The Pap Smear

In the United States in 2020, it is estimated that 13,800 cases of invasive cervical cancer will be diagnosed and that 4,290 women will die of the disease.

These rates have been improving steadily. This improvement has been attributed largely to screening with the Papanicolaou (Pap) test. When corrected for the prevalence of hysterectomy, the mortality rate for black women is nearly twice the mortality rate for white women.

Invasive squamous carcinoma of the cervix results from the progression of preinvasive precursor lesions called cervical intraepithelial neoplasia (CIN), or dysplasia. CIN is histologically graded into mild dysplasia (CIN 1), moderate dysplasia (CIN 2), or severe dysplasia (CIN 3). Not all of these lesions progress to invasive cancer; many mild and moderate lesions regress. A further categorization, the Bethesda system, is based on cytologic findings: atypical squamous cells of undetermined significance (ASCUS) or cannot rule out low-grade squamous intraepithelial lesions (LSILs), LSILs (consisting of cytologic atypia and CIN 1), and high-grade squamous intraepithelial lesions (HSILs), primarily CIN 2–3 plus carcinoma in situ.

The rate at which invasive cancer develops from CIN is usually slow, measured in years and perhaps decades. This long natural history provides the opportunity for screening to effectively detect this process during the preinvasive phase, thus allowing early treatment and cure. Because many of these preinvasive lesions (especially LSILs) would have never progressed to invasive cancer, screening also runs the risk of leading to treatment for women who do not need to be treated.

Human papillomavirus (HPV) is an oncogenic virus and the etiologic agent of cervical cancer and related premalignant disease. HPV is transmitted by sexual contact. Sexually inactive women rarely develop cervical cancer, while sexual activity at an early age with multiple sexual partners is a strong risk factor. Nearly all women with invasive cervical cancer have evidence of HPV infection. Most women with HPV infection, however, never develop cervical cancer; thus, this infection is necessary but not sufficient for the development of cancer.

Although cervical cancer mortality increases with age, the prevalence of CIN is highest among women in their 20s and 30s. Mortality is rare among women younger than 30 years; HSILs are rare among women older than 65 years who have been previously screened. About 70% of ASCUS and CIN 1 lesions regress within 6 years, while about 6% of CIN 1 lesions progress to CIN 3 or worse. In about 10% to 20% of women with CIN 3 lesions, the lesions progress to invasive cancer.

The Pap Test

Both incidence and mortality from cervical cancer have sharply decreased in a number of large populations after the introduction of well-run screening programs. Reductions in cervical cancer incidence and mortality were proportional to the intensity of screening.

Case-control studies have found that the risk of developing invasive cervical cancer is three to ten times higher in women who have not been screened. Risk also increases with long duration following the last normal Pap test, or similarly, with decreasing frequency of screening. Screening every 2 to 3 years, however, has not been found to significantly increase the risk of finding invasive cervical cancer above the risk expected with annual screening.

Accuracy of the Pap Test

Studies that compare the Pap test with repeat Pap testing have found that the sensitivity of any abnormality on a single test for detecting high-grade lesions is 55% to 80%. Because of the usual slow-growing nature of cervical cancer, the sensitivity of a program of regular Pap testing is likely higher.

To determine the sensitivity and specificity of the Pap smear, both a test threshold (i.e., the point at which the test will be considered to be positive) and a reference-standard threshold (i.e., the point at which the reference standard is considered to be positive) must be defined. In practice, ASCUS is often used as the test threshold, and CIN 1 is often used as the reference threshold. This combination gives a sensitivity of about 68% and a specificity of about 75%. A more appropriate test threshold may be LSIL, with a reference threshold of CIN 2–3. This combination gives a sensitivity of 70% to 80%, with a specificity of about 95%.

One important factor in the accuracy of the Pap test is the adequacy of the specimen obtained. Adequate training and using techniques such as the cytobrush may improve sensitivity.

New Screening Technologies

Newer techniques that employ liquid-based cytology (e.g., ThinPrep) have been developed to improve the sensitivity of screening. As with the Pap test, the optimal studies to determine the sensitivity and specificity of these technologies have not been conducted. Some less-than-optimal studies show that sensitivity is modestly higher for detecting any degree of CIN, with modestly lower specificity.

The evidence is also mixed about whether liquid-based techniques improve rates of test adequacy. One advantage of liquid-based cytology is that HPV testing can be performed on the same preparation; one disadvantage is that liquid-based approaches are more expensive than conventional Pap testing. No study has examined whether liquid-based cytology actually reduces the number of women dying of cervical cancer compared with conventional Pap testing.

Screening Women Who Have Had a Hysterectomy

Women who have had a hysterectomy with removal of the cervix for benign disease rarely have important abnormalities found on Pap testing. Several studies have shown that the rate of high-grade vaginal lesions or vaginal cancer is less than 1 in 1,000 tests; no study has shown that screening for vaginal cancer reduces mortality from this rare condition.

Screening Interval

Because cervical cancer is slow growing, considerable uncertainty surrounds the issue of the optimal screening interval. The most direct evidence about this issue comes from a prospective cohort analysis of an RCT. Among 2,561 women (mean age, 66.7 years) with normal Pap tests at baseline, 110 had an abnormal Pap test within the next 2 years. No woman was found to have CIN 2–3 or invasive cancer, and only one woman had CIN 1–2. Thus, the positive predictive value (PPV) of screening 1 year after a negative Pap test was 0%; after 2 years, the PPV was 0.9%. The authors concluded that Pap tests should not be repeated within 2 years of a negative test. A large (n = 332,000) prospective cohort study of cervical cytology and HPV DNA cotesting in U.S. women aged 30 years and older found that a negative Pap smear was associated with a low risk of developing CIN 3 or cancer (CIN 3+) for up to 5 years after the test (cumulative incidence of CIN 3+ at 3 and 5 years was 0.17% and 0.36%, respectively).

A large study that included data from the National Breast and Cervical Cancer Early Detection Program together with modeling found little further mortality reduction from cervical cancer for screening every year as compared with screening every 3 years. A similar modeling study from Australia found no differences between screening every 2 years and screening every 3 years.

HPV Testing

Noninvasive cervical squamous cell abnormalities are graded histologically as CIN 1, CIN 2, or CIN 3, according to the severity of the cell changes and the percent of the epithelium replaced by abnormal cell growth. CIN 3 is a reasonably reproducible diagnosis and, if untreated, has an approximate 30% risk of developing into invasive cancer over many years.CIN 2 has poor interobserver reproducibility, and the biologic behavior is variable CIN 3 is therefore a more rigorous endpoint for clinical trials, while CIN 2 represents the threshold for treatment to provide an additional measure of safety.

Approximately 15 cancer-associated (high-risk or carcinogenic) HPV genotypes cause virtually all cases of cervical cancer and precursor lesions of CIN 2 and CIN 3. However, carcinogenic HPV infections are very common, particularly in young women, and the majority clear on their own within 1 to 2 years. Therefore, the challenge of incorporating HPV testing in cervical screening programs is to balance sensitivity for detection of CIN 2 or CIN 2+ and to minimize the over-referral of women with transient HPV infections and cervical changes that are destined to regress.

The U.S. Food and Drug Administration (FDA) has approved several HPV tests. Most of these tests are based on the detection of DNA from one or more oncogenic types of HPV. One test detects HPV RNA. HPV testing is approved for use in two contexts: (1) as a second (i.e., triage) test after an equivocal cytology result of ASCUS; and (2) for primary screening in conjunction with cervical cytology for women aged 30 years and older.[45] Testing for low-risk HPV types does not identify women at risk of developing CIN 2 or 3.

Triage

A large randomized clinical trial, the ASCUS/LSIL Triage Study (ALTS), demonstrated the cost-effectiveness of using HPV testing to clarify the risk of an ASCUS Pap result. ALTS randomly assigned women with ASCUS to one of three management strategies: immediate colposcopy regardless of enrollment test results, referral to colposcopy if HPV test results were positive or if the enrollment cytology was HSIL, and referral to colposcopy only if the cytology was HSIL. The HPV triage strategy was as sensitive for detection of CIN 2+ as immediate colposcopy, while referring only about half of the women for the procedure. Repeat cytology with referral to colposcopy at the threshold of HSIL was less sensitive for CIN 3+ (60%) compared with HPV triage (92%); however, using a cytologic threshold of ASCUS for referral increased sensitivity but resulted in 72% of women with ASCUS undergoing colposcopy. HPV testing is not recommended for adolescent women with ASCUS because most of these women are HPV positive.

HPV DNA testing is generally not appropriate or clinically useful following cytology results of LSIL, which is more severe than ASCUS, and most of these women (84%–96%) are carcinogenic HPV DNA positive.One exception may be to clarify the risk for postmenopausal women with cytologic LSIL, which is an interpretation that can be falsely positive, presumably due to atrophic changes.

Primary Screening

Testing for HPV DNA as a primary screening test has been FDA approved only in conjunction with cervical cytology and only in women aged 30 years and older. Women who are negative by cytology and HPV testing are at extremely low risk of CIN 3+ and therefore may be screened less frequently. A prospective cohort study of nearly 332,000 U.S. women aged 30 years and older undergoing HPV DNA and cervical cytology cotesting every 3 years found that the cumulative incidence of CIN 3+ in women with negative results for both tests at baseline was 0.047% at 3 years and 0.16% at 5 years. A second study of more than 43,000 women aged 29 to 61 years, one-half of whom underwent three rounds of HPV DNA and cervical cytology cotesting every 5 years, found that the cumulative incidence of CIN 3+ in women with negative results for both tests at baseline was 0.01% (95% confidence interval [CI], 0.00%–0.05%) at 9 years and 0.07% (95% CI, 0.03%–0.17%) after 14 years of follow-up. Screening more frequently than every 3 years would not improve sensitivity significantly but would increase costs and overtreatment.

Numerous studies have demonstrated that, compared with cytology, HPV DNA testing is more sensitive for identifying women who have CIN 2+ (range of sensitivities, 84%–97%). In one randomized trial using both Pap and HPV testing in random order among women aged 30 to 69 years, sensitivity of HPV was 95% compared with 55% for Pap cytology. The combination of HPV and cytology had 100% sensitivity and a referral rate of 7.9%.

Screening Benefit According to Age

Cervical cancer mortality, usually occurring among unscreened women, increases with age, with the maximum mortality for white women between the ages of 45 years and 70 years, and for black women in their 70s.Mortality among women with negative Pap screening is low at all ages.

Screening by Pap testing with associated diagnostic testing and treatment is effective in reducing the incidence of all histologies and stages of invasive cervical cancer. The benefit increases with age. Whereas the odds ratio (OR) is 0.79 (95% CI, 0.57–1.1) among women screened at age 30 to 31 years for developing cancer at age 35 to 39 years, it improves to 0.26 (95% CI, 0.19–0.36) among women screened at age 52 to 54 years for developing cancer at age 55 to 59 years.

Women aged 20 years and younger are more likely to have Pap abnormalities leading to further testing and treatment (refer to the Evidence of Harm section of this summary for more information), so forgoing Pap testing in these women may improve the benefit-risk balance for this intervention. Women in this age group have a very low risk of cervical cancer and a high likelihood that cervical cell abnormalities will go away on their own.

HSILs are rare among women older than 65 years who have been previously screened. For women with a negative Pap test at age 60 years and older, the likelihood of having a new diagnosis of CIN 3+ on repeat screening is less than 1 in 1,000 (in some studies, as few as 2–6 in 10,000).

ACOG Pap Smear Guidelines