今日の臨床サポート

子宮頸がん検診、HPV検査

著者: 黒川哲司 福井大学 医学部産科婦人科

監修: 青木大輔 慶應義塾大学医学部産婦人科学教室

著者校正/監修レビュー済:2021/09/22
参考ガイドライン:
  1. 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2020
  1. 国立がん研究センター:有効性評価に基づく子宮頸がん検診ガイドライン更新版(2020年7月29日)
患者向け説明資料

概要・推奨   

  1. がん検診の感度を上げるために細胞診とハイリスクHPV検査を組み合わせ使用する(推奨度2)。
  1. 細胞診でASC-USの場合に、コルポスコピー・生検の必要性を判定するためにハイリスクHPV検査を行う(推奨度1)。
  1. 子宮頸部細胞診の細胞採取は、(妊娠女性以外では)ヘラもしくはブラシで行う(推奨度1)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
黒川哲司 : 特に申告事項無し[2021年]
監修:青木大輔 : 講演料(アストラゼネカ株式会社,武田薬品工業株式会社,中外製薬株式会社),研究費・助成金など(アストラゼネカ株式会社,中外製薬株式会社,インサイト・バイオサイエンシズ・ジャパン合同会社)[2021年]

改訂のポイント:
  1. 産婦人科診療ガイドライン 婦人科外来編に基づき、改定した。

まとめ

まとめ  
  1. 子宮頸がん検診は20歳以上の女性を対象に行う。わが国では年齢の上限はない。有効性評価に基づく子宮頸がん検診ガイドラインでは、細胞診を20~69歳、HPV検査を30~60歳にすることが望ましいとされている。
  1. 子宮全摘後の女性には通常子宮頸がん検診を行わない(ただし、子宮頸部病変で子宮全摘した女性ではフォローアップが必要)。
  1. 子宮頸部細胞診はブラシまたはヘラを使用して採取することが推奨されている[1]
  1. HPV検査は、ハイリスクHPV検査とHPVタイピング検査の2つに大きく分類される[2]
  1. 現在わが国で体外診断薬として承認されているHPV検査のうち、HPV DNAキアゲンHC II(キアゲン)、コバス4800システムHPV(ロシュ・ダイアグノスティック)、アキュジーンm-HPV(アボットジャパン)、アプティマHPV(ホロジックジャパン)、BD Onclarity HPV キット(日本BD)はハイリスクHPV検査に分類されるが、コバス4800システムHPV、アキュジーンm-HPV、BD Onclarity HPV キットでは、HPV-16陽性とHPV-18陽性を区別することができる(簡易ジェノタイピング)。クリニチップHPV(積水メディカル)、MEBGEN HPVキット(MBL)はHPVタイピング検査である。
  1. ハイリスクHPV検査が臨床において役に立つのは以下のような場合である[2]
  1. がん検診の感度を上げるために、細胞診にハイリスクHPV(HPV HR)検査を併用する。
  1. 細胞診でASC-USの場合に、コルポスコピー・生検の必要性を判定するためにハイリスクHPV検査を行う。ハイリスクHPV検査が陽性の場合にはただちにコルポスコピー・生検を行う。
  1. ASC-USの取り扱い:アルゴリズム[1]'>
  1. CIN2/3に対する円錐切除後の管理において、病変の残存・再発の早期発見のためにハイリスクHPV検査を行う。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

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文献 

著者: Marc Arbyn, Christine Bergeron, Paul Klinkhamer, Pierre Martin-Hirsch, Albertus G Siebers, Johan Bulten
雑誌名: 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.

PMID 18165406  Obstet Gynecol. 2008 Jan;111(1):167-77. doi: 10.1097/01・・・
著者: Thomas C Wright, Mark Schiffman, Diane Solomon, J Thomas Cox, Francisco Garcia, Sue Goldie, Kenneth Hatch, Kenneth L Noller, Nancy Roach, Carolyn Runowicz, Debbie Saslow
雑誌名: 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.

PMID 14754700  Obstet Gynecol. 2004 Feb;103(2):304-9. doi: 10.1097/01.・・・
著者: P Martin-Hirsch, R Lilford, G Jarvis, H C Kitchener
雑誌名: Lancet. 1999 Nov 20;354(9192):1763-70.
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.

PMID 10577637  Lancet. 1999 Nov 20;354(9192):1763-70.
著者: P P Koonings, K Dickinson, G d'Ablaing, J B Schlaerth
雑誌名: 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.

PMID 1635737  Obstet Gynecol. 1992 Aug;80(2):241-5.
著者: M Arbyn, A Herbert, U Schenck, P Nieminen, J Jordan, E Mcgoogan, J Patnick, C Bergeron, J-J Baldauf, P Klinkhamer, J Bulten, P Martin-Hirsch
雑誌名: 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.

PMID 17573762  Cytopathology. 2007 Jun;18(3):133-9. doi: 10.1111/j.136・・・
著者: Marie-Hélène Mayrand, Eliane Duarte-Franco, Isabel Rodrigues, Stephen D Walter, James Hanley, Alex Ferenczy, Sam Ratnam, François Coutlée, Eduardo L Franco, Canadian Cervical Cancer Screening Trial Study Group
雑誌名: 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.
PMID 17942871  N Engl J Med. 2007 Oct 18;357(16):1579-88. doi: 10.1056・・・
著者: T Kurokawa, T Onuma, A Shinagawa, Y Chino, M Kobayashi, Y Yoshida
雑誌名: 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.
PMID 29768678  Cytopathology. 2018 Aug;29(4):361-367. doi: 10.1111/cyt・・・
著者: Susanne Kjaer, Estrid Høgdall, Kirsten Frederiksen, Christian Munk, Adriaan van den Brule, Edith Svare, Chris Meijer, Attilla Lorincz, Thomas Iftner
雑誌名: 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.

PMID 17062559  Cancer Res. 2006 Nov 1;66(21):10630-6. doi: 10.1158/000・・・
著者: Michelle J Khan, Philip E Castle, Attila T Lorincz, Sholom Wacholder, Mark Sherman, David R Scott, Brenda B Rush, Andrew G Glass, Mark Schiffman
雑誌名: 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.

PMID 16030305  J Natl Cancer Inst. 2005 Jul 20;97(14):1072-9. doi: 10.・・・
著者: Jack Cuzick, Christine Clavel, Karl-Ulrich Petry, Chris J L M Meijer, Heike Hoyer, Samuel Ratnam, Anne Szarewski, Philippe Birembaut, Shalini Kulasingam, Peter Sasieni, Thomas Iftner
雑誌名: 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.
PMID 16586444  Int J Cancer. 2006 Sep 1;119(5):1095-101. doi: 10.1002/・・・
著者: J Thomas Cox, Mark Schiffman, Diane Solomon, ASCUS-LSIL Triage Study (ALTS) Group
雑誌名: Am J Obstet Gynecol. 2003 Jun;188(6):1406-12.
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.

PMID 12824970  Am J Obstet Gynecol. 2003 Jun;188(6):1406-12.
著者: Mahboobeh Safaeian, Diane Solomon, Sholom Wacholder, Mark Schiffman, Philip Castle
雑誌名: 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.

PMID 17540804  Obstet Gynecol. 2007 Jun;109(6):1325-31. doi: 10.1097/0・・・
著者: Thomas C Wright, L Stewart Massad, Charles J Dunton, Mark Spitzer, Edward J Wilkinson, Diane Solomon, 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference
雑誌名: 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.

PMID 17904957  Am J Obstet Gynecol. 2007 Oct;197(4):346-55. doi: 10.10・・・
著者: American College of Obstetricians and Gynecologists
雑誌名: Obstet Gynecol. 2008 Dec;112(6):1419-44. 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.

PMID 19037054  Obstet Gynecol. 2008 Dec;112(6):1419-44. doi: 10.1097/A・・・
著者: Anna-Barbara Moscicki, Stephen Shiboski, Nancy K Hills, Kimberly J Powell, Naomi Jay, Evelyn N Hanson, Susanna Miller, K Lisa Canjura-Clayton, Sepidah Farhat, Jeanette M Broering, Teresa M Darragh
雑誌名: Lancet. 2004 Nov 6-12;364(9446):1678-83. doi: 10.1016/S0140-6736(04)17354-6.
Abstract/Text BACKGROUND: The aim of this study was to assess the probability of low-grade squamous intra-epithelial lesion (LSIL) regression in young women, and to examine the factors associated with this regression.
METHODS: In a longitudinal study of human papilloma virus (HPV) infection, female adolescents aged 13-22 years were examined every 4 months by cytology, colposcopy, and HPV DNA status. Both prevalent and incident LSIL cases were included in the analysis, with regression defined as at least three consecutive normal Pap smears.
FINDINGS: Median follow-up time from baseline (defined as the time of first LSIL diagnosis) for the 187 women with LSIL was 61 months (IQR 34-80). Median time they had been sexually active at diagnosis was 3.2 years (2.6-6.5). Probability of regression for the entire cohort was 61% (95% CI 53-70) at 12 months and 91% (84-99) at 36 months of follow-up. No associations were found between LSIL regression and HPV status at baseline, sexual behaviour, contraceptive use, substance or cigarette use, incident sexually transmitted infection, or biopsy. Multivariate analysis showed that only HPV status at the current visit was associated with rate of regression, whether infection was caused by one or more viral types (relative hazard=0.3 [95% CI 0.21-0.42], and 0.14 [0.08-0.25], respectively).
INTERPRETATION: The high rate of regression recorded in this study lends support to observation by cytology in the management of LSIL in female adolescents. Negative HPV status was associated with regression, suggesting that HPV testing could be helpful in monitoring LSIL.

PMID 15530628  Lancet. 2004 Nov 6-12;364(9446):1678-83. doi: 10.1016/S・・・
著者: Koji Matsumoto, Akinori Oki, Reiko Furuta, Hiroo Maeda, Toshiharu Yasugi, Naoyoshi Takatsuka, Akira Mitsuhashi, Takuma Fujii, Yasuo Hirai, Tsuyoshi Iwasaka, Nobuo Yaegashi, Yoh Watanabe, Yutaka Nagai, Tomoyuki Kitagawa, Hiroyuki Yoshikawa, Japan HPV And Cervical Cancer Study Group
雑誌名: 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.
PMID 20734388  Int J Cancer. 2011 Jun 15;128(12):2898-910. doi: 10.100・・・
著者: Y Nagai, T Maehama, T Asato, K Kanazawa
雑誌名: Gynecol Oncol. 2000 Nov;79(2):294-9. doi: 10.1006/gyno.2000.5952.
Abstract/Text OBJECTIVE: The aims of this study were (1) to examine whether HPV DNA is persistently detected in the cervix after therapeutic conization for CIN 3 and (2) to explore whether a patient with persistence of HPV infection is at risk of developing recurrent disease.
METHODS: Of 74 patients referred with CIN 3, 58 who were tested for HPV DNA in the pretreatment cervical lesions were enrolled in the study. After standard therapeutic conization, patients were followed prospectively at the outpatient clinic. Our follow-up protocol was to follow patients without therapeutic intervention as long as they developed no recurrence or recurrence of CIN 1 or 2, while patients who experienced recurrence of CIN 3 were recommended for reconization or hysterectomy. The polymerase chain reaction for detecting HPV DNA was performed using fresh cell samples from the cervix.
RESULTS: In 56 of 58 patients (96.6%), HPV DNAs were detected in their primary cervical lesions prior to conization. With regard to the distribution of HPV types, HPV type 16 family (types 16, 31, and 35) was identified in 28 cases (50.0%), type 18 family (types 18, 33 and 58) in 15 (26.8%), and type X in 18 (32.1%). Up to August 1999, all of the 58 patients have been followed with a mean follow-up period of 31.8 months (range: 12 to 73 months). After treatment, HPV DNA was persistently detected in 11 (19.6%) but negative in 45 (80.4%) of 56 HPV DNA-positive patients. HPV DNA was not detected in both HPV DNA-negative patients. Five of 11 persistently HPV DNA-positive patients (45.5%) developed CIN recurrence, while none of 45 persistently HPV DNA-negative patients did. Thus, there was a significant difference between the recurrence rates of these two groups (P < 0.0001). Both patients who were initially HPV DNA-negative developed no recurrence. Accordingly, the overall recurrence following conservative treatment for CIN 3 was 5 of 58 patients (8.6%).
CONCLUSIONS: Patients with persistent HPV infection after conization for CIN 3 should be especially closely followed because they are at increased risk of developing disease recurrence.

Copyright 2000 Academic Press.
PMID 11063660  Gynecol Oncol. 2000 Nov;79(2):294-9. doi: 10.1006/gyno.・・・
著者: Aimée R Kreimer, Richard S Guido, Diane Solomon, Mark Schiffman, Sholom Wacholder, José Jeronimo, Cosette M Wheeler, Philip E Castle
雑誌名: Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):908-14. doi: 10.1158/1055-9965.EPI-05-0845.
Abstract/Text BACKGROUND: Loop electrosurgical excision procedure (LEEP) is the predominant treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN2+) in the United States, yet following treatment approximately 10% of women are diagnosed again with CIN2+, necessitating close follow-up of such patients.
METHODS: Surveillance strategies using cytology and/or human papillomavirus (HPV) testing were compared among women who underwent LEEP (n = 610) in the Atypical Squamous Cells of Undetermined Significance (ASCUS) Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. Cervical specimens, collected at 6-month visits for 2 years, were used for cytology, Hybrid Capture 2 (HC2) detection of carcinogenic HPVs, and PCR for genotyping of carcinogenic and noncarcinogenic HPV types. At exit, women had colposcopy for safety and disease ascertainment.
RESULTS: At the visit post-LEEP (median time: 4.5 months after LEEP), 36.9% [95% confidence interval (95% CI), 32.7-41.1%] of women were positive for carcinogenic HPV by PCR and 33.7% (95% CI, 29.7-37.9) had ASCUS or more severe (ASCUS+) cytology. The overall 2-year cumulative incidence of histologically confirmed posttreatment CIN2+ was 7.0%; this could be further stratified by the HPV risk category detected at the 6-month visit after LEEP. The 2-year risk associated with HPV16 positivity was 37.0%, significantly higher than for other carcinogenic HPV types (10.8%, P < 0.001), noncarcinogenic types (1.5%, P < 0.001), or testing HPV negative (0%). Post-LEEP cytology (using a positive threshold of ASCUS+) was 78.1% (95% CI, 60.0-90.7%) sensitive for detection of posttreatment CIN2+. By comparison, PCR for carcinogenic HPV and combination testing (using a positive result from carcinogenic HPV testing or cytology as the test threshold with HPV-negative ASCUS not referred) were significantly more sensitive (96.9% for each, P = 0.03); HC2 alone was nonsignificantly more sensitive (90.6%, P = 0.3). Specificity was similar for ASCUS+ cytology (69.1%, 95% CI, 64.6-73.3%) and PCR for carcinogenic HPV (67.1%, P = 0.5), yet was lower for HC2 (63.8%, P = 0.048) and combination testing (62.9%, P = 0.02).
CONCLUSION: Women who tested positive after LEEP for carcinogenic HPV types, especially HPV16, had high risk of subsequent CIN2+. HPV-based detection methods, alone or in combination with cytology, may be useful to incorporate in post-LEEP management strategies.

PMID 16702369  Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):908-14・・・
著者: Mariëlle Kocken, Margot H Uijterwaal, Anton L M de Vries, Johannes Berkhof, Johannes C F Ket, Theo J M Helmerhorst, Chris J L M Meijer
雑誌名: 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.
PMID 22266548  Gynecol Oncol. 2012 May;125(2):500-7. doi: 10.1016/j.yg・・・
著者: Shiho Miura, Koji Matsumoto, Akinori Oki, Toyomi Satoh, Hajime Tsunoda, Toshiharu Yasugi, Yuji Taketani, Hiroyuki Yoshikawa
雑誌名: Int J Cancer. 2006 Dec 1;119(11):2713-5. doi: 10.1002/ijc.22195.
Abstract/Text
PMID 16929495  Int J Cancer. 2006 Dec 1;119(11):2713-5. doi: 10.1002/i・・・
著者: Masatoshi Yokoyama, Tsuyoshi Iwasaka, Chisato Nagata, Shiro Nozawa, Soei Sekiya, Yasuo Hirai, Koji Kanazawa, Shinji Sato, Hiroshi Hoshiai, Motoyasu Sugase, Takashi Kawana, Hiroyuki Yoshikawa
雑誌名: Cancer Lett. 2003 Mar 31;192(2):171-9.
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.

PMID 12668281  Cancer Lett. 2003 Mar 31;192(2):171-9.
著者: Nubia Muñoz, F Xavier Bosch, Silvia de Sanjosé, Rolando Herrero, Xavier Castellsagué, Keerti V Shah, Peter J F Snijders, Chris J L M Meijer, International Agency for Research on Cancer Multicenter Cervical Cancer Study Group
雑誌名: 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
PMID 12571259  N Engl J Med. 2003 Feb 6;348(6):518-27. doi: 10.1056/NE・・・
著者:
雑誌名: 2020 Oct;13(4):22.
Abstract/Text
PMID 32765870  2020 Oct;13(4):22.
著者: N W J Bulkmans, J Berkhof, L Rozendaal, F J van Kemenade, A J P Boeke, S Bulk, F J Voorhorst, R H M Verheijen, K van Groningen, M E Boon, W Ruitinga, M van Ballegooijen, P J F Snijders, C J L M Meijer
雑誌名: 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.

PMID 17919718  Lancet. 2007 Nov 24;370(9601):1764-72. doi: 10.1016/S01・・・
著者: Dorien C Rijkaart, Johannes Berkhof, Lawrence Rozendaal, Folkert J van Kemenade, Nicole W J Bulkmans, Daniëlle A M Heideman, Gemma G Kenter, Jack Cuzick, Peter J F Snijders, Chris J L M Meijer
雑誌名: 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.
PMID 22177579  Lancet Oncol. 2012 Jan;13(1):78-88. doi: 10.1016/S1470-・・・
著者: Hormuzd A Katki, Walter K Kinney, Barbara Fetterman, Thomas Lorey, Nancy E Poitras, Li Cheung, Franklin Demuth, Mark Schiffman, Sholom Wacholder, Philip E Castle
雑誌名: 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.
PMID 21684207  Lancet Oncol. 2011 Jul;12(7):663-72. doi: 10.1016/S1470・・・
著者: Susanne K Kjær, Kirsten Frederiksen, Christian Munk, Thomas Iftner
雑誌名: 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.

PMID 20841605  J Natl Cancer Inst. 2010 Oct 6;102(19):1478-88. doi: 10・・・
著者: Thomas C Wright, Mark H Stoler, Abha Sharma, Guili Zhang, Catherine Behrens, Teresa L Wright, ATHENA (Addressing THE Need for Advanced HPV Diagnostics) Study Group
雑誌名: 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.

PMID 21917680  Am J Clin Pathol. 2011 Oct;136(4):578-86. doi: 10.1309/・・・
著者: Guglielmo Ronco, Paolo Giorgi-Rossi, Francesca Carozzi, Massimo Confortini, Paolo Dalla Palma, Annarosa Del Mistro, Bruno Ghiringhello, Salvatore Girlando, Anna Gillio-Tos, Laura De Marco, Carlo Naldoni, Paola Pierotti, Raffaella Rizzolo, Patrizia Schincaglia, Manuel Zorzi, Marco Zappa, Nereo Segnan, Jack Cuzick, New Technologies for Cervical Cancer screening (NTCC) Working Group
雑誌名: 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.
PMID 20089449  Lancet Oncol. 2010 Mar;11(3):249-57. doi: 10.1016/S1470・・・
著者: Henry C Kitchener, Maribel Almonte, Claire Thomson, Paula Wheeler, Alexandra Sargent, Boyka Stoykova, Clare Gilham, Helene Baysson, Christopher Roberts, Robin Dowie, Mina Desai, Jean Mather, Andrew Bailey, Andrew Turner, Sue Moss, Julian Peto
雑誌名: 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.

PMID 19540162  Lancet Oncol. 2009 Jul;10(7):672-82. doi: 10.1016/S1470・・・
著者: Pontus Naucler, Walter Ryd, Sven Törnberg, Anders Strand, Göran Wadell, Kristina Elfgren, Thomas Rådberg, Björn Strander, Bo Johansson, Ola Forslund, Bengt-Göran Hansson, Eva Rylander, Joakim Dillner
雑誌名: 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.
PMID 17942872  N Engl J Med. 2007 Oct 18;357(16):1589-97. doi: 10.1056・・・

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