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[ACOG] Cervical Cytology 2009.pdf CLINICAL MANAGEMENT GUIDELINES FOR OBSTETRICIAN–GYNECOLOGISTS NUMBER 109, DECEMBER 2009 (Replaces Practice Bulletin Number 45, August 2003, Committee Opinion Number 300, October 2004, and Committee Opinion Number 431, May 2009) This Practice Bulletin was devel- oped by the ACOG Committee on Practice Bulletins—Gynecology with the assistance of Alan Waxman, MD. The information is designed to aid practitioners in making deci- sions about appropriate obstetric and gynecologic care. These guide- lines should not be construed as dic- tating an exclusive course of treatment or procedure. Variations in practice may be warranted based on the needs of the individual patient, resources, and limitations unique to the institution or type of practice. Cervical Cytology Screening The incidence of cervical cancer has decreased more than 50% in the past 30 years because of widespread screening with cervical cytology. In 1975, the rate was 14.8 per 100,000 women in the United States; by 2006, it had been reduced to 6.5 per 100,000 women. Mortality from the disease has undergone a similar decrease (1). The American Cancer Society estimates 11,270 new cases of cer- vical cancer in the United States in 2009, with 4,070 deaths from the disease (2). Recent estimates worldwide, however, are of almost 500,000 new cases and 240,000 deaths from the disease per year (3). When cervical cytology screening programs have been introduced into communities, marked reductions in cervical cancer incidence have followed (4–6). New technology for performing cervical cancer screening is evolving rapidly, as are recommendations for classifying and interpreting the results. The pur- pose of this document is to provide a review of the best available evidence on screening for cervical cancer. Specific equipment and techniques for perform- ing cervical cytology and interpretation of the results are not discussed. Background Despite the demonstrated success of cervical cancer screening, it is estimated that 50% of the women in whom cervical cancer is diagnosed each year have never had cervical cytology testing. Another 10% had not been screened within the 5 years before diagnosis (7). Thus, one approach to reducing the incidence and mortality of cervical cancer would be to increase screening rates among women who currently are not screened or who are screened infrequently. Although rates of cervical cancer are on the decline in women born in the United States, women who are immigrants to the United States from countries where cervical cytology screening is not the norm are an especially high-risk group (8). ACOG PRACTICE BULLETIN THE AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS WOMEN’S HEALTH CARE PHYSICIANS 2 ACOG Practice Bulletin No. 109 Addressing Errors in Cervical Cytology In some cases, cervical cancer is undetected despite a recent screening test because of errors in sampling, inter- pretation, or follow-up. Sampling errors occur when dys- plastic cells on the cervix are not transferred to the slide; errors of interpretation are attributed to lack of recogni- tion of abnormal cells in the laboratory. These two sources of false-negative test results are associated with 30% of the new cases of cervical cancer each year (7, 9). The problem of errors in interpretation is compounded by inconsistency among cytologists. When results of monolayer cytology specimens were reviewed by quality control pathologists, only negative and low-grade squa- mous intraepithelial lesion (LSIL) readings had greater than 50% consistency (10). Most revised results were downgraded to lesser diagnoses. Of those reported as atypical squamous cells of undetermined significance (ASC-US), 39% were downgraded to negative on further review. Of those originally interpreted as high-grade squamous intraepithelial lesions (HSIL), 53% were rein- terpreted as LSIL, ASC-US, or negative (11). Natural History of Cervical Neoplasia Infection with human papillomavirus (HPV) is a neces- sary factor in the development of squamous cervical neo- plasia; however, most HPV-infected women will not develop significant cervical abnormalities (10, 12–15). The infection is easily transmitted during sexual inter- course. Most women, especially younger women, have an effective immune response that clears the infection or reduces the viral load to undetectable levels in an aver- age of 8–24 months (12, 16–22). Factors that determine which HPV infections will develop into squamous intraepithelial lesions have been poorly identified. The HPV type and the persistence of an HPV infection are perhaps the most important determinants of progression (12). Cigarette smoking may be a cofactor, and a com- promised immune system appears to play a role in some women (12). Despite decades of study, the natural history of cer- vical intraepithelial lesions is still not completely under- stood. The oncogenic agent is well established to be one of 15–18 “high-risk” types of HPV (23). The once widely held concept that low-grade lesions are necessary pre- cursors to the high-grade lesions and subsequent invasive cancer has been questioned (10, 12, 15, 24). Human papillomavirus infections are most common in teenagers and women in their early 20s, with preva- lence decreasing as women age (25–28). In adolescents and young women, HPV infections and dysplasia are likely to resolve spontaneously (16, 17, 19, 29–31). This suggests that HPV infections found in older women are more likely to reflect persistent infections acquired in the past, and correlates well with increasing rates of HSIL with increasing age. The recent introduction of a vaccine targeting HPV-16 and HPV-18, the two most common cancer causing HPV types, has advanced the promise of primary prevention of cervical cancer. The vaccine does not protect women against approximately 30% of cervical cancer caused by HPV types other than HPV-16 and HPV-18. Further- more, women already exposed to HPV-16 and HPV-18 can expect a lower level of protection from the vaccine than the nearly 100% protection demonstrated in clinical trials involving women not exposed to the virus (32, 33). If immunization is widely implemented, it has been pro- posed that the impact in terms of reduction in cervical cancer will not begin to be realized for another 15–20 years (34). In the meantime, secondary prevention, through a screening regimen of cervical cytology with or without concomitant HPV DNA testing remains the best approach to protecting women from cervical cancer. Women who have been immunized against HPV-16 and HPV-18 should be screened by the same regimen as non- immunized women. Understanding the natural history of HPV infection is important to establishing a balance between sufficient testing to prevent cancer, while avoid- ing overtesting with its increased cost and morbidity. Techniques of Cervical Cytology Both liquid-based and conventional methods of cervical cytology screening are acceptable for screening. The majority of cervical cytology screening performed in the United States uses a liquid-based process. According to a 2003 survey, nearly 90% of obstetrician—gynecolo- gists use liquid-based cytology (35). Exfoliated cells are collected from the transformation zone of the cervix and may be transferred to a vial of liquid preservative that is processed in the laboratory to produce a slide for inter- pretation—the liquid-based technique—or may be transferred directly to the slide and fixed using the con- ventional technique. Performance of conventional cervi- cal cytology requires avoidance of contaminating blood, discharge, and lubricant. The liquid-based technology will filter out most contaminating blood and inflammatory cells and debris. A small amount of lubricant may be used on the speculum and will remain on the vaginal walls prior to reaching the cervix. Lubricant on the cervix itself will interfere with the transfer of cells. Even with the liq- uid-based technique, heavy menstrual blood may limit the number of squamous cells available for interpretation. Prompt suspension of the cells in the liquid eliminates the problem of air drying artifact, which may limit the inter- pretation of conventional cervical cytology. ACOG Practice Bulletin No. 109 3 The use of liquid-based cytology has advantages and disadvantages compared with conventional cervical cytology screening. The principal disadvantages are the higher cost and a decreased specificity. The advantages are in the convenience of being able to test for HPV, gonorrhea, and chlamydial infection directly from the residual sample after the cells have been extracted for cytology. In addition, cytotechnologists find liquid-based tests easier to read. Some studies have found fewer “unsatisfactory” results, although this claim has not been consistent (36). Whether the liquid-based cytology tests are more sensitive or specific is unclear. A meta-analysis of eight studies identified by the authors to be method- ologically sound found no significant difference in sen- sitivity or specificity between the two technologies in their ability to diagnose cervical intraepithelial neoplasia 2 (CIN 2) or higher using a cytology threshold of LSIL or HSIL. If the threshold for colposcopy was lowered to ASC-US, however, the liquid-based cytology had a sig- nificantly lower specificity (37). Cytologic Reporting The nomenclature for reporting cervical cytology results has undergone several changes since the publication of the original Papanicolaou system. The Bethesda System of reporting is the most widely used system in the United States. First proposed in 1988, it was revised in 1991 and again in 2001 (38–40). Highlights of the 2001 Bethesda System classification are summarized as follows (40): • Specimen adequacy—Slides are to be reported as “sat- isfactory” or “unsatisfactory” for interpretation. The presence or absence of an endocervical or transforma- tion zone component is described in the narrative por- tion of the laboratory report, as are other quality indicators, such as partly obscuring inflammation or blood. If a slide is categorized as unsatisfactory, the reason should be specified. If abnormalities are found on an otherwise unsatisfactory slide, it will, by defini- tion, be considered satisfactory for interpretation. • Negative for intraepithelial lesion or malignancy— This designation should be used for slides with no cytologic evidence of neoplasia. When specific organisms are identified (eg, Trichomonas vaginalis, Candida species, shift in flora suggestive of bacter- ial vaginosis, bacteria consistent with Actinomyces species, and cellular changes consistent with herpes simplex virus), they are reported and categorized as “negative for intraepithelial lesion or malignancy.” Other nonneoplastic findings, including reactive cellular changes associated with inflammation, radi- ation, or an intrauterine device, as well as glandu- lar cells posthysterectomy or atrophy, also may be included in this category. Endometrial cells found in a woman aged 40 years or older will be listed under this category, but the finding of endometrial cells will not be reported routinely if noted in a woman younger than 40 years. A finding of endometrial cells on cytology in asymptomatic premenopausal women is rarely associated with significant pathology (41). • Atypical squamous cells (ASC)—The epithelial abnormality ASC is diagnosed when the degree of nuclear atypia is not sufficient to warrant a diag- nosis of squamous intraepithelial lesion. It is sub- categorized into “atypical squamous cells of undetermined significance” (ASC-US) and “atypi- cal squamous cells cannot exclude HSIL” (ASC-H). The category ASC-H includes those cytologic changes suggestive of HSIL but lacking sufficient criteria for definitive interpretation. The literature suggests ASC-H should represent 5–15% of the total pool of ASC but would have a significantly higher predictive value for diagnosing CIN 2 or CIN 3 than ASC-US (42, 43). • Atypical glandular cells—This term designates cells exhibiting atypia that are of glandular rather than squamous origin and replaces the term “atypical glandular cells of undetermined significance.” The finding of atypical glandular cells on cytology is more likely to be associated with both squamous and glandular abnormalities than is ASC-US, and the workup required of atypical glandular cells is more aggressive (44, 45). • The 2001 terminology subdivides atypical glandular cells by cell type, ie, atypical endocervical cells, atypical endometrial cells, or atypical glandular cells not otherwise specified. The subdivision of “favor neoplastic” is maintained in the 2001 report- ing system. Because sufficient cytologic criteria exist to designate endocervical adenocarcinoma and ade- nocarcinoma in situ, these two findings are reported when identified. • Low-grade squamous intraepithelial lesions—As in the original terminology, the 2001 nomenclature combines cytologic findings of CIN 1 (mild dyspla- sia) and those consistent with HPV infections into the category LSIL. • High-grade squamous intraepithelial lesions—The category of HSIL combines CIN 2 and CIN 3 (mod- erate dysplasia, severe dysplasia, and carcinoma in situ). • Squamous cell carcinoma • The absence of endocervical cells or a transforma- tion zone component may reflect that the transfor- 4 ACOG Practice Bulletin No. 109 mation zone was not well sampled. This finding is common in pregnant women and in postmenopausal women in whom the transformation zone has receded onto the canal. Data conflict as to whether the lack of these cells is associated with an increase in squa- mous intraepithelial lesions. Women with this find- ing whose recent cervical cytology test results have been normal without intervening findings of ASC-US or worse may be monitored by repeat cervical cytol- ogy screening in 1 year. Others, including those with incompletely evaluated abnormal test results, incom- pletely visualized cervix, immunocompromised status, and poor prior screening, should have repeat cervi- cal cytology screening within 6 months. Pregnant women lacking endocervical cells or transformation zone component should have repeat cervical cytol- ogy screening postpartum (45, 46). Clinical Considerations and Recommendations When should screening begin? Cervical cancer screening should begin at age 21 years. Cervical neoplasia develops in susceptible individuals in response to a sexually transmitted infection with a high- risk type of HPV (12–14, 20, 21). Human papillomavirus causes carcinogenesis in the transformation zone of the cervix, where the process of squamous metaplasia replaces columnar with squamous epithelium (12). Squa- mous metaplasia is active in the cervix during adolescence and early adulthood. Human papillomavirus infections are commonly acquired by young women shortly after the ini- tiation of vaginal intercourse (16–20) but, in most, they are cleared by the immune system within 1–2 years with- out producing neoplastic changes (12, 16, 17, 22). The risk of neoplastic transformation increases in those women whose infections persist (12, 47, 48). Further evidence for this model comes from studies of age-specific prevalence of HPV infections, which consistently show a high prevalence of infection in teenagers, peaking in the third decade of life with a sub- sequent decrease (25–28). In a report of 10,090 Pap tests in females aged 12–18 years, 422 (5.7%) were reported as LSIL and only 55 (0.7%) were HSIL (49). Moreover, most dysplasia in adolescents regresses spontaneously. A prospective study of 187 women aged 18–22 years with LSIL found that 61% and 91% had reverted to negative after 1 and 3 years of follow-up respectively. Only 3% progressed to CIN 3 (29). Two smaller studies of adoles- cents with biopsy confirmed CIN 2 showed 65% and 75% regression to negative after 18 months and 3 years respectively (30, 31). In contrast to the high rate of infection with HPV in sexually active adolescents, invasive cervical cancer is very rare in women younger than age 21 years. Only 0.1% of cases of cervical cancer occur before age 21 years (50). In a recent analysis of national data from 1998 through 2003, researchers from the Centers for Disease Control and Prevention identified an average of only 14 cases of invasive cancer each year in females aged 15–19 years. Cancer cases in adolescents younger than 15 years were too few to report. Based on this report and Surveillance Epidemiology and End Results (SEER) data from 2002–2006, this translates to an incidence rate of 1–2 cases of cervical cancer per 1,000,000 females aged 15–19 years (1, 50). The recommendation to start screening at age 21 years regardless of the age of onset of sexual intercourse is based in part on the very low incidence of cancer in younger women. It is also based on the potential for adverse effects associated with follow-up of young women with abnormal cytology screening results. The American College of Obstetricians and Gyne- cologists endorsed the 2006 recommendations of the American Society for Colposcopy and Cervical Path- ology regarding management of adolescents with abnor- mal cytology and cervical biopsy results (51). These guidelines stress a conservative approach to women younger than 21 years found to have ASC-US or LSIL on cytology and most with histology findings less than CIN 3. Delaying the onset of screening until age 21 years is a logical incremental step in practice guidelines, con- sistent with this conservative approach to management of adolescents with cervical test result abnormalities. Earlier onset of screening may increase anxiety, morbidity, and expense from the test itself and overuse of follow-up procedures. The emotional impact of labeling an adolescent with both a sexually transmitted infection and a potential precancer must be considered because adolescence is a time of heightened concern for self- image and emerging sexuality. Although cancer is rare in adolescents, dysplasia is not uncommon. An abnormal cervical cytology screening test leads to a sequence of additional tests designed to identify those with CIN 2 or worse. However, recent studies have documented a significant increase in premature births in women previously treated with excisional procedures for dysplasia (52). Because adolescents have most or all of their childbearing years ahead of them, it is important to avoid unnecessary excision or ablation of the cervix. Sexually active adolescents, ie, females younger than 21 years, should be counseled and tested for sexually transmitted infections, and should be counseled regard- ACOG Practice Bulletin No. 109 5 ing safe sex and contraception. These measures may be carried out without cervical cytology screening and, in the asymptomatic patient, without the use of a speculum. What is the optimal frequency of cervical cytology screening? Cervical cytology screening is recommended every 2 years for women aged 21–29 years, with either conven- tional or liquid-based cytology. Women aged 30 years and older who have had three consecutive cervical cytol- ogy test results that are negative for intraepithelial lesions and malignancy may be screened every 3 years. Certain risk factors have been associated with CIN in observational studies; women with any of the following risk factors may require more frequent cervical cytology screening: • Women who are infected with human immunodefi- ciency virus (HIV) • Women who are immunosuppressed (such as those who have received renal transplants) • Women who were exposed to diethylstilbestrol in utero • Women previously treated for CIN 2, CIN 3, or cancer Women infected with HIV should have cervical cyto- logy screening twice in the first year after diagnosis and annually thereafter (53). Women treated in the past for CIN 2, CIN 3, or cancer remain at risk for persistent or recurrent disease for at least 20 years after treatment and after initial posttreatment surveillance and should con- tinue to have annual screening for at least 20 years (54–58). The optimal number of negative cervical cytology test results needed to reduce the false-negative rate to a minimum has not been determined (59, 60). It has been demonstrated, however, that the rate of dysplasia decreases as the number of sequential negative Pap test results increases (61). Studies over the past several decades have shown that in an organized program of cervical can- cer screening, annual cytology examinations offer little advantage over screening performed at 2- or 3-year inter- vals (62–65). One study that did show an increase in relative risk of cancer with screening at a 3- versus 1-year intervals, found no significant difference between screening at 2- versus 3-years. The absolute risk in this well-screened population, however, was very low (66). An evaluation of 31,728 women aged 30–64 years screened in the National Breast and Cervical Cancer Early Detection Program, found a prevalence of CIN 2 and CIN 3 of 0.028% and 0.019%, respectively among those who had three or more negative Pap test results in a row. There were no cases of invasive cancer in this group. Using a computer model, they calculated the risk of these women developing invasive cancer and estimated 4 women with cancer per 100,000 women over the next 3 years with annual Pap screening and 8 women with cancer per 100,000 women with triennial screening. Although this represents a doubling of cases with pro- longing the interval to 3 years, the absolute number of cases, 4 women with cancer per 100,000 women, is very small, and the estimated cost of finding each additional case of cancer was large (61). Formal cost-effective analysis of data from this national program showed that the most cost-effective strategy for cervical cancer screening is cytology testing no more often than every 3 years in women with prior normal screening test results (67). Moreover, regardless of age, annual Pap testing was never found to be cost- effective (67). In several studies, age was shown to play a role in the sensitivity of screening. A negative cervical cytology screening result confers less protection on women younger than 30 years than in older women (61, 65, 68). A recent British study of 4,012 women aged 20–69 years with invasive cancer showed that whereas cytology screening in 3 years prior to diagnosis offered a 60% and 80% reduction in the incidence of cervical cancer at ages 40 years and 64 years respectively, screening between age 20 years and 24 years provided no significant reduc- tion in invasive cancer in women younger than 30 years (69). In a woman aged 30 years or older who is known to have multiple recent consecutive negative cervical cytol- ogy test results, the risk of developing CIN 3 or cancer is low, and screening at 3-year intervals is a safe, cost- effective approach, with either conventional or liquid- based cytology (37, 70). Published studies have assumed a program of cervi- cal cancer screening and follow-up. Most women in the United States get opportunistic screening as their insur- ance carriers and providers change. Patients are fre- quently inaccurate in recalling the timing and results of recent screening, more often underestimating the time elapsed and incorrectly recalling abnormal results as normal (71–74). Therefore, it is important for the physi- cian to assess a new patient’s screening history—ie, the date of her most recent cervical cytology test, frequency and results of her prior tests, or prior abnormal test results and management. It is important to educate patients about the nature of cervical cytology, its limitations, and the rationale for prolonging the screening interval beyond every year. In addition, regardless of the frequency of cervical cytology screening, physicians also should inform their patients ...