The Papanicolaou (Pap) test—the conventional screening method for cervical intraepithelial neoplasia (CIN)—is suboptimal due to high false-negative and false-positive test results due to the poor quality of sampling, preparation problems and errors in detection and interpretation. In a large number of studies, the diagnostic accuracy of an alternative procedure, liquid-based cytology, has been compared with the Pap test with conflicting results. Few of these studies, however, were randomized and none of the randomized trials were well designed. This cluster randomized controlled trial compared liquid-based cytology and the Pap test with respect to testing positivity rates, histologically confirmed detection rates, and positive predictive values (PPVs). The study subjects were women aged 30 to 60 years who were participants in the Dutch cervical screening program. Between 2004 and 2006, 49,222 patients at 122 practices were screened with liquid-based cytology and 40,562 patients at 124 practices were screened with the Pap test. Screen-positive women were followed prospectively for 18 months after initial screening. All medical personnel and others involved with follow-up of screen-positive women were blinded to the cytology screening system used and initial results. Both the intention-to-treat and per-protocol analysis were used. Multivariate logistic regression analysis was used to adjust for possible confounding factors (age, urbanization level, study site, and period). Detection rate ratios of verified cervical abnormalities were calculated for the liquid-based test relative to the Pap test for the primary histological outcome of CIN grades 1+, 2+, and 3+ and carcinoma. The adjusted positive predictive value (PPV) ratios were also calculated. PPV ratios were evaluated at different levels of test positivity and outcome thresholds. The adjusted detection rate ratio for CIN grade 1+ was 1.01, with a 95% confidence interval [CI] of 0.85–1.19); for CIN grade 2+, the rate ratio was 1.00 (95% CI, 0.84–1.20); for CIN grade 3+, the rate ratio was 1.05 (95% CI, 0.86–1.29); and for carcinoma, the rate was 1.69 (95% CI, 0.96–2.99). Comparable results were found for the PPV ratios. Both the detection rate and PPV ratios were close to one and none of the ratios significantly differed from unity. These findings demonstrate that liquid-based cytology is neither more sensitive nor more specific than the Pap test in detecting CIN or cancer.
Women with a deleterious germline mutation in BRCA1 or BRCA2 are candidates for bilateral salpingo-oophorectomy (BSO). To address the need for adjustment of the current BSO procedure, we investigated the length and the nature of the fallopian tube epithelium that is not removed by BSO. Fourteen consecutive hysterectomy specimens were collected. Complete cross-sections with a 3-mm interval were made of the tubal lumen from the outside of the uterus at the cutoff point of the current BSO procedure to the uterine cavity and examined for the presence or absence of tubal type (ciliated) epithelium and subepithelial endometrial stroma. The fallopian tube remnant had a median length of 12 mm (range 6–15 mm). Tubal type (ciliated) epithelium was shown to be present in all uteri in the first cross-section containing 100% endometrial stroma, as well as in the uterine cavity of all but two of the hysterectomy specimens. A substantial part of the fallopian tube remains in situ after prophylactic BSO and is covered with tubal type ciliated epithelium. More research is necessary to investigate the role of this remnant part of the tube for BRCA carriers.
Objective and reproducible assessment of cancer biomarkers may be performed using rare event detection systems. Because many biomarkers are not true ‘rare events’, in this study a semi‐rare event detection system was developed. The system is capable of assigning a discriminant score to detected positive cells, expressing the extent and intensity of the immunocytochemical staining. A gallery image is constructed showing the diagnostically most interesting cells as well as quantitative data expressing the biomarker staining pattern. To increase scanning speed, an adaptive scanning strategy is studied in which scanning is aborted when a sufficient number of positive cells has been identified. System performance was evaluated using liquid based cervical smears, stained with an antibody directed against p16 INK4a tumor suppressor protein. Overexpression of p16 INK4a in cervix is related to high‐risk HPV infection, which is associated with carcinogenesis. Reproducibility of the system was tested on specimens containing limited positivity. Quantitative analysis was evaluated using 10 cases within normal limits and 10 high grade lesions. The system was highly reproducible in detecting positive cells and in calculating discriminant scores (average CV 0.7%). Quantitative features were significantly increased in high grade lesions ( p < 0.001). Adaptive scanning decreased scanning time with only minor impact on scanning results. The system is capable of automated, objective and reproducible assessment of biomarker expression and may be useful for a variety of applications.
Aims The depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma (SCC). The threshold of 1 mm distinguishes between FIGO stages IA and ≥IB disease and guides the need for groin surgery. Therefore, high interobserver agreement is crucial. The conventional and the alternative method are described to measure the depth of invasion. The aims of this study were to assess interobserver agreement for classifying the depth of invasion using both methods and to identify pitfalls. Methods and results Fifty slides of vulvar SCC with a depth of invasion approximately 1 mm were selected, digitally scanned and independently assessed by 10 pathologists working in a referral or oncology centre and four pathologists in training. The depth of invasion was measured using both the conventional and alternative method in each slide and categorised into ≤1 and >1 mm. The percentage of agreement and Light’s kappa for multi‐rater agreement were calculated, and 95% confidence intervals were calculated by bootstrapping (1000 runs). The agreement using the conventional method was moderate (κ = 0.57, 95% confidence interval = 0.45–0.68). The percentage of agreement among the participating pathologists using the conventional method was 85.0% versus 89.4% using the alternative method. Six pitfalls were identified: disagreement concerning which invasive nest is deepest, recognition of invasive growth and where it starts, curved surface, carcinoma situated on the edge of the tissue block, ulceration and different measurement methods. Conclusions Pathologists reached only moderate agreement in determining the depth of invasion in vulvar SCC, without a notable difference between the two measurement methods.
Context Liquid-based cytology has been developed as an alternative for conventional cervical cytology.Despite numerous studies and systematic reviews, controversy remains about its diagnostic accuracy.Objective To assess the performance of liquid-based cytology compared with conventional cytology in terms of detection of histologically confirmed cervical intraepithelial neoplasia (CIN).Design, Setting, and Participants Cluster randomized controlled trial involving 89 784 women aged 30 to 60 years participating in the Dutch cervical screening program at 246 family practices.One hundred twenty-two practices were assigned to use liquid-based cytology and screened 49 222 patients and 124 practices were assigned to use the conventional Papanicolaou (Pap) test and screened 40 562 patients between April 2004 and July 1, 2006.Patients were followed up for 18 months through January 31, 2008.Intervention Screening for CIN using liquid-based cytology or conventional papanicolaou (Pap) test and the blinded review of all follow-up of screen-positive women (blinded to the type of cytology and the initial result). Main Outcome MeasuresIntention-to-treat and per-protocol analysis of the detection rates of and positive predictive values for histologically verified CIN in both cytology systems.Outcomes are presented as crude and adjusted rate ratios (adjustment for age, urbanization, study site, and period). ResultsThe adjusted detection rate ratios for CIN grade 1ϩ was 1.01 (95% confidence interval [CI], 0.85-1.19);for CIN grade 2ϩ, 1.00 (95% CI, 0.84-1.20);for CIN grade 3ϩ, 1.05 (95% CI, 0.86-1.29);and for carcinoma, 1.69 (95% CI, 0.96-2.99).The adjusted positive predictive value (PPV) ratios, considered at several cytological cutoffs and for various outcomes of CIN did not differ significantly from unity. ConclusionThis study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors.
