DNA定量分析联合高危型HPV检测对高级别CIN的检出价值

目的:研究宫颈细胞DNA定量分析联合高危型HPV检测在诊断高级别宫颈上皮内瘤变（cervical intraepithelial neoplasia,CIN）的应用价值。方法:收集220例有DNA定量分析、宫颈薄层液基细胞学检查（thinprep cytology test,TCT）、二代杂交捕获（hybrid capture II,HC2)检测高危型人乳头瘤病毒（human papillomavirus,HPV）及宫颈活检资料的病例。结果:以宫颈活检组织病理学为诊断标准,220例活检中60例病理组织学为高级别宫颈上皮内瘤变的病例,DNA定量分析对检测高级别CIN的敏感性为96.7%,特异性为25.0%,阳性预测值为32.6%,阴性预测值为95.2%,而TCT及HC2的敏感性、特异性、阳性预测值及阴性预测值分别为96.7%、3.8%、27.4%、75.0%及98.3%、38.8%、37.6%、98.4%。DNA定量分析除敏感性以外,其他指标均高于TCT检测,而低于HC2检测。DNA定量分析及HC2检测均阴性的病例,阴道镜活检无高级别鳞状上皮内瘤变病例。结论:DNA定量分析在诊断高级别宫颈上皮内瘤变中优于TCT,与HC2检测联用可提高诊断高级别宫颈上皮内瘤变的敏感性和特异性。     

Identification of progressive cervical epithelial cell abnormalities using DNA image cytometry

BACKGROUND: The objectives of the current study were to compare the capabilities of conventional cervical cytology and of DNA image cytometry (DNA-ICM) in the prediction of progressive or regressive behavior in atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL), and atypical glandular cells (AGC). METHODS: One hundred ninety-six women with Papanicolaou (Pap) smears that yielded diagnoses of ASC, LSIL, or AGC were included in a prospective cohort study. Slides were classified according to the Bethesda system. DNA-ICM was performed according to the consensus reports of the European Society of Analytical Cellular Pathology. RESULTS: Reference standard verification was available in 108 patients. The rate of DNA aneuploidy in Pap smears increased significantly from cervical intraepithelial neoplasia 1 (CIN1) (54%) and CIN2 (64.3%) to CIN3 or greater (CIN3+) (83.3%) in subsequent biopsies (P < 0.05). Using ASC, LSIL, and AGC as input cytologic diagnoses and >/= CIN2 as the output histologic diagnosis, the positive predictive values (PPVs) for conventional cytology and DNA-ICM were 35.2% and 65.9%, respectively (P < 0.001). The negative predictive value (NPV) of DNA-ICM was 85.0%. When >/= CIN3 was used as the output histologic diagnosis, conventional cytology had a PPV of 22.2%. The PPV and NPV of DNA-ICM were 43.9% and 93.3%, respectively. CONCLUSIONS: The results of the current study confirmed the prognostic validity of DNA image cytometry for differentiation between progressive and regressive lesions in patients with ASC, LSIL, and AGC diagnoses.     

Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients

In a prospective cohort study 8466 women attending routine cervical cancer screening were recruited. Colposcopy was performed on women with any degree of atypia on cytology and/or a positive high-risk human papillomavirus (HPV)-DNA test (HC2; Hybrid Capture 2((c))), and for a randomly selected sample of 3.4% women with negative findings on both. Quality control included reviews of cytology, histology, colposcopy images and retesting of samples with polymerase chain reaction. Test diagnostic performances were based on 7908 women who had complete baseline and follow-up results. Routine histology identified 86 women with high-grade cervical intraepithelial neoplasia (CIN2+), which was confirmed by review histology in only 46 cases. Sensitivity of routine cytology for the detection of CIN2+ was 43.5%, with a specificity, positive predictive value (PPV), negative predictive value (NPV) of 98.0, 11.4 and 99.7%, respectively. Sensitivity of the HC2 test for the detection of CIN2+ was 97.8%, with a specificity, PPV and NPV, of 95.3, 10.9 and 100%, respectively. No high-grade neoplasia was detected in the randomly selected control group. A negative HPV-test result, even in combination with a positive Papanicolaou (Pap) result, virtually excluded any risk of underlying high-grade disease, but this was not the case for a negative Pap result. These data show that HPV testing is of value for the detection or exclusion of prevalent CIN in a routine cervical cancer-screening setting and could be used for further risk classification of women for follow-up management.     

DNA倍体分析技术在门诊患者子宫颈癌筛查中的作用

目的 探讨DNA倍体分析在门诊患者子宫颈癌筛查中的应用价值.方法 对门诊行子宫颈癌筛查的2 692例女性就诊者同时进行液基薄层细胞学检查、DNA倍体分析,对其中可疑病变者840例进行子宫颈活组织检查.对参与子宫颈癌普查的妇女进行液基薄层制片,分别进行巴氏染色和Feulgen染色,由细胞学医师对巴氏染色片作常规细胞学诊断,应用全自动DNA倍体分析系统对Feulgen染色片进行自动扫描诊断.结果 840例患者子宫颈活组织病理检查结果分别为：慢性子宫颈炎554例（66.0％）,子宫颈上皮内瘤变（CIN）Ⅰ 25例（3.0％）,CINⅡ59例（7.0％）,CINⅢ100例（11.9％）,子宫颈癌102例（12.1％）.DNA倍体分析中可见DNA异倍体细胞者（DNA异倍体细胞阳性）486例,未见DNA异倍体细胞者（DNA异倍体细胞阴性）354例;DNA异倍体细胞阳性、异倍体细胞≥3个用于筛查CINⅡ及以上病变的敏感度、特异度、阳性预测值、阴性预测值分别为91.9％和89.2％、58.5％和35.8％、49.4％和57.3％、94.1％和77.2％;采用液基薄层细胞学检查LSIL及以上用于筛查CINⅡ及以上病变的敏感度、特异度、阳性预测值、阴性预测值分别为40.2％、90.0％、39.6％和76.9％.结论 DNA倍体定量分析技术较常规细胞学敏感性高,可作为子宫颈癌普查的指标之一.     

Validity of combined cytology and human papillomavirus (HPV) genotyping with adjuvant DNA-cytometry in routine cervical screening: results from 31031 women from the Bonn-region in West Germany

Our aim was to improve the accuracy of routine cervical screening by a risk-adapted multimodal protocol with special focus on possible reduction and prognostic assessment of false positive results. A cohort of 31031 women from the Bonn-region in West Germany, median age 36 years, were screened by cytology (conventional or liquid-based), followed by PCR-based HVP detection with genotyping and adjuvant DNA image cytometry, if indicated, in a sequential manner. The true prevalence of high-grade cervical intraepithelial neoplasia and carcinoma (>/=CIN2) was 0.32% in the population as projected from cervical biopsies of 123 women (0.4%), of whom 100 showed >/=CIN2. Sensitivity of the cytology screening program at PapIIID/HSIL threshold for detecting histologically confirmed >/=CIN2 cases was 81%, with specificity, positive predictive value (PPV) and negative predictive value (NPV) of 99, 20.9 and 99.9%, respectively. Of 38 women receiving the complete screening protocol, all the 31 >/=CIN2 cases were correctly detected by cytology alone, 30 by positive high-risk HPV genotype and 30 by aneuploid DNA profile. The combination of the three methods resulted in an up to 6.9% increase in PPV for >/=CIN2 at practically unchanged detection rate with the additional benefit of being able to predict the probable outcome of CIN1 lesions detected as false positives with any single test. Multimodal cervical screening might permit identification of those women with low-grade squamous intraepithelial lesions likely to progress at an earlier and curable stage of disease and lengthen the screening interval in those with transient minor lesions caused by productive HPV infection.     

Human papillomavirus testing using hybrid capture II with SurePath collection: initial evaluation and longitudinal data provide clinical validation for this method

BACKGROUND: Testing for human papillomavirus (HPV) is an integral part of equivocal cervical cytology triage. Clinical validation of non-FDA (Food and Drug Administration)-approved methods is therefore important because of the high volume of such tests and the implications for missed high-grade lesions if test performance is not optimal. METHODS: A preinitiation study and 17 months of follow-up data using Hybrid Capture II (HC II) HPV detection with SurePath (SP) sample collection were analyzed. Results of HPV tests on abnormal cytology samples were collected and compared with follow-up results. HPV-positive rates were determined in cases of low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL), and follow-up rates of cervical intraepithelial neoplasia (CIN) were determined in HPV-positive and -negative cases of atypical squamous cells of unknown significance (ASC-US). Rates were compared with published data using FDA-validated methods. RESULTS: The preinitiation study showed the test method to be 100% sensitive for the detection of LSIL (20 cases) and HSIL (8). The ASC-US follow-up study (2319 cases with 625 having biopsy results) showed that the rate of CIN III+ in HPV +/- cases was 7.8%/1.4%, and of CIN II+ was 17.5%/4.3%, respectively. The positive predictive values/negative predictive values (PPV/NPVs) (CIN II+) for the test were 17.5%/95.7%, respectively. CONCLUSIONS: Published FDA-validated HPV testing follow-up data show that the expected rates of CIN III+ and CIN II+ in the HPV-negative ASC-US population are 1.4% and 5%, respectively, with PPV/NPVs (CIN II+) of 20%/99%, respectively. By comparison, the present data using HC II with SP show strong similarity, indicating clinical validity for the use of this method.     

HPV prevalence and accuracy of HPV testing to detect high-grade cervical intraepithelial neoplasia

Concern was raised on using testing for high-risk (HR) human papillomavirus (HPV) in cervical cancer screening in populations where HPV prevalence is high. The impact of HR HPV prevalence on the efficiency of HPV test-based screening has never been directly evaluated. A meta-regression of the relationship between HR HPV prevalence and the specificity and positive predictive value (PPV) of HPV DNA testing for the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was performed. Only studies that used Hybrid Capture 2 (HC2) were included. Country income (low-medium vs. high) was used as a proxy of previous screening. Twenty-six populations from 20 studies were included. For a 10% increase in HR HPV prevalence, HC2 specificity decreased by 8.41% [95% confidence interval (CI): 8.02-8.81], whereas PPV increased by 4.74% (95% CI: 2.45-7.03). HR HPV prevalence explained 98% of the variability in HC2 specificity and 38% of the variability in PPV. Country income did not affect specificity, but low-medium income was associated with higher PPV (3.81%; 95% CI: 1.53-6.10) after adjustment for HR HPV prevalence. When HR HPV prevalence is high, the specificity of HPV testing for CIN2+ decreases, but PPV does not decrease and it is high in inadequately screened populations. The number of HPV-positive women needing further assessment or treatment per CIN2+ case detected will therefore decrease and screening efficiency will improve. This is explained by the fact that HR HPV causes CIN2+: an increase in HR HPV prevalence is inevitably accompanied by an increase in CIN2+.     

Cervical Cancer Detection between Conventional and Liquid Based Cervical Cytology: a 6-Year Experience in Northern Bangkok Thailand

Objectives: To determine the prevalence of abnormal Papanicolaou (Pap) smear, cervical intraepithelial neoplasia(CIN) 2 or higher and cancer between conventional Pap smear (CPP) and liquid based Pap smear (LBP). Methods: Thisretrospective study was conducted at Bhumibol Adulyadej Hospital, Bangkok, Thailand between January 2011 andDecember 2016. Data was collected from medical records of participants who attended for cervical cancer screening test.Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for detectingCIN 2 or higher were evaluated by using the most severity of histopathology reports. Results: A total of 28,564 caseswere recruited. Prevalence of abnormal Pap smear from CPP and LBP were 4.8 % (1,092/22,552) and 5.7 % (345/6,012),respectively. Percentage of unsatisfactory smears in CPP (52.3%) was higher than LBP (40.5%). From CPP and LBP,cervical cancer percentages were 0.2 and 0.1, respectively. Sensitivity, specificity, PPV, NPV and accuracy of CPP andLBP for detection cancer were 42.5 vs 26.1%, 99.9 vs 100.0%, 69.8vs 75.0%, 99.7 vs 100.0 % and 99.7 vs 99.7%,respectively. Conclusion: Prevalence of abnormal cervical cytology and cancer from CPP and LBP were 4.8/0.2and 5.7/0.1 percent, respectively. Unsatisfactory smear of LBP was less than CPP. Sensitivity, specificity, PPV, NPVand accuracy of CPP and LBP for detection CIN 2 or higher and cancer were comparable.     

Accuracy of Visual Inspection with Acetic acid in Detecting High-Grade Cervical Intraepithelial Neoplasia in Pre- and Post-Menopausal Thai Women with Minor Cervical CytologicalAbnormalities

Purpose: To determine the accuracy of visual inspection with acetic acid (VIA) in detecting high-gradecervical intraepithelial neoplasia (CIN) in pre- and post-menopausal women with atypical squamous cells ofundetermined significance (ASC-US) and low grade squamous intraepithelial lesion (LSIL) Papanicolaou (Pap)smears. Materials and Methods: Two hundred women (150 pre-menopausal and 50 post-menopausal) with ASCUSand LSIL cytology who attended the colposcopy clinic, Thammasat University Hospital, between March 2013and August 2014 were included. All women underwent VIA testing and colposcopy by gynecologic oncologists.Diagnostic values of VIA testing including sensitivity, specificity, positive predictive value (PPV) and negativepredictive value (NPV) for detecting high-grade CIN were determined using the histopathology obtained fromcolposcopic-directed biopsy as a gold standard. Results: VIA testing was positive in 54/150 (36%) pre-menopausalwomen and 5/50 (10%) post-menopausal women. Out of 54 pre-menopausal women with positive VIA testing,15 (27.8%) had high-grade CIN and 39 (72.2%) had either CIN 1 or insignificant pathology. Ten (10.4%), 43(44.8%) and 43 (44.8%) out of the remaining 96 pre-menopausal women with negative VIA testing had highgradeCIN, CIN 1 and insignificant pathology, respectively. Out of 5 post-menopausal women with positive VIAtesting, there were 4 (80%) women with high-grade CIN, and 1 (20%) women with insignificant pathology. Outof 45 VIA-negative post-menopausal women, 42 (93.3%) women had CIN 1 and insignificant pathology, and 3(6.7%) had high-grade CIN. Sensitivity, specificity, PPV and NPV of the VIA testing were 59.4%, 76.2%, 32.2%and 90.8%, respectively (60%, 68.8%, 27.8% and 89.6% in pre-menopausal women and 57.1%, 97.7%, 80%and 93.3% in post-menopausal women). Conclusions: VIA testing may be used as a screening tool for detectinghigh-grade CIN in women with minor cervical cytological abnormalities in a low-resource setting in order tolower the rate of colposcopy referral.     

Test positivity cutoff level of a high risk human papillomavirus test could be increased in routine cervical cancer screening

We present data on test positivity, relative sensitivity, rates of detection and relative specificity for primary human papillomavirus (HPV) testing with different cutoff levels for test positivity, in comparison to conventional cytology. In 2003-2004, 18,438 women were screened primarily with Hybrid Capture 2 (HC 2) assay, a test for oncogenic HPV DNA, and 21,446 with conventional cytology within the organised screening programme in Finland. A cytological triage test was performed for the HPV positives. Women with cytology equal to low grade squamous intraepithelial lesion (LSIL) or worse were referred for colposcopy. The relative sensitivity measured as relative risk (RR) of any cervical intraepithelial neoplasia (CIN) or cancer was 1.58 for the HPV test at the relative light units (rlu) ratio cutoff 1.00, in comparison to cytology. With the cutoff 3.00, all CIN 2+ lesions were detected. With cutoff 10.00, 2 of the 22 CIN 3+ lesions were missed. Relative specificity for HPV screening for any CIN was 92.6% at cutoff 1.00, 94.6% at cutoff 3.00 and 96.3% at cutoff 10.00. For CIN 3+ specificity estimates for these cutoffs were 92.1%, 94.1% and 95.8%, respectively. Used for routine screening as the sole test, the HPV test cutoff can be increased from the level recommended for clinical use. With HC 2, the detection rate at rlu ratio cutoff 10.00 is still at the level of high-quality conventional screening. At that level, the false positive rate is reduced by about half and the specificity of the HPV test becomes equal to the average specificity of conventional cytology.     

Is HPV DNA testing specificity comparable to that of cytological testing in primary cervical cancer screening? Results of a meta‐analysis of randomized controlled trials

Human‐papillomavirus (HPV) DNA testing has been proposed as an alternative to primary cervical cancer screening using cytological testing. Review of the evidence shows that available data are conflicting for some aspects. The overall goal of the study is to update the performance of HPV DNA as stand‐alone testing in primary cervical cancer screening, focusing particularly on the aspects related to the specificity profile of the HPV DNA testing in respect to cytology. We performed a meta‐analysis of randomized controlled clinical trials. Eight articles were included in the meta‐analysis. Three outcomes have been investigated: relative detection, relative specificity, and relative positive predictive value (PPV) of HPV DNA testing versus cytology. Overall evaluation of relative detection showed a significantly higher detection of CIN2+ and CIN3+ for HPV DNA testing versus cytology. Meta‐analyses that considered all age groups showed a relative specificity that favored the cytology in detecting both CIN2+ and CIN3+ lesions whereas, in the ≥30 years' group, specificity of HPV DNA and cytology tests was similar in detecting both CIN2+ and CIN3+ lesions. Results of the pooled analysis on relative PPV showed a not significantly lower PPV of HPV DNA test over cytology. A main key finding of the study is that in women aged ≥30, has been found an almost overlapping specificity between the two screening tests in detecting CIN2 and above‐grade lesions. Therefore, primary screening of cervical cancer by HPV DNA testing appears to offer the right balance between maximum detection of CIN2+ and adequate specificity, if performed in the age group ≥30 years.     

Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening

High-risk human papillomavirus (hrHPV) testing has a higher sensitivity but lower specificity than cytology for detection of high-grade intraepithelial neoplasia (CIN). To avoid over-referral to colposcopy and overtreatment, hrHPV-positive women require triage testing and/or followup. A total of 25,658 women (30-60 years) enrolled in a population-based cohort study had an adequate baseline Pap smear and hrHPV test. The end-point was cumulative two-year risk of CIN grade 3 or worse (CIN3+). In a post-hoc analysis, fourteen triage/followup strategies for hrHPV-positive women (n = 1,303) were evaluated for colposcopy referral rate, positive (PPV) and negative predictive value (NPV). Five strategies involved triage testing without a repeat test and nine strategies involved triage testing followed by one repeat testing. The tests were cytology, hrHPV, HPV16/18 genotyping and HPV16/18/31/33/45 genotyping. Results were adjusted for women in the cohort study who did not attend repeat testing. Of the strategies without repeat testing, combined cytology and HPV16/18/31/33/45 genotyping gave the highest NPV of 98.9% (95%CI 97.6-99.5%). The corresponding colposcopy referral rate was 58.1% (95%CI 55.4-60.8%). Eight of the nine strategies with retesting had an estimated NPV of at least 98%. Of those, cytology triage followed by cytology at 12 months had a markedly lower colposcopy referral rate of 33.4% (95%CI 30.2-36.7%) than the other strategies. The NPV of the latter strategy was 99.3% (95%CI 98.1-99.8%). Triage hrHPV-positive women with cytology, followed by repeat cytology testing yielded a high NPV and modest colposcopy referral rate and appear to be the most feasible management strategy.     

Efficacy of Pap test in combination with ThinPrep cytological test in screening for cervical cancer

Background: Our aim was to investigate the efficacy of the Pap test in combination with the ThinPrepcytological test (TCT) in screening for cervical cancer in China. Design: From March 2006 to October 2008,988 women with the mean age 46.4 ± 10.5 years (range, 23-80 years) were recruited to receive cervical cancerscreening. Pap test results ≥ grade III and TCT findings ≥ ASCUS/AGUS were considered abnormal. Subjectswith a Pap test result ≥ grade IIb received TCT. Colposcopy and biopsies were performed in all participants, andfinal diagnosis was based on pathological findings. The sensitivity, specificity, positive predictive value (PPV),negative predictive value (NPV) and Youden index for predicting CIN I or above were determined. Results:The sensitivity, specificity, PPV, NPV and Youden index of the Pap test were 43.1%, 97.2%, 70.0%, 91.9%, and40.3%, respectively. The same values for TCT in predicting CIN were 80.0%, 63.2%, 16.0%, 97.3%, and 43.2%,respectively. The two tests in combination gave values for predicting CIN of 64.8%, 87.6%, 43.6%, 94.4%, and53.5%, respectively. Combined testing exhibited the highest Youden index (53.4%). Conclusion: The Pap testwith a reduced threshold in combination with the TCT has high sensitivity and high specificity in screening forcervical cancer.     

Impact of utilizing p16INK4A immunohistochemistry on estimated performance of three cervical cancer screening tests

The histopathological diagnosis of cervical intraepithelial neoplasia grade 2,3 (CIN 2,3) is subjective and prone to variability. In our study, we analyzed the impact of utilizing a biomarker (p16(INK4A)) together with histopathology to refine the "gold standard" utilized for evaluating the performance of 3 different cervical cancer screening tests: cervical cytology, human papillomavirus (HPV) DNA testing and visual inspection with acetic acid (VIA). Cervical biopsies from 2 South African cervical cancer screening studies originally diagnosed by a single pathologist were reevaluated by a second pathologist and a consensus pathology diagnosis obtained. Immunohistochemical staining for p16(INK4A) was then performed. The estimated sensitivity of some cervical cancer screening tests was markedly impacted by the criteria utilized to define CIN 2,3. Use of routine histopathology markedly underestimated the sensitivity of both conventional cytology and HPV DNA testing compared to an improved gold standard of consensus pathology and p16(INK4A) positivity. In contrast, routine histopathology overestimated the sensitivity of VIA. Our results demonstrate that refining the diagnosis of CIN 2,3 through the use of consensus pathology and immunohistochemical staining for p16(INK4A) has an important impact on measurement of the performance of cervical cancer screening tests. The sensitivity of screening tests such as HPV DNA testing and conventional cytology may be underestimated when an imperfect gold standard (routine histopathology) is used. In contrast, the sensitivity of other tests, such as VIA, may be overestimated with an imperfect gold standard.     

高危型人乳头瘤病毒检测对宫颈上皮内瘤样病变诊断价值的探讨

目的:探讨在ASC-H患者中检测HR-HPV DNA预测宫颈上皮内瘤样病变(CIN)和浸润癌的价值,为完善CIN和浸润癌的筛查方案提供依据.方法:研究宫颈薄层液基细胞学诊断为ASC-H的患者68例,均进行HR-HPV DNA检测并在阴道镜下行宫颈组织活检,综合评价HR-HPV预测高级别CIN的价值.结果:在ASC-H中CIN发生率为52.9％(36/68),CINⅡ及以上病变(CINⅡ、CINⅢ及浸润癌)发生率为33.8％(23/68); HR-HPV检测阳性率为70.6％(48/68),HR-HPV阳性组CINⅡ及以上病变发生率为47.9％(23/48),HR-HPV阴性组CINⅡ及以上病变发生率为0(0/20),两组比较差异有统计学意义,x2=14.797,P=0.001,HR-HPV诊断CINⅡ及以上病变的敏感度和特异度分别为100.0％和44.4％,阳性预测价值和阴性预测价值分别为47.9％和100.0％.结论:初步研究结果提示,HR-HPV阳性ASC-H患者应高度警惕CINⅡ及以上病变发生,建议立即行阴道镜检查;而HR-HPV阴性患者可不进行阴道镜检查.     

Switch from cytology-based to human papillomavirus test-based cervical screening: implications for colposcopy

Human papillomavirus (HPV) testing is more sensitive than cytology; some cervical cancer prevention programs will switch from cytology to carcinogenic HPV test-based screening. The objective of our study is to evaluate the clinical implications of a switch to HPV test-based screening on performance and workload of colposcopy. Women in the population-based, 7-year Guanacaste cohort study were screened at enrollment using cytology. We also took another specimen for HPV DNA testing and collected magnified cervical photographic images (cervigrams). A final case diagnosis (≥cervical intraepithelial neoplasia [CIN] grade 3, CIN2, 相似文献   

Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment for a randomised controlled trial

BACKGROUND: Testing for human papillomavirus (HPV) DNA is more sensitive but less specific than cytological analysis. Loss in specificity is most relevant in women younger than 35 years because of increased HPV prevalence. We aimed to compare conventional screening with an experimental strategy in women aged 25-34 years, and investigate the effect of different criteria of referral to define the best methods of HPV screening. METHODS: Women were randomly assigned to the conventional procedure (standard cytology, with referral to colposcopy if cytology showed atypical squamous cells of undetermined significance or more [ASCUS+]) or an experimental procedure (liquid-based cytology and testing for high-risk HPV types, with referral to colposcopy with ASCUS+ cytology). Women positive for HPV (cutoff > or = 1 pg/mL) but with normal cytology were retested after 1 year. The main endpoint was the presence of cervical intraepithelial neoplasia at grade 2 or more (CIN2+) in reviewed histology. The main analysis was by intention to screen. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN81678807. FINDINGS: We randomly assigned 5808 women aged 25-34 years to the conventional group and 6002 to the experimental group. The experimental procedure was significantly more sensitive than the conventional procedure (55 vs 33 CIN2+ lesions detected; relative sensitivity 1.61 [95% CI 1.05-2.48]), but had a lower positive predictive value (PPV; relative PPV 0.55 [0.37-0.82]). HPV testing (> or = 1 pg/mL) with cytology triage was also more sensitive than conventional cytology (relative sensitivity 1.58 [1.03-2.44], relative PPV 0.78 [0.52-1.16]). Relative PPV could be improved, with minimum loss in sensitivity, by use of a 2 pg/mL cutoff for HPV testing. Compared with conventional cytology, liquid-based cytology had a relative sensitivity of 1.32 (0.84-2.06), relative PPV 0.58 [0.38-0.89]). INTERPRETATION: HPV testing alone with cytology triage could be a feasible alternative to conventional cytology for screening women younger than 35 years. Follow-up will provide data on possible overdiagnosis and on the feasibility of extended intervals.     

液基细胞学涂片DNA倍体分析与HPV检测在宫颈病变筛查中的比较

目的将细胞核DNA倍体分析与高危型人类乳头瘤状病毒检测用于宫颈上皮内瘤变筛查,为提高筛查的准确性探寻一种更有效的方法。方法抽取同时具有宫颈脱落细胞学诊断、高危型人类乳头瘤状病毒检测和组织活检病理诊断结果的209例病例,每例各制备两份宫颈脱落细胞涂片,一份进行细胞学检测,另一份进行宫颈脱落细胞核DNA倍体分析。以组织活检病理诊断结果为＂金标准＂,对细胞核DNA倍体分析和高危型人类乳头瘤状病毒检测结果进行比较。结果年轻组与年老组的高危型HPV感染率的差异有统计学意义;细胞学检测与病理活检结果的一致性不能令人满意;DNA倍体分析与高危型HPV检测结果的差异有统计学意义;以病理活检结果为＂金标准＂,细胞核DNA倍体分析的灵敏度高于高危型人类乳头瘤状病毒检测,但其特异度较低。结论细胞核DNA倍体分析结合高危型人类乳头瘤状病毒检测,可提高宫颈内瘤样变筛查的灵敏性和特异性。     

Detection of cervical high-grade squamous intraepithelial lesions from cytologic samples using a novel immunocytochemical assay (ProEx C)

BACKGROUND: Routine liquid-based cytology (LBC) provides excellent sensitivity for the detection of cervical high-grade squamous intraepithelial lesion (HSIL); however, its specificity is low. Consequently, many women who have atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL) cytology undergo unnecessary colposcopy. The authors hypothesized that a novel immunocytochemical assay (ProEx C) that can be performed on LBC slides had a significantly higher positive predictive value (PPV) for biopsy-proven HSIL compared with routine LBC. METHODS: The ProEx C immunocytochemical assay utilizes a cocktail of monoclonal antibodies directed against proteins associated with aberrant S-phase cell cycle induction (topoisomerase IIA, minichromosome maintenance protein 2). The ProEx C reagents were validated in the authors' laboratory for staining and scoring reproducibility, open-vial stability, and accuracy before a retrospective analysis using these reagents was performed on 317 residual cytology samples. Sensitivity, specificity, PPV, and negative predictive value (NPV) for the detection of biopsy-proven HSIL were determined. RESULTS: The ProEx C assay was validated successfully in the authors' cytology laboratory. Using biopsy-proven HSIL as an endpoint, the ProEx C assay yielded a sensitivity of 85.3%, specificity of 71.7%, PPV of 44.6%, and NPV of 94.8%. Compared with the routine LBC results in the same cohort, the ProEx C sensitivity for biopsy-proven HSIL was 70.6% greater than HSIL+ cytology (50% vs. 85.3%). ProEx C also showed a 114% increase in PPV relative to ASC-US cytology (21.1% vs. 44.6%). CONCLUSIONS: The ProEx C immunocytochemical assay can be integrated into a clinical cytology laboratory and may increase the PPV of LBC for biopsy-proven HSIL.     

Long-term protective effect of high-risk human papillomavirus testing in population-based cervical screening

We prospectively evaluated the 5-year predictive values of adding high-risk human papillomavirus (hrHPV) testing to cytology for the detection of > or = cervical intraepithelial neoplasia (CIN)3 lesions in a population-based cohort of 2810 women. At baseline, nine (0.3%) women had prevalent lesions > or = CIN3, all being hrHPV positive. After 5 years of follow-up, four (6.5%) of the 62 hrHPV-positive women with normal cytology developed lesions > or = CIN3, vs only one (0.05%) of the 2175 hrHPV-negative women with normal cytology. High-risk human papillomavirus testing or combined screening revealed a much higher sensitivity, at the cost of a small decrease in specificity, and a higher negative predictive value for the detection of lesions > or = CIN3 till the next screening round (5 years) than cytology alone.