INTRODUCTION — Cervical cancer is common among women worldwide. Most cases occur in resource-limited countries [1]. In resource-rich countries, the decreases in cervical cancer incidence and mortality rates are related to the availability of primary prevention with human papillomavirus (HPV) vaccination and secondary prevention with screening.
Screening can detect precursors and early-stage disease for both types of cervical cancer: squamous cell carcinoma and adenocarcinoma. Treatment of precursors and can prevent the development of invasive cervical cancer and reduce cervical cancer mortality.
The available methods for cervical cancer screening HPV testing, and co-testing (with both cytology and HPV). Infection with oncogenic types of HPV (ie, high-risk HPV [hrHPV]) and persistence of hrHPV infection are the most important determinants of progression to cervical cancer [2-6].
Recommendations for screening, as well as specific screening strategies, balance the benefits from early detection of treatable lesions and reduction in incidence and mortality of cervical cancer with potential risks for false positives, unnecessary procedures, and other harms. Potential benefits and risks vary with age, medical history, and risk factors. However, there is debate about whom to screen, which testing methods are preferable (Pap test, HPV testing, or both), and how often to screen [7,8].
This topic will discuss screening in resource-rich settings, including appropriate ages to initiate and discontinue screening, frequency of screening, and screening methods.
Techniques for performing screening tests, interpreting test results, screening patients who are HIV positive, screening in resource-limited settings, and information about invasive cervical cancer are discussed in detail separately.
●(See "Screening for cervical cancer in resource-limited settings".)
●(See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing".)
●(See "Cervical cancer screening: The cytology and human papillomavirus report".)
●(See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states".)
●(See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)
●(Related Pathway(s): Cervical cancer screening in resource-rich settings: Screening asymptomatic patients who are at average risk for cervical cancer.)
●(Related Pathway(s): Cervical cancer screening: Follow-up of a Pap test reported as "unsatisfactory".)
●(Related Pathway(s): Cervical cancer screening: Follow-up of a Pap test showing partially obscuring blood or inflammation.)
●(Related Pathway(s): Cervical cancer screening: Follow-up of a Pap test with an absent endocervical transformation zone.)
RATIONALE FOR SCREENING AND POTENTIAL HARMS — The benefits of cervical cancer screening in decreasing the incidence, morbidity, and mortality of cervical cancer need to be weighed against the risks of false-positive screening results and subsequent unnecessary procedures.
●Mortality reduction – Multiple observational studies have shown reductions in cervical cancer mortality after national cervical cancer screening with systematic follow-up is implemented [9-19]. In the United States, mortality due to cervical cancer has continued to decrease since the 1970s (figure 1). Similar trends have been described in other resource-rich countries (figure 2) [20,21].
Additionally, systematic reviews and meta-analyses of observational studies and at least one randomized trial provide evidence that screening leads to a decrease in mortality due to cervical cancer [19,22,23]. However, the absolute risk reduction for the individual patient is small. Although no randomized trials have been conducted in resource-rich settings, in a randomized trial of over 130,000 patients in rural India, a single lifetime screen with human papillomavirus (HPV) testing reduced cervical cancer mortality by 50 percent compared with no screening (12.7 versus 25.8 per 100,000 person-years, hazard ratio [HR] 0.52, 95% CI 0.33-0.83) [23]. (See "Screening for cervical cancer in resource-limited settings", section on 'Efficacy'.)
●Cervical disease detection and incidence – Systematic reviews, meta-analyses, and observational studies consistently show that screening is associated with a decreased incidence of cervical cancer (figure 3) [19,22]. In the randomized trial from India discussed above, a single lifetime screen with HPV testing reduced the number of advanced cervical cancers detected by over 50 percent when compared with no screening (15 per 100,000 person-years with screening versus 32 per 100,000 person-years without screening, HR 0.47, 95% CI 0.32-0.69) [23]. (See "Screening for cervical cancer in resource-limited settings", section on 'Efficacy'.)
The United States adopted Pap test screening in the 1950s, and by the mid-1980s cervical cancer incidence decreased by 70 percent [24].
Observational studies also show that screening is associated with higher cure rates for invasive cervical cancer [25,26]. In a meta-analysis of 12 case-control studies, Pap testing was associated with a decreased risk of subsequent invasive cervical cancer (odds ratio [OR] 0.35, 95% CI 0.30-0.41) [19]. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Incidence and mortality'.)
●Potential harms
•Patient discomfort and psychosocial consequences – The discomforts and inconveniences of Pap test screening are apparent and increase with the frequency and duration of screening; this may be particularly relevant for adolescents and older adults. Screening also has psychosocial consequences. High levels of anxiety are associated with colposcopy referral for patients with high- or low-grade abnormalities as well as with surveillance for mild test abnormalities [27-29]. Anxiety is heightened in patients with a positive HPV test and in younger patients [28,30].
•Rising health care costs – The costs of cervical cancer screening include both monetary and opportunity costs. Monetary costs relate to screening and to procedures that result from screening. Opportunity costs relate to the possibility of overlooking more immediate health care issues during medical visits in which cervical cancer screening is discussed and performed.
•False-positive results – Both HPV testing and Pap testing are associated with false-positive results that lead to subsequent testing, follow-up examinations, and downstream interventions. This is discussed in more detail elsewhere, according to the method of screening performed. (See 'Relative risks and benefits of each method' below.)
•Risks of treatment on pregnancy outcomes – The harmful effects of treatment (ie, ablation, excision) on pregnancy outcomes include increased risk of second-trimester pregnancy loss, preterm premature rupture of membranes, preterm delivery, and perinatal mortality. This is discussed in more detail separately. (See "Reproductive effects of cervical excisional and ablative procedures".)
SCREENING METHODS — Available screening tests include Pap testing and high-risk human papillomavirus (hrHPV) testing, either alone or in combination with a Pap test. Screening refers to testing of asymptomatic patients whose prior cervical cancer screening tests were all normal. (See 'Defining average versus high risk for cervical cancer' below.)
Patients who have had prior abnormal results require active surveillance, and the recommended options and frequency differ based on the patient's previous results and underlying risk for developing cervical cancer. Only a minority of such patients will return to routine, age-based cervical cancer screening. (See 'Surveillance in patients with abnormal screening' below.)
Types of screening and frequency — The various screening methods are as follows:
●Pap testing alone – In Pap testing alone, cervical cytology is performed to assess for cellular abnormalities; the suggested screening interval for Pap testing alone is every three years.
The incidence of high-grade cytologic abnormalities is very low within three years of a normal Pap test (10 to 66 per 10,000) [31], and modeling studies have suggested cancer detection rates to be similar with annual or triennial screening, while doubling or tripling the number of downstream interventions, including colposcopies with annual screening [32-34]. A synthesis of several studies in patients aged 21 to 29 years predicted that the lifetime risk of death due to cervical cancer would be similar: 0.03, 0.05, and 0.05 per 1000 patients with screening annually, every two years, and every three years, respectively [35].
●Primary HPV testing – In primary HPV testing, an HPV test is performed alone, without cervical cytology; the suggested screening interval for primary HPV testing is every five years. Only certain HPV tests are approved by the US Food and Drug Administration (FDA) for primary hrHPV testing (ie, Cobas, BD Onclarity) (table 1). Many high-income countries (eg, Australia, Netherlands, United Kingdom) have transitioned to nationwide screening with this method.
FDA-approved tests for HPV genotyping have the ability to perform genotyping for HPV types 16 and 18. This is discussed in more detail elsewhere. (See 'Follow-up of abnormal results' below.)
Self-collection of HPV samples may be useful for patients with barriers to screening (eg, patients with limited access to health care, gender minority patients, patients with a history of abuse/trauma) [36]. Though not approved by the FDA, self-sampling devices are available in the Netherlands and Australia [37,38] and in some resource-limited settings. This is discussed in more detail elsewhere. (See "Screening for cervical cancer in resource-limited settings", section on 'Self-collected samples' and "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing", section on 'Cervical testing'.)
●Co-testing – In co-testing, both a Pap test and HPV test are collected, and results are provided concurrently; the suggested screening interval for co-testing is every five years. There are many tests that are approved by the FDA for co-testing (table 1). However, co-testing results in a doubling of tests being performed (Pap and HPV testing) and therefore may not be sustainable in all settings.
A United States Preventive Services Task Force (USPSTF) review of four randomized trials found a similar number of detected cancer cases with co-testing at a frequency of every five years compared with Pap testing alone every three years, although differences in study methodology (colposcopy referral methods and thresholds) made interpretation complex [39].
●Reflex HPV testing (also called triage HPV testing) – Reflex HPV testing is performed when a cervical cytology result returns positive for atypical squamous cells of undetermined significance (ASC-US); the HPV test is automatically performed on the sample that was collected for the cervical cytology.
●Single lifetime screening – World Health Organization guidelines state that screening even once in a lifetime is beneficial, and intervals may depend on available resources and infrastructure; decisions about the target ages, type, and frequency of screening depend on local burden of disease, costs, and infrastructure and are left to country-level decision makers [40]. This strategy may be particularly relevant in resource-limited settings and is discussed in detail elsewhere. (See "Screening for cervical cancer in resource-limited settings", section on 'Screening age and frequency'.)
Relative risks and benefits of each method
●Mortality reduction – There are no randomized trials comparing mortality rates among the various screening strategies in the United States. However, a microsimulation model for the USPSTF found that screening strategies that included HPV testing (ie, primary HPV testing or co-testing [Pap test with HPV testing]) were associated with fewer cervical cancer deaths compared with screening strategies that included Pap testing (ie, Pap testing alone or reflex HPV testing). In this model, cervical cancer deaths associated with screening that included HPV testing ranged from 0.23 to 0.29 deaths per 1000 patients versus 0.30 to 0.76 deaths per 1000 patients with screening that included Pap testing [7].
●Cervical disease detection and incidence – Primary HPV testing has been shown in several studies to be a very sensitive test for identifying potential precursors of cervical cancer during an initial round of screening [22,41-44]. In a systematic review including randomized trials and cohort studies for the USPSTF, primary HPV screening among patients aged 25 to 65 years was associated with increased detection of cervical intraepithelial neoplasia (CIN) 3+ compared with Pap testing alone in the initial round of screening; despite these findings, in other trials included in this review, co-testing did not increase the initial CIN3+ detection rate compared with Pap testing alone [45].
However, numerous observational studies have suggested that both co-testing and primary HPV testing improves early detection of CIN 3+. Although some studies suggest that co-testing or primary HPV testing may actually decrease the incidence of cervical cancer (by allowing for precursor lesions to be identified and treated) [46-54], other data suggest that the cumulative incidence is similar to Pap testing alone [42,55]. Examples of such studies include:
•At 48 months, the large HPV FOCAL Study found a lower incidence of CIN 3+ associated with initial primary HPV testing (incidence ratio [IR] 2.3/1000, 95% CI 1.5-3.5) than with initial Pap testing (IR 5.5/1000, 95% CI 4.2-7.2; risk ratio 0.42, 95% CI 0.25-0.69) [53]. The relative risk of CIN 2+ was also lower with primary HPV testing than with initial Pap testing.
•Similarly, in a large European meta-analysis, screening with HPV testing (largely as co-testing) was associated with a lower rate of incident cervical cancer compared with Pap testing at a median of 6.5 years of follow-up (rate ratio 0.60, 95% CI 0.40-0.89) [54].
•By contrast, in the Population-Based Screening Study Amsterdam, which compared initial testing with either co-testing or with Pap alone, followed by rescreening at five years with co-testing, those initially screened with co-testing had less CIN 3+ (88 versus 122 cases, relative risk [RR] 0.73, 95% CI 0.55-0.96) and less cervical cancer (4 versus 14 cancers, RR 0.29, 95% CI 0.10-0.87) [55]. However, the cumulative detection of CIN 3+ and cervical cancer over the two testing rounds did not differ between the two groups.
RNA-based methods are not approved for primary HPV testing. However, they may be as effective as DNA-based methods in detecting cervical disease. In a meta-analysis evaluating the accuracy of different screening methods for detecting CIN 2+ in clinician-obtained samples, testing with RNA compared with DNA-based assays had similar sensitivity and specificity, though internal controls for specimen adequacy were not available for most assays [56]. Sensitivity was lower for self-collected samples (0.84, 95% CI 0.74–0.96). Further studies evaluating RNA-based methods for primary HPV testing are needed.
●False-positive and colposcopy rates – Studies have found that primary HPV testing is associated with an increased number of positive results compared with cervical cytology [22,38,41,45,57-60]. However, some HPV infections identified in screening can lead to unnecessary procedures (eg, colposcopy, biopsy, treatment), particularly in younger patients in whom HPV infection often regresses. With appropriate quality colposcopy, the efficiency of screening improves.
For example, in a randomized trial of over 100,000 patients, the proportion of patients ages 30 to 34 years referred for colposcopy was higher after HPV testing compared with cytology alone (approximately 2.5 versus 1.8 percent, respectively) [60]. In patients ages 25 to 29 years, increased rates of intensified follow-up were also noted after HPV testing compared with cytology alone (22 versus 10 percent). Similarly, in a USPSTF systematic review comparing HPV testing with cytology alone, during first-round screening, there was an increase in false-positive rates with primary HPV testing (6.6 to 7.4 percent) compared with cytology alone (2.6 to 6.5 percent) [45].
In modeling studies of screening at various time intervals, decreasing the frequency of screening is associated with a decrease in colposcopy rates. In one modeling study of patients age >30 years, a combination of Pap and HPV testing every five years was as effective as screening with Pap testing alone every three years [39]. In another modeling study of patients age 40 years, co-testing every five years was associated with decreased colposcopies compared with co-testing every three years, with only a minimal change in lifetime cancer risk (0.39 versus 0.61 percent) [61]. However, some argue that the increased risk for cancer with less frequent screening is not minimal and that annual Pap testing should be the gold standard used for comparison in modeling studies [62].
DEFINING AVERAGE VERSUS HIGH RISK FOR CERVICAL CANCER — Cervical cancer screening recommendations differ for patients at average and high risk of developing cervical cancer. These two populations are defined as follows.
●Average risk – Screening recommendations for patients who are at average risk for cervical cancer apply to patients with a cervix who have all the following:
•Asymptomatic (ie, no signs or symptoms of cervical disease); symptomatic patients are discussed elsewhere (see 'Symptomatic patients' below).
•Immunocompetent.
•Have had all normal cervical cancer screening results in the past. The only situations in which patients are at sufficiently low risk to return to age-based routine screening are the following [63]:
-Patients age <25 years with human papillomavirus (HPV)-negative atypical squamous cells of undetermined significance (ASC-US (algorithm 1)).
-Patients age <25 years with low-grade squamous intraepithelial lesions (LSIL) or HPV-positive ASC-US, followed by two consecutive negative cytology results (algorithm 1).
-Patients age >25 years with LSIL followed by colposcopy in which CIN 2 or worse was not found and followed by three consecutive negative co-testing results.
●High risk – Screening recommendations for patients who are at high risk for cervical cancer apply to patients with a history of HIV or immunosuppression. These patients may need more frequent testing and are described in detail below. (See 'Screening in higher risk patients' below.)
Patients with a history of abnormal cervical cancer screening are managed with active surveillance, not screening; this is described in detail below. (See 'Surveillance in patients with abnormal screening' below.)
SCREENING IN AVERAGE-RISK PATIENTS — Cervical cancer screening recommendations in average-risk patients is generally based on the patient's age.
Age <21 — We suggest not screening for cervical cancer in asymptomatic, immunocompetent patients, <21 years, regardless of the age of initiation of sexual activity [64].
Observational studies suggest that the potential harms outweigh the potential benefits in this age group, due to their low incidence of cervical cancer [65]. The age-adjusted incidence of cervical cancer in patients ages 15 to <20 years in the United States is 0.1 per 100,000 (figure 4) [66]. Adolescents are also more likely to spontaneously clear human papillomavirus (HPV) infection and associated abnormalities. While rates of atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL) are consistently higher in adolescent patients than in adults, 90 to 95 percent of low-grade lesions in adolescent patients, as well as many high-grade lesions, regress spontaneously [67-71].
Age 21 to 29 — In asymptomatic, immunocompetent patients, the age at which to initiate cervical cancer screening and which testing method (eg, Pap smear, primary HPV testing) is preferable is unclear and recommendations from expert groups vary.
In our practice, we initiate cervical cancer screening at the age of 21 with cervical cytology every three years. Our approach is consistent with the 2018 United States Preventive Services Task Force (USPSTF) guidelines. Another acceptable approach is to initiate screening at age 25 with primary HPV testing every five years (consistent with the 2020 American Cancer Society [ACS] guidelines). However, the two tests approved by the US Food and Drug Administration (FDA) for primary HPV DNA testing (ie, Cobas, BD Onclarity) may not be available in some settings.
Given available data, our approach applies to patients irrespective of HPV vaccination status. As primary HPV testing becomes more widely available, and as the rate of HPV vaccination increases, our preference for testing method and age of initiation may change. (See 'Recipients of HPV vaccine' below.)
As mentioned above, recommendations from major expert groups differ.
●The USPSTF recommends initiating screening at the age of 21 with cervical cytology every three years through the age of 29 [8].
Rational for these recommendations include the following:
•Prior to the age of 21, cervical cancer is rare (0.1 percent of incident cancers are diagnosed in this age group) [8]. Starting at the age of 21, the benefits of cervical cancer screening outweigh the potential harms (ie, increased number of colposcopies and treatment procedures).
•Cytology, rather than HPV testing (either primary or co-testing), is preferred (for patients ages 21 through 29 years) based on a meta-analysis of randomized trials and observational studies that demonstrated higher false-positive rates with HPV testing because of the higher rates of transient infection in this age group [45].
•The USPSTF did not use HPV vaccination to adjust screening recommendations given the lack of data on the long-term efficacy and suboptimal rates of vaccination in the United States; in one study, the percentage of patients in the United States who received at least one dose was only 54 percent [72].
●The ACS recommends initiating screening at the age of 25 with FDA-approved primary HPV testing (ie, Cobas, BD Onclarity) every five years [64].
Rationale for these recommendations include the following:
•Between the ages of 20 and 24, the incidence of cervical cancer in the United States is low (0.8 percent of incident cancers are diagnosed in this age group) [64]. Therefore, the age at which cervical cancer screening is initiated is raised from 21 to 25 years by the ACS recommendations; observational studies show patients ages 20 to 24 spontaneously clear HPV infection and its associated abnormalities, and screening these patients does not substantially reduce their risk of cervical cancer [65,73-75].
•Primary HPV testing, rather than cytology, is preferred based on randomized trials which demonstrate HPV-based testing is more specific than cervical cytology alone [54,57]. This may be particularly important in HPV-vaccinated patients, as described below. (See 'Recipients of HPV vaccine' below.)
•The ACS used HPV vaccination as a factor for raising the age of initial screening, citing an increased uptake of HPV vaccination rates; in one 2018 study, 70 percent of female adolescents (ages 13 to 17) in the United States received at least one dose of the vaccine [76].
Guidelines from the major expert groups are summarized in the table (table 2) and in the society guideline links section [6,8,35,39,77,78]. (See "Society guideline links: Cervical cancer screening, prevention, and management".)
Age 30 to 65 — We recommend continuing cervical cancer screening in all asymptomatic, immunocompetent patients with a cervix between the ages of 30 and 65.
Any of the following strategies are acceptable for patients with all normal results in this age group [8,64]:
●Primary HPV testing (with an FDA-approved test) every five years; or
●Co-testing (Pap and HPV testing) every five years; or
●Pap test alone every three years
Each of these screening strategies is described elsewhere, and the approach is the same irrespective of HPV vaccination status. (See 'Types of screening and frequency' above and 'Recipients of HPV vaccine' below.)
The 2018 USPSTF recommendations do not prefer one method over another, while the 2020 ACS recommendations prefer primary HPV testing over the other strategies [8,64]. Other specialty society guidelines specify an interval of no sooner than every three years for primary HPV testing (table 2) [79].
Patients with abnormal, unsatisfactory, or satisfactory but limited findings require further follow-up. (See 'Follow-up of abnormal results' below.)
Patients should be screened even if they report sexual abstinence. Patients may have a variety of reasons for not disclosing prior sexual activity, including social, religious, or cultural norms or expectations regarding modesty, maintaining sexual abstinence, and shame as well as reluctance to acknowledge prior sexual abuse or rape [80]. Patients who have been sexually abused or raped are often reluctant to acknowledge this history, and abuse may underlie the decision to abstain from and not engage in subsequent sexual activity. Furthermore, HPV can be transmitted in skin-to-skin genital touching, which patients may not consider as sexual activity.
Age >65 years — The decision to discontinue screening in average-risk patients depends on the patient's prior results, life expectancy, and preferences in a shared decision-making discussion.
If adequate prior and all normal screening — We suggest discontinuing screening in average-risk patients over the age of 65 who have adequate prior screening (defined below) and no factors that warrant extended screening. While data are limited and potential harms of screening need to be considered (eg, false positives), some clinicians continue to offer screening through age 74 years for those with a life expectancy of at least 10 years. In addition, cervical cancer screening can be discontinued early for patients with a limited life expectancy.
Discontinuing screening is predicated upon meeting both of the following criteria:
●Having no history of cervical intraepithelial neoplasia (CIN) grade 2+ for the past 25 years (see 'Surveillance in patients with abnormal screening' below) and
●Having adequate prior screening, as defined by [64]:
•Two consecutive negative primary HPV tests within the past 10 years, with the most recent test within the previous five years or
•Two consecutive negative co-tests (Pap and HPV testing) within the past 10 years, with the most recent test within the previous five years or
•Three consecutive negative Pap tests within the past 10 years, with the most recent test within the previous three years
If the results of screening within the prior 10 years are not known, then prior screening is not considered adequate.
In the United States, guideline-issuing organizations recommend discontinuing screening after age 65 for patients who meet the above criteria (table 2) but that screening may be continued in patients without serious health issues or a limited life expectancy [63,81]. However, guidelines from some countries use an older age at which to stop screening. For example, in Australia, which has the lowest cervical cancer mortality rate in the world, guidelines advise discontinuing screening after age 74 years [82]. In addition, absent a nationwide integrated medical record or decades of care in one health system, it can be very difficult to know if a person has a history of abnormal testing. (See 'If inadequate prior screening or unknown screening' below.)
Our rationale for discontinuing screening at age 65 years in patients of average risk with adequate prior screening is that Pap test abnormalities among previously screened older patients may have poor positive predictive value (PPV) for significant pathology, while causing a need for follow-up testing [83,84]. Furthermore, high-grade lesions are rare among older patients who have been previously screened. A study in pre- and postmenopausal patients who had Pap tests showing "atypical squamous cells: cannot exclude high-grade lesion (ASC-H)" found high-grade histology in 22 percent of premenopausal patients, compared with 6 percent of postmenopausal patients [85].
However, we recognize that data about stopping age for cervical cancer screening are limited. A 2013 systematic review of 24 studies found no conclusive evidence to support a specific age to stop cervical cancer screening, as none of the reviewed studies looked specifically at this question [19]. Observational studies suggest that continued screening in older patients may be efficacious [86-91], although these studies have limitations. In a study that corrected for the estimated prevalence of hysterectomy, cervical cancer incidence in the United States peaked at ages 65 to 69 years (corrected rate of 27.4 cervical cancer cases per 100,000 women versus uncorrected rate of 14.8 per 100,000 women) [89]. In one study based on cancer registry information, almost 24 percent of cervical cancers were diagnosed in patients age ≥65 years [92]. These older patients were more likely to have higher-stage disease (stage II or greater) than younger patients (72 versus 44 percent). In other studies, close to 20 percent of cervical cancers occurred in patients ages 65 years and above [89,90]; invasive cervical cancer incidence did not decline with increasing age until at least age 85 years [91]. The primary limitation among these studies is that it is uncertain whether the patients who developed cervical cancer at an older age had been adequately screened through age 65 years; thus, the studies' implications are not necessarily applicable to patients over age 65 years whose prior screening was adequate and negative.
If inadequate prior screening or unknown screening — Patients over the age of 65 who have not had adequate prior screening or have an unknown screening history should continue with cervical cancer screening. For such patients, we perform co-testing annually for three years before spreading out the interval to every five years. Some clinicians continue screening such patients up to approximately age 80 years. The decision about how long to continue screening should be predicated on a life expectancy of at least 10 years and an informed decision-making discussion with the patient. (See 'If adequate prior and all normal screening' above.)
A substantial number of cervical cancers occur in patients >65 years (figure 4), many of whom have had inadequate prior screening. In a retrospective analysis of United States survey data, 18 percent of patients aged 61 to 65 years had not had a Pap test within the preceding five years (including those who had never had a Pap test); thus, these patients do not meet criteria for stopping screening at age 65 [91]. Screening therefore needs to continue (or be initiated) in these patients to prevent new cervical cancer cases and deaths.
SCREENING IN HIGHER RISK PATIENTS — Patients with HIV, immunosuppression, and in utero exposure to diethylstilbestrol (DES) are at an increased risk for developing cervical cancer; recommendations for what ages to initiate and discontinue screening and which screening method to choose may differ from the average-risk patient.
HIV — Patients with HIV are more likely to have persistent human papillomavirus (HPV) infection and increased rates of high-grade cervical dysplasia, and they are at increased risk for the development of cervical cancer. Screening for patients infected with HIV is described separately. (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states".)
Immunosuppressive therapy — Patients without HIV who are on long-term immunosuppressive therapy (eg, solid organ transplant, allogeneic hematopoietic stem cell transplant, systemic lupus erythematous, and those with inflammatory bowel disease or rheumatologic disease requiring current immunosuppressive treatments) have decreased rates of clearance of HPV infection and increased rates of cervical dysplasia and cancer [93-99].
For these patients, we follow the guidelines developed for cervical cancer screening in patients with HIV [99]. As with patients with HIV, these patients should have extended screening for cervical cancer (beyond age 65 years), although data are limited (table 3). (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states".)
Patients with inflammatory bowel disease or rheumatoid arthritis not actively on immunosuppressive therapy are not at higher risk for cervical cancer and should follow cervical cancer screening guidelines for average-risk patients. (See 'Screening in average-risk patients' above.)
SCREENING IN OTHER POPULATIONS
Prior benign hysterectomy — Patients who have a history of cervical intraepithelial neoplasia (CIN) require surveillance even after hysterectomy. (See 'Surveillance in patients with abnormal screening' below.)
For patients who have had a hysterectomy and have no history of cervical cancer or CIN our recommendations are based on type of hysterectomy:
●Total hysterectomy (with cervix removed) – We recommend that patients who have undergone total hysterectomy and have no history of cervical cancer or CIN not undergo screening for cervical cancer or screening for vaginal cancer.
Patients who have undergone a hysterectomy in which the cervix was removed and have never had any screening abnormality are at a very small risk of cervical cancer [100]. Although it was once believed that patients without a uterus were at increased risk for vaginal cancer [101-105], studies show no association between total hysterectomy for benign disease and subsequent vaginal carcinoma [105-110].
●Subtotal hysterectomy (cervix intact) – Patients who have undergone subtotal hysterectomy and have no history of CIN likely share the same risk of cervical cancer as patients with an intact uterus and cervix, and screening recommendations should follow the guidelines for average-risk and higher risk patients described above. (See 'Screening in average-risk patients' above and 'Screening in higher risk patients' above.)
Patients who are uncertain if their cervix was removed at the time of a benign hysterectomy should undergo an examination to determine if the cervix is present; if so, there is ongoing need for cervical cancer screening.
Recipients of HPV vaccine — The optimal approach to cervical cancer screening in patients who have received the human papillomavirus (HPV) vaccine or whose male partners received HPV vaccine remains uncertain [111]. Until data from clinical trials are available, current standard cervical cancer screening recommendations should be observed for patients who have received the HPV vaccine [6,35,39,64,112,113]. (See 'Screening in average-risk patients' above and 'Screening in higher risk patients' above.)
HPV vaccination of female and male adolescents reduces the risk of developing cervical dysplasia [114,115]. However, the vaccine does not provide immunity against all HPV types responsible for cervical cancers, and some vaccine recipients may already be infected with high-risk HPV [112]. (See "Human papillomavirus vaccination".)
HPV vaccination may lower the positive predictive value (PPV) of cervical cytology in predicting CIN, although further data are needed. In a prospective cohort study of over 150,000 patients (20,000 of whom had abnormal cervical cytology), the PPV of abnormal cytology for CIN 2+ was lower in HPV-vaccinated patients (57 to 65 percent, depending on age of vaccination) compared with unvaccinated patients (70 percent) [116]. Lower PPVs were also noted for patients with low-grade cervical lesion.
Further discussion about HPV vaccination in patients with CIN and management of sexual partners can be found elsewhere. (See "Cervical intraepithelial neoplasia: Management", section on 'Candidates for HPV vaccination'.)
Symptomatic patients — Patients of any age, including age <21 years, who have signs or symptoms of cervical disease (eg, abnormality on visualization or palpation of the cervix, abnormal or postmenopausal bleeding, abnormal discharge, pelvic pain, or change in bowel or bladder function) should undergo appropriate diagnostic evaluation regardless of prior screening history. This evaluation includes a diagnostic Pap test and evaluation for cervical biopsy; by definition, this diagnostic evaluation is not "screening" and may require additional follow-up. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)
ABNORMAL SCREENING RESULTS
Follow-up of abnormal results — Patients who have abnormal Pap and/or human papillomavirus (HPV) testing results need appropriate follow-up and possibly further subsequent evaluation. This following abnormal result categories are discussed in detail elsewhere (table 4):
●Pap test satisfactory for evaluation but limited (see "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Satisfactory for evaluation') (Related Pathway(s): Cervical cancer screening: Follow-up of a Pap test showing partially obscuring blood or inflammation and Cervical cancer screening: Follow-up of a Pap test with an absent endocervical transformation zone.)
●Pap test unsatisfactory (see "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Unsatisfactory for evaluation') (Related Pathway(s): Cervical cancer screening: Follow-up of a Pap test reported as "unsatisfactory".)
●Abnormal HPV testing but normal Pap testing
●Abnormal HPV testing without Pap test
●Abnormal Pap results
•Atypical squamous cells (categorized as either of undetermined significance [ASC-US] or cannot exclude high-grade lesion [ASC-H], low-grade squamous intraepithelial lesions (LSIL), and high-grade squamous intraepithelial lesions (HSIL) (see "Cervical cancer screening: Risk assessment, evaluation, and management after screening")
•Atypical and malignant glandular cells (see "Cervical cytology: Evaluation of atypical and malignant glandular cells")
●Cervical cancer (see "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Diagnosis')
Inadequate follow-up of abnormal Pap tests performed months or years before the diagnosis of cancer was found in up to 13 percent of patients with invasive cervical cancer [117-120]. In one study, the median time from the date of the "failed" follow-up for abnormal Pap test to the cancer diagnosis was 22 months; older age and poverty were associated with greater likelihood of a failed follow-up process [121].
Surveillance in patients with abnormal screening — After the evaluation of the abnormal screening result is complete, most patients will require long-term surveillance. Only a minority of patients will return to age-based cervical cancer screening, as detailed elsewhere (see 'Defining average versus high risk for cervical cancer' above). Management decisions for patients with abnormal screening and subsequent testing results are discussed in detail elsewhere:
●Cervical intraepithelial neoplasia (CIN 2, CIN 3) and treatment with excision, ablation or hysterectomy (see "Cervical intraepithelial neoplasia: Choosing excision versus ablation, and prognosis and follow-up after treatment", section on 'Type and duration of testing')
●Invasive cervical cancer (see "Invasive cervical cancer: Patterns of recurrence and post-treatment surveillance")
●Cervical adenocarcinoma in situ (AIS) (see "Cervical adenocarcinoma in situ", section on 'Monitoring post-hysterectomy' and "Cervical adenocarcinoma in situ", section on 'Monitoring post-excisional procedure')
●Vaginal intraepithelial neoplasia (VaIN) and vaginal cancer (see "Vaginal intraepithelial neoplasia", section on 'Posttreatment surveillance' and "Vaginal cancer", section on 'Post-treatment surveillance')
●Vulvar intraepithelial lesions/neoplasia and vulvar cancer (see "Vulvar squamous intraepithelial lesions (vulvar intraepithelial neoplasia)", section on 'Posttreatment surveillance' and "Squamous cell carcinoma of the vulva: Medical therapy and prognosis", section on 'Surveillance')
●Anal intraepithelial neoplasia (AIN) (see "Anal squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment", section on 'Post-treatment surveillance')
IMPROVING SCREENING RATES — More than one-half of patients who develop cervical cancer have not been screened adequately; among patients diagnosed with invasive cervical carcinoma, one-half have never had a Pap test and another 10 percent have not had a test in the past five years [117,122-124].
In a survey of screening in the United States in 2015, 83 percent of patients with a cervix aged 21 to 65 years reported having had a Pap test within the preceding three years or co-testing within five years [125]. Never-screened and under-screened patients tend to be older patients and those with no usual source of health care, the uninsured, and patients who immigrated to the United States within the past 10 years [126-128]. In Canada, screening rates are low in patients with disability and those with chronic conditions [129]. Globally, patients exposed to natural disasters (including the coronavirus disease 2019 [COVID-19] pandemic) experience disruptions in health care and may have lower screening rates [130,131].
Screening may also be lower in HPV-unvaccinated patients. In one United States survey in 2019 including over 4500 patients (ages 21 to 39), more unvaccinated compared with vaccinated patients had never received screening (21 to 29 years: 32 versus 18 percent; 30 to 39 years: 13 versus 5 percent) [132].
Various strategies can be used to increase screening rates.
●Actively inviting patients to schedule an appointment for cervical cancer screening is an effective way to increase participation in a screening program [133], though even active solicitation resulted in less than a 20 percent increase in screening in one systematic review [134]. The most effective single intervention used a dedicated nurse practitioner and offered same-day screening (33 percent increase in screening).
●Urgent care clinic visits can be used as an opportunity to screen patients who are unlikely to otherwise comply with cervical cancer screening recommendations [135]. However, patient follow-up in this setting can be difficult, and therefore, this option is not often utilized.
●Initiating a reminder system is helpful for ensuring compliance with follow-up [136]. A systematic review of 70 randomized trials of interventions to promote screening for cervical cancer found good evidence that invitation letters can increase cancer screening uptake, and more limited evidence that educational interventions are also effective [137]. In some areas where approved, self-sampling for HPV can fill gaps of care for cervical cancer screening.
"Over-screening" (ie, screening more frequently, initiating screening at an earlier age, or discontinuing screening at a later age than recommended) is also a concern [138,139]. In one cohort study including more than 2.2 million commercially insured patients in the United States at average risk for cervical cancer, the cumulative index of repeat testing within three years of index screening was 65 percent; over-screened patients were younger (age 30 to 39 years versus 60 to 64 years), without comorbidities, and screened with Pap testing alone [140]. (See "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Special considerations'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cervical cancer screening, prevention, and management".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Cervical cancer screening tests (The Basics)")
●Beyond the Basics topics (see "Patient education: Cervical cancer screening (Beyond the Basics)" and "Patient education: Management of a cervical biopsy with precancerous cells (Beyond the Basics)" and "Patient education: Follow-up of low-grade abnormal Pap tests (Beyond the Basics)" and "Patient education: Follow-up of high-grade or glandular cell abnormal Pap tests (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Rationale – Cervical cancer screening leads to a decrease in the incidence of, and mortality from, cervical cancer. (See 'Rationale for screening and potential harms' above.)
●Types of screening – Screening strategies for cervical cancer include Papanicolaou (Pap) testing alone, primary human papillomavirus (HPV) testing alone or co-testing (with Pap and HPV testing) (table 1). The frequency of testing depends on the test(s) chosen. (See 'Types of screening and frequency' above.)
●How to screen – For all patients with a cervix, we recommend screening for cervical cancer (Grade 1B). Even single lifetime screening is associated with a reduction in mortality. However, the absolute risk reduction for an individual patient is small, and positive results may lead to unnecessary procedures in some patients. Thus, some individuals may elect not to undergo screening or to be screened at less frequent intervals. The ages at which to initiate and discontinue screening, as well as which testing method (eg, Pap smear, primary HPV testing, co-testing) to use, are discussed below (table 2). (See 'Types of screening and frequency' above and 'Rationale for screening and potential harms' above and 'Relative risks and benefits of each method' above.)
•For patients <21 years, we do not screen for cervical cancer, regardless of the age of initiation of sexual activity. (See 'Age <21' above.)
•For patients ages 21 to 29, we initiate cervical cancer screening at the age of 21 with cervical cytology every three years. Our approach is consistent with the 2018 United States Preventive Services Task Force (USPSTF) guidelines. Another acceptable approach is to initiate screening at age 25 with primary HPV testing every five years (consistent with the 2020 American Cancer Society [ACS] guidelines). (See 'Age 21 to 29' above.)
•For patients ages 30 to 65, we continue cervical cancer screening with any of the following strategies (see 'Age 30 to 65' above):
-Primary HPV testing (with a test approved by the US Food and Drug Administration [FDA]) every five years; or
-Co-testing (Pap and HPV testing) every five years; or
-Pap test alone every three years
•For patients >65 years, the decision to discontinue screening depends on whether the patient has had adequate prior screening, life expectancy, and preferences in a shared decision-making discussion. (See 'Age >65 years' above.)
-For patients who have had adequate prior screening with all normal results and no cervical cancer risk factors, the optimal age to discontinue screening is uncertain. We screen through at least age 65 years. While data are limited and potential harms of screening need to be considered (eg, false positives), some UpToDate authors and editors continue to offer screening through age 74 years. (See 'If adequate prior and all normal screening' above.)
-For patients in whom screening is unknown or has not been adequate, we perform co-testing annually for three years before spreading out the interval to every five years, and we extend screening to age 70, or beyond. (See 'If inadequate prior screening or unknown screening' above.)
●Screening in higher risk patients – Higher risk patients (eg, HIV, immunosuppression) are at an increased risk for developing cervical cancer, and recommendations for which screening strategy to choose and what age to discontinue screening may differ from the average-risk patient (table 3). (See 'Screening in higher risk patients' above.)
●Symptomatic patients – Symptomatic patients should have Pap testing as part of a diagnostic workup, regardless of prior screening results. (See 'Symptomatic patients' above.)
●Abnormal results
•Patients with abnormal Pap and/or HPV testing results need appropriate follow-up and possibly further subsequent evaluation (eg, colposcopy, excision). (See 'Follow-up of abnormal results' above.)
•After the evaluation of the abnormal screening result is complete, most patients require long-term surveillance; only a minority of patients will return to routine age-based screening. (See 'Surveillance in patients with abnormal screening' above.)
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