The impact of loss to follow-up in the Dutch organised HPV-based cervical cancer screening programme.

Loss to follow-up (LTFU) within cervical screening programmes can result in missed clinically relevant lesions, potentially reducing programme effectiveness. To examine the health impact of losing women during the screening process, we determined the proportion of women LTFU per step of the Dutch hrHPV-based screening programme. We then determined the probability of being LTFU by age, screening history and sampling method (self- or clinician-sampled) using logistic regression analysis. Finally, we estimated the number of missed CIN2+/3+ lesions per LTFU moment by using the CIN-risk in women compliant with follow-up. Data from the Dutch nationwide pathology databank (Palga) was used. Women eligible for screening in 2017 and 2018 were included (N = 840,428). For clinician collected (CC) samples, the highest proportion LTFU was found following 'referral advice for colposcopy' (5.5% after indirect referral; 3.8% after direct referral). For self-sampling, the highest proportions LTFU were found following the advice for repeat cytology (13.6%) and after referral advice for colposcopy (8.2% after indirect referral; 4.3% after direct referral). Self-sampling users and women with no screening history had a higher LTFU-risk (OR: 3.87, CI: 3.55-4.23; OR: 1.39, CI: 1.20-1.61) compared to women that used CC sampling and women that have been screened before, respectively. Of all women LTFU in 2017/18, the total number of potentially missed CIN2+ was 844 (21% of women LTFU). Most lesions were missed after 'direct referral for colposcopy' (N = 462, 11.5% of women LTFU). So, this indicates a gap between the screening programme and clinical care which requires further attention, by improving monitoring of patients after referral.

Resilience of the Dutch HPV-based cervical screening programme during the COVID-19 pandemic.

OBJECTIVES: Organisation of a screening programme influences programme resilience to a disruption as COVID-19. Due to COVID-19, the Dutch human papillomavirus-based cervical screening programme was temporarily suspended. Afterwards, multiple measures have been taken to catch-up participation. This study aimed to investigate programme resilience by examining the effect of COVID-19 and programme measures taken on participation in cervical screening. STUDY DESIGN: Observational cohort study. METHODS: Data from the national screening registry and Dutch nationwide pathology databank (Palga) were used on invitations and follow-up in 2018/2019 (pre-COVID) and 2020 (COVID). Sending invitations, reminders and self-sampling kits were suspended from March to July 2020. Main outcome measures include distribution of participant characteristics (age, region and screening history), participation rates by age and region, time between invitation and participation (i.e. response time) and self-sampling use per month. RESULTS: Participation rate was significantly lower in 2020 (49.8%) compared to 2018/19 (56.8%, P < 0.001), in all ages and regions. Compared to 2018/19, participation rates decreased most in women invited from January to March 2020 (-6.7%, -9.1% and -10.4%, respectively). From August, participation rates started to recover (difference between -0.8% and -2.7%). Median response time was longer in February and March (2020: 143 and 173 days; 2018/19: 53 and 55 days) and comparable from July onwards (median difference 0-6 days). Self-sampling use was higher in 2020 (16.3%) compared to 2018/19 (7.6%). CONCLUSIONS: The pandemic impacted participation rates in the Dutch cervical screening programme, especially of women invited before the programme pause. Implementation of self-sampling in national cervical screening programmes could increase participation rates and could serve as an alternative screening method in times of exceptional health care circumstances, such as a pandemic. Due to the well-organised programme and measures taken to catch-up participation, the impact of COVID-19 on the screening programme remained small.

Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease.

BACKGROUND: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). AIM: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+ METHODS: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. RESULTS: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08-1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77-4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33-2.27) were also risk factors for CIN2+ detection. CONCLUSION: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.

Increased Risk of High-grade Cervical Neoplasia in Women with Inflammatory Bowel Disease: A Case-controlled Cohort Study.

BACKGROUND AND AIMS: Women with inflammatory bowel disease [IBD] may be at higher risk for cervical intraepithelial neoplasia [CIN]. However, data are conflicting. The aim of this study was to assess the risk of high-grade dysplasia and cancer [CIN2+] in IBD women and identify risk factors. METHODS: Clinical data from adult IBD women in a multicentre Dutch IBD prospective cohort [PSI] from 2007 onwards were linked to cervical cytology and histology records from the Dutch nationwide cytology and pathology database [PALGA], from 2000 to 2016. Patients were frequency-matched 1:4 to a general population cohort. Standardised detection rates [SDR] were calculated for CIN2+. Longitudinal data were assessed to calculate CIN2+ risk during follow-up using incidence rate ratios [IRR] and risk factors were identified in multivariable analysis. RESULTS: Cervical records were available from 2098 IBD women [77%] and 8379 in the matched cohort; median follow-up was 13 years. CIN2+ detection rate was higher in the IBD cohort than in the matched cohort (SDR 1.27, 95% confidence interval [CI] 1.05-1.52). Women with IBD had an increased risk of CIN2+ [IRR 1.66, 95% CI 1.21-2.25] and persistent or recurrent CIN during follow-up (odds ratio [OR] 1.89, 95% CI 1.06-3.38). Risk factors for CIN2+ in IBD women were smoking and disease location (ileocolonic [L3] or upper gastrointestinal [GI] [L4]). CIN2+ risk was not associated with exposure to immunosuppressants. CONCLUSIONS: Women with IBD are at increased risk for CIN2+ lesions. These results underline the importance of human papillomavirus [HPV] vaccination and adherence to cervical cancer screening guidelines in IBD women, regardless of exposure to immunosuppressants.

FAM19A4/miR124-2 methylation analysis as a triage test for HPV-positive women: cross-sectional and longitudinal data from a Dutch screening cohort.

OBJECTIVES: The aim was to evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening. METHODS: We conducted a post hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30-60 years (n = 979). Cross-sectional cervical intraepithelial neoplasia (CIN) 3+ sensitivity, specificity, positive predictive value and negative predictive value as well as cumulative CIN3+ or cervical cancer risks after 9 and 14 years were compared for three baseline triage strategies: (1) cytology, (2) FAM19A4/miR124-2 methylation analysis and (3) combined FAM19A4/miR124-2 methylation with cytology. RESULTS: CIN3+ sensitivity of FAM19A4/miR124-2 methylation analysis was similar to that of cytology (71.3% vs 76.0%, ratio 0.94, 95% CI 0.84 to 1.05), at a lower specificity (78.3% vs 87.0%, ratio 0.90, 95% CI 0.86 to 0.94). Combining FAM19A4/miR124-2 methylation analysis with cytology resulted in a CIN3+ sensitivity of 84.6% (95% CI 78.3 to 90.8) at a specificity of 69.6% (95% CI 66.5 to 72.7). Similar 9- and 14-year CIN3+ risks for baseline cytology-negative women and baseline FAM19A4/miR124-2 methylation-negative women were observed, with risk differences of -0.42% (95% CI -2.1 to 1.4) and -0.07% (95% CI -1.9 to 1.9), respectively. The 14-year cumulative cervical cancer incidence was significantly lower for methylation-negative women compared to cytology-negative women (risk difference 0.98%, 95% CI 0.26 to 2.0). DISCUSSION: FAM19A4/miR124-2 methylation analysis has a good triage performance on baseline screening samples, with a cross-sectional CIN3+ sensitivity and long-term triage-negative CIN3+ risk equalling cytology triage. Therefore, FAM19A4/miR124-2 methylation analysis appears to be a good and objective alternative to cytology in triage scenarios in HPV-based cervical screening.

Ovarian cancer risk after salpingectomy for ectopic pregnancy or hydrosalpinx: results of the OCASE nationwide population-based database study.

STUDY QUESTION: What is the effect of salpingectomy for ectopic pregnancy or hydrosalpinx at a young age on ovarian cancer risk compared to no salpingectomy for any reason? SUMMARY ANSWER: We found no significant reduction in ovarian cancer risk after salpingectomy for ectopic pregnancy or hydrosalpinx. WHAT IS KNOWN ALREADY: Salpingectomy may reduce ovarian cancer incidence, although the lag-time between intervention and therapeutic effect remains to be elucidated. STUDY DESIGN, SIZE, DURATION: This nationwide population-based database study uses the Dutch pathology database to identify all women who underwent salpingectomy for ectopic pregnancy or hydrosalpinx between January 1990 and December 2012 and compared ovarian cancer incidence to a control group of women who had a benign dermal nevus removed, matched for age at the time and year of procedure. PARTICIPANTS/MATERIALS, SETTING, METHODS: After selection and manual control of intervention and control group, ovarian cancer incidence was recorded. Hazard ratios (HRs) with 95% CI for the development of ovarian cancer were calculated with Cox regression analyses, both unadjusted and adjusted for age. Subgroup analyses were performed to investigate lag-time between intervention and protective effect. MAIN RESULTS AND THE ROLE OF CHANCE: In all, 18 961 women were included in the intervention group; 17 106 women had a unilateral salpingectomy and 1855 had a bilateral salpingectomy. The control group consisted of 23 686 women. With 14 ovarian cancer cases in the intervention group, the incidence rate (IR) of ovarian cancer was 5.4 (95% CI 3.1-8.9) per 100 000 person-years. In the control group, there were 24 ovarian cancer cases, resulting in an IR of 7.1 (95% CI 4.7-10.5) per 100 000 person-years (P = 0.34). The age-adjusted HR for ovarian cancer was 0.76 (95% CI 0.39-1.47) after salpingectomy. Unilateral salpingectomy resulted in an age-adjusted HR of 0.81 (95% CI 0.41-1.59) and bilateral salpingectomy resulted in an age-adjusted HR of 0.43 (95% CI 0.06-3.16) based on one case. None of our subgroup analysis for lag-time resulted in a significant difference in ovarian cancer incidence between intervention and control group. The difference in ovarian cancer incidence appeared largest in women with at least 8 years of follow-up (P = 0.08). LIMITATIONS, REASONS FOR CAUTION: Due to the young population, ovarian cancer incidence is low, even at the end of follow-up. Furthermore, due to the anonymous nature of the pathology registry, we were unable to adjust for confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: Although results did not reach statistical significance, they add to the available data on ovarian cancer incidence after salpingectomy. Our subgroup analysis suggests there may be no benefit in the first years following salpingectomy. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Reflex cytology for triage of high-risk human papillomavirus positive self-sampled material in cervical cancer screening: a prospective cohort study.

OBJECTIVE: High-risk human papillomavirus (HrHPV)-positive women detected by self-sampling require an extra visit at the general practitioner for additional cytology testing, but the loss to follow up within this triage is substantial. The aim of this study was to evaluate the clinical utility of reflex cytology on hrHPV-positive self-samples for immediate stratification of women who need referral for colposcopy. DESIGN: A prospective cohort study. SETTING: Two Dutch cervical cancer-screening laboratories. POPULATION: 1014 screenees who tested hrHPV-positive on self-samples between 1 December 2018 and 1 August 2019. METHODS: Self-samples were directly used for cytological analysis. Cytological and histological outcomes during follow up were obtained from the Dutch Pathology Registry (PALGA). MAIN OUTCOME MEASURES: Test performance of reflex cytology on self-samples was determined for different thresholds and compared with physician-taken cytology and histological outcomes. RESULTS: Reflex cytology on self-samples for detecting abnormal cytology showed a sensitivity of 26.4% (95% CI 21.8-31.3) and specificity of 90.5% (95% CI 87.7-92.8). Of all ≥CIN2 cases, 29.4% (95% CI 22.5-37.1) were detected with reflex cytology on self-samples. The positive predictive value for detection of ≥CIN2 was higher with cytology on self-collected samples than on physician-collected samples. Of women who were lost to follow up, 12.9% were found to have abnormal cytology on their self-sampled material. CONCLUSION: Cytology testing is achievable on hrHPV-positive self-samples, could decrease the loss to follow up in screening and is easily implementable in the current clinical practice. Of all hrHPV-positive women with abnormal cytology on additional physician-collected samples, 26.4% could have been directly referred for colposcopy if triage with reflex cytology on self-sampled material had been performed. TWEETABLE ABSTRACT: Reflex cytology for triage of hrHPV+ self-samples is of added value for direct referral of women for colposcopy.

Presence of koilocytosis in low-grade smears of high-risk HPV-positive women is a negative predictor for cervical intraepithelial neoplasia grade 3 or more.

OBJECTIVE: The Netherlands converted to high-risk (hr)HPV-based screening in 2017. An increase in referral of hrHPV-positive women with low risk for cervical intraepithelial neoplasia grade 3 or more (CIN3+) is anticipated and reduction of unjustified referrals will have priority. The relevance of koilocytosis in relation to the underlying risk of high-grade CIN in a primary HPV screening setting is unclear. The aim was to investigate whether the risk for CIN3+ differs between hrHPV-positive atypical squamous cells of undetermined significance (ASC-US)/low-grade squamous intraepithelial lesion (LSIL) with or without koilocytosis. METHODS: Retrospective cohort study, using data from the Dutch national pathology database (PALGA). The population was 1201 hrHPV-positive women with cytological diagnosis of ASC-US/LSIL. Reporting of koilocytosis was assessed as well as detection rates of CIN1 or less, CIN2 and CIN3+ for ASC-US/LSIL cytology stratified by presence or absence of koilocytosis. Crude and adjusted odds ratios were determined. RESULTS: Koilocytosis was present in 40.1% of ASC-US and 45.9% of LSIL cases. CIN3+ is significantly less often found when koilocytosis is present (7.8% for hrHPV-positive ASC-US with- vs 15.8% without koilocytosis). For hrHPV-positive LSIL this was 11.7% vs 20.2%. The crude and adjusted odds ratios for CIN3+ was 0.45 for hrHPV-positive ASC-US and 0.52 for hrHPV-positive LSIL. CONCLUSIONS: The presence of koilocytosis is a negative predictor of CIN3+. The risk of hrHPV-positive ASC-US with koilocytosis is in the same range as hrHPV-positive/cytology negative cases and in a setting of primary hrHPV screening these cases could be followed conservatively by repeat cytology. The results should be confirmed by the first data from the Dutch HPV-based screening programme.

RAS testing for colorectal cancer patients is reliable in European laboratories that pass external quality assessment.

Wild-type status of KRAS and the NRAS gene (exon 2, 3, and 4) in the tumor should be determined before treatment of metastatic colorectal cancer (mCRC) patients with EGFR-targeting agents. There is a large variation in test methods to determine RAS status, and more sensitive detection methods were recently introduced. Data from quality assessment programs indicate substantial error rates. This study assessed the completeness and correctness of RAS testing in European laboratories that successfully passed external quality assessment (EQA). Participants were requested to send material of their most recent ten patients with mCRC who had been tested for RAS status. Isolated DNA, a hematoxylin and eosin stained tissue slide with a marked area for macrodissection and accompanying patient reports were requested. Samples were reevaluated in a reference laboratory by using a next-generation sequencing approach. In total, 31 laboratories sent in the requested material (n = 309). Despite regulations for anti-EGFR therapy, one institute did not perform full RAS testing. Reanalysis was possible for 274 samples with sufficient DNA available. In the hotspot codons of KRAS and NRAS, seven discordant results were obtained in total, five of them leading to a different prediction of anti-EGFR therapy efficacy (2%; n = 274). Results show that oncologists can rely on the quality of laboratories with good performance in EQA. Oncologists need to be aware that the testing laboratory participates successfully in EQA programs. Some EQA providers list the good performing laboratories on their website.

High-risk human papillomavirus detection in self-sampling compared to physician-taken smear in a responder population of the Dutch cervical screening: Results of the VERA study.

In 2017 the cervical cancer screening program in The Netherlands will be revised. Cervical smears will primarily be tested for the presence of high-risk human papillomavirus (hrHPV) instead of cytology, and vaginal self-sampling will be offered to non-responders. This includes a potential risk that part of the women who would otherwise opt for a cervical smear will wait for self-sampling. However, self-sampling for hrHPV in a responder population has never been studied yet. The aim of this study was to investigate the applicability and accuracy of self-sampling in detecting hrHPV in a screening responder population. A total of 2049 women, aged 30-60years, participating in the screening program in The Netherlands were included from April 2013 to May 2015. After they had their cervical smear taken, women self-collected a cervicovaginal sample with a brush-based device, the Evalyn Brush. Both the cervical smear and self-sample specimen were tested with the COBAS 4800 HPV platform. The hrHPV prevalence was 8.0% (95% CI 6.9-9.2) among the physician-taken samples, and 10.0% (95% CI 8.7-11.3) among the self-samples. There was 96.8% (95% CI 96.0-97.5) concordance of hrHPV prevalence between self-samples and physician-taken samples. Women in our study evaluated self-sampling as convenient (97.1%), user-friendly (98.5%), and 62.8% preferred self-sampling over a physician-taken sampling for the next screening round. In conclusion, self-sampling showed high concordance with physician-taken sampling for hrHPV detection in a responder screening population and highly acceptable to women. Implementation of HPV-self-sampling for the responder population as a primary screening tool may be considered.

How we do: optimizing bone marrow biopsy logistics for sign-out within 2 days.

Since the introduction of fast diagnostic tracks in many areas of oncology, the traditional processing of bone marrow biopsies (BMB), requiring either resin embedding or lengthy fixation and decalcification, is due to an upgrade. Thanks to a growing number of new commercially available tissue processors, microwave-enhanced processing is becoming a standard tool in the pathology laboratory, allowing rapid fixation and decalcification of BMB with preserved morphology and antigens. In this short report, we describe the use of a commercially available EDTA-based decalcification fluid (USEDECALC, Medite, Orlando, USA) in combination with the LOGOS J (Milestone, Bergamo, Italy), a closed microwave-enhanced tissue processor, for overnight fixation, decalcification, and paraffin impregnation of the BMB. This allows next-day reporting without impaired morphology or immunohistochemistry, and even improved DNA quality of the BMB.

The value of fine needle aspiration cytology diagnosis in ovarian masses in children and adolescents.

STUDY QUESTION: Is ovarian cytology a reliable predictor for a malignant ovarian mass? SUMMARY ANSWER: Cytology of an ovarian mass in children and adolescents cannot be used to exclude malignancy. WHAT IS KNOWN ALREADY: It is hard to predict malignancy in case of an ovarian mass in a child or adolescent. The most common reason to perform fine needle aspiration cytology (FNAC) is to exclude malignancy. Ovarian cytology has shown varying results in adults, but test performance in a younger population is unknown. STUDY DESIGN, SIZE, DURATION: This was a retrospective diagnostic test accuracy study. We used a nationwide registry, the PALGA database, to select girls aged 18 or younger with matching ovarian cytology and histology reports available between 1990 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Histology diagnoses were classified according to the WHO classification of ovarian pathology. Cytology diagnoses were classified as benign, borderline malignant or malignant. Cases with inconclusive cytology diagnoses were excluded from the analysis of diagnostic accuracy. Diagnostic accuracy was calculated using a 2 × 2 table. MAIN RESULTS AND THE ROLE OF CHANCE: Included were 552 girls under the age of 18 who had a cytology and a histology report of the same ovary available in the PALGA database. In 523 (94.7%) patients the mass was benign; 19 (3.4%) patients had a borderline malignancy and 9 (1.7%) patients had a malignant tumour. The histology diagnosis was unknown in one patient due to torsion of the ovary. Cytological diagnosis was inconclusive in 96 patients (17.4%). Cytology had a sensitivity of 32.0% and a specificity of 99.8%. Post-test probability of malignancy with positive cytology was 88.9%; the post-test probability of a malignancy with negative cytology was 3.8%, compared with a pre-test probability of 5.5%. LIMITATIONS, REASONS FOR CAUTION: This study was retrospective, using data gathered over 24 years. Cytology was retrieved during surgery or at the pathology department in 86.6% of the cases and pathologists were not blinded, which can be a cause for bias. WIDER IMPLICATIONS OF THE FINDINGS: Since the sensitivity is low, FNAC is not a recommended diagnostic tool in children. The post-test probability of a negative test compared with the incidence in our population resulted in a minimal difference not worth an invasive procedure. STUDY FUNDING/COMPETING INTERESTS: No study funding was received and no competing interests are present. TRIAL REGISTRATION NUMBER: NA.

Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.

BACKGROUND: Gestational trophoblastic disease (GTD) represents a heterogeneous group of disorders. Wide variations in incidence rates are reported worldwide, probably explained by a lack of centralized databases and heterogeneity in case definition. The aim of the present study was to determine the trends in incidence of GTD in the last 20 years with the use of population-based data. PATIENTS AND METHODS: Data on patients with pathologically confirmed diagnosis of GTD between 1994 and 2013 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. RESULTS: In the 20-year period 6343 cases were registered with GTD, representing an overall incidence rate of 1.67 per 1000 deliveries per year. An initial rise in incidence rate was seen over the first 10 years (0.075 per year, 95% CI 0.040-0.109), followed by a stabilization from 2004 to 2013 (increase per year 0.011, 95% CI -0.017-0.040). Although partial hydatidiform mole (HM) was more common in earlier years, complete and partial HM reached comparable incidence rates of 0.68 and 0.64 per 1000 deliveries respectively from 2009 onwards. In the last decade, unspecified HM diagnosis declined significantly from 0.14 per 1000 deliveries in 2003 to 0.03 per 1000 deliveries (per year -0.011, CI -0.016-0.06), suggesting improved diagnostic analyses. CONCLUSION: After an initial rise in GTD incidence in the Netherlands rates remained steady from 2004 onwards. As pathological confirmation is currently the norm and advanced pathological techniques are now widely available, true steady incidence rates may have been reached.

European consensus conference for external quality assessment in molecular pathology.

Molecular testing of tumor samples to guide treatment decisions is of increasing importance. Several drugs have been approved for treatment of molecularly defined subgroups of patients, and the number of agents requiring companion diagnostics for their prescription is expected to rapidly increase. The results of such testing directly influence the management of individual patients, with both false-negative and false-positive results being harmful for patients. In this respect, external quality assurance (EQA) programs are essential to guarantee optimal quality of testing. There are several EQA schemes available in Europe, but they vary in scope, size and execution. During a conference held in early 2012, medical oncologists, pathologists, geneticists, molecular biologists, EQA providers and representatives from pharmaceutical industries developed a guideline to harmonize the standards applied by EQA schemes in molecular pathology. The guideline comprises recommendations on the organization of an EQA scheme, defining the criteria for reference laboratories, requirements for EQA test samples and the number of samples that are needed for an EQA scheme. Furthermore, a scoring system is proposed and consequences of poor performance are formulated. Lastly, the contents of an EQA report, communication of the EQA results, EQA databases and participant manual are given.

Accurate assessment of cell density in low cellular liquid-based cervical cytology.

OBJECTIVE: Scant cellularity is the most important source of unsatisfactory liquid-based cytology. Although still being debated, low cellularity is thought to compromise the detection of squamous lesions. Thus, reliable assessment of cellularity is essential. The aim of the present study was to determine the cellularity range for ThinPrep(®) slides of low cellularity and to establish the most accurate cell-counting protocol. METHODS: A series of 60 ThinPrep cases representing the full spectrum of adequate, 'satisfactory but limited by' (SBLB) and unsatisfactory reports were included. Two cell-counting protocols with three different magnifications, using ×10, ×20 and ×40 objectives, were evaluated and related to the true cellularity, together with a reassessment of the degree of adequacy originally reported. The cell-counting protocol that showed the highest correlation coefficient was considered the most accurate. RESULTS: Based on seven (re)assessments a majority score for adequacy was established. There were 42 cases with a majority score 'unsatisfactory' or 'SBLB' (low cellularity) of which 41 contained fewer than 20 000 squamous cells; and 18 cases with a majority score 'satisfactory' of which one had fewer than 20 000 cells. The cell-counting protocol that showed the significantly highest correlation with the reference standard was the Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek (SKML) protocol with a ×10 objective. CONCLUSIONS: ThinPrep slides reported as unsatisfactory or SBLB were shown to contain fewer than 20000 squamous cells. The most accurate protocol for estimating the cellularity of these slides was cell counting in five non-adjacent microscope fields along the horizontal axis and five along the vertical axis of the slide with a ×10 objective and applying a correction factor of 1.24× to correct for underestimation of the true cellularity.

Age-specific patterns of unsatisfactory results for conventional Pap smears and liquid-based cytology: data from two randomised clinical trials.

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.

Patients with usual vulvar intraepithelial neoplasia-related vulvar cancer have an increased risk of cervical abnormalities.

BACKGROUND: Vulvar squamous cell carcinoma (SCC) originates the following two pathways, related to differentiated (d) vulvar intraepithelial neoplasia (VIN) or to human papillomavirus (HPV)-related usual (u) VIN. Multicentric HPV infections (cervix, vagina and vulva) are common. We hypothesise that patients with a uVIN-related vulvar SCC more often have cervical high-grade squamous intraepithelial lesions (HSILs) compared with women with dVIN-related vulvar SCC. METHODS: All vulvar SCCs (201) were classified to be dVIN- (n=164) or uVIN related (n=37). Data with regard to the smear history and cervical histology were retrieved from PALGA, the nationwide Netherlands database of histo- and cytopathology. For HSIL cervical smears of which histology was taken, HPV DNA analysis on both the vulvar and cervical specimens was performed. RESULTS: At least one smear was available in 145 (72%) of the 201 patients. Patients with a uVIN-related vulvar SCC more often had an HSIL compared with patients with a dVIN-related SCC (35 vs 2%, P<0.001). A total of 10 of the 13 HSILs were histologically assessed and identical HPV types were found in the vulva and cervix. CONCLUSION: These data emphasise the necessity to differentiate between dVIN- and uVIN-related vulvar tumours and to examine the entire lower female ano-genital tract once an uVIN-related lesion is found.

Significant decrease of adenocarcinoma in situ not reflected in cervical adenocarcinoma incidence in the Netherlands 1989-2003.

Over the period 1989-2003, the incidence of cervical adenocarcinoma (n=1615) was stable whereas that of cervical adenocarcinoma in situ (n=1884) significantly decreased (P=0.008), mainly caused by adenocarcinoma in situ lesions with a concurrent squamous dysplasia.

Referral compliance, outcome and predictors of CIN after repeated borderline cervical smears in the Netherlands.

BACKGROUND: Borderline cytological abnormalities are diagnosed very frequently but have limited predictive value for high-grade cervical lesions, resulting in high costs, patient anxiety and over treatment. A conservative management strategy for the Dutch diagnostic equivalent of borderline nuclear changes (BNC) was introduced in the Netherlands in 1996, with repeat cytology at 6 and 18 months and referral for colposcopy if BNC is persistent. OBJECTIVE: To analyse compliance with the current guidelines for referral, as well as the outcome after repeated BNC. Concurrently we investigated whether other variables are predictive of high-grade lesions. METHODS: We retrieved 1898 eligible cases of repeated BNC with 4 years follow-up from the national pathology database (PALGA) and performed a nationwide survey. RESULTS: The management strategy for women with repeated BNC in the Netherlands has been accepted and supported. Seventy-seven per cent (77%) of the patients had visited a gynaecologist within 1 year and only 4.3% were lost to follow-up. We found that 25.2% of the patients had a low-grade lesion or worse (CIN 1+) and 10.2% had a high-grade lesion or worse (CIN 2+), among which were four malignancies. The only variable associated with CIN or worse was age. Women under 40 years were found to be at a higher risk. CONCLUSION: This finding may be used for prioritizing women for colposcopy on the basis of their age. More stringent use of the diagnosis of BNC, higher thresholds for colposcopically directed biopsy and introduction of HPV triage, combined with more specific new techniques or combination of techniques such as molecular markers for P16, MIB-1 and L1 may reduce the unnecessary high referral rate and over treatment of healthy women.

Normal appearing endometrial cells in cervical smears of asymptomatic postmenopausal women have predictive value for significant endometrial pathology.

The objective of this study was to determine whether postmenopausal asymptomatic women with normal endometrial cells in their smear are at higher risk for endometrial pathology compared with women without these cells. Histologic follow-up outcome and otherwise cytologic follow-up of 29,144 asymptomatic postmenopausal women was determined. Presence of normal endometrial cells, age, use of hormones, and reported elevated maturation index were assessed. The effect of each variable on outcome as well as the combined effect were evaluated. Prevalence rate of (pre)malignant uterine disease was significantly higher when normal endometrial cells were found in the cervical smear (6.5%) as compared to smears without these cells (0.2%), resulting in a relative risk of 40.2 (95% CI 9.4-172.2). Neither age nor hormone use or elevated maturation index showed significant impact on the outcome. Asymptomatic postmenopausal women with normal endometrial cells in their smear are at significant higher risk for (pre)cancerous endometrial lesion than women without these cells. These cases should be reported to the physician with an explicit comment that normal endometrial cells in a smear of a postmenopausal woman is an abnormal finding, possibly associated with significant endometrial pathology. It raises the question whether further gynecological examination would be more appropriate.