植田政嗣，田路英作，野田 定：子宮頸癌の発生・進展とHPV感染．臨床検査, 2007;51:811-816.
植田政嗣，田路英作，布引 治ほか：頸部細胞診異常．産婦人科の実際, 2010;59:1725-1731.
植田政嗣，田路英作，布引 治ほか：子宮頸癌検診の現状と展望．産婦人科治療, 2011;102:910-916.
植田政嗣：子宮頸部異形成とその対策．産婦人科治療, 2006;93:622-627.
植田政嗣，田路英作，野田 定：子宮頸部異形成の診断と治療．産婦人科治療, 2007;95:237-243.
鈴木光明，今野 良，平井康夫ほか：ベセスダシステム2001準拠子宮頚部細胞診報告様式の理解のために. 日本産婦人科医会編, 2008.
Solomon D, Nayar D: ベセスダシステム2001アトラス.平井康夫監訳, スプリンガー・ジャパン, 2007.
Thomas C Wright, J Thomas Cox, L Stewart Massad, Leo B Twiggs, Edward J Wilkinson, ASCCP-Sponsored Consensus Conference
2001 Consensus Guidelines for the management of women with cervical cytological abnormalities.
JAMA. 2002 Apr 24;287(16):2120-9.
Abstract/Text
OBJECTIVE: To provide evidence-based consensus guidelines for the management of women with cervical cytological abnormalities and cervical cancer precursors.
PARTICIPANTS: A panel of 121 experts in the diagnosis and management of cervical cancer precursors, including representatives from 29 professional organizations, federal agencies, and national and international health organizations, were invited to participate in a consensus conference sponsored by the American Society for Colposcopy and Cervical Pathology (ASCCP).
EVIDENCE AND CONSENSUS PROCESS: Guidelines for the management of women with cervical cytological abnormalities were developed through a multistep process. Starting 6 months before the conference, working groups developed draft management guidelines based on formal literature reviews of English-language articles published in 1988-2001, as well as input from the professional community at large, obtained using interactive Internet-based bulletin boards. On September 6-8, 2001, the ASCCP Consensus Conference was held in Bethesda, Md. Guidelines with supporting evidence were presented and underwent discussion, revision, and voting.
CONCLUSIONS: Management of women with atypical squamous cells (ASC) depends on whether the Papanicolaou test is subcategorized as of undetermined significance (ASC-US) or as cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H). Women with ASC-US should be managed using a program of 2 repeat cytology tests, immediate colposcopy, or DNA testing for high-risk types of human papillomavirus (HPV). Testing for HPV DNA is the preferred approach when liquid-based cytology is used for screening. In most instances, women with ASC-H, low-grade squamous intraepithelial lesion, HSIL, and atypical glandular cells should be referred for immediate colposcopic evaluation.
Perkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, Huh WK, Kim JJ, Moscicki AB, Nayar R, Saraiya M, Sawaya GF, Wentzensen N, Schiffman M; 2019 ASCCP Risk-Based Management Consensus Guidelines Committee.
2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors.
J Low Genit Tract Dis. 2020 Apr;24(2):102-131. doi: 10.1097/LGT.0000000000000525.
Abstract/Text
Korenaga TK, Tewari KS.
Gynecologic cancer in pregnancy.
Gynecol Oncol. 2020 Jun;157(3):799-809. doi: 10.1016/j.ygyno.2020.03.015. Epub 2020 Apr 5.
Abstract/Text
Cancer complicates 1 in 1000 pregnancies. Multidisciplinary consensus comprised of Gynecologic Oncology, Pathology, Neonatology, Radiology, Anesthesiology, Maternal Fetal Medicine, and Social Work should be convened. Pregnancy provides an opportunity for cervical cancer screening, with deliberate delays in treatment permissible for early stage carcinoma. Vaginal delivery is contraindicated in the presence of gross lesion(s) and radical hysterectomy with lymphadenectomy at cesarean delivery is recommended. Women with locally advanced and metastatic/recurrent disease should commence treatment at diagnosis with chemoradiation and systemic therapy, respectively; neoadjuvant chemotherapy to permit gestational advancement may be considered in select cases. Most adnexal masses are benign and resolve by the second trimester. Persistent, asymptomatic, benign-appearing masses can be managed conservatively; surgery, if indicated, is best deferred to 15-20 weeks, with laparoscopy preferable over laparotomy whenever possible. Benign and malignant germ cell tumors and borderline tumors are occasionally encountered, with unilateral adnexectomy and preservation of the uterus and contralateral ovary being the rule. Epithelial ovarian cancer is exceedingly rare. Ultrasonography and magnetic resonance imaging lack ionizing radiation and can be employed to evaluate disease extent. Tumor markers, including CA-125, AFP, LDH, inhibin-B, and even CEA and ßhCG may be informative. If required, chemotherapy can be administered following organogenesis during the second and third trimesters. Because platinum and other anti-neoplastic agents cross the placenta, chemotherapy should be withheld after 34 weeks to avoid neonatal myelosuppression. Bevacizumab, immune checkpoint inhibitors, and PARP inhibitors should be avoided throughout pregnancy. Although antenatal glucocorticoids to facilitate fetal pulmonary maturation and amniotic fluid index assessment can be considered, there is no demonstrable benefit of tocolytics, antepartum fetal heart rate monitoring, and/or amniocentesis. Endometrial, vulvar, and vaginal cancer in pregnancy are curiosities, although leiomyosarcoma and the dreaded twin fetus/hydatidiform mole have been reported. For gynecologic malignancies, pregnancy does not impart aggressive clinical behavior and/or worse prognosis.
Copyright © 2020 Elsevier Inc. All rights reserved.
日本婦人科腫瘍学会編：妊娠合併子宮頸癌の治療 子宮頸癌治療ガイドライン2022年版、189-198、東京 金原出版、2022.
Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP).
Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep. 2007 Mar 23;56(RR-2):1-24.
Abstract/Text
These recommendations represent the first statement by the Advisory Committee on Immunization Practices (ACIP) on the use of a quadrivalent human papillomavirus (HPV) vaccine licensed by the U.S. Food and Drug Administration on June 8, 2006. This report summarizes the epidemiology of HPV and associated diseases, describes the licensed HPV vaccine, and provides recommendations for its use for vaccination among females aged 9-26 years in the United States. Genital HPV is the most common sexually transmitted infection in the United States; an estimated 6.2 million persons are newly infected every year. Although the majority of infections cause no clinical symptoms and are self-limited, persistent infection with oncogenic types can cause cervical cancer in women. HPV infection also is the cause of genital warts and is associated with other anogenital cancers. Cervical cancer rates have decreased in the United States because of widespread use of Papanicolaou testing, which can detect precancerous lesions of the cervix before they develop into cancer; nevertheless, during 2007, an estimated 11,100 new cases will be diagnosed and approximately 3,700 women will die from cervical cancer. In certain countries where cervical cancer screening is not routine, cervical cancer is a common cancer in women. The licensed HPV vaccine is composed of the HPV L1 protein, the major capsid protein of HPV. Expression of the L1 protein in yeast using recombinant DNA technology produces noninfectious virus-like particles (VLP) that resemble HPV virions. The quadrivalent HPV vaccine is a mixture of four HPV type-specific VLPs prepared from the L1 proteins of HPV 6, 11, 16, and 18 combined with an aluminum adjuvant. Clinical trials indicate that the vaccine has high efficacy in preventing persistent HPV infection, cervical cancer precursor lesions, vaginal and vulvar cancer precursor lesions, and genital warts caused by HPV types 6, 11, 16, or 18 among females who have not already been infected with the respective HPV type. No evidence exists of protection against disease caused by HPV types with which females are infected at the time of vaccination. However, females infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types. The vaccine is administered by intramuscular injection, and the recommended schedule is a 3-dose series with the second and third doses administered 2 and 6 months after the first dose. The recommended age for vaccination of females is 11-12 years. Vaccine can be administered as young as age 9 years. Catch-up vaccination is recommended for females aged 13--26 years who have not been previously vaccinated. Vaccination is not a substitute for routine cervical cancer screening, and vaccinated females should have cervical cancer screening as recommended.
日本産科婦人科学会／日本産婦人科医会編：産婦人科診療ガイドライン 婦人科外来編2017、2017.
日本産科婦人科学会／日本産婦人科医会編：産婦人科診療ガイドライン 婦人科外来編2023、2023.
Committee on Practice Bulletins—Gynecology
ACOG Practice Bulletin Number 131: Screening for cervical cancer.
Obstet Gynecol. 2012 Nov;120(5):1222-38. doi: http://10.1097/AOG.0b013e318277c92a.
Abstract/Text
The incidence of cervical cancer in the United States has decreased more than 50% in the past 30 years because of widespread screening with cervical cytology. In 1975, the rate was 14.8 per 100,000 women. By 2008, it had been reduced to 6.6 per 100,000 women. Mortality from the disease has undergone a similar decrease from 5.55 per 100,000 women in 1975 to 2.38 per 100,000 women in 2008 (1). The American Cancer Society (ACS) estimates that there will be 12,170 new cases of cervical cancer in the United States in 2012, with 4,220 deaths from the disease (2). Cervical cancer is much more common worldwide, particularly in countries without screening programs, with an estimated 530,000 new cases of the disease and 275,000 resultant deaths each year (3, 4). When cervical cancer screening programs have been introduced into communities, marked reductions in cervical cancer incidence have followed (5, 6). New technologies for cervical cancer screening continue to evolve as do recommendations for managing the results. In addition, there are different risk-benefit considerations for women at different ages, as reflected in age-specific screening recommendations. The ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) have recently updated their joint guidelines for cervical cancer screening (7), and an update to the U.S. Preventive Services Task Force recommendations also has been issued (8). The purpose of this document is to provide a review of the best available evidence regarding screening for cervical cancer.
P Sasieni, J Adams, J Cuzick
Benefit of cervical screening at different ages: evidence from the UK audit of screening histories.
Br J Cancer. 2003 Jul 7;89(1):88-93. doi: 10.1038/sj.bjc.6600974.
Abstract/Text
While most experts agree that cervical screening is effective, there remains controversy over the most appropriate screening interval. Annual screening is common in North America. In England, some argue for 3-yearly screening while others believe 5-yearly screening is adequate, and the frequency varies from one part of the country to another. Screening histories of 1305 women aged 20-69 years, diagnosed with frankly invasive cervical cancer and 2532 age-matched controls were obtained from UK screening programme databases. Data were analysed in terms of time since last negative, and time since last screening smear. Five-yearly screening offers considerable protection (83%) against cancer at ages 55-69 years and even annual screening offers only modest additional protection (87%). Three-yearly screening offers additional protection (84%) over 5-yearly screening (73%) for cancers at ages 40-54 years, but is almost as good as annual screening (88%). In women aged 20-39 years, even annual screening is not as effective (76%) as 3-yearly screening in older women, and 3 years after screening cancer rates return to those in unscreened women. This calls into question the policy of having a uniform screening interval from age 20 to 64 years and stresses the value of screening in middle-aged women. British Journal of Cancer (2003) 89, 88-93. doi:10.1038/sj.bjc.6600974 www.bjcancer.com
George F Sawaya, K John McConnell, Shalini L Kulasingam, Herschel W Lawson, Karla Kerlikowske, Joy Melnikow, Nancy C Lee, Ginny Gildengorin, Evan R Myers, A Eugene Washington
Risk of cervical cancer associated with extending the interval between cervical-cancer screenings.
N Engl J Med. 2003 Oct 16;349(16):1501-9. doi: 10.1056/NEJMoa035419.
Abstract/Text
BACKGROUND: Although contemporary guidelines suggest that the intervals between Papanicolaou tests can be extended to three years among low-risk women with previous negative tests, the excess risk of cervical cancer associated with less frequent than annual screening is uncertain.
METHODS: We determined the prevalence of biopsy-proven cervical neoplasia among 938,576 women younger than 65 years of age, stratified according to the number of previous consecutive negative Papanicolaou tests. Using a Markov model that estimates the rate at which dysplasia will progress to cancer, we estimated the risk of cancer within three years after one or more negative Papanicolaou tests, as well as the number of additional Papanicolaou tests and colposcopic examinations that would be required to avert one case of cancer given a particular interval between screenings.
RESULTS: Among 31,728 women 30 to 64 years of age who had had three or more consecutive negative tests, the prevalence of biopsy-proven cervical intraepithelial neoplasia of grade 2 was 0.028 percent and the prevalence of grade 3 neoplasia was 0.019 percent; none of the women had invasive cervical cancer. According to our model, the estimated risk of cancer with annual Papanicolaou tests for three years was 2 in 100,000 among women 30 to 44 years of age, 1 in 100,000 among women 45 to 59 years of age, and 1 in 100,000 among women 60 to 64 years of age; these risks would be 5 in 100,000, 2 in 100,000, and 1 in 100,000, respectively, if screening were performed once three years after the last negative test. To avert one additional case of cancer by screening 100,000 women annually for three years rather than once three years after the last negative test, an average of 69,665 additional Papanicolaou tests and 3861 colposcopic examinations would be needed in women 30 to 44 years of age and an average of 209,324 additional Papanicolaou tests and 11,502 colposcopic examinations in women 45 to 59 years of age.
CONCLUSIONS: As compared with annual screening for three years, screening performed once three years after the last negative test in women 30 to 64 years of age who have had three or more consecutive negative Papanicolaou tests is associated with an average excess risk of cervical cancer of approximately 3 in 100,000.
Copyright 2003 Massachusetts Medical Society
L Stewart Massad, Mark H Einstein, Warner K Huh, Hormuzd A Katki, Walter K Kinney, Mark Schiffman, Diane Solomon, Nicolas Wentzensen, Herschel W Lawson, 2012 ASCCP Consensus Guidelines Conference
2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors.
Obstet Gynecol. 2013 Apr;121(4):829-46. doi: 10.1097/AOG.0b013e3182883a34.
Abstract/Text
A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The group's goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up.
American College of Obstetricians and Gynecologists.
Practice Bulletin No. 140: management of abnormal cervical cancer screening test results and cervical cancer precursors.
Obstet Gynecol. 2013 Dec;122(6):1338-67. doi: 10.1097/01.AOG.0000438960.31355.9e.
Abstract/Text
Bentley J; EXECUTIVE COUNCIL OF THE SOCIETY OF CANADIAN COLPOSCOPISTS; SPECIAL CONTRIBUTORS.
Colposcopic management of abnormal cervical cytology and histology.
J Obstet Gynaecol Can. 2012 Dec;34(12):1188-1202. doi: 10.1016/S1701-2163(16)35468-8.
Abstract/Text
OBJECTIVE: To provide a guideline for managing abnormal cytology results after screening for cervical cancer, to clarify the appropriate algorithms for follow-up after treatment, and to promote the best possible care for women while ensuring efficient use of available resources.
OUTCOMES: Women with abnormal cytology are at risk of developing cervical cancer; appropriate triage and treatment will reduce this risk. This guideline will facilitate implementation of common standards across Canada, moving away from the current trend of individual guidelines in each province and territory.
EVIDENCE: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in October 2008 using appropriate controlled vocabulary (e.g., colposcopy, cervical dysplasia) and key words (e.g., colposcopy management, CIN, AGC, cervical dysplasia, LEEP, LLETZ, HPV testing, cervical dysplasia triage). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to July 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, and national and international medical specialty societies. Expert opinion from published peer-reviewed literature and evidence from clinical trials is summarized. Consensus opinion is outlined when evidence is insufficient.
VALUES: The quality of the evidence is rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1).
VALIDATION: This guideline has been reviewed for accuracy from content experts in cytology, pathology, and cervical screening programs. Guideline content was also compared with similar documents from other organizations including the American Society for Colposcopy and Cervical Pathology, the British Society for Colposcopy and Cervical Pathology, and the European Cancer Network.
Hunter MI, Monk BJ, Tewari KS.
Cervical neoplasia in pregnancy. Part 1: screening and management of preinvasive disease.
Am J Obstet Gynecol. 2008 Jul;199(1):3-9. doi: 10.1016/j.ajog.2008.04.010.
Abstract/Text
Cervical cancer screening is an essential component of prenatal care. The diagnosis and management of cervical intraepithelial neoplasia (CIN) during pregnancy are challenging, and sufficient information does not exist to allow for a definitive evidence-based approach. The American Society for Colposcopy and Cervical Pathology has recently published guidelines regarding the evaluation of abnormal Papanicolaou tests and the treatment of CIN in this setting. Many techniques traditionally recommended in the evaluation of abnormal cervical cytology and the treatment of CIN in the nonpregnant woman, such as colposcopy, cervical biopsy, and electrosurgical excision, can be applied to the pregnant patient with important exceptions. The vascular cervix associated with the gravid condition and the risk of premature pregnancy loss mandates deviation from existing consensus guidelines in screening for cervical cancer in pregnancy and treating associated CIN. In the present review, current guidelines regarding cervical cancer screening are reviewed, and data from studies of pregnant populations are summarized.
M E Sherman, D Solomon, M Schiffman, ASCUS LSIL Triage Study Group
Qualification of ASCUS. A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage Study.
Am J Clin Pathol. 2001 Sep;116(3):386-94. doi: 10.1309/JM3V-U4HP-W8HJ-68XV.
Abstract/Text
Cytologic detection of high-grade squamous intraepithelial lesions (HSILs) is critical to cervical cancer prevention. Therefore, identifying "equivocal HSIL" (ASCUS [atypical squamous cells of undetermined significance]-H) may be useful. Accordingly, we compared findings associated with "equivocal low-grade SIL" (ASCUS-L), ASCUS-H, and HSIL using data from the ASCUS LSIL (low-grade squamous intraepithelial lesion) Triage Study. The frequency of oncogenic human papillomavirus (HPV) DNA detection and underlying lesions cervical intraepithelial neoplasia (CIN) 2 or worse or CIN 3 or worse in women with ASCUS-H was intermediate between that of ASCUS-L and HSIL. Oncogenic HPV DNA was associated with 85.6% of ASCUS-H ThinPreps and 69.8% of ASCUS-H smears. Histopathologic lesions CIN 2 or worse were associated with 40.5% of ASCUS-H ThinPreps and 27.2% of ASCUS-H smears (mostly CIN 3). Nevertheless, numerically more lesions CIN 2 or worse were preceded by ASCUS-L than by ASCUS-H because ASCUS-L was more common. ASCUS-H is an uncommon interpretation that derives clinical usefulness from its high positive predictive value for lesions CIN 2 or worse.
ASCUS-LSIL Traige 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 Jun;188(6):1383-92.
Abstract/Text
OBJECTIVE: This study was undertaken to compare alternative strategies for the initial management of a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS).
STUDY DESIGN: A total of 3488 women with a community-based ASCUS interpretation were randomly assigned to immediate colposcopy, triage that was based on enrollment HPV DNA testing and liquid-based cytology at a colposcopy referral threshold of high-grade squamous intraepithelial lesion (HSIL), or conservative management based on repeat cytology at a referral threshold of HSIL. All arms included 2 years of semiannual follow-up and colposcopy at exit. Loop electrosurgical excision procedure was offered to women with histologic diagnoses of cervical intraepithelial neoplasia (CIN) grade 2 or 3 at any visit or persistent CIN grade 1 at exit. The study end point was 2-year cumulative diagnosis of CIN grade 3.
RESULTS: The 2-year cumulative diagnosis of CIN grade 3 was 8% to 9% in all study arms. The immediate colposcopy strategy yielded 53.6% sensitivity for cumulative cases of CIN grade 3 diagnosed over 2 years. The human papillomavirus (HPV) triage strategy referred 55.6% of women and detected 72.3% of cumulative cases of CIN grade 3. A conservative management strategy of repeat cytology at the HSIL threshold referred 12.3% of women while detecting 54.6% of cumulative CIN grade 3. To compare triage tests, we re-estimated the performance of HPV and cytology in successfully referring women with underlying CIN grade 3 (ie, ignoring the insensitivity we discovered in colposcopically directed biopsies). A single enrollment HPV test identified 92.4% of the women diagnosed with CIN grade 3. Serial cytology, even at an ASCUS threshold, would have required two visits to achieve similar sensitivity (95.4%) and would have referred 67.1% to colposcopy.
CONCLUSION: HPV triage is at least as sensitive as immediate colposcopy for detecting CIN grade 3 and refers about half as many women to colposcopy. Follow-up that used repeat cytology is sensitive at an ASCUS referral threshold but requires two follow-up visits and ultimately more colposcopic examinations than HPV triage.
Philip E Castle, Barbara Fetterman, Nancy Poitras, Thomas Lorey, Ruth Shaber, Walter Kinney
Relationship of atypical glandular cell cytology, age, and human papillomavirus detection to cervical and endometrial cancer risks.
Obstet Gynecol. 2010 Feb;115(2 Pt 1):243-8. doi: 10.1097/AOG.0b013e3181c799a3.
Abstract/Text
OBJECTIVE: To quantify the age-specific and reproductive organ-specific cancer risk after an atypical glandular cell (AGC) cytologic interpretation in large clinic-based sample in which routine high-risk human papillomavirus (HPV) testing is conducted.
METHODS: : To estimate the absolute risk of cervical precancer, cervical cancer, and endometrial cancer in women with AGC cytology, we conducted a cross-sectional study of women with AGC cytology (n=1,422) in a large health maintenance organization that introduced high-risk HPV DNA testing into cervical cancer screening in 2003. Risks and binomial exact 95% confidence intervals (CIs) of cervical intraepithelial neoplasia grade 2 or more severe (CIN 2 or worse) and endometrial cancer were calculated.
RESULTS: A total of 238 women with AGC cytology (16.7%, 95% CI 14.8-18.8%) were diagnosed with CIN 2 or worse, endometrial cancer, or other cancers. Among women aged 50 years or older, 420 high-risk HPV-negative women were at a 10.5% (95% CI 7.7-13.8%) risk of endometrial cancer, and 77 high-risk HPV-positive women were at a 10.4% (95% CI 4.6-19.4%) risk of cervical cancer and 0% (95% CI 0.0-4.7%) risk of endometrial cancer.
CONCLUSION: High-risk HPV testing may distinguish between risk of endometrial cancer and cervical cancer in women with AGC cervical cytology, particularly in women aged 50 years or older.
LEVEL OF EVIDENCE: III.
Mody DR, Ramzy I: Glandular neoplasia or the uterus and adnexa. In: Ramzy I, ed. Clinical Cytopathology and Aspiration Biopsy, 2nd Ed. New York: McGraw-Hill, 2001:97-117.
杉本澄美玲, 若狹朋子, 浦雅彦ほか：Atypical glandular cellsの病理組織学的転帰と臨床意義. 日本臨床細胞学会雑誌 2018, 57(5): 245-250.
Matsumoto K, Oki A, Furuta R, Maeda H, Yasugi T, Takatsuka N, Mitsuhashi A, Fujii T, Hirai Y, Iwasaka T, Yaegashi N, Watanabe Y, Nagai Y, Kitagawa T, Yoshikawa H. Predicting the progression of cervical precursor lesions by human papillomavirus genotyping: A prospective cohort study. Int J Cancer [Internet]. 2011 Jun 15 [cited 2019 Feb 26];128(12):2898–2910. Available from: http://doi.wiley.com/10.1002/ijc.25630
Hosaka M, Fujita H, Hanley SJ, Sasaki T, Shirakawa Y, Abiko M, Kudo M, Kaneuchi M, Watari H, Kikuchi K, Sakuragi N.
Incidence risk of cervical intraepithelial neoplasia 3 or more severe lesions is a function of human papillomavirus genotypes and severity of cytological and histological abnormalities in adult Japanese women.
Int J Cancer. 2013 Jan 15;132(2):327-34. doi: 10.1002/ijc.27680. Epub 2012 Jul 3.
Abstract/Text
We examined incidence probabilities of cervical intraepithelial neoplasia 3 (CIN3) or more severe lesions (CIN3+) in 1,467 adult Japanese women with abnormal cytology in relation to seven common human papillomavirus (HPV) infections (16/18/31/33/35/52/58) between April 2000 and March 2008. Sixty-seven patients with multiple HPV infection were excluded from the risk factor analysis. Incidence of CIN3+ in 1,400 patients including 68 with ASCUS, 969 with low grade squamous intraepithelial lesion (LSIL), 132 with HSIL without histology-proven CIN2 (HSIL/CIN2(-)) and 231 with HSIL with histology-proven CIN2 (HSIL/CIN2(+)) was investigated. In both high grade squamous intraepithelial lesion (HSIL)/CIN2(-) and HSIL/CIN2(+), HPV16/18/33 was associated with a significantly earlier and higher incidence of CIN3+ than HPV31/35/52/58 (p = 0.049 and p = 0.0060, respectively). This association was also observed in LSIL (p = 0.0002). The 1-year cumulative incidence rate (CIR) of CIN3+ in HSIL/CIN2(-) and HSIL/CIN2(+) according to HPV genotypes (16/18/33 vs. 31/35/52/58) were 27.1% vs. 7.5% and 46.6% vs. 19.2%, respectively. In contrast, progression of HSIL/CIN2(+) to CIN3+ was infrequent when HPV DNA was undetected: 0% of 1-year CIR and 8.1% of 5-year CIR. All cervical cancer occurred in HSIL cases of seven high-risk HPVs (11/198) but not in cases of other HPV or undetectable/negative-HPV (0/165) (p = 0.0013). In conclusion, incidence of CIN3+ depends on HPV genotypes, severity of cytological abnormalities and histology of CIN2. HSIL/CIN2(+) associated with HPV16/18/33 may justify early therapeutic intervention, while HSIL/CIN2(-) harboring these HPV genotypes needs close observation to detect incidence of CIN3+. A therapeutic intervention is not indicated for CIN2 without HPV DNA.
Copyright © 2012 UICC.
日本婦人科腫瘍学会編：子宮頸癌治療ガイドライン 2011年版、金原出版、2011.
L Stewart Massad, Yvonne C Collins
Using history and colposcopy to select women for endocervical curettage. Results from 2,287 cases.
J Reprod Med. 2003 Jan;48(1):1-6.
Abstract/Text
OBJECTIVE: To enhance the yield of endocervical curettage (ECC) by defining risks for abnormality.
STUDY DESIGN: Demographic and medical information collected at colposcopy and subsequent histology were reviewed retrospectively. Statistical analysis was by t and chi 2 tests.
RESULTS: Among 2,287 women undergoing ECC at colposcopy, in only 105 (5%) did positive ECC require excisional therapy that would not otherwise have been recommended. Women with positive ECC were older (mean, 39.0 vs. 33.2 years; P < .001) and of higher parity (mean, 3.0 vs. 2.0 births; P < .001), with earlier first intercourse (at 16.6 vs. 17.2 years, P = .006), more unsatisfactory colposcopy (148 [27%] of 545 women with unsatisfactory colposcopy vs. 183 [12%] of 1,523 women with satisfactory colposcopy; P < .001) and more colposcopic impressions of cervical intraepithelial neoplasia (CIN) 2-3 (163 [51%] of 323 vs. 443 [25.6%] of 1,730 women with low grade or a negative impression; P < .001). The likelihood of missed CIN 2-3 was 0.4%, with no missed cancers among women with satisfactory colposcopy and either a normal colposcopic impression (1/254) or nulliparity (2/474).
CONCLUSION: ECC identifies otherwise-undetected preinvasive and invasive lesions but may be avoided in women with satisfactory colposcopy who are nulliparous or have no colposcopic lesions.
Robert G Pretorius, Wen-Hua Zhang, Jerome L Belinson, Man-Ni Huang, Ling-Ying Wu, Xun Zhang, You-Lin Qiao
Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse.
Am J Obstet Gynecol. 2004 Aug;191(2):430-4. doi: 10.1016/j.ajog.2004.02.065.
Abstract/Text
OBJECTIVES: The purpose of this study was to determine the relative importance of colposcopically directed biopsy, random biopsy, and endocervical curettage (ECC) in diagnosing > or =cervical intraepithelial neoplasia (CIN) II. Study design During a screening study, 364 women with satisfactory colposcopy and > or =CIN II were diagnosed. All colposcopically detected lesions were biopsied. If colposcopy showed no lesion in a cervical quadrant, a random biopsy was obtained at the squamocolumnar junction in that quadrant. ECC was then performed.
RESULTS: The diagnosis of > or =CIN II was made on a colposcopically directed biopsy in 57.1%, random biopsy in 37.4%, and ECC in 5.5% of women. The yield of > or =CIN II for random biopsy when cytology was high grade (17.6%) exceeded that when cytology was low grade (2.8%). One of 20 women diagnosed solely by ECC had invasive cancer.
CONCLUSION: Even when colposcopy is satisfactory, ECC should be performed. If cytology is high grade, random biopsies should be considered.
M Kyrgiou, G Koliopoulos, P Martin-Hirsch, M Arbyn, W Prendiville, E Paraskevaidis
Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis.
Lancet. 2006 Feb 11;367(9509):489-98. doi: 10.1016/S0140-6736(06)68181-6.
Abstract/Text
BACKGROUND: Conservative methods to treat cervical intraepithelial neoplasia and microinvasive cervical cancer are commonly used in young women because of the advent of effective screening programmes. In a meta-analysis, we investigated the effect of these procedures on subsequent fertility and pregnancy outcomes.
METHODS: We searched for studies in MEDLINE and EMBASE and classified them by the conservative method used and the outcome measure studied regarding both fertility and pregnancy. Pooled relative risks and 95% CIs were calculated with a random-effects model and interstudy heterogeneity was assessed with Cochrane's Q test.
FINDINGS: We identified 27 studies. Cold knife conisation was significantly associated with preterm delivery (<37 weeks; relative risk 2.59, 95% CI 1.80-3.72, 100/704 [14%] vs 1494/27 674 [5%]), low birthweight (<2500 g; 2.53, 1.19-5.36, 32/261 [12%] vs 905/13 229 [7%]), and caesarean section (3.17, 1.07-9.40, 31/350 [9%] vs 22/670 [3%]). Large loop excision of the transformation zone (LLETZ) was also significantly associated with preterm delivery (1.70, 1.24-2.35, 156/1402 [11%] vs 120/1739 [7%]), low birthweight (1.82, 1.09-3.06, 77/996 [8%] vs 49/1192 [4%]), and premature rupture of the membranes (2.69, 1.62-4.46, 48/905 [5%] vs 22/1038 [2%]). Similar but marginally non-significant adverse effects were recorded for laser conisation (preterm delivery 1.71, 0.93-3.14). We did not detect significantly increased risks for obstetric outcomes after laser ablation. Although severe outcomes such as admission to a neonatal intensive care unit or perinatal mortality showed adverse trends, these changes were not significant.
INTERPRETATION: All the excisional procedures to treat cervical intraepithelial neoplasia present similar pregnancy-related morbidity without apparent neonatal morbidity. Caution in the treatment of young women with mild cervical abnormalities should be recommended. Clinicians now have the evidence base to counsel women appropriately.
M Arbyn, M Kyrgiou, C Simoens, A O Raifu, G Koliopoulos, P Martin-Hirsch, W Prendiville, E Paraskevaidis
Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis.
BMJ. 2008 Sep 18;337:a1284. Epub 2008 Sep 18.
Abstract/Text
OBJECTIVE: To assess the relative risk of perinatal mortality, severe preterm delivery, and low birth weight associated with previous treatment for precursors of cervical cancer.
DATA SOURCES: Medline and Embase citation tracking from January 1960 to December 2007. Selection criteria Eligible studies had data on severe pregnancy outcomes for women with and without previous treatment for cervical intraepithelial neoplasia. Considered outcomes were perinatal mortality, severe preterm delivery (<32/34 weeks), extreme preterm delivery (<28/30 weeks), and low birth weight (<2000 g, <1500 g, and <1000 g). Excisional and ablative treatment procedures were distinguished.
RESULTS: One prospective cohort and 19 retrospective studies were retrieved. Cold knife conisation was associated with a significantly increased risk of perinatal mortality (relative risk 2.87, 95% confidence interval 1.42 to 5.81) and a significantly higher risk of severe preterm delivery (2.78, 1.72 to 4.51), extreme preterm delivery (5.33, 1.63 to 17.40), and low birth weight of <2000 g (2.86, 1.37 to 5.97). Laser conisation, described in only one study, was also followed by a significantly increased chance of low birth weight of <2000 g and <1500 g. Large loop excision of the transformation zone and ablative treatment with cryotherapy or laser were not associated with a significantly increased risk of serious adverse pregnancy outcomes. Ablation by radical diathermy was associated with a significantly higher frequency of perinatal mortality, severe and extreme preterm delivery, and low birth weight below 2000 g or 1500 g.
CONCLUSIONS: In the treatment of cervical intraepithelial neoplasia, cold knife conisation and probably both laser conisation and radical diathermy are associated with an increased risk of subsequent perinatal mortality and other serious pregnancy outcomes, unlike laser ablation and cryotherapy. Large loop excision of the transformation zone cannot be considered as completely free of adverse outcomes.
Maija Jakobsson, Mika Gissler, Jorma Paavonen, Anna-Maija Tapper
Loop electrosurgical excision procedure and the risk for preterm birth.
Obstet Gynecol. 2009 Sep;114(3):504-10. doi: 10.1097/AOG.0b013e3181b052de.
Abstract/Text
OBJECTIVE: To study whether loop electrosurgical excision procedure (LEEP) conization is associated with preterm birth and to study the effect of cone size on preterm birth.
METHODS: This was a retrospective cohort study from Southern Finland conducted from 1997 to 2003, with a follow-up for subsequent births until 2006. We identified the cases from the Hospital Discharge Register and Medical Birth Register and collected additional information from the hospital records. Our cohort consisted of 624 women who delivered after LEEP conization. We calculated expected preterm birth rates by using the Medical Birth Register data. In subgroup analysis (n=258 women) we used internal controls, ie, deliveries before the treatment. The main outcome measure was preterm birth rate in different subgroups.
RESULTS: The risk for preterm delivery (before 37 weeks) was increased almost threefold (relative risk [RR] 2.61, 95% confidence interval [CI] 2.02-3.20; number needed to treat for harm=14) and repeat treatments more than fivefold (RR 5.15, 95% CI 2.45-7.84; number needed to treat for harm=5) after LEEP conization compared with the background rate of preterm birth (4.61%). Large or repeat cones increased the risk twofold (RR 2.45, 95% CI 1.38-3.53) when compared with small or medium-sized cones. For women having a birth before and after LEEP conization, the preterm birth rate was 6.5% before and 12.0% after the procedure (RR 1.94, 95% CI 1.10-3.40; number needed to treat for harm=18). Adjusting for maternal age, parity, or both did not change the results. The risk for preterm birth was especially increased (RR 3.38, 95% CI 2.31-4.94) among women without previous preterm birth.
CONCLUSION: Loop electrosurgical excision procedure surgery of the cervix predisposes patients to preterm birth. Loop electrosurgical excision procedure conization increased the risk for preterm birth especially among women without previous preterm birth. The rates were highest after repeat procedures.
LEVEL OF EVIDENCE: II.
Masatsugu Ueda, Ken Ueki, Masanori Kanemura, Shinji Izuma, Hiroyuki Yamaguchi, Koji Nishiyama, Yoshimichi Tanaka, Yoshito Terai, Minoru Ueki
Diagnostic and therapeutic laser conization for cervical intraepithelial neoplasia.
Gynecol Oncol. 2006 Apr;101(1):143-6. doi: 10.1016/j.ygyno.2005.10.001. Epub 2005 Nov 2.
Abstract/Text
OBJECTIVE: The clinical efficacy of conservative treatment using Nd-YAG laser technique for cervical intraepithelial neoplasia (CIN) was evaluated in a large series of CIN patients based on the long-term follow-up results.
METHODS: We have treated 2107 women preoperatively diagnosed as having CIN by Nd-YAG contact laser conization with vaporization of the base. Their postoperative histologic findings and clinical outcomes were evaluated.
RESULTS: The cone specimen was reported as showing that 1956 (92.8%) of 2107 cases had no CIN or CIN 1-3 and 151 (7.2%) cases had invasive diseases. 1956 cases without invasive diseases were followed up for 16 to 252 months. Incomplete excision occurred in 230 (12.3%) of 1874 patients with CIN lesion in the cone specimen, but failure rate (persistence or recurrence) was only 1.2%. 192 (83.5%) of 230 postoperative CIN patients with positive surgical margins showed no abnormal cytology or colposcopy during follow-up period. Preoperative underdiagnosis of biopsy results compared with cytologic or colposcopic findings elevated the risk for incomplete excision and failure rate.
CONCLUSION: The combination of laser excision and vaporization of the base was useful to detect unexpected invasive disease and revealed excellent therapeutic effects for CIN. Preoperative cytologic or colposcopic findings should be taken into account for the conservative treatment of CIN.
H Yamaguchi, M Ueda, M Kanemura, S Izuma, K Nishiyama, Y Tanaka, S Noda
Clinical efficacy of conservative laser therapy for early-stage cervical cancer.
Int J Gynecol Cancer. 2007 Mar-Apr;17(2):455-9. doi: 10.1111/j.1525-1438.2006.00868.x. Epub 2007 Feb 19.
Abstract/Text
The objective of this study was to evaluate the clinical efficacy of conservative laser therapy for early-stage cervical cancer. Seven hundred fifty-two and 271 patients with carcinoma in situ (CIS) and microinvasive squamous cell carcinoma (MIC), respectively, were treated by laser conization with vaporization. One hundred eighty-four patients with preclinical invasive diseases underwent radical surgery without conization. Their postoperative histologic findings and clinical outcomes were evaluated retrospectively. The cone specimens of 1023 cases were reported as showing that 54 had dysplasia, 663 had CIS, 239 had stage Ia1 without lymph vascular space invasion (LVSI), 14 had stage Ia1 with LVSI, 14 had stage Ia2, and 39 had stage Ib1 diseases. Incomplete excision occurred in 4 (7.4%) of 54 dysplasia, 48 (7.2%) of 663 CIS, and 16 (6.7%) of 239 stage Ia1 cases, but failure rates were only 1 (1.9%), 8 (1.2%), and 4 (1.7%), respectively. The other 67 of 1023 cases underwent abdominal operation. Final pathology results were analyzed for 67 and 184 cases with stages Ia1 to Ib1 receiving radical surgery with or without initial laser therapy. Lymph node metastasis was not observed in 154 Ia1 and 30 Ia2 with stromal invasion of under 4 mm in depth regardless of LVSI, but was detected in 2 of 16 Ia2 with stromal invasion of over 4 mm in depth and in 9 of 51 Ib1 cases. CIS and Ia1 disease without LVSI can be treated only by laser therapy. The limit of stromal invasion for conservative laser therapy in stage Ia cancer may be 4 mm in depth regardless of LVSI.
日本産婦人科医会刊：ベセスダシステム2001 準拠子宮頸部細胞診報告様式の理解のために. 2008.
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
2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests.
Am J Obstet Gynecol. 2007 Oct;197(4):346-55. doi: 10.1016/j.ajog.2007.07.047.
Abstract/Text
A group of 146 experts representing 29 organizations and professional societies met September 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. Recommendations for managing atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion (LSIL) are essentially unchanged. Changes were made for managing these conditions in adolescents for whom cytological follow-up for 2 years was approved. Recommendations for managing high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells (AGC) also underwent only minor modifications. More emphasis is placed on immediate screen-and-treat approaches for HSIL. Human papillomavirus (HPV) testing is incorporated into the management of AGC after their initial evaluation with colposcopy and endometrial sampling. The 2004 Interim Guidance for HPV testing as an adjunct to cervical cytology for screening in women 30 years of age and older was formally adopted with only very minor modifications.
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
2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ.
Am J Obstet Gynecol. 2007 Oct;197(4):340-5. doi: 10.1016/j.ajog.2007.07.050.
Abstract/Text
A group of 146 experts representing 29 organizations and professional societies met Sept. 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. The management of low-grade cervical intraepithelial neoplasia (CIN) grade 1 has been modified significantly. Previously, management depended on whether colposcopy was satisfactory and treatment using ablative or excisional was acceptable for all women with CIN 1. In the new guidelines, cytological follow-up is the only recommended management option for women with CIN 1 who have low-grade referral cervical cytology, regardless of whether the colposcopic examination is satisfactory. Treatment is particularly discouraged in adolescents. The basic management of women in the general population with CIN 2,3 underwent only minor modifications, but options for the conservative management of adolescents with CIN 2,3 have been expanded. Moreover, management recommendations for women with biopsy-confirmed adenocarcinoma in situ are now included.
Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK.
Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines.
J Low Genit Tract Dis. 2013 Apr;17(5 Suppl 1):S28-35. doi: 10.1097/LGT.0b013e318285423c.
Abstract/Text
OBJECTIVE: In 2012, the US Preventive Services Task Force (USPSTF) and a consensus of 25 organizations endorsed concurrent cytology and human papillomavirus (HPV) testing ("cotesting") for cervical cancer screening. Past screening and management guidelines were implicitly based on risks defined by Pap-alone, without consideration of HPV test results. To promote management that is consistent with accepted practice, new guidelines incorporating cotesting should aim to achieve equal management of women at equal risk of cervical intraepithelial neoplasia grade 3 and cancer (CIN 3+).
METHODS: We estimated cumulative 5-year risks of CIN 3+ for 965,360 women aged 30 to 64 years undergoing cotesting at Kaiser Permanente Northern California over 2003 to 2010. We calculated the implicit risk thresholds for Pap-alone and applied them for new management guidance on HPV and Pap cotesting, citing 2 examples: HPV-positive/atypical squamous cells of undetermined significance (ASC-US) and HPV-negative/Pap-negative. We call this guidance process "benchmarking."
RESULTS: A low-grade squamous intraepithelial lesion result, for which immediate colposcopy is prescribed, carries a 5-year CIN 3+ risk of 5.2%, suggesting that test results with similar risks should be managed with colposcopy. Similarly, ASC-US (2.6% risk) is managed with a 6- to 12-month follow-up visit and Pap-negative (0.26% risk) is managed with a 3-year follow-up visit. The 5-year CIN 3+ risk for women with HPV-positive/ASC-US was 6.8% (95% confidence interval = 6.2%-7.6%). This is greater than the 5.2% risk implicitly leading to referral to colposcopy, consistent with current management recommendations that HPV-positive/ASC-US should be referred for immediate colposcopy. The 5-year CIN 3+ risk for women with HPV-negative/Pap-negative was 0.08% (95% confidence interval = 0.07%-0.09%), far below the 0.26% implicitly required for a 3-year return and justifying a longer (e.g., 5-year) return.
CONCLUSIONS: Using the principle of "equal management of equal risks," benchmarking to implicit risk thresholds based on Pap-alone can be used to achieve safe and consistent incorporation of cotesting.
Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK.
Five-year risks of CIN 3+ and cervical cancer among women who test Pap-negative but are HPV-positive.
J Low Genit Tract Dis. 2013 Apr;17(5 Suppl 1):S56-63. doi: 10.1097/LGT.0b013e318285437b.
Abstract/Text
OBJECTIVE: Current US guidelines for cotesting recommend that the large numbers of women who test Pap-negative, but human papillomavirus (HPV)-positive, return in 1 year, and those who remain HPV-positive or have low-grade squamous intraepithelial lesion (LSIL) or worse Pap results be referred for colposcopy. However, the performance of these guidelines in routine clinical practice has not been evaluated.
METHODS: We estimated cumulative 5-year risks of cervical intraepithelial neoplasia grade 3 or worse (CIN 3+) among 32,374 women aged 30 to 64 years with HPV-positive/Pap-negative cotest results at Kaiser Permanente Northern California during 2003 to 2010.
RESULTS: The 5-year CIN 3+ risk after an HPV-positive/Pap-negative cotest result, which was found in 3.6% of women, was 4.5% (95% confidence interval [CI] = 4.2%-4.8%). The 5-year cancer risk was 0.34% (95% CI = 0.26%-0.45%), and half of the cases were adenocarcinoma. Overall, 48% of the women remained HPV-positive on return (median = 418 days after baseline), a percentage that varied little over ages 30 to 64 years. At the return after a baseline HPV-positive/Pap-negative result, almost every repeat cotest result predicted greater subsequent 5-year CIN 3+ risk than the same cotest result had at baseline (HPV-positive/LSIL, 9.2% vs 6.1%, p = .01; HPV-positive/atypical squamous cells of undetermined significance [ASC-US], 7.9% vs 6.8%, p = .2; HPV-positive/Pap-negative, 7.4% vs 4.5%, p < .0001; HPV-negative/LSIL,1.7% vs 2.0%, p = .8; HPV-negative/ASC-US, 2.9% vs 0.43%, p = .0005; HPV-negative/Pap-negative, 0.93% vs 0.08%, p < .0001).
CONCLUSIONS: Using the principle of "equal management of equal risks," women testing HPV-positive/Pap-negative had a subsequent CIN 3+ risk consistent with risk thresholds for a 1-year return. However, on returning in approximately 1 year, about one-half of women will be referred for colposcopy because of continued HPV positivity or Pap abnormality. Clinicians should keep in mind that cotest results at the return after a baseline HPV-positive/Pap-negative finding are riskier than the same baseline cotest results in the general population, supporting intensified clinical management at return testing.
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
Regression of low-grade squamous intra-epithelial lesions in young women.
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.
Nicolas F Schlecht, Robert W Platt, Eliane Duarte-Franco, Maria C Costa, João P Sobrinho, José C M Prado, Alex Ferenczy, Thomas E Rohan, Luisa L Villa, Eduardo L Franco
Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia.
J Natl Cancer Inst. 2003 Sep 3;95(17):1336-43.
Abstract/Text
BACKGROUND: Little is known about the duration of precancerous cervical lesions in relation to human papillomavirus (HPV) infection. We estimated rates of progression and regression and sojourn times of cervical squamous intraepithelial lesions (SILs) according to HPV status.
METHODS: We used data from a longitudinal study of HPV infection and cervical neoplasia in São Paulo, Brazil. Cervical specimens were taken from 2404 women for Pap cytology and polymerase chain reaction-based HPV testing every 4-6 months over a period of 8 years. We used actuarial and non-actuarial analyses to measure time to and rates of lesion progression and regression according to status and type of HPV infection.
RESULTS: During follow-up, 118 low-grade SIL (LSIL), 24 high-grade SIL (HSIL), and 173 atypical squamous cells of undetermined significance (ASCUS) events were detected. Mean time to progression from ASCUS to LSIL or worse and from LSIL to HSIL or worse was shorter in women with oncogenic HPV types than in women with no HPV infection (mean times for ASCUS progression were 67.0 and 88.0 months, respectively, in women with oncogenic HPV and no HPV, difference = 21.0 months, 95% confidence interval [CI] = 11.3 to 30.7 months; mean times for LSIL progression were 73.3 and 83.5 months, respectively, difference = 10.2 months, 95% CI = -0.15 to 20.6 months). Half of the LSILs regressed to normal or ASCUS within 6 months. Mean times for regression from ASCUS to normal, from LSIL to ASCUS or normal, and from HSIL/cervical intraepithelial neoplasia 2 to ASCUS or normal were longer for women with oncogenic HPV types (16.8 months, 95% CI = 7.5 to 26.2 months; 13.8 months, 95% CI = 8.8 to 18.7 months; and 17.1 months, 95% CI = 4.1 to 30.1 months, respectively) than for women with non-oncogenic HPV types (7.7 months, 95% CI = 5.2 to 10.2 months; 7.8 months, 95% CI = 5.3 to 10.2 months; 8.9 months, 95% CI = 3.3 to 14.6 months) or for women with no HPV infection (7.6 months, 95% CI = 6.9 to 8.4 months; 7.6 months, 95% CI = 6.4 to 8.7 months; and 7.0 months, 95% CI = 5.0 to 8.9 months, respectively).
CONCLUSION: Precursor lesions of the cervix persist longer and progress more quickly in women with oncogenic HPV infections than in women with non-oncogenic infections or without HPV. Testing cervical lesions for oncogenic HPVs may help identify those that are likely to progress rapidly.
沖明典：コホート研究に基づくCIN1/2 の管理方針と高危険群の抽出．日産婦誌, 2006；58 1739-1744.
A G Ostör
Natural history of cervical intraepithelial neoplasia: a critical review.
Int J Gynecol Pathol. 1993 Apr;12(2):186-92.
Abstract/Text
The literature dealing with the natural history of cervical intraepithelial neoplasia (CIN) since 1950 is reviewed, in particular from the viewpoint of regression, persistence, and progression. When stratified into the various grades of severity, the composite data indicate the approximate likelihood of regression of CIN 1 is 60%, persistence 30%, progression to CIN 3 10%, and progression to invasion 1%. The corresponding approximations for CIN 2 are 40%, 40%, 20%, and 5%, respectively. The likelihood of CIN 3 regressing is 33% and progressing to invasion greater than 12%. It is obvious from the above figures that the probability of an atypical epithelium becoming invasive increases with the severity of the atypia, but does not occur in every case. Even the higher degrees of atypia may regress in a significant proportion of cases. As morphology by itself does not predict which lesion will progress or regress, future efforts should seek factors other than morphological to determine the prognosis in individual patients.
P Holowaty, A B Miller, T Rohan, T To
Natural history of dysplasia of the uterine cervix.
J Natl Cancer Inst. 1999 Feb 3;91(3):252-8.
Abstract/Text
BACKGROUND: A historical cohort of Toronto (Ontario, Canada) women whose Pap smear histories were recorded at a major cytopathology laboratory provided the opportunity to study progression and regression of cervical dysplasia in an era (1962-1980) during which cervical squamous lesions were managed conservatively.
METHODS: Actuarial and Cox's survival analyses were used to estimate the rates and relative risks of progression and regression of mild (cervical intraepithelial neoplasia 1 [CIN1]) and moderate (CIN2) dysplasias. In addition, more than 17,000 women with a history of Pap smears between 1970 and 1980 inclusive and who were diagnosed as having mild, moderate, or severe dysplasia were linked to the Ontario Cancer Registry for the outcome of any subsequent cervical cancers occurring through 1989.
RESULTS: Both mild and moderate dysplasias were more likely to regress than to progress. The risk of progression from mild to severe dysplasia or worse was only 1% per year, but the risk of progression from moderate dysplasia was 16% within 2 years and 25% within 5 years. Most of the excess risk of cervical cancer for severe and moderate dysplasias occurred within 2 years of the initial dysplastic smear. After 2 years, in comparison with mild dysplasia, the relative risks for progression from severe or moderate dysplasia to cervical cancer in situ or worse was 4.2 (95% confidence interval [CI] = 3.0-5.7) and 2.5 (95% CI = 2.2-3.0), respectively.
CONCLUSION: The risk of progression for moderate dysplasia was intermediate between the risks for mild and severe dysplasia; thus, the moderate category may represent a clinically useful distinction. The majority of untreated mild dysplasias were recorded as regressing to yield a normal smear within 2 years.
J Melnikow, J Nuovo, A R Willan, B K Chan, L P Howell
Natural history of cervical squamous intraepithelial lesions: a meta-analysis.
Obstet Gynecol. 1998 Oct;92(4 Pt 2):727-35.
Abstract/Text
OBJECTIVE: To define the strengths and weaknesses of existing research on the natural history of cervical squamous intraepithelial lesions (SIL) and to estimate rates of progression and regression without treatment.
DATA SOURCES: Studies of women whose cervical smears showed squamous atypia or worse and who were observed for a minimum of 6 months were identified by a search of MEDLINE from 1966 to 1996, Current Contents, the Federal Research in Progress database, and references of review articles and identified studies, and by experts in the field.
METHODS OF STUDY SELECTION: Fifteen of 81 studies were eligible for data extraction. To be eligible, studies had to report a minimum of 6 months' follow-up without treatment; relate entry cytologic findings to outcomes; and report entry cytologic findings so that the study population could be stratified into categories of atypical cells of undetermined significance (ASCUS), low-grade SIL, or high-grade SIL. Studies published before 1970 were excluded.
TABULATION, INTEGRATION, AND RESULTS: Eligible studies, representing 27,929 patients, were stratified according to entry cytologic findings. The following rates of progression to high-grade SIL at 24 months were found: ASCUS, 7.13% (95% confidence interval [CI] 0.8%, 13.5%); low-grade SIL, 20.81% (6.08%, 35.55%); and high-grade SIL, 23.37% (12.82%, 32.92%). The following rates of invasive cancer at 24 months were found: ASCUS, 0.25% (0%, 2.25%); low-grade SIL, 0.15% (0%, 0.71%); and high-grade SIL, 1.44% (0%, 3.95%). The following rates of regression to normal were found: ASCUS, 68.19% (57.51%, 78.86%); low-grade SIL, 47.39% (35.92%, 58.86%); and high-grade SIL, 35.03% (16.57%, 53.49%). Study heterogeneity was not explained by regression analysis of study level variables.
CONCLUSION: Our findings for borderline and low-grade abnormal cervical cytologic results suggest a relatively low risk of invasive cervical cancer with observation up to 24 months and support the clinical policy of early colposcopy for high-grade lesions.
N P Yost, J T Santoso, D D McIntire, F A Iliya
Postpartum regression rates of antepartum cervical intraepithelial neoplasia II and III lesions.
Obstet Gynecol. 1999 Mar;93(3):359-62.
Abstract/Text
OBJECTIVE: To study the histologic regression and progression rates of cervical intraepithelial neoplasia (CIN) II and III after delivery and the effect the route of delivery has on the regression rates of CIN.
METHODS: Pregnant patients with satisfactory colposcopic examinations and biopsy-proven CIN II and III were identified. Delivery information and postpartum biopsy results were obtained by chart review.
RESULTS: Two hundred seventy-nine patients had antepartum biopsies of CIN II or CIN III. Of these, 126 women were excluded for the following reasons: lost to follow-up (75), human immunodeficiency virus positive (two), cesarean hysterectomy (four), and inadequate postpartum follow-up (45). This yielded a study group of 153 patients consisting of 82 with CIN II and 71 with CIN III. The regression rates were 68% and 70% among CIN II and CIN III patients (P = .78), respectively. Seven percent of patients with CIN II progressed to CIN III on postpartum evaluation. Twenty-five percent of those patients with CIN II and 30% of those with CIN III remained the same postpartum. No CIN lesions progressed to invasive carcinoma. There were no differences in regression rates or progression rates among the women who had vaginal deliveries (130), women who labored and then underwent cesarean (17), or women who proceeded to a cesarean without laboring (six).
CONCLUSION: We found similar high postpartum regression rates despite the route of delivery. We recommend conservative antepartum management with postpartum colposcopic evaluation regardless of route of delivery because we are unable to predict which of these lesions are more likely to regress.
J Peto, C Gilham, J Deacon, C Taylor, C Evans, W Binns, M Haywood, N Elanko, D Coleman, R Yule, M Desai
Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort.
Br J Cancer. 2004 Aug 31;91(5):942-53. doi: 10.1038/sj.bjc.6602049.
Abstract/Text
Cytology and histology records and cervical samples for HPV assay were obtained from a prospective cohort of 49 655 women attending clinics for routine cervical cytology in or near Manchester between 1988 and 1993. The women were followed up for cytological abnormality and neoplasia through the cytology laboratory's records. HPV at entry was assayed in an age- and period-stratified random sample of 7278 women and in prevalent and incident CIN3 cases. The prevalence of newly diagnosed CIN3 increased with time since last normal smear, indicating that most cases persist for several years. CIN3 prevalence did not increase further for screening intervals exceeding 5 years, however, suggesting that CIN3 eventually regresses cytologically. CIN2 prevalence increased less steeply with screening interval, while the prevalence of lesser abnormality was almost independent of screening interval. The prevalence of oncogenic HPV at entry declined from 19% among women aged under 25 to less than 3% at age 40 or above. Oncogenic HPV infection was strongly predictive of subsequent CIN3 (OR 17.2, 95% CI 10.4-28.4), but only weakly related to CIN2 (OR 2.3, 95% CI 0.5-10.7) and lesser abnormality (OR 1.4, 95% CI 0.8-2.5). At current incidence rates, the lifetime risk of developing CIN3 will be 9% in this population. The cumulative risk of CIN3 diagnosis among cytologically normal women with oncogenic HPV detected at entry was 28% (CI 18-43%) after 14 years. Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN3 and invasive cancer.
Jennifer S Smith, Lisa Lindsay, Brooke Hoots, Jessica Keys, Silvia Franceschi, Rachel Winer, Gary M Clifford
Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update.
Int J Cancer. 2007 Aug 1;121(3):621-32. doi: 10.1002/ijc.22527.
Abstract/Text
Data on human papillomavirus (HPV) type distribution in invasive and pre-invasive cervical cancer is essential to predict the future impact of HPV16/18 vaccines and HPV-based screening tests. A meta-analyses of HPV type distribution in invasive cervical cancer (ICC) and high-grade squamous intraepithelial lesions (HSIL) identified a total of 14,595 and 7,094 cases, respectively. In ICC, HPV16 was the most common, and HPV18 the second most common, type in all continents. Combined HPV16/18 prevalence among ICC cases was slightly higher in Europe, North America and Australia (74-77%) than in Africa, Asia and South/Central America (65-70%). The next most common HPV types were the same in each continent, namely HPV31, 33, 35, 45, 52 and 58, although their relative importance differed somewhat by region. HPV18 was significantly more prevalent in adeno/adenosquamous carcinoma than in squamous cell carcinoma, with the reverse being true for HPV16, 31, 33, 52 and 58. Among HSIL cases, HPV16/18 prevalence was 52%. However, HPV 16, 18 and 45 were significantly under-represented, and other high-risk HPV types significantly over-represented in HSIL compared to ICC, suggesting differences in type-specific risks for progression. Data on HPV-typed ICC and HSIL cases were particularly scarce from large regions of Africa and Central Asia.
Copyright (c) 2007 Wiley-Liss, Inc.
Cosette M Wheeler, William C Hunt, Mark Schiffman, Philip E Castle, Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study Group
Human papillomavirus genotypes and the cumulative 2-year risk of cervical precancer.
J Infect Dis. 2006 Nov 1;194(9):1291-9. doi: 10.1086/507909. Epub 2006 Sep 27.
Abstract/Text
BACKGROUND: Prospective data on the risks of cervical precancer associated with specific human papillomavirus (HPV) genotypes are limited.
METHODS: In 5060 women participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS), we determined the cumulative 2-year risks of cervical intraepithelial neoplasia (CIN) grade 2 or more severe (> or =CIN2) and of grade 3 or more severe (> or =CIN3) for 38 individual HPV genotypes, as detected by polymerase chain reaction.
RESULTS: The most common HPV genotypes detected at baseline, in descending order of prevalence, were 16, 52, 51, 31, 18, 53, 39, 56, 62, 59, and 58. When detected as a single-type HPV infection, HPV-16 had a 2-year cumulative risk of 50.6% (95% confidence interval [CI], 44.1%-57.2%) for > or =CIN2 and 39.1% (95% CI, 32.9%-45.7%) for > or =CIN3. For other singly detected carcinogenic HPV types, the risk of > or =CIN2 ranged from 4.7% (for HPV-59) to 29.5% (for HPV-31), and the risk of > or =CIN3 ranged from 0.0% (for HPV-59) to 14.8% (for HPV-31). Multiple infections with HPV genotypes of different risk classes resulted in a risk that was similar to, and not significantly different from, the risk observed for the HPV genotype of the highest risk class.
CONCLUSIONS: Genotype-specific HPV testing may be useful for identifying women with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions who are at higher and lower risk of prevalent and incipient cervical precancer.
Shiho Miura, Koji Matsumoto, Akinori Oki, Toyomi Satoh, Hajime Tsunoda, Toshiharu Yasugi, Yuji Taketani, Hiroyuki Yoshikawa
Do we need a different strategy for HPV screening and vaccination in East Asia?
Int J Cancer. 2006 Dec 1;119(11):2713-5. doi: 10.1002/ijc.22195.
Abstract/Text
Y Nagai, T Maehama, T Asato, K Kanazawa
Persistence of human papillomavirus infection after therapeutic conization for CIN 3: is it an alarm for disease recurrence?
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.
石井賢治，工藤一弥，菊池義公ほか：妊婦の頸部細胞診異常の取り扱いについて．日臨細胞誌, 1994;33:474-478.
森本晶子，榎本隆之，吉野 潔ほか：妊娠を合併した子宮頸癌の取り扱い．産婦人科治療, 2011;102:961-965.
日本産科婦人科学会／日本産婦人科医会編：産婦人科診療ガイドライン 産科編2008、2008.
日本産科婦人科学会／日本産婦人科医会編：産婦人科診療ガイドライン 産科編2023、2023.
