Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results

CONTEXT: A Papanicolaou (Pap) test result of atypical squamous cells of undetermined significance (ASCUS) presents a clinical challenge. Only 5% to 10% of women with ASCUS harbor serious cervical disease, but more than one third of the high-grade squamous intraepithelial lesions (HSILs) in screening populations are identified from ASCUS Pap test results. OBJECTIVE: To determine whether human papillomavirus (HPV) DNA testing of residual material from liquid-based Pap tests and referral of cases found to be HPV-positive directly to colposcopy could provide sensitive detection of underlying HSILs in women with ASCUS Pap results, compared with repeat Pap testing. DESIGN AND SETTING: Natural history of women with ASCUS Pap smear results, all of whom had liquid-based cytology, HPV testing, and subsequent repeat Pap tests and colposcopy with histologic evaluation, conducted at 12 gynecology clinics in a large managed care organization between October 1995 and June 1996. PARTICIPANTS: From a cohort of 46009 women who had routine cervical examinations, 995 women with Pap test results of ASCUS who consented to participate were identified. MAIN OUTCOME MEASURES: Cervical histology, HPV test results, and repeat Pap smear results, and sensitivity of HPV testing to identify patients found to have HSIL+ histology. RESULTS: Of 995 participants with ASCUS Pap test results, 973 had both a definitive histologic diagnosis and HPV result. Sixty-five (6.7%) had histologic HSIL or cancer. For women with histologic HSIL+, the HPV test was positive in 89.2% (95% confidence interval [CI], 78.4%-95.2%), and the specificity was 64.1 % (95% CI, 60.9%-67.2%). The repeat Pap smear result was abnormal in 76.2% (95% CI, 63.5%-85.7%). Triage based on HPV testing only or on repeat Pap testing only would refer similar proportions (approximately 39%) to colposcopy. The sensitivity of HPV DNA testing for HSIL was equivalent to, if not greater than, that of the repeat Pap test. We further estimated that an HPV-based algorithm including the immediate colposcopy of HPV-positive women, and then repeat Pap testing of all others, would provide an overall sensitivity of 96.9% (95% CI, 88.3%-99.5%). CONCLUSIONS: For women with ASCUS Pap tests, HPV DNA testing of residual specimens collected for routine cervical cytology can help identify those who have underlying HSIL. By testing the specimen collected at initial screening, the majority of high-risk cases can be identified and referred for colposcopy based on a single screening.     

宝鸡地区宫颈癌筛查方案的可行性研究

目的探讨宝鸡地区宫颈癌筛查方案的可行性。方法收集分析2010年1月-2013年11月在宝鸡市妇幼保健院进行宫颈癌筛查的患者资料,筛查方法包括巴氏细胞学、液基细胞学、高危型HPV检测,多功能醋酸白肉眼检测法,并经阴道镜检查,病理确诊宫颈癌及癌前病变。结果共筛查89714例,其中组织性筛查59745例,机会性筛查29969例,筛查方法依次为巴氏细胞学69285例,液基细胞学16114例,HPV检测625例,多功能醋酸白肉眼检测3604例。最常用的筛查方案是细胞学检查占95.19％。组织性筛查检出宫宫颈癌前病变（CINⅠ＋CINⅡ＋CINⅢ）916例（1.53％）,宫颈癌96例（0.16％）,机会性筛查检出颈癌前病变（CINⅠ＋CINⅡ＋CINⅢ）892例（2.98％）,宫颈癌159例（0.53％）。结论巴氏细胞学仍为经济欠发达地区主要的宫颈癌筛查方法,机会性筛查宫颈病变检出率高,但仍不能忽视组织性筛查。     

The 'Pap' or cervical smear and the role of colposcopy in screening for carcinoma of the cervix

Cervical cancer is the commonest female genital tract cancer in Singaporean women with an annual age-standardized rate of 17.4 per 100,000. High risk factors are early sexual intercourse, multiple sexual partners and cigarette smoking. Population screening with annual cervical (Pap) smears after beginning sexual activity until age 35 and at 5 year intervals after that can reduce both incidence and mortality rate from invasive cervical cancer. Benign, premalignant and malignant conditions may be identified in smears. The term cervical intra-epithelial neoplasia (CIN) reflects better the continuum of change in precursor lesions and is preferred over the older dual terminology of dysplasia/carcinoma-in-situ for precursors of cervical cancer. Colposcopy is essential for evaluation of all patients with abnormal cervical smears. Colposcopy is used to identify the site, severity and extent of abnormality as well as to aid directed biopsy, plan treatment and allow use of conservative methods to treat the precursor lesions. Colposcopy however, has no role as a primary screening procedure for cervical cancer but instead cervical smears are used for screening.     

Molecular testing of human papillomavirus in cervical specimens

OBJECTIVE: To improve the diagnosis of cervical neoplasia by early detection of human papillomavirus (HPV) in uterine cervix, by adding molecular testing of HPV using hybrid capture 2 (HC2) and polymerase chain reaction (PCR) tests to Papanicolaou (Pap) test. METHODS: One hundred women were enrolled in this study. The mean age (mean +/- SD) was 41.97 +/- 8.76 years and the range was 27-65 years. All women had undergone cervical cytological screening with cervical cytology, HPV DNA testing by HC2 and PCR, during the period from January - December 2006, at King Abdul-Aziz University Hospital (KAAUH) and King Fahd Research Centre, Jeddah, Saudi Arabia. RESULTS: The results we obtained by HC2 for detection of HPV were 5 (5%) high-risk HPV, one low-risk HPV (1%) and 94 (94%) negative cases. The PCR detected only 4 (4%) cases. Using the HC2 test as a reference, the sensitivity, specificity, positive predictive, negative predictive values and accuracy of baseline Pap were 50, 85, 17.7, 96.4, and 83%; of final Pap smear were 100, 96.8, 66.7, 100, 97%, and for PCR were 66.7, 100, 100, 97.9, and 98%. The Pap test was repeated within a year for patients with abnormal Pap or negative Pap test with positive HPV DNA. CONCLUSION: Combined screening by cytology and HPV testing using both HC2 and PCR sensitively detects women with existing disease. The absence of HPV DNA provides reassurance that patients are unlikely to develop cancer for several years. We suggest using Pap with HC2 and PCR in screening programs to ensure that women with the double negative result at baseline might safely be screened at longer intervals.     

高危型人乳头瘤病毒检测在子宫颈病变筛查和处理中的意义及作用

人乳头瘤病毒(HPV)感染是子宫颈癌发生的必要因素,HPV检测可最大程度优化子宫颈筛查和子宫颈异常细胞学的临床处理。对于30岁以上妇女,如HPV检测为阴性且子宫颈细胞学检查正常,可安全地将子宫颈筛查间隔延长至3年。但是,由于HPV病毒感染在年轻妇女中常见且多为一过性感染,因此不建议将HPV检测作为年龄小于30岁妇女的子宫颈筛查内容。对于任何年龄妇女,建议将HPV检测作为未明确诊断的不典型鳞状上皮细胞患者的分流检测方法,同时对于不能除外高度鳞状上皮内病变的不典型鳞状上皮细胞、鳞状上皮内低度病变或不典型腺细胞而未发现中或重度不典型增生的患者,HPV也是随诊方法之一。对于治疗后患者,HPV检测也和阴道镜及子宫颈细胞学一样,可作为随诊方法。HPV检测的正确使用可促进异常子宫颈细胞学的处理。     

宫颈疾病筛查项目在妇科专项体检中的应用状况

 目的 调查宫颈疾病筛查项目在常规体检中的应用状况。方法 回顾分析2010年1月1日至2011年12月31日复旦大学附属妇产科医院体检中心所有参加体检的24 135例次资料,调查其宫颈疾病筛查项目状况,包括巴氏涂片检查(Papanicolaou smear,Pap)、液基细胞学检测(thinprep cytology test,TCT)、人乳头瘤病毒(human papillomavirus,HPV)检测及联合检测(HPV+Pap或HPV+TCT)的应用情况,同时计算HPV检测人群中病毒负荷量的分布情况。结果 行Pap检查者12 967例次(53.7%),TCT检测者9 516例次(39.4%),HPV检测者5 517例次(22.9%),联合检测共计5 461例次(22.7%)。宫颈异常阳性检出率TCT高于Pap (χ2=3.866,P=0.049)。分层分析表明,HPV+Pap或HPV+TCT的联合检测法均显著优于单纯Pap或TCT检测(χ2=419.954, P=0.000;χ2=588.001,P=0.000),提示HPV检测的重要性。结论 妇科专项体检中宫颈疾病筛查方法传统,HPV检测和联合检测应用率偏低,应引起重视。同时,对于HPV负荷量≤100 RLU/CO的高危人群宜跟踪随访,以早期发现病变、降低宫颈癌发病风险。     

Benefits and costs of using HPV testing to screen for cervical cancer

CONTEXT: Despite quality assurance standards, Papanicolaou (Pap) test characteristics remain less than optimal. OBJECTIVE: To compare the societal costs and benefits of human papillomavirus (HPV) testing, Pap testing, and their combination to screen for cervical cancer. DESIGN, SETTING, AND POPULATION: A simulation model of neoplasia natural history was used to estimate the societal costs and quality-adjusted life expectancy associated with 18 different general population screening strategies: Pap plus HPV testing, Pap testing alone, and HPV testing alone every 2 or 3 years among hypothetical longitudinal cohorts of US women beginning at age 20 years and continuing to 65 years, 75 years, or death. MAIN OUTCOME MEASURE: Discounted costs per quality-adjusted life-year (QALY) saved of each screening strategy. RESULTS: Maximal savings in lives were achieved by screening every 2 years until death with combined HPV and Pap testing at an incremental cost of $76 183 per QALY compared with Pap testing alone every 2 years. Stopping biennial screening with HPV and Pap testing at age 75 years captures 97.8% of the benefits of lifetime screening at a cost of $70 347 per QALY. Combined biennial HPV and Pap testing to age 65 years captures 86.6% of the benefits achievable by continuing to screen until age 75 years. Human papillomavirus screening alone was equally effective as Pap testing alone at any given screening interval or age of screening cessation but was more costly and therefore was dominated. In sensitivity analyses, HPV testing would be more effective and less costly than Pap testing at a cost threshold of $5 for an HPV test. CONCLUSIONS: Screening with HPV plus Pap tests every 2 years appears to save additional years of life at reasonable costs compared with Pap testing alone. Applying age limits to screening is a viable option to maintain benefits while reducing costs.     

Role of VIA in cervical cancer screening in low-resource countries

Cervical cancer is one of the few highly preventable cancers. The early detection and removal of precancerous cervical lesions effectively abolish the development of invasive cervical cancer. The Pap test has been the standard screening test in the Western world for the last five decades. Visual inspection of cervix with acetic acid (VIA) is currently more popular method of cervical cancer of screening test in low resource countries. Cervical cancer incidence and mortality have been reduced dramatically as a result of successful screening in many countries. Cancer cervix can be prevented through both primary prevention using human papilloma virus (HPV) vaccine and early detection using screening techniques. Several screening modalities are now available for early detection of cervical cancer and its precursor lesions. They all differ with regard to their test characteristics, feasibility and economic considerations. This review has different aspects of these screening modalities and provides different options considering mass application. In developed countries, Pap smear cytology is used for cervical cancer screening. But in low-resource country, like Bangladesh, it is too expensive and is not feasible. VIA, a non-cytological test is a simple and inexpensive test which can be provided by trained paramedical personnel with a short training. So VIA can be done in low-resource countries for screening of cervical cancer as an alternative to Pap smear cytology.     

Cervical cancer screening in developing countries: why is it ineffective? The case of Mexico.

BACKGROUND: Mexico established a national cervical cancer-screening program in 1974. Despite the implementation of the program, there was a steady mortality trend of 16 per 100,000 women over 15 years. METHODS: A diagnostic procedure of the pitfalls was applied to the following steps of the screening procedure: Pap sampling quality; cytological diagnosis validity; compliance of women; and determinants of non-participation. RESULTS: The low effectiveness of screening on cervical cancer is principally due to factors associated with quality and coverage. Pap quality is deficient; 64% of a random sample of specimens lacked endocervical cells. Reading centers presented false negative indices of between 10 and 54%. Women seek screening in a late stage of disease (55% with cervical cancer seek care because they have symptoms). In addition, coverage is low; in women between 15 and 49 years of age in Mexico City, 64.2% have a history of Pap, compared with 30% in rural areas. Knowledge of what the Pap is used for strongly determines the use of screening. In rural areas, only 40% of women are informed about the purpose of the Pap test. CONCLUSIONS: A proposal to reorganize Mexico's screening program includes the following five main strategies: (a) increased coverage; (b) improved quality control of how cervical smears are taken; (c) better interpretation of Pap tests; (d) guaranteed treatment for those whose tests show abnormalities, and (e) improved follow-up.     

三种方法在鲁西南地区宫颈癌筛查中的可用性分析

目的 了解鲁西南地区的宫颈癌流行状况,比较3种流行筛查方法的优劣,为宫颈癌的防治提供依据.方法 鲁西南地区选取890名适龄妇女进行宫颈癌筛查,以阴道镜检查的病理组织学结果为金标准,比较巴氏涂片、液基细胞学、肉眼观察辅以醋酸白染色3种方法的可用性.结果 三种方法对宫颈上皮内高度病变的敏感度、特异度、阳性预测值、阴性预测值分别为:巴氏涂片:27.8％,87.5％,29.9％,98.1％；液基细胞学:79.6％,91.2％,38.4％,99.3％；肉眼观察辅以醋酸白染色:67.2％,78.5％,9.2％,99.6％.结论 液基细胞学的诊断价值最高,可作为首选的宫颈癌筛查方法；肉眼观察辅以醋酸白染色简单易行,适用于贫困地区的宫颈癌筛查工作.     

TCT和HPV-DNA检测及阴道镜联合应用在妇女宫颈癌普查中的作用

目的评价液基细胞学检测、HPV检测、阴道镜联合应用在宫颈癌普查中的作用。方法在我院进行妇女病普查的女工为研究对象,比较液基细胞学检测、HPV检测、宫颈刮片3种方法的检出敏感性及阳性符合率。结果它们检出敏感性分别为17.67%、14.31%、6.03%,检出宫颈高度病变的阳性符合率分别为30.3%、19.8%、11.62%。结论 TCT、HPV-DNA检测联合阴道镜检查是进行宫颈病变筛查行之有效的方法。     

宫颈脱落细胞学阴性生殖道高危型人乳头瘤病毒阳性患者的临床病理特征

目的 探讨宫颈脱落细胞学阴性（pap smear negative,Pap-）、人乳头瘤病毒阳性（high risk human papilloma virus positive,HPV+）女性的临床病理特征。方法 纳入1 128例Pap-/HPV+女性,阴道镜下可疑部位活检。分析Pap-/HPV+状态下HPV的流行病学特征及宫颈病变的临床病理特征。结果 Pap-/HPV+女性HPV的流行特征,HPV-16所占比例较高（χ²=16.81,P=0.000）,患者年龄偏大（χ²=20.72,P=0.000）,单一病毒感染比例较高（χ²=8.93,P=0.01）。506例患者接受阴道镜下活检,高度鳞状上皮病变（high grade squamous intraepithelial lesion,HSIL）病例254例（50.19%）,其中7例宫颈浸润癌。HSIL的发生率与年龄有关,年轻患者HSIL比例更高,与年龄呈负相关（r=-0.254,P=0.000）。各HPV亚型发生HSIL的比例不同,HPV-16型发生HSIL的比例最高（64.7%）。与对照组比较,Pap-/HPV+女性感染HPV-16、18、31、33、52、58型显著增加HSIL病变的危险。结论 Pap-/HPV+女性HPV的流行病学特征不同,具有宫颈高级别病变的危险。     

人乳头瘤病毒检测在宫颈癌筛查中的作用

目的探讨人乳头瘤病毒(HPV)在宫颈癌筛查中的作用。方法用薄层液基细胞涂片法进行宫颈细胞学检查,对细胞学异常患者采用第二代杂交捕获试验检测高危型HPV DNA。 HPVDNA检测阳性和细胞学检测结果为非典型鳞状细胞或低度鳞状上皮内病变(LISL)以上患者,均行阴道镜下活组织病理检查。分析HPV感染与宫颈上皮内瘤变的关系。结果HPV DNA检出率随宫颈病变程度加重呈上升趋势。非典型鳞状细胞者中HPV检测阳性为31.4％,HPV阳性的非典型鳞状细胞患者中51.1％为宫颈上皮内瘤变或更严重病变。结论HPV DNA检测在宫颈癌筛查中可作为细胞学的辅助手段提高诊断准确性,减少细胞学结果为轻度异常患者不必要的阴道镜检查。高危型HPV检测可指导早期HPV感染者的治疗及用于惠者的追踪随访。     

芜湖地区823名妇女宫颈HPV感染状况的调查分析

目的调查芜湖地区妇女宫颈HPV感染情况,评价TCT联合HPV分型测试对宫颈病变筛查的效力。方法对2009年11月～2010年5月在弋矶山医院门诊体检的823名女性,进行HPV、TCT、电子阴道镜及宫颈组织病理诊断,分析HPV感染率及评价HPV联合TCT在宫颈病变筛查中的意义。结果823例妇女共检出HPV感染者253人（包含60例混合感染）,感染率为30．74％,从高到低分别为HP＇V16、52、68型。病理诊断出慢性炎症92例,CINI6例,CINⅡ～CINⅢ47例,宫颈浸润癌22例。结论芜湖地区妇女宫颈HPV感染以HPVl6、52、68型为主,以35～40岁及45岁以后年龄段为感染高峰;HPV分型联合TCT检测可提高宫颈病变的诊断率。     

薄层液基细胞学与人乳头瘤病毒联合检测在宫颈上皮病变筛查中的应用

目的探讨薄层液基细胞学（TCT）与人乳头瘤病毒（HPV）联合检测在宫颈上皮病变筛查中的应用。方法对在我院妇科门诊就诊和体检进行TCT联合HPV检测的妇女,选择单纯TCT阳性者121例为TCT组,单纯HPV阳性者169例为HPV组,两者均阳性者92例为TCT联合HPV组,三组均经阴道镜下取活检,以组织病理学为金标准,比较三组与组织病理学诊断的阳性预测值。分析TCT联合HPV检测双阳性与TCT和HPV单纯阳性在宫颈上皮病变筛查效果中有无差异。结果TCT组、HPV组、TCT联合HPV组与组织病理学诊断的阳性预测值分别为57．02％、30．77％、75．00％。TCT联合HPV组与TCT组比较差异有统计学意义（Х^2=7．40,P〈0．05）,TCT联合HPV组与HPV组比较差异有统计学意义（Х^2=46．87,P〈0．05）。结论TCT联合HPV检测筛查宫颈上皮病变明显优于TCT和HPV的单纯检测,是宫颈癌及癌前病变筛查较理想的方法。     

南宁市城市人群宫颈癌筛查方法的探讨

目的从经济学的角度探讨在南宁市进行人群宫颈癌筛查的最佳方法。方法选择2006～2009年以单位工会或社区统一组织的适龄妇女进行宫颈癌筛查的人群为对象，按自愿选择新柏氏薄层液基细胞学（TCT）＋人乳头瘤病毒（HPV）、TCT、宫颈刮片＋HPV、宫颈刮片、醋酸染色肉眼观察法（VIA）＋碘染色肉眼观察法（VIM）五种宫颈癌筛查方法进行筛查，细胞学诊断≥ASCUS，VIA或VILI阳性的妇女进行阴道镜检查＋活检。以病理诊断为金标准。对选择宫颈癌筛查五种方式的团体个数进行比较分析。结果506个团体进行宫颈癌筛查的25—59岁妇女共12507人，五种宫颈癌筛查方法的团体个数分别为43、59、60、182和162个，五种宫颈癌筛查方法的阳性率分别为10．32％、9．52％、5．48％、2．69％和4．48％。结论从经济学角度出发，VIA＋VILI宫颈癌筛查方法是最适宜在南宁市开展人群宫颈癌筛查的方法。     

宫颈癌及癌前病变细胞学筛查分析

目的比较巴氏手工涂片和液基薄层制片筛查对宫颈癌及癌前病变的应用价值。方法巴氏手工涂片和液基薄层制片按相关文献方法进行。结果巴氏手工涂片检查4965例,异常179例,宫颈病变发病率为3．6％,液基薄层制片法检查2022例,异常101例,宫颈病变发病率为5．0％,巴氏手工涂片发现宫颈病变发病率明显低于液基薄层制片法法,两者比较,差异有统计学意义（P〈0．05）;对L／SH和HISL的诊断准确率,液基薄层涂片为93．8％（15n6）和100．0％（19／19）,与巴氏手工涂片的84．0％（21／25）和89．5％（17／19）相比,差异有统计学意义（P〈0．05）。结论巴氏手工涂片检测较液基薄层制片筛查宫颈癌及癌前病变简便,但时LISH和HISL期的病漏检明显,有条件单位应开展液基薄层制片筛查。     

上虞市2300例宫颈癌筛查诊断结果分析

目的探讨改良巴氏涂片法在宫颈癌筛查中的作用。方法对上虞市2 300例年龄35-64岁的农村妇女进行采用以一次性宫颈采样拭取材方式的改良巴氏涂片法且应用TBS诊断报告模式,并全程质量控制。结果2 300例宫颈癌筛查者中,细胞学异常210例并全部进行阴道镜检查,109例阴道镜活检标本中,组织学诊断除炎症外异常病例数共计25例,其中,CINⅠ5例、CINⅡ8例、CINⅢ11例、早期浸润性鳞癌1例。结论采用以一次性宫颈采样拭取材方式的改良巴氏涂片法并结合全程质量控制不失为宫颈癌筛查的良好方法。     

hTERC基因与LCT、HPV检测在宫颈高级别病变筛查中的价值

目的 评价人端粒酶基因（human telomerase RNA component,hTERC）及液基细胞学（liquid-based cytology test,LCT）、HPV检测在宫颈高级别病变（≥CINⅡ）筛查中的价值.方法 收集在厦门市妇幼保健院就诊并接受LCT和HPV检测宫颈病变患者115例,运用FISH技术检测宫颈病变组织hTERC基因扩增情况.以病理结果为标准,评价3种方法不同组合方案在筛查≥CINⅡ病变中的价值.结果 单一方法筛查时,HPV敏感度最高（91.2％）,hTERC基因的特异性（86.5％）和阳性预测值（88.1％）最高;两种方法联合筛查时,LCT＋ HPV的敏感度最高（98.4％）,但特异性最低（37.5％）;任意两种方法联合筛查均能明显提高敏感度和阴性预测值,但不能提高特异性.诊断≥CINⅡ的受试者工作特征（receiver operating characteristic,ROC）曲线下面积以hTERC基因最高（0.85）,筛查效率最高（P＜0.05）;联合筛查则LCT＋ hTERC基因筛查效率最高,但联合筛查方案的筛查效率与单一筛查方案相比差异无统计学意义（P＞0.05）.结论 LCT、HPV与hTERC基因均是筛查≥CINⅡ病变的有效方法,hTERC基因的效率最高,但成本最高,可作为常规筛查的补充;联合筛查能提高敏感度和阴性预测值,提高对≥CINⅡ的检出率,但不能提高筛查效率.LCT＋ HPV联合筛查是一种相对经济和高效的方案,可作为基础筛查进行.     

福州地区健康体检女性HPV-DNA检测联合宫颈液基细胞学检查对宫颈病变筛查的结果分析

目的 分析健康体检女性宫颈癌筛查人群HPV感染情况及与宫颈病变的关系,筛查并识别目标人群。方法 选取2018年1月～2020年1月福建省立医院9355例行HPV-DNA检测联合宫颈液基细胞学检查(Thinprep cytologic test,TCT)的健康体检女性为研究对象。结果 9355例受检者中,HPV感染1366例,感染率为14.60%,检出全部27种HPV亚型;高危型HPV前5位的亚型依次是HPV 52、HPV 58、HPV 53、HPV 56、HPV 39;单一感染1057例(77.38%),多重感染中二重感染最常见(17.42%)。宫颈改变219例(2.34%),165例合并HPV感染,感染率为74.43%;在LSIL、HSIL、SCC中,高危型HPV感染率分别为80.00%、96.00%、100.00%,单一感染率分别为62.50%、84.00%、100.00%,HPV16占比分别为7.50%、28.00%、100.00%(P0.05)。46～50岁高危型HPV、单一感染和多重感染人数最多;AGO、ASC-US、LSIL在此组最多。LSIL及以上级别宫颈病变以51～55岁最多。结论 福州地区宫颈癌筛查的目标人群是46～55岁女性,加强对此年龄段宫颈癌筛查女性健康管理、转诊、随访有重要意义。