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INTRODUCTION
Unlike other gynecological cancers, cervical cancer has some distinct characteristics. First, sexual activity is strongly related to the development of this cancer. Second, cervical cancer is almost always preceded by precancerous lesions, namely, cervical intraepithelial neoplasias (CIN). Third, the precancerous stage is quite long and ranges from 7 to 20 years, which enables early diagnosis at this stage [1]. Fourth, as compared with other organs, the cervix can be easily exposed using a speculum, which makes clinical procedures more feasible.
Various screening guidelines for abnormal cervical cytology have been developed for the early diagnosis and treatment of precancerous lesions, and these guidelines are used worldwide [2-5]. However, most of the current guidelines were developed in the United States; thus, these guidelines may not be useful for Koreans. For example, the incidence of cervical cancer in Korea is much higher than that in Western countries, although it has been decreasing gradually over the past decade [6,7]. Moreover, the costs associated with the Papanicolaou (Pap) test, human papillomavirus (HPV) DNA test, and colposcopy are lower in Korea than that in the United States. Consequently, the development of Korean-specific guidelines for cervical cancer screening is necessary.
GUIDELINE DEVELOPMENT PROCESS
Since the reconvening of the consensus guideline development committee in March 2012, numerous workshops and conferences have been held. Many experts, including gynecologic oncologists representing the Korean Society of Gynecologic Oncology, pathologists representing the Korean Society for Cytopathology, and statisticians working in preventive medicine, were involved in this committee. The committee was further divided into the 5 subcommittees for the following themes: 1) cervical cancer screening tests, 2) atypical squamous cells (ASC) and atypical glandular cells (AGC), 3) low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL), 4) HPV DNA tests, and 5) special situations including those involving adolescent and pregnant women. Each subcommittee consisted of 1 chairperson, 1 secretary, and 4-5 members.
The guidelines were developed based on preexisting guidelines developed by the American Society for Colposcopy and Cervical Pathology [2], the National Comprehensive Cancer Network [3], the United States Preventive Services Task Force [4], and the Institute for Clinical Systems Improvement [5]. Some guidelines were created de novo, whereas some were adaptations of the aforementioned guidelines. In either case, every effort was made to reflect specific situations in Korea, for example, the high incidence of cervical cancer, low medical costs, and distinct characteristics of the medical service systems.
Each subcommittee created several key questions and performed a literature review to provide supporting evidence. Recommendations were then developed, revised, and approved through vigorous discussions among members at multiple workshops, small group meetings, and public hearings as well as through a web-based survey. Each recommendation was rated as "H (high)," "M (moderate)," "L (low)," "VL (very low)," or "E (expert consensus or lack of evidence)" according to the level of evidence [8,9]. Each recommendation was also rated as "S (strong)" or "W (weak)" following discussions among members of each subcommittee. In this paper, the ratings for each recommendation are provided as VLS, MS, etc. within parenthesis, where VLS stands for very low and strong, MS for moderate and strong, and so on.
The terminology used for this guideline adhered to the 2001 Bethesda system. Abnormal morphology that may represent preinvasive squamous disease fell into 4 descriptive categories: ASC, AGC, LSIL, and HSIL. Clinical judgment should be used first when applying a guideline to an individual patient because the guideline may not reflect all situations.
CONSENSUS GUIDELINES
1. General screening guidelines
All women ≥20 years of age who have commenced sexual activities should undergo cervical cancer screening tests (VLS) [10-15]. In contrast, routine cervical cancer screening tests are not recommended for women under 20 years of age because despite the high incidence of HPV infection, spontaneous regression occurs frequently, and there is a very low incidence of invasive cervical cancer. Screening tests can however be performed when cervical cancer or preinvasive disease is suspected. Cervical cancer screening tests can be discontinued in women ≥70 years old after 3 consecutive negative Pap tests within 10 years (ES). However, a woman should continue undergoing screening tests regardless of age if she has a history of CIN grade 2 or greater or if she does not know her previous Pap test results. Considering the relatively high incidence of cervical cancer in Korea, easy access to the screening test, and relatively low medical cost, annual screening using the Pap test alone is recommended for 20-year-old to 70-year-old women. However, a 3-year interval is recommended in Western countries (ES).
According to the previous literature, liquid-based cytology did not show improved sensitivity or specificity when compared with conventional cytology [16-20]. However, the use of liquid-based cytology decreases the number of inadequate specimens. Considering the situation in Korea, either test can be chosen as a screening test (MS). A combination of cervical cytology and cervicography is not generally recommended due to increased false-positive results and low cost-effectiveness; however, this combination might be beneficial in terms of sensitivity (LW) [21-23].
Most newly acquired HPV infections regress spontaneously, and HPV DNA positivity decreases with age following a peak in adolescents and in women in their 20s [24]. Therefore, the HPV DNA test in combination with a cervical cytology test is recommended for women ≥30 years old (HS) [25-43]. When both tests are negative, the screening interval can be extended to 2 years (HS). Although the prevalence of invasive cervical cancer and preinvasive diseases is expected to decrease due to vaccination, a change in the screening interval should be considered after more clinical data have accumulated (EW). A woman who has undergone hysterectomy should continue with screening tests if she has a history of CIN grade 2 or greater or if she does not know her previous cytology results (ES).
2. Atypical squamous cells
ASC is further divided into ASC-undetermined significance (ASC-US) and ASC-cannot exclude a high grade squamous intraepithelial lesion (ASC-H). The risks of high-grade CIN and invasive cervical cancer are low in women with ASC-US versus those with ASC-H [44]. Excision or ablative therapies are not recommended for these patients in order to avoid potential overtreatment. Because of the high prevalence of CIN grades 2 and 3 among women with ASC-H, the management of these patients is almost the same as that of patients with HSIL.
1) Recommended management of women with ASC-US
Repeat cytological tests, a high-risk HPV DNA test, and an immediate colposcopy are all acceptable management strategies for ≥20-year-old women with ASC-US (HS) [45-48]. When repeat cytology with a 6-month interval is chosen, colposcopy should be performed if the result of repeat cytology is ASC-US or greater [2]. After 2 consecutive "negative for intraepithelial lesion or malignancy" cytology results, the patient can return to routine screening. When an HPV DNA test is chosen for follow-up, a colposcopy should be performed if high-risk HPV is detected [2]. If immediate colposcopy is required and the colposcopy is satisfactory, the recommended management of women with CIN grade 1 or less is either an HPV DNA test at 12 months or repeat cytological tests at 6 and 12 months (MS) [49,50]. Women can return to routine screening after 2 consecutive "negative for intraepithelial lesion or malignancy" cytology results 6 months apart or a negative HPV DNA test result at 12 months (ES). However, if CIN grade 2 or 3 is identified, a diagnostic excisional procedure should be performed.
2) Recommended management of women with ASC-H
The recommended management of women with ASC-H is referral for a colposcopic examination [2]. A review of cytological, histological, and colposcopic findings can be performed if a colposcopy-directed biopsy did not indicate CIN grade 2 or greater (EW). Cervical cytology and colposcopy can be performed at 6-month intervals if a colposcopy-directed biopsy did not indicate CIN grade 2 or greater (ES). These women can return to routine screening if 2 consecutive cytology and colposcopy results obtained 6 months apart are negative (ES). If CIN grade 2 or 3 is identified after colposcopy-directed biopsy, a diagnostic excisional procedure should be performed.
3. Atypical glandular cells
Although AGC frequently arise due to benign conditions such as reactive cellular changes or polyps, they are associated with a clinically significant lesion (including CIN, cervical adenocarcinoma in situ [AIS], cervical cancer, and endometrial, ovarian, and fallopian tube cancers) in 45% of patients [2,51]. Previous studies have noted that 9%-38% of women with AGC have a clinically significant neoplasia such as CIN grade 2 or 3, AIS, or cancer [2]. Gynecologic cancer is less common in women ≤35 years of age compared to women above 35 years of age [2]. No single test has sufficient sensitivity to be utilized as an initial triage for women with AGC [52]. Therefore, multiple testing modalities should be used during the initial evaluation.
1) Recommended management of women with AGC
For women with cytological AGC, an HPV DNA test, colposcopy, and endocervical curettage (ECC) are recommended (VLS) [44,53-56]. An endometrial biopsy is also recommended for women ≥35 years of age (VLS) [44,55,56]. However, it is only recommended for women <35 years of age if they have risk factors for endometrial cancer such as obesity, infertility, anovulation, or polycystic ovarian syndrome; if they have undergone tamoxifen therapy; or if they have abnormal vaginal bleeding or atypical endometrial cells; or if they have family history of colorectal or endometrial cancer [3]. If colposcopy-directed biopsy and ECC identify CIN grades 1-3 or AIS, a diagnostic excisional procedure should be performed. However, women with satisfactory colposcopy results revealing CIN grade 1 and negative ECC may be managed conservatively either with repeat cervical cytology every 6 months or with an HPV DNA test at 12 months. Colposcopy is recommended for women with a follow-up cytology indicating ASC-US or greater [3].
4. Low-grade squamous intraepithelial lesion
An LSIL is closely associated with a high risk of HPV infection. A recent meta-analysis showed that the overall HPV prevalence and the estimated HPV 16/18-positive fractions were 72.9% and 26.7%, respectively, in women with LSIL [57]. Based on colposcopy-directed biopsy, the rate of CIN grade 2, CIN grade 3, or cancer in women with LSIL was reported to be 11%-14% [58,59].
1) Recommended management of women with LSIL
Colposcopy is recommended for women with LSIL (MS) [60]. The management of those with LSIL depends on whether the full transformation zone can be visualized by colposcopic examination, i.e., whether a satisfactory colposcopy can be achieved. ECC should be considered for patients in whom no lesions are identified and for those with an unsatisfactory colposcopy (with the exception of pregnant women) [2,3]. When CIN grade 2 or 3 is identified by ECC, excisional procedures should be performed. Repeat cervical cytology at 6 and 12 months or an HPV DNA test at 12 months is recommended as follow-up management for patients in whom CIN grade 2 or 3 is not detected by colposcopy-directed biopsy or in whom biopsy is not performed (ES). Excision or ablation is not recommended for these women. A return to routine screening is recommended if 2 consecutive cervical cytological tests are negative for intraepithelial lesions or malignancies or if an HPV DNA test is negative during follow-up. Referral for colposcopy is recommended if ASC-US or greater is identified by follow-up cytology or if an HPV DNA test is positive. If CIN grade 2 or 3 is detected following colposcopy-directed biopsy, a diagnostic excisional procedure is recommended [2,3].
5. High-grade squamous intraepithelial lesion
Cytological HSIL is accompanied by a significant risk of high-grade cervical disease or cancer. Histological CIN grade 2 or greater can be identified in 60%-70% of women with HSIL by colposcopy-directed biopsy, and CIN 2 or greater is diagnosed in 84%-97% of women who underwent a loop electrosurgical excision procedure [2,61]. Up to 18.8% of women with HSIL have invasive cervical cancer [62]. Therefore, follow-up of women with HSIL with an HPV DNA test or cervical cytology is inappropriate. Because colposcopy can miss a significant number of high-grade lesions, a majority of women will eventually undergo diagnostic excisional procedures [2].
1) Recommended management of women with HSIL
In cases of HSIL (with the exception of adolescent women), immediate diagnostic excisional procedures, including loop electrosurgical excision or conization, can be performed without colposcopic examination [63-65] (VLS). If colposcopic examination is elected, management of women with HSIL depends on whether the colposcopic examination was satisfactory or unsatisfactory. For those with a satisfactory colposcopy, management depends on whether the lesion was observable or not. When lesions cannot be visualized by colposcopy, ECC should be performed in women with no lesions or in those who have not undergone biopsy [3]. If ECC is negative, cytology and colposcopy should be repeated every 6 months until 2 consecutive negative results can be confirmed. If ECC is positive for CIN, diagnostic excisional procedures should be performed. When lesions are observable, 3 management options can be chosen if CIN grade 2 or greater is not identified following colposcopy-directed biopsy: diagnostic excisional procedures (VLS), review of cytological and histological specimens (ES), or observation with colposcopy and cytology at 6-month intervals for 1 year (ES). After 1 year of observation, women with 2 consecutive "negative for intraepithelial lesion or malignancy" cytological tests or negative colposcopy results can return to a routine screening program (ES). However, a diagnostic excisional procedure should be performed if the follow-up cytology shows HSIL. If CIN grade 2 or 3 is detected by colposcopy-directed biopsy at initial presentation, treatment with an excisional procedure should be performed [66]. When the presence of residual disease at the resection margin after an excisional procedure cannot be determined, cervical cytology can be performed at 6 months or an HPV DNA test can be performed at 12 months (ES).
6. HPV DNA test
Although cervical cytology has contributed to the early detection of CIN and cervical cancer, its shortcomings as a screening test (e.g., high false-negativity) are not negligible [67]. Moreover, because infection with high-risk HPV is now considered a necessary cause of cervical cancer, tests for high-risk HPV have been proposed as adjuncts to cervical cytology tests. Evidence from previous literature indicates that the HPV DNA test has superior sensitivity for the detection of CIN grade 2 or greater as compared with cervical cytology [17,68-73]. A Canadian randomized study comparing cervical cytology with the HPV DNA test in 9,667 women aged 30-69 years demonstrated that the sensitivities of cervical cytology, the HPV DNA test, and both tests combined for the detection of CIN grade 2 or greater were 56.4%, 97.4%, and 100%, respectively [70], while their specificities were 97.3%, 94.3%, and 92.5%, respectively. Women who are negative for both cytology and the HPV DNA test have a less than 1 in 1,000 risk of having CIN grade 2 or greater, and the risk of developing CIN grade 3 is very low [74,75].
An HPV DNA test can be performed as an adjunct test to cervical cytology in women aged 30 years and older to reduce the high false-negativity of cytology (HS) [68-73]. In addition to the Hybrid Capture 2 (HC2; Qiagen, Gaithersburg, MD, USA) test approved by the United States Food and Drug Administration, other HPV DNA detection methods including HPV DNA chip tests and polymerase chain reaction (PCR)-based HPV detection kits are commonly used in Korea. These tests were comparable to the HC2 test with respect to their sensitivity and specificity for the detection of CIN grade 2 or greater and their concordance with HPV positivity [62,76-78]. Considering the specific situation in Korea and evidence from previous validation studies, HPV DNA chip tests and various PCR-based HPV detection kits can be used for the detection of HPV infection (LW) [76-79].
Many women in the screened populations who are positive for HPV infection show negative cervical cytology. The overall prevalence of HPV positivity was 6.5%, and 58% of HPV-positive women had negative cytology [80]. Moreover, the risk of missing the diagnosis of CIN grade 2 or greater during routine screening is quite low (2.4%-5.1%) in women who are cytology-negative and HPV-positive [81,82]. It is important to determine which of these women are more likely to develop high-grade CIN or cancer. During a 10-year follow-up of cytology-negative, HPV-positive women ≥30 years of age, CIN grade 3 was detected in 21% and 18% of those carrying HPV 16 and 18, respectively [75]. In contrast, the risk of CIN grade 3 in women with other high-risk HPVs was only 1.5%. Based on these results, which indicate a differential risk of developing high-grade CIN depending on HPV genotype, an HPV genotyping test is recommended for cytology-negative, HPV-positive women (LS) [74,75,83,84]. If HPV 16 or 18 is detected, referral to a gynecologic oncologist and a colposcopic examination are recommended (LS). In women who are positive for HPVs other than HPV 16 or 18, an HPV DNA test and HPV genotyping test can be performed 1 year later (LS).
7. Special situations
1) Management of adolescent women
The management of cervical abnormalities requires special consideration in adolescents and women younger than 20 years of age. Previous studies indicate that the majority of young women will be infected with HPV within several years of commencement of sexual activities [69,85,86]. Because of the high prevalence of HPV and frequent regression in these women, routine HPV DNA testing is not recommended for those with cytological ASC-US or LSIL (LS) [86-88]. Instead, a regular follow-up with annual cytology is recommended. If cytology results at 12 months indicate HSIL or greater, the patient should be referred for colposcopy [2,3]. If cytology results at 24 months indicate ASC-US or greater, referral for colposcopy is also recommended [2,3].
Colposcopy is recommended if the initial cytology reveals ASC-H because of the increased risk of CIN grade 2 or greater [3]. When colposcopy is satisfactory, repeat cytology at 6 months is recommended if CIN grade 2 or 3 is not identified. The patient can return to routine screening after 2 consecutive negative cytology tests. However, colposcopy should be performed if cytology at 6 months reveals ASC-US or greater. When CIN grade 2 or 3 is identified, there are 2 management options: 1) excision or ablation, or 2) observation with cytology and colposcopy every 6 months. Patients with unsatisfactory colposcopy results should undergo ECC and cervical biopsy [3].
In adolescents with HSIL, colposcopy is recommended [2,3], although immediate excisional procedures are not. If histological CIN grade 2 or 3 is not identified, follow-up with cytology and colposcopy at 6-month intervals for up to 2 years is preferred. During follow-up, if a high-grade colposcopic lesion is identified or if HSIL persists for 1 year, biopsy should be performed. When HSIL persists for 24 months without identifiable CIN grade 2 or 3, excisional procedures should be performed. After 2 consecutive negative cytology results and no evidence of high-grade colposcopic abnormalities, adolescents can return to routine screening. When CIN grade 2 or 3 is histologically confirmed, either excision/ablation or cytology and colposcopy every 6 months up to 24 months can be selected. Patients with unsatisfactory colposcopy results should undergo ECC and cervical biopsy [3].
2) Management of pregnant women
The management of nonadolescent pregnant women with ASC-US or LSIL is identical to that of nonpregnant women with ASC-US or LSIL. ECC is not permitted in pregnant women. Deferring the initial colposcopy until at least 6 weeks postpartum is a safe and acceptable management option for pregnant women with either ASC-US or LSIL (LS) [89,90]. Colposcopy is recommended for pregnant women with HSIL, and biopsy should be performed if high-grade CIN or cancer is suspected [2,3]. Among 78 women with histologically proven CIN grade 2 or 3, 48 (62%) showed disease regression during postpartum assessment [91]. No cases of invasive cancer were identified during follow-up. According to another prospective study on pregnant women with CIN grade 2 or 3 who were followed-up with colposcopy and/or cytology, nearly half of the enrolled women showed regression of the initial disease, and none showed progression to invasive cancer [92]. If CIN grade 2 or 3 (but not invasive cancer) is identified histologically, diagnostic excisional procedures can be deferred until postpartum (LS).
8. Follow-up after treatment of CIN with excisional procedures or ablation
When ablative treatments such as laser therapy or cryotherapy are performed, the surgical margins cannot be assessed. In these cases, follow-up with cervical cytology at 6 months or an HPV DNA test at 12 months is recommended [93]. Treatment of women initially managed with excisional procedures, such as the loop electrosurgical excisional procedure or conization, depends on the status of the resection margins. Cervical cytology at 6 months or an HPV DNA test at 12 months is recommended for women with CIN grade 2 or 3 with negative margins and for all women with CIN grade 1 [3]. For women with CIN grade 2 or 3 with positive margins, 3 options are available: 1) cervical cytology at 6 months, 2) ECC, or 3) re-excision if invasion is suspected or hysterectomy after a consultation with a specialist. If cervical cytology at 6 months indicates ASC-US or greater, management should be performed as per the guidelines previously mentioned. For women with negative cytology results or a negative HPV DNA test, routine screening can be resumed. If an HPV DNA test is positive at 12 months, the patient should be referred for colposcopy.
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