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Vesco KK, Whitlock EP, Eder M, et al. Screening for Cervical Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 May. (Evidence Syntheses, No. 86.)

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Screening for Cervical Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force [Internet].

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1Introduction

Scope and Purpose

We undertook this systematic review to assist the U.S. Preventive Services Task Force (USPSTF) in updating its 2003 recommendation on cervical cancer screening. During the planning phase of this evidence review on cervical cancer screening, the Agency for Healthcare Research and Quality (AHRQ) decided to fund a separate modeling study to be conducted simultaneously. The USPSTF determined that the scope for both the systematic review and the modeling study would focus on important clinical questions that could inform effective use of screening in practice. This systematic review focuses on when to begin screening and on updating test accuracy and harms data on liquid-based cytology (LBC) and human papillomavirus (HPV) testing, either alone or in combination with cytology. The modeling study focuses on the effectiveness of strategies that use different ages at which to begin screening and different screening intervals.1 These two reports are intended to provide the USPSTF with complementary information to update its recommendation on cervical cancer screening.

Background

Condition Definition

Two primary histologic abnormalities account for the majority of cancer of the uterine cervix—squamous cell carcinoma (SCC) and adenocarcinoma. The majority of cervical cancer cases (70% or more) are SCC, which is thought to arise from the transformation zone of the cervix.2,3 The transformation zone is the region between the original and subsequent locations of the junction between the squamous and columnar cells of the cervix (squamocolumnar junction), which migrates from the exocervix to the distal endocervical canal with advancing age.4 Adenocarcinoma, which develops from the mucus-producing cells of the endocervix, accounts for approximately 18 percent of cervical carcinomas. The remainder of cervical carcinomas are adenosquamous (4%) and other carcinomas (5%) or malignancies (1.5%).4

Cervical cancer does not develop suddenly2 and is preceded by precancerous changes of the cervix. Precancerous changes of the cervix are histologically defined as cervical intraepithelial neoplasia (CIN) and are identified at varying levels of severity: CIN1, CIN2, and CIN3. The latter includes CIS (carcinoma in situ, a preinvasive carcinomatous change of the cervix).5,6 Progression of neoplasia to invasive cervical cancer (ICC) is slow. The rate of progression of CIN3 to cancer has recently been estimated as 31.3 percent in 30 years. This rate was determined using retrospective data from an unethical clinical study in New Zealand between 1965 and 1974 that left a number of women with CIN3 disease incompletely treated or untreated.6 Other rough estimates from early studies of precancer suggest a 20 to 30 percent risk of invasion over a 5- to 10-year timeframe.7,8

Screening for cancerous or precancerous changes of the cervix has traditionally been performed by scraping cells from the cervix and fixing them to a glass slide in a method developed by Papanicolaou called the Pap smear. The Pap smear is a cytologic screening test used to detect CIN and early cervical cancer so that these conditions can be managed or treated to prevent disease progression due to invasive cancer. Cervical cytology results are not diagnostic of CIN or cancer, as biopsy and histologic confirmation are required for diagnosis. While the incidence of SCC of the cervix has declined significantly since the introduction of the Pap smear,9 the incidence of adenocarcinoma has risen, leaving the optimal method of screening to detect adenocarcinoma of the cervix uncertain.9

The terminology for reporting the spectrum of cervical cytologic abnormalities is derived from the Bethesda System and is displayed in Table 1.10 The 2001 Bethesda Workshop was convened to update terminology initially established in 1988 and revised in 1991.11 Atypical squamous cells of undetermined significance, or ASC-US, is the least reproducible of all the cytologic categories and emphasizes that a specific diagnosis cannot be made. Atypical glandular cell (AGC) abnormalities (previously called AGUS) may be reported as endocervical, endometrial, or not otherwise specified. The percentage of AGC Pap smears associated with underlying high-grade disease (CIN2 or worse) is higher than for ASC-US.10 High-grade squamous or glandular lesions can be seen in 10 to 39 percent of cases of AGC.10 The term LSIL, or low-grade squamous intraepithelial lesion, includes cellular HPV changes and CIN1. The term HSIL, or high-grade squamous intraepithelial lesion, includes CIN2 and CIN3. While LSIL and HSIL are terms generally used to describe cytology, they have also been used to describe histology. The term CIN2+ is used to indicate CIN2 or worse (CIN2, CIN3, or cancer), and CIN3+ is used to indicate CIN3 or worse (CIN3 or cancer). Similarly, the term ASC-US+ is used to indicate ASC-US or worse cytology, LSIL+ to indicate LSIL or worse, and HSIL+ to indicate HSIL or worse.

Table 1. Cervical Pathology: Comparison of Cytologic and Histologic Test Results and Current U.S. Guidelines for Management of Cytologic Abnormalities.

Table 1

Cervical Pathology: Comparison of Cytologic and Histologic Test Results and Current U.S. Guidelines for Management of Cytologic Abnormalities.

Prevalence and Burden of Disease/Illness

The incidence and associated mortality of cervical cancer have continued to decrease in the United States since the introduction of cervical cytology screening programs in the 1950s and 60s. In 1950, the Centers for Disease Control (CDC) “Vital Statistics of the United States” reported an unadjusted death rate of 10.2 per 100,000 for white women and 18.0 for nonwhite women (age-adjusted mortality not reported).12 In 2007, age-adjusted mortality had dropped to 2.2 for white women, 4.3 for black women, and 2.4 overall.13 Although these results are based on ecologic data, these changes have been seen in the United States and other countries with longstanding population screening and attributed to that screening.14

However, cervical cancer still remains a significant public health issue. Incidence figures for 2000 to 2008 from the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) database suggest that incidence varies significantly by age and race/ethnicity (Table 2 and Figure 1). The overall age-adjusted incidence rate of cervical cancer is 8.4 per 100,000 women per year. The incidence is highest among Hispanics (12.1 per 100,000 women) and blacks (10.7) and lowest among nonHispanic whites (7.5), American Indians and Alaska Natives (7.5), and Asian and Pacific Islanders (7.7) (Figure 1).15 Based on 2004 to 2008 SEER data, the median age at diagnosis for cervical cancer in all women was 48 years.16 Half of all incident cervical cancer cases between 2004 and 2008 occurred in women between the ages of 35 and 55 years. The age-adjusted death rate for cervical cancer was 2.5 per 100,000 women in 200717 and the median age for mortality was 57 years.16 Mortality rates increase with age (Figure 2) and also vary by race and ethnicity (Figure 3).17 The national target established in Healthy People 2010 was a mortality reduction to 2.0 deaths per 100,000 women. For 2010, SEER data estimate 12,200 new cases of cervical cancer and 4,210 deaths.15

Table 2. U.S. Age-Specific Crude Invasive Cervical Cancer Incidence Rates By Race, 2000–2008.

Table 2

U.S. Age-Specific Crude Invasive Cervical Cancer Incidence Rates By Race, 2000–2008.

Figure 1 displays the age-adjusted incidence rates of cervical cancer by age and race in the United States. The overall incidence is highest among Hispanics (12.1 per 100,000 women) and blacks (10.7) and lowest among nonHispanic whites (7.5), American Indians and Alaska Natives (7.5), and Asian and Pacific Islanders (7.7).

Figure 1

U.S. Age-Adjusted Cervical Cancer Incidence Rates By Age and Race/Ethnicity (SEER 2000–2008). Rates are expressed as cases per 100,000 women; age-adjusted to 2000 US Standard Population *American Indian/Alaska Native statistics only include cases (more...)

Figure 2 displays the age-adjusted incidence and death rates of invasive cervical cancer in the United States in 5-year age groups. The incidence of invasive cervical cancer peaks among U.S. women aged 40 to 44 years and few cases of cervical cancer are detected in women younger than age 20 (age-adjusted incidence rate of squamous cell carcinoma, 0.05 cases per 100,000 U.S. women). Mortality from cervical cancer increases with increasing age.

Figure 2

U.S. Age-Adjusted Incidence and Death Rates of Invasive Cervical Cancer By Age (SEER 2000–2008).

Figure 3 displays the age-adjusted mortality rates of cervical cancer by age and race in the United States. The age-adjusted death rate for cervical cancer was 2.5 per 100,000 women in 2007. Mortality rates increase with age and vary by race and ethnicity. The overall mortality is highest among blacks (4.7 per 100,000), American Indians and Alaskan Natives (3.6) and Hispanics (3.2) and lowest among Asian and Pacific Islanders (2.3) and nonHispanic whites (2.2).

Figure 3

U.S. Age-Adjusted Cervical Cancer Mortality Rates By Age and Race/Ethnicity (SEER 2000–2008). Rates are expressed as cases per 100,000 women; age-adjusted to 2000 U.S. Standard Population. Data not yet updated for 2008. *American Indian/Alaska (more...)

Studies of screening history of women diagnosed with ICC repeatedly show that at least half have been inadequately screened. Studies of women diagnosed with ICC in the 1980s and 1990s in Connecticut18 and California19,20 showed that 50 to 60 percent had not been screened within 3 years of diagnosis. For comparison, the CDC’s 2008 Behavioral Risk Factor Surveillance System found that just 17 percent of all adult women in the United States had not had a Pap test within the past 3 years.21 In the Connecticut study, about half of women diagnosed with ICC had no screening within 5 years, and about 30 percent had never been screened.18 A recent study of a high-risk urban population in London diagnosed with ICC between 1999 and 2007 showed very similar results, with 47 percent of women having no screening within 5 years and 31 percent with no prior screening.22 Inadequate screening might be less of a contributing factor to cancer diagnosis for younger women. Sasieni and colleagues, for example, found that just 7 percent of women aged 20 to 24 years diagnosed with cervical cancer had never been screened or had had a lapse in screening.23 These data also indirectly suggest that relatively rare rapid-onset cancer in younger women may be less amenable to earlier screening.24

Risk Factors

It is well recognized that infection with oncogenic HPV types is a necessary, although not sufficient, cause of virtually all cervical cancer.25 The 12 HPV types most strongly associated with cervical cancer are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Other potentially carcinogenic HPV types include 26, 53, 66, 67, 68, 70, 73, and 82.26–28 Eight HPV types (16, 18, 45, 31, 33, 35, 52, and 58) account for 95 percent of SCCs positive for HPV deoxyribonucleic acid (DNA).26 HPV types 16 and 18 alone are responsible for approximately 70 percent of cervical cancer cases.29,30 Results from a large international collection of cervical tumor specimens also revealed the presence of HPV DNA in 99.7 percent of cases.31

The prevalence of HPV infection declines with increasing age.32–34 A cross-sectional study of 9,657 women screened for 13 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 ) in 26 sexually transmitted infection, family planning, and primary care clinics in six U.S. cities demonstrated that the prevalence of high-risk HPV was highest among women aged 14 to 19 years (35% [95% confidence interval (CI), 32 to 38]), and lowest among women aged 50 to 65 years (6% [95% CI, 4 to 8]) (Figure 4).34

Figure 4 displays the decreasing prevalence of high-risk human papillomavirus (HPV) with increasing age as reported in a cross-sectional study by Datta and colleagues. In this study, 9,657 women screened for 13 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 ) in 26 sexually transmitted infection, family planning, and primary care clinics in six U.S. cities. The results demonstrated that the prevalence of high-risk HPV was highest among women aged 14 to 19 years (35% [95% confidence interval (CI) 32 to 38]), and lowest among women aged 50 to 65 years (6% [95% CI 4 to 8]).

Figure 4

Prevalence of High-Risk Human Papillomavirus By Age.

Although we have not identified a published systematic review of other cervical cancer risk factors, pooled analyses of data from observational studies worldwide have been conducted by the International Collaboration of Epidemiological Studies of Cervical Cancer35–37 and the International Agency for Research on Cancer.38–41 Based on these and other reviews, cervical cancer risk factors may affect the risk of HPV acquisition, its persistence, or the likelihood of progression to neoplasia and cancer; however, the specific mechanisms underlying measured associations with risk are poorly understood.

The risk of acquiring HPV dramatically increases with the number of lifetime sexual partners.35,42 Coinfection with other sexually transmitted agents such as chlamydia trachomatis and herpes simplex virus may also be associated with risk of HPV infection.25,38,43,44 Other risk factors for cervical cancer include high parity (five or more pregnancies) and long-term oral contraceptive use, each associated with a two- to three-fold higher overall risk of precancer or cancer,35,36,38,40,41,45 along with younger age at first intercourse and at first pregnancy.35,36 Smoking is clearly associated with increased risk of SCC, but shows no association with the risk of cervical adenocarcinoma.35,37–39 For SCC, the larger pooled studies show risk increases of 50 to 60 percent for current smokers.35,37 In a pooled analysis restricted to HPV positive women, smoking was associated with a larger risk increase (relative risk [RR], 1.95 [95% CI, 1.43 to 2.65]), suggesting that smoking affects HPV persistence or disease progression more than HPV acquisition.37 Reduced risk of both types of cervical cancer is seen with a history of cervical screening, although the reduction is larger for SCC than for adenocarcinoma.35

Etiology and Natural History

The progression from HPV infection to cervical cancer occurs over a series of four steps: 1) HPV transmission, 2) acute HPV infection, 3) persistent HPV infection leading to precancerous changes, and 4) ICC.45 Transmission of HPV to the anogenital region occurs primarily as a result of skin-to-skin or mucosa-to-mucosa contact.45 Malignant transformation of HPV-infected cells is believed to be mediated by the integration of the viral DNA into the host genome. The virus reproduces separately in most low-grade lesions, but the HPV genome may be integrated into the host’s DNA in many advanced precancerous lesions and most cancer cases.46

A high proportion of sexually active women become infected with HPV, but only a small proportion of HPV infections become persistent. Among 4,504 women aged 18 years and older with a cytologic diagnosis of ASC-US or LSIL, 91 percent of prevalent HPV infections detected at enrollment cleared within 24 months.47 The probability of persistent infection increased with duration of infection, such that about two-thirds of infections that had persisted to 18 months were still present at 24 months. Also, odds of persistent infection were highest in the 50 years and older age group, compared with those aged 20 years and younger (odds ratio [OR], 1.47 [95% CI, 1.11 to 1.94]).

HPV-associated risks are type-specific, with types 16 and 18 conferring the highest risk for HPV persistence and progression to high-grade lesions. In an HPV 16 vaccine trial, women aged 16 to 23 years had HPV DNA testing at 6-month intervals for up to 4 years. Among unvaccinated women in the placebo arm, the mean duration of incident HPV infections was 17.1 months (95% CI, 15.0 to 19.2) for HPV 16 and 16.6 months (95% CI, 13.4 to 19.7) for HPV 18.48 The proportion cleared at 36 months was 85.3 percent (95% CI, 75.0 to 91.5) for HPV 16 and 91.1 percent (95% CI, 84.6 to 94.9) for HPV 18.48 These studies illustrate that even high-risk HPV types are quite likely to clear in younger women.

In the same HPV 16 vaccination trial, the rate of progression to CIN2+ at 36 months was 16.5 percent for HPV 16 and 8.2 percent for HPV 18.48 In a U.S. cohort of 20,514 women aged 16 years and older (median age, 34 years) tested at baseline for 13 oncogenic HPV types, the 10-year cumulative incidence rates of CIN3+ were 17.2 percent (95% CI, 11.5 to 22.9) among HPV 16 positive women and 13.6 percent (95% CI, 3.6 to 23.7) among HPV 18 positive women, but only 3 percent (95% CI, 1.9 to 4.2) among women who were positive for an HPV type other than 16 or 18.49 Repeated HPV testing is required to identify type-specific incident infection and clearance.

These data illustrate that HPV infections are very likely to regress, and persistence of HPV infection is more likely to occur in older women. While HPV 16 and 18 are most likely to persist and be associated with CIN3 or cancer, a high proportion of HPV 16 and 18 infections also regress. Regression of HPV infection is presumably due to a successfully mounted immune response,50,51 and increased incidence and persistence of HPV infections are observed in immunocompromised populations.42,52 It is unknown whether viral infections resolve as a result of complete clearance of the virus or by maintenance of the virus in a latent state.45 While cohort studies have demonstrated that a viral type can reappear even after it has been thought to have cleared,53 incident HPV infections may not confer a great deal of risk given the high probability of clearance and the long time period between HPV infection and cancer development, particularly among older women.24

Numerous analyses, including large cohort studies, have demonstrated that CIN not only progresses, but may also regress. In an historical cohort of about 20,000 Toronto women during a period when lesions were managed conservatively, CIN2 progression to ICC was 0.3 percent within 2 years, 0.7 percent within 5 years, and 1.2 percent within 10 years.54 Rates of CIN3 progression to ICC were considerably higher (1.6% within 2 years, 2.6% within 5 years, and 9.9% within 10 years). Regression from CIN2 to a second normal smear occurred in 6.9 percent within 2 years, 29.0 percent within 5 years, and 53.7 percent within 10 years.

Using composite data from cytology, histology, or both to define CIN lesions, a review summarized studies published between 1950 and 1990 on persistence, regression, and progression of CIN.55 Over followup from 1 to 25 years, regression or persistence was most common for CIN1 (57% regressed, 32% persisted, and 1% progressed). For CIN2, 43 percent regressed, 35 percent persisted, and 5 percent progressed to cancer. For CIN3, regression rates were 32 percent, persistence rates were 56 percent, and progression rates were greater than 12 percent. Neither the Holowaty54 nor Ostor55 reports discuss treatment for CIN3 specifically, or its effect on the results reported. The results from an unethical New Zealand study,6 in which women with CIN3 were untreated or inadequately treated, estimated that 31.3 percent of these women progressed to cancer within 30 years, compared to 0.7 percent in those with adequate treatment.

Newer data suggest that CIN1 does not predict any meaningful risk of CIN3.45,56 In addition, CIN1 diagnoses in the United States are poorly reproduced,45,56 which has also been established recently for CIN2 diagnoses in the United States and other countries.57,58 Despite poor reproducibility, data from the ASCUS-LSIL Triage Study (ALTS) trial have been used to estimate that up to 40 percent of CIN2 detected through colposcopy referral after positive primary screening tests (cytology and HPV) in younger women may regress, particularly in the presence of less severe cytology such as ASC-US+, LSIL+, or HPV positive tests that are not HPV 16 positive.59

Current Screening Uptake in U.S. Women

While it is estimated that around 80 percent of U.S. women have had cervical cytology screening within the past 3 years,60 screening history varies by educational attainment, race/ethnicity, and age.61 In 2008, women with low educational attainment (a high-school diploma, general equivalency diploma, or less) were less likely to report a Pap test within 3 years than those with some college or more; fewer Asian and American Indian/Alaskan Native women reported recent Pap smears than other racial/ethnic groups. While 80 to 85 percent of women aged 18 to 64 years reported at least one Pap test within 3 years in 2008, the proportion of women aged 65 years and older reporting a similarly recent Pap history was about 50 percent (down from about 65 percent in 2000). Given the 2003 USPSTF recommendation against ongoing cervical cancer screening in women aged 65 years and older with a previously adequate history, it is unclear how to interpret this age difference. Updated information on the screening history of women with ICC in all age groups will continue to be important in monitoring the overall success of cervical cancer screening in the United States.

Rationale for and Types of Screening/Screening Strategies

While the great majority of U.S. women have had recent cytology screening, the majority of cervical cancer cases occur in those without such a history. Access to health care may be one concern.62 Even among women with no health care access barriers to screening, however, the reasons for screening failures are similar. Among 833 women in a health maintenance organization diagnosed with ICC from 1995 to 2000, most (56%) had no Pap smear within the previous 36 months, while about one-third represented Pap test failures, and the remainder failure to followup.63 Race/ethnicity was not a predictor of any type of failure, although high-poverty area of residence, lower education, and age older than 40 at diagnosis were associated with lack of recent screening. Data on false-negative results of one-time Pap smears suggest a failure rate of about 28 to 41 percent in developed countries.20,64 Imperfect sensitivity as well as errors in sample collection and interpretation across settings underpin the need for frequent repeated screening and underscore interest in developing more accurate, reliable screening tests.65 To address these issues, researchers have begun to look for technological advances, such as using LBC and high-risk HPV tests.65

LBC differs from CC in how the cervical specimen is sent to the cytology laboratory for evaluation. For CC, the cervical specimen is smeared onto a glass slide immediately after collection and the slide is either sprayed with or placed in fixative. For LBC, the sample collected from the cervix is suspended in fixative either by swirling the collection device in the fixative (ThinPrep, Hologic, Inc., Bedford, MA)66 or by placing the collection device in the fixative (SurePath, TriPath Imaging, Burlington, NC).67 In the laboratory, the cells in the fixative are dispersed and suspended, collected by filtration on a membrane, and then transferred onto a microscope slide in a monolayer.

In recent years, high-risk HPV testing has been incorporated into screening and screening triage algorithms by the American Society for Colposcopy and Cervical Pathology (ASCCP), as well as in post-colposcopy and post-treatment surveillance.68,69 High-risk HPV testing is specified for use as a combined test (co-test) in women aged 30 years and older to determine rescreening interval in women who are cytology negative and as one possible triage strategy to determine colposcopy in women with ASC-US+ cytology (discussed more below). Additionally, HPV genotyping for types 16 and 18 is specified for use as a triage to colposcopy in women aged 30 years or older who have cytology negative, high-risk HPV positive screening results.

There are many methods available for detecting HPV, including in situ hybridization, polymerase chain reaction (PCR), and Hybrid Capture technology. Hybrid Capture technology uses specific ribonucleic acid (RNA) probes, hybridization, antibody capture, and signal amplification to allow rapid, standardized testing of genetic material. The Digene Hybrid Capture 2 (HC2) high-risk HPV DNA test (Qiagen Inc., Germantown, MD) is the most commonly used in the United States. In 2000, the Food and Drug Administration (FDA) approved HC2 for testing patients with ASC-US Pap smear results to determine the need for referral to colposcopy. In addition, the HC2 high-risk HPV DNA test was approved in 2003 for use in women aged 30 years or older in conjunction with the Pap smear to assess the absence or presence of high-risk HPV types.70,71 The high-risk HPV types identified by HC2 include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. In 2009, the FDA approved Cervista HR HPV (Hologic, Inc., Bedford, MA) for HPV testing for the same indications as HC2.72 Cervista HR HPV tests for 14 high-risk HPV types, including type 66 as well as those identified by HC2. There is also an FDA-approved Cervista HPV 16/18 test that individually identifies these two high-risk HPV types.73 Other HPV test systems are also under development. For example, Roche Diagnostics manufactures Amplicor HPV, a PCR-based test for 13 high-risk HPV types approved for use in Europe, Canada, and Japan. There are also two tests in use in Europe that identify specific HPV types—the Cobas 4800 HPV and Linear Array HPV genotyping tests. Roche has announced FDA reviews of all three of its tests, and received FDA approval in April 2011 for the Cobas 4800 HPV test (which reports results for HPV 16 and 18 and pooled results for 12 other high-risk HPV types [31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68]).74

Gen-Probe’s APTIMA HPV assay detects 14 high-risk HPV types and also messenger RNA (mRNA) from viral oncogenes E6 and E7. The assay is approved for use in Europe, and Gen-Probe applied for FDA approval in late 2010.

Management of Abnormal Cervical Cytology

According to the American Congress of Obstetricians and Gynecologists (ACOG), colposcopy with directed biopsy has been the criterion for disease diagnosis and remains the technique of choice for treatment decisions.75

The process of triaging women with abnormal cytology to colposcopy is now being influenced by HPV testing.76 Consensus guidelines developed by ASCCP in 2006 state that either HPV testing or repeat cytology at 6 and 12 months (or immediate colposcopy) are acceptable for managing ASC-US cytology in women older than age 20 years, although HPV testing is preferred if LBC or co-collection is available.68 This is because HPV testing may be performed “reflexively” if the cytologic specimen collected was liquid-based and a residual sample is still available for HPV testing, or if a separate specimen was collected at the time CC was performed.

According to the ASCCP algorithm, women with their first ASC-US cytology result and a negative high-risk HPV DNA test should undergo repeat cytology at 12 months. Women with a positive high-risk HPV DNA test or a second cytology result of ASC-US or worse within 6 or 12 months should undergo colposcopy. In 2009, ACOG generally supported a similar algorithm (i.e., immediate colposcopy, high-risk HPV DNA testing with colposcopy if positive, or repeat cytology in 6 and 12 months).77 Neither ASCCP nor ACOG support HPV DNA testing in adolescents, and both recommend that adolescents with ASC-US or LSIL cytology have repeat cytology in 12 months and should only undergo colposcopy if followup cytology is HSIL or greater at 12 months or ASC-US or greater at 24 months.

According to ASCCP and ACOG, women with ASC-H (atypical squamous cells-cannot exclude HSIL), LSIL, HSIL, or AGC should undergo colposcopy.68 There are two categories of women for which alternative strategies for management of LSIL cytology exist—adolescents and postmenopausal women. ASCCP now makes the same recommendations for LSIL in adolescents as they do for ASC-US. Postmenopausal women with LSIL may undergo reflex high-risk HPV DNA testing, repeat cytology at 6 and 12 months, or immediate colposcopy.

Interventions/Treatment of Cervical Intraepithelial Neoplasia

Once identified, CIN may be treated by ablative (cryotherapy or laser ablation) or excisional modalities (loop electrosurgical excision [LEEP], laser conization, or cold knife conization [CKC] of the cervix).76 Current guidelines recommend observation of CIN1, as it is highly likely to regress spontaneously without treatment.68 Treatment of CIN2 and CIN3 is advised, and both ablative and excisional modalities are acceptable. If CIN2 or CIN3 recurs, however, excision is preferred.68 In adolescents, CIN2 may be observed and treated only if it persists for 24 months or progresses to CIN3.68

A randomized controlled trial (RCT) of cryotherapy, laser, and LEEP reported similar success rates (less than 5% rate of persistence of CIN, less than 20% rate of recurrence of CIN over approximately 3 years) and no significant difference in complication rates among the three treatment modalities.78 Risk of persistent disease was higher among women with large lesions (risk ratio, 18.9 [95% CI, 3.2 to 110.6]). Recurrence risk was higher among women aged 30 years and older (risk ratio, 2.1 [95% CI, 1.2 to 4.3]), those with HPV type 16 or 18 (risk ratio, 2.1 [95% CI, 1.1 to 4.0]), and those who had had prior treatment for CIN (risk ratio, 2.1 [95% CI, 1.1 to 3.9]).

A systematic review published in 2000 of controlled and randomized studies of cone biopsy, cryotherapy, laser, and LEEP of the cervix found no substantive differences in the persistence or resolution of CIN among these modalities.79 The pooled rates of resolution for low- and high-grade lesions or mixed histology ranged from 85 to 95 percent. The median duration of followup for these studies ranged from 2 to 45 months. A more recent Cochrane Collaboration review published in 2010 found no difference in residual disease between 1) LEEP, laser, or CKC or 2) laser ablation and laser, cold knife, or LEEP conization procedures.80 There was no difference in residual disease between cryotherapy and laser ablation or between cryotherapy and LEEP at 6 months. However, there was a significantly lower risk of residual disease at 12 months among women who underwent LEEP compared to cryotherapy (risk ratio, 0.32 [95% CI, 0.13 to 0.78]).

A recently published retrospective cohort study used data from the British Columbia Cancer Agency cytology database to determine long-term risk of CIN recurrence among women with CIN1 to CIN3 treated by various modalities (cryotherapy, LEEP, CKC, and laser vaporization or excision).81 The authors compared 37,142 women who underwent treatment for CIN1 to CIN3 between 1986 and 2000 with 71,213 women with normal cytology and no previous CIN using followup data through the end of 2004. The overall incidence of invasive cancer (per 100,000 woman-years) was higher among women with a history of CIN (37 cases [95% CI, 30.6 to 42.5]) than in the comparison cohort (6 cases [95% CI, 4.3 to 7.7]). Among all methods evaluated, cryotherapy was associated with the highest rate of subsequent disease (adjusted odds rate for invasive cancer, 2.98 [95% CI, 2.09 to 4.60]).

As the risk of ICC persists after treatment of CIN,81–83 post-treatment followup is advised.68,82 There is no specific treatment for HPV in the absence of CIN. Since current treatment only targets CIN after it has developed, the prevention of HPV infection and, consequently, the development of CIN is important.

Potential Harms Related to Diagnosis and Treatment of CIN

Risks of colposcopy and cervical biopsy include pain, bleeding, infection, failure to diagnose (inadequate sampling), and cost to the patient (e.g., time off work and psychological impact). One large, multicenter trial of 4,439 women aged 20 to 59 years with low-grade cervical abnormalities who were randomized to cytologic surveillance versus immediate referral (Trial of Management of Borderline and Other Low-Grade Abnormal Smears [TOMBOLA]) attempted to quantify the potential harms (i.e., clinically significant anxiety and depression and self-reported after effects such as pain, bleeding, and vaginal discharge) associated with colposcopic evaluation versus surveillance.84 Results from the TOMBOLA group indicated similar proportions of women with depression in the surveillance and immediate colposcopy groups at 6 weeks after the procedure, although women in the surveillance group were more likely to be anxious (13.4 vs. 7.9%; p<0.001). Significantly lower proportions of women in the surveillance group reported any pain (15.0 vs. 38.9%; p<0.001), bleeding (17.2 vs. 46.9%; p<0.001), or discharge (8.6 vs. 34.2%; p<0.001), compared with women in the immediate colposcopy arm. Within the TOMBOLA cohort, an observational study (n=929) compared the physical after effects (pain, bleeding, and discharge) of colposcopic examination only, cervical punch biopsies, and LEEP.85 Among women aged 20 to 59 years with colposcopy and no biopsy, 14 to 18 percent reported pain, bleeding, or discharge at 6 weeks. In those with colposcopic biopsy, 53 percent reported pain, 79 percent reported bleeding, and 46 percent reported discharge. For women who had LEEP, these numbers were 67, 87, and 63 percent, respectively. The duration of bleeding and discharge was longer for women treated by LEEP than women in the other groups reporting these symptoms.

Potential harms of treatment of CIN include immediate, short-term, and long-term risks. These risks may include pain, injury to adjacent organs such as the bowel or bladder, infection, bleeding, adverse reactions to medications used during the treatment procedure, incomplete treatment (i.e., residual disease after treatment) requiring additional testing or treatment, cervical stenosis resulting in difficulties with future attempts at endocervical (or endometrial) assessment, and cervical shortening with possible subsequent increased risk for preterm birth. Other potential issues to consider are the cost to the patient for time off of work, treatment of lesions that might regress on their own, and the psychological impact of the diagnosis or procedure.

One review of obstetrical outcomes published in 2006 evaluated cold knife and laser conization, laser ablation, and LEEP. CKC was significantly associated with preterm delivery (less than 37 weeks: 8 studies; RR, 2.59 [95% CI, 1.80 to 3.72]), low birthweight (less than 2,500 grams: 4 studies; RR, 2.53 [95% CI, 1.19 to 5.36]), and cesarean delivery (4 studies; RR, 3.17 [95% CI, 1.07 to 9.40]), but no increase in perinatal mortality.86 LEEP was also significantly associated with preterm delivery (8 studies; RR, 1.7 [95% CI, 1.24 to 2.35]), low birthweight (6 studies; RR, 1.82 [95% CI, 1.09 to 3.06]), and premature rupture of membranes (3 studies; RR, 2.69 [95% CI, 1.62 to 4.46]), but not cesarean delivery or perinatal mortality. Similar effects on preterm delivery were noted for laser conization, but these were not statistically significant. No increased risk for adverse obstetric outcomes was detected among women who underwent laser ablation.

A 2008 review of excisional or ablative therapies found that CKC was associated with an increased risk of preterm birth prior to 30 weeks (4 studies; RR, 5.33 [95% CI, 1.63 to 17.40]) and prior to 34 weeks (5 studies; RR, 2.78 [95% CI, 1.72 to 4.51]), birthweight less than 2,000 grams (1 study; RR, 2.86 [95% CI, 1.37 to 5.97]), and perinatal mortality (7 studies; RR, 2.87 [95% CI, 1.42 to 5.81]).87 LEEP was not associated with an increased risk of perinatal mortality, preterm birth prior to 32 to 34 weeks, or preterm labor prior to 28 to 30 weeks. One included study evaluated the impact of LEEP on low birthweight and found no significant increased risk of low birthweight less than 2,000 or 1,500 grams. Ablative procedures (2 studies of cryotherapy and 4 of laser ablation) were not associated with an increased risk of preterm birth, perinatal mortality, or low birthweight.

Neither of the two reviews addressed the relationship between the depth of the tissue specimen excised and preterm birth, or addressed important confounders such as socioeconomic status and previous preterm birth. One recent large retrospective U.S. cohort study, published after these two reviews, found no increased risk of preterm birth associated with LEEP.88

Efforts to Prevent HPV Infection

HPV vaccination may allow disease prevention early in the progression to cervical cancer, before persistent HPV infection is established. In 2006, the FDA approved the Merck vaccine GARDASIL for multiple indications, including use in females aged 9 to 26 years for prevention of diseases including CIN and cervical cancer. GARDASIL is a quadrivalent vaccine against HPV types 6, 11, 16, and 18 and is given in a three-dose schedule.89 More recently (2009), CERVARIX by GlaxoSmithKline, a bivalent vaccine against HPV types 16 and 18, has also been approved for the prevention of CIN and cervical cancer in females aged 10 to 25 years.90

Clinical trials of GARDASIL,91 CERVARIX,92 and their precursors showed vaccine efficacy of close to 100 percent for prevention of CIN2+ related to HPV 16 or 18 among women who were HPV negative at enrollment. Among all women enrolled, regardless of baseline HPV status, efficacy was much lower: 44 percent for GARDASIL and 53 percent for CERVARIX. Thus, HPV vaccination93 is expected to be most effective before HPV exposure. Sexually active women, however, can also receive and benefit from vaccination. Since the two approved vaccines protect against just two of the 15 common oncogenic HPV types, efficacy against cervical lesions irrespective of HPV type is also lower, about 20 to 30 percent among all women enrolled.

Current Clinical Practice

A 2004 survey of 2,980 nonfederal, nonmilitary U.S. clinicians performing cervical cancer screening indicates that LBC is the primary screening modality used by the majority of clinicians surveyed. In addition, the majority reported that they had ordered an HPV test in response to abnormal cytology. According to the survey, 22 percent (range, 8 to 42% by specialty) of clinicians used CC only, and 65 percent (range, 45 to 78%) used LBC only.94 Of the various clinical specialties surveyed, 78 percent of obstetricians reported use of LBC only, versus 45 percent of adolescent medicine specialists. Overall, 21 percent of clinicians (range, 11 to 37%) ever ordered or collected an HPV DNA test as an adjunct to cytology to be run regardless of the cytology result, and 63 percent (range, 44 to 91%) ever ordered or collected an HPV DNA test to be run in response to abnormal or borderline cervical cytology results. Of the 21 percent of clinicians who reported ever using HPV tests as an adjunct to cytology, more reported testing women younger than age 30 years (35% [range, 27 to 46%]) than women aged 30 years or older (29% [range, 9 to 36%]). Currently, the FDA has only approved the HPV DNA test (HC2) for 1) screening patients with ASC-US cytology to determine the need for referral to colposcopy, and 2) use in women aged 30 years or older as an adjunct to cytology to assess the absence or presence of high-risk HPV types.70,71 Clearly, current use is beyond FDA approval.

Previous USPSTF Recommendation

In 2003, the USPSTF found good evidence that screening with cervical cytology reduces incidence of, and mortality from, cervical cancer.94 It strongly recommended screening for cervical cancer in women who have been sexually active and have a cervix (A recommendation). The USPSTF found limited evidence to determine the benefits of continued screening in women older than age 65 years and fair evidence that screening in this age group is associated with an increased risk for potential harms; thus, it recommended against routinely screening women older than age 65 years for cervical cancer if they have had adequate recent screening with normal Pap smears and are not otherwise at high risk for cervical cancer (D recommendation). The USPSTF found fair evidence that the yield of cytologic screening in women after hysterectomy is very low. It found poor evidence that screening to detect vaginal cancer improves health outcomes, and recommended against routine screening in women who have had a total hysterectomy for benign disease (D recommendation). The USPSTF concluded that the evidence was insufficient to recommend for or against the routine use of new technologies (such as LBC or automated screening) to screen for cervical cancer (I statement). Finally, the USPSTF concluded that the evidence was insufficient to recommend for or against the routine use of HPV testing as a primary screening test for cervical cancer (I statement).

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