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.     

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.     

Evaluation of the cervical cytology screening programme in an inner city health district.

District health authorities have been instructed to operate a cervical cytology call and recall screening programme using the age-sex registers held by family practitioner committees. A detailed evaluation of implementation in an inner London district showed that 477 out of 687 (69%) invitation letters sent to women by the family practitioner committee were either inaccurate or inappropriate: almost half of the recorded addresses were incorrect and a further fifth of the women were not eligible for a test. Overall, 90 women had a smear, which is only 13% of the total but 43% of those found to be eligible. The findings did not differ significantly with age. The findings have major implications not only for the effectiveness of call and recall for screening for cervical cancer but also for the future development of screening for breast cancer in such areas.     

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.     

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).     

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.     

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.     

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.     

Reasons for variation in coverage in the NHS cervical screening programme

In order to investigate reasons for variation in coverage of cervical screening, data from standard Department of Health returns were obtained for all Health Authorities for 1998/1999. Approximately 80% of the variation between health authorities is explained by differences in age distribution and area classification. Considerable differences between Health Authority and Office of National Statistics (ONS) population figures in City and Urban (London) areas for the age group 25-29 years and for City (London) for age group 30-34 years, suggest an effect of list inflation in these groups. Coverage as a performance indicator may be more accurately represented using the age range 35-64 years. Using this narrower age range, the percentage of health authorities meeting the 80% 5-year coverage target increases from 87% to 90%.     

Estimation of disease severity in the NHS cervical screening programme. Part I: artificial cut‐off points and semi‐quantitative solutions

R. G. Blanks
Estimation of disease severity in the NHS cervical screening programme. Part I: artificial cut‐off points and semi‐quantitative solutions Objective: Current cytology and histology classifications are based on ordered categories and have a strong emphasis on providing information that decides a woman's management rather than the best estimate of disease severity. This two‐part paper explores the use of a quantitative approach to both cytology and histology disease severity measurements. Methods: In Part I the problem of artificial cut‐off points is discussed and a simple semi‐quantitative solution to the problem is proposed. This closely relates to the revised British Society for Clinical Cytology (BSCC) terminology. The estimates of disease severity are designed as extensions of the existing methods, with an emphasis on probability rather than certainty, as a more natural way of approaching the problem. Borderline changes are treated as categorical variables, but koilocytosis, mild, moderate and severe dyskaryosis, and ?invasive as quasi‐continuous and the disease severity estimated as a grade number (GN) with any value between 0–4 and the margin of error as a calculated grade range (CGR). Results: As an example, if the reader is unsure between moderate dyskaryosis (HSIL favouring CIN2) and mild dyskaryosis (LSIL favouring CIN1) they can register this uncertainty as a probability, such as 60%/40% moderate/mild. With 2 and 1 as the mid‐points of the grade numbers for moderate and mild dyskaryosis the GN value is ((60 × 2) + (40 × 1))/100 = 1.6. The CGR is 1.5 ? 0.4 to 1.5 + 0.6 = 1.1 to 2.1. The GN (CGR) estimate of disease severity is therefore 1.6 (1.1–2.1). In a similar manner the disease severity from all slides showing koilocytosis or dyskaryosis can be estimated as a number between 0 and 4 with an associated error. Histology can be treated in a similar way. Conclusions: This semi‐quantitative approach provides a framework more suitable for research and audit of disease severity estimates. It avoids the paradox inherent in the current systems using artificial cut‐points to produce categories whereby increasing agreement can only be achieved by losing information.     

Test characteristics of various screening modalities for cervical cancer: a feasibility study to develop an alternative strategy for resource-limited settings

OBJECTIVE: To determine test characteristics - sensitivity, specificity, positive and negative predictive values - of different screening modalities to detect cervical precancerous and cancerous lesions in order to devise an effective alternative strategy for cervical cancer screening in resource-poor settings. METHODS: A total of 472 women presenting with nonspecific gynecologic symptoms were screened by cytology, visual inspection with acetic acid application (VIA), VIA with magnification (VIAM) and human papillomavirus (HPV)-DNA testing. Colposcopic examination was performed in all and on-site biopsy was taken if any grade I and above lesion was detected on colposcopy (230). On histopathological examination, 105 showed cervical intraepithelial neoplasia II and above lesions. Sensitivity, specificity and predictive values for each test were calculated taking colposcopy and or directed biopsy as the gold standard. Comparisons were made with cytology in order to assess the feasibility of alternative strategies in resource-poor settings. RESULTS: VIA was less sensitive (86.7% versus 91.4%) but more specific (90.7% versus 86.6%) than cytology at low grade squamous intraepithelial lesion (LSIL) threshold but the difference was not statistically significant (P > 0.01). HPV testing improved the sensitivity over cytology (97.1% versus 91.4%) but there was a nonsignificant loss of specificity (84.2% versus 86.6%). Results of VIAM were more or less similar to VIA. CONCLUSION: VIA can be used as a mass screening tool for cervical cancer in resource-poor settings.     

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.     

Comparison of conventional Papanicolaou smear and SurePath® liquid-based cytology in the Copenhagen population screening programme for cervical cancer

OBJECTIVE: To compare diagnostic performance of conventional Papanicolaou smear with SurePath liquid-based cytology in a population screening programme. METHODS: A retrospective comparison was performed on data from two 18-month periods of the screening programme for cervical cancer in the municipality of Copenhagen with conventional Papanicolaou technique (n = 82,116) and liquid-based cytology (n = 84,414). RESULTS: After the conversion to liquid-based cytology the percentage of unsatisfactory samples decreased from 2.3% to 0.3% (P < 0.001), whereas the number of normal cervical samples lacking an endocervical component increased from 8.5% to 8.9% (P < 0.005). The percentage of samples with atypical cells and cells suspicious for malignancy increased from 3% to 4.2% (P < 0.001) and from 1.9% to 2.4% (P < 0.001), respectively. The subsequent histological follow-up showed normal findings decreased from 70.5% to 68.9% and from 28.0% to 26.1%, respectively. However, in relation to the entire screening populations, there was an increase of normal findings from 2.12% to 2.89% after primary atypical diagnosis and from 0.53% to 0.62% after diagnosis of suspicious cells after conversion to the liquid-based technique. CONCLUSIONS: This study showed the number of unsatisfactory samples to be significantly reduced with the liquid-based technique. The data suggest that there is an increased detection rate of cervical precancerous lesions with liquid-based cytology, but the number of false positive tests is still high. The specificity of the two tests seems similar, but this cannot be ascertained exactly, because of the fact that follow-up of negative cases is unavailable.     

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.     

Using a graph of the abnormal predictive value versus the positive predictive value for the determination of outlier laboratories in the National Health Service cervical screening programme

R.G. Blanks Using a graph of the abnormal predictive value versus the positive predictive value for the determination of outlier laboratories in the National Health Service cervical screening programme. Objective: The positive predictive value (PPV) for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse of referral to colposcopy from moderate dyskaryosis or worse (equivalent to high‐grade squamous intraepithelial lesion or worse) is a standard performance measure in the National Health Service cervical screening programme. The current target is to examine ‘outlier’ laboratories with PPVs outside the 10th–90th percentile, which automatically identifies 20% of laboratories for further investigation. A more targeted method of identifying outliers may be more useful. Methods: A similar measure to the PPV, the abnormal predictive value (APV), can be defined as the predictive value for CIN2 or worse for referrals from borderline (includes atypical squamous and glandular cells) and mild dyskaryosis (equivalent to low‐grade squamous intraepithelial lesion) combined. A scatter plot of the APV versus the PPV can be produced (the APV‐PPV diagram). Three kinds of ‘outlier’ can be defined on the diagram to help determine laboratories with unusual data. These are termed a true outlier value (TOV) or an extreme value (EV) for either PPV or APV, or a residual extreme value (REV) from the APV‐PPV best line of fit. Results: Using annual return information for 2007/8 from 124 laboratories, two were defined as having EVs for PPV (both had a relatively low PPV of 62%). For APV, four laboratories were considered to have EVs of 34%, 34%, 34% and 4% and one was considered to be a TO with an APV of 45%. Five were identified as REV laboratories, although three of these were also identified as having extreme or outlier values, leaving two that had not been identified by the other methods. A total of eight (6%) laboratories were therefore identified as meriting further investigation using this methodology. Conclusions: The method proposed could be a useful alternative to the current method of identifying outliers. Slide exchange studies between the identified laboratories, particularly those at opposing ends of the diagram, or other further investigations of such laboratories, may be instructive in understanding why such variation occurs, and could therefore potentially, lead to improvements in the national programme.     

Predictors of non-participation in cervical screening in Denmark

PurposeThe aims of this study were to identify demographic and socio-economic predictors of non-participation in cervical screening in Denmark, and to evaluate the influence of health care use on screening participation.MethodsA population based register study was undertaken using data from the Central Population Register, the national Patobank, and Statistics Denmark. The study included women aged 25–54 years on 1st of January 2002, living in Denmark during the next 5 years, and without a history of total hysterectomy, N = 1,052,447. Independent variables included age, civil status, nationality, level of education, and use of health care. Associations with non-participation in screening were determined with logistic regression.ResultsMain predictors of non-participation were limited or no contact with dental services (odds ratio (OR) = 2.36), general practitioners (OR = 1.75), and high age (OR = 1.98). Other important factors for non-participation were primary school education only (OR = 1.53), not being married (OR = 1.49), and foreign nationality (OR = 1.32).ConclusionA 2–1.5-fold difference in non-participation in cervical screening in Denmark was found across various population sub-groups. Increased screening compliance among women with primary school education only, and limited or no use of primary health care services in general could potentially diminish the current social inequalities in cervical cancer incidence, and thus decrease the overall high incidence of this disease in Denmark.     

Primary HPV testing: a proposal for co‐testing in initial rounds of screening to optimise sensitivity of cervical cancer screening

As explained by Kitchener in a previous issue of Cytopathology (2015; 26 :4‐6), primary human papillomavirus (HPV) testing is likely to be introduced in the UK for all women aged 25–64 years following pilot site studies already in place. This will be necessary when the prevalence of cervical cancer and its precursors declines when vaccination takes effect but there is a risk in abandoning cytology as a primary test: a risk that would be most apparent in the present unvaccinated population in which the prevalence of cervical cancer and its precursors is exceptionally high. HPV testing is more sensitive than cytology but has a significant false‐negative rate that could be detrimental to a successful screening programme if introduced without cytology backup. Accurate cytology would be needed for triage and could be compromised if HPV‐negative tests were excluded from examination. This article proposes a compromise: cytology and HPV co‐testing for the first two screening tests to optimise the sensitivity of the test as a whole. Registrations of invasive and in situ carcinoma of the uterine cervix in England indicate that the prevalence of the disease is highest in young women in the early rounds of screening. Calculations of the likely impact on the workload of this proposal have been based on a service evaluation of 295 cytology tests received at St Thomas’ Hospital, which suggests that the volume of cytology tests would be reduced by approximately 60% compared with 80% for primary HPV testing alone. This proposal should be debated openly before irrevocable changes are made to a skilled workforce.