untitled

Transcription

1 ( 대한부인종양학회, 대한산부인과학회, 대한세포병리학회 2012 년 ) Practice guidelines for the early detection of cervical cancer in Korea: Korean Societyof Gynecologic Oncology, Korean Society of Obstetrics and Gynecology, and the Korean Society for Cytopathology 2012 edition

2 발간사 최근우리나라국민의자궁경부암유병률은지속적으로감소하고있지만여전히선진국에비해높은상태를유지하고있습니다. 국내에서는 2001년에개발된자궁경부암선별검사지침이있지만최근의발전된의료상황을반영하기어려워대부분의임상의사들이자궁경부암조기검진을위한선별검사의진료기준으로미국종합암네트워크 (National Comprehensive Cancer Network, NCCN) 의기준을따르고있지만국내자궁경부암발생률이높은편에속하는호발국가인점과낮은의료수가로인해산부인과로의접근성이외국에비해높아서외국의가이드라인을국내에그대로적용하기에는무리가있습니다. 대한부인종양학회에서는 2010년자궁경부암을비롯한부인암진료권고안을수립하여환자진료의질향상이외에한국형치료모델제시, 국내의료자원의효율적이용등에기여를하고있습니다. 그러나, 직접적으로자궁경부암의발생률을감소시킬수있는비정상자궁경부선별검사결과에따른추적관찰및자궁경부상피내종양에대한국내임상진료지침의부재로자궁경부암의발생률및사망률을감소시킬수있는기회를놓치고있는사정이있습니다. 이에대한부인종양학회, 대한세포병리학회및대한산부인과학회에서는근거창출임상연구국가사업단의도움을받아 2012년 3월진료권고안개발위원회를구성하고국내와외국의최신연구결과들에대해근거중심의평가과정을거쳐을만들게되었습니다. 이는과학적근거에기반을둔진료방식과진료과정의효율화를가져와서결국자궁경부암의발생률을낮추고환자의생존율과치료율을증대시킬것이라믿습니다. 대한부인종양학회에서는기회가있을때마다이번개발된진료권고안의보급및활성화를위하여노력을할것이며향후등장하는새로운자료와의료환경을더욱반영할수있는진료권고안으로개정하기위해노력할것입니다. 본진료권고안이자궁경부암선별검사를시행하시는모든선생님들께유용한자료가되기를바라며, 권고안을개발하기위해수고를아끼지않은진료권고안개발위원회위원님들과근거창출임상연구국가사업단에다시한번감사의말씀을전합니다 년 4 월 대한부인종양학회회장유희석

3 인사말 자궁경부암은오랫동안우리나라여성암중가장흔한암이었으나최근국가암조기검진사업이활발해지면서그빈도가점차감소하고는있지만아직도부인암중에서는가장높은이환율을보이고있습니다. 자궁경부암선별검사는간단하고저렴하면서도정확하여가장이상적인암선별검사방법으로오랫동안많이이용되고있는훌륭한검사방법입니다. 자궁경부암은비교적긴전암기간을갖고있는특성때문에정기적인검사만받는다면전암단계에서치료가가능하기때문에예방이가능하고, 최근개발된예방백신과함께널리이용된다면자궁경부암으로부터모든여성을해방시킬수있는날도멀지않은것같습니다. 따라서이미외국의많은나라에서는이자궁경부암선별검사에따른진료권고안이개발되어실제로임상에많이이용되고있으나, 그간우리나라에서는외국의것들을참고하여이용하고있었을뿐우리고유의현실에맞는자체진료권고안이없었던현실입니다. 이에보건복지부근거창출임상연구국가사업단의임상진료지침개발사업의일환으로대한부인종양학회를중심으로대한산부인과학회, 대한병리학회, 대한세포병리학회와예방의학전문가들의도움으로늦었지만이제라도우리실정에맞는진료권고안을개발하여발표하게되었음을기쁘게생각합니다. 약 1년가까운기간동안많은회의와토론과정을거치고워크샵과공청회를개최하느라고생하신여러개발위원들께깊은감사를드리며, 특히모든과정을주도하느라애쓰신고려의대이재관교수께심심한감사와함께그간보여주신그열정과헌신에사의를표하는바입니다. 이제처음으로만든권고안이기때문에다소부족한점이라든지또는현실에조금맞지않는점이있을지모르겠으나이를바탕으로필요한점들을수정, 보완하여나간다면보다완벽한우리의진료권고안이될수있지않을까생각합니다. 이진료권고안이앞으로여러산부인과선생님들의진료에실질적인많은도움이될수있기를기대하면서발간에즈음한인사에대신하고자합니다 년 4 월 대한부인종양학회진료권고안개발위원장남주현

4 CONTENTS 총론 1 진료권고안 12 References 20 Appendix A (Evidence Table) 29 Appendix B (Diagram) 70

5 총 론

6 총 론 개발위원회총괄간사 이재관 ( 고려의대 ) 자궁경부암은다른부인암과는다르게몇가지뚜렷한특징을갖고있다. 인유두종바이러스지속감염이암의발생과강력하게연관되어있으며, 대부분의경우자궁경부상피내종양 (Cervical Intraepithelial Neoplasia, CIN) 으로불리는전암단계가존재한다는점, 그리고이전암단계가 7년에서길게는 20년까지지속되어이런단계에서조기진단이가능하다는것이다 [1]. 또한다른장기와비교하여자궁경부는육안적으로관찰이가능하여임상적시술을시행하기가용이하다. 전암병변의조기진단과치료를위해전세계적으로비정상자궁경부세포검사에대한다양한선별검사권고안이개발되어사용되고있다 [2-5]. 그러나, 대부분의진료권고안은미국에서개발된것으로, 이권고안을다른진료환경을가지고있는나라에그대로적용하는것은무리가있다. 예를들어, 우리나라에서자궁경부암의발생률은, 비록수십년동안감소하고있지만, 서구국가에비해더높다 [6,7]. 더욱이자궁경부암선별검사에반드시필요한 Papanicolaou (Pap) 검사와, 인유두종바이러스검사, 질확대경검사의의료수가가미국에비해매우낮게책정되어있다. 또한, 병원에대한접근성이좋아미국에비해쉽게진료를받을수있다는점도우리나라의의료환경의차별점이다. 따라서, 자궁경부암조기검진에대하여우리나라의의료환경에맞는진료권고안을개발해야한다. 진료권고안개발과정 ( 주제선정 ) 근거창출임상연구국가사업단 (National Strategic Coordinating Center of Clinical Research, NSCR) 에서공모한 2011년임상진료지침개발사업에대한부인종양학회를대표하여 비정상자궁경부세포검사의임상진료지침개발 을주제로이재관 ( 고려의대 ) 교수가연구책임자에선정되었다 (1차실무회의 ) 개발위원회는위원장남주현 ( 울산의대 ) 과소위원회 5개팀 ( 선별검사, ASC/AGC, LSIL/HSIL, HPV, Special Situation) 으로구성하기로하였다. 각팀의팀장은이재관 ( 고려의대 ), 김재원 ( 서울의대 ), 김재훈 ( 연세의대 ), 김용만 ( 울산의대 ), 김병기 ( 성균관의대 ) 로정하였다. 각팀은팀장 1명과간사 1명, 실무위원 4-5 명으로하기로하였다. 권고안작성은기존의진료권고안이 2001년국립암센터와대한산부인과학회에서작성한권고안 (2006년대한의협회지에게재 ) 을기초로하여최근판 National Comprehensive Cancer Network (NCCN) 권고안, American Society for Colposcopy and Cervical 2

7 총 론 Pathology (ASCCP) 권고안, Institute for Clinical System Improvement (ICSI) 권고안, National Health and Medical Research Council (NHMRC) 권고안, U.S. Preventive Services Task Force (USPSTF) 권고안, 새로운임상연구결과, meta-analysis, 국내연구결과를조사하여내용을전면적으로검토수정하기로하였다. 자궁경부암세포검사결과의기준은 2001년 Bethesda system을이용하기로하였다. 대한부인종양학회장 : 남주현 ( 울산의대 ) 자문위원 : 홍성란 ( 관동의대병리과 ) 윤혜경 ( 인제의대병리과 ) 안형식 ( 고려의대예방의학 ) 김현정 ( 고려의대예방의학 ) 선별검사 이재관 ( 고려의대 ) 이택상 ( 서울의대 ) 김태헌 ( 중문의대병리과 ) 송재윤 ( 고려의대 ) 유종우 ( 국립암센터병리과 ) 김현정 ( 고려의대예방의학 ) ASC/AGC 김재원 ( 서울의대 ) 임명철 ( 국립암센터 ) 강석범 ( 국립암센터 ) 이아원 ( 가톨릭의대병리과 ) 정현훈 ( 서울의대 ) 김현정 ( 고려의대예방의학 ) LSIL/HSIL 김재훈 ( 연세의대 ) 이정원 ( 성균관의대 ) 이용희 ( 아주의대병리과 ) 이인호 ( 관동의대 ) 장석준 ( 아주의대 ) 김현정 ( 고려의대예방의학 ) HPV 김용만 ( 울산의대 ) 이근호 ( 가톨릭의대 ) 김대연 ( 울산의대 ) 김혜선 ( 관동의대병리과 ) 주희재 ( 아주의대병리과 ) 허수영 ( 가톨릭의대 ) 김현정 ( 고려의대예방의학 ) Special Situation (Pregnant, Young, Old age) 김병기 ( 성균관의대 ) 김성훈 ( 연세의대 ) 김태진 ( 관동의대 ) 김혜선 ( 관동의대병리과 ) 주웅 ( 이화의대 ) 장기홍 ( 아주의대 ) 김현정 ( 고려의대예방의학 ) 3

8 Bethesda classification of cervical cytology Specimen type Conventional smear, liquid-based, or other technique Specimen adequacy Satisfactory for evaluation (description includes quality indicators, including endocervical/transformation zone component and obscuring blood or inflammation) Unsatisfactory due to... (specify reason) General categorization (optional) Negative for intraepithelial lesion or malignancy Epithelial cell abnormality (specify squamous or glandular) Other: see interpretation/result (eg, endometrial cells in woman age 40) Automated review If examined by a device, specify device and result Ancillary testing Describe method and result (eg, molecular testing) Interpretation/result Negative for intraepithelial lesion or malignancy (when there is absence of neoplasia this should be stated specifically, regardless of other findings) In addition describe, if present: Infection (Trichomonas vaginalis, Candida spp, shift in flora consistent with bacterial vaginosis, Actinomyces spp, cellular changes) Other nonneoplastic findings, such as, but not limited to: Reactive cellular changes associated with inflammation/cellular repair, radiation, or an intrauterine contraceptive device Glandular cells after hysterectomy Atrophy Other Endometrial cells (in a woman age 40) and specify whether negative for squamous intraepithelial lesion Epithelial cell abnormalities Squamous cell Atypical squamous cells (ASC) of undetermined significance (ASC-US) Atypical squamous cells (ASC), cannot exclude HSIL (ASC-H) 4

9 총 론 Low grade squamous intraepithelial lesion (LSIL) cellular changes consistent with HPV, mild dysplasia, CIN 1 High grade squamous intraepithelial lesion (HSIL) moderate/severe dysplasia, CIN 2, CIN 3, CIS indicate if there are features suspicious for invasion (if invasion suspected) Squamous cell carcinoma Glandular cell Atypical Endocervical cells Endometrial cells Not otherwise specified Atypical, favor neoplastic Endocervical cells Not otherwise specified Endocervical adenocarcinoma in situ (AIS) Adenocarcinoma Other malignant neoplasms (specify) Educational notes and suggestions Suggestions should be concise and consistent with clinical follow-up guidelines published by professional organizations Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda system: terminology for reporting results of cervical cytology. JAMA 2002; 287: (1차 workshop) 진료권고안개발위원들에게기존의경과및계획을보고하고, 권고안개발을위한방법에대해교육을하 며, 향후일정등에대해공유하고자제1차 workshop을개최하였다. 6:00 6:30 저녁식사 6:30 6:40 대한부인종양학회장인사말 울산의대 남주현 6:40 6:50 대한세포병리학회대표인사말 관동의대 홍성란 6:50 7:00 경과및계획보고 고려의대 이재관 7:00 7:20 부인암진료권고안개발경험 성균관의대 이정원 7:20 7:40 ASCCP 및 NCCN 권고안검토 국립암센터 임명철 7:40 8:00 권고안개발의병리적고려사항 가톨릭의대 이아원 8:00 8:20 권고안개발과정의개략 고려의대 김현정 8:40 9:00 Workshop 평가, 질의응답핵심질문 (Key Question) 선정작업일정안내 5

10 워크숍후추진계획 : 문헌의질이높다고알려진 Cochrane review를우선적으로적용하기로하였다. 문헌고찰및향후메타분석시행후얻어진결과를권고안작성시논의를통해적용할수있도록하였다. 다른나라의진료권고안작성예를조사하기로하였으며향후각소위원회별로핵심질문을선정후근거를조사하고수준을평가하기로하였다. 근거수준을평가하기위한프로그램으로 GRADE pro를사용하기로하였다 (2 차실무회의 ) 각소위원회별로작성된 Key Question 작성현황에대해토론하였으며향후진행일정에대해논의하였다 ( 팀장회의 ) 현재까지진행된경과에대해보고하였으며각소위원회별로 Key Question 현황에대해향후진행방향을토론하였다. 또한, 선별검사에대한내용이포함되어있기때문에기존의 비정상자궁경부세포검사진료권고안 의제목으로는적합하지않아 으로수정하기로결정하였다 ( 간사회의 ) 각소위원회별 Key Question별 Adaptation 및 De novo 결정상황및그에따라작성한근거표및권고 안초안에대해논의하였다. 또한, 향후가안작성및 7월 7일 2차워크샵에서발표할최종본을작성하여각 소위원회별로분임토의를진행하기로하였다. 6:30 6:40 회의시작및경과보고 고려의대 이재관 6:40 7:00 진행현황 Screening 서울의대 이택상 7:00 7:20 진행현황 ASC/AGC 국립암센터 임명철 7:20 7:40 진행현황 LSIL/HSIL 성균관의대 이정원 7:40 8:00 진행현황 HPV 가톨릭의대 이근호 8:00 8:20 진행현황 Special Situation 연세의대 김성훈 8:20 8:30 향후일정토의 (2차 workshop) 각소위원별로작성된내용을토론하였다. 그중서론에는이권고안은강제성을띌수는없기때문에임상의사의소견이우선한다는문구를삽입하기로하였다. 7월 7일 19:00 석식 20:00-1차소위원회별분임토의 7월 8일 07:30-2차소위원회별분임토의 12:30 13:30 점심식사 6

11 총 론 14:00 14:30 3차소위원회별분임토의 각소위원회간사 14:30 14:40 대한부인종양학회장인사말 울산의대 남주현 14:40 14:50 경과보고 고려의대 이재관 14:50 15:20 요약본발표 Screening 서울의대 이택상 15:20 15:50 요약본발표 ASC/AGC 국립암센터 임명철 15:50 16:20 요약본발표 LSIL/HSIL 관동의대 이인호 16:20 16:30 휴식 16:30 17:00 요약본발표 HPV 가톨릭의대 이근호 17:00 17:30 요약본발표 Pregnant, young, old age 연세의대 김성훈 17:30 18:00 국가암검진권고안개정 국립암센터 전재관 18:00 18:10 향후일정발표 18:00 토론 ( 설문조사시행 ) 개발된내용을바탕으로대한산부인과학회전체회원, 대한세포병리학회전체회원, 대한예방의학회전체 회원을대상으로 2 번의온라인설문조사를시행하였다 ( 전문가Consensus 미팅 - 대한부인종양학회 ) 개발된내용을바탕으로대한부인종양학회상임이사진을대상으로전문가 Consensus 미팅을진행하였다. 각항목및핵심질문에대해토론을진행하였으며수정사항은향후공청회및학술대회발표시에적용하기로하였다 ( 전문가Consensus 미팅 - 대한세포병리학회 ) 개발된내용을바탕으로대한세포병리학회상임이사진을대상으로전문가 Consensus 미팅을진행하였다. 각항목및핵심질문에대해토론을진행하였으며수정사항은향후공청회및학술대회발표시에적용하기로하였다 ( 제 98차대한산부인과학회학술대회발표 ) 개발된내용을바탕으로제 98차대한산부인과학회학술대회에서이정원 ( 성균관의대 ) 의발표로첫공표하였다. 이자리에서나온질문및토론내용과설문조사내용에대해다시토론을거쳐적용할부분은향후적용하기로하였다. 7

12 ( 공청회 ) 그동안진행되어왔던진료권고안에대해최종공청회를가지면서내용에대해참석자들의확인을받았다. 13:00 13:05 대한부인종양학회장인사말 울산의대 남주현 13:05 13:10 대한세포병리학회대표인사말 관동의대 홍성란 13:10 13:20 경과보고 고려의대 이재관 13:20 13:30 권고안개발과정요약 고려의대 김현정 13:30 13:40 국가암검진권고안개정시고려사항 국립암센터 전재관 13:40 13:50 세포검사와 HPV 검사의정도관리방안 관동의대 홍성란 13:50 14:00 요약본발표 Screening 소위원회 서울의대 이택상 14:00 14:10 질의응답 14:10 14:30 Coffee break 14:30 14:40 요약본발표 ASC/AGC 소위원회 국립암센터 임명철 14:40 14:50 질의응답 14:50 15:00 요약본발표 LSIL/HSIL 소위원회 성균관의대 이정원 15:00 15:10 질의응답 15:10 15:20 요약본발표 HPV 소위원회 가톨릭의대 이근호 15:20 15:30 질의응답 15:30 15:40 요약본발표 Special situation 소위원회 연세의대 김성훈 15:40 15:50 질의응답 15:50 16:00 토론및향후일정발표 (3 차 workshop) 향후권고안의유지발전을위한워크샵을개최하였으며선별검사의정도관리방안에대해토론을하였으 며이후 2013 년계획을토론하였다. 8

13 총 론 진료지침의범위와목적설정 본진료지침은자궁경부암및자궁경부상피내종양을포함하며, 그목적은국내에서행하여지는자궁경부 암 " 선별검사 " 분야의진료의표준화및그수순의향상에있다. 핵심질문선정과정 각팀별로기존권고안의문제점분석, 최근발표된중요한임상연구결과, 대표적인관련학회진료지침을 분석한후팀별위원들의토론을통하여 Key question 을선정하였다. 근거검색 1. 검색전략해당주제에대한위원장과간사및위원회의검증절차를통해검색어를결정하였으며이를 Cochrane Library CENTRAL과 MEDLINE을통해일차자료를검색하였으며, DARE, Cochrane Library를통해메타분석및체계적문헌고찰을검색하였다. 추가적으로 2012년도 NCCN 가이드라인, ASCCP 가이드라인, USPSTF 가이드라인, 일본부인종양학회가이드라인, 호주가이드라인을참조하였다. 2. 근거의선택기준및배제기준포함기준 : 연구설계의종류 : Systemic review, RCT, observational study 연도 : 최근 10년이내언어 : 영어기타기준 근거평가방법 1. 문헌의질평가개별연구는연구설계에따라무작위임상실험의경우 Cochrane 방법론을적용하여비뚫림의위험을평가하였으며무작위임상실험을제외한비무작위연구는뉴캐슬오타와척도 (Newcastle-Ottawa Scale) 를이용하여평가하였다. 9

14 2. 근거의수준평가근거의수준평가는이상의개별연구에대한연구설계에따른근거평가를바탕으로근거의수준을평가하였다. 근거수준평가는 Grade Group에서제시한근거수준의방법론에적용하여평가하였다. 근거수준은대상질문에서의개별연구의연구설계를기반으로연구결과간의일관성및연구대상및중재적용의직접성, 출판편견의가능성, 연구결과의정확성, 포함된문헌의질평가에따른비뚫림의가능성을평가하여 4개의근거수준으로구분하였다. Level A: High-quality evidence Level B: Moderate-quality evidence Level C: Low-quality evidence Level D: Very low-quality evidence Level E: No evidence or difficult to analysis (Expert Consensus; 단, 권위있는전문가의임상경험에기초한의견이나, 전문가로구성된위원회에서발표된연구결과나보고자료에서얻은근거 ) 권고안등급결정및합의안도출과정 권고의등급결정은 Grade Group에서제시한권고안도출의방법론을적용하였다. 근거의수준을기반으 로해당중재의적용대상, 위해, 편익, 사회적개인적비용, 환자의기호를고려하여권고의등급을결정하였 으며권고의수준은강력한권고, 권고로구분하였다. 권고등급의결정은해당위원회협의를통해최종확 정하였다. HS Strong Rx (S) / High-quality evidence (H) MS Strong Rx (S) / Mod-quality evidence (M) LS Strong Rx (S) / Low-quality evidence (L) VLS Strong Rx (S) / Very low-quality evidence (VL) ES Strong Rx / Expert Consensus or lack of evidence (E) HW Weak Rx (W) / High-quality evidence (H) MW Weak Rx (W) / Mod-quality evidence (M) LW Weak Rx (W) / Low-quality evidence (L) VLW Weak Rx (W) / Very low-quality evidence (VL) EW Weak Rx (W) / Expert Consensus or lack of evidence (E) 10

15 총 론 내외부검토와승인과정 권고안가안을작성후 2 회의공청회를부인종양학회전체회원및관련학회대표자를초청하여가진후 회의내용을추가보완하였다. 진료지침의적용및보급확산 상기진료권고안은부인종양학회전위원을포함하여자궁경부암일차진료를할수있는모든산부인과학 회회원들에게배포예정. 또한자궁경부암진료에관여하는관련학회위원에게도배포할것이다. 보급전략및방법 - 인쇄자료배포 : 2013년 3월말인쇄후발송예정 - 온라인자료배포 2013년 5월말대한부인종양학회및대한산부인과학회홈페이지에배포예정 - 학회발표개정된 자궁경부암조기검진을진료권고안 은향후한글판부인종양교과서에부록으로수록한다. 11

16 (PRACTICE GUIDELINE)

17 (PRACTICE GUIDELINE) 일반선별검사가이드라인 자궁경부암선별검사의대상은만 20세이상의성경험이있는모든여성으로한다 (VLS) [10-15]. 20세미만의여성의경우매우높은 HPV 감염율과그에상응하는높은자연치유율, 또한자궁경부침윤암의매우낮은발생빈도를고려할때선별검사의시행은권장되지않으나자궁경부암및전암병변이의심되는경우시행할수있다 (VLW). 자궁경부암선별검사는최근 10년간세번이상의연속된자궁경부세포검사에서음성으로판정된경우 70세에종료할수있다 (ES). 단, 최근 20년간중등도이상의상피내종양병력이있는여성의경우혹은세포검사의결과를알수없는경우연령에관계없이선별검사를지속한다 (EW). 서양의권고안이세포검사단독으로 3년주기를권장하고있으나, 상대적으로높은우리나라의자궁경부암발생빈도, 선별검사를위한접근성의용이함, 상대적으로저렴한선별검사수가를고려할때만 20세이상 70세이하의여성에서매 1년간격으로세포검사를시행할것을권장한다 (ES). 현재까지의연구결과액상세포검사는기존의세포검사방법에비하여민감도, 특이도를높이지않는것으로알려져있다 [16-20]. 다만부적절한검체의발생빈도를줄이는효과가있다. 우리나라현실을반영할때 conventional Pap test와 Liquid-based technology 모두세포검사방법으로선택할수있다 (MS). 자궁경부암조기검진을위하여자궁경부세포검사와자궁경부확대촬영 (Cervicography) 을병행하는것은위양성율의증가와비용효과를고려할때통상적으로권장되지않으나민감도의측면에서유리할수있다 (LW) [21-23]. 30세미만의여성에서는 HPV 검사의높은위양성률과 HPV 감염의자연치유율을고려할때 [24], HPV 검사가선별검사에이용되는것이권고되지않으며, 30세이상의여성에서기존세포검사와병합하여시행한경우두가지검사모두에서음성을보이면선별검사의주기를 2년으로늘일수있다 (HS) [25-43]. 백신의접종으로향후자궁경부상피내종양및자궁경부암발생율의감소가예상되나선별검사의주기의변경은현행검진주기를원칙으로하며향후임상적데이터가축적된후다시검토한다 (EW). 자궁경부를포함한자궁적출술을시행한여성의경우라하더라도중등도상피내종양이상의병력이있는경우이거나, 과거선별검사의결과를알수없는경우에는선별검사를지속한다 (ES). 13

18 Atypical squamous cells (ASC) ASC는 ASC-US (Atypical Squamous Cells of Undetermined Significance) 와 ASC-H (Atypical Squamous Cells, cannot rule out a high grade lesion) 로구분된다. ASC-H와비교하여 ASC-US 결과를보이는여성은고등급자궁경부상피내종양이나침윤성자궁경부암의가능성이더낮다 [44]. 따라서, 이런환자에게는 ASC-US 세포검사결과만으로절제술등의치료를권하지않으며, 질확대경등조직검사소견을기반으로치료방침을결정해야한다. 반면, ASC-H를보이는여성에서는고등급병변 (CIN2/3) 의가능성이높기때문에이런환자들은 HSIL (High grade Squamous Intraepithelial Lesion) 을보이는환자들과같은방법으로관리해야한다. 1. Recommended management of women with ASC-US 자궁경부세포검사결과가 ASC-US로나왔을경우반복적인자궁경부세포검사, 고위험군인유두종바이러스검사, 즉각적인질확대경검사 (Colposcopy) 모두시행할수있다 (HS) [45-48]. 6개월마다반복적으로자궁경부세포검사를시행하였을때이후검사에서 ASC-US 이상으로세포검사결과가나온다면질확대경검사를반드시시행해야한다 [2]. 2회연속으로결과가음성 (negative for intraepithelial lesion or malignancy) 으로나왔을경우에는일반선별검사프로그램으로복귀할수있다. 추가검사로고위험군인유두종바이러스검사를선택하여양성으로결과가나온경우에도반드시질확대경검사를시행해야한다 [2]. 즉각적인질확대경검사를시행한경우에만족스러운검사과정 (satisfactory colposcopy) 이면서조직검사에서경증자궁경부상피내종양 (CIN1) 이하의병변으로나온다면 12개월에인유두종바이러스검사를시행하거나 6개월마다 2차례반복세포검사를시행할수있다 (MS) [49,50]. 위의검사에서모두정상으로나온다면일반선별검사프로그램으로복귀할수있다 (ES). 그러나, CIN2/3 병변으로나온경우에는반드시진단및치료목적의절제술을시행해야한다. 2. Recommended management of women with ASC-H 세포검사결과가 ASC-H로나왔을경우권고하는추가검사는질확대경검사이다 [2]. 조직검사에서 CIN2 이상의병변이나오지않을경우세포검사, 조직검사및질확대경검사소견을재판독할수있다 (EW). 또한, 이런경우에는 6개월간격으로자궁경부세포검사와질확대경검사를시행할수있다 (ES). 6개월간격으로 2회연속정상으로판독될경우일반선별검사프로그램으로복귀할수있다 (ES). 만약 CIN2 이상의병변으로확인된경우라면진단목적의절제술을반드시시행하여야한다. 14

19 자궁경부암선별검사진료권고안 Atypical glandular cells (AGC) 비록반응성세포변화또는용종같은양성질환에의하여 AGC가나오는경우가종종있지만, 약 45% 의환자에서는자궁경부상피내종양, 자궁경부암, 자궁경부선상피내암, 자궁내막암, 난소암, 난관암등과관계된경우가있다 [2,51]. 이전연구결과에따르면 AGC로나온여성의 9-38% 에서고등급자궁경부상피내종양, 자궁경부선상피내암, 악성종양등이발견되었다 [2]. 아직 AGC를보이는여성에서시행하는검사중충분한민감도를갖는단일검사는없다 [52]. 따라서, AGC의결과를갖는여성에서는여러검사를복합적으로시행해야한다. 1. Recommended management of women with AGC 세포검사에서 AGC가나온경우, 인유두종바이러스검사, 질확대경검사, 자궁내경관소파술 (endocervical curettage, ECC) 을시행해야한다 (VLS) [44,53-56]. 자궁내막조직검사도 35세이상의여성에서는반드시시행하여야한다 (VLS) [44,55,56]. 35세이하의여성에서자궁내막조직검사는비만, 불임, 타목시펜복용, 무월경, 다낭성난소증후군같은자궁내막암의위험인자를갖고있거나비정상적인질출혈의병력이있는경우또는비정상자궁내막세포가보인경우에는반드시시행해야한다 [3]. 질확대경하조직검사와자궁내경관소파술에서자궁경부상피내종양이나선상피내암이발견된경우진단목적의절제술이반드시시행되어야한다. 하지만, 만족스러운질확대경검사조건에서 CIN1과음성의자궁내경관소파술을보이는경우에는 6개월간격으로반복자궁경부세포검사를시행하거나 12개월에인유두종바이러스검사를시행할수있다. 경과관찰위해시행한자궁경부세포검사에서 ASC-US이상으로나온경우질확대경검사를시행해야한다 [3]. Low-grade squamous intraepithelial lesion (LSIL) LSIL은고위험군인유두종바이러스감염과매우밀접한관계를갖고있다. 최근메타분석에따르면 LSIL 여성에서인유두종바이러스감염율과 16/18번인유두종바이러스추정감염율이각각 72.9% 와 26.7% 에이른다 [57]. 또한, LSIL 여성에서질확대경하조직검사를시행할경우고등급병변이상의결과가나올확률은 11-14% 에이른다 [58,59]. 1. Recommended management of women with LSIL LSIL 결과를갖는여성에서는질확대경검사가반드시시행되어야한다 (MS) [60]. LSIL 환자의추가검사는질확대경검사에전체변이대가충분히관찰되는지여부에따라달라진다. 자궁내경관소파술은임산부를제외하고, 자궁경부에병변이관찰되지않거나만족스럽지않은질확대경검사결과 (unsatisfactory colposcopy) 를보이는여성에서고려해야한다 [2,3]. 자궁내경관소파술에서 CIN2/3 같은고등급병변이확인되 15

20 었을때는절제술이반드시이뤄져야한다. 고등급병변이관찰되지않거나조직검사를시행하지않은경우에는 6개월마다반복자궁경부세포검사를시행하거나 12개월에인유두종바이러스검사를시행하여경과관찰할수있다 (ES). 이런경우에는절제술이권고되지않는다. 두차례의연속된세포검사에서정상으로나오거나인유두종바이러스검사가음성으로나온경우에는일반선별검사프로그램으로복귀할수있다. 만약, 경과관찰도중세포검사에서 ASC-US 이상의결과가나오거나인유두종바이러스검사가양성으로나온다면질확대경검사를시행해야한다. 질확대경검사를통한조직검사에서 CIN2/3가발견된다면, 진단목적의절제술이시행되어야한다 [2,3]. High-grade squamous intraepithelial lesion (HSIL) 세포검사에서 HSIL이관찰되는것은고등급병변이나침윤성암의가능성이높다는점을의미한다. HSIL 의결과가나온여성에서질확대경하조직검사에의해고등급병변이확인되는경우는 60-70% 정도해당되며루프환상절제술에의한경우는 84-97% 정도발견된다 [2,61]. 또한, HSIL 여성에서최대 18.8% 에서침윤성자궁경부암으로나온다 [62]. 따라서, HSIL이나온여성에서는세포검사나인유두종바이러스검사를통해경과관찰하는것은적절하지않다. 질확대경검사가고등급병변을놓칠수있는경우가많기때문에이런여성의대부분에서는결과적으로진단목적의절제술이시행하게된다 [2]. 1. Recommended management of women with HSIL HSIL이나온경우, 청소년시기의여성을제외하고, 질확대경검사없이 (VLS) 루프환상절제술이나원추절제술을포함한즉각적인진단목적의절제술을시행할수있다 [63-65]. HSIL 여성의추가검사는질확대경검사의만족여부에따라달라진다. 만족스러운질확대경검사가시행된여성의경우추가검사는병변이보이는지여부에따른다. 질확대경검사에서병변이관찰되지않는다면자궁내경관소파술을반드시시행해야한다 [3]. 만약자궁내경관소파술에서정상으로나온다면세포검사와질확대경검사를 6개월마다, 2회연속정상으로나올때까지시행할수있다. 자궁경관소파술에서자궁경부상피내종양으로진단된다면진단목적의절제술을시행해야한다. 병변이질확대경검사에서관찰되고조직검사에서고등급병변으로나오지않는다면경과진단목적의절제술 (VLS), 세포검사와조직검사검체의재검 (ES), 또는 1년간 6개월마다반복적인세포검사와질확대경검사방법으로관찰할수있다. 1년간의경과관찰이후세포검사결과가 2번의연속적인음성으로나오거나질확대경검사가정상으로나온다면일반선별검사프로그램으로복귀할수있다 (ES). 그러나, 경과관찰을위한세포검사에서 HSIL로나온다면반드시진단목적의절제술을시행해야한다. 초기질확대경검사에서 CIN2/3의고등급병변으로나왔을경우절제술을통한치료를시행해야한다 [66]. 절제술후경계부위에병변이남았을경우 6개월후자궁경부세포검사또는 12개월후인유두종바이러스검사를통해경과관찰할수있다 (ES). 16

21 자궁경부암선별검사진료권고안 HPV DNA test 자궁경부세포검사가선별검사로시행된이후자궁경부상피내종양과자궁경부암의조기진단이이뤄진점은있지만, 세포검사가갖고있는높은위음성률같은단점은무시할수없다 [67]. 더욱고위험군인유두종바이러스감염이자궁경부암의필요조건으로알려져있기때문에고위험군인유두종바이러스검사가자궁경부세포검사의보조방법으로제안되고있다. 이전의많은연구결과인유두종바이러스검사가 CIN2 이상의고등급병변을발견하는데세포검사에비해더욱뛰어난민감도를갖는다 [17,68-73] 세사이의 9,667명의여성에서자궁경부세포검사와인유두종바이러스검사를비교한무작위연구에서 CIN2 이상의병변을발견하는민감도가자궁경부세포검사, 인유두종바이러스검사, 두가지방법의복합할경우에각각 56.4%, 97.4%, 100% 로나왔다 [70]. 위세가지경우의특이도는 97.3%, 94.3%, 92.5% 이었다. 세포검사와인유두종바이러스검사모두음성인여성은 CIN2가발견될확률이 1,000 분의 1이하였고 CIN3의경우는더욱낮았다 [74,75]. 30세이상의여성에서세포검사의높은위음성률을낮추기위한방법으로인유두종바이러스검사를시행할수있다 (HS) [68-73]. 미국식약청 (FDA) 에서승인받은 Hybrid Capture 2 (HC2) 외에도 chip 검사와 PCR (Polymerase-Chain Reaction) 기반의검사모두인유두종바이러스감염을진단하기위해사용할수있다 (LW) [76-79]. 인유두종바이러스감염이된여성중많은수에서정상의세포검사결과를보인다. 인유두종바이러스감염율은 6.5% 이며인유두종바이러스양성인여성의 58% 에서정상세포검사결과를보인다 [80]. 더욱, 정상세포검사와양성인유두종바이러스검사결과를갖는여성에서 CIN2 이상의병변을놓칠확률은 % 정도로매우낮다 [81,82]. 따라서, 이런여성에서고등급병변이나악성종양이발생할수있는가능성이높은여성을구분하는게중요하다. 30세이상의정상세포검사 / 양성인유두종바이러스검사결과를보이는여성에서 10년이내 CIN3가관찰되는확률은 16번 /18번인유두종바이러스각각 21% 와 18% 정도해당된다 [75]. 반면그외의고위험군인유두종바이러스에감염된여성에서는단지 1.5% 정도에해당된다. 인유두종바이러스의유전자형에따라고등급병변이발생하는확률이다른결과에근거하여, 정상세포검사 / 양성인유두종바이러스의결과를보이는여성에서는인유두종바이러스유전자형검사를시행할수있다 (LS) [74,75,83,84]. 만약 16번이나 18번인유두종바이러스가발견되었다면부인종양전문의에게의뢰하여질확대경검사를시행해야한다 (LS). 16이나 18번이외의고위험인유두종바이러스에감염된여성에서는인유두종바이러스검사와유전자형검사를 1년후에시행할수있다 (LS). 17

22 Special situations 1. Management of adolescent women 20세이하의여성에서자궁경부검사결과가비정상일때는특별한상황을고려해서처치해야한다. 이전연구결과에따르면젊은여성의대부분이성관계를시작한지몇년내에인유두종바이러스에감염이된다 [85-87]. 이런여성에서는인유두종바이러스감염율과자연치유율이높기때문에세포검사에서 ASC-US/ LSIL일경우에도인유두종바이러스검사를권유하지않는다 (LS) [86,88,89]. 대신, 매년세포검사를통한경과관찰을권유할수있다. 12개월에시행한세포검사에서 HSIL 이상의결과가나온다면반드시질확대경검사를시행해야한다 [2,3]. 또한, 24개월에시행한세포검사에서 ASC-US 이상으로결과가나온다면반드시질확대경검사를위한전원을고려해야한다 [2,3]. 만약초기검사에서 ASC-H로나왔다면 CIN2 이상의병변이나올확률이높기때문에질확대경검사를시행해야한다 [3]. 질확대경검사가만족스럽고 CIN2/3의고등급병변이관찰되지않을때는 6개월후세포검사를시행할수있다. 또한, 2번연속적으로세포검사에서음성으로나온다면일반선별검사프로그램으로복귀할수있다. 여기에서 ASC-US 이상의결과가나온경우에는질확대경검사를시행해야한다. 그결과 CIN2/3가발견된다면 (1) 절제술또는소작술, (2) 6개월마다세포검사와질확대경검사를반복하면서경과관찰하기등두가지의치료방법을사용할수있다. 만족스럽지않은질확대경검사결과를보이는경우에는반드시자궁내경관소파술과자궁경부조직검사를고려해야한다 [3]. 청소년에서 HSIL의결과가나온경우, 질확대경검사를시행해야한다 [2,3]. 즉각적인절제술은권장되지않는다. 여기에서조직학적으로 CIN2/3의결과가나오지않는다면 6개월간격으로 2년까지세포검사와질확대경검사를시행하면서경과관찰할수있다. 이과정중고등급병변이관찰되거나 HSIL이 1년동안지속된다면조직검사를시행해야한다. 2번의연속검사에서세포검사가정상이고질확대경검사에서고등급병변이관찰되지않는다면일반선별검사프로그램으로돌아갈수있다. 반면 CIN2/3가확인된경우에는절제술 / 소작술을시행하거나 24개월까지 6개월마다세포검사와질확대경검사를시행할수있다. 만족스럽지않은질확대경검사결과를보이는경우에는반드시자궁내경관소파술과자궁경부조직검사를고려해야한다 [3]. 만족스럽지않은질확대경검사결과를보이는경우에는반드시자궁내경관소파술과자궁경부조직검사를고려해야한다 [3]. 2. Management of pregnant women 청소년기를지난임산부에서 ASC-US/LSIL이나온경우에는임산부가아닌여성의경우와똑같이추가검사를시행한다. 자궁내경관소파술은임산부에서는시행하지않는다. 분만후 6주까지초기질확대경검사를연기하는것은안전하며임산부에서시행할수있는처치방법중하나이다 (LS) [90,91]. HSIL의결과가있는임산부에서는질확대경검사를시행해야하며조직검사는반드시고등급병변이나침윤성악성종양이의심되는경우에만시행해야한다 [2,3]. 조직학적으로 CIN2/3로진단된 78명의임산부중 48명 (62%) 이분만후 18

23 자궁경부암선별검사진료권고안 정상으로복귀되었다 [92]. 경과관찰기간도중침윤성악성종양이관찰된경우는없었다. 또다른 CIN2/3 를갖는임산부에대한전향연구에따르면거의절반정도의여성이초기질환이사라졌으며침윤성악성종양으로진행된경우는없었다 [93]. 만약침윤성악성종양이아닌 CIN2/3의고등급병변이확인되었다면분만후까지진단목적의절제술을연기할수있다 (LS). Follow-up after treatment of CIN with excisional procedures or ablation 레이저치료나냉동치료같은소작술이후수술경계부위에대해병변유무의판단은할수가없다. 이런경우에는 6개월이후세포검사또는 12개월후인유두종바이러스검사를시행할수있다 [94]. 또한, CIN2/3 환자에서수술경계가음성이거나모든 CIN1 환자의경우에는 6개월후세포검사또는 12개월후인유두종바이러스검사로경과관찰할수있다 [3]. CIN2/3 환자에서수술경계에병변이있는경우 (1) 6개월후세포검사를하거나, (2) 자궁내경관소파술을고려하거나, (3) 침윤암이의심되는경우에는재시술을시행하거나전문가에게자문을구한후자궁적출술을시행할수있다. 6개월후시행한세포검사에서 ASC-US 이상으로나온다면추가검사는이전에언급한권고안에따라야한다. 세포검사또는인유두종바이러스검사가음성일경우에는일반선별검사프로그램으로복귀할수있으며 12개월후에시행한인유두종바이러스검사가양성으로나온다면질확대경검사를시행해야한다. 19

24 REFERENCES

25 REFERENCES 1. Schiffman M, Castle PE. The promise of global cervical-cancer prevention. N Engl J Med (20): Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D Consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol (4): Partridge EE, Abu-Rustum NR, Campos SM, Fahey PJ, Farmer M, Garcia RL, et al. Cervical cancer screening. J Natl Compr Canc Netw 20108(12): Moyer VA; U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;156(12): Health Care Guideline: Initial management of abnormal cervical cytology (Pap test) and HPV test in adult and adolescent females. Available from: ( cervical_ cytology_pap_smear_and_hpv_testing_initial_management_of_abnormal_pdf_.html) 6. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin (2): Lee YH, Choi KS, Lee HY, Jun JK. Current status of the National Cancer Screening Program for cervical cancer in Korea, J Gynecol Oncol (1): Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-ytter Y, Schunemann HJ. What is "quality of evidence" and why is it important to clinicians? BMJ (7651): Schunemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, Vist GE, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ (7653): Insinga RP, Glass AG, Rush BB. Diagnoses and outcomes in cervical caner screening: a population-based study. Am J Obstet Gynecol 2004;191: Sigurdsson K. Cervical cancer: cytological cervical screening in Iceland and implications of HPV vaccines. Cytopathology 2010;21: Sigurdsson K, Sigvaldason H. Is it rational to start population-based cervical cancer screening at or soon after age 20? Analysis of time trends in preinvasive and invasive diseases. Eur J Cancer 2007;43:

26 13. Peto J, Gilham C, Deacon J, Taylor C, Evans C, Binns W, et al. Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort. Brit J Cancer 2004;91: Woodman CB, Collins S, Winter H, Bailey A, Ellis J, Prior P, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001;357: Sasieni P, Castanon A, Cuzick J.Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data. BMJ 2009;339:b Taylor S, Kuhn L, Dupree W, Denny L, De Souza M, Wright TC Jr. Direct comparison of liquid-based and conventional cytology in a South African screening trial. Int J Cancer 2006; 118: Coste J, Cochand-Priollet B, Cremoux P, Le Gales C, Cartier I, Molinie V, et al. Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirusdna testing for cervical cancer screening. BMJ 2003;326: Cochand-priollet B, Le Gales C, de Cremoux P, Molinie V, Sastre-Garau X, Vacher-Lavenu MC, et al. Cost-effectiveness of monolayers and human papillomavirus testing compared to that of conventional Papanicolaou smears for cervical cancer screening: protocol of the study of the French Society of Clinical Cytology. Diagn Cytopathol 2001;24: Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla Palma P, Naldoni C, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomizedcontrolled trial. BMJ 2007;335: Siebers AG, Klinkhamer PJ, Grefte JM, Massuger LF, Vedder JE, Beijers-Broos A, et al. Comparisonof liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. JAMA 2009;302: Baldauf JJ, Dreyfus M, Lehmann M, Ritter J, Philippe E. Cervical cancer screening with cervicography and cytology. Eur J Obstet Gynecol Reprod Biol 1995;58: Autier P, Coibion M, De Sutter P, Wayemberg M. Cytology alone versus cytology and cervicography for cervical and cervicography for cervical cancer screening: a randomized study. European Society for Oncological Research. Obstet Gynecol 1999;93: Kim YT, Kim JW, Kim SH, Kim YR, Kim JH, Yoon BS, et al. Clinical usefulness of cervicogram as a primary screening test for cervical neoplasia. Yonsei Med J 2005;46: Moscicki AB, Schiffman M, Kjaer S, Villa LL. Updating the natural history of HPV and anogenital cancer. Chapter 5. Vaccine 2006;24(Suppl 3):S Ronco G, Segnan N, Giorgi-Rossi P, Zappa M, Casadei GP, Carozzi F, et al. Human papillo- 22

27 REFERENCES mavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial. J Natl Cancer Inst 2006;98: Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 2010;11: Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A et al. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test. J Natl Cancer I 2008; 100: Ronco G, Cuzick J, Segnan N, Brezzi S, Carozzi F, Folicaldi S, et al. HPV triage for low grade (L-SIL) cytology is appropriate for women over 35 in mass cervical cancer screening using liquid based cytology. European Journal of Cancer 2007;43: Ronco G, Brezzi S, Carozzi F, Dalla Palma P, Giorgi-Rossi P, Minucci D, et al. The New Technologies for Cervical Cancer Screening randomised controlled trial. An overview of results during the first phase of recruitment. Gynecol Oncol 2007;107:S Kotaniemi-Talonen L, Anttila A, Malila N, Tarkkanen J, Laurila P, Hakama M, et al. Screening with a primary human papillomavirus test does not increase detection of cervical cancer and intraepithelial neoplasia 3. Eur J Cancer 2008;44: Leinonen M, Nieminen P, Kotaniemi-Talonen L, Malila N, Tarkkanen J, Laurila P, et al. Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J Natl Cancer Inst 2009;101: Anttila A, Kotaniemi-Talonen L, Leinonen M, Hakama M, Laurila P, Tarkkanen J, et al. Rate of cervical cancer, severe intraepithelial neoplasia, and adenocarcinoma in situ in primary HPV DNA screening with cytology triage: randomised study within organised screening programme. BMJ 2010;340:c Anttila A, Hakama M, Kotaniemi-Talonen L, Nieminen P. Alternative technologies in cervical cancer screening: a randomised evaluation trial. BMC Public Health 2006;6: Kotaniemi-Talonen L, Nieminen P, Anttila A, HakamaM. Routine cervical screening with primary HPV testing and cytology triage protocol in a randomised setting. Br J Cancer 2005;93: Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, et al. Human papillomavirus DNA testing forthe detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007;370: Bulkmans NW, Rozendaal L, Snijders PJ, Voorhorst FJ, Boeke AJ, Zandwijken GR, et al. 23

28 POBASCAM, a population-based randomized controlled trial for implementation of high-risk HPV testing in cervical screening: design, methods and baseline data of 44,102 women. Int J Cancer 2004;110: Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007;357: Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst 2009;101: Elfgren K, Rylander E, Radberg T, Strander B, Strand A, Paajanen K, et al. Colposcopic and histopathologic evaluation of women participating in population-based screening for human papillomavirus deoxyribonucleic acid persistence. Am J Obstet Gynecol 2005;193: Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A, Stoykova B, et al. HPV testing in combination with liquid-based cytology in primarycervical screening (ARTISTIC): a randomised controlled trial. Lancet Oncol 2009;10: Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, et al. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening. Health Technol Assess 2009;13:1-150, iii-iv. 42. Kitchener HC, Almonte M, Wheeler P, Desai M, Gilham C, Bailey A, et al. HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial. Br J Cancer 2006;95: Sargent A, Bailey A, Almonte M, Turner A, Thomson C, Peto J, et al. Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial. Br J Cancer 2008;98: Jones BA, Novis DA. Follow-up of abnormal gynecologic cytology: a college of American pathologists Q-probes study of cases from 306 laboratories. Arch Pathol Lab Med 2000;124: ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188: Ferris DG, Wright TC, Jr., Litaker MS, Richart RM, Lorincz AT, Sun XW, et al. Triage of women with ASCUS and LSIL on Pap smear reports: management by repeat Pap smear, HPV DNA testing, or colposcopy? J Fam Pract 1998;46: Manos MM, Kinney WK, Hurley LB, Sherman ME, Shieh-Ngai J, Kurman RJ, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA 1999;281:

29 REFERENCES 48. Lonky NM, Felix JC, Naidu YM, Wolde-Tsadik G. Triage of atypical squamous cells of undetermined significance with hybrid capture II: colposcopy and histologic human papillomavirus correlation. Obstet Gynecol 2003;101: Jeronimo J, Khan MJ, Schiffman M, Solomon D. Does the interval between papanicolaou tests influence the quality of cytology? Cancer 2005;105: Guido R, Schiffman M, Solomon D, Burke L. Postcolposcopy management strategies for women referred with low-grade squamous intraepithelial lesions or human papillomavirus DNA-positive atypical squamous cells of undetermined significance: a two-year prospective study. Am J Obstet Gynecol 2003;188: Veljovich DS, Stoler MH, Anderson WA, Covell JL, Rice LW. Atypical glandular cells of undetermined significance: a five-year retrospective histopathologic study. Am J Obstet Gynecol 1998;179: Sharpless KE, Schnatz PF, Mandavilli S, Greene JF, Soroski JI. Dysplasia associated with atypical glandular cells on cervical cytology. Obstet Gynecol 2005;105: Derchain SF, Rabelo-Santos SH, Sarian LO, Zeferino LC, de Oliveira Zambeli ER, do Amaral Westin MC, et al. Human papillomavirus DNAdetection and histological findings in women referred for atypical glandular cells or adenocarinima in situ in their Pap smears. Gynecol Oncol 2004;95: Mulhem E, Amin M, Copeland J, Sharma J, Hunter S. Type-specific human papillomavirus DNA detected in atypical glandular cell Pap tests. Acta Cytol 2012;56: Ronnett BM, Manos MM, Ransley JE, Fetterman BJ, Kinney WK, Hurley LB, et al. Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papillomavirus DNA detection. Hum Pathol 1999;30: Chhieng DC, Elgert P, Cohen JM, Cangiarella JF. Clinical significance of atypical glandular cells of undetermined significance in postmenopausal women. Cancer 2001;93: Sharpless KE, Schnatz PF, Mandavilli S, Greene JF, Sorosky JI. Lack of adherence to practice guidelines for women with atypical glandular cells on cervical cytology. Obstet Gynecol 2005;105: Bao YP, Smith JS, Qiao YL; ACCPAB members. Human papillomavirus type distribution in women from Asia: a meta-analysis. Int J Gynecol Cancer 2008;18(1): Alvarez RD, Wright TC; Optical Detection Group. Effective cervical neoplasia detection with a novel optical detection system: a randomized trial. Gynecol Oncol 2007;104(2): ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol 2003;188(6): 25

30 Chute DJ, Covell J, Pambuccian SE, Stelow EB. Cytologic-histologic correlation of screening and diagnostic Papanicolaou tests. Diagn Cytopathol 2006;34(7): Lee JK, Kim MK, Song SH, Hong JH, Min KJ, Kim JH, et al. Comparison of human papillomavirusdetection and typing by hybrid capture 2, linear array, DNA chip, and cycle sequencing in cervical swab samples. Int J Gynecol Cancer 2009;19: Numnum TM, Kirby TO, Leath CA, 3rd, Huh WK, Alvarez RD, Straughn JM, Jr. A prospective evaluation of "see and treat" in women with HSIL Pap smear results: is this an appropriate strategy? J Low Genit Tract Dis 2005;9: Holschneider CH, Ghosh K, Montz FJ. See-and-treat in the management of high-grade squamousintraepithelial lesions of the cervix: a resource utilization analysis. Obstet Gynecol 1999;94: Dunn TS, Burke M, Shwayder J. A "see and treat" management for high-grade squamous intraepithelial lesion pap smears. J Low Genit Tract Dis 2003;7: Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D Consensus guidelines for the management of women with cervical intraepithelial neoplasia and adenocarcinoma in situ. Am J Obstet Gynecol 2007;197(4): Cervix cancer screening IARC handbooks of cancer. Vol 10. Lyons (France), IARC, Bigras G, de Marval F. The probability for a Pap test to be abnormal is directly proportional to HPV viral load: results from a Swiss study comparing HPV testing and liquid-based cytology to detect cervical cancer precursors in 13,842 women. Br J Cancer 2005;93: Kulasingam SL, Hughes JP, Kiviat NB, Mao C, Weiss NS, Kuypers JM, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA 2002;288: Mayrand MH, Duarte-Franco E, Coutlee F, Rodrigues I, Walter SD, Ratnam S, et al. Randomized controlled trial of human papillomavirus testing versus Pap cytology in the primary screening for cervical cancer precursors: design, methods and preliminary accrual results of the Canadian cervical cancer screening trial (CCCaST). Int J Cancer 2006;119: Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 2007;357: Cardenas-Turanzas M, Nogueras-Gonzalez GM, Scheurer ME, Adler-Storthz K, Benedet JL, Beck JR, et al. The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings. Cancer Epidemiol Biomarkers Prev 2008;17:

31 REFERENCES 73. Petry KU, Menton S, Menton M, de Carvalho Gomes H, Holz B, Schopp B, et al. Inclusionof HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients. Br J Cancer 2003;88: Kjaer S, Hogdall E, Frederiksen K, Munk C, van den Brule A, Svare E, et al. The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period. Cancer Res 2006;66: Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005;97: Cho EJ, Do JH, Kim YS, Bae S, Ahn WS. Evaluation of a liquid bead array system for high-risk human papillomavirus detection and genotyping in comparison with Hybrid Capture II, DNA chip and sequencing methods. J Med Microbiol 2011;60: Hong JH, Song SH, Kim JK, Han JH, Lee JK. Comparison of the novel human papillomavirus 4 auto-capillary electrophoresis test with the hybrid capture 2 assay and with the PCR HPV typing set test in the detection of high-risk HPV including HPV 16 and 18 genotypes in cervical specimens. J Korean Med Sci 2009;24: Song SH, Hong JH, Kwak SH, Lee JK, Kim MK. Clinical performance assessment of five human papillomavirus DNA tests using liquid-based cytology samples. J Obstet Gynaecol Res 2012;38: Castle PE, Stoler MH, Wright TC, Jr., Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 2011;12: Fetterman B, Shaber R, Pawlick G, Kinney W. Human papillomavirus DNA testingin routine clinical practice for prediction of underlying cervical intraepithelial neoplasia 2, 3+ at initial evaluation and in follow-up of women with atypical glandular cell Papanicolaou tests. J Low Genit Tract Dis 2006;3: Cuzick J, Szarewski A, Cubie H, Hulman G, Kitchener H, Luesley D, et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet 2003;362: Clavel C, Masure M, Bory JP, Putaud I, Mangeonjean C, Lorenzato M, et al. Human papillomavirus testing in primary screening for the detection of high-grade cervical lesions: as study of 7932 women. Br J Cancer 2001;89:

32 83. Wright TC, Jr., Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol 2012;206:46 e1- e Kjaer 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;102: Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157: Brown DR, Shew ML, Qadadri B, Neptune N, Vargas M, Tu W, et al. A longitudinal study of genital human papillomavirus infection in cohort of closely followed adolescent women. J Infect Dis 2005;191(2): Kulasingam SL, Hughes JP, Kiviat NB, Mao C, Weiss NS, Kuypers JM, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA 2002;288: Sellors JW, Karwalajtys TL, Kaczorowski J, Mahony JB, Lytwyn A, Chong S,et al. Incidence, clearance and predictors of human papillomavirus infection in women. CMAJ 2003;168: Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338: Wetta LA, Matthews KS, Kemper ML, Whitworth JM, Fain ET, Huh WK, et al. The management of cervical intraepithelial neoplasia during pregnancy: is colposcopy necessary? J Low Genit Tract Dis 2009;13: Fader AN, Alward EK, Niederhauser A, Chirico C, Lesnock JL, Zwiesler DJ, et al. Cervical dysplasia in pregnancy: a multi-institutional evaluation. Am J Obstet Gynecol 2010;203:113 e Vlahos G, Rodolakis A, Diakomanolis E, Stefanidis K, Haidopoulos D, Abela K, et al. Conservative management of cervical intraepithelial neoplasia (CIN(2-3)) in pregnant women. Gynecol Obstet Invest 2002;54: Serati M, Uccella S, Laterza RM, Salvatore S, Beretta P, Riva C, et al. Natural history of cervical intraepithelial neoplasia during pregnancy. Acta Obstet Gynecol Scand 2008;87: Kreimer AR, Guido RS, Solomon D, Schiffman M, Wacholder S, Jeronimo J, et al. Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia grade 2 or 3 disease. Cancer Epidemiol Biomarkers Prev 2006;15:

33 Appendix A (Evidence Table)

34 30

35 31 Appendix A (Evidence Table)

36 32

37 33 Appendix A (Evidence Table)

38 34

39 35 Appendix A (Evidence Table)

40 36

41 37 Appendix A (Evidence Table)

42 38

43 39 Appendix A (Evidence Table)

44 40

45 41 Appendix A (Evidence Table)

46 42

47 43 Appendix A (Evidence Table)

48 44

49 45 Appendix A (Evidence Table)

50 46

51 47 Appendix A (Evidence Table)

52 48

53 49 Appendix A (Evidence Table)

54 50

55 51 Appendix A (Evidence Table)

56 52

57 53 Appendix A (Evidence Table)

58 54

59 55 Appendix A (Evidence Table)

60 56

61 57 Appendix A (Evidence Table)

62 58

63 59 Appendix A (Evidence Table)

64 60

65 61 Appendix A (Evidence Table)

66 62

67 63 Appendix A (Evidence Table)

68 64

69 65 Appendix A (Evidence Table)

70 66

71 67 Appendix A (Evidence Table)

72 68

73 69 Appendix A (Evidence Table)

74 Appendix B (Diagram)

75 71 Appendix B (Diagram)

76 72

77 73 Appendix B (Diagram)

78 74

79 75 Appendix B (Diagram)

80 76

81 77 Appendix B (Diagram)

82 78

83 79 Appendix B (Diagram)

84 80

85 81 Appendix B (Diagram)