Conventional Papanicolaou Smear Research Articles

Liquid-based cervical cytologic smear study and conventional Papanicolaou smears: A metaanalysis of prospective studies comparing cytologic diagnosis and sample adequacy

Objective: We sought to evaluate the cytologic diagnosis and sample adequacy of the liquid-based cervical cytologic smear (ThinPrep) compared with that of the conventional Papanicolaou smear. Study Design: Prospective studies of ThinPrep and conventional Papanicolaou smears were analyzed for cytologic diagnosis and sample adequacy. Computerized databases, references in published studies, and index reviews published in English were used to identify direct-to-vial and split-sample clinical trials of cervical smears performed by conventional and liquid-based techniques. Only published studies that used the Bethesda system nomenclature with clearly documented outcome data were included. Each trial was assessed for the quality of its method, inclusion and exclusion criteria, adequacy of randomization, sampling protocols, definition of outcome, and statistical analyses. Results: Twenty-five studies met inclusion criteria for this review. Odds ratios with 95% confidence intervals were calculated for each outcome. Estimates of odds ratios and risk differences for dichotomous outcomes were calculated by use of random and fixed-effects models. Homogeneity was tested across the studies. Results indicate that the ThinPrep test is as good as or superior to the conventional Papanicolaou smear in diagnosing uterine cervical premalignant abnormalities. Also the ThinPrep test provides improved sample adequacy when compared with the conventional Papanicolaou test. Conclusion: The ThinPrep test improved sample adequacy and led to improved diagnosis of low-grade and high-grade squamous intraepithelial lesions. However, there is no difference in the rate of atypical cells of undetermined significance diagnosis between ThinPrep and conventional smear groups. The added cost of ThinPrep cytologic screening and, hence, its cost-effectiveness are not evaluated in this study. (Am J Obstet Gynecol 2001;185:308-17.)

Impact of increasing Papanicolaou test sensitivity and compliance: a modeled cost and outcomes analysis

Objective: To model the impact of increasing screening compliance or implementing liquid-based cytology in populations with known compliance patterns and risk profiles on rates of detection of cervical precancers. Methods: An adaptation of a time-varying Markov model was used to follow a theoretic cohort of 100,000 women from age 20 through age 80. Separate analyses of all women, white, and black women were completed using three compliance rates (self-reported, Healthy People 2000, and Healthy People 2010 compliance) and two Papanicolaou test sensitivities (conventional Papanicolaou smear and liquid-based cytology). Results: All populations benefited from both increased compliance and liquid-based cytology use. Increasing compliance to Healthy People 2010 goals resulted in 23%, 21.7%, and 17% reductions in cervical cancer incidence for all women, white, and black women, respectively. Substituting liquid-based cytology for traditional Papanicolaou smear collection and processing with no change in compliance resulted in 32%, 32%, and 33% reductions in cervical cancer incidence for the same three subpopulations. In addition, cost-effectiveness of the liquid-based technology indirectly related to the risk profile of the population: for black women, the cost-effectiveness ratio was $10,335 per life year saved, whereas for white women, the ratio was $17,967 per life year saved. Conclusion: Using liquid-based cytology in all populations would be cost-effective in improving outcomes from cervical cancer. In high-risk populations, this new technology may represent the most cost-effective approach to improve cervical cancer outcomes.

Setting the Target for a Better Cervical Screening Test: Characteristics of a Cost-Effective Test for Cervical Neoplasia Screening

Abstract Objective: To determine the potential effects on costs and outcomes of changes in sensitivity and specificity with new screening methods for cervical cancer. Methods: Using a Markov model of the natural history of cervical cancer, we estimated the effects of sensitivity, specificity, and screening frequency on cost-effectiveness. Our estimates of conventional Papanicolaou test sensitivity of 51% and specificity of 97% were obtained from a meta-analysis. We estimated the effect of reducing false-negative rates from 40–90% and increasing false-positive rates by up to 20%, independently and jointly. We varied the marginal cost of improving sensitivity from $0 to $15. Results: When specificity was held constant, increasing sensitivity of the Papanicolaou test increased life expectancy and costs. When sensitivity was held constant, decreasing specificity of the Papanicolaou test increased costs, an effect that was more dramatic at more frequent intervals. Decreased specificity had a substantial effect on cost-effectiveness estimates of improved Papanicolaou test sensitivity. Most of those effects are related to the cost of evaluation and treatment of low-grade lesions. Conclusion: Policies or technologies that increased sensitivity of cervical cytologic screening increased overall costs, even if the cost of the technology was identical to that of conventional Papanicolaou smears. These effects appear to be caused by relatively high prevalence of low-grade lesions and are magnified at frequent screening intervals. Efficient cervical cancer screening requires methods with greater ability to detect lesions that are most likely to become cancerous.

Setting the target for a better cervical screening test: characteristics of a cost-effective test for cervical neoplasia screening

Objective: To determine the potential effects on costs and outcomes of changes in sensitivity and specificity with new screening methods for cervical cancer. Methods: Using a Markov model of the natural history of cervical cancer, we estimated the effects of sensitivity, specificity, and screening frequency on cost-effectiveness. Our estimates of conventional Papanicolaou test sensitivity of 51% and specificity of 97% were obtained from a meta-analysis. We estimated the effect of reducing false-negative rates from 40–90% and increasing false-positive rates by up to 20%, independently and jointly. We varied the marginal cost of improving sensitivity from $0 to $15. Results: When specificity was held constant, increasing sensitivity of the Papanicolaou test increased life expectancy and costs. When sensitivity was held constant, decreasing specificity of the Papanicolaou test increased costs, an effect that was more dramatic at more frequent intervals. Decreased specificity had a substantial effect on cost-effectiveness estimates of improved Papanicolaou test sensitivity. Most of those effects are related to the cost of evaluation and treatment of low-grade lesions. Conclusion: Policies or technologies that increased sensitivity of cervical cytologic screening increased overall costs, even if the cost of the technology was identical to that of conventional Papanicolaou smears. These effects appear to be caused by relatively high prevalence of low-grade lesions and are magnified at frequent screening intervals. Efficient cervical cancer screening requires methods with greater ability to detect lesions that are most likely to become cancerous.

Setting the Target for a Better Cervical Screening Test

In Brief Objective To determine the potential effects on costs and outcomes of changes in sensitivity and specificity with new screening methods for cervical cancer. Methods Using a Markov model of the natural history of cervical cancer, we estimated the effects of sensitivity, specificity, and screening frequency on cost-effectiveness. Our estimates of conventional Papanicolaou test sensitivity of 51% and specificity of 97% were obtained from a meta-analysis. We estimated the effect of reducing false-negative rates from 40–90% and increasing false-positive rates by up to 20%, independently and jointly. We varied the marginal cost of improving sensitivity from $0 to $15. Results When specificity was held constant, increasing sensitivity of the Papanicolaou test increased life expectancy and costs. When sensitivity was held constant, decreasing specificity of the Papanicolaou test increased costs, an effect that was more dramatic at more frequent intervals. Decreased specificity had a substantial effect on cost-effectiveness estimates of improved Papanicolaou test sensitivity. Most of those effects are related to the cost of evaluation and treatment of low-grade lesions. Conclusion Policies or technologies that increased sensitivity of cervical cytologic screening increased overall costs, even if the cost of the technology was identical to that of conventional Papanicolaou smears. These effects appear to be caused by relatively high prevalence of low-grade lesions and are magnified at frequent screening intervals. Efficient cervical cancer screening requires methods with greater ability to detect lesions that are most likely to become cancerous. Improving the sensitivity of conventional Papanicolaou tests with no improvement in specificity increases costs to cervical cancer prevention programs.

Prediction of cervical intraepithelial neoplasia grade 2–3 using risk assessment and human papillomavirus testing in women with atypia on papanicolaou smears

Objective: To determine whether human papillomavirus (HPV) DNA testing and risk assessment can predict cervical intraepithelial neoplasia (CIN) 2–3 on biopsies in women with atypia on Papanicolaou smears. Methods: One hundred ninety-five consenting women were referred for colposcopy because of atypia on Papanicolaou smears between September 1997 and April 1999. Before colposcopy, women completed risk assessments and had cervical swabs collected for HPV testing using the Hybrid Capture-II assay (Digene Corporation, Silver Spring, MD). Associations of demographic and clinical variables were assessed by χ 2 analysis, and logistic regression was used to assess factors associated with CIN 2–3. The cost-effectiveness of routine colposcopy versus reflex HPV testing by either conventional or liquid-based Papanicolaou smear media was compared. Results: Cervical intraepithelial neoplasia was diagnosed in 70 of 195 women (35.9%), 55 (28.2%) with CIN 1 and 15 (7.7%) with CIN 2–3. High-risk HPV types were detected in 31.3% of all subjects, 36.4% of those with CIN 1, and 93.3% of those with CIN 2–3. By logistic regression, CIN 2–3 was associated only with detection of high-risk HPV (odds ratio 110.08, 95% confidence interval 8.35, 999.00). The sensitivity of high-risk HPV for detecting CIN 2–3 was 93.3%, specificity 73.9%, positive predictive value 23.0%, and negative predictive value 99.3%. The cost of reflex HPV testing using conventional smear or liquid-based media was less than routine colposcopy ($4809 and $4308, respectively, versus $4875 per case detected). Conclusions: Triage based on HPV testing would result in referral of approximately 31% of patients to colposcopy and appears to be a sensitive and cost-effective alternative to colposcopy.

ThinPrep� pap test promotes detection of glandular lesions of the endocervix

The objectives of this study were to evaluate 1) the detection rate of atypical glandular cells of undetermined significance of endocervical cell type (AGUS-EC) and 2) the correlation between AGUS-EC on cytology and biopsy results using the conventional Papanicolaou (Pap) smear test vs. the ThinPrep Pap test (TPPT). Cervical-vaginal samples processed by the conventional Pap smear for 11 mo in 1996-1997 were identified, as were TPPTs collected for the same interval in 1997-1998. Biopsy results were compared after a 9-mo follow-up for both groups. There were 112 AGUS-EC cases from 82,754 conventional Pap smears (detection rate, 0.14%) compared with 58 cases from 82,252 TPPTs (detection rate, 0.07%) (P < 0.01). Biopsies were available in 72 of 112 patients from the conventional Pap smear group and 35 of 58 patients from the TPPT groups. Five dysplastic glandular lesions/ AIS were diagnosed by biopsy in the 35 patients (14.3%)from the TPPT group, compared with 2 of the 72 patients (2.8%) from the conventional Pap smear group (P < 0.05). There were no statistically significant differences between other follow-up diagnoses for the two methods. The use of TPPT resulted in fewer cases of AGUS-EC and better correlation with histology. The TPPT appears to be as sensitive as and more specific than the conventional Pap smear for detection of endocervical glandular lesions.

ThinPrep Pap Test: performance and biopsy follow-up in a university hospital.

The ThinPrep Pap Test (TP), a liquid-based cervical cytology preparation, was approved for use in the U.S. in 1996. The purpose of this study was to compare TP performance and biopsy follow-up studies with a similar population of high risk patients sampled by conventional Papanicolaou (Pap) smear (CS). Diagnostic and specimen adequacy interpretations for 2727 TP direct-to-vial Pap tests from a high risk university hospital practice were compared with 5000 CS preparations from the same physicians taken 1 year previously. Biopsy follow-up studies for the categories of squamous intraepithelial lesion (SIL), carcinoma, and atypical squamous cells of undetermined significance (ASCUS) for each time period and technique were contrasted. The SIL/carcinoma detection rate increased from 7.7% to 10.5% (P < 0.01) and the ASCUS rate decreased from 12.5% to 6.9% (P < 0.01); the percentage of satisfactory but limited specimens decreased from 19.4% to 10.5% (P < 0.01). Low grade SIL cases increased by 57% (P < 0.01) whereas the 26% increase in high grade SIL cases was not statistically significant. Greater than 90% of ungraded SIL, high grade SIL, and carcinoma cases had abnormal biopsies by both the TP and CS methods. The number of biopsy-confirmed high grade dysplasias and carcinomas was similar in the two groups. A low grade SIL detected by TP was less likely to have an abnormal biopsy (70% vs. 85% for CS). Nevertheless, the 57% increase in low grade SIL diagnoses by TP resulted in more TP patients with dysplastic biopsy diagnoses. Follow-up studies for ASCUS cases diagnosed by either TP or CS were similar, and 21-24% of patients eventually were found to have dysplasia. The TP technique appears to lead to the increased detection of low grade SIL lesions, decreased satisfactory but limited samples, and fewer equivocal specimens. No increase in biopsy-confirmed high grade dysplasias and carcinomas was found. Follow-up studies for the ASCUS category were nearly identical to those for CS.

Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for the detection of abnormal cervical lesions: systematic review and meta-analysis

Objective: The primary objective of this project was to determine the diagnostic accuracy of a fluid-based, thin-layer system (ThinPrep) compared to conventional Papanicolaou smears for the detection of abnormal (cancerous and pre-cancerous) cervical lesions. Methods: Five comparative studies including 12 study sites, screening centers, and high-risk hospital centers and 10,377 patients were included in a systematic review and meta-analysis examining the cytological diagnoses of ThinPrep with conventional smears using odds ratios (ORs) and risk differences (RDs). All abnormal samples (squamous intraepithelial neoplasia [SIL] or more severe abnormalities) classified by an independent pathologist reviewer were analyzed. Sensitivity analyses using jackknife techniques examined the robustness of the results. Logistic regression models were fit to the data using study level information and the individual patient data to examine the effect of baseline covariates on the results. Results: ThinPrep results were significantly better than conventional smears. For all abnormal diagnoses, the OR = 1.95 (95% CI: 1.40–2.70, P < .0001). For each SIL diagnostic subgroup, the results also strongly favored ThinPrep: LGSIL (OR = 2.20, 95% CI: 1.50–3.22, P = .001) and HGSIL (OR = 1.33, 95% CI: 0.85–2.07, P = .091). Analyses with RDs were similar and also statistically significant. Sensitivity analyses showed the studies to be homogeneous (using Cochran’s Q statistic = NS). Logistic regression models examining the meta-analysis results controlling for individual patient level and study level covariates increased the significance of the ThinPrep results. Conclusion: In a meta-analysis of the results of five comparative studies, the ThinPrep system showed significantly higher diagnostic accuracy for the detection of abnormal cervical lesions overall and by SIL diagnostic subgroups.

Diagnosis of invasive cervical carcinoma with fluid-based, thin-layer slide preparation method

Objectives: Although the main role of the Papanicolaou smear is to detect precursors of cervical cancer, the detection of invasive disease is important to identify women at the earliest stage of their disease. This study assesses the ability of the ThinPrep Papanicolaou test to identify invasive cervical cancer as compared to the Papanicolaou smear. Methods: A meta-analysis of five studies previously reviewed by the Food and Drug Administration was performed. There were 61 cases of cervical carcinoma processed by both conventional Papanicolaou smear and ThinPrep methods. Each case was reviewed by cytotechnologists and cytopathologists without knowledge of prior diagnoses. In a sub-study, the filtrate resulting from the preparation of the ThinPrep was analyzed to determine if diagnostic cells passed through the filter membrane. Results: With the ThinPrep method, a diagnosis of cancer was made in 54 cases (88.5%) as compared to a diagnosis of cancer in 52 of these cases with the conventional Papanicolaou smear method (85.2%). In those cases where diagnosis of invasive cancer was not made with the ThinPrep method, all cases were classified as abnormal, ranging from atypical glandular cells of undetermined significance to high-grade squamous intraepithelial lesions. The ThinPrep slides contained tumor diathesis and other contextual clues. Analysis of the ThinPrep filtrate demonstrated that cancer cells did not pass through the filter. Conclusions: These studies indicate that the ThinPrep method is at least equivalent to the conventional Papanicolaou smear method for the demonstration of squamous cell carcinoma, adenocarcinoma, and other cervical malignancies. Diagnostically important cells are not lost through the filter membrane during the preparation of the ThinPrep slide, because they are larger than the 8 μm pore size of the filter.

The AutoCyte Preparation System for Gynecologic Cytology

To determine if thin-layer processing of cervicovaginal samples improves detection of cytologic abnormalities by reducing problems related to direct smear preparation. Eight hundred fifty-two cervical samples were collected as part of a multicenter trial of the CytoRich/AutoCyte system. The Cervex Brush was used for specimen collection. Following preparation of a conventional Papanicolaou smear, the brush was placed in a vial of fixative. A thinlayer CytoRich preparation was prepared by sedimentation following centrifugation through a density gradient and then stained by the AutoCyte Preparation System according to the manufacturer's guidelines. The two preparations were masked and screened, and a diagnosis was rendered. Abnormal results from were reviewed by a pathologist. The specimens were later unmasked and the diagnoses compared. CytoRich and conventional cervical cytologic smears detected an equivalent number of squamous intraepithelial lesions (SILs) (27 vs. 29) and atypical squamous cells of undetermined significance (ASCUS) (19 vs. 21). Both methods missed an equivalent number of SILs (four vs. five). CytoRich detected more infections (151 vs. 115) and had 66% fewer nonspecific inflammatory diagnoses. CytoRich also had fewer "limited" adequacy evaluations (211 vs. 236). CytoRich preps improve adequacy; increase detection of infections, such as candidiasis and trichomoniasis; and are accurate in the diagnosis of SILs. CytoRich appears to be an equivalent and possibly better preparation for cervicovaginal cytology.

Improved Accuracy for Cervical Cytology with the ThinPrep Method and the Endocervical Brush-Spatula Collection Procedure.

Our objective was to assess the sensitivity of a fluid-based, thin-layer slide preparation system (ThinPrep; Cytyc Corporation, Boxborough, MA), as compared to conventional Papanicolaou smears obtained with the endocervical brush and spatula sampling devices. Two groups totaling 1,583 patients, all of whom were attending Planned Parenthood of the Rocky Mountains clinics, were included in the study. Cervical cell samples taken with the endocervical brush and plastic spatula were used first to make a conventional smear. Then the residual cells were rinsed into a vial containing preservative fluid, from which a ThinPrep slide was made. Screening and diagnosis of ThinPrep and conventional slides were blinded. The ThinPrep method demonstrated 110% greater detection of low-grade squamous intraepithelial lesions and more severe diagnoses as compared to the conventional smear. The ThinPrep method yielded 54% more high-grade squamous intraepithelial lesions than did the conventional smears. Review by an independent pathologist confirmed the significant increase in detection of low-grade squamous intraepithelial lesions and more severe diagnoses. The data from more than 1,500 patients indicate improved sensitivity for the detection of disease with the ThinPrep cervical slide preparation method.

Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for cervical cancer screening

To compare the cytologic diagnoses and specimen adequacy of a fluid-based, thin-layer preparation and conventional Papanicolaou tests. A total of 7360 women from six separate sites-three screening centers and three hospitals-participated in split-sample/matched-pair, double-masked clinical trials. A conventional Papanicolaou test was performed, after which residual material on the sampling device was rinsed into a fluid preservative from which a thin-layer slide (ThinPrep) was prepared using the ThinPrep 2000 automated slide processor (Cytyc Corp., Boxborough, MA). Conventional and ThinPrep slides were read independently. Cytologic diagnoses and specimen adequacy were classified using the Bethesda system. For the three screening centers, 65% more diagnoses of low-grade squamous intraepithelial lesions and higher were made on the ThinPrep slides (P < .001); for the three hospital centers, 6% more of these diagnoses were made with the ThinPrep method (P = .294). Comparison of specimen adequacy showed a significant increase in satisfactory specimens and a reduction in the number of "satisfactory but limited by" specimens using the ThinPrep method (P < .001). The fluid-based, ThinPrep method of sample preparation resulted in a statistically significant increase in cytologic diagnosis of cervical cancer precursors and in specimen adequacy compared with the conventional Papanicolaou testing method.

An Australian trial of ThinPrep: a new cytopreparatory technique

To evaluate the sensitivity and suitability of ThinPrep, a new slide preparation technique, 2026 paired cervical cytology slides were examined. After conventional Papanicolaou smears were prepared, the sampling instruments were rinsed in a fluid fixative. ThinPrep slides were then prepared in the laboratory from the surplus cells in the fixative. Compared with the Pap smears, ThinPrep slides were easier and quicker to screen, were inconclusive less often, and had similar rates for detecting abnormalities and infection. There were more unsatisfactory ThinPrep slides and more ThinPrep slides lacked endocervical cells. Both of these shortcomings were found to be linked to the choice of sampling implements. This study, in which a variety of sampling instruments was used, fails to confirm some of the previous claims made for the new technique.

Homogeneous sampling accounts for the increased diagnostic accuracy using the ThinPrep Processor.

Recent clinical trials indicated that the ThinPrep method of sample preparation has greater diagnostic sensitivity than the conventional direct Papanicolaou smear. The authors hypothesized that nonhomogeneous cell sampling during transfer from the sampling device to the microscope slide was a contributing factor to the reduced accuracy of the conventional direct Pap smears in these trials. To test this hypothesis, four direct smear methods were compared with the newly developed, fluid-based, filter-transfer method. Counts of epithelial cells on conventional smears showed that only a fraction of the available epithelial cells on the sampling devices (medians, 6.5% to 62.5%) was actually deposited on the slides. In all 27 cases studied with the ThinPrep method, equivalent diagnostic material was obtained on each of the replicate slides prepared per specimen. This identifies a new source of error, preparation error, in conventional smears.

ThinPrep™Processor:Clinical Trials Demonstrate an Increased Detection Rate of Abnormal Cervical Cytologic Specimens

The authors compared the accuracy of conventionally prepared smears and smears prepared by an automated, fluid-based, thin-layer processing device in the detection of cytologic abnormalities. A total of 3218 patients from five centers took part in this study, in which a single cervical sample was split into a matched pair. The conventional smear was made in the routine fashion; the remainder of the cells on the sampling device were rinsed into a transport-fixation fluid. A slide was then prepared from the solution using the thin-layer processor. Diagnostic findings identified on the two preparations were compared in a blinded fashion, and a discrepancy resolution procedure was used to eliminate screening differences. Overall, there was a high correlation in the diagnoses of the two methods. For low-grade or more severe disease, the thin-layer method resulted in a 13% increase in the rate of detection, as compared with the conventional Papanicolaou smear technique.

The pulse wash instrument. A new sampling method for uterine cervical cancer detection.

A new sampling method for uterine cervical cancer detection is described. In this method, sampling of cytologic material is done by using a pulse wash instrument. Liquid jets with a diameter of 0.2 mm at a speed of 20 m/s create a successful rinsing effect of cervical epithelial cells due to the high kinetic energy produced. Because cells are suspended in the flushing liquid it is possible to collect material for additional cytochemical, immunocytochemical, and microbiologic diagnostic techniques in addition to a conventional smear technique. Compared to a conventional Papanicolaou smear technique performed in 75 women at two cervical atypia clinics at the Karolinska Hospital, the pulse wash technique is suggested to result in a more representative cellular sample, thus offering a method to decrease false negative diagnoses in uterine cervical cancer detection.

Cytomorphologic results of preparation experiments for monolayer deposition of cervical material.

For automated prescreening methods by high resolution analysis serving as a detecting method in gynecologic mass screening programs a new monolayer deposition method of cervical material has been used. This method will be outlines briefly and the mode of evaluation as well as current cytomorphological findings will be presented. With regard to measurability of the slides prepared according to the new method a number of cytologic criteria were thought to be of particular importance. These criteria are delineated and compiled in a table. A form in which these criteria were listed was filled in by cytopathologists for each slide evaluated. When performing isolation and centrifugation procedures several new morphologic questions arose to the cytopathologist which can only partly be answered by now. If taking into account all criteria of evaluation it may be followed from the present experiences that slides of cervical material are much more suited for automated prescreening methods by high resolution analysis if prepared after isolation and centrifugation in macromolecular liquids than are conventional Papanicolaou smears or slides from suspensions with isolated cells that were not subjected to centrifugation procedures.