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Background: The study presents cross-sectional accuracy of E6 and E7 (E6/E7) mRNA detection and p16/ki67 dual staining, alone or in combination with cytology and human papillomavirus (HPV)16/18 genotyping, as a triage test in HPV DNA-positive women and their impact on cervical intraepithelial neoplasia (CIN2+) overdiagnosis., Methods: Women aged 25-64 years were recruited. HPV DNA-positive women were triaged with cytology and tested for E6/E7 mRNA and p16/ki67. Cytology positive women were referred to colposcopy, and negatives were randomly assigned to immediate colposcopy or to 1-year HPV retesting. Lesions found within 24 months since recruitment were included. All P values were 2-sided., Results: 40 509 women were recruited, and 3147 (7.8%) tested HPV DNA positive; 174 CIN2+ were found: sensitivity was 61.0% (95% confidence interval [CI] = 53.6 to 68.0), 94.4% (95% CI = 89.1 to 97.3), and 75.2% (95% CI = 68.1 to 81.6) for cytology, E6/E7 mRNA, and p16/ki67, respectively. Immediate referral was 25.6%, 66.8%, and 28.3%, respectively. Overall referral was 65.3%, 78.3%, and 63.3%, respectively. Cytology or p16/ki67, when combined with HPV16/18 typing, reached higher sensitivity with a small impact on referral. Among the 2306 HPV DNA-positive and cytology-negative women, relative CIN2+ detection in those randomly assigned at 1-year retesting vs immediate colposcopy suggests a -28% CIN2+ regression (95% CI = -57% to +20%); regression was higher in E6/E7 mRNA-negatives (Pinteraction = .29). HPV clearance at 1 year in E6/E7 mRNA and in p16/ki67 negative women was about 2 times higher than in positive women (Pinteraction < .001 for both)., Conclusions: p16/ki67 showed good performance as a triage test. E6/E7 mRNA showed the highest sensitivity, at the price of too high a positivity rate to be efficient for triage. However, when negative, it showed a good prognostic value for clearance and CIN2+ regression., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Birth cohorts vaccinated against human papillomavirus (HPV) are now entering cervical cancer screening. Assessment of (pre)cancer (CIN3+) risk is needed to assess the residual screening need in vaccinated women. We estimated the lifetime (screen-detected) CIN3+ risk under five-yearly primary HPV screening between age 30 and 60, using HPV genotyping and histology data of 21,287 women participating in a screening trial with two HPV-based screening rounds, 5 years apart. The maximum follow-up after an HPV-positive test was 9 years. We re-estimated the CIN3+ risk after projecting direct vaccine efficacy for the bivalent and the nonavalent HPV vaccines, assuming life-long protection. The lifetime CIN3+ risk was 4.1% (95% confidence interval 3.5-4.9) and declined by 53.5% and 70.5% after bivalent vaccination without and with cross-protection, respectively, translating into a residual lifetime CIN3+ risk of 1.9% (1.4-2.4) and 1.2% (0.9-1.5). The CIN3+ risk declined by 88.5% after nonavalent vaccination, translating into a residual lifetime CIN3+ risk of 0.5% (0.2-0.7). The latter risk increased to 1.6% when vaccine protection only lasted until the first screening round at age 30. Among HPV-positive women with abnormal adjunct cytology, the nine-year CIN3+ risk was 16.9% (8.7-32.4) after nonavalent vaccination. In conclusion, HPV vaccination will lead to a strong decline in the lifetime CIN3+ risk and the remaining absolute CIN3+ risk will be very low. Primary HPV testing combined with adjunct cytology at five-year intervals still seems feasible even after nonavalent vaccination, although unlikely to be cost-effective. Our results support a de-intensification of screening programs in settings with high vaccination coverage., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Human papillomavirus (HPV) testing is very sensitive for primary cervical screening but has low specificity. Triage tests that improve specificity but maintain high sensitivity are needed. Women enrolled in the experimental arm of Phase 2 of the New Technologies for Cervical Cancer randomized controlled cervical screening trial were tested for high-risk HPV (hrHPV) and referred to colposcopy if positive. hrHPV-positive women also had HPV genotyping (by polymerase chain reaction with GP5+/GP6+ primers and reverse line blotting), immunostaining for p16 overexpression and cytology. We computed sensitivity, specificity and positive predictive value (PPV) for different combinations of tests and determined potential hierarchical ordering of triage tests. A number of 1,091 HPV-positive women had valid tests for cytology, p16 and genotyping. Ninety-two of them had cervical intraepithelial neoplasia grade 2+ (CIN2+) histology and 40 of them had CIN grade 3+ (CIN3+) histology. The PPV for CIN2+ was >10% in hrHPV-positive women with positive high-grade squamous intraepithelial lesion (61.3%), positive low-grade squamous intraepithelial lesion (LSIL+) (18.3%) and positive atypical squamous cells of undetermined significance (14.8%) cytology, p16 positive (16.7%) and, hierarchically, for infections by HPV33, 16, 35, 59, 31 and 52 (in decreasing order). Referral of women positive for either p16 or LSIL+ cytology had 97.8% sensitivity for CIN2+ and women negative for both of these had a 3-year CIN3+ risk of 0.2%. Similar results were seen for women being either p16 or HPV16/33 positive. hrHPV-positive women who were negative for p16 and cytology (LSIL threshold) had a very low CIN3+ rate in the following 3 years. Recalling them after that interval and referring those positive for either test to immediate colposcopy seem to be an efficient triage strategy. The same applies to p16 and HPV16., (© 2020 UICC.)

Objective: To assess the 5-year risk of high-grade lesions in women with a transient high-risk HPV infection., Design: Population-based cohort study., Setting: HPV primary testing within population-based organised cervical cancer screening programmes., Population: Italian women enrolled in seven pilot projects and attending the second round., Methods: On the basis of the cytology triage performed on HPV-positive women, immediate colposcopy or HPV repeat at 12 months was recommended. Data were collected at the subsequent round 3-4 years after HPV infection clearance., Main Outcome Measures: Rates of HPV infection, CIN2+ and CIN3+ detection at subsequent round after HPV clearance, and relative risks (RR) in comparison with HPV-negative women (with 95% confidence interval)., Results: Data on 1230 women (1027 aged 25-64 years and 203 aged 35-64 years) have been analysed. Overall compliance with repeat HPV testing was 84%. In comparison with HPV-negative women, those with a transient HPV infection had higher proportions of HPV positivity (15% versus 3.7%) and of CIN2+ lesions (0.87% versus 0.23%) in round two; most of these (7/10) were CIN2; no cancers were detected, and CIN3 occurred in 3/1230 (0.24%)., Conclusions: HPV-based protocols for cervical cancer screening allow long intervals for HPV-negative women; it is important to monitor the clinical outcome in the women with transient high-risk HPV infection. CIN3 detection is similar to that observed in routine European cytology-based screening programmes (CIN3+: 2.7‰); 5-year intervals may provide reasonable protection but longer intervals are not recommended., Tweetable Abstract: A screening interval of 5 years (but no longer) appears safe in women with transient HPV detection., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Human papilloma virus (HPV) testing is more sensitive but less specific than cytology. We evaluated stand-alone genotyping as a possible triage method. During a multicentre randomised controlled trial comparing HPV testing to conventional cytology, HPV-positive women were referred to colposcopy and followed up if no high-grade lesion was detected. HPV-positive samples were genotyped by GP5+/GP6+ primed polymerase chain reaction followed by reverse line blot. Genotypes were hierarchically ordered by positive predictive value (PPV) for CIN grade 2 or more (CIN2+), and grouped by cluster analysis into three groups (A, B and C in decreasing order). Receiver operating characteristic curves were computed. Among 2,255 HPV-positive women with genotyping, 239 CIN2+ (including 113 CIN3+) were detected at baseline or during a 3-year follow-up. HPV33 had the highest PPV with CIN2+ and CIN3+ as the endpoint and when considering lesions detected at baseline or also during follow-up. HPV16 and HPV35 were the second and third, respectively. Cross-sectional sensitivity for CIN2+ at baseline was 67.3% (95% CI 59.7-74.2), 91.8% (95% CI 86.6-95.5) and 94.7% (95% CI 90.2-97.6), respectively, when considering as "positive" any of the HPV types in group A (33, 16 and 35), A or B (31, 52, 18, 59 and 58) and A or B or C (39, 51, 56, 45 and 68). The corresponding cross-sectional PPVs for CIN2+ were 15.8% 95% (CI 13.2-18.7), 12.0% (95% CI 10.3-13.9) and 9.6% (95% CI 8.2-11.1), respectively. HPV33, 16 and 35 confer a high probability of CIN2+ but this rapidly decreases when adding other genotypes., (© 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Women positive to human papillomavirus (HPV+) testing at cervical screening need triage, typically cytology and immediate colposcopy in case of atypical squamous cells of undetermined significance (ASCUS) or worse (ASCUS+) or, in cytology-normal HPV+ women, HPV test repeat after 1 year and colposcopy referral if still HPV+. Our hypothesis was that substantial variations in triage positivity and sensitivity may produce little variation in overall referral to colposcopy and on sensitivity of the entire screening process., Methods: Centre- and age-aggregated data from 72,869 women aged 35-64 years were derived from 10 organised screening programmes which have piloted HPV screening in Italy since 2012. Overall colposcopy referral was evaluated as a function of immediate colposcopy referral and overall CIN2+ detection as a function of the proportion of all CIN2+ detected by immediate referral (a proxy of cytology's sensitivity). We fitted additive regression models, adjusted for centre, age, compliance to HPV retesting and to colposcopy, by generalised estimation equations., Results: The proportion of HPV+ women directly referred to colposcopy varied across programmes (20-57%; average 37%) and so did CIN2+ detection (49-94%; average 77%). Overall, 63% (range 41-75%) of HPV+ were referred to colposcopy either immediately or at HPV repeat. An absolute 10% increase in immediate colposcopy referral resulted in 4.2% (95% CI: 3.3-5.1%) increase in overall referral. An absolute 10% increase in cytology's sensitivity resulted in a 1.1% (95% CI: 0.1-2.0%) increase in overall CIN2+ detection., Conclusions: Repeat HPV testing limits the effect of subjectivity of cytology interpretation on overall referral and sensitivity. These will change only slightly when replacing cytology with another test if the interval to HPV repeat remains unchanged., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Italian national guidelines recommend regional implementation of organized screening programmes for cervical cancer. As we have been doing since 1998, we collected aggregated tables of data from Italian organized cervical screening programmes in order to centrally compute process indicators. Data on women invited during 2011 and 2012 and screened up to April of the subsequent year were considered. In 2012, the target population of Italian organized screening programmes included 14,497,207 women, corresponding to 87.3% of Italian women aged 25-64 years. Compliance to invitation was 41.2%in 2011 and 40.8%in 2012, with a strong decreasing North-South trend. However, it should be considered that many women are screened outside any organized programmes. In 2012, of the women screened, 3.5% were referred for repeat cytology and 71.1% of them complied; 2.4% of screened women were referred to colposcopy. Compliance with colposcopy referral was 85.3%among women referred because of ASC-US or more severe cytology and 90.4% among those referred because of HSIL or more severe cytology. The positive predictive value (PPV) of referral because of ASC-US or more severe cytology for CIN2 or more severe histology was 16.9%. The unadjusted detection rate of CIN2 or more severe histology was 3.4 per 1,000 screened women (3.6 standardized on the Italian population, truncated 25-64). CIN2 or more severe histology was detected in 64.6% of colposcopies classified as grade 2 or higher. Of all colposcopies during which a CIN2 or more severe histology was obtained, 33.6% were classified as grade 2 or higher. Follow-up only was recommended to 81.7% of women with CIN1. Excision by radio-frequency device was the most common treatment for women with CIN2 (52.8%) and CIN3 (57.0%). However 0.4% of all CIN2 and 2.3% of all CIN3 had hysterectomy.

Compared to spontaneous screening, an organized screening programme is characterized by the presence of protocols and recommendations for all stages including follow-up. Despite the availability of well-functioning screening programmes throughout the country, the follow-up protocol after an abnormal Pap test and negative colposcopy is not clearly defined in Italy, and there is no uniformity of indications. HPV testing for oncogenic human papillomavirus (hr-HPV) has a high negative predictive value (NPV) and high positive predictive value (PPV) for CIN2+ and its employment can reduce follow-up assessments. In order to provide indications about the management of women with ASC-US+ and the follow-up of women with cytological abnormalities and negative colposcopy, a literature analysis was carried out, taking into consideration European and American guidelines and good practice recommendations from the most important scientific associations and regulatory agencies. GISCi (Italian Group for Cervical Screening) drafted recommendations for the management of women with ASC-US, L-SIL, ASC-H, AGC, and H-SIL until their return to the routine screening interval. This protocol can be applied not only in the management of abnormal Pap smears in cytology-based programmes, but also in the management of abnormal Pap test triage after HPV positive test when HPV is the primary screening test. The protocols approved within the screening programmes must have an extensive consensus among all involved professionals, including any that women might meet outside the programme.

Pilot HPV-based cervical screening programmes have recently started in Italy, partly on the strength of a large randomized trial. The Ministry of Health recommended that regions shift toward HPV-based screening in early 2013 and provided guidelines for its application (stand-alone HPV testing by validated methods, cytological triage of HPV positives, beginning at age 30-35, 5-year intervals). A first survey on the 2012 activity was conducted in 2013. In 2012, 19 Italian organized cervical screening programmes from 10 regional programmes invited 311,856 women (8.0%of all women invited for cervical screening in 2012 in Italy) for HPV-based screening; 41.5% complied, with a decreasing North-South trend. Among screened women, 7.9% (range 4.3%-13.9%) were HPV positive, decreasing to 6.6% (range 4.0%-12.4%) when considering women aged 35-64 years. Among HPV positive women, 34.8%(with high variability between programmes: range 11.1%-59.3%) were judged to have ASC-US or more severe cytology (5.3%ASC-US, 26.6%L-SIL, 5.2% H-SIL). Out of all screened women, those referred to colposcopy based on HPV and cytology results were 2.9% (range 0.6%-4.8%), whereas they were 2.0% when considering only women aged 35-64 years.

Background: Human papillomavirus (HPV)-based screening needs triage. In most randomized controlled trials (RCTs) on HPV testing with cytological triage, cytology interpretation has been blind to HPV status., Methods: Women age 25 to 60 years enrolled in the New Technology in Cervical Cancer (NTCC) RCT comparing HPV testing with cytology were referred to colposcopy if HPV positive and, if no cervical intraepithelial neoplasia (CIN) was detected, followed up until HPV negativity. Cytological slides taken at the first colposcopy were retrieved and independently interpreted by an external laboratory, which was only aware of patients' HPV positivity. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were computed for histologically proven CIN2+ with HPV status-informed cytology for women with a determination of atypical squamous cells of undetermined significance (ASCUS) or more severe. All statistical tests were two-sided., Results: Among HPV-positive women, informed cytology had cross-sectional sensitivity, specificity, PPV and 1-NPV for CIN2+ of 85.6% (95% confidence interval [CI] = 76.6 to 92.1), 65.9% (95% CI = 63.1 to 68.6), 16.2% (95% CI = 13.0 to 19.8), and 1.7 (95% CI = 0.9 to 2.8), respectively. Cytology was also associated with subsequent risk of newly diagnosed CIN2+ and CIN3+. The cross-sectional relative sensitivity for CIN2+ vs blind cytology obtained by referring to colposcopy and following up only HPV positive women who had HPV status-informed cytology greater than or equal to ASCUS was 1.58 (95% CI = 1.22 to 2.01), while the corresponding relative referral to colposcopy was 0.95 (95% CI = 0.86 to 1.04)., Conclusions: Cytology informed of HPV positivity is more sensitive than blind cytology and could allow longer intervals before retesting HPV-positive, cytology-negative women., (© The Author 2015. Published by Oxford University Press.)

Background: In four randomised trials, human papillomavirus (HPV)-based screening for cervical cancer was compared with cytology-based cervical screening, and precursors of cancer were the endpoint in every trial. However, direct estimates are missing of the relative efficacy of HPV-based versus cytology-based screening for prevention of invasive cancer in women who undergo regular screening, of modifiers (eg, age) of this relative efficacy, and of the duration of protection. We did a follow-up study of the four randomised trials to investigate these outcomes., Methods: 176,464 women aged 20-64 years were randomly assigned to HPV-based (experimental arm) or cytology-based (control arm) screening in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC). We followed up these women for a median of 6·5 years (1,214,415 person-years) and identified 107 invasive cervical carcinomas by linkage with screening, pathology, and cancer registries, by masked review of histological specimens, or from reports. Cumulative and study-adjusted rate ratios (experimental vs control) were calculated for incidence of invasive cervical carcinoma., Findings: The rate ratio for invasive cervical carcinoma among all women from recruitment to end of follow-up was 0·60 (95% CI 0·40-0·89), with no heterogeneity between studies (p=0·52). Detection of invasive cervical carcinoma was similar between screening methods during the first 2·5 years of follow-up (0·79, 0·46-1·36) but was significantly lower in the experimental arm thereafter (0·45, 0·25-0·81). In women with a negative screening test at entry, the rate ratio was 0·30 (0·15-0·60). The cumulative incidence of invasive cervical carcinoma in women with negative entry tests was 4·6 per 10(5) (1·1-12·1) and 8·7 per 10(5) (3·3-18·6) at 3·5 and 5·5 years, respectively, in the experimental arm, and 15·4 per 10(5) (7·9-27·0) and 36·0 per 10(5) (23·2-53·5), respectively, in the control arm. Rate ratios did not differ by cancer stage, but were lower for adenocarcinoma (0·31, 0·14-0·69) than for squamous-cell carcinoma (0·78, 0·49-1·25). The rate ratio was lowest in women aged 30-34 years (0·36, 0·14-0·94)., Interpretation: HPV-based screening provides 60-70% greater protection against invasive cervical carcinomas compared with cytology. Data of large-scale randomised trials support initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years., Funding: European Union, Belgian Foundation Against Cancer, KCE-Centre d'Expertise, IARC, The Netherlands Organisation for Health Research and Development, the Italian Ministry of Health., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Immunostaining for p16-INK4A (henceforth p16) is a sensitive and specific method for detection of high-grade cervical intraepithelial neoplasia (CIN) in women infected with human papillomavirus (HPV), but longitudinal data have not been obtained. We investigated the relation between p16 status and risk of CIN during 3 years of follow-up., Methods: Women aged 25-60 years were enrolled between June 10, 2003, and Dec 31, 2004, in a multicentre randomised trial comparing HPV testing with cytology. HPV-positive women were referred for colposcopy and, in seven of nine centres, were tested for p16 overexpression by immunostaining. If no CIN was detected, these women were followed up at yearly intervals until clearance of HPV infection. The primary endpoint was histologically confirmed CIN of grade 2 or worse (CIN of grade 2 [CIN2], CIN of grade 3 [CIN3], or invasive cervical cancer) at recruitment or during follow-up. We calculated the absolute and relative risks by p16 status at recruitment. We also calculated the longitudinal sensitivity of p16 testing. Additionally, we assessed the relative sensitivity of an alternative strategy (referral to colposcopy and follow-up of only HPV-positive, p16-positive women) versus conventional cytology in two age groups. Percentages were weighted by the inverse of the tested fraction. The trial in which this study is nested is registered, number ISRCTN81678807., Findings: Of 1042 HPV-positive women who were tested for p16 with no CIN detected during the first round of screening, 944 (91%) had further HPV tests. 793 (84%) of these 944 were followed up until detection of CIN2 or worse, HPV infection clearance, or for at least 3 years. CIN2 or worse was detected during follow-up in more p16-positive women (31 of 365, 8·8% [95% CI 5·8-11·8]) than in p16-negative women (17 of 579, 3·7% [1·9-5·4]; relative risk [RR] 2·61 [95% CI 1·49-4·59]). RR was higher in women aged 35-60 years at recruitment (3·37 [1·39-8·15]) than in those aged 25-34 years (2·15 [1·00-4·61]), but age was not a significant modifier. CIN3 or worse was detected during follow-up in more p16-positive women (16 of 365, 4·4% [2·3-6·6]) than in p16-negative women (six of 579, 1·3% [0·2-2·3]; RR 3·90 [95% CI 1·57-9·68]). Longitudinal sensitivity of p16 testing for detection of CIN3 or worse during follow-up at all ages was 77·8% (95% CI 63·9-91·6). The relative sensitivity of the alternative strategy compared with conventional cytology was 2·08 (1·13-3·56) in women aged 35-60 years and 2·86 (1·28-5·36) in those aged 25-34 years. HPV-positive, p16-negative women aged 35-60 years had a higher cumulative risk of CIN3 or worse during recruitment or follow-up (2·0%, 95% CI 0·3-3·7) than did HPV-negative women (0·01%, 0-0·04) or those who were cytologically normal (0·04%, 0·02-0·09) at recruitment., Interpretation: p16 overexpression is a marker for CIN2 or worse or for development of CIN2 or worse within 3 years in HPV-positive women, especially those aged 35-60 years. HPV-positive, p16-positive women need immediate colposcopy and, if the assessment is negative, annual follow-up. Immediate colposcopy can be avoided in HPV-positive, p16-negative women, who can be safely managed with repeat screening after 2-3 year intervals., Funding: European Union; Italian Ministry of Health; Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia Romagna; and Public Health Agency of Lazio Region., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Data were collected from organised Italian cervical screening programmes on: a) the correlation between colposcopic findings (according to the 1990 international classification) and histology, and (b) the treatment/management of screen-detected histologically-confirmed cervical intraepithelial neoplasia (CIN). Data routinely registered by organised programmes were obtained as aggregated tables. Of the 26,320 reported colposcopies, 39.6% were classified as normal and 11.2% as unsatisfactory. CIN2 or more severe histology was detected in 65.3% of colposcopies classified as grade 2 or higher. Of all colposcopies, the outcome of which was CIN2 or more severe histology, 42.7% were classified as grade 2 or higher. Of the 5,695 women with CIN1, 78.9% were recommended to have follow-up only. However, 1.4% of them had cold-knife conisation and 4.5% were treated by diathermocoagulation. Of the 3,841 women with CIN2 or CIN3, 6.4% had not yet been treated when data were collected, and no data rewere available for a further 12.7%. Excision by radio-frequency device was the most common treatment among these women (64.1% of those with known treatment). However, 0.7% of all CIN2 and 1.7% of all CIN3 had hysterectomy. Among the 151 women with invasive carcinoma, 10.6% plausibly with microinvasive disease, only one treatment LLETZ is reported.

OBJECTIVE OF THE PROJECT: Purpose of this Report is to evaluate the impact of the introduction of liquid-based cytology (LBC) in cervical cancer screening in terms of efficacy, undesired effects, costs and implications for organisation. EFFICACY AND UNDESIRED EFFECTS: LBC WITH MANUAL INTERPRETATION: The estimates of cross-sectional accuracy for high-grade intraepithelial neoplasia (CIN2 or more severe and CIN3 or more severe) obtained by a systematic review and meta-analysis published in 2008 were used. This review considered only studies in which all women underwent colposcopy or randomised controlled trials (RCTs) with complete verification of test positives. A systematic search of RCTs published thereafter was performed. Three RCTs were identified. One of these studies was conducted in 6 Italian regions and was of large size (45,174 women randomised); a second one was conducted in another Italian region (Abruzzo) and was of smaller size (8,654 women randomised); a third RCT was conducted in the Netherlands and was of large size (89,784 women randomised). No longitudinal study was available. There is currently no clear evidence that LBC increases the sensitivity of cytology and even less that its introduction increases the efficacy of cervical screening in preventing invasive cancers. The Italian randomised study NTCC showed a decrease in specificity, which was not observed in the other two RCTs available. In addition, the 2008 meta-analysis observed a reduction - even if minimal - in specificity just at the ASC-US cytological cut-off, but also a remarkable heterogeneity between studies. These results suggest that the effect of LBC on specificity is variable and plausibly related to the local style of cytology interpretation. There is evidence that LBC reduces the proportion of unsatisfactory slides, although the size of this effect varies remarkably. LBC WITH COMPUTER-ASSISTED INTERPRETATION: An Australian study, based on double testing, showed a statistically significant increase of the sensitivity for CIN2 or more of LBC with computer-assisted interpretation vs. conventional cytology with manual interpretation. However, an English RCT estimated that LBC with computer-assisted interpretation has a lower sensitivity than LBC with manual interpretation. COST AND ECONOMIC EVALUATION: In the current Italian situation the use of liquid-based cytology for primary screening is estimated to increase the costs of cytological screening. Liquid-based cytology needs shorter time for interpretation than conventional cytology. However, in the Italian situation, savings obtained from this time reduction and from the decreased number of repeats due to unsatisfactory slides are not currently sufficient to compensate the cost increase due to the prices currently applied by producers and to a possible greater number of colposcopies caused by LBC. In any case, at current prices, cost is estimated to increase even when assuming a referral rate to colposcopy with LBC similar or slightly lower than that with conventional cytology. For the costs of computer-assisted interpretation of liquid-based cytology, readers are referred to the relative HTA report (Epidemiol Prev 2012;36(5) Suppl 3:e1-43). ORGANISATIONAL AND ETHICAL ASPECTS: Ethical, legal and communication problems are judged to remain unchanged when compared to screening with conventional cytology. After having used the test for some time, interpreters prefer liquid-based to conventional cytology. Reduced time for interpretation makes the adoption of LBC a possible approach to deal with shortenings of cytology interpreters which is happening in Italy. However, alternative solutions, such as computer-assisted interpretation of cytology and the use of HPV as primary screening test, should be considered. Liquid-based cytology allows performing molecular tests, in particular the HPV test. This property allows triaging women with borderline or mild cytology by "reflex" molecular or immunocytochemical tests with no need to recall them. LBC sampling can be used also if HPV is applied as the primary screening test, allowing "reflex" triaging of HPV positive women by cytology with no need to recall them nor to take two samples, one for HPV testing and one for conventional cytology. This represents a remarkable advantage in terms of organization. However, costs are high because only 5-7% of women screened with this approach need interpretation of cytology. In addition, HPV testing with the Hybrid Capture assay on material preserved in LBC transport media needs a preliminary conversion phase, which limits the use of LBC for triaging HPV positive women. It is advisable that in the near future industry develops sampling/transport systems that allow performing both the HPV test and cytology or other validated triage tests without additional manipulations and at sustainable costs.

This study compares colposcopy referrals of 2 management strategies: oncogenic human papillomavirus (HPV)-DNA testing (Hybrid Capture 2 assay, Qiagen, Germantown, MD) and repeat cytology. In the New Technology in Cervical Cancer Trial, 22,708 subjects were randomly assigned to undergo both HPV and liquid-based cytologic testing. Women aged 35 to 60 years old with unsatisfactory cytologic findings were directly referred for colposcopy if the HPV test result was positive, and were referred for repeat cytologic examination if the HPV test result was negative; women aged 25 to 35 years old were referred for repeat cytologic examination independent of HPV test results. A positive or a second unsatisfactory cytologic examination referred women for colposcopy. Five hundred sixty women had unsatisfactory cytologic findings. Colposcopy referral was not significant and slightly higher with HPV testing than repeat cytologic test (9.8% vs 6.8%, P = .11). When cytologic testing was repeated 36.8% were unavailable for follow-up and most of the colposcopies were performed in HPV-negative women. For unsatisfactory cytologic findings, HPV triage is a more logical and efficient management strategy than a repeat cytologic test.

Unlabelled: OBJECTIVE OF THE PROJECT: The introduction of the HPV test as a primary screening test will cause important changes in the screening system based on cytology. The purposes of this report are: to define the best screening policies with HPV-based screening on the basis of the resulting efficacy and of undesired effects; comparing them to cytology-based screening; to identify their best conditions of application; to evaluate economic cost, feasibility and impact on the organisation of services of such policy in the Italian situation., Contents: This report contains a section on efficacy and undesired effects based on a systematic review of literature conducted in strict coordination with the preparation of a supplement to the European Guidelines for quality assurance in cervical cancer screening. This chapter corresponds to a preliminary version of the chapter of the European Guidelines on primary screening with HPV. The sections on costs, impact on organisation, and social, ethical and legal impact reflect the Italian situation; they are based on a review of the available Italian data (including unpublished data, mainly from on-going pilot projects) and on a structured analysis of what will result if the proposed protocol is applied to the Italian situation., Results: Efficacy and undesired effects. There is clear scientific evidence that a screening based on validated tests for the DNA of oncogenic HPV as primary test and applying an appropriate protocol is more effective than screening based on cytology in preventing invasive cancers of the uterine cervix. In addition, it entails a limited--if any--increase of the undesired effects both in terms of unneeded referral to diagnostic work-up and in terms of over-diagnosis and consequent overtreatment of spontaneously regressive lesions. The crucial elements of such protocol are the followings: HPV-positive women are not to be directly referred to colposcopy, but the use of triage systems is essential. The currently recommendable method is based on performing cytology in HPV positive women. If the result of this test is abnormal, the woman is immediately referred to colposcopy; if cytology is normal, the woman is invited to repeat a new HPV test after one year. In case such a test is still positive, the woman is referred to colposcopy; in case of negative result, the woman will be re-invited for a new screening round at the regular interval. In organised population-based screening programmes the interval after a negative primary HPV test should be at least 5 years. There is evidence that the 5-year cumulative risk of high-grade CIN after a negative HPV test is lower than the 3-year risk after a normal cytology. On the other hand, the probability of unneeded colposcopies and treatments would plausibly be relevant with 3-year intervals after a negative HPV test. HPV-based screening should not start before 30-35 years. There is evidence that below 30 years HPV-based screening leads to an increased overdiagnosis of CIN2 that would regress spontaneously, with consequent overtreatment. Some increase in overdiagnosis is plausible also between 30 and 34 years. Below such ages, cytological screening is the recommended test. Only tests for the DNA of oncogenic HPV, validated according to the European guidelines as for sensitivity and specificity for high-grade lesions, should be applied. There is no evidence that double testing with cytology and HPV is more protective than stand-alone HPV as primary test, although it entails a small and not relevant increase in sensitivity vs stand-alone HPV. On the contrary, there is evidence that double testing causes a substantial increase in referral to colposcopy and a decrease in its PPV. For this reason, if HPV is used as primary screening test, it is recommended not to add cytology in parallel. Cost and economic evaluation. It is estimated that, if the protocol described is applied, in the current Italian situation the overall costs of HPV-based screening are lower than those of conventional cytological screening applied at the current 3-year intervals, although the cost of each screening round is higher. Impact on organization. For reasons of quality and cost, both the interpretation of cytology and HPV testing require a centralisation. This need is particularly strong, in terms of costs, for HPV test execution. It is therefore recommended to perform the HPV test in a limited number of reference laboratories of large size. This also makes monitoring and evaluating the spontaneous activity easier. HPV-based screening entails problems of organisation related to the need of triage, to complex protocols and to reconversion of the activities of cytological interpretation. Social, ethical and legal impact. The communication of the result of the HPV test to women, particularly if positive, is a further crucial aspect in order to reduce not only the emotional impact, but also the possible risks that women are inappropriately managed or lost to follow-up. Great efforts must be put in the education of healthcare professionals, both directly involved in organised programmes or not, particularly private gynaecologists and general practitioners., Recommendations: In conclusion, the crucial requirement to introduce HPV-based screening programmes is the capacity to guarantee the application of appropriate screening protocols. If protocols do not respect the criteria described above they can cause relevant increase of undesired effects and costs compared to cytology-based screening. Therefore they should be avoided, except in studies able to provide clear evidence about human and economic costs. For this purpose, correct education and information both to healthcare professionals and to the population is needed. In the Italian situation, where organised screening and a relevant spontaneous activity coexist, their interaction is crucial. Actions directed to integrate them and to guarantee as more uniformity of interventions as possible are needed, in particular through the integration of registries and thorough monitoring and a progressive homogenization of protocols. In order to grant the safety of transition, it is needed that the HPV-based organised screening activities are strictly monitored and that the National Centre for Screening Monitoring (ONS) ensures coordination. Knowledge about HPV based screening is still rapidly evolving. It is possible that currently on-going researches suggest changes to the optimal protocols in the next few years, particularly as for the management of HPV positive women. In addition, studies on the validation of new assays were recently published and others are expected. It is suggested to exploit the organised screening activity to produce scientific evidence, in order to clarify the still uncertain aspects of optimal protocols. Different protocols in terms of screening intervals, age of application and management of HPV positive women should be studied in the frame of controlled implementation, through multicentre projects coordinated by ONS. Finally, it is suggested the creation of a National working group to promptly update the recommendations for screening and the list of assays to be considered as validated. On the bases of the results obtained in the first vaccinated cohorts reaching the screening age, for the future, it will be crucial to deliver specific recommendations to the population vaccinated against HPV during adolescence.

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+., (Copyright © 2011 UICC.)

Background: In the New Technologies for Cervical Cancer Screening (NTCC) randomized controlled trial, no significant increase in the sensitivity of liquid-based cytology (LBC) was observed compared with conventional cytology. Both were interpreted by cytologists who had limited previous LBC experience. The objective of the current study was to assess whether different results could be expected with experienced LBC interpreters., Methods: A stratified, random sample of 818 LBC slides from the NTCC study was obtained. These slides were reviewed blindly and independently by 3 international experts who did not participate in the NTCC. The sensitivity and specificity of external experts were estimated for cervical intraepithelial neoplasia grade 2 or greater (CIN2+) and for CIN3+ histology, and the differences were compared with the sensitivity and specificity of the original cytologic interpretation using cutoffs of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL)., Results: With the endpoint of CIN2+ histology, the difference in sensitivity between external experts and the original interpretation was -5.3 (95% confidence interval [CI], -16.0 to 5.4) with ASCUS as the cutoff and 3.8 (95% CI, -8.2 to 15.8) with LSIL as the cutoff. External experts had slightly lower specificity using ASCUS as the cutoff (-3.4; 95% CI, -3.9 to -2.9) and LSIL as the cutoff (-0.7; 95% CI, -1.0 to -0.4)., Conclusions: The accuracy of the external experts' interpretation was similar to that of the original interpretation. Therefore, the current results indicated that LBC is not expected to increase sensitivity even if it is used by interpreters who have extensive experience with this technique., ((c) 2010 American Cancer Society.)

Objective: To investigate the rate of unsatisfactory cervical cell samples in liquid-based cytology (LBC) versus conventional cytology (CC) by age., Design: Randomised clinical trials., Setting: Population-based cervical cancer screening in the Netherlands and Italy., Population: Asymptomatic women invited for screening enrolled in two randomised trials: Netherlands ThinPrep versus conventional cytology (NETHCON; 39 010 CC, 46 064 LBC) and New Technologies in Cervical Cancer Screening (NTCC; 22 771 CC, 22 403 LBC)., Methods: Comparison of categorical variables using Pearson's chi-square test, logistic regression and trend tests., Main Outcome Measures: Proportion of unsatisfactory samples, ratio of LBC versus CC, and variation by 5-year group., Results: In NETHCON, a lower percentage of LBC samples were judged to be unsatisfactory compared with CC samples (0.33 versus 1.11%). There was no significant trend in unsatisfactory results by age group for conventional cytology (P(trend) = 0.54), but there was a trend towards an increasing percentage of unsatisfactory results with increasing age for LBC (P(trend) < 0.001). In NTCC, a lower percentage of LBC samples were judged to be unsatisfactory compared with conventional cytology (2.59 versus 4.10%). There was a decrease in the unsatisfactory results by age group with conventional cytology (P(trend) < 0.001) and with LBC (P(trend) = 0.01), although the latter trend arose from the 55-60-years age group (P(trend) = 0.62 when excluding this group)., Conclusions: The clinical trial in which the results were collected and the cytologic method used were the most important determinants of unsatisfactory cytology. In all situations, the proportion of unsatisfactory samples was lower in LBC compared with CC. The effects of age depended on the criteria used to define unsatisfactory results.

The patterns of transmission, clearance, and progression of HPV infection and the related precancerous lesions are key to accurately model cervical cancer epidemiology and prevention. We have developed an age-structured dynamic model of the transmission of HPV-16 infection. This mathematical model accounts, for the first time, for the effect of infection and precancerous lesions duration on the natural history of HPV-16 infection and precancerous lesions. The model's output has been fitted to contemporaneous sets of data from Turin, Italy, to estimate parameters that have had been indirectly tested by comparing them with other estimates reported in the literature. The average probability of HPV-16 infection transmission per sexual partnership was about 40%. The HPV-16 clearance and progression rates decreased as the length of time with infection increased, clearance ranging between 1.6 per woman-year (in the first 6 months of infection) and 0.036 (after more than 6 years of infection), and progression between 0.072 and 0.018 per woman-year. The rate of clearance of precancerous lesions (CIN2+) was inversely dependent on age, while the progression of CIN2+ toward invasive cervical cancer increased as the precancerous lesions persisted. The present study also suggests that an exclusive role of women's age in shaping the rate of progression to cancer is unlikely. These results should inform future analyses. Including more accurately the role of the duration of infection and precancerous lesions as determinants of the cervical cancer occurrence in models of cervical cancer control may influence predictors of the effectiveness of intervention strategies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises approximately 250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community.

Background: Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing., Methods: Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807., Findings: In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing. 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together. At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two. At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two., Interpretation: HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2., Funding: European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Standardised tables of aggregated data were collected from 15 European national or regional cervical screening programmes and key performance indicators computed as reported in European Union (EU) Guidelines, 2nd edition. Cytological results varied widely between countries both for the total proportion of abnormal tests (from 1.2% in Germany (Mecklenburg-Vorpommern) to 11.7% in Ireland-Midwest Region) and for their distribution by grade. Referral rates for repeat cytology (ranging from 2.9% of screened women in the Netherlands to 16.6% in Slovenia) or for colposcopy (ranging from 0.8% in Finland to 4.4% in Romania-Cluj) and the Positive Predictive Value (PPV) of colposcopic attendance (ranging from 8% in Romania-Cluj to 52% in Lithuania) were strongly influenced by management protocols, in particular for atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology. However, cytology-specific PPV also showed remarkable variability. The detection rate of CIN2+ histology ranged from <0.1% of screened women in Poland to >1% in England and Denmark. Low attendance for colposcopy after referral was observed in some east-European countries. These comparisons may be useful for improving the performance of cervical screening in general and more so if new screening technologies and vaccination for Human Papillomavirus are introduced. Overall, quality was better in countries that have operated organised programmes for a longer time, plausibly as a result of long-lasting monitoring and quality assurance activities. Therefore, the availability of these data, the first comparing European countries, and the increased number of countries that can provide such data (only five in 2004) represent progress. Nevertheless, there is a clear need to standardise the cytological and histological classifications used in screening, as well as data registration systems across Europe.

Aim: To outline the perspectives for future control of cervical cancer in Europe., Methods: Review of current status for major cervical cancer control tools. The review was based on PubMed searches for cervical cancer prevention, Human Papillomavirus, HPV-test, HPV-vaccination, and treatment with large loop excision of the transformation zone, LLETZ., Results: Recent studies suggest that condom use offers some but not complete protection against HPV-infection. High quality cytology screening with good population coverage reduces the incidence and mortality of cervical cancer. Randomised controlled trials have found HPV-testing to increase the detection rate of cervical intraepithelial neoplasia grade 2+, CIN2+, compared with cytology. Two studies found a decreased detection rate of CIN3+ in the HPV-testing arm at the subsequent screening. Randomised controlled trials found that women not infected with vaccine HPV-types at vaccination are well protected against CIN2+ from these HPV-types, but the vaccine does not protect against CIN2+ from other HPV-types and neither does it protect already HPV infected women. There is an increased risk of adverse obstetric outcomes following excisional treatment., Conclusions: The future of cervical cancer control may become a diversified strategy, one for non-vaccinated birth cohorts and another for vaccinated cohorts. It will take another 50 years before the non-vaccinated cohorts have passed the screening age. With the current uncertainty concerning the long term protection from HPV-vaccination it will furthermore be precautionary to continue screening practice for the first cohorts of HPV-vaccinated women. Organised vaccination and screening programmes with good record keeping are necessary to optimise the future control of cervical cancer.

This report up-dates information on the national situation of cervical cancer screening in the member states of the European Union. There is yet high diversity in the status of cervical screening, and rapid changes expected to occur in the situation in many countries. It is important to underline differences in the health care and other components in order to allow a proper interpretation of the summary results published elsewhere in this Special Issue. The brief national descriptions along with up-dated information on the recent references are available from all but one member states.

The reproducibility of cervical histology diagnoses is critical for efficient screening and to evaluate the effectiveness of new technologies. The vast majority of cervical intraepithelial neoplasia (CIN) diagnoses reported in the New Technologies for Cervical Cancer study were blindly reviewed by 2 independent pathologists. Only H&E-stained slides were used for the review. The reviewers were asked to reclassify cases using the following categories: normal CIN 1, CIN 2, CIN 3, and squamous and glandular invasive cancer. We reviewed 1,003 cases. The interobserver agreement was 0.36 (95% confidence interval [CI], 0.32-0.40) with an unweighted kappa and 0.54 with a weighted kappa (95% CI, 0.50-0.58). The kappa values from dichotomous classifications with the threshold at CIN 2 were 0.69 (95% CI, 0.64-0.73) and 0.57 (95% CI, 0.51-0.63) with the threshold at CIN 3. The CIN 2 diagnosis had the lowest class-specific agreement, with fewer than 50% of cases confirmed by the panel members, which supports the fact that CIN 2 is not a well-defined stage in the pathogenesis of cervical neoplasia.

We collected from Italian organised cervical screening programmes data on the correlation between colposcopic findings (according to the 1990 international classification) and histology and on the treatment/management of screen-detected histologically confirmed cervical intraepithelial neoplasia (CIN). Data routinely registered by organised programmes were provided as aggregated tables. We obtained data on colpo-histological correlation from 72 programmes. Of the 18,340 reported colposcopies 37.9% were classified as normal and 20.9% as unsatisfactory. CIN2 or more severe histology was detected in 71.6% of colposcopies classified as grade 2 or higher. Of all colposcopies the outcome of which was CIN2 or more severe histology, 40.6% had a colposcopy classified as grade 2 or higher. We obtained data on treatment from 83 programmes. Of the 3,405 women with CIN1 69.3% had follow-up only. However 0.8% of them had cold-knife conisation, 7.5% were treated by diathermocoagulation and 0.1% had hysterectomy. Of the 2,597 women with CIN2 or CIN3 4.1% had not yet been treated when data were collected and no data were available for a further 8.1%. Excision by radio-frequency device was the most common treatment among these women (60.9% of those with known treatment). However 0.7% of all CIN2 and 3.4% of all CIN3 had hysterectomy. Among the 100 women with invasive carcinoma, 17% (plausibly with microinvasive disease) had only excisional treatment reported.

Italian national guidelines recommend to Regions the implementation of organised screening programmes for cervical cancer. As in previous years since 1998, we collected from Italian organised cervical screening programmes aggregated tables of data in order to centrally compute process indicators. Data on women invited during 2007 and screened up to April 2008 were considered. In 2007, the target population of Italian organised screening programmes included 11,872,810 women, corresponding to 71.8% of Italian women aged 25-64 years. Uptake of invitation was 39.8%, with a clear North-South decreasing trend. It should, however, be considered that many women are screened outside the organised programmes. Of the women screened, 5.0% were referred for repeat cytology and 60.4 % of them complied; 2.4% of screened women were referred to colposcopy. Compliance with colposcopy referral was 82.3% among women referred because of ASCUS or more severe cytology and 89.5% among those referred because of HSIL or more severe cytology. The positive predictive value (PPV) of referral because of ASCUS or more severe cytology for CIN2 or more severe histology was 16.0%. The unadjusted detection rate of CIN2 or more severe histology was 2.9 per 1,000 screened women (3.1 standardised on the Italian population, truncated 25-64).

Given the strong etiologic link between high-risk HPV infection and cervical cancer high-risk HPV testing is now being considered as an alternative for cytology-based cervical cancer screening. Many test systems have been developed that can detect the broad spectrum of hrHPV types in one assay. However, for screening purposes the detection of high-risk HPV is not inherently useful unless it is informative for the presence of high-grade cervical intraepithelial neoplasia (CIN 2/3) or cancer. Candidate high-risk HPV tests to be used for screening should reach an optimal balance between clinical sensitivity and specificity for detection of high-grade CIN and cervical cancer to minimize redundant or excessive follow-up procedures for high-risk HPV positive women without cervical lesions. Data from various large screening studies have shown that high-risk HPV testing by hybrid capture 2 and GP5+/6+-PCR yields considerably better results in the detection of CIN 2/3 than cytology. The data from these studies can be used to guide the translation of high-risk HPV testing into clinical practice by setting standards of test performance and characteristics. On the basis of these data we have developed guidelines for high-risk HPV test requirements for primary cervical screening and validation guidelines for candidate HPV assays., (Copyright (c) 2008 Wiley-Liss, Inc.)

Testing for the DNA of high-risk types of papilloma virus (HPV) is more sensitive than cytology in detecting pre-cancerous lesions. One of the main advantages will be the possibility of applying prolonged screening intervals. However adequate screening protocols (age of start and stop, screening intervals, management of HPV positive women) need to be applied in order to avoid over-referral to colposcopy and over-treatment and to maintain sustainable costs. Further follow-up of running trials and research on molecular markers will better define these parameters. The new situation will require organised screening programmes with rigorous protocols and monitoring. This will be even more needed when women vaccinated for HPV 16 and 18 will be screened. Research on how to best screen vaccinated women is a priority. This paper proposes an overview of the plausible impact of new technologies in cervical cancer screening in the near future and in the vaccinated cohorts.

Background: Human-papillomavirus (HPV) testing is more sensitive, but less specific, than conventional cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We assessed whether HPV testing with triage by p16-INK4A overexpression can increase specificity while maintaining sensitivity., Methods: HPV-positive women were enrolled between June 10, 2003, and Dec 31, 2004 in a multicentre randomised controlled trial, which compared stand-alone HPV testing by Hybrid Capture 2 (experimental group) with conventional cytology, were referred for colposcopy. In seven of nine centres, cytospin preparations from these women were tested for p16-INK4A overexpression by immunostaining. The sensitivity and specificity for CIN grade 2 or more, determined at blind review of histology, were calculated for these women. We also estimated the relative sensitivity and relative referral to colposcopy that would have been obtained by HPV testing with p16-INK4A triage compared with conventional cytology. This trial is registered as a Standard Randomised Controlled Trial, number ISRCTN81678807., Findings: 24 661 women were randomly assigned to the experimental group. 1137 women (74% of those undergoing colposcopy in relevant centres), including 50 with CIN2 and 42 with CIN3 or cancer, had valid p16-INK4A immunostaining. For the endpoint of CIN2+, sensitivity and specificity of p16-INK4A (deemed positive with any number of stained cells-except endocervical, metaplastic, and atrophic cells if morphologically normal) in HPV-positive women of any age were 88% (81 of 92; 95% CI 80-94) and 61% (633 of 1045; 57-64), respectively. In the 35-60-year age group, the relative sensitivity of HPV testing and p16-INK4A triage versus conventional cytology for CIN2+ was 1.53 (95% CI 1.15-2.02) and relative referral was 1.08 (0.96-1.21). In the 25-34-year age group, relative sensitivity was 3.01 (1.82-5.17) and relative referral was 1.15 (0.96-1.37). In the latter age group, when 5% or more stained cells were deemed positive, the corresponding values were 2.06 (1.20-3.68) and 0.58 (0.46-0.73), respectively., Interpretation: HPV testing with p16-INK4A triage produces a significant increase in sensitivity compared with conventional cytology, with no substantial increase in referral to colposcopy.

To assess the adequacy of a routine screening to identify cervical intraepithelial neoplasia 2 or worse (CIN2+) in women over 50 years of age, a retrospective cohort was set in six Italian organised population-based screening programmes. In all, 287 330 women (1 714 550 person-years of observation, 1110 cases) screened at age 25-64, with at least two cytological screening tests, the first negative, were followed from their first negative smear until a biopsy proven CIN2+ lesion or their last negative smear. For women aged 25-49 and 50-64 years, crude and age-standardised detection rate (DR), cumulative risk (CR), adjusted hazard risk for number of previous negative screens, probability of false-positive CIN2+ after two or more smear tests were calculated. Detection rate is significantly lower over 50 years of age. Multivariable analysis shows a significant protective effect from four screening episodes (DR=0.70, 95% CI: 0.51-0.97); the effect of age >or=50 is 0.29 (95% CI: 0.24-0.35). The CR of CIN2+ is at least eightfold higher in women <50 (CR=2.06, 95% CI: 1.88-2.23) after one previous negative test than in women >or=50 years with four screens (CR=0.23, 95% CI: 0.00-0.46). Over 50 years of age, after four tests at least three false-positive cases are diagnosed for every true positive. Benefits arising from cytological screening is uncertain in well-screened older women.

Background: In the first recruitment phase of a randomized trial of cervical cancer screening methods (New Technologies for Cervical Cancer Screening [NTCC] study), we compared screening with conventional cytology with screening by human papillomavirus (HPV) testing in combination with liquid-based cytology. HPV-positive women were directly referred to colposcopy if aged 35 or older; if younger, they were retested after 1 year., Methods: In the second recruitment phase of NTCC, we randomly assigned women to conventional cytology (n = 24,661) with referral to colposcopy if cytology indicated atypical squamous cells of undetermined significance or more severe abnormality or to testing for high-risk HPV DNA alone by Hybrid Capture 2 (n = 24,535) with referral to colposcopy if the test was positive at a concentration of HPV DNA 1 pg/mL or greater. For the main endpoint of the study, histologic detection of cervical intraepithelial neoplasia of grade 2 or more (CIN2+), we calculated and compared sensitivity and positive predictive value (PPV) of the two screening methods using HPV DNA cutoffs of 1 pg/mL and 2 pg/mL. All statistical tests were two-sided., Results: For women aged 35-60 years, the relative sensitivity of HPV testing for detection of CIN2+ at a cutoff of 1 pg/mL vs conventional cytology was 1.92 (95% CI = 1.28 to 2.87) and the relative PPV was 0.80 (95% CI = 0.55 to 1.18). At a cutoff of 2 pg/mL HPV DNA, the relative sensitivity was 1.81 (95% CI = 1.20 to 2.72) and the relative PPV was 0.99 (95% CI = 0.67 to 1.46). In this age group, there was no evidence of heterogeneity between study phases. Among women aged 25-34 years, the relative sensitivity for detection of CIN2+ of HPV testing at a cutoff of 1 pg/mL vs cytology was 3.50 (95% CI = 2.11 to 5.82), statistically significantly larger (P = .019) than that observed in phase 1 at this age (1.58; 95% CI = 1.03 to 2.44)., Conclusions: For women aged 35-60 years, HPV testing with a cutoff of 2 pg/mL achieves a substantial gain in sensitivity over cytology with only a small reduction in PPV. Among women aged 25-34 years, the large relative sensitivity of HPV testing compared with conventional cytology and the difference between relative sensitivity during phases 1 and 2 suggests that there is frequent regression of CIN2+ that are detected by direct referral of younger HPV-positive women to colposcopy. Thus, triage test or repeat testing is needed if HPV is to be used for primary testing in this context.

All cervical intraepithelial neoplasia (CIN) diagnoses identified during the New Technologies for Cervical Cancer trial (ISRCTN81678807) were blindly reviewed by 2 pathologists. Original diagnoses based on colposcopy-guided biopsies were compared with those made by the reviewers who had access to all clinical histologic samples (including postsurgical). Cases downgraded from CIN 2+ by the reviewers were considered indicative of unnecessary treatments. The analyses are presented according to the molecular (high-risk human papillomavirus [HPV]) and/or cytologic diagnosis used to refer the women for colposcopy. We reviewed 812 CIN 1 and 364 CIN 2 + diagnoses. The specificity of colposcopy-guided biopsy was 98% and the sensitivity, 84%. The probability of unnecessary treatment was 27% for women with atypical squamous cells of undetermined significance cytologic findings and 8% for women with low-grade squamous intraepithelial lesion or worse, 10% for HPV+ and positive cytologic findings, and 16% for HPV+ alone. The positive predictive value of the first-level screening test was inversely associated with probability of a histologic false-positive result (P = .015). In screening, a low positive predictive value of the colposcopy-referring test may result in unnecessary treatments.

Within a multicentre controlled trial framework, an external quality control (EQC) was scheduled to evaluate the interlaboratory reproducibility of liquid-based cytology. In particular, this EQC intended to evaluate the reproducibility of the ASCUS diagnosis.A selected set of 30 slides (4 within normal limit cases, 16 atypical squamous cells of undetermined significance; 4 low-grade squamous intraepithelial lesions and 6 high-grade squamous intraepithelial lesions) circulated among the 13 laboratories involved in the trial.Kappa values were obtained from the comparison between individual laboratory diagnoses and majority diagnoses with target diagnoses. Specific kappa values resulted moderate to high for HSIL and low to moderate for LSIL and WNL. Meanwhile, the specific kappa for ASCUS was below 0.4 in 12 of 13 participating laboratories. The lack of reproducibility for ASCUS was not a result of the introduction of this new technology but rather to the low reproducibility of the ASCUS category itself stemming from intrinsic uncertainties in the reporting criteria., ((c) 2007 Wiley-Liss, Inc.)

Objective: To compare the accuracy of conventional cytology with liquid based cytology for primary screening of cervical cancer., Design: Randomised controlled trial., Setting: Nine screening programmes in Italy., Participants: Women aged 25-60 attending for a new screening round: 22 466 were assigned to the conventional arm and 22 708 were assigned to the experimental arm., Interventions: Conventional cytology compared with liquid based cytology and testing for human papillomavirus., Main Outcome Measure: Relative sensitivity for cervical intraepithelial neoplasia of grade 2 or more at blindly reviewed histology, with atypical cells of undetermined significance or more severe cytology considered a positive result., Results: In an intention to screen analysis liquid based cytology showed no significant increase in sensitivity for cervical intraepithelial neoplasia of grade 2 or more (relative sensitivity 1.17, 95% confidence interval 0.87 to 1.56) whereas the positive predictive value was reduced (relative positive predictive value v conventional cytology 0.58, 0.44 to 0.77). Liquid based cytology detected more lesions of grade 1 or more (relative sensitivity 1.68, 1.40 to 2.02), with a larger increase among women aged 25-34 (P for heterogeneity 0.0006), but did not detect more lesions of grade 3 or more (relative sensitivity 0.84, 0.56 to 1.25). Results were similar when only low grade intraepithelial lesions or more severe cytology were considered a positive result. No evidence was found of heterogeneity between centres or of improvement with increasing time from start of the study. The relative frequency of women with at least one unsatisfactory result was lower with liquid based cytology (0.62, 0.56 to 0.69)., Conclusion: Liquid based cytology showed no statistically significant difference in sensitivity to conventional cytology for detection of cervical intraepithelial neoplasia of grade 2 or more. More positive results were found, however, leading to a lower positive predictive value. A large reduction in unsatisfactory smears was evident., Trial Registration: Current Controlled Trials ISRCTN81678807 [controlled-trials.com].

We collected from Italian organised cervical screening programmes data (a) on the correlation between colposcopic findings (according to the 1990 international classification) and histology and (b) on the treatment/management of screen-detected histologically confirmed cervical intraepithelial neoplasia (CIN). Data routinely recorded by organised programmes was provided as aggregated tables. We obtained data on colpo-histological correlation from 41 programmes. Of the 16,292 reported colposcopies, 43% were classified as normal and 23 % as unsatisfactory. CINI or more severe histology was detected in 2278/4449 (51%) of colposcopies classified as grade 1. CIN2 or more severe histology was detected in 651/1033 (63%) ofcolposcopies classified as grade 2 or higher. Ofall colposcopies that found CIN2 or more severe histology, 41% had a colposcopy classified as grade 2 or higher. We obtained data on treatment from 71 programmes. Of the 2,895 women with CINI, 73.4% had follow-up only, 14 (0.5%) of them had cold-knife conisation, 170 (5.9%) were treated by diathermocoagulation and 4 (0.1%) had hysterectomy. Of the 1972 women with CIN2 or CIN3, 4.8% had not yet been treated when data were collected and no data was available for a further 12.9%. Excision by radio-frequency device was the most common treatment among these women (58.7% of those with known treatment). However, 0.8% of women with CIN2 and 4.2% of women with CIN3 had hysterectomy. Of the 76 women with invasive carcinoma, 19.8%, plausibly with microinvasive disease, had excisional treatment only reported.

Since 1996, Italian national guidelines have recommended to regions the implementation of organised screening programmes for cervical cancer. As in the previous years, starting from 1998, we collected aggregated tables of data from Italian organised cervical screening programmes in order to centrally compute process indicators. In 2005, the target population of Italian organised screening programmes included 10,969,571 women, corresponding to 66.7% of Italian women aged 25-64 years. However, these programmes invited only 24.8% of their target population in 2005, vs. 33.3% expected in order to invite the entire target population in the 3-year recommended interval. Compliance to invitation was 36.7%, with a clear North-South decreasing trend. It must however be considered that many women are screened outside the organised programmes. The remaining process indicators deal with women invited during 2004 and screened up to April 2005. Unsatisfactory smears were 3.1%. It was recommended to 6.1% of women to repeat cytology, and 61% of them complied. Some (2.5%) of screened women were referred to colposcopy. Compliance to colposcopy was 84.7% among women referred because of ASCUS or more severe cytology and 88.2% among those referred because of HSIL or more severe cytology. The Positive Predictive Value (PPV) of referral because of ASCUS or more severe cytology for CIN2 or more severe histology was 15.5%. There was a relevant variability of both referral rate and PPV, that were inversely related, and 10 % ofprogrammes referred > 5% of women, suggesting too broad criteria of interpretation of cytology. The unadjusted detection rate ofhistologically confirmed CIN2 or more severe was 2.7 per 1000 screened women (3.0 per 1000, standardised on the Italian population, truncated 25-64).

In the experimental arm of a randomised trial, women were tested both for liquid-based cytology and human papillomavirus (HPV) DNA and referred for colposcopy if cytology was ASCUS (atypical cells of undetermined significance) or more severe. We considered those with ASCUS (757) or LSIL (low-grade squamous intraepithelial lesions) (485) and a valid HPV test who received colposcopy. We computed sensitivity, specificity and ROC curves with different values of relative light units (RLU, that are related to viral load) as cut off, using cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) at blind histology review as the endpoint. The area under the receiver operating characteristic (ROC) curve was significantly less among women aged 25-34 years than in those older, both considering ASCUS/AGUS (atypical glandular cells of undetermined significance) (p=0.0355) and LSIL (p=0.0009). At age 35-60 the curves for ASCUS and LSIL were similar, while at age 25-34 the area under the curve for LSIL was significantly less than for ASCUS (p=0.0084). With LSIL cytology, specificity of Hybrid Capture 2 with 2 RLU cut-off was 35.0% (95%CI 28.4-42.1) at age 25-34 and 64.5% (95%CI 58.3-70.3) at age 35-60. In conclusion, triaging by HPV testing performed better in women aged over 35 years than those younger. For older women, HPV triaging should also be considered for managing those with LSIL cytology.

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.

Background: Although testing for human papillomavirus (HPV) has higher sensitivity and lower specificity than cytology alone for detecting cervical intraepithelial neoplasia (CIN), studies comparing conventional and liquid-based cytology have had conflicting results., Methods: In the first phase of a two-phase multicenter randomized controlled trial, women aged 35-60 years in the conventional arm (n = 16,658) were screened using conventional cytology, and women in the experimental arm (n = 16,706) had liquid-based cytology and were tested for high-risk HPV types using the Hybrid Capture 2 assay. Women in the conventional arm were referred to colposcopy with atypical cells of undetermined significance (ASCUS) or higher and those in the experimental arm were referred with ASCUS or higher cytology or with a positive (> or = 1 pg/mL) HPV test. Sensitivity and positive predictive value (PPV) for detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) were calculated., Results: The screening methods and referral criterion applied in the experimental arm had higher sensitivity than that in the conventional arm (relative sensitivity = 1.47; 95% confidence interval [CI] = 1.03 to 2.09) but a lower PPV (relative PPV = 0.40; 95% CI = 0.23 to 0.66). With HPV testing alone at > or = 1 pg/mL and at > or = 2 pg/mL, the gain in sensitivity compared with the conventional arm remained similar (relative sensitivity = 1.43, 95% CI = 1.00 to 2.04 and relative sensitivity = 1.41, 95% CI = 0.98 to 2.01, respectively) but PPV progressively improved (relative PPV = 0.58, 95% CI = 0.33 to 0.98 and relative PPV = 0.75, 95% CI = 0.45 and 1.27, respectively). Referral based on liquid-based cytology alone did not increase sensitivity compared with conventional cytology (relative sensitivity = 1.06; 95% CI = 0.72 to 1.55) but reduced PPV (relative PPV = 0.57; 95% CI = 0.39 to 0.82)., Conclusions: HPV testing alone was more sensitive than conventional cytology among women 35-60 years old. Adding liquid-based cytology improved sensitivity only marginally but increased false-positives. HPV testing using Hybrid Capture 2 with a 2 pg/mL cutoff may be more appropriate than a 1 pg/mL cutoff for primary cervical cancer screening.

We collected, from the local registration systems of Italian organised cervical screening programmes, aggregated data (a) on the correlation between colposcopic grading and histology in routine colposcopies and (b) on treatment performed for screen-detected biopsy-proven cervical intraepithelial lesions (CIN). We obtained data on colpo-histological correlation from 40 programmes, reporting on 12,901 colposcopies, classified according to the 1990 international classification. Among them 37% were classified as normal and 25% as unsatisfactory (transformation zone not entirely visible). CIN1 or more severe histology was detected in 2273/4140 (65%) colposcopies classified as grade 1. CIN2 or more severe histology was detected in 566/853 (66.4%) colposcopies classified as grade 2. Of all women with CIN2 or more severe histology 42% had a colposcopy classified as grade 2 or higher. We obtained data on treatment from 57 programmes. Of the 2123 CIN1 cases 63% had follow-up only. However 20 (0.9%) had cold-knife conisation, 2 (0.1%) had hysterectomy and 191 (9.0%) were treated by diathermo-coagulation. Of the 1600 women with diagnosis of CIN2 or CIN3 4.2% had not been treated when data were collected and no data were available for another 8.2%. Electrosurgical excision was the most common treatment in these women (79% of those with known treatment). Some 0.7% of all CIN2 and 5.1% of all CIN3 had hysterectomy. Some 12% of the 111 invasive carcinoma, plausibly microinvasive, had excisional treatment only.