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Cervical Cancer Screening: Revised Guidelines

Sally Mravcak, MD

Current thought about the etiology of cervical cancer and what constitutes appropriate screening has evolved over the past several years. A number of key factors are driving current cervical cancer screening recommendations, including evidence establishing the link between human papillomavirus (HPV) and cervical cancer, revisions in the Bethesda-system terminology used to report Papanicolaou (Pap) results, new techniques for screening (eg, the ThinPrep liquid-based collection system, the hybrid capture 2 HPV DNA test), and updated guidelines for managing abnormal Pap smears.

EPIDEMIOLOGY

Cervical cancer is the third most common gynecologic malignancy in the United States. The incidence of cervical cancer is 9.2 per 100,000 (age-adjusted for the US standard population in 2000).¹ Largely because of screening, however, cervical cancer incidence has decreased by 77.7% from 1950 to 2001.² Since the advent of the Pap smear in the 1940s, the mortality from cervical cancer has been reduced by as much as 70%.³

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ETIOLOGY

Genital HPV can be divided into types that are oncogenic and associated with a high risk of cervical cancer (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), and types that are nononcogenic and associated with a low risk of cervical cancer (types 6, 11, 42, 43, and 44). The high-risk HPV types are found in 99.7% of cervical cancers, whereas the low-risk types usually cause benign condylomata.^4,5 This link between oncogenic HPV types and cervical cancer becomes clinically relevant when considering Pap smears reported as atypical squamous cells of undetermined significance.⁶

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DISEASE COURSE

The time to progression to cervical cancer is an important concept in understanding screening. It is well established that cervical infection with HPV causes cervical neoplasia. Cervical cancer arises from precursor lesions, which may be transient or may progress to high-grade, preinvasive lesions and eventually invasive cancer. Although HPV infection is necessary for the development of cervical cancer, many more women become infected with HPV compared with the number of women that ultimately develop cervical cancer.⁷ In a study of young women positive for HPV by Moscicki et al,⁸ up to 70% of low-grade squamous intraepithelial lesions (LSIL) resolved spontaneously during follow-up of 1 to 2 years. Persistently positive tests for oncogenic HPV types was a significant risk factor for the development of high-grade squamous intraepithelial lesions (HSIL).⁸

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REVISED TERMINOLOGY

Over the past few years, there have been several significant changes in the Bethesda Reporting System:

• Slides are now reported as "satisfactory" or "unsatisfactory," eliminating the descriptor "satisfactory but limited by..." If a slide is "unsatisfactory," the reason is specified.
• The description "benign cellular changes" has been eliminated. Slides with no cytologic evidence of malignancy are reported as "negative for intraepithelial lesion or malignancy."
• The general "atypical squamous cells of undetermined significance" designation has been replaced by "atypical squamous cells" (ASC), with subcategories "atypical squamous cells of undetermined significance" ASC-US and "atypical squamous cells, cannot rule out HSIL" (ASC-H). The term "favor reactive" has been eliminated when describing ASC.
• The cytologic description of LSIL is synonymous with the histologic description of "grade 1 cervical intraepithelial neoplasia" (CIN 1).
• The cytologic description of HSIL is synonymous with the histologic descriptions of grades 2 and 3 CIN (CIN 2, CIN 3).
• Atypical glandular cells (AGC) are noted with a subdivision describing the type of atypical cells (ie, "atypical endocervical cells," "atypical endometrial cells," or "atypical glandular cells not otherwise specified"). This replaces "atypical glandular cells of undetermined significance" (AGUS). The modifier "favor dysplasia" has been retained in this case.⁹

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SCREENING

The prevalence of genital HPV infection is highest among sexually active women in their teens and 20s, decreasing after age 30 years.7 Consideration of risk factors for cervical dysplasia should be a part of determining which women should be screened (Table 1). There are various recommendations by different organizations for the age to start screening for cervical cancer:

• The American Cancer Society (ACS) recommends initiation of cytology screening 3 years after the onset of vaginal intercourse, or no later than age 21 years.¹¹
• The United States Preventive Services Task Force (USPSTF) suggests starting screening in women who have been sexually active, and indicates that there is indirect evidence that screening should be started within 3 years of the onset of sexual activity or by age 21 years, although there is no direct evidence to determine the optimal starting age.¹²
• Recommendations by the American College of Obstetricians and Gynecologists (ACOG) echo those proposed by the ACS.⁹

• The ACS suggests discontinuation of screening in women older than age 70 years who have an intact uterus, three consecutive negative cytologic tests, and no positive tests in the previous 10 years. Screening should continue past age 70 years if the patient is in reasonably good health (without a life-limiting condition) and screening was never performed; if information about previous screening is not available; or if there is a history of cervical cancer, human immunodeficiency virus (HIV), immunosuppression, or in-utero exposure to diethylstilbestrol (DES).¹¹
• The USPSTF recommends discontinuing screening in women older than age 65 years if there has been adequate recent screening with normal Pap findings. Screening should continue if the patient has never been screened or if information about previous screenings is not available.¹²
• The ACOG recommendations endorse those of the ACS and USPSTF.⁹

• For the conventional Pap smear, the ACS suggests annual screening until age 30 years, then screening every 2 to 3 years if there are three consecutive negative test results. However, if there is a history of in-utero DES exposure, HIV, or immunosuppression, yearly or more frequent screening should continue.¹¹
• If using the liquid-based Pap technique, screening should occur every 2 years for women younger than age 30 years. The screening interval can be lengthened in women aged 30 years and older who have had three consecutive negative results every 2 to 3 years, unless there is a history of in-utero DES exposure, HIV, or immunosuppression.¹¹
• The USPSTF recommends screening at least every 3 years.¹²
• Unlike the ACS, ACOG does not base its recommendations on the screening method used (conventional versus liquid-based). The ACOG suggests annual screening before age 30 years, and screening every 2 to 3 years if three consecutive negative Pap results are obtained at age 30 years or older. More frequent screening should be performed in women with HIV, in-utero DES exposure, or immunosuppression .⁹

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SPECIAL POPULATIONS

Hysterectomy for Benign Reasons

If a patient undergoes a total hysterectomy (removal of the uterus and cervix) for benign reasons, continued screening depends on the history of results of previous Pap smears. Women with no history of HSIL who have undergone a total hysterectomy for benign reasons may discontinue screening.^9,11,12 If the patient has a history of HSIL prior to a hysterectomy for benign reasons, screening should continue until there are three consecutive negative Pap smears and no abnormal Pap tests in a 10-year period.^9,11 Screening should continue in women with in-utero exposure to DES and in women who had a supracervical hysterectomy (removal of the uterus but not the cervix).¹¹


Hysterectomy for Malignancy

Screening every 4 to 6 months is suggested if the reason for total hysterectomy was HSIL (CIN 2/3), and can be stopped when there are three documented, consecutive negative Pap smears and no Pap smears are abnormal within 18 to 24 months after the hysterectomy.¹¹


Human Immunodeficiency Virus

The screening recommendations for women with HIV are based on the consideration that decreased immunity is a risk for progression of cervical lesions.¹⁵ The prevalence of CIN in HIV-positive women rises as immunosuppression increases and cluster-of-differentiation-antigen-4 (CD4) counts decrease.¹⁶ Therefore, it is suggested that cervical cytology be performed twice in the first year after diagnosis of HIV, and annually thereafter if the first two Pap smears are normal.^9,16


Low-Resource Settings

Certainly it is desirable in a setting with limited resources to find the safest, most cost-effective way to decrease morbidity and mortality from cervical cancer. An ACOG policy statement has described the "single-visit approach" as a safe, acceptable, and cost-effective method of cervical cancer prevention that overcomes the obstacles found in cytology-based screening/treatment. The single-visit approach combines visual inspection of the cervix after washing with acetic acid, with immediate cryotherapy for any abnormal-appearing lesions.¹⁷

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TECHNIQUE

There are several technologies available for use in cervical cancer screening: the conventional Pap smear, the liquid-based Pap smear, HPV DNA testing, and PapSure. A health care provider must consider the pros and cons of each screening method carefully—including sensitivity, specificity, and cost—before choosing the screening method that will best fit his or her practice.


Conventional Papanicolaou Smear

The sensitivity of the conventional Pap smear is reportedly 80%, with a specificity of 99%.¹⁸ False-negative rates are high (up to 50%),¹⁹ mostly due to blood, mucus, inflammation, air-drying artifact, or areas of thick cellularity.²⁰ If the Pap smear result is ASC-US, HPV DNA testing is indicated in a follow-up visit.


Liquid-Based Papanicolaou Test

The liquid-based Pap test offers an interesting alternative to the conventional Pap smear. Cells are placed into a liquid fixative before transport to the laboratory. At the laboratory, samples are spun, filtered, and transferred to glass slides in an even distribution to create slides with a thin layer of cells.²¹ This process has several technical advantages, including decreased obscuring material (blood and mucus), no areas of thick cellularity, well preserved cellular morphology in a thin layer, and the absence of air-drying. Reportedly, the liquid-based Pap test also offers a higher sensitivity compared with the conventional Pap smear. The specificity is comparable to that of the conventional Pap smear, but some sources contend that the liquid-based test is slightly less specific while others state that it is more specific; these differences have not been shown to be statistically significant, however.²² Perhaps the greatest advantage of the liquid-based Pap test is that if the screening result is ASC-US, the clinician has the option to request that the laboratory undertake HPV testing using the previously collected specimen, saving the patient another visit to the office for HPV testing. The major disadvantage of liquid-based testing is its increased cost. A conventional Pap smear can cost $25 to $40, whereas the liquid-based test can cost $45 to $60—which may or may not be covered by medical insurance, in full or in part.

Seventeen studies show that results of the liquid-based Pap test and the conventional Pap smear agree in 90% of cases.^22,23 The liquid-based Pap test tended to have about 8% higher sensitivity. Interestingly, the liquid-based test classifies 6.5% of conventional Pap smears that were normal as abnormal (0.36% were HSIL, and 0.007% were invasive carcinoma). This implies that of the 45 million conventional Pap smears read as normal, 162,000 would show HSIL, and more than 3,000 would show invasive carcinoma.²² Economically, the liquid-based test is cost-effective if used at 3-year intervals.²³


Cytology Plus HPV DNA Testing

The use of HPV DNA testing has recently been approved for screening by the US Food and Drug Administration (FDA) for use in combination with cytology (either conventional Pap smear or liquid-based test). Human papillomavirus testing is widely used when a cytology result is read as ASC-US, but using HPV testing in conjunction with cytology screening regardless of cytology results is not yet a widely accepted practice. In light of this and the recent FDA approval, the National Institutes of Health/National Cancer Institute, American Society of Colposcopy and Cervical Pathology, and ACS developed a consensus recommendation for the use of HPV plus cytology until more research is completed.²⁴

According to the consensus recommendations, HPV DNA testing can be added to cytology for screening of women over age 30 years. If results are negative for both HPV DNA and cytology, there is no need to screen again for 3 years. If the cytology is negative but the HPV DNA test is positive, repeat screening with both cytology and HPV DNA testing is indicated in 6 to 12 months, as the likelihood of developing high-grade neoplasia is low. In the aforementioned scenario of negative cytology and a positive HPV DNA test, if repeated results are positive for either cytology or HPV DNA, the clinician should proceed to colposcopy.²⁴

There are several benefits to using cytology plus HPV DNA testing. Some studies have concluded that testing for high-risk HPV types alone identifies more women with HSIL than does a single cervical cytology test alone. When HPV DNA testing is used in addition to cytology, the sensitivity is improved compared with HPV testing alone.²⁴

Cytology in combination with HPV DNA testing does carry a potential negative impact, however. Because HPV is common, screening by testing for HPV will identify many women who are HPV-positive, few of whom will have cervical cancer or a high-grade lesion. Women positive for HPV DNA may be subjected to unnecessary intensive follow-up or treatment. When using HPV DNA testing plus cytology, the frequency of screening should be reduced and conservative follow-up recommendations should be developed for HPV-positive, cytology-negative women.²⁴

The USPSTF concluded that there is no significant evidence to recommend HPV testing as a primary screening test, whereas the ACS has stated that it is reasonable to use HPV testing plus cervical cytology in women aged 30 years and older. While ACOG has acknowledged the FDA approval of HPV DNA testing plus cervical cytology, no formal recommendations have been made.²⁴


Visual Screening

PapSure is an in-office, noninvasive method for performing a direct visual screening examination of the cervix; it has been approved by the FDA for use in all women undergoing Pap smears. Such screening is performed in addition to the Pap smear, and begins with activating and attaching a chemiluminescent light to the inside of the upper blade of the speculum. When the Pap smear is complete, the cervix is washed with acetic acid and inspected after 60 seconds for acetowhite areas using a 6X magnifying lens.²⁵

This visual technique may be an interesting screening option for the future. Two large-scale screening studies found that it more than doubled the sensitivity for detecting cervical abnormalities, with a small decrease in specificity.²⁵ Currently, this method of screening is not widely used, so information on cost-effectiveness and its impact on cervical cancer morbidity and mortality is not readily available. It is not currently recommended for screening by any major organizations.


Recommendations Summary

The USPSTF states that there is insufficient evidence to recommend for or against the routine use of new technologies to screen for cervical cancer,¹² but the ACS notes that liquid-based testing may be used instead of the conventional Pap smear as long as the screening interval is lengthened to every 2 years.¹¹ When deciding whether to use the conventional Pap smear versus liquid-based cytology, ACOG advises considering the patient's screening history, the cost of the test, and the possible impact of false-negative or false-positive results.⁹ Deciding on a screening method is not simple, and the well-informed clinician should consider sensitivity, specificity, cost, patient convenience, and expectations before choosing a cervical cancer screening method for the office.

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MANAGEMENT OF ABNORMAL FINDINGS

There are new guidelines for the management of an initial abnormal Pap smear (Figure).^6,26 Data from the ASCUS-LSIL Triage Study linking cervical cancer to infection with oncogenic HPV has changed the way ASC-US is handled.⁶

Click to enlarge

Figure. Management of initial abnormal Pap smear.

A Pap smear read as ASC-US should be tested for HPV. If the HPV DNA is negative for high-risk types, it is appropriate to repeat a Pap smear in 12 months. If the HPV DNA is positive for high-risk types, colposcopy is the next appropriate step. A patient with a Pap smear read as ASC-H should proceed directly to colposcopy, as ASC-H suggests that the pathologist could not rule out HSIL. Patients with Pap smears read as LSIL or HSIL should also proceed directly to colposcopy. In the case of a Pap smear reading atypical glandular cells, if the descriptors "not otherwise specified" or "favor neoplasia" are used, colposcopy, endocervical curettage, cervical biopsy when appropriate, and endometrial biopsy must be considered.^6,25 A full discussion of the management of AGC is beyond the scope of this article, as is the management of cervical dysplasia status-post colposcopy.

In the absence of endocervical cells or the presence of partially obscuring blood on a Pap smear, the clinician should consider the patient's previous Pap findings. If the previous cytology has been normal, a Pap smear should be repeated in 1 year. If there has been past ASC-US or worse, or if there are other incompletely evaluated tests, immunosuppression, or poor prior screening, the Pap smear should be repeated in 6 months.⁹

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CONCLUSION

Recommendations for cervical cancer screening and the reporting of results are in flux, and are likely to remain so for some time while techniques and the knowledge base continue to evolve. While disparities persist among recommendations by major national organizations (Table 2), clinicians must keep abreast of all of the latest information, selecting the approaches that best suit their individual patients and practice settings.

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Sally Mravcak, MD, is a women's health fellow, Department of Family Medicine, University of Medicine and Dentistry of New Jersey- Robert Wood Johnson Medical School, New Brunswick.

References

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