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.
In Brief OBJECTIVE: To compare test performance characteristics of conventional Pap tests and liquid-based cervical cytology samples. DATA SOURCES: Eligible studies, published between 1991 and 2007, were retrieved through PubMed/EmBase searching and completed by consultation of other sources. METHODS OF STUDY SELECTION: Studies were selected if a conventional and a liquid-based sample were prepared from the same woman or when one or the other type of sample was taken from a separate but similar cohort. The current systematic review and meta-analysis is restricted to studies where all subjects were submitted to gold standard verification, based on colposcopy and histology of colposcopy-targeted biopsies, allowing computation of absolute and relative test validity for cervical intraepithelial neoplasia grade 2 or worse. Randomized trials were selected as well if all test-positive cases were verified with the same gold standard, allowing computation of the relative sensitivity. Impact of study characteristics on accuracy was assessed by subgroup meta-analyses, meta-regression, and summary receiver operating characteristic curve regression. TABULATION, INTEGRATION, AND RESULTS: The relative sensitivity, pooled from eight studies, with complete gold standard verification and from one randomized clinical trial, did not differ significantly from unity. Also, the specificity, considering high-grade and low-grade squamous intraepithelial lesions as cutoff, was similar in conventional and liquid cytology. However, a lower pooled specificity was found for liquid-based cytology when presence of atypical squamous cells of undetermined significance was the cutoff (ratio 0.91, 95% confidence interval 0.84–0.98). Differences in study characteristics did not explain interstudy heterogeneity. CONCLUSION: Liquid-based cervical cytology is neither more sensitive nor more specific for detection of high-grade cervical intraepithelial neoplasia compared with the conventional Pap test. Liquid-based cervical cytology is neither more sensitive nor more specific for detection of high-grade cervical intraepithelial neoplasia compared with the conventional Pap test.
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.
Abstract Background Women with epithelial ovarian cancer (OC) have a higher chance to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as a prescreen for PARPi treatment and cancer predisposition testing. Methods Formalin-fixed paraffin-embedded tissue was obtained from OC patients in seven hospitals immediately after diagnosis or primary surgery. DNA was extracted, and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated. Results Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients, pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% of patients. Participating gynecologists and patients were overwhelmingly positive about the workflow. Conclusions Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective, and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.
In Brief OBJECTIVE: To compare test positivity rates of liquid-based and conventional cytology. METHODS: This study was a cluster randomized controlled trial with family practice as the unit of randomization, performed within the Dutch national cervical screening program. Women aged 30–60 years (n=89,784) recruited from 246 family practices were included. One-hundred twenty-two practices (49,222 individuals) were randomly assigned to the experimental arm, and 124 practices (40,562 participants), to the conventional arm. Inclusion was performed during a 3-year period between April 2003 and July 2006. Cytologic test positivity rates of liquid-based compared with conventional cytology was compared in terms of crude and adjusted odds ratios, applying a per-protocol analysis. RESULTS: Crude ratios of the odds of test positivity rates of liquid-based compared with conventional cytology for atypical squamous cells of undetermined significance or more severe, low-grade squamous intraepithelial lesion or more severe, and high-grade squamous intraepithelial lesion or more severe were 0.95 (95% confidence interval [CI] 0.82–1.10), 1.00 (95% CI 0.83–1.20), and 0.97 (95% CI 0.77–1.22), respectively. Liquid-based cytology resulted in fewer unsatisfactory tests (odds ratio 0.30, 95% CI 0.23–0.38). The results did not change when the odds ratios were adjusted for age, study site, study period, and urbanization level. Of 128 women screened with liquid-based cytology, one unsatisfactory preparation is avoided. CONCLUSION: This study found no statistically significant difference in cytologic test positivity rates between liquid-based and conventional cytology. However, liquid-based cytology resulted in significantly fewer unsatisfactory tests. CLINICAL TRIAL REGISTRATION: Nederlands Trial Register, www.trialregister.nl, NTR1032 LEVEL OF EVIDENCE: I Liquid-based and conventional cytology perform equally well in detecting cytologic abnormalities, but the proportion of unsatisfactory tests is significantly lower in the former.
Merkel cell carcinoma (MCC) is a malignant neuroendocrine carcinoma originating in the skin. It is typically aggressive with a tendency to recur locally and metastasise. There have been several case reports about spontaneous regression of MCC over the past years, but to the best of our knowledge this is the first case of a regional lymph node metastasised MCC with complete spontaneous regression and recurrence. In addition, the primary tumour has an unusual localisation on the foot.
Recent randomized controlled trials have shown a significant decrease in unsatisfactory rates for liquid-based cytology (LBC) compared with conventional Papanicolaou test (CP). The underlying causes and relevance of unsatisfactory results for LBC and CP have never been compared within the setting of a randomized controlled trial.To examine differences in causes and relevance of unsatisfactory and satisfactory but limited by (SBLB) results for LBC and CP.Data from the Netherlands ThinPrep Versus Conventional Cytology (NETHCON) trial were used, involving 89 784 women. Causes and relevance of unsatisfactory and SBLB results were analyzed.The primary cause for unsatisfactory results for CP and LBC was scant cellularity. Other causes for unsatisfactory CPs were virtually eliminated with LBC. The same was true for SBLB subcategories, with the exception of SBLB absence of transformation zone component and SBLB scant cellularity. The SBLB absence of transformation zone component showed a statistically significant 22% and SBLB scant cellularity a 12% nonsignificant increase with LBC. The detection rates of abnormalities found during 18 months of follow-up of unsatisfactory test results did not differ significantly between the 2 study arms, nor did they differ from the initial test positivity rates from the NETHCON trial.Liquid-based cytology shows an almost complete elimination of most causes for unsatisfactory CP, with scant cellularity remaining as the sole cause for unsatisfactory LBC. On the other hand, with LBC a significant increase of smears without a transformation zone component was noted. Women with an unsatisfactory test result are not at increased risk for cervical abnormalities either with LBC or with CP.Nederlands Trial Register, NTR1032, www.trialregister.nl .
OBJECTIVE: To compare test performance characteristics of conventional Pap tests and liquid-based cervical cytology samples. DATA SOURCES: Eligible studies, published between 1991 and 2007, were retrieved through PubMed/EmBase searching and completed by consultation of other sources. METHODS OF STUDY SELECTION: Studies were selected if a conventional and a liquid-based sample were prepared from the same woman or when one or the other type of sample was taken from a separate but similar cohort. The current systematic review and metaanalysis is restricted to studies where all subjects were submitted to gold standard verification, based on colposcopy and histology of colposcopy-targeted biopsies, allowing computation of absolute and relative test validity for cervical intraepithelial neoplasia grade 2 or worse. Randomized trials were selected as well if all test-positive cases were verified with the same gold standard, allowing computation of the relative sensitivity. Impact of study characteristics on accuracy was assessed by subgroup meta-analyses, meta-regression, and summary receiver operating characteristic curve regression. TABULATION, INTEGRATION, AND RESULTS: The relative sensitivity, pooled from eight studies, with complete gold standard verification and from one randomized clinical trial, did not differ significantly from unity. Also, the specificity, considering high-grade and lowgrade squamous intraepithelial lesions as cutoff, was similar in conventional and liquid cytology. However, a lower pooled specificity was found for liquid-based cytology when presence of atypical squamous cells of undetermined significance was the cutoff (ratio 0.91, 95% confidence interval 0.84–0.98). Differences in study characteristics did not explain interstudy heterogeneity. CONCLUSION: Liquid-based cervical cytology is neither more sensitive nor more specific for detection of highgrade cervical intraepithelial neoplasia compared with the conventional Pap test. (Obstet Gynecol 2008;111:167–77)
To investigate the expression of MMP-14 and CD44 as well as epithelial-to-mesenchymal transition(EMT)-like changes in ovarian cancer and to determine correlations with clinical outcome.In 97 patients with ovarian cancer, MMP-14 and CD44 expression as determined by immunohistochemistry was investigated in relation to EMT-like changes. To determine this, immunohistochemical staining of E-cadherin and vimentin was performed.Patients with expression of both MMP-14 and CD44 in their tumors had a poor prognosis despite complete debulking. Serous histology in advanced-stage tumors (FIGO IIB-IV) correlated with CD44 (rho .286, p < 0.01). Also, CD44 correlated with percentage vimentin expression (rho .217, p < 0.05). In logistic regression analysis with complete debulking as the outcome parameter, CD44 expression was found to be significant (OR 3,571 (95 % Confidence Interval 1,112-11,468) p = 0.032), though this was not the case for MMP-14 and EMT parameters.The subgroup of patients with double expression of MMP-14 and CD44 had a poor prognosis despite complete debulking. Serous subtype in advanced-stage patients and CD44 expression were found to be correlated with vimentin expression, and CD44 expression was found to be significantly correlated with complete debulking. However, a significant correlation between EMT and clinical parameters was not found.
