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Are Fluid-Based Cytologies Superior to the Conventional Papanicolaou Test? A Systematic Review
STUDY DESIGN: This was a systematic review of original research reports evaluating both conventional Pap and FBC with respect to specimen adequacy, comparison with a reference standard, or both. Two reviewers independently reviewed the articles to determine inclusion status, with differences resolved by consensus with a third author. Risk differences (RD) between occurrence rates for FBC and Pap were used for the specimen adequacy data.
DATA SOURCES: Studies published between 1985 and November 1999 were identified from MEDLINE, Best Evidence, EMBASE, Biological Abstracts/RRM, and The Cochrane Library.
OUTCOMES MEASURED: Sensitivity, specificity, area under the receiver operating characteristic curve (AuROC), and the proportion of satisfactory, unsatisfactory, and “satisfactory but limited by” test results were measured.
RESULTS: There was no significant difference in AuROC (p=.37). FBC specimens were more likely to be satisfactory (RD=0.06; 95% confidence interval [CI], 0.03-0.09) or to have absent endocervical cells (RD=0.06; 95% CI, 0.02-0.10) but had 10% fewer “satisfactory but limited by—other” reports (RD = -0.10; 95% CI, -0.14 to -0.06). There was no difference in unsatisfactory Pap test results.
CONCLUSIONS: For most women there is no reason to replace Pap with FBC. For women at high risk of cervical cancer or who are screened infrequently, the possible increase in FBC sensitivity may outweigh the potential harms from additional false positives.
Despite mass Papanicolaou (Pap) test screening, approximately 12,800 women are given the diagnosis of cervical cancer in the United States each year, and approximately 4600 die of the disease.1 Fahey and colleagues2 found an average sensitivity of 58% (range = 11%-99%). Nanda and coworkers3 reported a sensitivity of 30% to 87%, with a specificity of 86% to 100%. Follen Mitchell and colleagues4 reported sensitivities of 67% and specificities of 77%. Multiple factors including sampling technique, patient preparation, test fixation and staining, and interpretation accuracy5 can increase the false-negative rates of conventional Pap.
Fluid-based cytology (FBC) procedures use a fluid medium to capture and preserve the collected cells from the cervical-sampling device. The collected sample is homogenized using an automated device, and a subsample of cellular material is placed on a glass slide in a circumferential area. Because the technique provides a uniform thin layer and excludes obscuring debris, it eliminates problems often encountered with Pap including poor fixation, uneven thickness of the cellular spread, air-drying artifact, and obscuring of cells by blood or inflammatory exudates.6
We performed a systematic review to evaluate the accuracy of FBC (by comparing its sensitivity and specificity with Pap) and the specimen adequacy of this new method (by comparing the proportion of FBC and Pap slides reported as unsatisfactory or “satisfactory but limited” by either absence of endocervical cells or other factors).
Methods
Search Strategy
Our literature search was designed to find studies comparing FBC and Pap. The search was assisted by a medical librarian and used medical subject headings (MeSH) and text words. The search terms included monolayer technology, ThinPrep, CytoRich, Cytoprep, Autoprep, AutoCyte, Papanicolau/pap smear, liquid-based cytology, fluid-based cytology, cervical cancer screening, and vaginal smears. MEDLINE, Best Evidence, EMBASE, Biological Abstracts/RRM and The Cochrane Library were searched to retrieve all potentially relevant English-language articles published between 1985 (first literature published on fluid-based cytology) and November 1999. An attempt was made to contact both FBC manufacturers to find any other available articles and abstracts in publication. The authors of articles with incomplete data were contacted in an attempt to obtain missing information. The reference lists of retrieved articles were manually searched for additional citations.
Study Inclusion
Articles were reviewed for inclusion if they contained reports of original research evaluating both conventional and fluid-based cytology samples (either ThinPrep or AutoCyte). Studies in which both tests were simultaneously applied to the same group of women (split-sample studies) and those in which one group of women who received Pap was compared with a group that received FBC (cohort studies) were included. Two reviewers independently reviewed the titles. When either reviewer felt the study might merit inclusion, the full article was retrieved. The same authors independently reviewed each article to determine whether it met the inclusion criteria. Differences were resolved by consensus with a third author.
We used the entire set of studies to address the question of specimen adequacy. To address FBC accuracy, we identified the subset of articles that compared the 2 tests with an external reference standard. We excluded articles from this analysis unless they reported colposcopy and biopsy results for at least 50% of the women with a finding of high-grade squamous intraepithelial lesions or higher on either Pap or FBC. Because few studies subjected all women with normal Pap tests to colposcopy, we also included studies that provided colposcopy to a random sample of women with normal Pap or FBC tests and those that subjected normal tests to an independent consensus review by a panel of experienced cytology professionals.7
Study Quality Assessment
For the studies addressing accuracy, we developed a criteria form for extracting infusing criteria.8 Two points were assigned and summed to create an overall study quality score (maximum score = 13). Two reviewers independently assessed the quality of each article with differences resolved by consensus Table 1.
Data Extraction
Three reviewers independently extracted data using a structured form. Differences were resolved by consensus. Specimen adequacy was classified as satisfactory, satisfactory but limited by absence of endocervical cells (SBLB-absence), satisfactory but limited by other (SBLB-o), and unsatisfactory. SBLB-o included obscuring inflammatory exudate, blood, thick tests, scant cellularity, and air-drying artifact.
Data Synthesis and Analysis
Summary estimates of sensitivity and specificity were made from studies that used an appropriate reference standard using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using MetaTest software (version 0.6, Joseph Lau, MD, with permission). The MetaTest program was also used to calculate the area under receiver operating characteristic (AuROC) curves, and the difference between AuROC was calculated using ROCKET 0.9B software for ROC analysis (Charles E. Metz, Department of Radiology University of Chicago, March 1998). The AuROC is a measure of overall diagnostic accuracy, where 1.0 is a perfect test, and 0.5 is a test that is no better than chance at distinguishing normal from abnormal specimens. For analysis of specimen adequacy, we used the RevMan 4.1 software (Cochrane Collaboration, Update Software, Oxford, England) to calculate rate differences. Study homogeneity analyses were performed, and our analysis plan called for the use of a random effects model if significant heterogeneity (P >.05) was found.
Results
Search Strategy and Study Inclusion
We identified 62 articles for critical appraisal. Because some authors published more than one article from a single study9-23 and one author combined 2 studies into one article,24 the 62 articles represented 47 actual studies. Fifty-two articles met the initial inclusion criteria.6,9-59 Ten articles were excluded, because they did not contain a reference standard or specimen adequacy data, or they restricted their reports to only a subset of Pap results, such as atypical glandular cells of uncertain significance (AGUS) or atypical squamous cells of uncertain significance (ASCUS).24,39,61-68
Study Characteristics and Qualitative Synthesis
Most articles provided no systematic comparison with any reference standard and could therefore only be used to evaluate specimen adequacy. In some cases, histologic results were reported for some patients and compared with Pap and FBC reports; however, these appeared to be haphazard samples of patients with a positive result on one or both tests. Most articles compared the results obtained from FBC and Pap with the assumption that the better test was the one with the higher proportion of positives, ignoring the possibility of false-positive tests.
Five studies included a comparison with a reference standard.18,27,35,40,50 In all 5, both tests were performed at the same time in all patients. After the cervix was scraped in the usual fashion, the sampling device was wiped across a slide for the conventional Pap and then rinsed in a vial containing the appropriate solution for the FBC method.
Three studies systematically compared FBC and Pap results with colposcopy and biopsy. One12,35 involved women referred to a colposcopy clinic because of a previous abnormal test result; Pap and FBC Pap test results were obtained, and colposcopic examinations were done on all women referred. A second16,23,55 studied 782 patients referred for colposcopy after an abnormal Pap test result; colposcopy was performed, and biopsies were taken from 445 of these patients. In the third study40 A total of 8636 randomly selected Costa Rican women were each screened with Pap, FBC, and cervicography. All women with a suspicious physical examination for cancer or with any abnormality on any of the 3 tests were referred for colposcopy, along with a random sample of 150 women with no abnormalities.
The remaining 2 studies27,50 used consensus between independent reviewers of the Pap and FBC test results as the reference standard, with biopsy for at least 50% of the women with significant abnormalities on either or both tests. In the first study50 a total of 2778 split samples were obtained and evaluated in both Germany and the United States. In Germany, masked slides were reviewed by cytotechnologists, and pathologists reviewed all abnormal and discrepant slides. Masked review was repeated in the United States, and senior cytotechnologists and cytopathologists rescreened abnormal slides. The cases were then unmasked, and discrepant cases were reviewed. A subset of histologic data (1235 samples) was analyzed, and a final reference diagnosis was made. In the second study27 2009 sample pairs from a multicenter trial were evaluated blindly by 2 cytotechnologists, with all abnormal and 10% of normal slides reviewed by 1 of 6 pathologists. All sample pairs containing an abnormal result were then sent for a second masked opinion by cytotechnologists and pathologists. Consensus data were summarized and reported.
Study Quality Assessment
The total quality assessment scores of the 5 studies ranged from 7 to 10 out of a possible maximum score of 13. In general, the studies offered little or no description of the clinical characteristics of the women screened. Most did not even mention the women’s ages. All of the studies included at least some women who were at high risk for an abnormal Pap test result. Two of the studies included only women referred because of a previously abnormal result. Three studies included colposcopy clinics among their recruiting sites. One study was done in Costa Rica because of the known high prevalence of abnormal Pap test results in that country. One study specified that a consecutive series of patients was used, and one used a population-based random sample. The other 3 studies gave no details of how patients were selected for inclusion in the trial. All studies used prospectively collected data, and the methods used to actually perform the Pap and FBC tests were universally well described. Two of the studies used methods to minimize the effects of interobserver reliability in the evaluation of the test results, but none addressed this issue as it related to the assessment of the reference standard.
Sensitivity and Specificity
The ROC curves for FBC and Pap using all 5 of the above studies are displayed in Figure 1. The AuROC curves were similar (Pap=0.93; FBC= 0.91). This difference was not significant (P=.37), and the confidence interval (CI) was wide (95% CI, -0.33 to 0.80). FBC demonstrated higher sensitivity, 90% (95% CI, 0.77-0.96) versus 79% (95% CI, 0.59-0.91) for Pap. FBC had a lower specificity, 85% (95% CI, 0.74-0.92) versus 89% (95% CI, 0.75-0.96) for Pap.
Specimen Adequacy
FBC specimens were more likely to be reported as satisfactory (RD=0.06; 95% CI, 0.03-0.09; Figure 2. There was no significant difference in the number of unsatisfactory test results. There was a 6% higher rate of absence of endocervical cells (RD=0.06; 95% CI, 0.02-0.10) but a 10% decrease in reports of SBLB-o (RD = -0.10; 95% CI, -0.13 to -0.06) with FBC. The increase in absence of endocervical cells for FBC specimens was seen in all split-sample studies (RD= 0.08; 95% CI, 0.06-0.11) but not in the cohort studies (RD = -0.01; 95% CI -0.07 to 0.05).
Discussion
The use of FBC increases both true-positive and false-positive results when compared with Pap. These conclusions must be considered tentative because of the lack of statistical significance and the significant methodologic problems found in the studies used. Two recent meta-analyses have addressed the accuracy of FBC tests.3,60 Neither addressed the issue of specimen adequacy. Although neither included all 5 studies that we identified for our analysis of test accuracy, our findings of a possible increase in sensitivity with a decrease in specificity are consistent with the findings of the other 2 meta-analyses.
The possibility that FBC may increase sensitivity but decrease specificity should lead to caution in the adoption of this technology, especially for women at low risk for cervical cancer. For women with no history of abnormal findings on previous Pap tests (estimated prevalence of cervical cancer = 0.05%) more than 1800 FBC would be needed to detect one additional true positive. More than 50 additional false-positive test results (“cancer scares”) would accompany each additional true positive. The costs of follow-up investigations for these additional false-positive tests must be added to the additional cost of the test itself in assessing the potential impact of a widespread switch to this new technology. Many women are at risk because they fail to obtain regular Pap tests, often because of lack of insurance and cost barriers. Unfortunately, the higher cost of FBC may make these women even less likely to have screening performed. Thus widespread use of FBC could, paradoxically, lead to an increase rather than a decrease in cervical cancer deaths by decreasing the use of this important test by lower income women.
The trade-off between sensitivity and specificity is more favorable for women with higher disease rates. In a population with a 3% prevalence of cervical disease, only 300 FBC Pap tests would be required to detect one additional abnormality, and only 16 additional false-positive tests would result. Thus, for women who have had prior abnormal Pap test results or are known to be infrequent attenders, there may be a role for FBC.
Pap test results reported as less than satisfactory can present a significant problem with increased office return visits, increased psychologic trauma to the patient, and increased costs of repeated tests. Thus the decrease in “SBLB other” reports is a benefit of FBC, although it is partially offset by an increased absence of endocervical cells. Some have suggested that the absence of endocervical cells is an artifact of the study methods for split-sample studies (where the collection instrument is first wiped across a slide for the Pap and then inserted into the FBC vial). We do not understand why this process would preferentially extract endocervical cells. We did note that the cohort studies showed no increase in SBLB absence for FBC. However, in these studies, the Pap and FBC specimens were collected from different women and often involved different time periods and different physicians using different collection instruments. Both the degree of heterogeneity and the reported differences on all comparisons between Pap and FBC Pap tests were consistently larger in the cohort than in the split-sample studies.
FBC offers the advantage of doing HPV testing on the same Pap specimen in triaging the patient diagnosed with ASCUS. As shown in the ASCUS/LSIL Triage Study,61 patients with ASCUS Pap test results and negative human papillomavirus studies can be followed with annual Pap tests without colposcopy or more frequent screening.
Limitations
The greatest limitation of the studies was the lack of comparision of Pap test results and colposcopy with biopsy of any suspicious areas. We therefore also included studies that used an alternative reference standard for women with negative Pap results. However, the use of different reference standards for patients with positive and negative test results has been shown to result in overestimates of test sensitivity.8 The fact that none of the studies addressed the issue of blinding in interpretation of the reference standard is also of concern. Perhaps the most important limitation involves the fact that the patients included in these studies came from high-risk populations. It is not clear how well these results will generalize to the many women at low risk who receive Pap tests in the offices of American primary care physicians. An additional limitation of our study includes the potential for publication bias, since we included only those articles written in English.
Conclusions
Before widespread adoption of this new FBC technology, it would be advisable to have additional acceptable reference standards studies, designed to avoid verification bias and to ensure that equivalent specimen collection methods are used. Once reliable estimates of the relative sensitivity and specificity of the FBC Pap test are available from such investigations, a decision can be made about whether the benefits derived from widespread adoption would outweigh any disadvantages or additional costs.
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STUDY DESIGN: This was a systematic review of original research reports evaluating both conventional Pap and FBC with respect to specimen adequacy, comparison with a reference standard, or both. Two reviewers independently reviewed the articles to determine inclusion status, with differences resolved by consensus with a third author. Risk differences (RD) between occurrence rates for FBC and Pap were used for the specimen adequacy data.
DATA SOURCES: Studies published between 1985 and November 1999 were identified from MEDLINE, Best Evidence, EMBASE, Biological Abstracts/RRM, and The Cochrane Library.
OUTCOMES MEASURED: Sensitivity, specificity, area under the receiver operating characteristic curve (AuROC), and the proportion of satisfactory, unsatisfactory, and “satisfactory but limited by” test results were measured.
RESULTS: There was no significant difference in AuROC (p=.37). FBC specimens were more likely to be satisfactory (RD=0.06; 95% confidence interval [CI], 0.03-0.09) or to have absent endocervical cells (RD=0.06; 95% CI, 0.02-0.10) but had 10% fewer “satisfactory but limited by—other” reports (RD = -0.10; 95% CI, -0.14 to -0.06). There was no difference in unsatisfactory Pap test results.
CONCLUSIONS: For most women there is no reason to replace Pap with FBC. For women at high risk of cervical cancer or who are screened infrequently, the possible increase in FBC sensitivity may outweigh the potential harms from additional false positives.
Despite mass Papanicolaou (Pap) test screening, approximately 12,800 women are given the diagnosis of cervical cancer in the United States each year, and approximately 4600 die of the disease.1 Fahey and colleagues2 found an average sensitivity of 58% (range = 11%-99%). Nanda and coworkers3 reported a sensitivity of 30% to 87%, with a specificity of 86% to 100%. Follen Mitchell and colleagues4 reported sensitivities of 67% and specificities of 77%. Multiple factors including sampling technique, patient preparation, test fixation and staining, and interpretation accuracy5 can increase the false-negative rates of conventional Pap.
Fluid-based cytology (FBC) procedures use a fluid medium to capture and preserve the collected cells from the cervical-sampling device. The collected sample is homogenized using an automated device, and a subsample of cellular material is placed on a glass slide in a circumferential area. Because the technique provides a uniform thin layer and excludes obscuring debris, it eliminates problems often encountered with Pap including poor fixation, uneven thickness of the cellular spread, air-drying artifact, and obscuring of cells by blood or inflammatory exudates.6
We performed a systematic review to evaluate the accuracy of FBC (by comparing its sensitivity and specificity with Pap) and the specimen adequacy of this new method (by comparing the proportion of FBC and Pap slides reported as unsatisfactory or “satisfactory but limited” by either absence of endocervical cells or other factors).
Methods
Search Strategy
Our literature search was designed to find studies comparing FBC and Pap. The search was assisted by a medical librarian and used medical subject headings (MeSH) and text words. The search terms included monolayer technology, ThinPrep, CytoRich, Cytoprep, Autoprep, AutoCyte, Papanicolau/pap smear, liquid-based cytology, fluid-based cytology, cervical cancer screening, and vaginal smears. MEDLINE, Best Evidence, EMBASE, Biological Abstracts/RRM and The Cochrane Library were searched to retrieve all potentially relevant English-language articles published between 1985 (first literature published on fluid-based cytology) and November 1999. An attempt was made to contact both FBC manufacturers to find any other available articles and abstracts in publication. The authors of articles with incomplete data were contacted in an attempt to obtain missing information. The reference lists of retrieved articles were manually searched for additional citations.
Study Inclusion
Articles were reviewed for inclusion if they contained reports of original research evaluating both conventional and fluid-based cytology samples (either ThinPrep or AutoCyte). Studies in which both tests were simultaneously applied to the same group of women (split-sample studies) and those in which one group of women who received Pap was compared with a group that received FBC (cohort studies) were included. Two reviewers independently reviewed the titles. When either reviewer felt the study might merit inclusion, the full article was retrieved. The same authors independently reviewed each article to determine whether it met the inclusion criteria. Differences were resolved by consensus with a third author.
We used the entire set of studies to address the question of specimen adequacy. To address FBC accuracy, we identified the subset of articles that compared the 2 tests with an external reference standard. We excluded articles from this analysis unless they reported colposcopy and biopsy results for at least 50% of the women with a finding of high-grade squamous intraepithelial lesions or higher on either Pap or FBC. Because few studies subjected all women with normal Pap tests to colposcopy, we also included studies that provided colposcopy to a random sample of women with normal Pap or FBC tests and those that subjected normal tests to an independent consensus review by a panel of experienced cytology professionals.7
Study Quality Assessment
For the studies addressing accuracy, we developed a criteria form for extracting infusing criteria.8 Two points were assigned and summed to create an overall study quality score (maximum score = 13). Two reviewers independently assessed the quality of each article with differences resolved by consensus Table 1.
Data Extraction
Three reviewers independently extracted data using a structured form. Differences were resolved by consensus. Specimen adequacy was classified as satisfactory, satisfactory but limited by absence of endocervical cells (SBLB-absence), satisfactory but limited by other (SBLB-o), and unsatisfactory. SBLB-o included obscuring inflammatory exudate, blood, thick tests, scant cellularity, and air-drying artifact.
Data Synthesis and Analysis
Summary estimates of sensitivity and specificity were made from studies that used an appropriate reference standard using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using MetaTest software (version 0.6, Joseph Lau, MD, with permission). The MetaTest program was also used to calculate the area under receiver operating characteristic (AuROC) curves, and the difference between AuROC was calculated using ROCKET 0.9B software for ROC analysis (Charles E. Metz, Department of Radiology University of Chicago, March 1998). The AuROC is a measure of overall diagnostic accuracy, where 1.0 is a perfect test, and 0.5 is a test that is no better than chance at distinguishing normal from abnormal specimens. For analysis of specimen adequacy, we used the RevMan 4.1 software (Cochrane Collaboration, Update Software, Oxford, England) to calculate rate differences. Study homogeneity analyses were performed, and our analysis plan called for the use of a random effects model if significant heterogeneity (P >.05) was found.
Results
Search Strategy and Study Inclusion
We identified 62 articles for critical appraisal. Because some authors published more than one article from a single study9-23 and one author combined 2 studies into one article,24 the 62 articles represented 47 actual studies. Fifty-two articles met the initial inclusion criteria.6,9-59 Ten articles were excluded, because they did not contain a reference standard or specimen adequacy data, or they restricted their reports to only a subset of Pap results, such as atypical glandular cells of uncertain significance (AGUS) or atypical squamous cells of uncertain significance (ASCUS).24,39,61-68
Study Characteristics and Qualitative Synthesis
Most articles provided no systematic comparison with any reference standard and could therefore only be used to evaluate specimen adequacy. In some cases, histologic results were reported for some patients and compared with Pap and FBC reports; however, these appeared to be haphazard samples of patients with a positive result on one or both tests. Most articles compared the results obtained from FBC and Pap with the assumption that the better test was the one with the higher proportion of positives, ignoring the possibility of false-positive tests.
Five studies included a comparison with a reference standard.18,27,35,40,50 In all 5, both tests were performed at the same time in all patients. After the cervix was scraped in the usual fashion, the sampling device was wiped across a slide for the conventional Pap and then rinsed in a vial containing the appropriate solution for the FBC method.
Three studies systematically compared FBC and Pap results with colposcopy and biopsy. One12,35 involved women referred to a colposcopy clinic because of a previous abnormal test result; Pap and FBC Pap test results were obtained, and colposcopic examinations were done on all women referred. A second16,23,55 studied 782 patients referred for colposcopy after an abnormal Pap test result; colposcopy was performed, and biopsies were taken from 445 of these patients. In the third study40 A total of 8636 randomly selected Costa Rican women were each screened with Pap, FBC, and cervicography. All women with a suspicious physical examination for cancer or with any abnormality on any of the 3 tests were referred for colposcopy, along with a random sample of 150 women with no abnormalities.
The remaining 2 studies27,50 used consensus between independent reviewers of the Pap and FBC test results as the reference standard, with biopsy for at least 50% of the women with significant abnormalities on either or both tests. In the first study50 a total of 2778 split samples were obtained and evaluated in both Germany and the United States. In Germany, masked slides were reviewed by cytotechnologists, and pathologists reviewed all abnormal and discrepant slides. Masked review was repeated in the United States, and senior cytotechnologists and cytopathologists rescreened abnormal slides. The cases were then unmasked, and discrepant cases were reviewed. A subset of histologic data (1235 samples) was analyzed, and a final reference diagnosis was made. In the second study27 2009 sample pairs from a multicenter trial were evaluated blindly by 2 cytotechnologists, with all abnormal and 10% of normal slides reviewed by 1 of 6 pathologists. All sample pairs containing an abnormal result were then sent for a second masked opinion by cytotechnologists and pathologists. Consensus data were summarized and reported.
Study Quality Assessment
The total quality assessment scores of the 5 studies ranged from 7 to 10 out of a possible maximum score of 13. In general, the studies offered little or no description of the clinical characteristics of the women screened. Most did not even mention the women’s ages. All of the studies included at least some women who were at high risk for an abnormal Pap test result. Two of the studies included only women referred because of a previously abnormal result. Three studies included colposcopy clinics among their recruiting sites. One study was done in Costa Rica because of the known high prevalence of abnormal Pap test results in that country. One study specified that a consecutive series of patients was used, and one used a population-based random sample. The other 3 studies gave no details of how patients were selected for inclusion in the trial. All studies used prospectively collected data, and the methods used to actually perform the Pap and FBC tests were universally well described. Two of the studies used methods to minimize the effects of interobserver reliability in the evaluation of the test results, but none addressed this issue as it related to the assessment of the reference standard.
Sensitivity and Specificity
The ROC curves for FBC and Pap using all 5 of the above studies are displayed in Figure 1. The AuROC curves were similar (Pap=0.93; FBC= 0.91). This difference was not significant (P=.37), and the confidence interval (CI) was wide (95% CI, -0.33 to 0.80). FBC demonstrated higher sensitivity, 90% (95% CI, 0.77-0.96) versus 79% (95% CI, 0.59-0.91) for Pap. FBC had a lower specificity, 85% (95% CI, 0.74-0.92) versus 89% (95% CI, 0.75-0.96) for Pap.
Specimen Adequacy
FBC specimens were more likely to be reported as satisfactory (RD=0.06; 95% CI, 0.03-0.09; Figure 2. There was no significant difference in the number of unsatisfactory test results. There was a 6% higher rate of absence of endocervical cells (RD=0.06; 95% CI, 0.02-0.10) but a 10% decrease in reports of SBLB-o (RD = -0.10; 95% CI, -0.13 to -0.06) with FBC. The increase in absence of endocervical cells for FBC specimens was seen in all split-sample studies (RD= 0.08; 95% CI, 0.06-0.11) but not in the cohort studies (RD = -0.01; 95% CI -0.07 to 0.05).
Discussion
The use of FBC increases both true-positive and false-positive results when compared with Pap. These conclusions must be considered tentative because of the lack of statistical significance and the significant methodologic problems found in the studies used. Two recent meta-analyses have addressed the accuracy of FBC tests.3,60 Neither addressed the issue of specimen adequacy. Although neither included all 5 studies that we identified for our analysis of test accuracy, our findings of a possible increase in sensitivity with a decrease in specificity are consistent with the findings of the other 2 meta-analyses.
The possibility that FBC may increase sensitivity but decrease specificity should lead to caution in the adoption of this technology, especially for women at low risk for cervical cancer. For women with no history of abnormal findings on previous Pap tests (estimated prevalence of cervical cancer = 0.05%) more than 1800 FBC would be needed to detect one additional true positive. More than 50 additional false-positive test results (“cancer scares”) would accompany each additional true positive. The costs of follow-up investigations for these additional false-positive tests must be added to the additional cost of the test itself in assessing the potential impact of a widespread switch to this new technology. Many women are at risk because they fail to obtain regular Pap tests, often because of lack of insurance and cost barriers. Unfortunately, the higher cost of FBC may make these women even less likely to have screening performed. Thus widespread use of FBC could, paradoxically, lead to an increase rather than a decrease in cervical cancer deaths by decreasing the use of this important test by lower income women.
The trade-off between sensitivity and specificity is more favorable for women with higher disease rates. In a population with a 3% prevalence of cervical disease, only 300 FBC Pap tests would be required to detect one additional abnormality, and only 16 additional false-positive tests would result. Thus, for women who have had prior abnormal Pap test results or are known to be infrequent attenders, there may be a role for FBC.
Pap test results reported as less than satisfactory can present a significant problem with increased office return visits, increased psychologic trauma to the patient, and increased costs of repeated tests. Thus the decrease in “SBLB other” reports is a benefit of FBC, although it is partially offset by an increased absence of endocervical cells. Some have suggested that the absence of endocervical cells is an artifact of the study methods for split-sample studies (where the collection instrument is first wiped across a slide for the Pap and then inserted into the FBC vial). We do not understand why this process would preferentially extract endocervical cells. We did note that the cohort studies showed no increase in SBLB absence for FBC. However, in these studies, the Pap and FBC specimens were collected from different women and often involved different time periods and different physicians using different collection instruments. Both the degree of heterogeneity and the reported differences on all comparisons between Pap and FBC Pap tests were consistently larger in the cohort than in the split-sample studies.
FBC offers the advantage of doing HPV testing on the same Pap specimen in triaging the patient diagnosed with ASCUS. As shown in the ASCUS/LSIL Triage Study,61 patients with ASCUS Pap test results and negative human papillomavirus studies can be followed with annual Pap tests without colposcopy or more frequent screening.
Limitations
The greatest limitation of the studies was the lack of comparision of Pap test results and colposcopy with biopsy of any suspicious areas. We therefore also included studies that used an alternative reference standard for women with negative Pap results. However, the use of different reference standards for patients with positive and negative test results has been shown to result in overestimates of test sensitivity.8 The fact that none of the studies addressed the issue of blinding in interpretation of the reference standard is also of concern. Perhaps the most important limitation involves the fact that the patients included in these studies came from high-risk populations. It is not clear how well these results will generalize to the many women at low risk who receive Pap tests in the offices of American primary care physicians. An additional limitation of our study includes the potential for publication bias, since we included only those articles written in English.
Conclusions
Before widespread adoption of this new FBC technology, it would be advisable to have additional acceptable reference standards studies, designed to avoid verification bias and to ensure that equivalent specimen collection methods are used. Once reliable estimates of the relative sensitivity and specificity of the FBC Pap test are available from such investigations, a decision can be made about whether the benefits derived from widespread adoption would outweigh any disadvantages or additional costs.
STUDY DESIGN: This was a systematic review of original research reports evaluating both conventional Pap and FBC with respect to specimen adequacy, comparison with a reference standard, or both. Two reviewers independently reviewed the articles to determine inclusion status, with differences resolved by consensus with a third author. Risk differences (RD) between occurrence rates for FBC and Pap were used for the specimen adequacy data.
DATA SOURCES: Studies published between 1985 and November 1999 were identified from MEDLINE, Best Evidence, EMBASE, Biological Abstracts/RRM, and The Cochrane Library.
OUTCOMES MEASURED: Sensitivity, specificity, area under the receiver operating characteristic curve (AuROC), and the proportion of satisfactory, unsatisfactory, and “satisfactory but limited by” test results were measured.
RESULTS: There was no significant difference in AuROC (p=.37). FBC specimens were more likely to be satisfactory (RD=0.06; 95% confidence interval [CI], 0.03-0.09) or to have absent endocervical cells (RD=0.06; 95% CI, 0.02-0.10) but had 10% fewer “satisfactory but limited by—other” reports (RD = -0.10; 95% CI, -0.14 to -0.06). There was no difference in unsatisfactory Pap test results.
CONCLUSIONS: For most women there is no reason to replace Pap with FBC. For women at high risk of cervical cancer or who are screened infrequently, the possible increase in FBC sensitivity may outweigh the potential harms from additional false positives.
Despite mass Papanicolaou (Pap) test screening, approximately 12,800 women are given the diagnosis of cervical cancer in the United States each year, and approximately 4600 die of the disease.1 Fahey and colleagues2 found an average sensitivity of 58% (range = 11%-99%). Nanda and coworkers3 reported a sensitivity of 30% to 87%, with a specificity of 86% to 100%. Follen Mitchell and colleagues4 reported sensitivities of 67% and specificities of 77%. Multiple factors including sampling technique, patient preparation, test fixation and staining, and interpretation accuracy5 can increase the false-negative rates of conventional Pap.
Fluid-based cytology (FBC) procedures use a fluid medium to capture and preserve the collected cells from the cervical-sampling device. The collected sample is homogenized using an automated device, and a subsample of cellular material is placed on a glass slide in a circumferential area. Because the technique provides a uniform thin layer and excludes obscuring debris, it eliminates problems often encountered with Pap including poor fixation, uneven thickness of the cellular spread, air-drying artifact, and obscuring of cells by blood or inflammatory exudates.6
We performed a systematic review to evaluate the accuracy of FBC (by comparing its sensitivity and specificity with Pap) and the specimen adequacy of this new method (by comparing the proportion of FBC and Pap slides reported as unsatisfactory or “satisfactory but limited” by either absence of endocervical cells or other factors).
Methods
Search Strategy
Our literature search was designed to find studies comparing FBC and Pap. The search was assisted by a medical librarian and used medical subject headings (MeSH) and text words. The search terms included monolayer technology, ThinPrep, CytoRich, Cytoprep, Autoprep, AutoCyte, Papanicolau/pap smear, liquid-based cytology, fluid-based cytology, cervical cancer screening, and vaginal smears. MEDLINE, Best Evidence, EMBASE, Biological Abstracts/RRM and The Cochrane Library were searched to retrieve all potentially relevant English-language articles published between 1985 (first literature published on fluid-based cytology) and November 1999. An attempt was made to contact both FBC manufacturers to find any other available articles and abstracts in publication. The authors of articles with incomplete data were contacted in an attempt to obtain missing information. The reference lists of retrieved articles were manually searched for additional citations.
Study Inclusion
Articles were reviewed for inclusion if they contained reports of original research evaluating both conventional and fluid-based cytology samples (either ThinPrep or AutoCyte). Studies in which both tests were simultaneously applied to the same group of women (split-sample studies) and those in which one group of women who received Pap was compared with a group that received FBC (cohort studies) were included. Two reviewers independently reviewed the titles. When either reviewer felt the study might merit inclusion, the full article was retrieved. The same authors independently reviewed each article to determine whether it met the inclusion criteria. Differences were resolved by consensus with a third author.
We used the entire set of studies to address the question of specimen adequacy. To address FBC accuracy, we identified the subset of articles that compared the 2 tests with an external reference standard. We excluded articles from this analysis unless they reported colposcopy and biopsy results for at least 50% of the women with a finding of high-grade squamous intraepithelial lesions or higher on either Pap or FBC. Because few studies subjected all women with normal Pap tests to colposcopy, we also included studies that provided colposcopy to a random sample of women with normal Pap or FBC tests and those that subjected normal tests to an independent consensus review by a panel of experienced cytology professionals.7
Study Quality Assessment
For the studies addressing accuracy, we developed a criteria form for extracting infusing criteria.8 Two points were assigned and summed to create an overall study quality score (maximum score = 13). Two reviewers independently assessed the quality of each article with differences resolved by consensus Table 1.
Data Extraction
Three reviewers independently extracted data using a structured form. Differences were resolved by consensus. Specimen adequacy was classified as satisfactory, satisfactory but limited by absence of endocervical cells (SBLB-absence), satisfactory but limited by other (SBLB-o), and unsatisfactory. SBLB-o included obscuring inflammatory exudate, blood, thick tests, scant cellularity, and air-drying artifact.
Data Synthesis and Analysis
Summary estimates of sensitivity and specificity were made from studies that used an appropriate reference standard using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using MetaTest software (version 0.6, Joseph Lau, MD, with permission). The MetaTest program was also used to calculate the area under receiver operating characteristic (AuROC) curves, and the difference between AuROC was calculated using ROCKET 0.9B software for ROC analysis (Charles E. Metz, Department of Radiology University of Chicago, March 1998). The AuROC is a measure of overall diagnostic accuracy, where 1.0 is a perfect test, and 0.5 is a test that is no better than chance at distinguishing normal from abnormal specimens. For analysis of specimen adequacy, we used the RevMan 4.1 software (Cochrane Collaboration, Update Software, Oxford, England) to calculate rate differences. Study homogeneity analyses were performed, and our analysis plan called for the use of a random effects model if significant heterogeneity (P >.05) was found.
Results
Search Strategy and Study Inclusion
We identified 62 articles for critical appraisal. Because some authors published more than one article from a single study9-23 and one author combined 2 studies into one article,24 the 62 articles represented 47 actual studies. Fifty-two articles met the initial inclusion criteria.6,9-59 Ten articles were excluded, because they did not contain a reference standard or specimen adequacy data, or they restricted their reports to only a subset of Pap results, such as atypical glandular cells of uncertain significance (AGUS) or atypical squamous cells of uncertain significance (ASCUS).24,39,61-68
Study Characteristics and Qualitative Synthesis
Most articles provided no systematic comparison with any reference standard and could therefore only be used to evaluate specimen adequacy. In some cases, histologic results were reported for some patients and compared with Pap and FBC reports; however, these appeared to be haphazard samples of patients with a positive result on one or both tests. Most articles compared the results obtained from FBC and Pap with the assumption that the better test was the one with the higher proportion of positives, ignoring the possibility of false-positive tests.
Five studies included a comparison with a reference standard.18,27,35,40,50 In all 5, both tests were performed at the same time in all patients. After the cervix was scraped in the usual fashion, the sampling device was wiped across a slide for the conventional Pap and then rinsed in a vial containing the appropriate solution for the FBC method.
Three studies systematically compared FBC and Pap results with colposcopy and biopsy. One12,35 involved women referred to a colposcopy clinic because of a previous abnormal test result; Pap and FBC Pap test results were obtained, and colposcopic examinations were done on all women referred. A second16,23,55 studied 782 patients referred for colposcopy after an abnormal Pap test result; colposcopy was performed, and biopsies were taken from 445 of these patients. In the third study40 A total of 8636 randomly selected Costa Rican women were each screened with Pap, FBC, and cervicography. All women with a suspicious physical examination for cancer or with any abnormality on any of the 3 tests were referred for colposcopy, along with a random sample of 150 women with no abnormalities.
The remaining 2 studies27,50 used consensus between independent reviewers of the Pap and FBC test results as the reference standard, with biopsy for at least 50% of the women with significant abnormalities on either or both tests. In the first study50 a total of 2778 split samples were obtained and evaluated in both Germany and the United States. In Germany, masked slides were reviewed by cytotechnologists, and pathologists reviewed all abnormal and discrepant slides. Masked review was repeated in the United States, and senior cytotechnologists and cytopathologists rescreened abnormal slides. The cases were then unmasked, and discrepant cases were reviewed. A subset of histologic data (1235 samples) was analyzed, and a final reference diagnosis was made. In the second study27 2009 sample pairs from a multicenter trial were evaluated blindly by 2 cytotechnologists, with all abnormal and 10% of normal slides reviewed by 1 of 6 pathologists. All sample pairs containing an abnormal result were then sent for a second masked opinion by cytotechnologists and pathologists. Consensus data were summarized and reported.
Study Quality Assessment
The total quality assessment scores of the 5 studies ranged from 7 to 10 out of a possible maximum score of 13. In general, the studies offered little or no description of the clinical characteristics of the women screened. Most did not even mention the women’s ages. All of the studies included at least some women who were at high risk for an abnormal Pap test result. Two of the studies included only women referred because of a previously abnormal result. Three studies included colposcopy clinics among their recruiting sites. One study was done in Costa Rica because of the known high prevalence of abnormal Pap test results in that country. One study specified that a consecutive series of patients was used, and one used a population-based random sample. The other 3 studies gave no details of how patients were selected for inclusion in the trial. All studies used prospectively collected data, and the methods used to actually perform the Pap and FBC tests were universally well described. Two of the studies used methods to minimize the effects of interobserver reliability in the evaluation of the test results, but none addressed this issue as it related to the assessment of the reference standard.
Sensitivity and Specificity
The ROC curves for FBC and Pap using all 5 of the above studies are displayed in Figure 1. The AuROC curves were similar (Pap=0.93; FBC= 0.91). This difference was not significant (P=.37), and the confidence interval (CI) was wide (95% CI, -0.33 to 0.80). FBC demonstrated higher sensitivity, 90% (95% CI, 0.77-0.96) versus 79% (95% CI, 0.59-0.91) for Pap. FBC had a lower specificity, 85% (95% CI, 0.74-0.92) versus 89% (95% CI, 0.75-0.96) for Pap.
Specimen Adequacy
FBC specimens were more likely to be reported as satisfactory (RD=0.06; 95% CI, 0.03-0.09; Figure 2. There was no significant difference in the number of unsatisfactory test results. There was a 6% higher rate of absence of endocervical cells (RD=0.06; 95% CI, 0.02-0.10) but a 10% decrease in reports of SBLB-o (RD = -0.10; 95% CI, -0.13 to -0.06) with FBC. The increase in absence of endocervical cells for FBC specimens was seen in all split-sample studies (RD= 0.08; 95% CI, 0.06-0.11) but not in the cohort studies (RD = -0.01; 95% CI -0.07 to 0.05).
Discussion
The use of FBC increases both true-positive and false-positive results when compared with Pap. These conclusions must be considered tentative because of the lack of statistical significance and the significant methodologic problems found in the studies used. Two recent meta-analyses have addressed the accuracy of FBC tests.3,60 Neither addressed the issue of specimen adequacy. Although neither included all 5 studies that we identified for our analysis of test accuracy, our findings of a possible increase in sensitivity with a decrease in specificity are consistent with the findings of the other 2 meta-analyses.
The possibility that FBC may increase sensitivity but decrease specificity should lead to caution in the adoption of this technology, especially for women at low risk for cervical cancer. For women with no history of abnormal findings on previous Pap tests (estimated prevalence of cervical cancer = 0.05%) more than 1800 FBC would be needed to detect one additional true positive. More than 50 additional false-positive test results (“cancer scares”) would accompany each additional true positive. The costs of follow-up investigations for these additional false-positive tests must be added to the additional cost of the test itself in assessing the potential impact of a widespread switch to this new technology. Many women are at risk because they fail to obtain regular Pap tests, often because of lack of insurance and cost barriers. Unfortunately, the higher cost of FBC may make these women even less likely to have screening performed. Thus widespread use of FBC could, paradoxically, lead to an increase rather than a decrease in cervical cancer deaths by decreasing the use of this important test by lower income women.
The trade-off between sensitivity and specificity is more favorable for women with higher disease rates. In a population with a 3% prevalence of cervical disease, only 300 FBC Pap tests would be required to detect one additional abnormality, and only 16 additional false-positive tests would result. Thus, for women who have had prior abnormal Pap test results or are known to be infrequent attenders, there may be a role for FBC.
Pap test results reported as less than satisfactory can present a significant problem with increased office return visits, increased psychologic trauma to the patient, and increased costs of repeated tests. Thus the decrease in “SBLB other” reports is a benefit of FBC, although it is partially offset by an increased absence of endocervical cells. Some have suggested that the absence of endocervical cells is an artifact of the study methods for split-sample studies (where the collection instrument is first wiped across a slide for the Pap and then inserted into the FBC vial). We do not understand why this process would preferentially extract endocervical cells. We did note that the cohort studies showed no increase in SBLB absence for FBC. However, in these studies, the Pap and FBC specimens were collected from different women and often involved different time periods and different physicians using different collection instruments. Both the degree of heterogeneity and the reported differences on all comparisons between Pap and FBC Pap tests were consistently larger in the cohort than in the split-sample studies.
FBC offers the advantage of doing HPV testing on the same Pap specimen in triaging the patient diagnosed with ASCUS. As shown in the ASCUS/LSIL Triage Study,61 patients with ASCUS Pap test results and negative human papillomavirus studies can be followed with annual Pap tests without colposcopy or more frequent screening.
Limitations
The greatest limitation of the studies was the lack of comparision of Pap test results and colposcopy with biopsy of any suspicious areas. We therefore also included studies that used an alternative reference standard for women with negative Pap results. However, the use of different reference standards for patients with positive and negative test results has been shown to result in overestimates of test sensitivity.8 The fact that none of the studies addressed the issue of blinding in interpretation of the reference standard is also of concern. Perhaps the most important limitation involves the fact that the patients included in these studies came from high-risk populations. It is not clear how well these results will generalize to the many women at low risk who receive Pap tests in the offices of American primary care physicians. An additional limitation of our study includes the potential for publication bias, since we included only those articles written in English.
Conclusions
Before widespread adoption of this new FBC technology, it would be advisable to have additional acceptable reference standards studies, designed to avoid verification bias and to ensure that equivalent specimen collection methods are used. Once reliable estimates of the relative sensitivity and specificity of the FBC Pap test are available from such investigations, a decision can be made about whether the benefits derived from widespread adoption would outweigh any disadvantages or additional costs.
1. Greenlee R, Taylor M, Bolden S, Wingo P. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7-33.
2. Fahey M, Irwig L, Macaskill P. Meta-analysis of Pap test accuracy. Am J Epidemiol 1995;141:680-89.
3. Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolau test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000;132:810-19.
4. Follen Mitchell M, Cantor SB, Brookner C, Utzinger U, Schottenfeld D, Richards-Kortum R. Screening for squamous intraepithelial lesions with fluorescence spectroscopy. OB GYN 1999;94:889-96.
5. Gay JD, Donaldson LD, Goellner JR. False negative results in cervical cytologic studies. Acta Cytologica 1985;29:1043-46.
6. Dupree WB, Suprun HZ, Beckwith DG, Shane JJ, Lucente V. The promise and risk of a new technology: the Lehigh Valley Hospital’s experience with liquid-based cervical cytology. Cancer (Cancer Cytopathology) 1998;84:202-07.
7. Proposed guidelines for primary screening instruments for gynecologic cytology: Intersociety Working Group for Cytology Technologies Am J Clin Path 1997;109:10-15.
8. Lijmer J, Mol B, Heisterkamp S, et al. Empirical evidence of design-related bias in studies of diagnostic tests. JAMA 1999;282:1061-66.
9. Ashfaq R, Birdsong G, Corkill M, Inhorn S. Improved specimen adequacy with the ThinPrep 2000 System: reductions in satisfactory but limited by…interpretations (Abstract presentation at the 44th scientific meeting). Acta Cytologica 1996;40:1046-47.
10. Bishop JW, Cheuvront DA, Elston RJ. Utility of residual AutoCyte cervical cytology samples of image analysis. Acta Cytologica 1999;43:39-46.
11. Corkill M, Knapp D, Martin J, Hutchinson M. Speciman adequacy of ThinPrep sample preparations in a direct-to-vial study. Acta Cytologica 1997;41:39-44.
12. Ferenczy A, Robitaille J, Franco E, et al. Conventional cervical cytologic smears vs. ThinPrep smears: a paired comparison study on cervical cytology. Acta Cytologica 1996;40:1136-42.
13. Howell P, Belk T, Agdigos R, Davis R, Lowe J. AutoCyte interactive screening system: experience at a university hospital cytology laboratory. Acta Cytologica 1999;43:58-64.
14. Inhorn SL, Wilbur D, Zahniser D, Linder J. Validation of the ThinPrep Papanicolaou test for cervical cancer diagnosis. J Lower Genital Tract Dis 1998;2:208-12.
15. Inhorn SL, Sherman M. Independent Pathologist review of ThinPrep and conventional Pap smears from multisite clinical trials. Acta Cytologica (Abstract presentation at 44th annual scientific meeting) 1996;40:1044.-
16. Lee KL, Madge R, Sheets EE. Colposcopically directed biopsy as a basis for comparing the diagnostic accuracy of the ThinPrep and Papanicolaou smear methods. Acta Cytologica (Abstract presentation 44th annual scientific meeting) 1996;40:1047.-
17. Linder J. Recent advances in thin-layer cytology. Diagnostic Cytopathol 1998;18:24-32.
18. Sheets EE, Constantine NM, Dinisco S, Dean B, Cibas ES. Colposcopically directed biopsies provide a basis for comparing the accuracy of ThinPrep and Papanicolaou smears. J Gynecologic Techniques 1995;1:27-34.
19. Sherman ME, Schiffman MH, Lorincz AT, et al. Cervical specimens collected in liquid buffer are suitable for both cytologic screening and ancillary human papillomavirus testing. Cancer 1997;81:89-97.
20. Sherman ME, Mendoza M, Lee KR, et al. Performance of liquid-based, thin-layer cervical cytology: correlation with reference diagnoses and human papillomavirus testing. Mod Pathol 1998;11:837-43.
21. Sherman ME, Schiffman M, Herrero R, et al. Evaluation of conventional and novel cervical cancer screening methods in a population-based study of 10,000 Costa Rican women. ACTA Cytological Abstract Presentation 43rd Annual Scientific Meeting 1995;39:983.-
22. Vassilakos P, Griffin S, Megevand E, Campana A. CytoRich liquid-based cervical cytologic test: screening results in a routine cytopathology service. Acta Cytologica 1998;42:198-202.
23. Zahniser DJ, Sullivan PJ. CYTYC corporation. Acta Cytologica 1996;40:37-44.
24. Vassilakos P, Saurel J, Rondez R. Direct-to-vial use of the AutoCyte PREP liquid-based preparation for cervical-vaginal specimens in three European laboratories. Acta Cytologica 1999;43:65-68.
25. Aponte-Cipriani SL, Teplitz C, Rorat E, Scaino A, Jacobs AJ. Cervical smears prepared by an automated device versus the conventional method: a comparative analysis. Acta Cytologica 1995;39:623-30.
26. Awen C, Hathway S, Eddy W, Voskuil R, Janes C. Efficacy of ThinPrep preparation of cervical smears: a 1,000-case, investigator-sponsored study. Diagn Cytopathol 1993;11:33-36.
27. Bishop JW. Comparison of the CytoRich system with conventional cervical cytology: preliminary data on 2,032 cases from a clinical trial site. Acta Cytologica 1997;41:15-23.
28. Bishop JW, Bigner SH, Colgan TJ, et al. Multicenter masked evaluation of AutoCyte PREP thin layers with matched conventional smears: including initial biopsy results. Acta Cytologica 1998;42:189-97.
29. Bolick DR, Hellman DJ. Laboratory implementation and efficacy assessment of the Thin Prep cervical cancer screening system. Acta Cytologica 1998;42:209-13.1999;87:105-12.
30. Bur M, Knowles K, Pekow P, Corral O, Donovan J. Comparison of ThinPrep preparations with conventional cervicovaginal smears. Acta Cytologica 1995;39:631-42.
31. Candel A, Davis B, Baklios R, Selvaggi S. The ThinPrep Pap test: a cost savings perspective. Lab Invest 1998;78:36A.-
32. Carpenter AB, Davey DD. Thin Prep Pap test: performance and biopsy follow-up in a university hospital. Cancer 1999;87:105-12.
33. Diaz-Rosario LA, Kabawa SE. Performance of a fluid-based, Thin-Layer Papanicolaou smear method in the clinical setting of an independent laboratory and an outpatient screening population in New England. Arch Pathol Lab Med 1999;123:817-21.
34. Emery J, Banks H, Holz J, DePriest P, Davey DD. The ThinPrep method for cervical-vaginal specimens in a high risk population. Acta Cytologica (Abstract presentation 45th annual scientific meeting) 1997;41-1579.
35. Ferenczy A, Franco E, Arseneau J, Wright TC, Richart RM. Diagnostic performance of hybrid capture human papillomavirus deoxyribonucleic acid assay combined with liquid based cytologic study. Am J Obstet Gynecol 1996;175:651-56.
36. Geyer JW, Hancock F, Carrico C, Kirkpatrick M. Preliminary evaluation of Cyto-Rich: an improved automated cytology preparation. Diagn Cytopathol 1993;9:417-22.
37. Guidos BJ, Selvaggi SM. Use of the ThinPrep Pap test in clinical practice. Diagn Cytopathol 1999;20:70-73.
38. Howell LP, Davis RL, Belk TI, Agdigos R, Lowe J. The AutoCyte preparation system for gynecologic cytology. Acta Cytologica 1998;42:171-77.
39. Hutchinson ML, Agarwal P, Denault T, Berger B, Cibas ES. A new look at cervical cytology: ThinPrep multicenter trial results. Acta Cytologica 1992;36:499-504.
40. Hutchinson ML, Zahniser DJ, Sherman ME, et al. Utility of liquid-based cytology for cervical carcinoma: screening. Cancer Cytopathol 1999;87:48-55.
41. Johnson JE, Jones HW, Conrad KA, Huff BC. Increased rate of SIL detection with excellent biopsy correlation after implementation of direct-to-vial ThinPrep liquid-based preparation of cervicovaginal specimens at a university medical center. Acta Cytologica (Abstract presentation 46th scientific meeting) 1998;42:1242-43.
42. Laverty CRA, Farnsworth A, Thurloe JK, Grieves A, Bowditch R. Evaluation of the CytoRich slide preparation process. Analyt Quant Cytol Histol 1997;19:239-45.
43. Laverty CRA, Thurloe JK, Redman NL, Farnsworth A. An Australian trial of ThinPrep: a new cytopreparatory technique. Cytopathology 1995;6:140-48.
44. Lee KR, Ashfaqu R, Birdsong GG, Korkill ME, McIntosh KM, Inhorn SL. Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for cervical cancer Screening. Obstet Gynecol 1997;90:278-84.
45. McGoogan E, Reith A. Would monolayers provide more representative samples and improved preparations for cervical screening? Overview and evaluation of systems available. Acta Cytologica 1996;49:107-19.
46. Papillo JL, Zarka MA, St. John TL. Evaluation of the ThinPrep Pap test in clinical practice: a seven-month, 16,314-case experience in Northern Vermont. Acta Cytologica 1998;42:203-08.
47. Quddus MR, Xu B, Sung CJ, Boardman L, Lauchlan SC. Cytohisto correlations support the observation of increased detection of squamous intraepithelial lesions by the ThinPrep process. Acta Cytologica (Abstract presentation 46th annual scientific meeting) 1998;42:1243.-
48. Radio SJ, Burns KR, Munch TM, Quasi VM, Bohl KD, Severson MA. Paired comparison of conventional and ThinPrep cervical cytology in a high risk population. Lab Invest 1998;78:42A.-
49. Shield PW, Nolan GR, Phillips GE, Cummings MC. Improving cervical cytology screening in a remote, high risk population. MJA 1999;170:255-58.
50. Sprenger E, Schwarzmann P, Kirkpatrick M, et al. The false negative rate in cervical cytology: comparison of monolayers to conventional smears. Acta Cytologica 1996;40:81-89.
51. Stevens MW, Nespolon WW, Milne AJ, Rowland R. Evaluation of the CytoRich technique for cervical smears. Diagn Cytopathol 1998;18:236-42.
52. Vassilakos P, Cossali D, Albe X, Alonso L, Hohener R, Puget E. Efficacy of Monolayer preparations for cervical cytology: emphasis on suboptimal specimens. Acta Cytologica 1996;40:496-500.
53. Wang T-Y, Chen H-S, Yang Y-C, Tsou M-C. Comparison of fluid-based, Thin-Layer processing and conventional Papanicolaou methods for uterine cervical cytology. J Formos Med Assoc 1999;98:500-05.
54. Weintraub J. The coming evolution in cervical cytology: a pathologist’s guide for the clinician. En Gynecologie Obstetrique 1997;5:169-75.
55. Wilbur DC, Cibas ES, Merritt S, James LP, Berger BM, Bonfiglio TA. ThinPrep processor: clinical trials demonstrate an increased detection rate of abnormal cervical cytologic specimens. Am J Clin Pathol 1994;101:209-14.
56. Wilbur DC, Facik MC, Rutkowski MA, Mulford DK, Atkison KM. Clinical trials of the CytoRich specimen-preparation device for cervical cytology. Acta Cytologica 1997;41:24-29.
57. Wilbur DC, Dubesher B, Angel C, Atkison KM. Use of Thin-Layer preparations for gynecologic smears with emphasis on the cytomorphology of high-grade intraepithelial lesions and carcinomas. Diagn Cytopathol 1995;14:201-11.
58. Yang M, Zachariah S. Comparison of specimen adequacy between matched ThinPrep preparations and conventional cervicovaginal smears. Acta Cytologica (Abstract presentation 45th scientific meeting) 1997;41:1579.-
59. Hutchinson ML, Cassin CM, Ball HG. The efficacy of an automated preparation device for cervical cytology. Am J Clin Pathol 1991;96:300-05.
60. Roberts J, Gurley AM, Thurloe JK, Bowditch R, Laverty CA. Evaluation of the ThinPrep test as an adjunct to the conventional Pap smear. MJA 1997;167:466-69.
61. McCrory D, Bastian D, et al. Evaluation of cervical cytology: evidence report/technology assessment no. 5 (Prepared by Duke University under contract no. 290-97-0014). Rockville, Md: Agency for Health Care Policy and Research; 1999.
62. Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Instit 2001;93:293-99.
1. Greenlee R, Taylor M, Bolden S, Wingo P. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7-33.
2. Fahey M, Irwig L, Macaskill P. Meta-analysis of Pap test accuracy. Am J Epidemiol 1995;141:680-89.
3. Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolau test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000;132:810-19.
4. Follen Mitchell M, Cantor SB, Brookner C, Utzinger U, Schottenfeld D, Richards-Kortum R. Screening for squamous intraepithelial lesions with fluorescence spectroscopy. OB GYN 1999;94:889-96.
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6. Dupree WB, Suprun HZ, Beckwith DG, Shane JJ, Lucente V. The promise and risk of a new technology: the Lehigh Valley Hospital’s experience with liquid-based cervical cytology. Cancer (Cancer Cytopathology) 1998;84:202-07.
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9. Ashfaq R, Birdsong G, Corkill M, Inhorn S. Improved specimen adequacy with the ThinPrep 2000 System: reductions in satisfactory but limited by…interpretations (Abstract presentation at the 44th scientific meeting). Acta Cytologica 1996;40:1046-47.
10. Bishop JW, Cheuvront DA, Elston RJ. Utility of residual AutoCyte cervical cytology samples of image analysis. Acta Cytologica 1999;43:39-46.
11. Corkill M, Knapp D, Martin J, Hutchinson M. Speciman adequacy of ThinPrep sample preparations in a direct-to-vial study. Acta Cytologica 1997;41:39-44.
12. Ferenczy A, Robitaille J, Franco E, et al. Conventional cervical cytologic smears vs. ThinPrep smears: a paired comparison study on cervical cytology. Acta Cytologica 1996;40:1136-42.
13. Howell P, Belk T, Agdigos R, Davis R, Lowe J. AutoCyte interactive screening system: experience at a university hospital cytology laboratory. Acta Cytologica 1999;43:58-64.
14. Inhorn SL, Wilbur D, Zahniser D, Linder J. Validation of the ThinPrep Papanicolaou test for cervical cancer diagnosis. J Lower Genital Tract Dis 1998;2:208-12.
15. Inhorn SL, Sherman M. Independent Pathologist review of ThinPrep and conventional Pap smears from multisite clinical trials. Acta Cytologica (Abstract presentation at 44th annual scientific meeting) 1996;40:1044.-
16. Lee KL, Madge R, Sheets EE. Colposcopically directed biopsy as a basis for comparing the diagnostic accuracy of the ThinPrep and Papanicolaou smear methods. Acta Cytologica (Abstract presentation 44th annual scientific meeting) 1996;40:1047.-
17. Linder J. Recent advances in thin-layer cytology. Diagnostic Cytopathol 1998;18:24-32.
18. Sheets EE, Constantine NM, Dinisco S, Dean B, Cibas ES. Colposcopically directed biopsies provide a basis for comparing the accuracy of ThinPrep and Papanicolaou smears. J Gynecologic Techniques 1995;1:27-34.
19. Sherman ME, Schiffman MH, Lorincz AT, et al. Cervical specimens collected in liquid buffer are suitable for both cytologic screening and ancillary human papillomavirus testing. Cancer 1997;81:89-97.
20. Sherman ME, Mendoza M, Lee KR, et al. Performance of liquid-based, thin-layer cervical cytology: correlation with reference diagnoses and human papillomavirus testing. Mod Pathol 1998;11:837-43.
21. Sherman ME, Schiffman M, Herrero R, et al. Evaluation of conventional and novel cervical cancer screening methods in a population-based study of 10,000 Costa Rican women. ACTA Cytological Abstract Presentation 43rd Annual Scientific Meeting 1995;39:983.-
22. Vassilakos P, Griffin S, Megevand E, Campana A. CytoRich liquid-based cervical cytologic test: screening results in a routine cytopathology service. Acta Cytologica 1998;42:198-202.
23. Zahniser DJ, Sullivan PJ. CYTYC corporation. Acta Cytologica 1996;40:37-44.
24. Vassilakos P, Saurel J, Rondez R. Direct-to-vial use of the AutoCyte PREP liquid-based preparation for cervical-vaginal specimens in three European laboratories. Acta Cytologica 1999;43:65-68.
25. Aponte-Cipriani SL, Teplitz C, Rorat E, Scaino A, Jacobs AJ. Cervical smears prepared by an automated device versus the conventional method: a comparative analysis. Acta Cytologica 1995;39:623-30.
26. Awen C, Hathway S, Eddy W, Voskuil R, Janes C. Efficacy of ThinPrep preparation of cervical smears: a 1,000-case, investigator-sponsored study. Diagn Cytopathol 1993;11:33-36.
27. Bishop JW. Comparison of the CytoRich system with conventional cervical cytology: preliminary data on 2,032 cases from a clinical trial site. Acta Cytologica 1997;41:15-23.
28. Bishop JW, Bigner SH, Colgan TJ, et al. Multicenter masked evaluation of AutoCyte PREP thin layers with matched conventional smears: including initial biopsy results. Acta Cytologica 1998;42:189-97.
29. Bolick DR, Hellman DJ. Laboratory implementation and efficacy assessment of the Thin Prep cervical cancer screening system. Acta Cytologica 1998;42:209-13.1999;87:105-12.
30. Bur M, Knowles K, Pekow P, Corral O, Donovan J. Comparison of ThinPrep preparations with conventional cervicovaginal smears. Acta Cytologica 1995;39:631-42.
31. Candel A, Davis B, Baklios R, Selvaggi S. The ThinPrep Pap test: a cost savings perspective. Lab Invest 1998;78:36A.-
32. Carpenter AB, Davey DD. Thin Prep Pap test: performance and biopsy follow-up in a university hospital. Cancer 1999;87:105-12.
33. Diaz-Rosario LA, Kabawa SE. Performance of a fluid-based, Thin-Layer Papanicolaou smear method in the clinical setting of an independent laboratory and an outpatient screening population in New England. Arch Pathol Lab Med 1999;123:817-21.
34. Emery J, Banks H, Holz J, DePriest P, Davey DD. The ThinPrep method for cervical-vaginal specimens in a high risk population. Acta Cytologica (Abstract presentation 45th annual scientific meeting) 1997;41-1579.
35. Ferenczy A, Franco E, Arseneau J, Wright TC, Richart RM. Diagnostic performance of hybrid capture human papillomavirus deoxyribonucleic acid assay combined with liquid based cytologic study. Am J Obstet Gynecol 1996;175:651-56.
36. Geyer JW, Hancock F, Carrico C, Kirkpatrick M. Preliminary evaluation of Cyto-Rich: an improved automated cytology preparation. Diagn Cytopathol 1993;9:417-22.
37. Guidos BJ, Selvaggi SM. Use of the ThinPrep Pap test in clinical practice. Diagn Cytopathol 1999;20:70-73.
38. Howell LP, Davis RL, Belk TI, Agdigos R, Lowe J. The AutoCyte preparation system for gynecologic cytology. Acta Cytologica 1998;42:171-77.
39. Hutchinson ML, Agarwal P, Denault T, Berger B, Cibas ES. A new look at cervical cytology: ThinPrep multicenter trial results. Acta Cytologica 1992;36:499-504.
40. Hutchinson ML, Zahniser DJ, Sherman ME, et al. Utility of liquid-based cytology for cervical carcinoma: screening. Cancer Cytopathol 1999;87:48-55.
41. Johnson JE, Jones HW, Conrad KA, Huff BC. Increased rate of SIL detection with excellent biopsy correlation after implementation of direct-to-vial ThinPrep liquid-based preparation of cervicovaginal specimens at a university medical center. Acta Cytologica (Abstract presentation 46th scientific meeting) 1998;42:1242-43.
42. Laverty CRA, Farnsworth A, Thurloe JK, Grieves A, Bowditch R. Evaluation of the CytoRich slide preparation process. Analyt Quant Cytol Histol 1997;19:239-45.
43. Laverty CRA, Thurloe JK, Redman NL, Farnsworth A. An Australian trial of ThinPrep: a new cytopreparatory technique. Cytopathology 1995;6:140-48.
44. Lee KR, Ashfaqu R, Birdsong GG, Korkill ME, McIntosh KM, Inhorn SL. Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for cervical cancer Screening. Obstet Gynecol 1997;90:278-84.
45. McGoogan E, Reith A. Would monolayers provide more representative samples and improved preparations for cervical screening? Overview and evaluation of systems available. Acta Cytologica 1996;49:107-19.
46. Papillo JL, Zarka MA, St. John TL. Evaluation of the ThinPrep Pap test in clinical practice: a seven-month, 16,314-case experience in Northern Vermont. Acta Cytologica 1998;42:203-08.
47. Quddus MR, Xu B, Sung CJ, Boardman L, Lauchlan SC. Cytohisto correlations support the observation of increased detection of squamous intraepithelial lesions by the ThinPrep process. Acta Cytologica (Abstract presentation 46th annual scientific meeting) 1998;42:1243.-
48. Radio SJ, Burns KR, Munch TM, Quasi VM, Bohl KD, Severson MA. Paired comparison of conventional and ThinPrep cervical cytology in a high risk population. Lab Invest 1998;78:42A.-
49. Shield PW, Nolan GR, Phillips GE, Cummings MC. Improving cervical cytology screening in a remote, high risk population. MJA 1999;170:255-58.
50. Sprenger E, Schwarzmann P, Kirkpatrick M, et al. The false negative rate in cervical cytology: comparison of monolayers to conventional smears. Acta Cytologica 1996;40:81-89.
51. Stevens MW, Nespolon WW, Milne AJ, Rowland R. Evaluation of the CytoRich technique for cervical smears. Diagn Cytopathol 1998;18:236-42.
52. Vassilakos P, Cossali D, Albe X, Alonso L, Hohener R, Puget E. Efficacy of Monolayer preparations for cervical cytology: emphasis on suboptimal specimens. Acta Cytologica 1996;40:496-500.
53. Wang T-Y, Chen H-S, Yang Y-C, Tsou M-C. Comparison of fluid-based, Thin-Layer processing and conventional Papanicolaou methods for uterine cervical cytology. J Formos Med Assoc 1999;98:500-05.
54. Weintraub J. The coming evolution in cervical cytology: a pathologist’s guide for the clinician. En Gynecologie Obstetrique 1997;5:169-75.
55. Wilbur DC, Cibas ES, Merritt S, James LP, Berger BM, Bonfiglio TA. ThinPrep processor: clinical trials demonstrate an increased detection rate of abnormal cervical cytologic specimens. Am J Clin Pathol 1994;101:209-14.
56. Wilbur DC, Facik MC, Rutkowski MA, Mulford DK, Atkison KM. Clinical trials of the CytoRich specimen-preparation device for cervical cytology. Acta Cytologica 1997;41:24-29.
57. Wilbur DC, Dubesher B, Angel C, Atkison KM. Use of Thin-Layer preparations for gynecologic smears with emphasis on the cytomorphology of high-grade intraepithelial lesions and carcinomas. Diagn Cytopathol 1995;14:201-11.
58. Yang M, Zachariah S. Comparison of specimen adequacy between matched ThinPrep preparations and conventional cervicovaginal smears. Acta Cytologica (Abstract presentation 45th scientific meeting) 1997;41:1579.-
59. Hutchinson ML, Cassin CM, Ball HG. The efficacy of an automated preparation device for cervical cytology. Am J Clin Pathol 1991;96:300-05.
60. Roberts J, Gurley AM, Thurloe JK, Bowditch R, Laverty CA. Evaluation of the ThinPrep test as an adjunct to the conventional Pap smear. MJA 1997;167:466-69.
61. McCrory D, Bastian D, et al. Evaluation of cervical cytology: evidence report/technology assessment no. 5 (Prepared by Duke University under contract no. 290-97-0014). Rockville, Md: Agency for Health Care Policy and Research; 1999.
62. Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Instit 2001;93:293-99.