Review of negative and low‐grade cervical smears in women with invasive cervical cancer after the first 3 years of the national cervical screening programme in Slovenia

A. Repše‐Fokter, A. Pogačnik, V. Snoj, M. Primic‐Žakelj and M. S. Fležar
Review of negative and low‐grade cervical smears in women with invasive cervical cancer after the first 3 years of the national cervical screening programme in Slovenia Objective: The purpose of the study was to perform a national review of negative, low‐grade and inadequate smears reported during the latest screening period before cervical cancer diagnosis in 2006, after the first 3 years of the screening programme. Methods: Among 162 new cervical cancer cases there were 47 (29%) without previous cytology, 47 (29%) with one high‐grade smear prior to diagnosis and 68 (42.0%) with at least one previous negative, low‐grade, atypical or inadequate smear 1–40 months before diagnosis. Of the latter 68 cases, 37 patients with 59 smears (together with 118 control slides) were included in the review as 31 had smears reported at laboratories no longer operating. Findings were related to the last cytology report before diagnosis as well as to histological type and stage of the cancer. Results: In our study group, 19 (51%) of 37 patients had squamous cell carcinoma, 15 (41%) adenocarcinoma and 3 (8%) adenosquamous carcinoma, compared with 121 (75%), 26 (16%), 12 (7%), respectively, and 3 (2%) other types, for all carcinomas. Twenty‐one of 37 women also had high‐grade cytology prior to diagnosis of cancer. Women with previous cytology (with or without recent high‐grade smears) were more likely to have stage I cancers than those without cytology (P < 0.0001). The expert group upgraded 17/33 smears in the patients with squamous carcinomas, which was more than in those with adeno‐ and adenosquamous carcinomas (5/24, P < 0.05). Conclusion: As expected, a higher proportion of smears preceding adenocarcinomas were true negative. Under‐diagnosed smears were not related to cancer stage or last cytology report before diagnosis.     

How complete can cervical screening be? The outcome of a call screening programme for women aged 20–60 years in Perth and Kinross

In this paper a computer system for cervical screening call and recall based on the Community Health Index (CHI) population data-base is described. It allows the unscreened population to be identified and located on an individual general practice basis. The results of the call programme on 9517 women aged 20-60 years listed on the CHI and with no record of a cervical smear is described. There was a 24% smear uptake in the call programme which meant that after the call programme the total population cover had risen from 71% to 78%. In addition, if women with a valid reason are excluded, and the data-base corrected for women no longer in the area, the true cover rises to 88%. An analysis of the percentage cover in each GP practice is described with the implications for implementation of screening targets for primary care.     

Rates and outcomes of testing for lynch syndrome in a national colorectal cancer screening programme

BackgroundLynch Syndrome (LS), the most common cause of hereditary colorectal cancer (CRC), is characterised by pathogenic variants in mismatch repair (MMR) genes. Universal testing of all CRCs for LS can increase detection. Rates and outcomes of testing in Ireland’s national CRC screening programme have not been examined previously.MethodsCRCs diagnosed at two screening sites between 2015 and 2020 were identified. Patient records were used to determine if CRCs had been tested for MMR deficiency and if detected, what downstream testing to rule out LS or genetic testing to confirm LS was undertaken.ResultsOver five years, 206 CRCs were diagnosed. Testing for LS was carried out for 100% of CRCs at site A and 69% of CRCs at site B. Of CRCs tested for LS, 14 (8%) were MMR deficient. After downstream testing for BRAF mutation or hypermethylation of MLH1, three CRCs were identified as potentially LS-related. Of these two individuals declined genetic testing and one was lost to follow-up.ConclusionsBy 2020 both sites had implemented universal testing of all CRCs for LS. A small number of individuals were identified as being eligible for genetic testing for LS, however those offered declined testing and one individual was lost to follow up. This highlights the importance of universal testing and the need for referral pathways to ensure all appropriate individuals are referred onwards to genetic services.     

Cervical cancer screening in Mediterranean countries: implications for the future

K. Syrjänen, L. Di Bonito, L. Gonçalves, L. Murjal, M. Santamaria, V. Mahovlic, P. Karakitsos, B. Önal and F. C. Schmitt Cervical cancer screening in Mediterranean countries: implications for the future Prompted by feedback from the 34th European Congress of Cytology (ECC), the practice of including a special symposium in the programme was continued in the 35th ECC in Lisbon (2009) by arranging a satellite symposium entitled ‘Cervical Cancer Screening in the Mediterranean Countries’. Because of the importance to the future of this discipline, it was felt appropriate to summarize the highlights of this symposium here. Cervical cancer prevention strategies in the countries participating in the symposium (Portugal, Spain, Italy, Croatia, Greece and Turkey) appear to be highly variable. As yet, none of these countries can demonstrate a fully implemented national screening programme, but all are in different phases of designing and/or setting up such a programme, which is important. At present, the time‐honoured concept of cervical cancer prevention by Pap smear screening is under review, because prophylactic human papillomavirus (HPV) vaccines demonstrate a potential to prevent the vast majority (albeit not all) of cases of cervical cancer in the foreseeable future. Cervical cancer screening is still needed in this emerging era of HPV vaccination, but clearly the existing screening strategies must be modified to provide a cost‐effective combination of vaccination and screening. If the currently evaluated new screening strategies, such as HPV testing followed by cytology triage, become a reality, there is the likelihood that the Pap test will have only a secondary role, subordinate to HPV testing. Supporters of this scenario claim that Pap test performance will deteriorate in vaccinated populations. Reduced positive predictive value (PPV), due to lower disease prevalence, is inevitable, however, and this would also affect HPV tests. Any decline in sensitivity and specificity depends on human performance, and as such is avoidable by taking appropriate preventive measures. As clinical cytologists, we should focus attention on minimizing the risk to the Pap test of falling sensitivity because of unfamiliarity with abnormal cells, and also of reduced specificity if the fear of missing significant disease leads to overcalling of benign abnormalities.     

Rapid pre-screening of cervical smears as a method of internal quality control in a cervical screening programme

Objective:  To evaluate the performance of rapid pre-screening (RPS) as a method of internal quality control in the cytopathological examination of cervical smears for cervical cancer screening.
Methods:  The sample consisted of 6135 cervical smears submitted to RPS and routine screening (RS) methods. The smears classified as negative in RPS and RS were considered final diagnoses, and were not, therefore, submitted to any additional review. The smears identified as suspect or unsatisfactory according to RPS were analysed separately by two different cytologists irrespective of the diagnosis reached in RS. Smears considered abnormal or unsatisfactory at RS were also reviewed. When both cytologists issued concordant diagnoses, this was considered the final diagnosis. Discordant results were analysed by a third cytologist and a consensus meeting was held to define the final diagnosis.
Results:  Taking abnormalities detected by RS as the denominator, RPS had a sensitivity of 63.0% for the detection of all abnormal smears and 96.7% for high grade squamous intraepithelial lesion (HSIL). When compared with the final diagnosis, sensitivity of RPS for all abnormal smears was 74.9% and for HSIL 95.0%. Of the 529 abnormal smears confirmed in the final diagnosis, 2.15% were detected only by the RPS.
Conclusion:  RPS is an effective alternative method of internal quality control with high sensitivity for the detection of more severe lesions. It also permits monitoring of the laboratory rate of false-negative results, and allows constant evaluation of the performance both of the pre-screening and RS cytologists.     

A pilot study of cervical screening in an inner city area—lessons for a national programme

The objectives of this study were to examine aspects of organization of a proposed national screening programme based in general practice. The target population of women aged 25–59 years and their general practitioners (GPs), in a defined inner city area, was identified from a population register of persons eligible for free medical services; a computerized system was developed for invitations and record linkage of cytology results. Smears were examined in one laboratory and follow up of women with abnormal smears was undertaken by one gynaecologist. A random sample of non‐responders was surveyed by questionnaire. Response following two invitations was only 20%. Practices with male doctors only had significantly lower reponse rates ( P <0.001) than those with a female doctor/nurse. A survey of non‐responders showed that over 20% of addresses were incorrect and 16% of those interviewed were ineligible for smear tests. A preference for a female to undertake smears was expressed by 67%, and 77% believed that the purpose of the cervical smear was to detect cancer. An accurate population register, health promotion, support for GP practices, provision of alternative venues for smear tests, development of computer systems, accurate data entry and fail‐safe follow up are aspects of a cervical screening service which must be addressed prior to setting up a national service.     

Costs and benefits of cervical screening. I. The costs of the cervical screening programme

In 1991, the average total Health Service cost of a cervical smear, including follow up at the colposcopy clinic, was almost £22.70 in the Perth and Kinross district of Scotland. The average cost per colposcopy clinic visit was £30. The main cost elements were in general practice (55% of total) and the laboratory (33%), and most of the cost was for staff time.     

The use of screening episodes linked to CIN3 and invasive cancer registrations to study outcomes from the NHS Cervical Screening Programme

Objective: To examine how NHS cervical screening data can be collected and analysed in order to evaluate women’s screening histories as episodes rather than as individual smears. Design: Analysis of routine cervical screening data grouped into screening episodes for a cohort of women regarding episodes starting in a given year. Setting: NHS Cervical Screening Programme. Population: Data from four Health Authorities (now eight Primary Care Trusts) from the NHS Cervical Screening Programme with primary smears (first in an episode) taken between 1 April 1999 and 31 March 2000. Methods: Cytology information obtained from the call/recall (‘Exeter’) computer system was linked to cervical intraepithelial neoplasia (CIN) 3 and invasive cancer outcome information obtained from cancer registries. Screening histories were divided into episodes, each starting with a primary smear that was followed up to episode closure or, for episodes still open followed for an average 4.25 years, from the primary smear. The episode was divided into two parts (up to referral to colposcopy and following the referral). The outcomes of the episodes are described including referral rate to colposcopy and CIN3 and invasive cancer rates by factors such as age. Main outcome measures: Episode histories and rates of referral to colposcopy, CIN3 and invasive cancer. Results: There were 176 923 episodes from 176 319 women (1.003 episodes per woman) followed up to March 2004, the date at which the first phase of information accrual ceased. Of these episodes, 172 100 (97.3%) were closed either by a negative smear referring the woman back to routine recall or by default (defined as no smear recorded within 21 months following a smear requiring an action of repeat or refer to colposcopy). The remaining 4823 (2.7%) of episodes were still open, of which in 3121 (1.8%) the woman had been referred to colposcopy and in 1702 (1.0%) no referral decision had been made. Referral rates to colposcopy varied by age from 5.7% in women aged 20–24 years down to 0.9% in women aged 60–64 years. The overall efficiency of screening was highest for woman aged about 30 years, with a CIN3 detection rate of eight per 1000 women and a positive predictive value (for CIN3 or worse) of referral to colposcopy of 21%. Conclusion: The study has shown that routinely collected NHS cervical screening data can be combined to give information on complete episodes, allowing important performance measures to be studied. We suggest that in future information in the NHS screening system should be structured to facilitate such analysis and to allow cytology and histology information to be readily linked.     

Cervical cancer: cytological cervical screening in Iceland and implications of HPV vaccines

K. Sigurdsson
Cervical cancer: cytological cervical screening in Iceland and implications of HPV vaccines This paper reviews the Icelandic experience regarding the age‐specific effectiveness, optimal targeted age range and intervals in cervical cancer screening and the screening implications of the HPV16/18 vaccines. The background material is based on data from a screening programme with centralized records dating back to 1964, as well as from population‐based studies on the distribution of oncogenic HPV types in cancer and histologically verified CIN2‐3 lesions and from the Icelandic arm of the Future II trial with Gardasil^®. The findings confirm significant increased rates in the screened population of CIN2‐3, stage IA (microinvasive) cancer since 1979, mainly in the age group 20–34 years. These lesions start to accumulate within 3 years of a normal smear. Studies on the distribution of HPV types indicate that the marketed vaccines could lower the incidence of cancer and CIN2‐3 by about 67% and 53%, respectively, after taking into account reported cross‐protection. About 65% of women below 25 years of age had lesions related to the non‐vaccine types and after the last normal smear these cases accumulated at the same frequency as cases with vaccine‐included types. Cases with combined vaccine and non‐vaccine types accumulated at a slower rate. We conclude that screening should continue to start at age 20 years, with invitations at 2‐year intervals up to age 39 years and thereafter at 4‐year intervals up to age 65–69 years. Current data support the conclusion that the optimal age for catch‐up HPV vaccination should be considered in the context of sexual practices and the data do not support changes in the lower age limit or screening intervals for the vaccinated women.     

Costs and benefits of cervical screening IV: valuation by women of the cervical screening programme

OBJECTIVES: To assess the value of the cervical smear test to women, taking account of the positive and negative aspects of the cervical screening service. DESIGN: A postal survey. SETTING: Tayside Health Board region of Scotland. PARTICIPANTS: A sample of 2000 women aged 20-59. MAIN OUTCOME MEASURES: Maximum willingness to pay (WTP) for a cervical smear test. RESULTS: Women were prepared to pay 50.20 British pounds per smear on a 3-yearly basis. Willingness to pay was positively related to income, but unrelated to age and whether or not the respondent had previously had a smear. CONCLUSIONS: Previous studies have estimated the cost per screen or cost per life year saved by cervical screening. This study used the economic instrument of WTP to take account of other potential (dis)benefits to women. The value women place on having a smear was more than the cost to the National Health Service (NHS) of providing the service. The output of a WTP study is potentially useful at the policy level. Future work should explore both the value of alternative approaches to cervical screening, and the value of competing health care interventions.     

A study of the effect of introducing a restrictive cervical screening policy on laboratory workload and cervical cancer detection rates

This study examines the effect of a change in screening policy on the detection rate of severe dyskaryosis. During 1987 a total of 423 cases of severe dyskaryosis were identified by the Avon Screening Programme. Eleven per cent of these abnormal smears were repeat smears taken without clinical indication within the recommended 5 year recall period (interval smears). In a comparable control group of negative smears 31% were interval smears. Twenty-five per cent of the dyskaryotic interval smears (3% of the total severely dyskaryotic smears) were taken within 3 years of the previous negative smear, compared with 50% of the control group. By discouraging opportunistic smears within 5 years of the previous smear, the laboratory workload could be reduced by 30%, or within 3 years of the previous smear by 15%. There is, however, a risk of 11% and 3% respectively of missing a significant lesion (severe dyskaryosis).     

Effectiveness of population-based colorectal cancer screening programme in down-staging

BackgroundThis is the first evaluation study to assess the demographic characteristics of the colorectal cancer (CRC) cases detected in the prevalent round of the population-based Colorectal Cancer Screening Programme (CRCSP) in Hong Kong and to explore the effectiveness of the programme on the stage distribution of CRC.MethodsThis study covered the period between 28 September 2016 and 31 December 2018. Information on CRC diagnosis, age and stage at diagnosis were retrieved and reviewed by the Hong Kong Cancer Registry (HKCaR). The CRC detection rate among CRCSP-screened participants and incidence rate among the Hong Kong general population were calculated respectively. The odds ratio (OR) was calculated to measure the strength of association and quantify the effect of CRCSP on stage shift between CRCSP-detected CRC cases and an age-matched cohort of CRC cases diagnosed outside the programme.ResultsThe CRC detection rate among participants of the CRCSP during the study period was 736.0/100,000, whereas the overall CRC incidence rate among general population of similar age groups was 393.7/100,000. For all ages and both sexes, the OR of stage I CRCSP-detected CRC compared to the CRC from the age-matched cohort was 3.91 (95%CI=3.41–4.48) and the OR dropped to 0.54 (95%CI=0.41–0.70) at stage IV. Meanwhile, the overall OR of CRCSP-detected CRC compared to CRC from the age-matched cohort dropped from 2.24 (95%CI=1.97–2.56) to 1.62 (95%CI=1.40–1.87) with increasing age.ConclusionThe present study has demonstrated the initial impact of the CRCSP on shifting the stage at diagnosis towards earlier stage. The benefit of stage-shift was similar for all ages from 60 to 77 in both sexes and seems to increase with younger age. Given the stage-dependent survival outcomes, this stage-shift could lead to a reduction in CRC-associated mortality in Hong Kong in future.     

The ideal strategy for cervical cancer screening in Japan: Result from the Fukui Cervical Cancer Screening Study

Introduction

The aims of the Fukui Cervical Cancer Screening (FCCS) study are to determine the frequency of women with high‐risk HPV (hrHPV), whether HPV16 or HPV18 (HPV16/18), in the Japanese cancer screening population for the first time and to identify the best strategy for cervical cancer screening in Japan.

Methods

This study enrolled 7584 women aged ≥25 years who were undergoing routine screening. All women underwent LBC and cobas HPV tests. Women with abnormal cytology, whether hrHPV positive or negative; women with hrHPV positivity with either normal or abnormal cytology; and women randomly selected from women with normal cytology and negative hrHPV negative were referred for colposcopy.

Results

The prevalences of hrHPV positivity and HPV16/18 positivity were 6.8% and 1.7%, respectively. The baseline data from the FCCS study showed that the combination of HPV tests and cytology was more sensitive than cytology with respect to the detection of intraepithelial neoplasia grade 2 or worse. However, the specificity (94.1%) of the co‐testing strategy that required all women with abnormal cytology or hrHPV positivity to be referred for colposcopy was much lower than that (97.8%) of cytology. The sensitivity and specificity of the co‐testing strategy that required only women with abnormal cytology or HPV16/18 positivity to undergo colposcopy were 85.5% and 97.0%, respectively.

Conclusion

The baseline data from the FCCS study suggest that a cervical cancer screening strategy in which only women with abnormal cytology or HPV16/18 positivity undergo colposcopy offers a more balanced sensitivity and specificity than other strategies.     

Implementation of liquid-based cytology in the screening programme against cervical cancer in the County of Funen, Denmark, and status for the first year

As one of the first laboratories in Denmark (and Scandinavia), we have gradually implemented liquid-based cytology into the screening programme against cervical cancer in the County of Funen since 1 June 2001. This paper describes the course of the implementation period in the different steps in the screening programme, and the preliminary results obtained after the first year. We conclude that the new technique has improved the specimen and diagnostic quality. As a result of the reduction of the screening time, the workload in the laboratory is in balance although we have introduced a rapid review as a quality control. Besides, the reduction in the number of repeated cytological tests and follow-up visits at the gynaecologist means a saving for the screening programme as a whole. From our point of view the implementation of ThinPrep method is economically neutral.     

Ethnic factors in the pathology of the uterine cervix cervical screening: a population at variance with national targets

In recent years, it has been noted that the rate of detection of high-grade uterine cervical abnormalities by screening in the Newham and Tower Hamlets districts have been much lower than the national average. Whilst the national average for the detection rate of moderate and severe dyskaryosis has been around 1.6%, the detection rate in Newham and Tower Hamlets has consistently been substantially lower, at 0.6-1.0%. This discrepancy may be explained on demographic grounds. The ethnic make up of the two districts differs from the national average. Newham has a mixed ethnic structure: Moslem (11%). Asian non-Moslem (12%) and other groups (77%). The population of Tower Hamlets is made up of Moslem (23%), Asian non-Moslem ( 11%) and other groups (66%). In both districts, the rate of detection of moderate and severe dyskaryosis in these population subgroups between 1997 and 1999 was 0.57% for Moslem women, 0.52% for Asian non-Moslem women and 1.18% for other women. This study attempts to confirm the effects of social factors in the differences in rates of detection of cervical intraepithelial neoplasia (CIN) in Newham and Tower Hamlets.     

Large performance variation does not affect outcome in the Finnish cervical cancer screening programme

S. Lönnberg, P. Nieminen, L. Kotaniemi‐Talonen, H. Kujari, J. Melkko, G. Granroth, M. Vornanen, T. Pietiläinen, J. Arola, J. Tarkkanen, T. Luostarinen and A. Anttila Large performance variation does not affect outcome in the Finnish cervical cancer screening programme Objective: Cytology screening for prevention of cervical cancer can reduce incidence and mortality by more than 80% in settings with good organization and rigorous quality control. Audit studies are essential for reaching and maintaining a high quality of screening. The aim of this study was to evaluate variation in performance indicators by screening laboratory and assess the impact on the effectiveness of screening as indicated by cervical intraepithelial neoplasia grade 3 and above (CIN3+) rates after a negative screen. Methods: Seven cytology screening laboratories operating during 1990–1999 with a total of 953 610 screening tests performed were included in the study. By linking screening and cancer register files, all cases of CIN3+ diagnosed in the screened population were identified. For 395 CIN3+ cases with a preceding negative screen and 787 controls, a re‐evaluation of smears was undertaken to uncover false negative screening tests. Performance parameters and rates of CIN3+ after a negative screen were analysed for interlaboratory heterogeneity. Results: The rates of follow‐up recommendations and referrals varied by up to 3.6‐ (2.8–10.2%) and 4.0‐fold (0.03–0.12%), respectively. CIN1, CIN2 and CIN3+ screen detection rates differed by up to 8.5‐ (0.02–0.17%), 5.4‐ (0.05–0.25%) and 3.3‐fold (0.05–0.18%). False negative rates determined by re‐evaluation showed up to 2.1‐fold differences (29–62%). Rates of CIN3+ after a negative screen (0.023–0.048%) and as a proportion of total CIN3+ (15–31%) in the screened population were low and did not vary significantly. Conclusions: There were large variations in the sensitivity–specificity trade‐off between laboratories, reflected in all performance indicators as well as in the test validity estimates of the re‐evaluation phase, but not in screening effectiveness. Even though performance variations do not always have an impact on the effectiveness of screening, they lead to variations in cost, treatment and psychological burden, and should be addressed.     

Trends in incidence of,and mortality from,cervical lesions in Ireland: Baseline data for future evaluation of the national cervical screening programme

AimTo investigate incidence and mortality trends for cervical lesions in Ireland in the period 1994–2008.MethodsWe used data from the National Cancer Registry, Ireland and national death registration data to calculate age-standardised rates for the periods of interest. We used standardised rate ratios to test whether incidence was associated with socio-demographic variables and used Joinpoint to examine trends by morphology grouping.ResultsIncidence of cervical cancer and cervical intraepithelial neoplasia (CIN3) rose over the period 1994–2008. The annual percentage change for cervical cancer was 1.8% and that for CIN3 was 3.8%. Women resident in the most deprived areas had invasive cervical cancer incidence almost twice as high as those resident in the least deprived areas (standardised rate ratio (SRR) = 1.8). Comparing incidence in Ireland to England and Wales, Northern Ireland and Scotland in the three years 2005–2007, the SRRs (other areas vs. Ireland) were 0.70, 0.88 and 0.84 respectively. Cervical cancer rates have fallen in these countries in the same period that there is a rise demonstrated in Ireland.ConclusionIncidence rates of cervical cancer rose in Ireland steadily, albeit modestly, during 1994–2008, most likely due to long-term changes in patterns of sexual behaviour and contraceptive use. A more pronounced rise in CIN3 rates point to considerable levels of opportunistic screening during this period. Mortality rates have changed little over the past four decades, in contrast to trends in countries with well-organised screening programmes.