Population-based Cervical Screening Program Research Articles

Diagnostic Accuracy of DNA-Methylation in Detection of Cervical Dysplasia: Findings from a Population-Based Screening Program.

Epigenetic biomarkers in cancer have emerged as promising tools for early detection, prognosis, and treatment response prediction. In cervical cells, hypermethylation of the host and viral HPV-genome increases with the severity of lesions, providing a useful biomarker in the triage of hr-HPV-positive women and during treatment. The present study focuses on evaluating the clinical performance of the FAM19A4/miR124-2 methylation test in a population-based cervical screening program. Previously collected cervical samples, after bisulfite-converted DNA, were analyzed by PreCursor-M+ kit (distributed by Fujirebio Europe), for DNA methylation. The sensitivity, specificity, and negative/positive predictive values of DNA methylation were compared to histology, colposcopy, the HPV-DNA test, and cytology results. Among the 61-sample set, the specificity of methylation vs. positive histology (≥CIN2) and colposcopy (≥G2) were 87% and 90%, whereas the sensitivity was 50% and 33.3%, respectively. The combination of methylation analysis with standard methods increases diagnostic accuracy. Overall, we found a good specificity of DNA methylation in comparison to currently used techniques. Further larger studies could support the use of FAM19A4/miR124-2 as reliable biomarkers in the prevention of cervical cancer as triage in the screening protocol.

Interval cancer audit and disclosure in cervical screening programmes: An international survey.

Legal cases involving the National Cervical Screening Programme in Ireland following non-disclosure of an interval cervical cancer audit prompted this first international comparative survey of interval cervical cancer audit. A survey of 22 international population-based cervical screening programmes was conducted, to determine if they undertook audit of invasive cervical cancers. Those countries/regions that perform reviews were asked (i) how the audit was undertaken, including how the reviews were performed and how they controlled for retrospective bias, (ii) how women are informed of the audit process and how their consent is obtained, and (iii) how audit results were disclosed to patients. Seventeen countries/regions invited completed the survey (77%); 65% (11/17) have an audit process for interval cervical cancers. Five perform individual patient reviews; three perform programme-wide review, with calculation of interval cancer detection rates; one routinely performs programme-wide review with calculation of interval cancer detection rates and offers individual reviews, and one routinely performs local hospital-level reviews. In the remaining country/region, hospital laboratories audit cancers, with a national audit process for all cervical cancers. Varying methodologies for retrospective cytology review were employed; four include control samples, with a ratio varying from 1:1 to 1:2. Three conduct a blinded review. Most countries/regions do not discuss interval cancer audit with participants and 3/11 (27.3%) inform women when a cervical cancer audit takes place. Disclosure is limited and variable. The responses suggest that there is no consistent approach to audit of interval cervical cancers or to disclosure of audit results.

Preferences and Experiences Regarding the Use of the Self-Sampling Device in hrHPV Screening for Cervical Cancer.

BackgroundTo improve participation in the Dutch cervical cancer screening, a self-sampling device (SSD) was introduced in 2017 into the Dutch population-based screening programme (PBS) for the early detection of cervical cancer. The aim of this study was to gather potential preferences and experiences that might influence a woman’s decision to use the SSD in the Dutch PBS.MethodsA scoping review was performed in the PubMed database. Studies that assessed preferences and experiences of women regarding the SSD were included, and preferences and experiences were extracted. In addition, in a qualitative study, the list of potential preferences and experiences specific for the Dutch PBS was extended based on semi-structured interviews with SSD users as well as non-SSD users who recently participated in the PBS, analysed in a structured manner by translating full sentences to key words.ResultsNinety-eight studies were included in the scoping review and 16 interviews were performed. Frequently mentioned reasons for using the SSD, in both the interviews and the literature, were practicality and comfort. Frequently mentioned reasons for not using the SSD were fear of not performing the SSD procedure correctly and doubts on whether the results of the high-risk human papillomavirus (hrHPV) test will be reliable. A new positive experience elicited in the interviews was accessibility. Negative preferences and experiences were not being aware the SSD was an option, and the inconvenience that after an hrHPV-positive test result of the SSD, an additional smear test at the GP is necessary.ConclusionSeveral preferences and experiences play a role in the choice whether or not to use the SSD. Based on the currently found preferences and experiences, an app will be developed in order to assess which of these are the most important for women participating in the Dutch population-based cervical screening programme.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40271-021-00550-y.

European trends in cervical cancer mortality in relation to national screening programs, 1985–2014

BackgroundCervical cancer is the fourth leading oncological cause of death in women. Variable trends in cervical cancer mortality have been observed across Europe, despite the widespread adoption of screening programs. This variability has previously been attributed to heterogeneity in the quality of screening programs. MethodsAge-standardized cervical cancer death rates for European countries between 1985 and 2014 were analyzed using Joinpoint regression. Countries were dichotomized based on year of implementation and population invitational coverage of national population-based cervical cancer screening programs. National cervical cancer mortality trends during the study period were compared based on this classification. ResultsDecreasing trends in mortality were observed in all European countries with the specific exceptions of Bulgaria, Greece and Latvia. The highest rates of cervical cancer mortality throughout the study period were in Romania (16.0-14.9/100,000) and the lowest rates in Italy (1.4-1.2/100,000). The greatest percentage decline in mortality was observed in the United Kingdom and the greatest absolute reduction in mortality was seen in Hungary. European countries which implemented a national population-based cervical cancer screening program prior to 2009 demonstrated greater improvements in cervical cancer mortality outcomes compared to those that did not (p = 0.016). ConclusionCervical cancer mortality is improving in most European countries; however, substantial variation remains. Trends in mortality were associated with the time of implementation of national population-based cervical screening programs.

Cervical screening for HIV-positive women in the transition to primary HPV testing in Ireland

Abstract Background CervicalCheck, Ireland's national cervical cancer screening programme, will transition to primary HPV testing in March 2020. CervicalCheck sought an evidence review to inform the screening pathway for HIV-positive women in this context, with regard to age of initiation and frequency of screening. Currently, HIV-positive women commence cervical screening at age 20 in Ireland with annual screening thereafter. Methods An electronic literature search was conducted to identify relevant peer-reviewed publications using the database Pubmed. A hand search of reference lists of suitable articles and international cervical screening guidelines was conducted to check for additional material. Publications pertaining to international cervical screening guidance and practice were sourced via internet searches using Google. The relevant grey literature was also explored. Results The prevalence of multiple and more persistent high-risk HPV types is higher among HIV-positive women compared to HIV-negative women. HIV-positive women are also at an increased risk of progression and post-treatment recurrence of HPV-associated cervical lesions. The degree of immunosuppression is a key factor in the relationship between HPV and HIV. There is significant heterogeneity internationally as regards cervical screening pathways for HIV-positive women. Many programmes commence screening at the time of diagnosis with HIV. Most developed countries screen HIV-positive women more frequently than HIV-negative women, although the screening interval varies. Conclusions HIV-positive women warrant special attention within an organised population-based cervical screening programme. The evidence synthesised in this review was used to inform change to the screening pathway for HIV-positive women as part of the planned transition to primary HPV testing. Cervical screening for these women using primary HPV testing will now commence at the time of diagnosis with HIV, with annual screening thereafter. Key messages HIV-positive women warrant special attention within an organised population-based cervical screening programme. The evidence synthesised in this review was used to inform change to the screening pathway for HIV-positive women as part of the planned transition to primary HPV testing in Ireland.

HPV testing for cervical cancer screening: technical improvement of laboratory logistics and good clinical performance of the cobas 6800 in comparison to the 4800 system

BackgroundEuropean guidelines for cervical cancer screening now recommend the use of clinically validated assays for high-risk HPV-DNA sequences as primary test in women older than 30 years, performed in centralized laboratories, and run on systems providing automated solutions for all steps.MethodsWe conducted a comparison study, according to the international guidelines, nested within the organized population-based cervical screening program, between the cobas 4800 and 6800 systems (Roche Diagnostics), to evaluate accuracy and reproducibility of HPV test results and laboratory workflow. In Italy implementation of HPV cervical screening is under way on a regional basis; in Veneto it started in June 2015, following a piloting phase; the assay in use in the three centralized laboratories is the cobas 4800 HPV test, run on the cobas 4800 system. Comparison of HPV results with a new version of the assay (cobas 6800/8800 HPV) run on the cobas 6800 system, and intra- and inter-reproducibility analyses have been conducted in samples collected in PreservCyt medium (Hologic) from women without and with a subsequent diagnosis of high-grade lesion.ResultsSamples from women older than 30 years attending organized cervical cancer screening were used. Clinical sensitivity and specificity were evaluated on 60 cases and 925 controls, respectively; intra-laboratory reproducibility and inter-laboratory agreement by the 6800 system were evaluated on 593 and 460 specimens, respectively. Our results showed a very high agreement (> 98%) for overall qualitative results between the two systems; clinical sensitivity and specificity of the HPV assay run on 6800 were non-inferior to those of the HPV assay run on 4800 (p = 0,0157 and p = 0,0056, respectively, at the recommended thresholds of 90 and 98%); kappa values of 0.967 and 0.969 were obtained for intra- and inter-laboratory reproducibility analyses in the 6800 system. The 6800 platform displayed several technological improvements over the 4800 system, with higher throughput and laboratory productivity, and lower operator’s hands-on time.ConclusionsThe new cobas 6800/8800 HPV assay run on the 6800 instrument is suitable for use in large centralized laboratories included within population-based cervical cancer screening programs.

Genotyping for Human Papillomavirus (HPV) 16/18/52/58 Has a Higher Performance than HPV16/18 Genotyping in Triaging Women with Positive High-risk HPV Test in Northern Thailand.

BackgroundTesting for high-risk human papillomavirus DNA (HPV test) has gained increasing acceptance as an alternative method to cytology in cervical cancer screening. Compared to cytology, HPV test has a higher sensitivity for the detection of histologic high-grade squamous intraepithelial lesion or worse (HSIL+), but this could lead to a large colposcopy burden. Genotyping for HPV16/18 has been recommended in triaging HPV-positive women. This study was aimed to evaluate the screening performance of HPV testing and the role of genotyping triage in Northern Thailand.MethodsA population-based cervical screening program was performed in Chiang Mai (Northern Thailand) using cytology (conventional Pap test) and HPV test (Hybrid Capture 2). Women who had abnormal cytology or were HPV-positive were referred for colposcopy. Cervical samples from these women were genotyped using the Linear Array assay.ResultsOf 5,456 women, 2.0% had abnormal Pap test results and 6.5% tested positive with Hybrid Capture 2. Of 5,433 women eligible for analysis, 355 with any positive test had histologic confirmation and 57 of these had histologic HSIL+. The sensitivity for histologic HSIL+ detection was 64.9% for Pap test and 100% for Hybrid Capture 2, but the ratio of colposcopy per detection of each HSIL+ was more than two-fold higher with Hybrid Capture 2 than Pap test (5.9 versus 2.8). Genotyping results were available in 316 samples. HPV52, HPV16, and HPV58 were the three most common genotypes among women with histologic HSIL+. Performance of genotyping triage using HPV16/18/52/58 was superior to that of HPV16/18, with a higher sensitivity (85.7% versus 28.6%) and negative predictive value (94.2% versus 83.9%).ConclusionsIn Northern Thailand, HPV testing with genotyping triage shows better screening performance than cervical cytology alone. In this region, the addition of genotyping for HPV52/58 to HPV16/18 is deemed necessary in triaging women with positive HPV test.

The Clinical Role of HPV Testing in Primary and Secondary Cervical Cancer Screening

Traditional population-based cervical screening programs, based on cytology, have successfully reduced the burden of cervical cancer. Nevertheless limitations remain and new screening methods are emerging. Despite vaccination against the 2 most oncogenic types (HPV 16/18), cervical cancer screening will have to continue as an essential public health strategy. As the acquisition of an HR-HPV infection is critical in the progression to (pre-)cancerous cervical lesions, recent research has focused on HR-HPV detection. The sensitivity of HPV testing in primary and secondary prevention outweighs that of cytology, at the cost of slightly lower specificity. Although most of the HR-HPV infections are cleared after conization, new evidence from numerous studies encourages the implementation of HR-HPV testing and genotyping to improve posttreatment surveillance. An HR-HPV test 6 months after conization is a promising useful clinical marker to detect persistence and prevent progression. This review highlights the clinical role of HPV testing in primary and secondary cervical cancer screening.

Impact of media reporting of cervical cancer in a UK celebrity on a population-based cervical screening programme

To determine the impact of media reporting of cervical cancer in a UK celebrity on cervical screening uptake, response time and colposcopy referral and attendance. Population-based national cervical screening programme for women in Wales, UK. A time series regression analysis of the Welsh national cervical screening and colposcopy databases was used to examine the number of smear tests carried out between 2000 and 2010, stratified by age group and deprivation indicators. Logistic regression was used to analyse colposcopy attendance. Over 33,000 more cervical screening tests than expected were carried out in the year of media reporting (2008/9), 11,539 (35%) of which were in the month of Jade Goody's death. The largest increase was evident in women aged 35-39 years (475 additional tests per month, 95% CI 331-619). Impacts were similar across deprivation quintiles. Colposcopy referrals increased by 18% during the year of media reporting. Increases were observed for all smear test results in 2008/9, particularly among younger women, and further rises were evident in 2009/10 for smear tests showing borderline changes and mild dyskaryosis. The proportion of women attending colposcopy appointments rose in the year of media reporting (χ(2) = 45.8, P < 0.001). Mass media reporting of cervical cancer in a UK celebrity was associated with a significant, but transient, increase in screening uptake and colposcopy referral and attendance. Mass media reporting can play a role in enhanced detection of abnormalities, but public health messages must be communicated effectively to minimize anxiety whilst maximizing case-finding and uptake among non-responders.

Risk Factors for Cervical Abnormalities Among Hong Kong Chinese Women: A Large-Scale Community-Based Cervical Screening Program

We sought to identify the prevalence of and risk factors associated with cervical abnormalities among Chinese women in Hong Kong. A community-based cervical screening program was offered free of charge in Hong Kong. Information on the demographics, sexual experience, and obstetrical history of women who attended the Cervical Screening Clinic were collected and tabulated with their Pap smear results to establish the risk factors associated with cervical abnormalities among Hong Kong Chinese women. A total of 44,219 women attended the Cervical Screening Clinic for their first Pap smear tests over an 8-year period, with the prevalence of cervical abnormality at 4.51%. Adjusted for all associating factors, the significant risk factors of cervical abnormalities identified among Hong Kong Chinese women are being aged 40-49 (odds ratio [OR] 1.53), being single (OR 1.52) or cohabiting (OR 1.52), having received primary school education only (OR 1.53), having had three or more sexual partners (OR 1.52), onset of sexual activity at age ≤18 (OR 1.53), having reported bleeding after intercourse (OR 1.44), and having had more than three pregnancies (OR 1.47). Condom use was identified as the single most significant protective factor reducing the risk of cervical abnormalities among these women (OR 0.76). This first population study in Hong Kong provides a better understanding of the risk factors associated with cervical abnormalities among Hong Kong Chinese women. A primary preventive strategy to reduce cervical cancer incidence should focus on modifying these preventable risk factors, complemented by population-based cervical screening programs to increase the coverage rate to 80% in the long term, together with human papillomavirus (HPV) vaccination.

PVIII-1 Detection of EBV DNA in patients with hodgkin lymphoma in the Czech Republic: frequency, quantity in plasma, whole blood and lymph node

Objective: The purpose of this study was to determine the long-term tendency for cervical human papillomavirus infections to persist in the general population. Study Design: From 500 women who participated in a 1991 population-based survey, 90 healthy women with normal results of cytologic examination (women with human papillomavirus deoxyribonucleic acid detected and age-matched control women without human papillomavirus deoxyribonucleic acid detected) were interviewed and examined 5 years later colposcopically, cytologically, and with human papillomavirus serologic testing and human papillomavirus deoxyribonucleic acid testing by polymerase chain reaction with 2 different consensus primer pairs (MY09 and MY11 and GP5+ and GP6+), type-specific polymerase chain reaction, and deoxyribonucleic acid sequencing. Results: The 5-year human papillomavirus clearance rate was 92%. Only human papillomavirus type 16 infections persisted. Colposcopic impression of grade 2 cervical intraepithelial neoplasia was associated with persistent human papillomavirus 16 infection (P <.03). Human papillomavirus detection was associated with sexual history. Human papillomavirus type was the only determinant of human papillomavirus persistence. Conclusion: The high clearance rates in a population-based setting with a 5-year follow-up period imply that inclusion of human papillomavirus deoxyribonucleic acid testing in population-based cervical screening programs should target persistent infection. (Am J Obstet Gynecol 2000;183:561-7.)

Interlaboratory reproducibility of atypical glandular cells of undetermined significance: a national survey

The aim of this study was to evaluate the inter-laboratory reproducibility for atypical glandular cells (AGC) (The Bethesda System (TBS) 2001) of the laboratories involved in the screening programmes in Italy. A set of 35 selected slides were circulated among 167 laboratories involved in local population-based cervical screening programmes. Each laboratory provided one single diagnosis per smear. The smears were read blind to the original diagnosis and to the diagnoses provided by other laboratories. A 'majority' diagnosis was defined for each case and assumed as the reference standard. The diagnosis provided from each laboratory was compared with the majority diagnosis. According to the majority report the 35 slides in the set were classified as negative in nine cases, AGC in eight, adenocarcinoma in eight, and squamous lesion or squamous + glandular lesion in 10. The crude agreement between all pairs of laboratories was 49.43%. K-values were 0.46, 0.21, 0.34, 0.36 and 0.32 for negative, AGC/AIS (adenocarcinoma in situ of endocervix), AdenoCa, Sq/Sq + Gl and all reporting categories respectively. Concordance according to overall K was moderate to substantial in 77% of the participating laboratories. The present study shows that the AGC category is not easily reproducible. The data confirmed the importance, in a screening scenario, of AGC/AIS diagnoses, but also presented difficulties in differentiating between the two diagnoses. In addition to the results obtained from the circulation of the slides, laboratories which had annually a low number of cervical smears were able to gain experience focused on particular morphological pictures.

Cross-Sectional Comparison of an Automated Hybrid Capture 2 Assay and the Consensus GP5+/6+ PCR Method in a Population-Based Cervical Screening Program

In this cross-sectional study, clinical performances of the hybrid capture 2 assay using an automated instrument (i.e., rapid capture system) (hc2-RCS) and the high-risk human papillomavirus GP5+/6+ PCR-enzyme immunoassay (EIA) test were compared using cervical scrape specimens from 8,132 women that participated in a population-based screening trial. The hc2-RCS test scored significantly more samples positive (6.8%) than the GP5+/6+ PCR-EIA (4.8%) (P < 0.0005). This could be attributed largely to a higher positivity rate by the hc2-RCS test for women with cytologically normal, borderline, or mild dyskaryosis. A receiver operator characteristics analysis of the semiquantitative hc2-RCS results in relation to different cytology categories revealed that these differences are owing to differences in assay thresholds. For women classified as having moderate dyskaryosis or worse who also had underlying histologically confirmed cervical intraepithelial neoplasia grade 3 or cervical cancer (> or =CIN3), the hc2-RCS scored 97% (31/32) of samples positive, versus 91% (29/32) by GP5+/6+ PCR-EIA. However, this difference was not significant (P = 0.25). After increasing the hc2-RCS cutoff from 1.0 to 2.0 relative light units/cutoff value of the HPV16 calibrator (RLU/CO), no additional CIN3 lesions were missed by hc2-RCS, but the number of test-positive women with normal, borderline, or mild dyskaryosis was significantly decreased (P < 0.0005). However, at this RLU/CO, the difference in test positivity between hc2-RCS and the GP5+/6+ PCR-EIA was still significant (P = 0.02). The use of an RLU/CO value of 3.0 revealed no significant difference between hc2-RCS and GP5+/6+ PCR-EIA results, and equal numbers of smears classified as > or =CIN3 (i.e., 29/32) were detected by both methods. In summary, both assays perform very well for the detection of >or =CIN3 in a population-based cervical screening setting. However, adjustment of the hc2-RCS threshold to an RLU/CO value of 2.0 or 3.0 seems to produce an improved balance between the clinical sensitivity and specificity for > or =CIN3 in population-based cervical screening.

Human papillomavirus in cervical screening and vaccination

Recent decades have witnessed a reduction in the incidence of cervical cancer in countries where screening programmes have achieved broad coverage. The recognized importance of high-risk HPV (human papillomavirus) infection in the aetiology of cervical cancer may introduce a role for HPV DNA testing in cervical screening programmes. Positive HPV DNA tests indicate women at risk of cervical cancer with greater sensitivity, but reduced specificity, compared with exfoliative cytology. Combining HPV testing with cytology may be useful in the triage of minor cytological abnormalities into those requiring referral to colposcopy (HPV positive) compared with those who can be safely managed by cytological surveillance (HPV negative). With its high sensitivity and high-negative-predictive value, HPV testing may also be useful for predicting treatment failure, since residual disease is very unlikely in the event of a negative HPV test. Ultimately, prevention is better than cure, and the advent of HPV prophylactic vaccines may obviate the need for population-based cervical screening programmes in the future. A multivalent vaccine administered to adolescents prior to the onset of sexual activity and boosted at regular intervals throughout their sexually active life may provide protection against type-specific HPV infection, malignant precursors and invasive cervical disease. Several large randomized placebo-controlled trials have been conducted with promising results. For those generations of women already exposed to high-risk HPV infection, therapeutic vaccines may offer advantages over conventional treatment, although much work still needs to be done.

Prevalence of types 16 and 33 is increased in high‐risk human papillomavirus positive women with cervical intraepithelial neoplasia grade 2 or worse

High-risk human papillomavirus (hrHPV) types are causally related to cervical cancer and its high-grade precursor lesions. The risk posed by the different hrHPV types for the development of cervical intraepithelial neoplasia grade 2 or worse (> or =CIN2) needs to be established. Here, we present the hrHPV type-distribution in relation to cytology and histology for women participating in a cervical screening program. From 44,102 women who participated in a population-based cervical screening program in the Netherlands, 2,154 hrHPV GP5+/6+ PCR positive women were recruited to determine the distribution of 14 hrHPV types by reverse line blotting of GP5+/6+ PCR products. For each HPV type, associations with cytology and histologically confirmed > or =CIN2 were measured by odds ratios. HPV types 16 and 33 were more prevalent in women, amongst those containing a single hrHPV type, with moderate dyskaryosis or worse (>BMD) than in women with normal cytology, but only in case of underlying > or =CIN2 (OR 4.10, 95%CI 2.98-5.64 and OR 2.68, 95%CI 1.39-5.15, respectively). Similar results were obtained for women with double infections (OR 3.29, 95% CI 1.61-6.75 and OR 4.37, 95% CI 1.17-16.34). Coexisting types did not influence the prevalence of > or =CIN2 in HPV 16 or 33 positive women. The increased prevalence of type 16 and 33 in hrHPV positive women with > or =CIN2, compared to women with normal cytology, suggests that infection with these types confers an increased risk for development of > or =CIN2. Distinguishing these types may therefore have implications for future cervical screening strategies.

A population-based five-year follow-up study of cervical human papillomavirus infection

Objective: The purpose of this study was to determine the long-term tendency for cervical human papillomavirus infections to persist in the general population. Study Design: From 500 women who participated in a 1991 population-based survey, 90 healthy women with normal results of cytologic examination (women with human papillomavirus deoxyribonucleic acid detected and age-matched control women without human papillomavirus deoxyribonucleic acid detected) were interviewed and examined 5 years later colposcopically, cytologically, and with human papillomavirus serologic testing and human papillomavirus deoxyribonucleic acid testing by polymerase chain reaction with 2 different consensus primer pairs (MY09 and MY11 and GP5+ and GP6+), type-specific polymerase chain reaction, and deoxyribonucleic acid sequencing. Results: The 5-year human papillomavirus clearance rate was 92%. Only human papillomavirus type 16 infections persisted. Colposcopic impression of grade 2 cervical intraepithelial neoplasia was associated with persistent human papillomavirus 16 infection (P <.03). Human papillomavirus detection was associated with sexual history. Human papillomavirus type was the only determinant of human papillomavirus persistence. Conclusion: The high clearance rates in a population-based setting with a 5-year follow-up period imply that inclusion of human papillomavirus deoxyribonucleic acid testing in population-based cervical screening programs should target persistent infection. (Am J Obstet Gynecol 2000;183:561-7.)

Clinical Impact of Quality Assurance in an Organized Cervical Screening Program

To increase the efficiency of the population-based cervical screening program that has been in place in a small rural district of Sweden since 1971, the procedures for handling abnormal cytologic results were revised in 1991. This article compares the findings from the 5 years preceding institution of the new guidelines with those from the first 5-year period under the new procedures. A preliminary study had found that neglected low-grade positive smears, or unfulfilled requests for new smears, were seen 10 times more often in the clinical history of women with cancer than in healthy women. A history of an equivocal smear was seen in about 30 percent of both groups of women. In 1991, the referral protocols for colposcopy were revised to include women with positive cervical smears who had not been examined by colposcopy. The clinical history of each woman who had a cervical smear, with a focus on previous smears, cervical biopsies, and treatments, automatically accompanied each cytology report. Women with previously neglected low-grade positive smears were thus identified and referred for colposcopy. Women with invasive cervical cancer from 1987 to 1992 served as control subjects. The case histories of these women were compared with those of women with cancer diagnosed between 1992 and 1997. All records were reviewed for information about squamous or other epithelial histologic findings, previously treated cervical intraepithelial neoplasia, age at diagnosis, time since and age at last smear, neglected positive or equivocal smears, stage, and death within 18 months of diagnosis. There was a significant reduction, from 18 per 100,000 women screened to 11 per 100,000 women screened, in the incidence of invasive cancer with the introduction of monitoring of screening history (P = .014). The incidence of squamous cell cancer fell from 16.6 per 100,000 to 8.0 per 100,000 (P = .001). Because there were no neglected positive or equivocal smears in the second period, the number of women under age 50 diagnosed with squamous cell cancer decreased by more than one-third, from 38 in the first period to only 11 in the second period (P < .001). The decline among older women (more than 53 years of age) was less. In 1996, the screening age limit was increased from 50 to 59 years. Women who were presenting for their first-ever cervical smear or who had not had a cervical smear taken for at least 3 years had a significantly greater incidence of cancer in the first study period than in the second period (P = .037). Only 3 of the 33 cases of advanced or aggressive squamous cancers found in this study occurred in women who had ever been screened. In the first period, 18 of the 22 stage II to stage IV squamous cell cancers were in women who had no recent or previous smears. In the second period, all 11 women with squamous cell cancer were having a cervical smear for the first time ever. The incidence of adenocarcinoma did not change significantly in the two study periods. In this study of 123 women with cervical cancer, 20 adenocarcinomas were seen.

Costs and benefits of cervical screening. III. Cost/benefit analysis of a call of previously unscreened women.

A population-based cervical screening programme issued invitations to women with no record of a previous smear. This call was very good value, at 5780 Pounds per life saved or 159 Pounds per life-year saved at 1991 prices. The first priority for the cervical screening service should be comprehensive coverage.