior screening and no history of CIN2+ within the last 20 years should not be screened for cervical cancer with any modality. Once screening is discontinued it should not resume for any reason, even if a woman reports having a new sexual partner.*

Women over age 65 with a history of CIN2, CIN3, or adenocarcinoma in situ


Following spontaneous regression or appropriate management of CIN2, CIN3, or adenocarcinoma in situ (AIS), routine screening should continue for at least 20 years (even if this extends screening past age 65).


In well-screened women older than the age of 65 in the United States, CIN2+ prevalence is low29,113 and cervical cancer is rare.1 In the US, cervical cancer is most commonly diagnosed in unscreened and under-screened women.114-116 In contrast, the potential harms from screening of this population, in addition to those already specified, include discomfort during cytology sampling and false-positive screening tests. Based on the extended natural history of the disease, it is improbable that incident HPV infections and newly detected CIN3 after the age of 65 will have sufficient time to progress to invasive cancer in the woman's lifetime but it is unlikely that there will ever be a clinical trial to demonstrate this directly. Finally, one modeling study concluded that for women who have been screened every 3 years prior to age 65 years, the ratio of colposcopies to years of life gained associated with further screening was large (or the years of life gained per colposcopy small) because of the small gains in life expectancy.63

The age at which to discontinue screening is based on the opinions of the expert panel members and was chosen to balance the benefits and harms of screening older women. Women who discontinue cervical cancer screening should continue to obtain age-appropriate health care.

While women with adequate negative prior screening have a very low risk of cervical cancer, those who have been treated for CIN2+ in the past 20 years (or had it resolve spontaneously) remain at approximately a 5- to 10-fold higher risk for cervical cancer than the general population.117,118 (We note that these studies were based on cytology alone; future studies incorporating HPV testing may yield different risks.) We endorse the ASCCP guidelines for continued regular screening of these women for 20 years after an initial period of more intense surveillance, even if that extends screening past age 65. We define regular screening as screening every five years using cotesting (preferred) or every three years using cytology alone (acceptable).

Recent evidence suggests that the natural history of incident HPV infections is unaffected by a woman's age at acquisition.94,119 A new carcinogenic HPV infection in a woman aged 65 years or older with a cervix should clear spontaneously in most cases, and only a small percentage of women should have a persistent infection. Since the transformation zone of older women is smaller and less accessible than in younger women, and since cervical cancer develops many years after an incident infection, screening this population would detect a very small number of new cases of CIN2+ and prevent very few cervical cancers and even fewer cancer deaths.


Table 6 (63) shows patient outcomes, number of studies and quality of the evidence. Mathematical modeling63 among women screened with cytology every three years prior to age 65 demonstrates that continued screening even to age 90 prevents only 1.6 cancer cases and 0.5 cancer deaths per 1000 women. For every 1000 women, continued screening extends life expectancy by only one year, while resulting in 58 extra false positives, 127 extra colposcopies and 13 extra CIN2/3 diagnoses requiring treatment.

Table 6
Evidence for stopping screening

With respect to newly acquired HPV infection in women who have discontinued screening, indirect evidence regarding the risk of not resuming screening in this population is found in the report by Chen et al. In a large-scale community-based cohort of women followed for up to 16 years after receiving cytology and HPV testing at baseline and two years later, newly detected infections were associated with very low absolute risks of persistence and CIN3+ regardless of the woman's age. Furthermore, in women aged 55 and older after two negative HPV tests two years apart, the risk of subsequently developing CIN3 or cervical cancer was only 0.08%, with only one woman developing CIN3 after 9.6 years.94 In another large 7-year, population-based cohort study, newly detected infections were associated with very low absolute risks of persistence or progression. The rate of progression to CIN2+ (or CIN3+) after 3 years of follow-up was not higher for women aged 34 years and older than for younger women.119 Therefore, most new carcinogenic HPV infections in women age 65 years or older should clear spontaneously, and only a small percentage is likely to persist. Since the transformation zone of older women is smaller and less accessible than in younger women and since cervical cancer develops at a median 15-25 years after an incident infection, screening this population would detect a very small number of new cases of CIN2+ and prevent very few cancers and even fewer cancer deaths. The risks associated with over-treatment in the elderly population outweigh the benefits.

Women who have undergone hysterectomy and have no history of CIN2+


Women at any age following a hysterectomy with removal of the cervix who have no history of CIN2+ should not be screened for vaginal cancer using any modality. Evidence of adequate negative prior screening is not required. Once screening is discontinued it should not resume for any reason, including if a woman reports having a new sexual partner.


In women who have undergone hysterectomy with removal of the cervix for reasons other than CIN2+, vaginal cytology screens for primary vaginal cancer. Vaginal cancer is an uncommon gynecologic malignancy. Its age-specific incidence is similar to or less than that of other cancers for which screening is not performed, such as breast cancer in men. Abnormal vaginal cytology is rarely of clinical importance. Therefore, there is no justification for continuing to screen these women for lower genital tract malignancies. Women who have had a hysterectomy for cervical intraepithelial lesions may be at increased risk of vaginal cancer, but the data are limited. Women who discontinue screening should continue to obtain age-appropriate preventive health care.


The incidence rates for all vaginal cancers combined were 0.18 per 100,000 female population for in situ cases and 0.69 for invasive cases.120 A retrospective cohort study of vaginal cuff cytology in 5,862 women post-hysterectomy for benign disease reported abnormal cytology among 79 women (1.1% of all smears). The mean length of time from hysterectomy to abnormal cytology result was 19 years. The positive predictive value of vaginal cuff cytology for detection of vaginal cancer was 0 (95% CI 0 to 33%).121 A 10-year retrospective study among 697 women after hysterectomy for benign disease found that 663 vaginal cuff cytology tests were needed to detect one case of vaginal dysplasia.122 A retrospective study of 220 women selected at random from 2,066 women with a previous hysterectomy for benign conditions and followed for an average of 89 months identified seven patients (3%) with intraepithelial cytologic abnormalities, but no vaginal cancers. No benefit in patient outcomes was observed.123 A cross-sectional study of 5,330 screening cytology tests in women after a hysterectomy found one case of dysplasia and no cancers.124

In a study of 193 women with CIN at hysterectomy, the incidence of abnormal vaginal cuff cytology at least two years after hysterectomy was 0.7 per 1,000; at 20 years, 96.5 percent of the women continued to have normal cytology.125 Thus, even if women with hysterectomy were at an increased risk of vaginal cancer, there is no proven method to effectively intervene before vaginal cancer develops.

Screening following vaccination: looking to the future


Recommended screening practices should not change on the basis of HPV vaccination status.


Two HPV vaccines have been licensed in the US; both are highly effective at preventing infection with the two most carcinogenic HPV types, HPV16 and HPV18, which cause about 70% of all cervical cancers. Randomized clinical trials have also shown that HPV16/18 vaccination is highly effective in preventing CIN2 and CIN3 among women not previously exposed to these types. In vaccinated populations, it is plausible that women protected by vaccination could have less intensive screening and also start screening at a later age, since they will likely experience a lower risk of cervical cancer in the future. However, a number of arguments preclude a more permissive screening policy at this time among a vaccinated cohort in the US. About 30% of cervical cancers will continue to occur, because the first generation of vaccines covers only HPV16 and HPV18. As Advisory Committee on Immunization Practices (ACIP) recommendations include vaccinating women up to 26 years, many women may be vaccinated after HPV infection has already occurred, when efficacy declines. Moreover, coverage of HPV vaccination in the US has yet to reach levels comparable to those of countries, like Australia and the United Kingdom, which have publicly-funded, school-based vaccination programs that guarantee high coverage of pre-adolescents and young women. On average for all states in the U.S. in 2010, only 32% of eligible girls and women had received all 3 doses of the vaccines, and HPV vaccination is largely opportunistic, not necessarily targeting girls and young women before the onset of sexual activity.126 There are also geographic and socioeconomic disparities in vaccination coverage.

Thus, there are no data at this time that support changes in the age when screening is to be initiated or in the screening interval for U.S. women that have been vaccinated. The same recommendation applies to the individual woman who reports having been vaccinated. Overall practice recommendations for age at initiation of screening, interval, and acceptable screening technologies are described elsewhere in this article and should be followed in populations with access to HPV vaccination as well as for individual women with known vaccination.


Table 7(126-151) shows patient outcomes, number of studies and quality of the evidence. The low HPV vaccine coverage in the U.S. remains a barrier for proposing population-based changes in cervical cancer screening among those receiving the vaccine. Moreover, the coverage threshold at which changes would be cost-effective for the population and yet safe for the individual remains unknown. At low coverage, herd immunity will not occur and there will be little impact on HPV transmission rates and consequently on the incidence of CIN3+. Even in countries with high HPV vaccination coverage, changes to cervical screening practices are not immediately anticipated. Surveillance systems, such as the New Mexico HPV and Pap Registry,152 the establishment of sentinel CIN3 registries, and HPV Vaccine Impact Monitoring Project Across Connecticut (HPV-IMPACT), a sentinel surveillance system for monitoring HPV vaccine impact on HPV type-specific CIN2+ established by the Centers for Disease Control,153 will be critical for monitoring the impact of vaccination.

Table 7
Evidence for women who have been vaccinated against HPV types 16 and 18

Although mathematical models suggest that current cervical cancer screening recommendations could be modified following HPV vaccination, there is no consensus on screening recommendations in a vaccinated cohort. There is agreement among modelers that it will take more than a decade to see the full impact of vaccination on screening outcomes. As a result, changes in screening recommendations in the HPV vaccination era, although attractive, will likely not be warranted in the immediate future. It is also important to ensure that the benefits of vaccination are not offset by reductions in screening coverage due to complacency or an erroneous belief that vaccination eliminates the need for screening. One study suggested that with vaccine coverage of 84% among12-year-old girls, a reduction of screening from about 80% coverage to about 60% coverage could lead to reductions in life expectancy compared to no HPV vaccination with 80% screening coverage.147 Likewise, another study found that the quality-adjusted life expectancy was lower for certain age groups under conditions in which there was lower participation in screening (<70%) and incomplete vaccine coverage (<75%) compared to current screening practice without vaccination.148

Another important argument against modifying screening recommendations based on introduction of HPV vaccines is the lack of empirical data on the performance of screening tests among a vaccinated cohort. Mathematical models149,150 indicate that vaccination is expected to reduce the prevalence of high-grade cervical lesions over time, which will have a deleterious influence on the positive predictive value of screening tests, thus increasing the proportion of false positive results. Although not empirically based, these models provide insights concerning the role of cytology or other screening technologies and raise awareness about the need to reassess future screening practices to guarantee acceptable performance quality and safety. The guidelines presented elsewhere in this report emphasize the need for less intensive screening, setting the stage for reducing the harms that would come from the expected loss in screening test performance.

Despite the rationale for changes in screening practices among vaccinated women, agreeing on a recommendation would have to be based on high quality evidence on the critical outcomes, including duration of protection and reduction of risk of CIN3+. A key question is the duration of protection following HPV vaccination, especially in girls ages 11-12, and the impact on age-specific cancer risks. In addition, reliable documentation of fully vaccinated status at an age likely to be prior to HPV exposure would be needed. Evidence is also needed on (1) the effect of vaccination on the HPV genotype distribution, (2) the impact of vaccination on the performance of cytology and HPV testing (the two methods recommended in the updated guidelines), and (3) the effect of vaccination on screening adherence. It is expected that epidemiologic surveillance via linkage of vaccination registries with screening and HPV testing databases or electronic medical records from managed care organizations, and collection and reporting of screening data by vaccination status will permit comparisons of HPV type distributions, screening behaviors, and lesion prevalence between vaccinated and unvaccinated individuals. Having such data sources would permit tailoring of screening recommendations for women with a documented history of HPV vaccination. In addition to registries, clinic-based systems and large screening programs such as Title X Family Planning, the CDC's National Center of Chronic Disease Prevention and Health Promotion, Planned Parenthood, and managed care organizations should begin reporting screening data by HPV vaccination status. Such guidance is already being provided by the Public Health Agency of Canada.154


These updated guideline recommendations were motivated by an increased understanding of the natural history of HPV infection and cervical carcinogenesis, and by an expanding knowledge of the relative performance of different screening tests. Evident and important remaining research priorities include the following:

  1. The most important research priority involves identifying strategies to increase screening coverage in unscreened or under-screened women, in whom a significant proportion of invasive cancers occur. Novel strategies utilizing HPV testing and other molecular approaches should be examined. Specifically, self-collection of cervico-vaginal specimens coupled with HPV testing can achieve sensitivity that is comparable to or better than that of cytology-based screening.155 Self-collection with HPV testing might be used to increase screening coverage and address these cancer health disparities.156 Future studies need to evaluate the scale-up, implementation, and acceptability of such programs targeting these populations.
  2. How best to manage women with HPV-positive, cytology-negative cotesting results. We need to determine the relative performance of reflex HPV typing for the most carcinogenic types versus follow-up repeat cotesting at different intervals. Future research on the use of novel biomarkers is also necessary.
  3. In available studies, most of the sensitivity of cotesting derives from the HPV test rather than the cytology test. Future research might support HPV testing alone for screening, especially if it can show that longer screening intervals offset the potential harms that follow lower specificity of a highly sensitive test. It will be important to verify that the expected, very small decrement in sensitivity compared with cotesting is acceptable in the U.S.
  4. The incidence of new infections declines sharply with increasing age. They are usually benign regardless of a woman's age. It is long-term HPV persistence that causes cervical cancer, and carcinogenesis typically takes decades from infection to cancer. The great majority of cervical cancer cases arise from HPV infections that persist from acquisition at younger ages. Thus, it might be safe for consistently HPV-negative women to stop cervical cancer screening at younger ages than the 65 years recommended in these guidelines. Prospective studies among older women are needed to establish the optimal age to cease screening among known HPV-negative women.
  5. HPV vaccination decreases the efficiency of current methods of cervical cancer screening, but conference participants judged that it is premature to modify screening in the U.S. based on vaccination history. For example, it might eventually make sense to initiate screening in vaccinated cohorts at older ages (>21 years) because of their lowered risk of cancer. For proper integration of screening and prevention, we need to study how to modify cervical screening in optimally vaccinated women. To do so, it will be necessary to implement an epidemiologic surveillance system with vaccination and screening registries whose data can be linked for efficient assessment of the impact of vaccination on lesion incidence and screening performance and/or use data from managed care organizations with excellent electronic medical records.
  6. There is a continuing need to validate HPV tests. Researchers must establish which ones are acceptably reproducible and accurate. We need to ensure that the HPV tests in clinical use afford the same protection against cancer at longer time intervals as those used in research studies.
  7. Large trials are unlikely to be conducted to answer all of these applied research questions. Cervical cancer screening should become an active area of comparative effectiveness and cost-effectiveness analysis, including focused health decision modeling and efficient use of observational data from surveillance systems.
  8. Acceptance of the extended screening intervals requires a change in thinking among women, their clinicians, and insurers. It will be important to study to what degree the guidelines are followed, and reasons for non-compliance, as part of fostering acceptance. In these screening guidelines, one of our underlying principles (see section on Risk-based strategies) is that women with equal risk of CIN3+ should be managed similarly. As part of guideline development, patient risks are considered explicitly (e.g., HPV-negative ASC-US has similar risk as HPV negative, cytology negative, and therefore both groups should be re-screened at the same interval) or else implicitly (when evaluating acceptable screening intervals). In the future, patient characteristics and their cervical cancer risk will change, e.g., HPV vaccination and a history of negative HPV tests. New screening tests will continue to be developed that may have different performance characteristics. These changes will need to be fit into recommended risk thresholds for clinical decision-making. Because of their central place in guidelines, more research on appropriate risk thresholds for referral to colposcopy and on performance of colposcopy in these referral populations is warranted. If feasible, the development of novel risk estimation software to support decision-making would be helpful.


The process used to develop these recommendations represents a transitional stage in guidelines development for the American Cancer Society. Previous guidelines have been developed using a consensus process involving experts in the field along with key stakeholders; although these recommendations were based on evidence, there was not a formalized process for evaluating the evidence and incorporating it into the recommendations. The group developing these guidelines also consisted of experts and stakeholders; the key difference was in the use of the principles of the GRADE guideline development process to more formally evaluate the evidence and incorporate the quality of the evidence into the recommendations. Beginning in 2012, the ACS will be using a new guidelines process, involving a standing group of non-specialists and a formal process for evidence review;157 this change comes in response to Institute of Medicine recommendations for improving guideline transparency, clarity, and reducing potential conflict of interest.

One of the key principles outlined in the IOM report was the need for timely updating of guidelines as new evidence becomes available. Particularly for areas where uncertainty remains, there are large ongoing trials that either were published after our final update for the conference,158 or will publish results in the next 1-2 years. One advantage of using a structured evidence evaluation process such as GRADE is that it facilitates identifying the key research needs that will lead to changes in recommendations; this should help expedite the updating process.

Until the next update, these recommendations reflect the participants’ judgment of the best evidence-based practice for the prevention of cervical cancer morbidity and mortality through currently available screening tests that maximizes protection against cervical cancer while minimizing the potential harms associated with false-positive results and overtreatment.


  • The cervix is the lower part of the uterus or womb. It is located at the top of the vagina. Cancer that starts in the cells of the cervix is called cervical cancer.
  • Changes in the cells of the cervix are responsible for the development of cervical cancer. These cell changes are caused by a virus called the Human Papilloma Virus (HPV).
  • If cervical cancer occurs, there are tests to find it early when it is small and easier to treat. These tests can also find cell changes before they become cancer, so cancer can be prevented.
  • Most deaths from cervical cancer could be prevented if more women had tests to find cervical cancer early.


Most HPV infections go away by themselves and cause no symptoms or pre-cancerous cell changes. However, long-lasting infection with certain types of HPV can lead to changes in the cells of the cervix. These changes, called pre-cancers or high-grade lesions, may progress over many years to cervical cancer if not treated. It often takes 10 years or more for pre-cancer to turn into cancer. The goal of cervical cancer screening is to find pre-cancers so they can be treated before they progress to cancer.


There are 2 types of tests for cervical cancer screening. Both tests are done on samples of cells that a doctor, nurse, or physician assistant removes from your cervix by gently scraping or brushing it with a special instrument.

  1. The Pap test: The test can find early cell changes that are not yet cancer. If cell changes are found, they can be treated, which can prevent them from becoming cervical cancer. This test also can find cervical cancer at a stage that is easy to treat.
  2. The HPV test: This test finds certain HPV infections that can lead to cell changes. These cell changes can progress to cervical cancer if not treated. If cell changes are found, they can be removed from the cervix, which can prevent them from becoming cervical cancer. HPV infections are very common. Most HPV infections go away by themselves and cause no symptoms or cell changes, and in most cases do not go on to cause cancer.

These tests are good, but they are not perfect. They can sometimes report that there are pre-cancerous cells present, when they really are not. These “false positive” results can lead to treatments that are not needed. Pap tests have been done yearly in the past, but now we know that yearly Pap tests are not needed. In fact, if done yearly, they can lead to harm from unneeded treatment of cell changes that would never go on to cause cancer. The new screening recommendations (below) maintain the benefit of testing but lower the risks of unneeded treatment (called “over-treatment”).

Regular cervical cancer screening is not helpful before age 21. Women should start screening at age 21 and be tested every 3 years with a Pap test. At age 30, HPV tests are a useful addition to Pap tests. (They are not useful for screening in younger women.) If a woman tests positive for HPV, she will need further testing to find out if she is likely to have a pre-cancer. If she tests negative on both the Pap and an HPV test, her risk of pre-cancer and cancer is so low that she does not need to be tested again for another 5 years.


  1. Cervical cancer screening should begin at age 21. Women under age 21 should not be screened with either the Pap test or the HPV test.
  2. Women between ages 21 and 29 should have a Pap test every 3 years. HPV testing should not be used in this age group unless it is needed after an abnormal Pap test result.
  3. Women between the ages of 30 and 65 should have a Pap test plus an HPV test (called “co-testing”) every 5 years. This is the preferred approach, but it is also acceptable to continue to have Pap tests alone every 3 years.
  4. Women over age 65 who have had regular screening with normal results should not be screened for cervical cancer. Once screening is stopped, it should not be started again. Women with a history of a serious cervical pre-cancer should continue to be screened for at least 20 years after that diagnosis, even if screening continues past age 65.
  5. A woman who has had a hysterectomy (with removal of the cervix) for reasons not related to cervical cancer and who has no history of cervical cancer or serious pre-cancer should not be screened.
  6. A woman who has been vaccinated against HPV should still follow the screening recommendations for her age group.


There are things you can do to make your Pap test as accurate as possible:

  • Try not to schedule your appointment for a time during your menstrual period.
  • Do not douche for 48 hours (or 2 days) prior to the test.
  • Do not have sex for 48 hours (or 2 days) before the test.
  • Do not use tampons, birth control foams, jellies, or other vaginal creams or vaginal medications for 48 hours (or 2 days) before the test.


Many people confuse pelvic exams with Pap tests. The pelvic exam may be a part of a woman's health care exam, and may be done even if a Pap and HPV test are not done. The pelvic exam alone will not find cervical cancer at an early stage, and cannot find abnormal cells of the cervix. Only Pap tests, or Pap plus HPV tests, can find early cervical cancers or pre-cancers.

Supplementary Material



We would like to thank the following members of the Working Group on the Impact of HPV vaccination on future screening practices: Dr. Mona Saraiya for serving as Co-chair of this working group, Dr. Harrell Chesson for his important modeling contributions, and Dr. Donatus Ekwueme for serving on this group. We thank Dr. Tom Wright and Dr. Ronald Luff for their invaluable contribution to the initial planning of the Guidelines effort; Kim Andrews for her contribution to the initial literature search; Lisa Oliver for her assistance in preparing the manuscript and online supplement; and Debbie McClain for her work with the web-based bulletin board and onsite audience voting system.

Working Group 1: Maureen Killackey, MD (Co-Chair), Memorial Sloan Kettering Cancer Center, New York, NY; Shalini L. Kulasingam, PhD (Co-Chair), University of Minnesota, Minneapolis, MN; Patricia Fontaine, MD, MS, HealthPartners Research Foundation, Bloomington, MN; Richard S. Guido, MD, Magee-Womens Hospital of the UPMC Health System, University of Pittsburgh, Pittsburgh, PA; Abbe Herzig, PhD, Health Ratings Center, Consumer Reports, Yonkers, NY; Herschel W. Lawson, MD, Emory University School of Medicine, Atlanta, GA; Dina R. Mody, MD, The Methodist Hospital, Houston, TX; Jeffrey Waldman, MD, Planned Parenthood, University of California, SanFrancisco, CA; Mark H. Stoler, MD (liaison), University of Virginia Health System, Charlottesville, VA

Working Group 2: Joanna M. Cain, MD, FACOG (Co-Chair), University of Massachusetts School of Medicine, Worcester, MA; Walter Kinney, MD (Co-Chair, liaison), University of California, The Permanente Medical Group, Sacramento, CA; George Birdsong, MD, Emory University School of Medicine, Grady Health System, Atlanta, GA; Wendy R. Brewster, MD, PhD, University of North Carolina, Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC; David Chelmow, MD, Virginia Commonwealth University School of Medicine, Richmond, VA; Valerie J. King, MD, MPH, Oregon Health & Science University, Portland, OR; Robert G. Pretorius, MD, Southern California Permanente Medical Group, Fontana, CA; Cosette M. Wheeler, PhD, University of New Mexico Health Sciences Center, Albuquerque, NM; Barbara A. Winkler, MD, Mount Kisco Medical Group, Mount Kisco, NY

Working Group 3a: Alan G. Waxman, MD, MPH (Chair), University of New Mexico School of Medicine, Albuquerque, NM; Jane J. Kim, PhD, Harvard School of Public Health, Boston, MA; Nicolas Wentzensen, MD, PhD, MS, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD; Philip E. Castle, PhD, MPH (liaison), American Society for Clinical Pathology, Washington, DC

Working Group 3b: David C. Wilbur, MD (Chair), Massachusetts General Hospital, Harvard Medical School, Boston, MA; J. Thomas Cox, MD, University of California, Santa Barbara, CA; Isam A. Eltoum, MD, MBA, University of Alabama at Birmingham, Birmingham, AL; Philip E. Castle, PhD, MPH (liaison), American Society for Clinical Pathology, Washington, DC

Working Group 4: Levi S. Downs, Jr, MD (Co-Chair), Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN; Mark Spitzer, MD (Co-Chair), Weill Medical College of Cornell University, Brookdale University Hospital and Medical Center, Brooklyn, NY; Teresa M. Darragh, MD, University of California, San Francisco, CA; Shirley E. Greening, MS, JD, CFIAC, Jefferson School of Health Professions, Philadelphia, PA; Hope K. Haefner, MD, The University of Michigan Hospitals, Ann Arbor, MI; E.J. Mayeaux, Jr., M.D., DABFM, FAAFP, Louisiana State University Health Sciences Center, Shreveport, LA; Laurie Zephyrin, MD, MPH, MBA, New York-Presbyterian/Columbia, New York, NY; Debbie Saslow, PhD (liaison), American Cancer Society, Atlanta, GA

Working Group 5: Anna-Barbara Moscicki, MD (Co-Chair), University of California, San Francisco, CA; Mona Saraiya, MD, MPH (Co-Chair), Centers for Disease Control and Prevention, Atlanta, GA; Kevin A. Ault, MD, Emory University, Atlanta, GA; Myriam Chevarie-Davis, MD, McGill University, Montreal, Canada; Donatus U. Ekwueme, PhD, MS, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA; Eduardo L. Franco, DrPH, McGill University, Montreal, Canada; Michael A. Gold, MD, Vanderbilt University Medical Center, Nashville, TN; Warner K. Huh, MD; University of Alabama, Birmingham, AL; Diane Solomon, MD (liaison), Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD

Working Group 6: Francisco A. R. Garcia, MD, MPH (Co-Chair); Center of Excellence in Women's Health, University of Arizona, Tucson, AZ; Ann T. Moriarty, MD (Co-Chair), Ameripath, Indianapolis, IN; Terence J. Colgan, MD, Mount Sinai Hospital, Toronto, Ontario, Canada; Mark H. Einstein, MD, MS, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY; Michael R. Henry, MD, Mayo Medical Laboratories, Rochester, MN; L. Stewart Massad, MD, Washington University School of Medicine, St. Louis, MO; Kate Simon, PhD, Microbiology Division, OIVD, CDRH, Food and Drug Administration, Silver Spring, MD; Patti Gravitt, PhD, MS (liaison), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Data Group: Herschel W. Lawson, MD (Co-Chair), Emory University School of Medicine, Atlanta, GA; Debbie Saslow, PhD (Co-Chair), American Cancer Society, Atlanta, GA; Philip E. Castle, PhD, MPH, American Society for Clinical Pathology, Washington, DC; Jack Cuzick, PhD, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London; Patti Gravitt, PhD, MS, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Walter Kinney, MD, University of California, The Permanente Medical Group, Sacramento, CA; Evan R. Myers, MD, MPH, Duke University Medical Center, Durham, NC; Kathleen G. Poole, MALS, American Society for Colposcopy and Cervical Pathology, Hagerstown, MD; Mark Schiffman, MD, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; Diane Solomon, MD, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD; Mark H. Stoler, MD, University of Virginia Health System, Charlottesville, VA

Steering Committee: Diane Solomon, MD (Co-Chair), Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD; Debbie Saslow, PhD (Co-Chair), American Cancer Society, Atlanta, GA; Philip E. Castle, PhD, MPH, American Society for Clinical Pathology, Washington, DC; Carmel J. Cohen, MD, Mount Sinai School of Medicine; Ruttenberg Cancer Center, New York, NY; Mitchell I. Edelson, MD, Hanjani Institute for Gynecologic Oncology, Abington Memorial Hospital, Abington, PA; Francisco A. R. Garcia, MD, MPH, Center of Excellence in Women's Health, University of Arizona, Tucson, AZ; E. Blair Holladay, Ph.D., SCT(ASCP)CM, American Society for Clinical Pathology, Chicago, IL; Walter Kinney, MD, University of California, The Permanente Medical Group, Sacramento, CA; Herschel W. Lawson, MD, Emory University School of Medicine, Atlanta, GA; Kenneth L. Noller, MD, MS, American Board of Obstetrics and Gynecology, Dallas, TX; Edward E. Partridge, MD, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; Kathleen G. Poole, MALS, American Society for Colposcopy and Cervical Pathology, Hagerstown, MD; Carolyn D. Runowicz, MD, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, Mona Saraiya MD, MPH, Centers for Disease Control and Prevention, Atlanta, GA; Robert A. Smith, PhD, American Cancer Society, Atlanta, GA; Alan G. Waxman, MD, MPH, University of New Mexico School of Medicine, Albuquerque, NM

Writing Committee: Philip E. Castle, PhD, MPH (Co-Chair), American Society for Clinical Pathology, Washington, DC; Evan R. Myers, MD, MPH (Co-Chair), Duke University Medical Center, Durham, NC; Debbie Saslow, PhD (Co-Chair), American Cancer Society, Atlanta, GA; David Chelmow, MD, Virginia Commonwealth University School of Medicine, Richmond, VA; Eduardo L. Franco, DrPH, McGill University, Montreal, Canada; Francisco A. R. Garcia, MD, MPH, Center of Excellence in Women's Health, University of Arizona, Tucson, AZ; Abbe Herzig, PhD, Health Ratings Center, Consumer Reports, Yonkers, NY; Jane J. Kim, PhD, Harvard School of Public Health, Boston, MA; Walter Kinney, University of California, The Permanente Medical Group, Sacramento, CA; Herschel W. Lawson, MD, Emory University School of Medicine, Atlanta, GA; Mark Schiffman, MD, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; Mark Spitzer, MD, Weill Medical College of Cornell University, Brookdale University Hospital and Medical Center, Brooklyn, NY; Jeffrey Waldman, MD, Planned Parenthood , University of California, San Francisco, CA; Nicolas Wentzensen, MD, PhD, MS, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD; David C. Wilbur, MD, Massachusetts General Hospital, Harvard Medical School, Boston, MA


Disclaimers: The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention, National Institutes of Health, the U.S. Government, or any medical or academic institutions.

Author Disclosures

The following reported no financial relationships or potential conflicts of interest to disclose: D Saslow, E Partridge, B Holladay, W Kinney, H Lawson, K Noller, E Myers, A Waxman, K Poole, R Smith, P Fontaine, A Herzig, M Killackey, S Kulasingam, D McCoy, W Brewster, J Cain, D Chelmow, V King, R Pretorius, B Winkler, I Eltoum, J Kim, N Wentzensen, L Downs, S Greening, H Haefner, L Zephyrin, M Chevarie-Davis, D Ekwueme, T Colgan, M Henry, S Massad, K Simon.

P Castle receives payment for service on the Data Monitoring and Safety Board for Merck Sharp & Dohme. C Cohen serves as a speaker for Merck, Inc and receives honoraria. M Edelson's spouse is employed and receives salary from Merck, Inc. F Garcia is employed by the University of Arizona, which holds contracts for the performance of research with Roche Pharmaceutical/Roche Molecular, Hologic, Third Wave, MTM, Qiagen, Becton Dickson, and Medispectra/Luma. Dr. Garcia also serves on the speakers’ list for Qiagen and receives honoraria. J Cuzick serves on advisory boards and as an ad-hoc consultant for Qiagen, Roche, Gen-Probe, BD, and Abbott, with research funds provided to his institution from Qiagen, Roche, Gen-Probe, BD, and Abbott. P Gravitt provides service on the scientific advisory board from Qiagen and for which she received honoraria. E Myers received research support for investigations for Gen-Probe, Inc. and from GSK, Inc. He served as a speaker for and received honoraria from Gen-Probe, Inc., and has served as a consultant for Merck, Inc., for which he received an honorarium. M Schiffman holds a research agreement to serve as a Medical Monitor in the NCI vaccine trial through GSK; Dr. Schiffman also receives research support from Qiagen for CareHPV research in Nigeria. D Solomon serves as a Medical Monitor for the National Cancer Institute's HPV Vaccine Trial in Costa Rica: the trial receives vaccine from GlaxoSmithKline. M Stoler received fees for serving as a consultant to Merck Research Labs, Roche, Ventana Medical Systems, BD, Hologic, MTM, and Gen-Probe. D Mody conducted lectures/workshops for CAP, ASCP and ASC for which she received honoraria and/or travel expenses. G Birdsong's employer receives funding for contracted research performed by Dr. Birdsong for BD Diagnostics. C Wheeler is an employee of University of New Mexico, which is contracted by GlaxoSmith Kline, Inc. for its vaccine trials and receives equipment/reagents from Roche Molecular Systems for HPV genotyping. D Wilbur serves on the scientific advisory board for Corista, LLC. T Darragh received Thin Prep supplies for research from Hologic. She serves on an advisory board from OncoHealth and has received stock options as payment. E Mayeaux serves on the speakers’ advisory board for both Merck, Inc., and Pharmaderm and he receives honoraria from both companies for his service. M Spitzer serves as a speaker for both Merck, Inc and Qiagen and receives honoraria. K Ault received clinical research grants from NIAID, GenProbe, Merck, Inc., and Roche and served as a site principal investigator for the research. All grants were provided to his employer, Emory University. E Franco received honorarium as a Study Steering Committee member for GlaxoSmithKline; Dr. Franco serves on the advisory boards of Merck, Inc., Roche, and Gen-Probe and from which he receives honoraria. M Gold received honorarium for serving as a speaker and consultant for Hologic. W Huh serves as a consultant to Roche, Qiagen, Merck, Inc., and Inovio and receives honoraria from all four companies. A-B Moscicki received honorarium for serving as a consultant to an advisory board for Merck, Inc. M Einstein has advised or participated in educational speaking activities, but does not receive an honorarium from any companies. His employer, Montefiore Medical Center, has received payment for his time spent on activities for Merck, Inc., GlaxoSmithKline, Roche, Bristol-Myers Squibb, Hologic, Advaxis, Aura Biosciences, Inovio, Photocure, Neodiagnostix, and PDS Biotechnologies. A Moriarty received honorarium as a speaker for the American Society of Cytopathology.

*HPV refers only to high-risk HPV. Other HPV types are unrelated to cervical cancer and should not be used in cervical cancer screening. Testing for low-risk HPV types has no clinical role in cervical cancer screening or evaluation of women with abnormal cytology.

*The majority of recommendations are “strong.” The strength of each recommendation is noted in the individual working group reports in the online supplement.

*The majority of recommendations are “strong.” The strength of each recommendation is noted in the individual working group reports in the online supplement.

*HPV positive OR LSIL or more severe cytology

**HPV negative AND ASCUS or negative cytology

*Adequate negative prior screening is defined as 3 consecutive negative cytology results or 2 consecutive negative cotests within the 10 years before ceasing screening, with the most recent test occurring within the past 5 years.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


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;52:342–362. [PubMed]
2. Wright TC, Jr., Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical screening tests. J Low Genit Tract Dis. 2007;11:201–222. [PubMed]
3. Gustafsson L, Ponten J, Bergstrom R, Adami HO. International incidence rates of invasive cervical cancer before cytological screening. Int J Cancer. 1997;71:159–165. [PubMed]
4. Gustafsson L, Ponten J, Zack M, Adami HO. International incidence rates of invasive cervical cancer after introduction of cytological screening. Cancer Causes Control. 1997;8:755–763. [PubMed]
5. Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine. 2006;24(Suppl 3):S3/11–25. [PubMed]
6. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. [PubMed]
7. American Cancer Society . Cancer Facts & Figures 2012. American Cancer Society; Atlanta, GA: 2012.
8. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19. [PubMed]
9. de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048–1056. [PubMed]
10. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–527. [PubMed]
11. Wright TC, Jr., Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003;348:489–490. [PubMed]
12. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370:890–907. [PubMed]
13. Mosher WD, Chandra A, Jones J. Advance Data from Vital and Health Statistics. 362. National Center for Health Statistics; Hyattsville, MD: 2005. Sexual behavior and selected health measures: men and women 15-44 years of age, United States, 2002. [PubMed]
14. Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM. A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis. 2007;195:1582–1589. [PubMed]
15. Rodriguez AC, Schiffman M, Herrero R, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst. 2008;100:513–517. [PMC free article] [PubMed]
16. Castle PE, Rodriguez AC, Burk RD, et al. Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study. BMJ. 2009;339:b2569. [PubMed]
17. Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102:1478–1488. [PMC free article] [PubMed]
18. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9:425–434. [PubMed]
19. Castle PE, Fetterman B, Thomas Cox J, et al. The age-specific relationships of abnormal cytology and human papillomavirus DNA results to the risk of cervical precancer and cancer. Obstet Gynecol. 2010;116:76–84. [PubMed]
20. ASCUS-LSIL Triage Study (ALTS) Group Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188:1383–1392. [PubMed]
21. Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003;95:46–52. [PubMed]
22. Dillner J, Rebolj M, Birembaut P, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754. [PubMed]
23. Schiffman M, Glass AG, Wentzensen N, et al. A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study. Cancer Epidemiol Biomarkers Prev. 2011;20:1398–1409. [PMC free article] [PubMed]
24. Freeman H, Wingrove B. Excess Cervical Cancer Mortality: A Marker for Low Access to Health Care in Poor Communities. National Cancer Institute; Rockville, MD: 2005.
25. [January 19, 2012];Division of Cancer Prevention and Control, National Center for Disease Prevention and Health Promotion. 2011
26. Spence AR, Goggin P, Franco EL. Process of care failures in invasive cervical cancer: systematic review and meta-analysis. Prev Med. 2007;45:93–106. [PubMed]
27. Scarinci IC, Garcia FA, Kobetz E, et al. Cervical cancer prevention: new tools and old barriers. Cancer. 2010;116:2531–2542. [PMC free article] [PubMed]
28. Castle PE, Stoler MH, Solomon D, Schiffman M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2007;127:805–815. [PubMed]
29. Castle PE, Schiffman M, Wheeler CM, Solomon D. Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol. 2009;113:18–25. [PMC free article] [PubMed]
30. Trimble CL, Piantadosi S, Gravitt P, et al. Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype. Clin Cancer Res. 2005;11:4717–4723. [PMC free article] [PubMed]
31. Arbyn M, Kyrgiou M, Simoens C, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ. 2008;337:a1284. [PubMed]
32. Sirovich BE, Woloshin S, Schwartz LM. Screening for cervical cancer: will women accept less? Am J Med. 2005;118:151–158. [PubMed]
33. Moscicki AB, Cox JT. Practice improvement in cervical screening and management (PICSM): symposium on management of cervical abnormalities in adolescents and young women. J Low Genit Tract Dis. 2010;14:73–80. [PMC free article] [PubMed]
34. ACOG Practice Bulletin no. 109: Cervical cytology screening. Obstet. Gynecol. 2009;114:1409–1420. [PubMed]
35. Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol. 2008;111:167–177. [PubMed]
36. Siebers AG, Klinkhamer PJ, Grefte JM, et al. Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. JAMA. 2009;302:1757–1764. [PubMed]
37. Cuzick J, Clavel C, Petry KU, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer. 2006;119:1095–1101. [PubMed]
38. Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357:1579–1588. [PubMed]
39. Naucler P, Ryd W, Tornberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;357:1589–1597. [PubMed]
40. Bulkmans NW, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet. 2007;370:1764–1772. [PubMed]
41. Ronco G, Giorgi-Rossi P, Carozzi F, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. 2010;11:249–257. [PubMed]
42. Anttila A, Kotaniemi-Talonen L, Leinonen M, et al. Rate of cervical cancer, severe intraepithelial neoplasia, and adenocarcinoma in situ in primary HPV DNA screening with cytology triage: randomised study within organised screening programme. BMJ. 2010;340:c1804. [PubMed]
43. Castle PE, Stoler MH, Wright TC, Jr., Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol. 2011;12:880–890. [PubMed]
44. Stoler MH. HPV for cervical cancer screening: is the era of the molecular pap smear upon us? J Histochem Cytochem. 2001;49:1197–1198. [PubMed]
45. Castle PE, Wheeler CM, Solomon D, Schiffman M, Peyton CL. Interlaboratory reliability of Hybrid Capture 2. Am J Clin Pathol. 2004;122:238–245. [PubMed]
46. Carozzi FM, Del Mistro A, Confortini M, et al. Reproducibility of HPV DNA Testing by Hybrid Capture 2 in a Screening Setting. Am J Clin. Pathol. 2005;124:716–721. [PubMed]
47. Meijer CJ, Berkhof J, Castle PE, et al. Guidelines for human papillomavirus DNA test requirements for primary cervical cancer screening in women 30 years and older. Int J Cancer. 2009;124:516–520. [PMC free article] [PubMed]
48. Stoler MH, Castle PE, Solomon D, Schiffman M. The expanded use of HPV testing in gynecologic practice per ASCCP-guided management requires the use of well-validated assays. Am J Clin Pathol. 2007;127:335–337. [PubMed]
49. Kinney W, Stoler MH, Castle PE. Special commentary: patient safety and the next generation of HPV DNA tests. Am J Clin Pathol. 2010;134:193–199. [PubMed]
50. Cubie HA, Moore C, Waller M, Moss S. The development of a quality assurance programme for HPV testing within the UK NHS cervical screening LBC/HPV studies. J Clin Virol. 2005;33:287–292. [PubMed]
51. Guyatt GH, Oxman AD, Kunz R, et al. Going from evidence to recommendations. BMJ. 2008;336:1049–1051. [PMC free article] [PubMed]
52. Guyatt GH, Oxman AD, Kunz R, et al. Incorporating considerations of resources use into grading recommendations. BMJ. 2008;336:1170–1173. [PMC free article] [PubMed]
53. Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schunemann HJ. What is “quality of evidence” and why is it important to clinicians? BMJ. 2008;336:995–998. [PMC free article] [PubMed]
54. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–926. [PMC free article] [PubMed]
55. Jaeschke R, Guyatt GH, Dellinger P, et al. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ. 2008;337:a744. [PubMed]
56. Schunemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336:1106–1110. [PMC free article] [PubMed]
57. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1–207. [PubMed]
58. Castle PE, Carreon JD. Practice improvement in cervical screening and management: symposium on management of cervical abnormalities in adolescents and young women. J Low Genit Tract Dis. 2010;14:238–240. [PubMed]
59. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data. BMJ. 2009;339:b2968. [PubMed]
60. 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;57:7–28. [PubMed]
61. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-2):1–24. [PubMed]
62. Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks. Arch Intern Med. 2008;168:1881–1889. [PMC free article] [PubMed]
63. Kulasingam S, Havrilesky L, Ghebre R, Myers E. Screening for Cervical Cancer: A Decision Analysis for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality; Rockville, MD: 2011. AHRQ Publication No.11-05157-EF-1. [PubMed]
64. Sasieni PD, Cuzick J, Lynch-Farmery E. Estimating the efficacy of screening by auditing smear histories of women with and without cervical cancer. The National Co-ordinating Network for Cervical Screening Working Group. Br J Cancer. 1996;73:1001–1005. [PMC free article] [PubMed]
65. Sasieni P, Adams J, Cuzick J. Benefit of cervical screening at different ages: evidence from the UK audit of screening histories. Br J Cancer. 2003;89:88–93. [PMC free article] [PubMed]
66. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007;297:813–819. [PubMed]
67. Peyton CL, Gravitt PE, Hunt WC, et al. Determinants of genital human papillomavirus detection in a US population. J Infect Dis. 2001;183:1554–1564. [PubMed]
68. Canfell K, Barnabas R, Patnick J, Beral V. The predicted effect of changes in cervical screening practice in the UK: results from a modelling study. Br J Cancer. 2004;91:530–536. [PMC free article] [PubMed]
69. Goldie SJ, Kim JJ, Wright TC. Cost-effectiveness of human papillomavirus DNA testing for cervical cancer screening in women aged 30 years or more. Obstet Gynecol. 2004;103:619–631. [PubMed]
70. Kim JJ, Wright TC, Goldie SJ. Cost-effectiveness of human papillomavirus DNA testing in the United Kingdom, The Netherlands, France, and Italy. J Natl Cancer Inst. 2005;97:888–895. [PubMed]
71. Miller MG, Sung HY, Sawaya GF, Kearney KA, Kinney W, Hiatt RA. Screening interval and risk of invasive squamous cell cervical cancer. Obstet Gynecol. 2003;101:29–37. [PubMed]
72. Gram IT, Macaluso M, Stalsberg H. Incidence of cervical intraepithelial neoplasia grade III, and cancer of the cervix uteri following a negative Pap-smear in an opportunistic screening. Acta Obstet Gynecol Scand. 1998;77:228–232. [PubMed]
73. Sawaya GF, McConnell KJ, Kulasingam SL, et al. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med. 2003;349:1501–1509. [PubMed]
74. Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12:663–672. [PMC free article] [PubMed]
75. Cervical screening in Australia 2008–2009. Australian Institute of Health and Welfare; Canberra: 2011.
76. Bray F, Carstensen B, Moller H, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev. 2005;14:2191–2199. [PubMed]
77. Wang SS, Sherman ME, Hildesheim A, Lacey JV, Jr., Devesa S. Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976-2000. Cancer. 2004;100:1035–1044. [PubMed]
78. 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;103:304–309. [PubMed]
79. Saraiya M, Berkowitz Z, Yabroff KR, Wideroff L, Kobrin S, Benard V. Cervical cancer screening with both human papillomavirus and Papanicolaou testing vs Papanicolaou testing alone: what screening intervals are physicians recommending? Arch Intern Med. 2010;17:977–985. [PubMed]
80. Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine. 2006;24(Suppl 3):S3/78–89. [PubMed]
81. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA. 2001;285:1500–1505. [PubMed]
82. Kitchener HC, Almonte M, Thomson C, et al. HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. Lancet Oncol. 2009;10:672–682. [PubMed]
83. Sasieni P, Castle PE, Cuzick J. Further analysis of the ARTISTIC trial. Lancet Oncol. 2009;10:841–842. [PubMed]
84. Vijayaraghavan A, Efrusy MB, Mayrand MH, Santas CC, Goggin P. Cost-effectiveness of high-risk human papillomavirus testing for cervical cancer screening in Quebec, Canada. Can J Public Health. 2010;101:220–225. [PubMed]
85. Koliopoulos G, Arbyn M, Martin-Hirsch P, Kyrgiou M, Prendiville W, Paraskevaidis E. Diagnostic accuracy of human papillomavirus testing in primary cervical screening: a systematic review and meta-analysis of non-randomized studies. Gynecol Oncol. 2007;104:232–246. [PubMed]
86. Mitchell H, Medley G, Gordon I, Giles G. Cervical cytology reported as negative and risk of adenocarcinoma of the cervix: no strong evidence of benefit. Br J Cancer. 1995;71:894–897. [PMC free article] [PubMed]
87. Zappa M, Visioli CB, Ciatto S, Iossa A, Paci E, Sasieni P. Lower protection of cytological screening for adenocarcinomas and shorter protection for younger women: the results of a case-control study in Florence. Br J Cancer. 2004;90:1784–1786. [PMC free article] [PubMed]
88. International Collaboration of Epidemiological Studies of Cervical Cancer Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer. 2007;120:885–891. [PubMed]
89. Castellsague X, Diaz M, de Sanjose S, et al. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst. 2006;98:303–315. [PubMed]
90. ASCUS-LSIL Triage Study (ALTS) Group A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2003;188:1393–1400. [PubMed]
91. Maucort-Boulch D, Plummer M, Castle PE, et al. Predictors of human papillomavirus persistence among women with equivocal or mildly abnormal cytology. Int J Cancer. 2010;126:684–691. [PubMed]
92. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072–1079. [PubMed]
93. Wright TC, Jr., Stoler MH, Sharma A, Zhang G, Behrens C, Wright TL. Evaluation of HPV-16 and HPV-18 Genotyping for the Triage of Women With High-Risk HPV+ Cytology-Negative Results. Am J Clin Pathol. 2011;136:578–586. [PubMed]
94. Chen HC, Schiffman M, Lin CY, et al. Persistence of type-specific Human papillomavirus infection and increased long-term risk of cervical cancer. J Natl Cancer Inst. 2011;103:1387–1396. [PMC free article] [PubMed]
95. Wheeler CM, Hunt WC, Joste NE, Key CR, Quint WG, Castle PE. Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst. 2009;101:475–487. [PMC free article] [PubMed]
96. Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication. Int J Cancer. 2011;128:927–935. [PubMed]
97. Clavel C, Masure M, Bory JP, et al. Hybrid Capture II-based human papillomavirus detection, a sensitive test to detect in routine high-grade cervical lesions: a preliminary study on 1518 women. Br J Cancer. 1999;80(9):1306–1311. [PMC free article] [PubMed]
98. Cuzick J, Szarewski A, Cubie H, et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet. 2003;362:1871–1876. [PubMed]
99. Thrall MJ, Russell DK, Facik MS, et al. High-risk HPV testing in women 30 years or older with negative Papanicolaou tests: initial clinical experience with 18-month follow-up. Am J Clin Pathol. 2010;133:894–898. [PubMed]
100. Kjaer S, Hogdall E, Frederiksen K, et al. The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period. Cancer Res. 2006;66:10630–10636. [PubMed]
101. Rozendaal L, Walboomers JM, van der Linden JC, et al. PCR-based high-risk HPV test in cervical cancer screening gives objective risk assessment of women with cytomorphologically normal cervical smears. Int J Cancer. 1996;68:766–769. [PubMed]
102. Peto J, Gilham C, Deacon J, et al. Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort. Br J Cancer. 2004;91:942–953. [PMC free article] [PubMed]
103. Stoler MH, Wright TC, Jr., Sharma A, Apple R, Gutekunst K, Wright TL. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol. 2011;135:468–475. [PubMed]
104. Safaeian M, Solomon D, Wacholder S, Schiffman M, Castle P. Risk of precancer and follow-up management strategies for women with human papillomavirus-negative atypical squamous cells of undetermined significance. Obstet Gynecol. 2007;109:1325–1331. [PubMed]
105. Castle PE, Solomon D, Schiffman M, Wheeler CM. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities. J Natl Cancer Inst. 2005;97:1066–1071. [PubMed]
106. Castle PE, Fetterman B, Poitras N, Lorey T, Shaber R, Kinney W. Five-year experience of human papillomavirus DNA and Papanicolaou test cotesting. Obstet Gynecol. 2009;113:595–600. [PMC free article] [PubMed]
107. Datta SD, Koutsky LA, Ratelle S, et al. Human papillomavirus infection and cervical cytology in women screened for cervical cancer in the United States, 2003-2005. Ann Intern Med. 2008;148:493–500. [PubMed]
108. Carozzi F, Confortini M, Dalla Palma P, et al. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol. 2008;9:937–945. [PubMed]
109. Leinonen M, Nieminen P, Kotaniemi-Talonen L, et al. Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J Natl Cancer Inst. 2009;101:1612–1623. [PubMed]
110. Kitchener HC, Gilham C, Sargent A, et al. A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: extended follow up in the ARTISTIC trial. Eur J Cancer. 2011;47:864–871. [PubMed]
111. Vesco K, Whitlock E, Eder M, et al. Screening for Cervical Cancer: A systematic evidence review for the US Preventive Services Task Force. Agency for Healthcare Research and Quality; Rockville, MD: May, 2011. Evidence Synthesis Number 86. AHRQ Publication No. 11-05156-EF-1. [PubMed]
112. Sorbye SW, Fismen S, Gutteberg T, Mortensen ES. Triage of women with minor cervical lesions: data suggesting a “test and treat” approach for HPV E6/E7 mRNA testing. PLoS One. 2010;5:e12724. [PMC free article] [PubMed]
113. Copeland G, Datta SD, Spivak G, Garvin AD, Cote ML. Total burden and incidence of in situ and invasive cervical carcinoma in Michigan, 1985-2003. Cancer. 2008;113(10Suppl):2946–2954. [PubMed]
114. Mandelblatt J, Gopaul I, Wistreich M. Gynecological care of elderly women. Another look at Papanicolaou smear testing. JAMA. 1986;256:367–371. [PubMed]
115. Sawaya GF, Kerlikowske K, Lee NC, Gildengorin G, Washington AE. Frequency of cervical smear abnormalities within 3 years of normal cytology. Obstet Gynecol. 2000;96:219–223. [PubMed]
116. Leyden WA, Manos MM, Geiger AM, et al. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. J Natl Cancer Inst. 2005;97:675–683. [PubMed]
117. Melnikow J, McGahan C, Sawaya GF, Ehlen T, Coldman A. Cervical intraepithelial neoplasia outcomes after treatment: long-term follow-up from the British Columbia Cohort Study. J Natl Cancer Inst. 2009;101:721–728. [PMC free article] [PubMed]
118. Soutter WP, Sasieni P, Panoskaltsis T. Long-term risk of invasive cervical cancer after treatment of squamous cervical intraepithelial neoplasia. Int J Cancer. 2006;118:2048–2055. [PubMed]
119. Rodriguez AC, Schiffman M, Herrero R, et al. Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection. J Natl Cancer Inst. 2010;102:315–324. [PMC free article] [PubMed]
120. Wu X, Matanoski G, Chen VW, et al. Descriptive epidemiology of vaginal cancer incidence and survival by race, ethnicity, and age in the United States. Cancer. 2008;113(10 Suppl):2873–2882. [PubMed]
121. Pearce KF, Haefner HK, Sarwar SF, Nolan TE. Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gynecologic disease. N Engl J Med. 1996;335:1559–1562. [PubMed]
122. Piscitelli JT, Bastian LA, Wilkes A, Simel DL. Cytologic screening after hysterectomy for benign disease. Am J Obstet Gynecol. 1995;173:424–430. [PubMed]
123. Videlefsky A, Grossl N, Denniston M, Sehgal R, Lane JM, Goodenough G. Routine vaginal cuff smear testing in post-hysterectomy patients with benign uterine conditions: when is it indicated? J Am Board Fam Pract. 2000;13:233–238. [PubMed]
124. Fox J, Remington P, Layde P, Klein G. The effect of hysterectomy on the risk of an abnormal screening Papanicolaou test result. Am.J Obstet Gynecol. 1999;180:1104–1109. [PubMed]
125. Wiener JJ, Sweetnam PM, Jones JM. Long term follow up of women after hysterectomy with a history of pre-invasive cancer of the cervix. Br J Obstet Gynaecol. 1992;99:907–910. [PubMed]
126. National and state vaccination coverage among adolescents aged 13 through 17 years--United States, 2010. MMWR. Morb Mortal Wkly Rep. 2011;60:1117–1123. [PubMed]
127. Future II Study Group Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356:1915–1927. [PubMed]
128. Future II Study Group Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection. J Infect Dis. 2007;196:1438–1446. [PubMed]
129. Ault KA. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet. 2007;369:1861–1868. [PubMed]
130. Brown DR, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. J Infect Dis. 2009;199:926–935. [PubMed]
131. Munoz N, Kjaer SK, Sigurdsson K, et al. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst. 2010;102:325–339. [PubMed]
132. Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009;374:301–314. [PubMed]
133. Romanowski B, de Borba PC, Naud PS, et al. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet. 2009;374:1975–1985. [PubMed]
134. Gauthier A, Martin-Escudero V, Moore L, et al. Long-term clinical impact of introducing a human papillomavirus 16/18 AS04 adjuvant cervical cancer vaccine in Spain. Eur J Public Health. 2008;18:674–680. [PubMed]
135. Brisson M, Van de Velde N, De Wals P, Boily MC. The potential cost-effectiveness of prophylactic human papillomavirus vaccines in Canada. Vaccine. 2007;25:5399–5408. [PubMed]
136. Cuzick J, Castanon A, Sasieni P. Predicted impact of vaccination against human papillomavirus 16/18 on cancer incidence and cervical abnormalities in women aged 20-29 in the UK. Br J Cancer. 2010;102:933–939. [PMC free article] [PubMed]
137. Chesson HW, Ekwueme DU, Saraiya M, Dunne EF, Markowitz LE. The cost-effectiveness of male HPV vaccination in the United States. Vaccine. 2011;29:8443–8450. [PubMed]
138. Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis. 2007;13:28–41. [PMC free article] [PubMed]
139. Brisson M, Van de Velde N, Boily MC. Economic evaluation of human papillomavirus vaccination in developed countries. Public Health Genomics. 2009;12:343–351. [PubMed]
140. Sigurdsson K, Sigvaldason H, Gudmundsdottir T, Sigurdsson R, Briem H. The efficacy of HPV 16/18 vaccines on sexually active 18-23 year old women and the impact of HPV vaccination on organized cervical cancer screening. Acta Obstet Gynecol Scand. 2009;88:27–35. [PubMed]
141. Goldie SJ, Kohli M, Grima D, et al. Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine. J Natl Cancer Inst. 2004;96:604–615. [PubMed]
142. Kulasingam SL, Myers ER. Potential health and economic impact of adding a human papillomavirus vaccine to screening programs. JAMA. 2003;290:781–789. [PubMed]
143. Coupe VM, Berkhof J, Bulkmans NW, Snijders PJ, Meijer CJ. Age-dependent prevalence of 14 high-risk HPV types in the Netherlands: implications for prophylactic vaccination and screening. Br J Cancer. 2008;98:646–651. [PMC free article] [PubMed]
144. Diaz M, de Sanjose S, Ortendahl J, et al. Cost-effectiveness of human papillomavirus vaccination and screening in Spain. Eur J Cancer. 2010;46:2973–2985. [PubMed]
145. Kulasingam S, Connelly L, Conway E, et al. A cost-effectiveness analysis of adding a human papillomavirus vaccine to the Australian National Cervical Cancer Screening Program. Sex Health. 2007;4:165–175. [PubMed]
146. Kulasingam SL, Pagliusi S, Myers E. Potential effects of decreased cervical cancer screening participation after HPV vaccination: an example from the U.S. Vaccine. 2007;25:8110–8113. [PubMed]
147. Thiry N, De Laet C, Hulstaert F, Neyt M, Huybrechts M, Cleemput I. Cost-effectiveness of human papillomavirus vaccination in Belgium: do not forget about cervical cancer screening. Int J Technol Assess Health Care. 2009;25:161–170. [PubMed]
148. Goldhaber-Fiebert JD, Stout NK, Salomon JA, Kuntz KM, Goldie SJ. Cost-effectiveness of cervical cancer screening with human papillomavirus DNA testing and HPV-16,18 vaccination. J Natl Cancer Inst. 2008;100:308–320. [PMC free article] [PubMed]
149. Franco EL, Cuzick J, Hildesheim A, de Sanjose S. Chapter 20: Issues in planning cervical cancer screening in the era of HPV vaccination. Vaccine. 2006;24(Suppl 3):S3/171–177. [PubMed]
150. Franco EL, Mahmud SM, Tota J, Ferenczy A, Coutlee F. The expected impact of HPV vaccination on the accuracy of cervical cancer screening: the need for a paradigm change. Arch Med Res. 2009;40:478–485. [PubMed]
151. Coupe VM, van Ginkel J, de Melker HE, Snijders PJ, Meijer CJ, Berkhof J. HPV16/18 vaccination to prevent cervical cancer in The Netherlands: model-based cost-effectiveness. Int J Cancer. 2009;124:970–978. [PubMed]
152. [01/15/2012];New Mexico Human Papillomavirus (HPV) Pap Registry (NMHPVPR) and HOPE Clinic (House of Prevention Epidemiology) 2008
153. Hariri S, Unger ER, Powell SE, et al. The HPV vaccine impact monitoring project (HPV-IMPACT): assessing early evidence of vaccination impact on HPV-associated cervical cancer precursor lesions. Cancer Causes Control. 2012;23:281–288. [PubMed]
154. Performance Monitoring for Cervical Cancer Screening Programs in Canada: Report from the Screening Performance Indicators Working Group, Cervical Cancer Prevention and Control Network. Public Health Agency of Canada; 2009.
155. Belinson JL, Du H, Yang B, et al. Improved sensitivity of vaginal self-collection and high-risk human papillomavirus testing. Int J Cancer. 2011 May 31; [Epub ahead of print] [PubMed]
156. Castle PE, Rausa A, Walls T, et al. Comparative community outreach to increase cervical cancer screening in the Mississippi Delta. Prev Med. 2011;52:452–455. [PMC free article] [PubMed]
157. Brawley O, Byers T, Chen A, et al. New American Cancer Society process for creating trustworthy cancer screening guidelines. JAMA. 2011;306:2495–2499. [PubMed]
158. Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 2012;13:78–88. [PubMed]