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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.)

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.)

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.

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.

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).

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.

The decision to introduce liquid-based cytology (LBC) and HPV as screening tests involves criteria based on resource consumption. We used cross-sectional data at recruitment from the NTCC trial [ISRCTN81678807] on 28,000 women aged 35-60, randomised to receive a conventional Pap test or LBC plus HPV. We computed the resources employed to detect a CIN2+ with different screening strategies. In order to result in the same overall cost per CIN2+ detected as screening by conventional cytology, the unit cost of LBC used alone should be less than that of a conventional Pap while its unit cost may be up to 20% higher if HPV-triage for Atypical Squamous Cells of Undetermined Significance is applied together. With the same criterion the unit cost of HPV used alone may be about 20% higher than that of a Pap-test using a 1 pg/ml cut-off and over 40% higher using a 10 pg/ml cut-off. If HPV testing is applied with cytology-triage, a single HPV test may cost 20-30% more than a conventional Pap to result in the same overall cost per CIN2+ detected., ((c) 2007 Wiley-Liss, Inc.)

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.)

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).

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.

Within a large Italian randomized trial on new technologies for cervical cancer screening involving 7 laboratories with different levels of experience, an intralaboratory and interlaboratory quality control program for human papillomavirus (HPV) DNA testing by Hybrid Capture 2 (HC2; Digene, Gaithersburg, MD) was implemented. To monitor the hybridization and detection steps, target samples containing purified, concentration-defined, HPV DNA were introduced in each test run. Only 3 of 1,024 showed a mistake in a positive vs negative classification with a 1 relative light unit (RLU)/positive control specimen (PC) ratio cutoff. To monitor the preanalytic steps (particularly denaturation), blinded specimens (33 collected in PreservCyt (Cytyc, Boxborough, MA) and 36 in Specimen Transport Medium (STM, Digene) were centrally prepared, divided into aliquots, and sent to each laboratory. The multiple-rater scores for negative (<1 RLU/PC), low-positive (1 to <11 RLU/PC), and high-positive (> or =11 RLU/PC) samples, respectively, were 0.91, 0.60, and 0.69 with PreservCyt and 0.93, 0.87, and 0.90 with STM. Our data showed high reliability and reproducibility with HC2, with values higher for STM than ThinPrep (Cytyc) samples.

The study was aimed at assessing interlaboratory reproducibility in the reporting of cervical smears in the atypical squamous cells of undetermined significance (ASCUS) category. A set of 50 selected slides circulated among 89 laboratories, currently involved in population-based screening programmes for cervical cancer, which provided a diagnostic report according to four main reporting categories based on the 1991 Bethesda system. Interlaboratory agreement was determined according to kappa (K) statistics: overall and weighted K values were determined for each laboratory and for single reporting categories. The results showed a very low reproducibility for the ASCUS category. This finding supports the Bethesda system 1991 recommendation to limit the use of this reporting category and suggests that the clinical response to ASCUS reports should be decided locally, based on the observed positive predictive value for cervical intraepithelial neoplasia 2 or more severe lesions.

The study objective was assessing whether circulation of smears and discussion of those with differing interpretation can increase reproducibility between laboratories. The study included: the blind interpretation of a first set of 194 smears among seven laboratories, the discussion of smears with discrepant diagnoses during the previous phase and the blind interpretation of a second set of smears of same size and characteristics. After discussions, the overall weighted kappa increased in five laboratories (substantially in three : +50%, +27% and +20%). However, no change was observed in one laboratory and a slight decrease (-4%) in another. The latter interpreted the second set of smears at a longer time interval from discussions. Agreement improved for all diagnostic classes except low grade intraepithelial neoplasia (LSIL). Overall, the intervention increased diagnostic agreement, but its effect varied with laboratory and by diagnostic class and could be transient. Continued programmes of smear exchange and discussion appear to be advisable.

Background: AutoPap (currently Focalpoint) is a computerized scanning system for the primary screening of cervicovaginal smears. For smears indicated to require further review, the system provides maps (PapMaps) to identify the most abnormal areas of the smear., Methods: To study the effect of PapMaps on diagnosis, 481 smears (from 4656 successfully processed smears using AutoPap) were first classified by conventional manual interpretation and then reinterpreted blind by the same cytologist who limited his examination to only the fields of view marked by the PapMaps. The interpretation time with and without PapMaps was measured on another simple random sample of 188 smears., Results: The interpretation time was reduced significantly, by approximately 40% using PapMaps (average reduction, 136 seconds per smear, 95% confidence interval [CI], 123-150). No cases manually classified as low-grade squamous intraepithelial lesions (LSIL) or worse and 20% of those manually classified as atypical squamous cells of undertermined significance (ASCUS) were judged as completely normal on the basis of fields of visions marked by PapMaps. In none of the latter was a histologically confirmed intraepithelial lesion identified. In relation to detailed diagnosis, the weighted kappa between manual and PapMap-aided interpretation was 0.745 (95% CI 0.687-0.804). Systematic differences were found (symmetry chi-square(10d.f) =19.11, P = 0.039): 48% of smears classified as ASCUS and 23% classified as LSIL by conventional diagnosis were classified as less severe (including normal) on the basis of PapMaps., Conclusions: Use of PapMaps resulted in a substantial reduction in interpretation time. PapMaps showed good sensitivity (100% for squamous intraepithelial lesions and 80% for ACSUC) for selecting abnormal slides. The latter require full examination: detailed diagnosis based only on areas marked by PapMaps could lead to under-grading., (Copyright 2003 American Cancer Society.)

Interobserver disagreement on smear adequacy may influence the evaluation of the performance of samplers as well as Pap test sensitivity and follow-up. In 1998, the Italian Group for Cervical Cancer Screening (GISCi) promoted a study on the reproducibility of adequacy criteria using a modified version of the Bethesda system. A set of 200 smears was circulated among six Italian laboratories situated in different parts of the country. For each smear, participants were requested to provide a summary judgment on its adequacy and on the cause(s) of inadequacy, if any. Agreement was measured using kappa-type statistics. The agreement among laboratories was generally good. In comparisons, among five laboratories, kappa values ranged from 0.47 to 0.66. At the consensus meeting on 42 slides, on which at least 2 laboratories dissented from the majority, agreement was reached unanimously for 31 reviewed slides and among 5-6 centers for 11. In this article, some guidance is given in order to attribute to one of the two categories satisfactory/unsatisfactory those smears that have been traditionally considered as candidates for the category of "satisfactory but limited by em leader " (SBLB). New Italian guidelines on adequacy proposed the GISCi are presented and the recommendation is made to eliminate the SBLB category., (Copyright 2003 Wiley-Liss, Inc.)

The objective of this study was to estimate: (i) the sensitivity of cytologists in recognizing abnormal smears; (ii) the sensitivity of cervical cytology as a method of detecting abnormal smears among those obtained in the presence of cervical intraepithelial neoplasia (CIN). Study subjects were 61 women with a histologically confirmed CIN identified through colpohistological and cytologic screening. For objective (i) new smears were taken from study subjects just before treatment, mixed with routine preparations, interpreted by unaware cytologists and then blindly reviewed by a group of three expert supervisors, who reached a consensus diagnosis. Cytologists classified as positive for squamous intraepithelial lesion (SIL) 30 of the 34 smears judged as positive by supervisors (100% of smears classified as high-grade and 67% of smears classified as low-grade SIL by the supervisors). Our approach, based on creating a set of smears with a high a priori probability of being positive, proved to be an efficient way of estimating errors of interpretation. For objective (ii), smears taken at the moment of diagnosis, just before biopsy, were also reviewed by the same supervisors. These CIN cases were identified among asymptomatic women independently of cytological findings and results are therefore not subject to verification bias. Among the 33 histological CINII/III, four (12%) smears had no atypical cells (three negatives and one unsatisfactory) at review. The same proportion was 26% (four negatives and one unsatisfactory) among the 19 histological CINI. No significant differences in smear content were found between the seven 'false negatives' and a sample of 'true positive' and 'true negatives' for a number of formal adequacy criteria (including presence of endocervical cells). Strong differences were found between positive smears taken just before biopsy and those taken just before treatment (in 11 women the first smear only was positive, while the opposite was never observed), suggesting an effect of punch biopsy in removing lesions.

A pilot phase of a population-based organized screening programme for cervical cancer was run in Turin, Italy, in May-June 1991. Based on the city population lists, 1181 women 25 to 64 years old were invited in two family clinics. Overall compliance to invitation was 41.7%. In order to study the determinants of compliance, a random sample of 372 compliers and 398 non-compliers was interviewed. Interval since last Pap-test was strongly associated with compliance (ORs of complying were 2.52, 1.53, 1.41, 0.50 and 0.16 for intervals longer than 3 years, 1-3 years, 6 months-1 year, 3-6 months and less than 3 months respectively vs. never having had a Pap-test, p < 0.001). Estimated compliance was 39% among never screened women and 65% among those tested since more than 3 years, leading to an over 70% overall estimated coverage (women who complied or had a spontaneous test within 3 years). On the other hand, the effect of a number of sociodemographic variables (age, education, place of birth, marital status) was very weak or opposite (lower compliance among younger and more educated women) to what we found in a previous study on spontaneous Pap-testing. The clinic allocated to pre-fixed appointments had a higher compliance than the clinic with appointments to be arranged (OR = 2.36 95% c.i. 1.66-3.36). Anxiety caused by periodic controls for early diagnosis of cancer was an important negative determinant of compliance (ORs of complying were 0.85, 0.49, and 0.16 for those with mild, moderate and severe levels of anxiety vs. those reassured by the test). We concluded that personal invitations were actually able to reach those women who have a poor level of spontaneous practice and could reduce the selection in access to this preventive practice.

Characteristics associated with the use of Pap tests were studied in a random sample of 581 women 18-69 years old; residents of Turin, Italy. There has been no organized screening programme in the area. (Tests possibly related to symptoms were not considered). Data were analysed by multiple logistic regression. Some 48% of women had never had a smear. The prevalence of women ever undergoing a Pap test was higher in middle-aged, married and more educated women (p less than 0.001 in all these cases). We found a linear trend (p less than 0.05) related to time since last visit to the family physician. A number of 'preventive' behavioural practices (physical exercise, no alcohol consumption) and experience of early diagnostic procedures for cancer e.g. BSE and mammography, were also associated with ever having had a Pap smear. The prevalence of ever-tested women was significantly lower among lifetime non-smokers than among ex-smokers and current smokers who planned to stop smoking but not lower than in current smokers who did not plan to stop. Results were similar when having had a test within the last three years was taken as the outcome. These results may be useful in planning screening strategies and educational programmes designed to improve attendance in an organized screening programme.