日本産科婦人科学会/日本産婦人科医会：産婦人科診療ガイドライン婦人科外来編2023、 CQ201 p35-37.
日本産科婦人科学会/日本産婦人科医会：産婦人科診療ガイドライン婦人科外来編2023、 CQ203 p41-43.
日本産科婦人科学会/日本産婦人科医会：産婦人科診療ガイドライン婦人科外来編2023、 CQ204 p44-46.
日本産科婦人科学会/日本産婦人科医会：産婦人科診療ガイドライン婦人科外来編2023、 CQ208 p55-57.
Fontham ETH, Wolf AMD, Church TR, Etzioni R, Flowers CR, Herzig A, Guerra CE, Oeffinger KC, Shih YT, Walter LC, Kim JJ, Andrews KS, DeSantis CE, Fedewa SA, Manassaram-Baptiste D, Saslow D, Wender RC, Smith RA.
Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society.
CA Cancer J Clin. 2020 Sep;70(5):321-346. doi: 10.3322/caac.21628. Epub 2020 Jul 30.
Abstract/Text
The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation). The ACS recommends that individuals aged >65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening (qualified recommendation). These new screening recommendations differ in 4 important respects compared with the 2012 recommendations: 1) The preferred screening strategy is primary HPV testing every 5 years, with cotesting and cytology alone acceptable where access to US Food and Drug Administration-approved primary HPV testing is not yet available; 2) the recommended age to start screening is 25 years rather than 21 years; 3) primary HPV testing, as well as cotesting or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years; and 4) the guideline is transitional, ie, options for screening with cotesting or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers. Evidence related to other relevant issues was reviewed, and no changes were made to recommendations for screening intervals, age or criteria for screening cessation, screening based on vaccination status, or screening after hysterectomy. Follow-up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.
© 2020 American Cancer Society.
Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J.
Liquid compared with conventional cervical cytology: a systematic review and meta-analysis.
Obstet Gynecol. 2008 Jan;111(1):167-77. doi: 10.1097/01.AOG.0000296488.85807.b3.
Abstract/Text
OBJECTIVE: To compare test performance characteristics of conventional Pap tests and liquid-based cervical cytology samples.
DATA SOURCES: Eligible studies, published between 1991 and 2007, were retrieved through PubMed/EmBase searching and completed by consultation of other sources.
METHODS OF STUDY SELECTION: Studies were selected if a conventional and a liquid-based sample were prepared from the same woman or when one or the other type of sample was taken from a separate but similar cohort. The current systematic review and meta-analysis is restricted to studies where all subjects were submitted to gold standard verification, based on colposcopy and histology of colposcopy-targeted biopsies, allowing computation of absolute and relative test validity for cervical intraepithelial neoplasia grade 2 or worse. Randomized trials were selected as well if all test-positive cases were verified with the same gold standard, allowing computation of the relative sensitivity. Impact of study characteristics on accuracy was assessed by subgroup meta-analyses, meta-regression, and summary receiver operating characteristic curve regression.
TABULATION, INTEGRATION, AND RESULTS: The relative sensitivity, pooled from eight studies, with complete gold standard verification and from one randomized clinical trial, did not differ significantly from unity. Also, the specificity, considering high-grade and low-grade squamous intraepithelial lesions as cutoff, was similar in conventional and liquid cytology. However, a lower pooled specificity was found for liquid-based cytology when presence of atypical squamous cells of undetermined significance was the cutoff (ratio 0.91, 95% confidence interval 0.84-0.98). Differences in study characteristics did not explain interstudy heterogeneity.
CONCLUSION: Liquid-based cervical cytology is neither more sensitive nor more specific for detection of high-grade cervical intraepithelial neoplasia compared with the conventional Pap test.
Wright TC Jr, Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, Hatch K, Noller KL, Roach N, Runowicz C, Saslow D.
Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening.
Obstet Gynecol. 2004 Feb;103(2):304-9. doi: 10.1097/01.AOG.0000109426.82624.f8.
Abstract/Text
Human papillomavirus (HPV) DNA testing was recently approved by the Food and Drug Administration for use as an adjunct to cytology for cervical cancer screening. To help provide guidance to clinicians and patients when using HPV DNA testing as an adjunct to cervical cytology for screening, a workshop was cosponsored by the National Institutes of Health-National Cancer Institute, American Society of Colposcopy and Cervical Pathology (ASCCP), and American Cancer Society. Consensus was reached based on a literature review, expert opinion, and unpublished results from large ongoing screening studies. The conclusions of the workshop were that HPV DNA testing may be added to cervical cytology for screening in women aged 30 years or more. Women whose results are negative by both HPV DNA testing and cytology should not be rescreened before 3 years. Women whose results are negative by cytology, but are high-risk HPV DNA positive, are at a relatively low risk of having high-grade cervical neoplasia, and colposcopy should not be performed routinely in this setting. Instead, HPV DNA testing along with cervical cytology should be repeated in these women at 6 to 12 months. If test results of either are abnormal, colposcopy should then be performed. This guidance should assist clinicians in utilizing HPV DNA testing in an effective manner, while minimizing unnecessary evaluations and treatments.
宮城悦子：子宮頸がん予防―日本はどうする？. 産婦人科の実際. 2020, 69(3): p219.
Martin-Hirsch P, Lilford R, Jarvis G, Kitchener HC.
Efficacy of cervical-smear collection devices: a systematic review and meta-analysis.
Lancet. 1999 Nov 20;354(9192):1763-70. doi: 10.1016/s0140-6736(99)02353-3.
Abstract/Text
BACKGROUND: Few randomised controlled trials have sufficient power to show clear advantages of different designs of cervical-smear collection devices. We studied by systematic review whether the design of cervical-smear devices affects rates of inadequate smears and detection of disease and whether the presence of endocervical cells in the smear affects detection of disease.
METHODS: We sought relevant randomised controlled trials by computer literature review by MEDLINE backed up by a manual search of 16 journals. Each trial was classified according to methodological quality criteria. Odds ratios were calculated where data allowed.
FINDINGS: 34 randomised controlled trials investigating cervical Papanicolaou smear collection devices were identified. All 34 trials compared the ability of devices to collect endocervical cells, and 19 compared the ability of devices to detect dyskaryosis. Meta-analyses showed that compared with other collection devices, the Ayre's spatula is an ineffective device for collecting endocervical cells (for example, odds ratio for comparison of extended-tip spatulas vs Ayre's spatula 2.25 [95% CI 2.06-2.44]) and also gives a lower yield of dyskaryosis (odds ratio for comparison of extended-tip spatulas vs Ayre's spatula 1.21 [1.20-1.33]). Devices that effectively collect endocervical cells also detect a higher proportion of abnormal cytology than those that do not.
INTERPRETATION: The widely used Ayre's spatula is the least effective device for cervical sampling and should be superseded by extended-tip spatulas for primary screening and investigation of women before and after treatment for cervical intraepithelial neoplasia. The presence of endocervical cells is a valid and convenient surrogate for the ability to detect dyskaryosis.
Koonings PP, Dickinson K, d'Ablaing G 3rd, Schlaerth JB.
A randomized clinical trial comparing the Cytobrush and cotton swab for Papanicolaou smears.
Obstet Gynecol. 1992 Aug;80(2):241-5.
Abstract/Text
OBJECTIVE: We sought to determine whether use of the Cytobrush/spatula or the cotton swab/spatula is better in obtaining satisfactory Papanicolaou smears as defined by the Bethesda System.
METHODS: This 1-year randomized trial was performed at the Los Angeles County + University of Southern California Women's Hospital colposcopy clinic. Participants were all nonpregnant patients referred to the colposcopy clinic for abnormal Papanicolaou smears. The main outcome measurement was the effectiveness in obtaining satisfactory Papanicolaou smears as defined by the Bethesda System. Data were analyzed using the Pearson chi 2 test.
RESULTS: The sampling methods had similar abilities to obtain a satisfactory smear (Cytobrush/spatula 63%, cotton swab/spatula 57%; P = .23). Less-than-optimal smears accounted for 28% of the Cytobrush group and 38% of the cotton-swab group. The Cytobrush was superior in its ability to obtain endocervical cells (Cytobrush 80%, cotton swab 60%; P less than .01). Both sampling methods had similar rates of correlation with histologic diagnosis. No complications were associated with either technique.
CONCLUSIONS: The Cytobrush/spatula is superior to the cotton swab/spatula in obtaining endocervical cells. There appears to be no difference in each method's ability to obtain satisfactory smears. Application of the Bethesda System results in a significant number of less-than-optimal smears using either technique.
Arbyn M, Herbert A, Schenck U, Nieminen P, Jordan J, Mcgoogan E, Patnick J, Bergeron C, Baldauf JJ, Klinkhamer P, Bulten J, Martin-Hirsch P.
European guidelines for quality assurance in cervical cancer screening: recommendations for collecting samples for conventional and liquid-based cytology.
Cytopathology. 2007 Jun;18(3):133-9. doi: 10.1111/j.1365-2303.2007.00464.x.
Abstract/Text
The current paper presents an annex in the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. It provides guidance on how to make a satisfactory conventional Pap smear or a liquid-based cytology (LBC) sample. Practitioners taking samples for cytology should first explain to the woman the purpose, the procedure and how the result will be communicated. Three sampling methods are considered as acceptable for preparing conventional Pap smears: (i) the cervical broom; (ii) the combination of a spatula and an endocervical brush; and (iii) the extended tip spatula. Smear takers should take care to sample the entire circumference of the transformation zone, to quickly spread the cellular material over a glass slide, and to fix the preparation within a few seconds to avoid drying artefacts. According to local guidelines, one of these three methods may be preferred. Sampling with a cotton tip applicator is inappropriate. Similar procedures should be followed for sampling cells for LBC, but only plastic devices may be used. The collected cells should be quickly transferred into a vial with fixative liquid according to the instructions of the manufacturer of the LBC system. Subsequently, the slide or vial and the completed request form are sent to the laboratory for cytological interpretation.
有効性評価に基づく子宮頸がん検診ガイドライン2019年度版.
Kjaer S, Høgdall E, Frederiksen K, Munk C, van den Brule A, Svare E, Meijer C, Lorincz A, Iftner T.
The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period.
Cancer Res. 2006 Nov 1;66(21):10630-6. doi: 10.1158/0008-5472.CAN-06-1057. Epub 2006 Oct 23.
Abstract/Text
In spite of the success of cervical cytology as a cancer-screening tool, it has important limitations, and human papillomavirus (HPV) testing may be valuable in future screening. The majority of women in screened populations, who test HPV positive, will have a concurrent normal smear, and we need more information about the risk for subsequent high-grade cervical lesions in these women. We examined 8,656 younger women (22-32 years old) and 1,578 older women (40-50 years old) who were followed for development of cervical neoplasia (cytology and/or histology) through the Danish Pathology Data Bank. We estimated the proportion of women developing cervical lesions of different types before a given time point as a function of time. Among women with normal cytology and positive high-risk Hybrid Capture 2 (HC2) test, 17.7% and 24.5% of younger and older women, respectively, had a subsequent abnormal Pap smear within 5 years. The risk of CIN3 or cancer within 10 years among younger women with positive HC2 test was 13.6% (10.9-16.2) and 21.2% (2.7-36.1) among older women. An analysis among younger women also being HC2-positive 2 years before baseline showed a subsequent 10-year risk of > or =CIN3 of 18% (14.6-21.5). Among older women where HPV may be added to general screening, the estimated absolute risk of > or =CIN3 in HC2-positive women was more than 20% within 10 years. These results indicate that even a single positive HPV test in cytologically negative women is substantially predictive of high-grade CIN and suggest that HC2 testing can help stratify women into different risk categories.
Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, Rush BB, Glass AG, Schiffman M.
The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice.
J Natl Cancer Inst. 2005 Jul 20;97(14):1072-9. doi: 10.1093/jnci/dji187.
Abstract/Text
BACKGROUND: Human papillomavirus (HPV) types 16 and 18 cause 60%-70% of cervical cancer worldwide, and other HPV types cause virtually all remaining cases. Pooled HPV testing for 13 oncogenic types, including HPV16 and 18, is currently used in clinical practice for triage of equivocal cytology and, in conjunction with Pap tests, is an option for general screening among women 30 years of age and older. It is not clear to what extent individual identification of HPV16 or HPV18 as an adjunct to pooled oncogenic HPV testing might effectively identify women at particularly high risk of cervical cancer or its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3).
METHODS: From April 1, 1989, to November 2, 1990, a total of 20 810 women in the Kaiser Permanente health plan in Portland, OR, enrolled in a cohort study of HPV and cervical neoplasia. Women were tested for 13 oncogenic HPV types by Hybrid Capture 2 (HC2), and those women with a positive HC2 test were tested for HPV16 and 18. Enrollment Pap smear interpretation and HPV test results were linked to histologically confirmed CIN3 and cervical cancer (> or = CIN3) occurring during 10 years of cytologic follow-up. We calculated cumulative incidence rates with 95% confidence intervals for each interval up to 122 months using Kaplan-Meier methods.
RESULTS: The 10-year cumulative incidence rates of > or = CIN3 were 17.2% (95% confidence interval [CI] = 11.5% to 22.9%) among HPV16+ women and 13.6% (95% CI = 3.6% to 23.7%) among HPV18+ (HPV16-) women, but only 3.0% (95% CI = 1.9% to 4.2%) among HC2+ women negative for HPV16 or HPV18. The 10-year cumulative incidence among HC2- women was 0.8% (95% CI = 0.6% to 1.1%). A subanalysis among women 30 years of age and older with normal cytology at enrollment strengthened the observed risk differences.
CONCLUSIONS: HPV screening that distinguishes HPV16 and HPV18 from other oncogenic HPV types may identify women at the greatest risk of > or = CIN3 and may permit less aggressive management of other women with oncogenic HPV infections.
Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, Szarewski A, Birembaut P, Kulasingam S, Sasieni P, Iftner T.
Overview of the European and North American studies on HPV testing in primary cervical cancer screening.
Int J Cancer. 2006 Sep 1;119(5):1095-101. doi: 10.1002/ijc.21955.
Abstract/Text
Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35-49 and 50+. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy.
Copyright 2006 Wiley-Liss, Inc.
Cox JT, Schiffman M, Solomon D; ASCUS-LSIL Triage Study (ALTS) Group.
Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy.
Am J Obstet Gynecol. 2003 Jun;188(6):1406-12. doi: 10.1067/mob.2003.461.
Abstract/Text
OBJECTIVE: The purpose of this study was to determine the risk of cumulative cervical intraepithelial neoplasia (CIN) grade 2 or 3 according to initial colposcopy and directed biopsy results among women with low-grade squamous intraepithelial lesions (LSIL) or human papillomavirus (HPV) DNA positive atypical squamous cells of undetermined significance (ASCUS).
STUDY DESIGN: A 2-year follow-up of 897 cases of LSIL and 1193 cases of HPV DNA positive ASCUS from the ASCUS/LSIL Triage Study was used to simulate American Society for Colposcopy and Cervical Pathology Consensus Conference recommendations. Women with CIN grade 1 or less were followed up for 2 years by semiannual cytologic examination, with universal exit colposcopy. The clinical end point was a cumulative clinical center histologic diagnosis of CIN grade 2 or 3.
RESULTS: The cumulative risk of CIN grade 2 or 3 was equivalent for LSIL (27.6%) and HPV positive ASCUS (26.7%). After excluding the women with a diagnosis of CIN grade 2 or 3 at initial colposcopy and directed biopsy (17.9%), the remaining women were at nearly identical risk for subsequent CIN grade 2 or 3 regardless of initial colposcopy result (completely negative colposcopy-11.3%; negative colposcopically directed biopsy-11.7%; and CIN grade 1 biopsy-13.0%).
CONCLUSION: LSIL and HPV positive ASCUS are clinically equivalent. Initial colposcopic detection of obviously prevalent CIN grade 2 or 3 reduces risk. However, for the remaining women who have CIN grade 1 or less on colposcopy and directed biopsy, the risk for subsequent CIN grade 2 or 3 (whether missed, prevalent, or truly incident) is approximately 12% over 2 years. This risk does not vary meaningfully by initial distinction of histologic CIN grade 1 from negative colposcopy and biopsy.
Safaeian M, Solomon D, Wacholder S, Schiffman M, Castle P.
Risk of precancer and follow-up management strategies for women with human papillomavirus-negative atypical squamous cells of undetermined significance.
Obstet Gynecol. 2007 Jun;109(6):1325-31. doi: 10.1097/01.AOG.0000263461.71732.40.
Abstract/Text
OBJECTIVE: To investigate the relative performances of follow-up cytology and carcinogenic human papillomavirus (HPV) DNA testing among carcinogenic HPV-negative women with atypical squamous cells of undetermined significance (ASCUS), for detection of cervical precancer.
METHODS: Twelve-month follow-up management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3) or worse using cytology or HPV testing or both were compared among women with HPV-negative ASCUS in the Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study.
RESULTS: Overall only 22 of 1,559 (1.4%) HPV-negative ASCUS women developed CIN grade 3 or worse during follow-up compared with 269 of 1,767 (15.2%) HPV-positive ASCUS women (P<.001). Because of the low risk of disease among HPV-negative ASCUS women, only 7 cases of CIN3 were diagnosed between 12 and 24 months of follow-up, limiting power to distinguish meaningful differences in sensitivity among 12-month testing strategies. The specificity of HPV testing (84%) was significantly higher than cytology using an ASCUS threshold (71%) (P<.001). Cotesting with cytology and HPV testing at 12 months resulted in even lower specificity (61%). Because cases were uncommon, the positive predictive value for subsequent CIN3 or worse was low for cytology (2.6%), Hybrid Capture 2 (3.8%), and cotesting with cytology and HPV testing (2.2%). The negative predictive value for all three management strategies was very high (99.70%, 99.82%, and 100.0% for HPV testing, cytology, or cotesting, respectively.)
CONCLUSION: Women with HPV-negative ASCUS have very low absolute risk of subsequently detected CIN3 or worse in the subsequent 2 years, similar to women with a negative cytology in the absence of HPV testing. The results suggest that women with HPV-negative ASCUS should return to routine screening intervals which may be longer than 1 year depending on age and screening history. However, if increased surveillance is chosen, a single HPV test for carcinogenic types at 12 months has significantly higher specificity and lower referrals than cytology.
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D; 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference.
2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests.
Am J Obstet Gynecol. 2007 Oct;197(4):346-55. doi: 10.1016/j.ajog.2007.07.047.
Abstract/Text
A group of 146 experts representing 29 organizations and professional societies met September 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. Recommendations for managing atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion (LSIL) are essentially unchanged. Changes were made for managing these conditions in adolescents for whom cytological follow-up for 2 years was approved. Recommendations for managing high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells (AGC) also underwent only minor modifications. More emphasis is placed on immediate screen-and-treat approaches for HSIL. Human papillomavirus (HPV) testing is incorporated into the management of AGC after their initial evaluation with colposcopy and endometrial sampling. The 2004 Interim Guidance for HPV testing as an adjunct to cervical cytology for screening in women 30 years of age and older was formally adopted with only very minor modifications.
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ACOG Practice Bulletin No. 99: management of abnormal cervical cytology and histology.
Obstet Gynecol. 2008 Dec;112(6):1419-1444. doi: 10.1097/AOG.0b013e318192497c.
Abstract/Text
Recent evidence has shown that the risk of malignant and premalignant cervical disease and human papillomavirus (HPV) infections varies significantly with age (1,2). Furthermore, evidence now shows that treatment for cervical disease carries significant risk for future pregnancies (3-7). These factors have led to a re-evaluation of the guidelines for the management of premalignant cervical disease. The purpose of this document is to define strategies for diagnosis and management of abnormal cervical cytology and histology results. In this document, HPV refers to high-risk oncogenic forms of the virus.
日本産科婦人科学会/日本産婦人科医会：産婦人科診療ガイドライン婦人科外来編2023、CQ203 p41-43.
Arbyn M, Redman CWE, Verdoodt F, Kyrgiou M, Tzafetas M, Ghaem-Maghami S, Petry KU, Leeson S, Bergeron C, Nieminen P, Gondry J, Reich O, Moss EL.
Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis.
Lancet Oncol. 2017 Dec;18(12):1665-1679. doi: 10.1016/S1470-2045(17)30700-3. Epub 2017 Nov 7.
Abstract/Text
BACKGROUND: Incomplete excision of cervical precancer is associated with therapeutic failure and is therefore considered as a quality indicator of clinical practice. Conversely, the risk of preterm birth is reported to correlate with size of cervical excision and therefore balancing the risk of adequate treatment with iatrogenic harm is challenging. We reviewed the literature with an aim to reveal whether incomplete excision, reflected by presence of precancerous tissue at the section margins, or post-treatment HPV testing are accurate predictors of treatment failure.
METHODS: We did a systematic review and meta-analysis to assess the risk of therapeutic failure associated with the histological status of the margins of the tissue excised to treat cervical precancer. We estimated the accuracy of the margin status to predict occurrence of residual or recurrent high-grade cervical intraepithelial neoplasia of grade two or worse (CIN2+) and compared it with post-treatment high-risk human papillomavirus (HPV) testing. We searched for published systematic reviews and new references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 1975, until Feb 1, 2016. Studies were eligible if women underwent treatment by excision of a histologically confirmed CIN2+ lesion, with verification of presence or absence of CIN at the resection margins; were tested by cytology or HPV assay between 3 months and 9 months after treatment; and had subsequent follow-up of at least 18 months post-treatment including histological confirmation of the occurrence of CIN2+. Primary endpoints were the proportion of positive section margins and the occurrence of treatment failure associated with the marginal status, in which treatment failure was defined as occurrence of residual or recurrent CIN2+. Information about positive resection margins and subsequent treatment failure was pooled using procedures for meta-analysis of binomial data and analysed using random-effects models.
FINDINGS: 97 studies were eligible for inclusion in the meta-analysis and included 44 446 women treated for cervical precancer. The proportion of positive margins was 23·1% (95% CI 20·4-25·9) overall and varied by treatment procedure (ranging from 17·8% [12·9-23·2] for laser conisation to 25·9% [22·3-29·6] for large loop excision of the transformation zone) and increased by the severity of the treated lesion. The overall risk of residual or recurrent CIN2+ was 6·6% (95% CI 4·9-8·4) and was increased with positive compared with negative resection margins (relative risk 4·8, 95% CI 3·2-7·2). The pooled sensitivity and specificity to predict residual or recurrent CIN2+ was 55·8% (95% CI 45·8-65·5) and 84·4% (79·5-88·4), respectively, for the margin status, and 91·0% (82·3-95·5) and 83·8% (77·7-88·7), respectively, for high-risk HPV testing. A negative high-risk HPV test post treatment was associated with a risk of CIN2+ of 0·8%, whereas this risk was 3·7% when margins were free.
INTERPRETATION: The risk of residual or recurrent CIN2+ is significantly greater with involved margins on excisional treatment; however, high-risk HPV post-treatment predicts treatment failure more accurately than margin status.
FUNDING: European Federation for Colposcopy and Institut national du Cancer (INCA).
Copyright © 2017 Elsevier Ltd. All rights reserved.
Kocken M, Uijterwaal MH, de Vries AL, Berkhof J, Ket JC, Helmerhorst TJ, Meijer CJ.
High-risk human papillomavirus testing versus cytology in predicting post-treatment disease in women treated for high-grade cervical disease: a systematic review and meta-analysis.
Gynecol Oncol. 2012 May;125(2):500-7. doi: 10.1016/j.ygyno.2012.01.015. Epub 2012 Jan 18.
Abstract/Text
OBJECTIVE: Currently, women treated for high-grade cervical intraepithelial neoplasia (CIN 2/3) are followed-up by cytology to monitor them for residual and recurrent (post-treatment) disease. This systematic review and meta-analysis determine the test performance of testing for high-risk types of the human papillomavirus (hrHPV), cytology and co-testing (combined hrHPV testing and cytology) in predicting high-grade post-treatment disease (CIN2+).
METHODS: Studies that compared at least two of three post-treatment surveillance methods, and were published between January 2003 and May 2011, were identified through a bibliographic database search (PubMed, Embase.com and Wiley/Cochrane Library). Identification of relevant studies was conducted independently by two reviewers with a multi-step process. The reference standard used to diagnose post-treatment disease was histologically confirmed CIN2+. Sensitivity, specificity, diagnostic odds ratios and relative sensitivity and specificity were calculated for each study. Pooled estimates were calculated using a random effects model if heterogeneity among studies was significant, otherwise by using a fixed effects model. Estimates were reported with 95% confidence intervals (95%CI).
RESULTS: Out of 2410 potentially relevant citations, 8 publications, incorporating 1513 treated women, were included. Pooled sensitivities were 0.79 (95%CI 0.72-0.85) for cytology, 0.92 (0.87-0.96) for hrHPV testing, and 0.95 (0.91-0.98) for co-testing. HrHPV testing was more sensitive than cytology to predict post-treatment CIN2+ (relative sensitivity 1.15; 95%CI 1.06-1.25). Pooled specificities were 0.81 (95%CI 0.74-0.86) for cytology, 0.76 (0.67-0.84) for hrHPV testing and 0.67 (0.60-0.74) for co-testing. HrHPV testing and cytology had a similar specificity (relative specificity 0.95, 95%CI 0.88-1.02).
CONCLUSIONS: This review indicates that the hrHPV test should be included in post-treatment testing 6months after treatment, because hrHPV testing has a higher sensitivity than cytology in detecting high-grade post-treatment disease and has a similar specificity.
Copyright © 2012 Elsevier Inc. All rights reserved.
Onuki M, Matsumoto K, Sakurai M, Ochi H, Minaguchi T, Satoh T, Yoshikawa H.
Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis.
J Gynecol Oncol. 2016 Jan;27(1):e3. doi: 10.3802/jgo.2016.27.e3. Epub 2015 Oct 8.
Abstract/Text
OBJECTIVE: We conducted a pooled analysis of published studies to compare the performance of human papillomavirus (HPV) testing and cytology in detecting residual or recurrent diseases after treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3).
METHODS: Source articles presenting data on posttreatment HPV testing were identified from the National Library of Medicine (PubMed) database. We included 5,319 cases from 33 articles published between 1996 and 2013.
RESULTS: The pooled sensitivity of high-risk HPV testing (0.92; 95% confidence interval [CI], 0.90 to 0.94) for detecting posttreatment CIN 2 or worse (CIN 2+) was much higher than that of cytology (0.76; 95% CI, 0.71 to 0.80). Co-testing of HPV testing and cytology maximized the sensitivity (0.93; 95% CI, 0.87 to 0.96), while HPV genotyping (detection of the same genotype between pre- and posttreatments) did not improve the sensitivity (0.89; 95% CI, 0.82 to 0.94) compared with high-risk HPV testing alone. The specificity of high-risk HPV testing (0.83; 95% CI, 0.82 to 0.84) was similar to that of cytology (0.85; 95% CI, 0.84 to 0.87) and HPV genotyping (0.83; 95% CI, 0.81 to 0.85), while co-testing had reduced specificity (0.76; 95% CI, 0.75 to 0.78). For women with positive surgical margins, high-risk HPV testing provided remarkable risk discrimination between test-positives and test-negatives (absolute risk of residual CIN 2+ 74.4% [95% CI, 64.0 to 82.6] vs. 0.8% [95% CI, 0.15 to 4.6]; p<0.001).
CONCLUSION: Our findings recommend the addition of high-risk HPV testing, either alone or in conjunction with cytology, to posttreatment surveillance strategies. HPV testing can identify populations at greatest risk of posttreatment CIN 2+ lesions, especially among women with positive section margins.
Perkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, Huh WK, Kim JJ, Moscicki AB, Nayar R, Saraiya M, Sawaya GF, Wentzensen N, Schiffman M; 2019 ASCCP Risk-Based Management Consensus Guidelines Committee.
2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors.
J Low Genit Tract Dis. 2020 Apr;24(2):102-131. doi: 10.1097/LGT.0000000000000525.
Abstract/Text
Miura S, Matsumoto K, Oki A, Satoh T, Tsunoda H, Yasugi T, Taketani Y, Yoshikawa H.
Do we need a different strategy for HPV screening and vaccination in East Asia?
Int J Cancer. 2006 Dec 1;119(11):2713-5. doi: 10.1002/ijc.22195.
Abstract/Text
Yokoyama M, Iwasaka T, Nagata C, Nozawa S, Sekiya S, Hirai Y, Kanazawa K, Sato S, Hoshiai H, Sugase M, Kawana T, Yoshikawa H.
Prognostic factors associated with the clinical outcome of cervical intraepithelial neoplasia: a cohort study in Japan.
Cancer Lett. 2003 Mar 31;192(2):171-9. doi: 10.1016/s0304-3835(02)00715-2.
Abstract/Text
One hundred and eighty-five Japanese women with cervical intraepithelial neoplasia (CIN) were enrolled in this follow-up study. On the basis of the prevalence of human papillomavirus (HPV) DNA in Japanese cervical cancer patients, HPV types were categorized into three groups as follows: (1) high risk (types 16, 18, 33, 52, and 58), (2) intermediate risk (types 31, 35, 39, 51, 56, 59, 68, and 70), (3) low risk (type 6, 30, 42, 53, 54, 55, 66 and unclassified types). High-risk HPV infection was a risk factor for progression of the disease. The regression rate in the HPV negative group was higher (83.3%) than those in the HPV positive groups, but the differences in regression were no longer significant after adjustment for age and CIN grade. It is also noted that a lower cytomegalovirus IgG level and a smaller number of past pregnancies might be associated with the regression of CIN lesions.
Matsumoto K, Oki A, Furuta R, Maeda H, Yasugi T, Takatsuka N, Mitsuhashi A, Fujii T, Hirai Y, Iwasaka T, Yaegashi N, Watanabe Y, Nagai Y, Kitagawa T, Yoshikawa H; Japan HPV And Cervical Cancer Study Group.
Predicting the progression of cervical precursor lesions by human papillomavirus genotyping: a prospective cohort study.
Int J Cancer. 2011 Jun 15;128(12):2898-910. doi: 10.1002/ijc.25630. Epub 2010 Oct 13.
Abstract/Text
Only a subset of cervical precursor lesions progress to cervical cancer and because of the lack of the predictive markers, it cannot be ascertained which lesions will progress or not. To estimate the risk of disease progression associated with human papillomavirus (HPV) genotypes, we followed 570 Japanese women with cytological LSIL (low-grade squamous intraepithelial lesion) and histological CIN (cervical intraepithelial neoplasia) grade 1-2 lesions (479 CIN 1; 91 CIN 2) at 3 to 4 month intervals for a mean follow-up period of 39.1 months. At entry, we detected HPV DNA in cervical samples by polymerase chain reaction-based methodology. Over the period of follow-up period, 46 lesions progressed to CIN 3 while 362 regressed to normal cytology. Women with multiple HPV infections were more likely to have persistent lesions (hazard ratio [HR] for regression, 0.65; 95% confidence interval [CI], 0.42-1.02; p = 0.07); however, multiple infections did not increase the risk of progression (HR for progression, 1.04; 95% CI, 0.37-2.94; p = 0.94). After adjusting for CIN grade and women's age, HRs for progression to CIN 3 (vs. women with low-risk types or negative for HPV DNA) varied markedly by HPV genotype: type 16 (11.1, 95% CI: 1.39-88.3); 18 (14.1, 0.65-306); 31 (24.7, 2.51-243); 33 (20.3, 1.78-231); 35 (13.7, 0.75-251); 52 (11.6, 1.45-93.3); 58 (8.85, 1.01-77.6); other high-risk types (4.04, 0.47-34.7). HPV 45 was not detected in our study subjects. The cumulative probability of CIN 3 within 5 years was 20.5% for HPV 16, 18, 31, 33, 35, 52 and 58; 6.0% for other high-risk types; 1.7% for low-risk types (p = 0.0001). In conclusion, type-specific HPV testing for women with LSIL/CIN 1-2 lesions is useful for identifying populations at increased or decreased risk of disease progression.
Copyright © 2010 UICC.
Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group.
Epidemiologic classification of human papillomavirus types associated with cervical cancer.
N Engl J Med. 2003 Feb 6;348(6):518-27. doi: 10.1056/NEJMoa021641.
Abstract/Text
BACKGROUND: Infection with human papilloma virus (HPV) is the main cause of cervical cancer, but the risk associated with the various HPV types has not been adequately assessed.
METHODS: We pooled data from 11 case-control studies from nine countries involving 1918 women with histologically confirmed squamous-cell cervical cancer and 1928 control women. A common protocol and questionnaire were used. Information on risk factors was obtained by personal interviews, and cervical cells were collected for detection of HPV DNA and typing in a central laboratory by polymerase-chain-reaction-based assays (with MY09/MY11 and GP5+/6+ primers).
RESULTS: HPV DNA was detected in 1739 of the 1918 patients with cervical cancer (90.7 percent) and in 259 of the 1928 control women (13.4 percent). With the GP5+/6+ primer, HPV DNA was detected in 96.6 percent of the patients and 15.6 percent of the controls. The most common HPV types in patients, in descending order of frequency, were types 16, 18, 45, 31, 33, 52, 58, and 35. Among control women, types 16, 18, 45, 31, 6, 58, 35, and 33 were the most common. For studies using the GP5+/6+ primer, the pooled odds ratio for cervical cancer associated with the presence of any HPV was 158.2 (95 percent confidence interval, 113.4 to 220.6). The odds ratios were over 45 for the most common and least common HPV types. Fifteen HPV types were classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82); 3 were classified as probable high-risk types (26, 53, and 66); and 12 were classified as low-risk types (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108). There was good agreement between our epidemiologic classification and the classification based on phylogenetic grouping.
CONCLUSIONS: In addition to HPV types 16 and 18, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should be considered carcinogenic, or high-risk, types, and types 26, 53, and 66 should be considered probably carcinogenic.
Copyright 2003 Massachusetts Medical Society
日本産科婦人科学会／日本産婦人科医会編集・監修：産婦人科診療ガイドライン婦人科外来編2020、CQ204, p40-42.
Kurokawa T, Yoshida Y, Iwanari O, Oishi T, Kasai T, Hamada M, Fujita H, Fujiwara H, Yokoyama M, Sakuragi N, Kigawa J, Suzuki M.
Implementation of primary HPV testing in Japan.
Mol Clin Oncol. 2020 Oct;13(4):22. doi: 10.3892/mco.2020.2092. Epub 2020 Jul 16.
Abstract/Text
Cervical cancer screening has been shifting from primary cytology to primary HPV testing worldwide as primary HPV testing is more sensitive than primary cytology. To the best of our knowledge, the current study is the first in Japan to examine the feasibility of primary HPV testing. One of the disadvantages of this shift is that hrHPV-/≥LSIL/CIN2+ (high-risk HPV negative cancers or pre-cancerous lesions with abnormal cytology results) can be missed. The objectives of the present study are to clarify in detail CIN2+ missed by this shift and to evaluate the feasibility of primary HPV testing in Japan. Data from 115,273 women who underwent co-testing with cytology and HPV testing in cancer screening were used in the current study. The cases with hrHPV-/≥LSIL ('hrHPV-/≥L-SIL' include CIN2-, in contrast, 'hrHPV-/≥L-SIL/CIN2+' doesn't include CIN2-) were analysed in detail. Women with hrHPV-/≥LSIL comprised 0.3% of the total. The prevalence of CIN2, CIN3, SCC or cervical adenocarcinomas in the lesions with HPV-/≥LSIL was 0.03% in the cancer screening group. Only one case of 14 cervical adenocarcinomas in ≥LSIL was hrHPV-. The prevalence of cancer missed by the shift in patients >50 years of age was significantly higher compared with patients younger than 49 years. In conclusion, the prevalence of CIN2+, which might be missed by the shift from primary cytology to primary HPV testing, was remarkably low in this Japanese cancer screening. The data indicated that primary HPV testing, which was more sensitive for CIN2+ than primary cytology, was a feasible method that can be used in Japan. In particular, primary HPV testing should be introduced for women <50 years old.
Copyright: © Kurokawa et al.
Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, Voorhorst FJ, Verheijen RH, van Groningen K, Boon ME, Ruitinga W, van Ballegooijen M, Snijders PJ, Meijer CJ.
Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial.
Lancet. 2007 Nov 24;370(9601):1764-72. doi: 10.1016/S0140-6736(07)61450-0. Epub 2007 Oct 4.
Abstract/Text
BACKGROUND: Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented.
METHODS: Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131.
FINDINGS: 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups.
INTERPRETATION: The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.
Rijkaart DC, Berkhof J, Rozendaal L, van Kemenade FJ, Bulkmans NW, Heideman DA, Kenter GG, Cuzick J, Snijders PJ, Meijer CJ.
Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial.
Lancet Oncol. 2012 Jan;13(1):78-88. doi: 10.1016/S1470-2045(11)70296-0. Epub 2011 Dec 14.
Abstract/Text
BACKGROUND: Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening.
METHODS: In this randomised trial, women aged 29-56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131.
FINDINGS: 22,420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20,106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19,731 in the control group were eligible, of whom 16,750 and 16,743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19,731 in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19,731; 0·29, 0·10-0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20,106; 1·15, 0·92-1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19,286 vs 12 of 19,373; 2·85, 1·47-5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20,106; 1·25, 1·05-1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57-1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20,106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20,106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2 or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 or worse in women aged 34-56 years: 157 of 16,860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 or worse in women aged 34-56 years: 274 of 16,860 vs 248 of 16 978; 1·11, 0·94-1·32).
INTERPRETATION: Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older.
FUNDING: Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development).
Copyright © 2012 Elsevier Ltd. All rights reserved.
Katki HA, Kinney WK, Fetterman B, Lorey T, Poitras NE, Cheung L, Demuth F, Schiffman M, Wacholder S, Castle PE.
Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice.
Lancet Oncol. 2011 Jul;12(7):663-72. doi: 10.1016/S1470-2045(11)70145-0. Epub 2011 Jun 16.
Abstract/Text
BACKGROUND: Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years.
METHODS: We assessed the 5-year cumulative incidence, starting in 2003-05, of cervical cancer and CIN3 or worse for 331,818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models.
FINDINGS: In 315,061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3.8 per 100,000 women per year, slightly higher than for the 306,969 who were both negative by HPV and Pap testing (3.2 per 100,000), and half the cancer risk of the 319,177 who were negative by Pap testing (7.5 per 100,000). 313,465 (99.5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16,757 positive by HPV testing (12.1%vs 5.9%; p<0.0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0.86%vs 0.16%; p=0.004). 12,208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or adenocarcinoma in situ, [corrected] 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas.
INTERPRETATION: For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer.
FUNDING: Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Kjær SK, Frederiksen K, Munk C, Iftner T.
Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence.
J Natl Cancer Inst. 2010 Oct 6;102(19):1478-88. doi: 10.1093/jnci/djq356. Epub 2010 Sep 14.
Abstract/Text
BACKGROUND: Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type-specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types.
METHODS: A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time.
RESULTS: For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow-up was 26.7% (95% confidence interval [CI] = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%).
CONCLUSION: HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA-negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary.
Wright TC Jr, Stoler MH, Sharma A, Zhang G, Behrens C, Wright TL; ATHENA (Addressing THE Need for Advanced HPV Diagnostics) Study Group.
Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results.
Am J Clin Pathol. 2011 Oct;136(4):578-86. doi: 10.1309/AJCPTUS5EXAS6DKZ.
Abstract/Text
The ATHENA (Addressing THE Need for Advanced HPV Diagnostics) HPV study evaluated the clinical usefulness of the cobas HPV Test (Roche Molecular Systems, Pleasanton, CA) for high-risk human papillomavirus (HR-HPV) testing (14 HR types) and individual HPV-16/HPV-18 genotyping in women undergoing routine cervical cytology screening in the United States. For the study, 47,208 women were recruited, including 32,260 women 30 years or older with negative cytology. All women with positive results for HR-HPV (n = 4,219) plus a subset of HR-HPV- women (n = 886) were referred for colposcopy and biopsy. The overall prevalence of HR-HPV was 6.7% and of HPV-16/HPV-18 was 1.5%. Cervical intraepithelial neoplasia grade 2 (CIN 2) or worse was found in 1.2% of women examined. The estimated absolute risk of CIN 2 or worse in HPV-16+ and/or HPV-18+ women was 11.4% (95% confidence interval [CI], 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) in HR-HPV+ and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV- women. These analyses validate the 2006 American Society of Colposcopy and Cervical Pathology guidelines for HPV-16/HPV-18 genotyping, which recommend referral to colposcopy of HPV-16/HPV-18+ women with negative cytology.
Kurokawa T, Onuma T, Shinagawa A, Chino Y, Kobayashi M, Yoshida Y.
The ideal strategy for cervical cancer screening in Japan: Result from the Fukui Cervical Cancer Screening Study.
Cytopathology. 2018 Aug;29(4):361-367. doi: 10.1111/cyt.12576. Epub 2018 Jun 21.
Abstract/Text
INTRODUCTION: The aims of the Fukui Cervical Cancer Screening (FCCS) study are to determine the frequency of women with high-risk HPV (hrHPV), whether HPV16 or HPV18 (HPV16/18), in the Japanese cancer screening population for the first time and to identify the best strategy for cervical cancer screening in Japan.
METHODS: This study enrolled 7584 women aged ≥25 years who were undergoing routine screening. All women underwent LBC and cobas HPV tests. Women with abnormal cytology, whether hrHPV positive or negative; women with hrHPV positivity with either normal or abnormal cytology; and women randomly selected from women with normal cytology and negative hrHPV negative were referred for colposcopy.
RESULTS: The prevalences of hrHPV positivity and HPV16/18 positivity were 6.8% and 1.7%, respectively. The baseline data from the FCCS study showed that the combination of HPV tests and cytology was more sensitive than cytology with respect to the detection of intraepithelial neoplasia grade 2 or worse. However, the specificity (94.1%) of the co-testing strategy that required all women with abnormal cytology or hrHPV positivity to be referred for colposcopy was much lower than that (97.8%) of cytology. The sensitivity and specificity of the co-testing strategy that required only women with abnormal cytology or HPV16/18 positivity to undergo colposcopy were 85.5% and 97.0%, respectively.
CONCLUSION: The baseline data from the FCCS study suggest that a cervical cancer screening strategy in which only women with abnormal cytology or HPV16/18 positivity undergo colposcopy offers a more balanced sensitivity and specificity than other strategies.
© 2018 The Authors. Cytopathology Published by John Wiley & Sons Ltd.
日本産科婦人科学会/日本産婦人科医会：産婦人科診療ガイドライン婦人科外来編2023、 CQ202 p38-40.
Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, Ghiringhello B, Girlando S, Gillio-Tos A, De Marco L, Naldoni C, Pierotti P, Rizzolo R, Schincaglia P, Zorzi M, Zappa M, Segnan N, Cuzick J; New Technologies for Cervical Cancer screening (NTCC) Working Group.
Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial.
Lancet Oncol. 2010 Mar;11(3):249-57. doi: 10.1016/S1470-2045(09)70360-2. Epub 2010 Jan 18.
Abstract/Text
BACKGROUND: Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing.
METHODS: Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807.
FINDINGS: In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing. 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together. At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two. At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two.
INTERPRETATION: HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2.
FUNDING: European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.
Copyright 2010 Elsevier Ltd. All rights reserved.
Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A, Stoykova B, Gilham C, Baysson H, Roberts C, Dowie R, Desai M, Mather J, Bailey A, Turner A, Moss S, Peto J.
HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial.
Lancet Oncol. 2009 Jul;10(7):672-82. doi: 10.1016/S1470-2045(09)70156-1. Epub 2009 Jun 17.
Abstract/Text
BACKGROUND: Testing for human papillomavirus (HPV) DNA is reportedly more sensitive than cytology for the detection of high-grade cervical intraepithelial neoplasia (CIN). The effectiveness of HPV testing in primary cervical screening was assessed in the ARTISTIC trial, which was done over two screening rounds approximately 3 years apart (2001-03 and 2004-07) by comparing liquid-based cytology (LBC) combined with HPV testing against LBC alone.
METHODS: Women aged 20-64 years who were undergoing routine screening as part of the English National Health Service Cervical Screening Programme in Greater Manchester were randomly assigned (between July, 2001, and September, 2003) in a ratio of 3:1 to either combined LBC and HPV testing in which the results were revealed and acted on, or to combined LBC and HPV testing where the HPV result was concealed from the patient and investigator. The primary outcome was the detection rate of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in the second screening round, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821.
FINDINGS: There were 24 510 eligible women at entry (18 386 in the revealed group, 6124 in the concealed group). In the first round of screening 233 women (1.27%) in the revealed group had CIN3+, compared with 80 (1.31%) women in the concealed group (odds ratio [OR] 0.97, 95% CI 0.75-1.25; p>0.2). There was an unexpectedly large drop in the proportion of women with CIN3+ between the first and second rounds of screening in both groups, at 0.25% (29 of 11 676) in the revealed group and 0.47% (18 of 3866 women) in the concealed group (OR 0.53, 95% CI 0.30-0.96; p=0.042). For both rounds combined, the proportion of women with CIN3+ were 1.51% (revealed) and 1.77% (concealed) (OR 0.85, 95% CI 0.67-1.08; p>0.2).
INTERPRETATION: LBC combined with HPV testing resulted in a significantly lower detection rate of CIN3+ in the second round of screening compared with LBC screening alone, but the effect was small. Over the two screening rounds combined, co-testing did not detect a higher rate of CIN3+ or CIN2+ than LBC alone. Potential changes in screening methodology should be assessed over at least two screening rounds.
FUNDING: National Institute of Health Research Health Technology Assessment Programme.
Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Elfgren K, Rådberg T, Strander B, Johansson B, Forslund O, Hansson BG, Rylander E, Dillner J.
Human papillomavirus and Papanicolaou tests to screen for cervical cancer.
N Engl J Med. 2007 Oct 18;357(16):1589-97. doi: 10.1056/NEJMoa073204.
Abstract/Text
BACKGROUND: Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown.
METHODS: In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated.
RESULTS: At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy.
CONCLUSIONS: The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).
Copyright 2007 Massachusetts Medical Society.
Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, Ratnam S, Coutlée F, Franco EL; Canadian Cervical Cancer Screening Trial Study Group.
Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer.
N Engl J Med. 2007 Oct 18;357(16):1579-88. doi: 10.1056/NEJMoa071430.
Abstract/Text
BACKGROUND: To determine whether testing for DNA of oncogenic human papillomaviruses (HPV) is superior to the Papanicolaou (Pap) test for cervical-cancer screening, we conducted a randomized trial comparing the two methods.
METHODS: We compared HPV testing, using an assay approved by the Food and Drug Administration, with conventional Pap testing as a screening method to identify high-grade cervical intraepithelial neoplasia in women ages 30 to 69 years in Montreal and St. John's, Canada. Women with abnormal Pap test results or a positive HPV test (at least 1 pg of high-risk HPV DNA per milliliter) underwent colposcopy and biopsy, as did a random sample of women with negative tests. Sensitivity and specificity estimates were corrected for verification bias.
RESULTS: A total of 10,154 women were randomly assigned to testing. Both tests were performed on all women in a randomly assigned sequence at the same session. The sensitivity of HPV testing for cervical intraepithelial neoplasia of grade 2 or 3 was 94.6% (95% confidence interval [CI], 84.2 to 100), whereas the sensitivity of Pap testing was 55.4% (95% CI, 33.6 to 77.2; P=0.01). The specificity was 94.1% (95% CI, 93.4 to 94.8) for HPV testing and 96.8% (95% CI, 96.3 to 97.3; P<0.001) for Pap testing. Performance was unaffected by the sequence of the tests. The sensitivity of both tests used together was 100%, and the specificity was 92.5%. Triage procedures for Pap or HPV testing resulted in fewer referrals for colposcopy than did either test alone but were less sensitive. No adverse events were reported.
CONCLUSIONS: As compared with Pap testing, HPV testing has greater sensitivity for the detection of cervical intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN57612064 [controlled-trials.com].).
Copyright 2007 Massachusetts Medical Society.
日本産婦人科医会がん対策委員会:子宮頸がん検診リコメンデーション-HPV-DNA検査併用検診に向けて-、日本産婦人科医会発刊No.1111、2011.
