Improvement in the routine screening of cervical smears: A study using rapid prescreening and 100% rapid review as internal quality control methods

Background:

High rates of false‐negative results constitute a routine problem in cytology laboratories. Of currently available internal quality control methods, 10% random review is the least effective in detecting false‐negatives in routine screening. There is evidence that 100% rapid review and rapid prescreening perform well for this purpose. This study compared the performance of rapid prescreening and 100% rapid review as internal quality control methods for cervical cytology exams.

Methods:

Over 27 months, 12,208 cervical cytology smears were submitted to rapid prescreening and routine screening. The 100% rapid review method was performed on all smears classified as negative or unsatisfactory at routine screening. Conflicting results obtained with either method were reviewed in detail to define final diagnosis, which was considered the gold standard for evaluating the performance of rapid prescreening and 100% rapid review.

Results:

Compared with final diagnosis, the sensitivity of routine screening and rapid prescreening was 72.9% and 75.6%, respectively. Considering only smears classified as negative or unsatisfactory at routine screening, the sensitivity of rapid prescreening and 100% rapid review was 90.2% and 57,0%, respectively. Of 244 cases (2.0%) of false‐negative results at routine screening, rapid prescreening identified 220 cases (1.80%), whereas 100% rapid review identified 140 (1.15%). Rapid prescreening detected all cases of HSIL identified as false‐negatives.

Conclusions:

Rapid prescreening is more effective than 100% rapid review for the detection of false‐negatives at routine screening, thus providing subsidies for the performance of cervical cytology, the principal function of which is to detect precursor lesions of cervical cancer. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

Measuring the significance of workload on performance of cytotechnologists in gynecologic cytology

BACKGROUND.

Workload is extensively regulated and often used as a measure of quality in gynecologic cytology. Whether workload correlates with the sensitivity of screening in gynecologic cytology is not known.

METHODS.

The sensitivity of gynecologic cytology screening was measured over an 8‐month period using the result of full screening coupled with the results of rapid prescreening. Sensitivity results were then correlated with daily workload volumes and the experience level of individual cytotechnologists.

RESULTS.

Rapid prescreening had an average sensitivity of 41.9% for atypical squamous cells of undetermined significance (ASCUS) and above. Full screening had a corrected sensitivity of 82.2% for ASCUS and above. Rapid prescreening increased the sensitivity of the laboratory to 89.9%. The sensitivity of full screening was significantly different between cytotechnologists (79.2% vs 99%, P < .001), but was not correlated with years of experience, sensitivity of rapid prescreening, or workload (all P > .05). When sensitivity and workload were examined on a monthly basis, there was no significant difference between sensitivity either as a group or individually at the highest and lowest workloads (P > .40 for all).

CONCLUSIONS.

Screeners sensitivity in gynecologic cytology appears to be unrelated to the experience level of individual cytotechnologists or to their workload at the levels examined. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

Changing the cytology laboratory information system to improve cytology performance

A central tenet in the Patient Protection and Affordable Care Act is the increased use of information technology to improve patient care. However, areas for improvement in cytology are not well defined. Improvements in information technology could improve quality assessment in gynecologic cytology, but the cytology community must identify and ask for changes in information technology that can improve the care of patients. Cancer (Cancer Cytopathol) 2014;122:87–91. © 2013 American Cancer Society.     

Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients

In a prospective cohort study 8466 women attending routine cervical cancer screening were recruited. Colposcopy was performed on women with any degree of atypia on cytology and/or a positive high-risk human papillomavirus (HPV)-DNA test (HC2; Hybrid Capture 2((c))), and for a randomly selected sample of 3.4% women with negative findings on both. Quality control included reviews of cytology, histology, colposcopy images and retesting of samples with polymerase chain reaction. Test diagnostic performances were based on 7908 women who had complete baseline and follow-up results. Routine histology identified 86 women with high-grade cervical intraepithelial neoplasia (CIN2+), which was confirmed by review histology in only 46 cases. Sensitivity of routine cytology for the detection of CIN2+ was 43.5%, with a specificity, positive predictive value (PPV), negative predictive value (NPV) of 98.0, 11.4 and 99.7%, respectively. Sensitivity of the HC2 test for the detection of CIN2+ was 97.8%, with a specificity, PPV and NPV, of 95.3, 10.9 and 100%, respectively. No high-grade neoplasia was detected in the randomly selected control group. A negative HPV-test result, even in combination with a positive Papanicolaou (Pap) result, virtually excluded any risk of underlying high-grade disease, but this was not the case for a negative Pap result. These data show that HPV testing is of value for the detection or exclusion of prevalent CIN in a routine cervical cancer-screening setting and could be used for further risk classification of women for follow-up management.     

A validation study of the FocalPoint GS imaging system for gynecologic cytology screening

BACKGROUND:

Studies of the performance of the automated FocalPoint Guided Screening (FPGS) imaging system in gynecologic cytology screening relative to manual screening have yielded conflicting results. In view of this uncertainty, a validation study of the FPGS was conducted before its potential adoption in 2 large laboratories in Ontario.

METHODS:

After an intense period of laboratory training, a cohort of 10,233 current and seeded abnormal slides were classified initially by FPGS. Manual screening and reclassification blinded to the FPGS results were then performed. Any adequacy and/or cytodiagnostic discrepancy between the 2 screening methods subsequently was resolved through a consensus process (truth). The performance of each method's adequacy and cytodiagnosis vis‐a‐vis the truth was established. The sensitivity and specificity of each method at 4 cytodiagnostic thresholds (atypical squamous cells of undetermined significance or worse [ASC‐US+], low‐grade squamous intraepithelial lesion or worse [LSIL+], high‐grade squamous intraepithelial lesion or worse [HSIL+], and carcinoma) were compared. The false‐negative rate for each cytodiagnosis was determined.

RESULTS:

The performance of FPGS in detecting carcinoma, HSIL+, and LSIL+ was no different from the performance of manual screening, but the false‐negative rates for LSIL and ASC‐US were higher with FPGS than with manual screening.

CONCLUSIONS:

The results from this validation study in the authors' laboratory environment provided no evidence that FPGS has diagnostic performance that differs from manual screening in detecting LSIL+, HSIL+, or carcinoma. Cancer (Cancer Cytopathol) 2013;121:189–196. © 2013 American Cancer Society.     

HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial

To evaluate the effectiveness of human papillomavirus (HPV) testing in primary cervical screening. This was a cross-sectional study from the recruitment phase of a prospective randomised trial. Women were screened for HPV in addition to routine cervical cytology testing. Greater Manchester, attendees at routine NHS Cervical Screening Programme. In all, 24 510 women aged 20-64 screened with liquid-based cytology (LBC) and HPV testing at entry. HPV testing in primary cervical screening. Type-specific HPV prevalence rates are presented in relation to age as well as cytological and histological findings at entry. In all, 24 510 women had adequate cytology and HPV results. Cytology results at entry were: 87% normal, 11% borderline or mild, 1.1% moderate and 0.6% severe dyskaryosis or worse. Prevalence of HPV decreased sharply with age, from 40% at age 20-24 to 12% at 35-39 and 7% or less above age 50. It increased with cytological grade, from 10% of normal cytology and 31% of borderline to 70% mild, 86% moderate, and 96% of severe dyskaryosis or worse. HPV 16 or HPV 18 accounted for 64% of infections in women with severe or worse cytology, and one or both were found in 61% of women with severe dyskaryosis but in only 2.2% of those with normal cytology. The majority of young women in Greater Manchester have been infected with a high-risk HPV by the age of 30. HPV testing is practicable as a primary routine screening test, but in women aged under 30 years, this would lead to a substantial increase in retesting and referral rates. HPV 16 and HPV 18 are more predictive of underlying disease, but other HPV types account for 30% of high-grade disease.     

Increasing cytotechnologist workload above 100 slides per day using the ThinPrep imaging system leads to significant reductions in screening accuracy

BACKGROUND:

With the current and projected shortage of a cytotechnologist (CT) workforce and the desire to reduce laboratory costs, increased productivity with automated assisted primary screening has become an attractive option for many laboratories. To the best of the authors' knowledge, longitudinal studies examining the effect of increasing workload on the performance of individual CTs have not been performed previously.

METHODS:

Using the ThinPrep imaging system (TIS), the performance of 3 CTs with variable levels of experience were evaluated. Their productivity was noted to increase from an average of 87 to 118 slides per day. The analysis included comparisons of error rates, screening rates, and screening times, including a review of 22 fields of view (FOV). Poststudy interviews of the CTs were also performed.

RESULTS:

Increased workload was found to be proportional to the decreased percentage of cases that underwent full manual review (25.2% to 20.1%; P < .001), and decreased actual screening times (7.3 hours/day to 6.7 hours/day, and 5.0 minutes/slideto 3.7 minutes/slide). This resulted in a lower detection of total abnormal findings (10.4% to 8.3%; P < .001), atypical squamous cells (6.7% to 4.9%; P < .001), and high?grade squamous intraepithelial lesion (0.9 %to 0.7%; P = .37), as well as an increased false‐negative fraction rate (3.8% to 7.0%; P = .08).

CONCLUSIONS:

The results of the current study indicate that an increased average CT workload >100 slides per day with the TIS appears to have been accomplished mostly through a reduction in the amount of time spent reviewing the 22 FOV and the percentage of cases that underwent full manual review, which resulted in a significantly reduced screening performance. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

Validating automated screening for psychological distress by means of computer touchscreens for use in routine oncology practice.

The aim of the study was to confirm the validity of using touchscreen computers for screening for clinically significant levels of distress among cancer patients in routine oncology practice. The Hospital Anxiety and Depression Scale (HADS), EORTC Quality of Life questionnaire (QLQ-C30), Mental Health Inventory-MHI5 and a Concerns Checklist were administered via touchscreen computer to 172 chemotherapy out-patients, twice, 2-4 weeks apart. A standard psychiatric interview (Present State Examination - PSE) was conducted within a week of the second assessment. On interview, 23% of patients were identified as 'cases'. Using the available data (questionnaires, sociodemographic details, self-reported past psychiatric history), the best screening strategy combined scores from MHI-5 and HADS from a single time-point with the following rules: if MHI-5 < 11 = non-case; if MHI-5 > or = 11 then use HADS; then, if HADS > or = 9 = 'case' (sensitivity 85%; specificity 71%; misclassification rate 26%; positive predictive value 47%). The computerized screening system enabled data to be collected, scored, collated and reported in real time to identify patients who warrant further clinical assessment. It offers the potential for improving 'case' detection in routine oncology practice while reducing the burden of questions put to 'non-cases'. Further work is needed to develop optimal choice of screening questions for this purpose.     

Assessing the time dependence of prognostic values of cytology and human papillomavirus testing in cervical cancer screening

Accurate assessment of risks for developing cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) after a given set of screening test results is instrumental to reaching valid conclusions and informing cervical cancer screening recommendations. Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we assessed prognostic values of enrollment screening test results to predict CIN2+ among women attending routine cervical screening using multivariable Cox proportional hazards (PH) regression and its flexible extension during each of two follow-up periods (protocol-defined and extended). Nonproportional (time-dependent (TD)) and/or nonlinear effects were modeled, as appropriate. Women with abnormal cytology had hazard ratios (HRs) for CIN2+ detection of 17.61 (95% CI: 11.25–27.57) and 10.46 (95% CI: 5.41–20.24) relative to women with normal cytology during the protocol-defined and extended follow-up periods, respectively. High-risk human papillomavirus (HR-HPV) positivity was an even stronger predictor of CIN2+ risk, with significant TD effects during both follow-up periods (p <0.001 for both TD effects). Risks among women co-testing HR-HPV+ with and without abnormal cytology (relative to women co-testing negative) were highest immediately after baseline, and decreased significantly thereafter (p <0.001 for both TD effects). HRs for HPV16+ and HPV18+ women (relative to those testing HR-HPV-) did not vary significantly over time (HR = 182.96; 95% CI: 95.16–351.77 and HR = 111.81; 95% CI: 44.60–280.31, respectively). Due to TD effects, conventional Cox model estimates considerably underestimated adjusted HRs associated with positive HR-HPV testing results early on in the follow-up periods.     

Test positivity cutoff level of a high risk human papillomavirus test could be increased in routine cervical cancer screening

We present data on test positivity, relative sensitivity, rates of detection and relative specificity for primary human papillomavirus (HPV) testing with different cutoff levels for test positivity, in comparison to conventional cytology. In 2003-2004, 18,438 women were screened primarily with Hybrid Capture 2 (HC 2) assay, a test for oncogenic HPV DNA, and 21,446 with conventional cytology within the organised screening programme in Finland. A cytological triage test was performed for the HPV positives. Women with cytology equal to low grade squamous intraepithelial lesion (LSIL) or worse were referred for colposcopy. The relative sensitivity measured as relative risk (RR) of any cervical intraepithelial neoplasia (CIN) or cancer was 1.58 for the HPV test at the relative light units (rlu) ratio cutoff 1.00, in comparison to cytology. With the cutoff 3.00, all CIN 2+ lesions were detected. With cutoff 10.00, 2 of the 22 CIN 3+ lesions were missed. Relative specificity for HPV screening for any CIN was 92.6% at cutoff 1.00, 94.6% at cutoff 3.00 and 96.3% at cutoff 10.00. For CIN 3+ specificity estimates for these cutoffs were 92.1%, 94.1% and 95.8%, respectively. Used for routine screening as the sole test, the HPV test cutoff can be increased from the level recommended for clinical use. With HC 2, the detection rate at rlu ratio cutoff 10.00 is still at the level of high-quality conventional screening. At that level, the false positive rate is reduced by about half and the specificity of the HPV test becomes equal to the average specificity of conventional cytology.     

Development and evaluation of safety and effectiveness of novel cancer screening tests for routine clinical use with applications to multicancer detection technologies

Multicancer screening is a promising approach to improving the detection of preclinical disease, but current technologies have limited ability to identify precursor or early stage lesions, and approaches for developing the evidentiary chain are unclear. Frameworks to enable development and evaluation from discovery through evidence of clinical effectiveness are discussed.     

Impact of HPV testing in opportunistic cervical screening: Support for primary HPV screening in the United States

Human papillomavirus (HPV) testing for cervical screening increases diagnosis of precancer and reduces the incidence of cervical cancer more than cytology alone. However, real-world evidence from diverse practice settings is lacking for the United States (U.S.) to support clinician adoption of primary HPV screening. Using a population-based registry, which captures all cervical cytology (with or without HPV testing) and all cervical biopsies, we conducted a real-world evidence study of screening in women aged 30 to 64 years across the entire state of New Mexico. Negative cytology was used to distinguish cotests from reflex HPV tests. A total of 264 198 cervical screening tests (with exclusions based on clinical history) were recorded as the first screening test between 2014 and 2017. Diagnoses of cervical intraepithelial neoplasia grades 2 or 3 or greater (CIN2+, CIN3+) from 2014 to 2019 were the main outcomes. Of cytology-negative screens, 165 595 (67.1%) were cotests and 4.8% of these led to biopsy within 2 years vs 3.2% in the cytology-only group. Among cytology-negative, HPV tested women, 347 of 398 (87.2%) CIN2+ cases were diagnosed in HPV-positive women, as were 147 of 164 (89.6%) CIN3+ cases. Only 29/921 (3.2%) CIN3+ and 67/1964 (3.4%) CIN2+ cases were diagnosed in HPV-negative, cytology-positive women with biopsies. Under U.S. opportunistic screening, across a diversity of health care delivery practices, and in a population suffering multiple disparities, we show adding HPV testing to cytology substantially increased the yield of CIN2+ and CIN3+. CIN3+ was rarely diagnosed in HPV-negative women with abnormal cytology, supporting U.S. primary HPV-only screening.     

Comparing sensitivity and specificity of screening mammography in the United States and Denmark

Delivery of screening mammography differs substantially between the United States (US) and Denmark. We evaluated whether there are differences in screening sensitivity and specificity. We included screens from women screened at age 50–69 years during 1996–2008/2009 in the US Breast Cancer Surveillance Consortium (BCSC) (n = 2,872,791), and from two population‐based mammography screening programs in Denmark (Copenhagen, n = 148,156 and Funen, n = 275,553). Women were followed‐up for 1 year. For initial screens, recall rate was significantly higher in BCSC (17.6%) than in Copenhagen (4.3%) and Funen (3.1%). Sensitivity was fairly similar in BCSC (91.8%) and Copenhagen (90.5%) and Funen (92.5%). At subsequent screens, recall rates were 8.8%, 1.8% and 1.4% in BCSC, Copenhagen and Funen, respectively. The BCSC sensitivity (82.3%) was lower compared with that in Copenhagen (88.9%) and Funen (86.9%), but when stratified by time since last screen, the sensitivity was similar. For both initial and subsequent screenings, the specificity of screening in BCSC (83.2% and 91.6%) was significantly lower than that in Copenhagen (96.6% and 98.8%) and Funen (97.9% and 99.2%). By taking time since last screen into account, it was found that American and Danish women had the same probability of having their asymptomatic cancers detected at screening. However, the majority of women free of asymptomatic cancers experienced more harms in terms of false‐positive findings in the US than in Denmark.     

Benefit of cervical screening at different ages: evidence from the UK audit of screening histories

While most experts agree that cervical screening is effective, there remains controversy over the most appropriate screening interval. Annual screening is common in North America. In England, some argue for 3-yearly screening while others believe 5-yearly screening is adequate, and the frequency varies from one part of the country to another. Screening histories of 1305 women aged 20-69 years, diagnosed with frankly invasive cervical cancer and 2532 age-matched controls were obtained from UK screening programme databases. Data were analysed in terms of time since last negative, and time since last screening smear. Five-yearly screening offers considerable protection (83%) against cancer at ages 55-69 years and even annual screening offers only modest additional protection (87%). Three-yearly screening offers additional protection (84%) over 5-yearly screening (73%) for cancers at ages 40-54 years, but is almost as good as annual screening (88%). In women aged 20-39 years, even annual screening is not as effective (76%) as 3-yearly screening in older women, and 3 years after screening cancer rates return to those in unscreened women. This calls into question the policy of having a uniform screening interval from age 20 to 64 years and stresses the value of screening in middle-aged women.British Journal of Cancer (2003) 89, 88-93. doi:10.1038/sj.bjc.6600974 www.bjcancer.com     

Evidence-based diagnostic performance of novel biomarkers for the diagnosis of malignant mesothelioma in effusion cytology

Cytology effusions are often the only material available for diagnosing malignant pleural mesothelioma (MPM). However, the cytomorphological features alone are not always diagnostic, and cytology samples preclude an assessment for pleural tissue invasion. Accordingly, immunohistochemical, soluble, and molecular biomarkers have been developed. The aim of this study is to provide quantitative evidence regarding the diagnostic performance of novel biomarkers. To that end, a systematic literature review was performed of articles dealing with a loss of BRCA1-associated protein 1 (BAP1), methylthioadenosine (MTAP), 5-hydroxymethylcitosine (5-hmC), glucose transporter 1 (GLUT1), insulin like-growth factor II messenger RNA–binding protein 3 (IMP3), enhanced zeste homologue 2 (EZH2) staining, cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletion (HD) testing, soluble mesothelin, and microRNA quantification in cytological samples for the diagnosis of MPM versus reactive atypical mesothelial cells. Sensitivity and specificity were extracted, and a meta-analysis was performed. The quality of the studies was assessed with Quality Assessment of Diagnostic Accuracy Studies 2, and the quality of the evidence was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation approach. Seventy-one studies were included. BAP1 loss showed a sensitivity of 0.65 (confidence interval [CI], 0.59-0.71) and a specificity of 0.99 (CI, 0.93-1.00). MTAP loss and p16 HD showed 100% specificity with sensitivities of 0.47 (CI, 0.38-0.57) and 0.62 (CI, 0.53-0.71), respectively. BAP1 loss and CDKN2A HD combined showed maximal specificity and a sensitivity of 0.83 (CI, 0.78-0.89). GLUT1 and IMP3 showed sensitivities of 0.82 (CI, 0.70-0.90) and 0.65 (CI, 0.41-0.90), respectively, with comparable specificity. Mesothelin showed a sensitivity of 0.73 (CI, 0.68-0.77) and a specificity of 0.90 (CI, 0.84-0.93). In conclusion, some of the recently emerging biomarkers are close to 1.00 specificity. Their moderate sensitivity on their own, however, can be significantly improved by the use of 2 biomarkers, such as a combination of BAP1 and CDKN2A with fluorescence in situ hybridization or a combination of BAP1 and MTAP immunohistochemistry.     

Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: results from a multicenter study in India

The knowledge that cervical neoplasia are caused by human papillomavirus (HPV) infection has led to the evaluation of its role in screening. We evaluated the accuracy of HPV testing by Hybrid capture II (HC II) method in detecting cervical intraepithelial neoplasia grade 2 and 3 (CIN 2 and 3) lesions in 4 cross-sectional studies with common protocol and questionnaire in 3 different locations (Kolkata, Mumbai and Trivandrum) in India. These studies involved 18,085 women aged 25-65 years. The reference standard for final diagnosis was a combination of colposcopy/biopsy. All women were investigated with colposcopy and 3,116 received directed biopsy. The sensitivity of HPV testing for detecting CIN 2-3 lesions varied from 45.7% to 80.9% across the study sites; the specificity varied from 91.7% to 94.6% and the positive predictive value from 6.7% to 13.7%. Retesting of 298 randomly chosen denatured samples in France revealed an agreement rate of 85.9% and a kappa-value of 0.72. Although HPV testing seems to be a promising approach for cervical cancer prevention, a large range in sensitivity was observed in our study, possibly due to variations in the quality of specimen collection and reference standards. A higher sensitivity was associated with the center performing the test well. Further developments in terms of more reproducible, less expensive and less sophisticated testing are essential to make the test feasible and effective in low-resource settings.