Daron G. Ferris, MD

Telemedicine enables doctors in rural areas or areas with poor medical service to consult with experts at distant locations. Telecolposcopy and cervicography both enable remote diagnoses of the cervix. The 2 methods differ in equipment, operations, image format, timeliness of consultation, and probably cost. However, these diagnostic approaches have not been compared previously. The purpose of this study was to compare the accuracy of telecolposcopy and cervicography with on-site colposcopy in the remote evaluation of women with potential cervical neoplasia.

Telecolposcopy and cervicography

Telecolposcopy involves a distant expert colposcopist’s evaluation of women with potential lower genital tract neoplasia.¹ Existing telemedicine network and computer systems provide an audiovisual interface between local colposcopists and expert colposcopists at other locations.² For health systems already using computer or video networks, telecolposcopic consultation can be implemented with only small additional charges per examination.² Telecolposcopy services may improve health care access for women in medically underserved areas.¹

Cervicography is distant evaluation of 2 photographs taken of the cervix following 5% acetic acid application.³ A special 35-mm camera is used to take these images. The end product, developed at a central processing center, resembles a low-magnification colposcopic photograph. Certified evaluators interpret these images, classifying them as negative, atypical, or positive. Cervicography is used primarily as an adjunct test to the Papanicolaou (Pap) smear.⁴ It has also been evaluated as an intermediate triage test for evaluating women with mildly abnormal Pap smear results.^5-8

Methods

Women aged 18 years or older who came to 1 of 2 rural clinic sites for a colposcopic examination were enrolled in the trial after signing an institutional review board–approved informed consent document. We included women with a recent abnormal Pap smear report or a lower genital tract finding that required further evaluation by colposcopy. The exclusion criteria were pregnancy, severe cervicitis, heavy menses, refusal to participate, or technical problems with the telecolposcopy or cervicography equipment.

Both clinics were part of the Medical College of Georgia Telemedicine Network. This system uses sophisticated telecommunications equipment to provide distant consultation services to clinicians practicing in rural areas of the state.¹ Small change-coupled device cameras were attached to the colposcopes at the 2 clinics.

For network telecolposcopy, images were transmitted using the network’s existing hardware and high-speed telecommunication lines. For computer telecolposcopy, personal computers (DIMS, DenVu, Tucson, Ariz) were also used to capture and transmit images to a computer at the Telemedicine Center. These digitized images were transmitted by modem via telephone lines.² Cerviscopes (35-mm cameras) supplied by the manufacturer (NTL Worldwide, Fenton, Mo) were used to acquire cervigrams (photographs).

Pertinent clinicians received appropriate training to take cervigrams. Certified evaluators interpreted the images according to company protocol and returned a standardized report to the investigators at a later date.

Study design

The study design has been described in detail previously.^1,2 Briefly, subjects were initially examined by 1 of 3 on-site, university-based expert colposcopists, who took 2 cervigrams of each patient, and then conducted a colposcopic examination independently.

A local clinician then completed another colposcopic examination, including histologic sampling, if indicated. This examination was observed simultaneously by another expert at a telemedicine center. Prior to obtaining histologic samples or using dilute Lugol’s iodine solution, the local clinician captured 2 cervical images (low and high magnification) using the computer telemedicine system. These images were then transmitted to the expert at the telemedicine center for independent interpretation.

A third expert colposcopist interpreted the video and computer images at a later time. However, these third interpretations were not considered in this report. Colposcopists were blinded to each other’s clinical diagnoses. However, all colposcopists were informed of the subject’s referral cervical cytology results and other pertinent history.

Data analysis

Each subject had 2 observations using each of the 3 colposcopy methods (on-site, network, and computer-based), and a single observation using cervicography. On-site colposcopy, consisting of the observations of the on-site expert and local colposcopist, was considered for reference purposes. Agreement with histologic results was calculated for each method, across all histologic diagnoses together and separately by diagnosis.

Sensitivity and specificity estimates were calculated using 2 definitions of disease: (1) normal versus any other histologic diagnosis, and (2) normal or cervical intraepithelial neoplasia 1 (CIN 1) versus any more severe diagnosis. The primary analysis model was complete block analysis of variance, with subjects included as blocks in the analysis to account for the multiple observations on the same subjects. Nonparametric comparisons of proportions of agreement with histology, sensitivity, and specificity among the methods were made using permutation tests. Post-hoc comparisons were made using a Tukey test; 95% confidence intervals (CIs) were calculated for all point estimates. Adjustment for dependence among multiple observations per subject was made by basing these tests and CIs on least-squares means.

The available sample sizes for all analyses were adequate to ensure approximate normality of the estimated means. Power to detect, at Α=.05, a difference in agreement of 15% between cervigram and the other evaluation methods, was estimated using Monte Carlo simulations. Data were simulated using the observed levels of agreement for on-site, network, and computer telecolposcopy, and specifying a difference of 15% between cervicography agreement and the maximum of the other methods’ agreement. Power estimates were based on analysis of 1000 simulations. SAS release 8.02 was used for all calculations (SAS, Inc, Cary, NC).

Results

A total of 264 subjects were enrolled in the trial, but the total number of subjects considered differed depending on the various analyses of interest. The demographic data of this study cohort have been published previously.¹

Briefly, the subjects’ mean age was 31.7 years and mean parity was 2.1. Subjects presented with a wide range of prior cervical cytology results: 20.4% normal, 29.2% atypical squamous cells of undetermined significance, 40.4% low-grade squamous intraepithelial lesion, 7.3% high-grade squamous intraepithelial lesion, and 2.7% atypical glandular cells of undetermined significance. Histology results included all levels of CIN (52.9% CIN 1 and 13.4% CIN 2 or 3), and endocervical histologic sampling results were reported as both positive and negative for neoplasia.

The agreement between telecolposcopic/cervicography impressions and histology were estimated (Table 1). Data for on-site colposcopy was also considered for reference purposes.

When all histologic diagnoses were considered, there was no statistically significant difference in the rates of agreement for colposcopy, the 2 types of telecolposcopy, and cervicography. This was also true if only cases of CIN 1 were examined.

However, a statistically significant difference was noted between agreement rates for computer-based telecolposcopy (63.95%) and on-site colposcopy (47.7%, P=.03, Tukey test) for normal histology. A statistically significant difference was also found between agreement rates for on-site colposcopy (50.0%) and cervicography (19.1%, P=.04, Tukey test) for women with biopsy-proven CIN 2 or 3. If all histologic diagnoses were considered, the study provided 85% power to detect a difference in agreement of 15% among the evaluation methods.

We also estimated the sensitivity and specificity of the four diagnostic methods to detect cervical neoplasia (Table 2). A statistically significant difference was found in observed sensitivity between on-site colposcopy (47.7%) and cervicography (18.2%, P=.04, Tukey test) when a positive threshold of at least CIN 2 was considered. The difference was not significant, however, if the lower positive test threshold of at least CIN 1 was considered.

A statistically significant difference in specificity was noted between computer-based telecolposcopy (64.0%) and on-site colposcopy (47.7%, P=.03, Tukey test) at a positive threshold of at least CIN 1. The study provided a power of 71% and 60% to detect differences of 15% in sensitivity and specificity, respectively, using the CIN 1 threshold. Using CIN 2 as the positive threshold, the power to detect this 15% difference was 24% and 81% for sensitivity and specificity, respectively.

TABLE 1
Colposcopic, telecolposcopic, and cervicographic agreement with histology

TABLE 2
Sensitivity and specificity of tests to detect cervical neoplasia

Discussion

Until recently, cervicography had been the only type of remote diagnostic system available for the evaluation of women with potential lower genital tract neoplasia. With the advent of telemedicine during the past decade, expert-level health care has now become more readily available to patients previously isolated from this important resource.

The future of telecolposcopy

Because of its nature, telecolposcopy may also be well suited to assist in the evaluation and management of women with lower genital tract neoplasia. Computer-based telecolposcopy has the potential to support clinical sites located wherever standard telephone service exists. Cellular telephone systems now broaden access to nearglobal availability. Soon, assuming sufficient funding is obtained, the provision of expertenhanced colposcopy may become a reality for all women. However, universal availability may be irrelevant if computer-based telecolposcopy performs at a substandard level.

Telecolposcopy vs cervicography

We have demonstrated that telecolposcopy was at least as effective as cervicography for detecting cervical cancer precursors. Although the difference was not statistically significant, both network and computer-based telecolposcopy systems detected a higher percentage of women with CIN 2 or 3 than cervicography.

Our results also included on-site colposcopy. As anticipated, on-site colposcopy had the greatest sensitivity for disease detection at either positive test thresholds (at least CIN 1 and CIN 2). Ability to manipulate the cervix, stereoscopic viewing, longitudinal observation after 5% acetic acid application, and better resolution of the cervical epithelium and vascularity all favor on-site colposcopic diagnoses. Of the 2 telecolposcopy systems, network telecolposcopy had a slightly, but not significantly, greater sensitivity for detecting cervical cancer precursors compared with computer-based telecolposcopy.

Expert colposcopists’ accuracy with interpretation of network (real-time) cervical images was similar to that for on-site colposcopy, as might be expected. Network telecolposcopy might be equated with remote video colposcopy. Previously we have shown that traditional optical colposcopy is equivalent to video colposcopy with respect to colposcopic/histologic agreement.⁹

Comparison of telecolposcopy systems

The computer-based telecolposcopy system used in our study was, in all fairness, more similar to cervicography. Each method involves evaluation of 2 static images. Computer-based telecolposcopy provides 2 digitized images, but of a low- and high-power magnification view of the cervix. In comparison, cervicography produces dual low-power magnification celluloid images (2 x 2 slides) of the cervix. The provision of a high-power cervical image may explain the better sensitivity of computer-based telecolposcopy. This one feature may be more valuable than the better image resolution obtained from cervicography. However, computer-based resolution appears to be sufficient to render diagnoses at a level equivalent to or better than cervicography.

These 2 “static” systems differ in other aspects as well. First, computer-based systems are nonproprietary. Several systems are commercially available and other colposcopists have devised their own unique systems using modifications of off-the-shelf technology. Although not available at the initiation of our trial, computerbased systems now have the capability of capturing short video streams. These video segments should help improve the diagnostic ability of consulting colposcopists as demonstrated by our study.

Second, computer-based telecolposcopy can provide instantaneous consultation as opposed to cervicography, which generally takes a minimum of several weeks to receive a report. Computerbased telecolposcopy also allows interaction between the on-site provider and remote expert.

Third, cervicography is a screening test adjunct. The computer-based system was used as a colposcopy diagnostic adjunct. However, colposcopy could easily be adapted to provide the function of cervicography. A simple handheld miniature change-coupled device camera and light source could potentially replace a more expensive colposcope and video camera, or video colposcope. With an average laptop computer (with appropriate software) and cellular phone, health care providers of potentially all women in the world could have access to expert-level cervical evaluation services.

Finally, computer-based telecolposcopy images and associated data automatically become part of a modern electronic medical record. This format is more conducive to the direction toward which contemporary medicine is rapidly shifting. Consequently, computer-based telecolposcopy may offer clinicians superior, modern diagnostic services not previously available to women.

Acknowledgments

Special thanks to Dr. Debra Crawley and Diane Watson, MSN, for rural site participation.

Telemedicine enables doctors in rural areas or areas with poor medical service to consult with experts at distant locations. Telecolposcopy and cervicography both enable remote diagnoses of the cervix. The 2 methods differ in equipment, operations, image format, timeliness of consultation, and probably cost. However, these diagnostic approaches have not been compared previously. The purpose of this study was to compare the accuracy of telecolposcopy and cervicography with on-site colposcopy in the remote evaluation of women with potential cervical neoplasia.

Telecolposcopy and cervicography

Telecolposcopy involves a distant expert colposcopist’s evaluation of women with potential lower genital tract neoplasia.¹ Existing telemedicine network and computer systems provide an audiovisual interface between local colposcopists and expert colposcopists at other locations.² For health systems already using computer or video networks, telecolposcopic consultation can be implemented with only small additional charges per examination.² Telecolposcopy services may improve health care access for women in medically underserved areas.¹

Cervicography is distant evaluation of 2 photographs taken of the cervix following 5% acetic acid application.³ A special 35-mm camera is used to take these images. The end product, developed at a central processing center, resembles a low-magnification colposcopic photograph. Certified evaluators interpret these images, classifying them as negative, atypical, or positive. Cervicography is used primarily as an adjunct test to the Papanicolaou (Pap) smear.⁴ It has also been evaluated as an intermediate triage test for evaluating women with mildly abnormal Pap smear results.^5-8

Methods

Women aged 18 years or older who came to 1 of 2 rural clinic sites for a colposcopic examination were enrolled in the trial after signing an institutional review board–approved informed consent document. We included women with a recent abnormal Pap smear report or a lower genital tract finding that required further evaluation by colposcopy. The exclusion criteria were pregnancy, severe cervicitis, heavy menses, refusal to participate, or technical problems with the telecolposcopy or cervicography equipment.

Both clinics were part of the Medical College of Georgia Telemedicine Network. This system uses sophisticated telecommunications equipment to provide distant consultation services to clinicians practicing in rural areas of the state.¹ Small change-coupled device cameras were attached to the colposcopes at the 2 clinics.

For network telecolposcopy, images were transmitted using the network’s existing hardware and high-speed telecommunication lines. For computer telecolposcopy, personal computers (DIMS, DenVu, Tucson, Ariz) were also used to capture and transmit images to a computer at the Telemedicine Center. These digitized images were transmitted by modem via telephone lines.² Cerviscopes (35-mm cameras) supplied by the manufacturer (NTL Worldwide, Fenton, Mo) were used to acquire cervigrams (photographs).

Pertinent clinicians received appropriate training to take cervigrams. Certified evaluators interpreted the images according to company protocol and returned a standardized report to the investigators at a later date.

Study design

The study design has been described in detail previously.^1,2 Briefly, subjects were initially examined by 1 of 3 on-site, university-based expert colposcopists, who took 2 cervigrams of each patient, and then conducted a colposcopic examination independently.

A local clinician then completed another colposcopic examination, including histologic sampling, if indicated. This examination was observed simultaneously by another expert at a telemedicine center. Prior to obtaining histologic samples or using dilute Lugol’s iodine solution, the local clinician captured 2 cervical images (low and high magnification) using the computer telemedicine system. These images were then transmitted to the expert at the telemedicine center for independent interpretation.

A third expert colposcopist interpreted the video and computer images at a later time. However, these third interpretations were not considered in this report. Colposcopists were blinded to each other’s clinical diagnoses. However, all colposcopists were informed of the subject’s referral cervical cytology results and other pertinent history.

Data analysis

Each subject had 2 observations using each of the 3 colposcopy methods (on-site, network, and computer-based), and a single observation using cervicography. On-site colposcopy, consisting of the observations of the on-site expert and local colposcopist, was considered for reference purposes. Agreement with histologic results was calculated for each method, across all histologic diagnoses together and separately by diagnosis.

Sensitivity and specificity estimates were calculated using 2 definitions of disease: (1) normal versus any other histologic diagnosis, and (2) normal or cervical intraepithelial neoplasia 1 (CIN 1) versus any more severe diagnosis. The primary analysis model was complete block analysis of variance, with subjects included as blocks in the analysis to account for the multiple observations on the same subjects. Nonparametric comparisons of proportions of agreement with histology, sensitivity, and specificity among the methods were made using permutation tests. Post-hoc comparisons were made using a Tukey test; 95% confidence intervals (CIs) were calculated for all point estimates. Adjustment for dependence among multiple observations per subject was made by basing these tests and CIs on least-squares means.

The available sample sizes for all analyses were adequate to ensure approximate normality of the estimated means. Power to detect, at Α=.05, a difference in agreement of 15% between cervigram and the other evaluation methods, was estimated using Monte Carlo simulations. Data were simulated using the observed levels of agreement for on-site, network, and computer telecolposcopy, and specifying a difference of 15% between cervicography agreement and the maximum of the other methods’ agreement. Power estimates were based on analysis of 1000 simulations. SAS release 8.02 was used for all calculations (SAS, Inc, Cary, NC).

Results

A total of 264 subjects were enrolled in the trial, but the total number of subjects considered differed depending on the various analyses of interest. The demographic data of this study cohort have been published previously.¹

Briefly, the subjects’ mean age was 31.7 years and mean parity was 2.1. Subjects presented with a wide range of prior cervical cytology results: 20.4% normal, 29.2% atypical squamous cells of undetermined significance, 40.4% low-grade squamous intraepithelial lesion, 7.3% high-grade squamous intraepithelial lesion, and 2.7% atypical glandular cells of undetermined significance. Histology results included all levels of CIN (52.9% CIN 1 and 13.4% CIN 2 or 3), and endocervical histologic sampling results were reported as both positive and negative for neoplasia.

The agreement between telecolposcopic/cervicography impressions and histology were estimated (Table 1). Data for on-site colposcopy was also considered for reference purposes.

When all histologic diagnoses were considered, there was no statistically significant difference in the rates of agreement for colposcopy, the 2 types of telecolposcopy, and cervicography. This was also true if only cases of CIN 1 were examined.

However, a statistically significant difference was noted between agreement rates for computer-based telecolposcopy (63.95%) and on-site colposcopy (47.7%, P=.03, Tukey test) for normal histology. A statistically significant difference was also found between agreement rates for on-site colposcopy (50.0%) and cervicography (19.1%, P=.04, Tukey test) for women with biopsy-proven CIN 2 or 3. If all histologic diagnoses were considered, the study provided 85% power to detect a difference in agreement of 15% among the evaluation methods.

We also estimated the sensitivity and specificity of the four diagnostic methods to detect cervical neoplasia (Table 2). A statistically significant difference was found in observed sensitivity between on-site colposcopy (47.7%) and cervicography (18.2%, P=.04, Tukey test) when a positive threshold of at least CIN 2 was considered. The difference was not significant, however, if the lower positive test threshold of at least CIN 1 was considered.

A statistically significant difference in specificity was noted between computer-based telecolposcopy (64.0%) and on-site colposcopy (47.7%, P=.03, Tukey test) at a positive threshold of at least CIN 1. The study provided a power of 71% and 60% to detect differences of 15% in sensitivity and specificity, respectively, using the CIN 1 threshold. Using CIN 2 as the positive threshold, the power to detect this 15% difference was 24% and 81% for sensitivity and specificity, respectively.

TABLE 1
Colposcopic, telecolposcopic, and cervicographic agreement with histology

TABLE 2
Sensitivity and specificity of tests to detect cervical neoplasia

Discussion

Until recently, cervicography had been the only type of remote diagnostic system available for the evaluation of women with potential lower genital tract neoplasia. With the advent of telemedicine during the past decade, expert-level health care has now become more readily available to patients previously isolated from this important resource.

The future of telecolposcopy

Because of its nature, telecolposcopy may also be well suited to assist in the evaluation and management of women with lower genital tract neoplasia. Computer-based telecolposcopy has the potential to support clinical sites located wherever standard telephone service exists. Cellular telephone systems now broaden access to nearglobal availability. Soon, assuming sufficient funding is obtained, the provision of expertenhanced colposcopy may become a reality for all women. However, universal availability may be irrelevant if computer-based telecolposcopy performs at a substandard level.

Telecolposcopy vs cervicography

We have demonstrated that telecolposcopy was at least as effective as cervicography for detecting cervical cancer precursors. Although the difference was not statistically significant, both network and computer-based telecolposcopy systems detected a higher percentage of women with CIN 2 or 3 than cervicography.

Our results also included on-site colposcopy. As anticipated, on-site colposcopy had the greatest sensitivity for disease detection at either positive test thresholds (at least CIN 1 and CIN 2). Ability to manipulate the cervix, stereoscopic viewing, longitudinal observation after 5% acetic acid application, and better resolution of the cervical epithelium and vascularity all favor on-site colposcopic diagnoses. Of the 2 telecolposcopy systems, network telecolposcopy had a slightly, but not significantly, greater sensitivity for detecting cervical cancer precursors compared with computer-based telecolposcopy.

Expert colposcopists’ accuracy with interpretation of network (real-time) cervical images was similar to that for on-site colposcopy, as might be expected. Network telecolposcopy might be equated with remote video colposcopy. Previously we have shown that traditional optical colposcopy is equivalent to video colposcopy with respect to colposcopic/histologic agreement.⁹

Comparison of telecolposcopy systems

The computer-based telecolposcopy system used in our study was, in all fairness, more similar to cervicography. Each method involves evaluation of 2 static images. Computer-based telecolposcopy provides 2 digitized images, but of a low- and high-power magnification view of the cervix. In comparison, cervicography produces dual low-power magnification celluloid images (2 x 2 slides) of the cervix. The provision of a high-power cervical image may explain the better sensitivity of computer-based telecolposcopy. This one feature may be more valuable than the better image resolution obtained from cervicography. However, computer-based resolution appears to be sufficient to render diagnoses at a level equivalent to or better than cervicography.

These 2 “static” systems differ in other aspects as well. First, computer-based systems are nonproprietary. Several systems are commercially available and other colposcopists have devised their own unique systems using modifications of off-the-shelf technology. Although not available at the initiation of our trial, computerbased systems now have the capability of capturing short video streams. These video segments should help improve the diagnostic ability of consulting colposcopists as demonstrated by our study.

Second, computer-based telecolposcopy can provide instantaneous consultation as opposed to cervicography, which generally takes a minimum of several weeks to receive a report. Computerbased telecolposcopy also allows interaction between the on-site provider and remote expert.

Third, cervicography is a screening test adjunct. The computer-based system was used as a colposcopy diagnostic adjunct. However, colposcopy could easily be adapted to provide the function of cervicography. A simple handheld miniature change-coupled device camera and light source could potentially replace a more expensive colposcope and video camera, or video colposcope. With an average laptop computer (with appropriate software) and cellular phone, health care providers of potentially all women in the world could have access to expert-level cervical evaluation services.

Finally, computer-based telecolposcopy images and associated data automatically become part of a modern electronic medical record. This format is more conducive to the direction toward which contemporary medicine is rapidly shifting. Consequently, computer-based telecolposcopy may offer clinicians superior, modern diagnostic services not previously available to women.

Acknowledgments

Special thanks to Dr. Debra Crawley and Diane Watson, MSN, for rural site participation.

Telemedicine enables doctors in rural areas or areas with poor medical service to consult with experts at distant locations. Telecolposcopy and cervicography both enable remote diagnoses of the cervix. The 2 methods differ in equipment, operations, image format, timeliness of consultation, and probably cost. However, these diagnostic approaches have not been compared previously. The purpose of this study was to compare the accuracy of telecolposcopy and cervicography with on-site colposcopy in the remote evaluation of women with potential cervical neoplasia.

Telecolposcopy and cervicography

Telecolposcopy involves a distant expert colposcopist’s evaluation of women with potential lower genital tract neoplasia.¹ Existing telemedicine network and computer systems provide an audiovisual interface between local colposcopists and expert colposcopists at other locations.² For health systems already using computer or video networks, telecolposcopic consultation can be implemented with only small additional charges per examination.² Telecolposcopy services may improve health care access for women in medically underserved areas.¹

Cervicography is distant evaluation of 2 photographs taken of the cervix following 5% acetic acid application.³ A special 35-mm camera is used to take these images. The end product, developed at a central processing center, resembles a low-magnification colposcopic photograph. Certified evaluators interpret these images, classifying them as negative, atypical, or positive. Cervicography is used primarily as an adjunct test to the Papanicolaou (Pap) smear.⁴ It has also been evaluated as an intermediate triage test for evaluating women with mildly abnormal Pap smear results.^5-8

Methods

Women aged 18 years or older who came to 1 of 2 rural clinic sites for a colposcopic examination were enrolled in the trial after signing an institutional review board–approved informed consent document. We included women with a recent abnormal Pap smear report or a lower genital tract finding that required further evaluation by colposcopy. The exclusion criteria were pregnancy, severe cervicitis, heavy menses, refusal to participate, or technical problems with the telecolposcopy or cervicography equipment.

Both clinics were part of the Medical College of Georgia Telemedicine Network. This system uses sophisticated telecommunications equipment to provide distant consultation services to clinicians practicing in rural areas of the state.¹ Small change-coupled device cameras were attached to the colposcopes at the 2 clinics.

For network telecolposcopy, images were transmitted using the network’s existing hardware and high-speed telecommunication lines. For computer telecolposcopy, personal computers (DIMS, DenVu, Tucson, Ariz) were also used to capture and transmit images to a computer at the Telemedicine Center. These digitized images were transmitted by modem via telephone lines.² Cerviscopes (35-mm cameras) supplied by the manufacturer (NTL Worldwide, Fenton, Mo) were used to acquire cervigrams (photographs).

Pertinent clinicians received appropriate training to take cervigrams. Certified evaluators interpreted the images according to company protocol and returned a standardized report to the investigators at a later date.

Study design

The study design has been described in detail previously.^1,2 Briefly, subjects were initially examined by 1 of 3 on-site, university-based expert colposcopists, who took 2 cervigrams of each patient, and then conducted a colposcopic examination independently.

A local clinician then completed another colposcopic examination, including histologic sampling, if indicated. This examination was observed simultaneously by another expert at a telemedicine center. Prior to obtaining histologic samples or using dilute Lugol’s iodine solution, the local clinician captured 2 cervical images (low and high magnification) using the computer telemedicine system. These images were then transmitted to the expert at the telemedicine center for independent interpretation.

A third expert colposcopist interpreted the video and computer images at a later time. However, these third interpretations were not considered in this report. Colposcopists were blinded to each other’s clinical diagnoses. However, all colposcopists were informed of the subject’s referral cervical cytology results and other pertinent history.

Data analysis

Each subject had 2 observations using each of the 3 colposcopy methods (on-site, network, and computer-based), and a single observation using cervicography. On-site colposcopy, consisting of the observations of the on-site expert and local colposcopist, was considered for reference purposes. Agreement with histologic results was calculated for each method, across all histologic diagnoses together and separately by diagnosis.

Sensitivity and specificity estimates were calculated using 2 definitions of disease: (1) normal versus any other histologic diagnosis, and (2) normal or cervical intraepithelial neoplasia 1 (CIN 1) versus any more severe diagnosis. The primary analysis model was complete block analysis of variance, with subjects included as blocks in the analysis to account for the multiple observations on the same subjects. Nonparametric comparisons of proportions of agreement with histology, sensitivity, and specificity among the methods were made using permutation tests. Post-hoc comparisons were made using a Tukey test; 95% confidence intervals (CIs) were calculated for all point estimates. Adjustment for dependence among multiple observations per subject was made by basing these tests and CIs on least-squares means.

The available sample sizes for all analyses were adequate to ensure approximate normality of the estimated means. Power to detect, at Α=.05, a difference in agreement of 15% between cervigram and the other evaluation methods, was estimated using Monte Carlo simulations. Data were simulated using the observed levels of agreement for on-site, network, and computer telecolposcopy, and specifying a difference of 15% between cervicography agreement and the maximum of the other methods’ agreement. Power estimates were based on analysis of 1000 simulations. SAS release 8.02 was used for all calculations (SAS, Inc, Cary, NC).

Results

A total of 264 subjects were enrolled in the trial, but the total number of subjects considered differed depending on the various analyses of interest. The demographic data of this study cohort have been published previously.¹

Briefly, the subjects’ mean age was 31.7 years and mean parity was 2.1. Subjects presented with a wide range of prior cervical cytology results: 20.4% normal, 29.2% atypical squamous cells of undetermined significance, 40.4% low-grade squamous intraepithelial lesion, 7.3% high-grade squamous intraepithelial lesion, and 2.7% atypical glandular cells of undetermined significance. Histology results included all levels of CIN (52.9% CIN 1 and 13.4% CIN 2 or 3), and endocervical histologic sampling results were reported as both positive and negative for neoplasia.

The agreement between telecolposcopic/cervicography impressions and histology were estimated (Table 1). Data for on-site colposcopy was also considered for reference purposes.

When all histologic diagnoses were considered, there was no statistically significant difference in the rates of agreement for colposcopy, the 2 types of telecolposcopy, and cervicography. This was also true if only cases of CIN 1 were examined.

However, a statistically significant difference was noted between agreement rates for computer-based telecolposcopy (63.95%) and on-site colposcopy (47.7%, P=.03, Tukey test) for normal histology. A statistically significant difference was also found between agreement rates for on-site colposcopy (50.0%) and cervicography (19.1%, P=.04, Tukey test) for women with biopsy-proven CIN 2 or 3. If all histologic diagnoses were considered, the study provided 85% power to detect a difference in agreement of 15% among the evaluation methods.

We also estimated the sensitivity and specificity of the four diagnostic methods to detect cervical neoplasia (Table 2). A statistically significant difference was found in observed sensitivity between on-site colposcopy (47.7%) and cervicography (18.2%, P=.04, Tukey test) when a positive threshold of at least CIN 2 was considered. The difference was not significant, however, if the lower positive test threshold of at least CIN 1 was considered.

A statistically significant difference in specificity was noted between computer-based telecolposcopy (64.0%) and on-site colposcopy (47.7%, P=.03, Tukey test) at a positive threshold of at least CIN 1. The study provided a power of 71% and 60% to detect differences of 15% in sensitivity and specificity, respectively, using the CIN 1 threshold. Using CIN 2 as the positive threshold, the power to detect this 15% difference was 24% and 81% for sensitivity and specificity, respectively.

TABLE 1
Colposcopic, telecolposcopic, and cervicographic agreement with histology

TABLE 2
Sensitivity and specificity of tests to detect cervical neoplasia

Discussion

Until recently, cervicography had been the only type of remote diagnostic system available for the evaluation of women with potential lower genital tract neoplasia. With the advent of telemedicine during the past decade, expert-level health care has now become more readily available to patients previously isolated from this important resource.

The future of telecolposcopy

Because of its nature, telecolposcopy may also be well suited to assist in the evaluation and management of women with lower genital tract neoplasia. Computer-based telecolposcopy has the potential to support clinical sites located wherever standard telephone service exists. Cellular telephone systems now broaden access to nearglobal availability. Soon, assuming sufficient funding is obtained, the provision of expertenhanced colposcopy may become a reality for all women. However, universal availability may be irrelevant if computer-based telecolposcopy performs at a substandard level.

Telecolposcopy vs cervicography

We have demonstrated that telecolposcopy was at least as effective as cervicography for detecting cervical cancer precursors. Although the difference was not statistically significant, both network and computer-based telecolposcopy systems detected a higher percentage of women with CIN 2 or 3 than cervicography.

Our results also included on-site colposcopy. As anticipated, on-site colposcopy had the greatest sensitivity for disease detection at either positive test thresholds (at least CIN 1 and CIN 2). Ability to manipulate the cervix, stereoscopic viewing, longitudinal observation after 5% acetic acid application, and better resolution of the cervical epithelium and vascularity all favor on-site colposcopic diagnoses. Of the 2 telecolposcopy systems, network telecolposcopy had a slightly, but not significantly, greater sensitivity for detecting cervical cancer precursors compared with computer-based telecolposcopy.

Expert colposcopists’ accuracy with interpretation of network (real-time) cervical images was similar to that for on-site colposcopy, as might be expected. Network telecolposcopy might be equated with remote video colposcopy. Previously we have shown that traditional optical colposcopy is equivalent to video colposcopy with respect to colposcopic/histologic agreement.⁹

Comparison of telecolposcopy systems

The computer-based telecolposcopy system used in our study was, in all fairness, more similar to cervicography. Each method involves evaluation of 2 static images. Computer-based telecolposcopy provides 2 digitized images, but of a low- and high-power magnification view of the cervix. In comparison, cervicography produces dual low-power magnification celluloid images (2 x 2 slides) of the cervix. The provision of a high-power cervical image may explain the better sensitivity of computer-based telecolposcopy. This one feature may be more valuable than the better image resolution obtained from cervicography. However, computer-based resolution appears to be sufficient to render diagnoses at a level equivalent to or better than cervicography.

These 2 “static” systems differ in other aspects as well. First, computer-based systems are nonproprietary. Several systems are commercially available and other colposcopists have devised their own unique systems using modifications of off-the-shelf technology. Although not available at the initiation of our trial, computerbased systems now have the capability of capturing short video streams. These video segments should help improve the diagnostic ability of consulting colposcopists as demonstrated by our study.

Second, computer-based telecolposcopy can provide instantaneous consultation as opposed to cervicography, which generally takes a minimum of several weeks to receive a report. Computerbased telecolposcopy also allows interaction between the on-site provider and remote expert.

Third, cervicography is a screening test adjunct. The computer-based system was used as a colposcopy diagnostic adjunct. However, colposcopy could easily be adapted to provide the function of cervicography. A simple handheld miniature change-coupled device camera and light source could potentially replace a more expensive colposcope and video camera, or video colposcope. With an average laptop computer (with appropriate software) and cellular phone, health care providers of potentially all women in the world could have access to expert-level cervical evaluation services.

Finally, computer-based telecolposcopy images and associated data automatically become part of a modern electronic medical record. This format is more conducive to the direction toward which contemporary medicine is rapidly shifting. Consequently, computer-based telecolposcopy may offer clinicians superior, modern diagnostic services not previously available to women.

Acknowledgments

Special thanks to Dr. Debra Crawley and Diane Watson, MSN, for rural site participation.

The Papanicolaou (Pap) test is one of the most common and effective cancer screening tests used by primary care clinicians. However, a recent study conducted through the Agency for Health Care Policy and Research¹ estimated that the true sensitivity of the Pap test is only 51%. Two thirds of the false-negative results occur because of sampling error. The first liquid-based cervical cytology (LBCC) test was approved for clinical use by the United States Food and Drug Administration in 1996.² With LBCC, standard cervical cytology sampling devices are used to obtain a sample from the cervix. The sampling devices are then rinsed in a buffered alcohol transport and preservative solution instead of immediately transferring the cells to a glass slide. Sampling error is reduced, since all the cells are transferred into solution, in contrast with the conventional Pap test (CPT), in which only 20% of the cells are actually transferred to the glass slide.³ The cytologic specimen in solution is then sent to the laboratory where most of the debris, leukocytes, and erythrocytes are filtered from the specimen and a thin layer Pap test is prepared using a special processor. The cells are dispersed evenly with relatively little clumping or overlapping or obscuring debris (Figures 1A and B). The resulting clean smear is circular and contains approximately half the number of representative cells of a CPT. Residual cervical cells in solution that are not initially used for the Pap test may be tested at a later date for lower genital tract pathogens, such as carcinogenic human papillomavirus.^4,5

Liquid-based thin layer cervical cytology has performed favorably in studies using split sample collection techniques.^6-9 With the split sample technique, the cytologic specimen is first transferred to a glass slide for the CPT before transferring the remaining cervical cells to the liquid transport fluid. Evaluation of the LBCC Pap test using this nonrandom study design may be biased, since it is based solely on cells normally discarded. The CPT slides receive the first and perhaps better cellular sample; thus, the quality of that specimen may be vastly different than that available for LBCC. Currently, there are minimal data available in which LBCC was evaluated as it was intended to be used, for a primary cytologic specimen.^10,11 Thus, the full diagnostic potential of this new Pap test technique has not been fully realized. The purpose of our trial was to determine the rates of specimen adequacy and cervical cytologic and histologically confirmed diagnoses obtained with LBCC using a direct-to-vial collection technique and compare these results with those obtained using the CPT.

Methods

Subjects

In our clinical study one group of women was enrolled prospectively, and a second group was considered retrospectively. The first group (LBCC) consisted of 1004 nonpregnant women aged 18 years or older with an intact cervix. The second group consisted of 2110 women with a similar patient profile who had a CPT collected at the same clinics during the 2 years immediately preceding the initiation of the trial.

To ensure an enriched sample of women with cervical neoplasia, approximately 20% of the subjects in both cohorts were included from women presenting consecutively for a colposcopy examination following an abnormal CPT result. The remaining 80% of the subjects represented a general screening population of women presenting for a routine Pap test. All subjects were seen at 1 of 3 clinics: the Family Medicine Center, the Obstetrics and Gynecology Clinic, or the Comprehensive Cancer Center at the Medical College of Georgia in Augusta.

Equipment and Materials

Samples for CPTs and LBCC (ThinPrep Pap Test, Cytyc Corporation, Boxborough, Mass) were collected using a plastic Ayre spatula and cytobrush (Medscand, North Hollywood, Fla). Cervical cells from the second group were processed by CPT methods. Cervical cells from the prospectively enrolled group were preserved and transferred in LBCC solution (PreservCyt, Cytyc Corporation). Cervical samples for the LBCC test were processed using the ThinPrep 2000 Processor (Cytyc Corporation).¹²

Study Design

Eligible prospectively enrolled women presenting consecutively for a routine Pap test or colposcopy examination at any of the 3 designated clinics signed an internal review board-approved informed consent form before participating. After properly visualizing the cervix, a plastic Ayre spatula was used to collect an ectocervical sample. Another sample was collected using a cytobrush rotated 90° to 180° within the endocervical canal. The spatula and cytobrush were then immediately rinsed vigorously in the LBCC solution. The container was sealed, labeled, and sent to the cytology laboratory for processing according to the manufacturer’s instructions.¹² Cytotechnicians or pathologists in the Department of Pathology, Medical College of Georgia (MCG), evaluated all cytology and histology specimens. Cervical cytology was reported using the Bethesda System.

Computerized records from the MCG Cytology Laboratory were used to establish the second group. CPT records with similar patient profiles and clinic affiliation were selected chronologically beginning the day before the initiation of the trial and working backward in time until 2110 records were obtained (approximately 2 years). Cervical specimens were collected previously from this group using the same types of collection devices and technique as that for the LBCC group. However, immediately following sample collection these endocervical and ectocervical cells were plated on a glass slide, fixed, and sent to the cytology laboratory for Pap staining and diagnosis.

Statistical Analysis

The proportion of subjects in each of the Pap test adequacy groups (satisfactory, unsatisfactory, and satisfactory but limited by [SBLB]) were compared between the sample and control groups for the total study group, the colposcopy and general screening cohorts, and the 3 age groups (18-30 years, 31-40 years, 41 years or older). The chi-square statistic was used to compare the proportions unless the tables included cells with expected counts less than 5; for those cases we used the Fisher exact test as extended to tables larger than 2×2. A summary comparison controlling for age group was made using the Cohran-Mantel-Haenszel chi-square statistic. Average age was compared between the groups using the Student t test. At the given sample size the power was calculated to be 80% or greater for detecting a difference in positive rates of 3.5% between the LBCC and the CPT.

Results

Subjects in both groups were comparable by type of clinical visit. Consequently, 1004 LBCC subjects and 2110 CPT subjects were included in the data analysis. The routine Pap test screening group consisted of 796 and 1585 subjects in the LBCC and CPT groups, respectively, representing 79.0% of each population. Approximately 21.0% of the LBCC and CPT subjects (208 and 425, respectively) were represented by women presenting for colposcopy examination following an abnormal Pap test result. Subjects were also stratified into 1 of 3 age ranges for analytic purposes. Thus, 423 and 602 subjects were aged between 18 and 30 years; 287 and 523 subjects were aged 31 to 40 years; and 294 and 885 subjects were aged 41 years or older for the LBCC and CPT populations, respectively. A statistically significant difference between the age distributions was noted (P <.001) with a greater proportion of younger subjects in the LBCC group (mean age=35.0 years) than in the CPT cohort (mean age=39.8 years).

A greater percentage of satisfactory Pap tests were obtained when using LBCC (84.0%) compared with the CPT (60.5%), P ".001 (Figure 1). Also, significantly fewer unsatisfactory and SBLB Pap tests were reported using LBCC (1.2% and 14.8%) compared with the CPT (3.8% and 35.7%). For the colposcopy group, significantly more satisfactory Pap tests were reported for LBCC compared with the CPT (81.7% and 55.3%, respectively; P <.001). Similar results were also noted for the screening group. These significant results were maintained when the data were adjusted for the 3 age groups (Table 1).

The frequencies of cytologic diagnoses for LBCC and the CPT are seen in Table 2. The LBCC method detected a significantly greater percentage of women with low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) Pap tests results (7.4% and 3.7%, respectively) compared with the CPT (1.7% and 1.7%, respectively). Similar significant results were noted when the LBCC and CPT groups were stratified into the screening and colposcopy populations. When both groups were adjusted for age, a greater percentage of LSIL and HSIL diagnoses were noted for LBCC in all 3 age ranges compared with the CPT (Table 4). The classification of atypical squamous cells of undetermined significance (ASCUS) cases was not modified by LBCC compared with the CPT. Because of the limited number of squamous cell carcinoma diagnoses reported, a comparison between the 2 groups was not possible.

The frequency of histologic diagnoses in the 2 groups closely paralleled Pap test diagnoses in the same populations. The LBCC and CPT groups had 5.4% and 1.0% cervical intraepithelial neoplasia 1 (CIN 1) histologic diagnoses, respectively, while 5.9% and 1.7% of the women had histologic diagnoses of CIN 2 and 3, respectively. These results were also maintained consistently across all 3 age ranges. The predictive value of a positive LBCC test (93.9%) was similar to that for the predictive value of a positive CPT (87.8%) when based on available histology results (Table 5). The sensitivity and specificity were equivalent for each test. Of all women with an LSIL or more severe Pap test result in each group, 1.9% of women in the CPT group and 6.5% of women in the LBCC group had cervical biopsies indicating CIN 1 or more severe disease.

Discussion

Pap test specimen adequacy results reflect whether the most likely site for neoplasia of the cervix—the transformation zone—has been sampled properly. LBCC provided significantly greater rates of satisfactory specimen adequacy than the CPT. Also, compared with the CPT, LBCC effectively reduced the number of SBLB and unsatisfactory specimen adequacy reports. Our findings are consistent with those of studies published previously that used split sample collection techniques.^6,7 The improvement of Pap test adequacy using LBCC may be because a clearer inspection of pertinent normal and abnormal cells is achieved by eliminating or minimizing obscuring inflammatory cells, red blood cells, other debris, and clumped or overlapped cells.¹³ A significant decrease in unsatisfactory Pap tests reduces the extra cost, time, and patient and clinician inconvenience incurred from the necessity of repeating a nonrepresentative Pap test. These advantages may be of particular importance to patients, clinicians, and third-party payers.

Also, in regard to specimen adequacy, LBCC performed better than the CPT for women of all age ranges. This is especially important for older women who typically have a greater frequency of unsatisfactory Pap tests because their active transformation zones are positioned deeply within the endocervical canal and are often inaccessible to comprehensive sampling. In addition, a thin atrophic epithelium (commonly seen in the older age group) is more easily traumatized during sampling, which causes potentially obscuring bleeding. Yet, LBCC reduced the rate of unsatisfactory Pap tests by approximately 50% for women older than 40 years. Other than the advantage of filtering unwanted cells, the difference may be explained by the fact that 80% of cervical cells are discarded with the collection devices and not transferred to a glass slide using the CPT method.³ In contrast, nearly all cells are transferred to solution with LBCC. Thus, the larger specimen obtained with the sampling method used in LBCC increases the availability of a typically limited number of endocervical cells retrieved from post-treatment and postmenopausal women who are routinely more difficult to sample.

The ability of the Pap test to detect cytologic changes consistent with neoplasia, when present, is critically important. In our trial, the LBCC method detected a greater percentage of women with LSIL and HSIL compared with the CPT. Approximately 4 times the number of women with LSIL and twice the number of cases of HSIL were detected by LBCC compared with the CPT. These results replicate or surpass those found in studies that evaluated LBCC using a split sample method.^6-9 Twice the rate of neoplasia detection by LBCC has been reported in studies using the split sample method. Our results, based on a direct-to-vial study design, may portray the true potential for LBCC to detect cervical neoplasia. A cleaner monolayer Pap test with a more comprehensive cellular specimen likely accounts for these remarkable differences. Similarly, the reduced number of unsatisfactory and SBLB Pap tests using LBCC may contribute to the greater yield of SILs. Of note, LBCC did not detect a significantly greater rate of ASCUS Pap test results; this may create problematic management decisions for some clinicians.¹⁴ The ability of LBCC to detect a greater percentage of women with SILs was maintained for the general screening population, the colposcopy cohort, and across the 3 age ranges. LBCC may be better able to detect women with HSIL, a lesion unlikely to resolve spontaneously. Women with HSIL (Figures 2A and B) and a comparable histologic diagnosis deserve prompt therapy for this true cancer precursor. Although many women with LSIL have disease that may regress to normal, as many as 20% to 40% of these women will have histologically confirmed CIN 2 or 3 that deserves treatment as well.¹⁵

Limitations

Our study is subject to several limitations. Most important, the observed differences in Pap test performance may have been because of actual differences of cervical neoplasia prevalences between the 2 groups, rather than a difference between Pap tests. Our subjects were selected from comparable patient populations by a study design that other researchers^10,11,16-20 have used to evaluate the direct-to-vial technique. Other than sampling a population of women with LBCC and then having them return for a CPT 1 month later, which risks compliance failure and spectrum of cervical disease changes or acquisition of new disease, there is no other study design to evaluate a direct-to-vial technique. One may question whether our increased rate of neoplasia detection demonstrated by LBCC is due to a substantial number of LBCC false-positive results.²¹ Yet, because the positive predictive values for the LBCC and CPT were similar and there were 3 times as many women with biopsy results of CIN 1 or greater in the LBCC group compared with the CPT group when only women with LSIL or greater Pap test results were considered, the increased rates of SIL detection using LBCC appear to represent an increased detection of true disease and not false-positive results, further validating our findings.²¹ The equivalent results for LBCC and CPT specificity (99%) indicate that the increased rate of SIL detection by LBCC was not due to a reduced specificity. Also, the favorable test results demonstrated for LBCC are not entirely dissimilar from those of other studies that used a split sample technique, a more biased study design for LBCC.^6-9 Studies by Vassilakos and colleagues¹⁶ and Papillo and coworkers¹⁰ demonstrated that a liquid-based thin layer cytologic report of LSIL or more severe disease correlated better with histologic results of CIN 1 or greater (80.5% and 80.2%, respectively) than CPTs (71.7% and 72.2%, respectively). Finally, because of the limited number of women with cervical caner in this study population, we were unable to determine if there were any differences between LBCC and the CPT in their ability to detect cervical cancer.

Conclusions

Compared with the CPT, LBCC detected a significantly greater percentage of satisfactory Pap tests and significantly reduced the number of unsatisfactory and SBLB tests. These findings demonstrate that LBCC significantly improves the adequacy of Pap tests and may increase the rate of detection of cervical neoplasia compared with CPT. Further study is necessary and warranted, since failure to detect cancer in a timely fashion affects ultimate cure rates, medical costs, quality of life, and perhaps medicolegal expenses. Although liquid-based thin layer cervical cytology is rapidly replacing the glass slide method throughout the United States, additional studies are also necessary to determine whether LBCC reduces the incidence of cervical cancer.

Acknowledgments

We appreciate the assistance of Cytyc Corporation in providing the supplies and grant support necessary for completion of this study.

We would like to thank the faculty and residents in the Family Medicine Center and OB/GYN Clinic who assisted with specimen collection, Jim Best for processing and interpreting cytologic specimens, Aisha Lavin for data management assistance, and April Dean for manuscript preparation.

The Papanicolaou (Pap) test is one of the most common and effective cancer screening tests used by primary care clinicians. However, a recent study conducted through the Agency for Health Care Policy and Research¹ estimated that the true sensitivity of the Pap test is only 51%. Two thirds of the false-negative results occur because of sampling error. The first liquid-based cervical cytology (LBCC) test was approved for clinical use by the United States Food and Drug Administration in 1996.² With LBCC, standard cervical cytology sampling devices are used to obtain a sample from the cervix. The sampling devices are then rinsed in a buffered alcohol transport and preservative solution instead of immediately transferring the cells to a glass slide. Sampling error is reduced, since all the cells are transferred into solution, in contrast with the conventional Pap test (CPT), in which only 20% of the cells are actually transferred to the glass slide.³ The cytologic specimen in solution is then sent to the laboratory where most of the debris, leukocytes, and erythrocytes are filtered from the specimen and a thin layer Pap test is prepared using a special processor. The cells are dispersed evenly with relatively little clumping or overlapping or obscuring debris (Figures 1A and B). The resulting clean smear is circular and contains approximately half the number of representative cells of a CPT. Residual cervical cells in solution that are not initially used for the Pap test may be tested at a later date for lower genital tract pathogens, such as carcinogenic human papillomavirus.^4,5

Liquid-based thin layer cervical cytology has performed favorably in studies using split sample collection techniques.^6-9 With the split sample technique, the cytologic specimen is first transferred to a glass slide for the CPT before transferring the remaining cervical cells to the liquid transport fluid. Evaluation of the LBCC Pap test using this nonrandom study design may be biased, since it is based solely on cells normally discarded. The CPT slides receive the first and perhaps better cellular sample; thus, the quality of that specimen may be vastly different than that available for LBCC. Currently, there are minimal data available in which LBCC was evaluated as it was intended to be used, for a primary cytologic specimen.^10,11 Thus, the full diagnostic potential of this new Pap test technique has not been fully realized. The purpose of our trial was to determine the rates of specimen adequacy and cervical cytologic and histologically confirmed diagnoses obtained with LBCC using a direct-to-vial collection technique and compare these results with those obtained using the CPT.

Methods

Subjects

In our clinical study one group of women was enrolled prospectively, and a second group was considered retrospectively. The first group (LBCC) consisted of 1004 nonpregnant women aged 18 years or older with an intact cervix. The second group consisted of 2110 women with a similar patient profile who had a CPT collected at the same clinics during the 2 years immediately preceding the initiation of the trial.

To ensure an enriched sample of women with cervical neoplasia, approximately 20% of the subjects in both cohorts were included from women presenting consecutively for a colposcopy examination following an abnormal CPT result. The remaining 80% of the subjects represented a general screening population of women presenting for a routine Pap test. All subjects were seen at 1 of 3 clinics: the Family Medicine Center, the Obstetrics and Gynecology Clinic, or the Comprehensive Cancer Center at the Medical College of Georgia in Augusta.

Equipment and Materials

Samples for CPTs and LBCC (ThinPrep Pap Test, Cytyc Corporation, Boxborough, Mass) were collected using a plastic Ayre spatula and cytobrush (Medscand, North Hollywood, Fla). Cervical cells from the second group were processed by CPT methods. Cervical cells from the prospectively enrolled group were preserved and transferred in LBCC solution (PreservCyt, Cytyc Corporation). Cervical samples for the LBCC test were processed using the ThinPrep 2000 Processor (Cytyc Corporation).¹²

Study Design

Eligible prospectively enrolled women presenting consecutively for a routine Pap test or colposcopy examination at any of the 3 designated clinics signed an internal review board-approved informed consent form before participating. After properly visualizing the cervix, a plastic Ayre spatula was used to collect an ectocervical sample. Another sample was collected using a cytobrush rotated 90° to 180° within the endocervical canal. The spatula and cytobrush were then immediately rinsed vigorously in the LBCC solution. The container was sealed, labeled, and sent to the cytology laboratory for processing according to the manufacturer’s instructions.¹² Cytotechnicians or pathologists in the Department of Pathology, Medical College of Georgia (MCG), evaluated all cytology and histology specimens. Cervical cytology was reported using the Bethesda System.

Computerized records from the MCG Cytology Laboratory were used to establish the second group. CPT records with similar patient profiles and clinic affiliation were selected chronologically beginning the day before the initiation of the trial and working backward in time until 2110 records were obtained (approximately 2 years). Cervical specimens were collected previously from this group using the same types of collection devices and technique as that for the LBCC group. However, immediately following sample collection these endocervical and ectocervical cells were plated on a glass slide, fixed, and sent to the cytology laboratory for Pap staining and diagnosis.

Statistical Analysis

The proportion of subjects in each of the Pap test adequacy groups (satisfactory, unsatisfactory, and satisfactory but limited by [SBLB]) were compared between the sample and control groups for the total study group, the colposcopy and general screening cohorts, and the 3 age groups (18-30 years, 31-40 years, 41 years or older). The chi-square statistic was used to compare the proportions unless the tables included cells with expected counts less than 5; for those cases we used the Fisher exact test as extended to tables larger than 2×2. A summary comparison controlling for age group was made using the Cohran-Mantel-Haenszel chi-square statistic. Average age was compared between the groups using the Student t test. At the given sample size the power was calculated to be 80% or greater for detecting a difference in positive rates of 3.5% between the LBCC and the CPT.

Results

Subjects in both groups were comparable by type of clinical visit. Consequently, 1004 LBCC subjects and 2110 CPT subjects were included in the data analysis. The routine Pap test screening group consisted of 796 and 1585 subjects in the LBCC and CPT groups, respectively, representing 79.0% of each population. Approximately 21.0% of the LBCC and CPT subjects (208 and 425, respectively) were represented by women presenting for colposcopy examination following an abnormal Pap test result. Subjects were also stratified into 1 of 3 age ranges for analytic purposes. Thus, 423 and 602 subjects were aged between 18 and 30 years; 287 and 523 subjects were aged 31 to 40 years; and 294 and 885 subjects were aged 41 years or older for the LBCC and CPT populations, respectively. A statistically significant difference between the age distributions was noted (P <.001) with a greater proportion of younger subjects in the LBCC group (mean age=35.0 years) than in the CPT cohort (mean age=39.8 years).

A greater percentage of satisfactory Pap tests were obtained when using LBCC (84.0%) compared with the CPT (60.5%), P ".001 (Figure 1). Also, significantly fewer unsatisfactory and SBLB Pap tests were reported using LBCC (1.2% and 14.8%) compared with the CPT (3.8% and 35.7%). For the colposcopy group, significantly more satisfactory Pap tests were reported for LBCC compared with the CPT (81.7% and 55.3%, respectively; P <.001). Similar results were also noted for the screening group. These significant results were maintained when the data were adjusted for the 3 age groups (Table 1).

The frequencies of cytologic diagnoses for LBCC and the CPT are seen in Table 2. The LBCC method detected a significantly greater percentage of women with low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) Pap tests results (7.4% and 3.7%, respectively) compared with the CPT (1.7% and 1.7%, respectively). Similar significant results were noted when the LBCC and CPT groups were stratified into the screening and colposcopy populations. When both groups were adjusted for age, a greater percentage of LSIL and HSIL diagnoses were noted for LBCC in all 3 age ranges compared with the CPT (Table 4). The classification of atypical squamous cells of undetermined significance (ASCUS) cases was not modified by LBCC compared with the CPT. Because of the limited number of squamous cell carcinoma diagnoses reported, a comparison between the 2 groups was not possible.

The frequency of histologic diagnoses in the 2 groups closely paralleled Pap test diagnoses in the same populations. The LBCC and CPT groups had 5.4% and 1.0% cervical intraepithelial neoplasia 1 (CIN 1) histologic diagnoses, respectively, while 5.9% and 1.7% of the women had histologic diagnoses of CIN 2 and 3, respectively. These results were also maintained consistently across all 3 age ranges. The predictive value of a positive LBCC test (93.9%) was similar to that for the predictive value of a positive CPT (87.8%) when based on available histology results (Table 5). The sensitivity and specificity were equivalent for each test. Of all women with an LSIL or more severe Pap test result in each group, 1.9% of women in the CPT group and 6.5% of women in the LBCC group had cervical biopsies indicating CIN 1 or more severe disease.

Discussion

Pap test specimen adequacy results reflect whether the most likely site for neoplasia of the cervix—the transformation zone—has been sampled properly. LBCC provided significantly greater rates of satisfactory specimen adequacy than the CPT. Also, compared with the CPT, LBCC effectively reduced the number of SBLB and unsatisfactory specimen adequacy reports. Our findings are consistent with those of studies published previously that used split sample collection techniques.^6,7 The improvement of Pap test adequacy using LBCC may be because a clearer inspection of pertinent normal and abnormal cells is achieved by eliminating or minimizing obscuring inflammatory cells, red blood cells, other debris, and clumped or overlapped cells.¹³ A significant decrease in unsatisfactory Pap tests reduces the extra cost, time, and patient and clinician inconvenience incurred from the necessity of repeating a nonrepresentative Pap test. These advantages may be of particular importance to patients, clinicians, and third-party payers.

Also, in regard to specimen adequacy, LBCC performed better than the CPT for women of all age ranges. This is especially important for older women who typically have a greater frequency of unsatisfactory Pap tests because their active transformation zones are positioned deeply within the endocervical canal and are often inaccessible to comprehensive sampling. In addition, a thin atrophic epithelium (commonly seen in the older age group) is more easily traumatized during sampling, which causes potentially obscuring bleeding. Yet, LBCC reduced the rate of unsatisfactory Pap tests by approximately 50% for women older than 40 years. Other than the advantage of filtering unwanted cells, the difference may be explained by the fact that 80% of cervical cells are discarded with the collection devices and not transferred to a glass slide using the CPT method.³ In contrast, nearly all cells are transferred to solution with LBCC. Thus, the larger specimen obtained with the sampling method used in LBCC increases the availability of a typically limited number of endocervical cells retrieved from post-treatment and postmenopausal women who are routinely more difficult to sample.

The ability of the Pap test to detect cytologic changes consistent with neoplasia, when present, is critically important. In our trial, the LBCC method detected a greater percentage of women with LSIL and HSIL compared with the CPT. Approximately 4 times the number of women with LSIL and twice the number of cases of HSIL were detected by LBCC compared with the CPT. These results replicate or surpass those found in studies that evaluated LBCC using a split sample method.^6-9 Twice the rate of neoplasia detection by LBCC has been reported in studies using the split sample method. Our results, based on a direct-to-vial study design, may portray the true potential for LBCC to detect cervical neoplasia. A cleaner monolayer Pap test with a more comprehensive cellular specimen likely accounts for these remarkable differences. Similarly, the reduced number of unsatisfactory and SBLB Pap tests using LBCC may contribute to the greater yield of SILs. Of note, LBCC did not detect a significantly greater rate of ASCUS Pap test results; this may create problematic management decisions for some clinicians.¹⁴ The ability of LBCC to detect a greater percentage of women with SILs was maintained for the general screening population, the colposcopy cohort, and across the 3 age ranges. LBCC may be better able to detect women with HSIL, a lesion unlikely to resolve spontaneously. Women with HSIL (Figures 2A and B) and a comparable histologic diagnosis deserve prompt therapy for this true cancer precursor. Although many women with LSIL have disease that may regress to normal, as many as 20% to 40% of these women will have histologically confirmed CIN 2 or 3 that deserves treatment as well.¹⁵

Limitations

Our study is subject to several limitations. Most important, the observed differences in Pap test performance may have been because of actual differences of cervical neoplasia prevalences between the 2 groups, rather than a difference between Pap tests. Our subjects were selected from comparable patient populations by a study design that other researchers^10,11,16-20 have used to evaluate the direct-to-vial technique. Other than sampling a population of women with LBCC and then having them return for a CPT 1 month later, which risks compliance failure and spectrum of cervical disease changes or acquisition of new disease, there is no other study design to evaluate a direct-to-vial technique. One may question whether our increased rate of neoplasia detection demonstrated by LBCC is due to a substantial number of LBCC false-positive results.²¹ Yet, because the positive predictive values for the LBCC and CPT were similar and there were 3 times as many women with biopsy results of CIN 1 or greater in the LBCC group compared with the CPT group when only women with LSIL or greater Pap test results were considered, the increased rates of SIL detection using LBCC appear to represent an increased detection of true disease and not false-positive results, further validating our findings.²¹ The equivalent results for LBCC and CPT specificity (99%) indicate that the increased rate of SIL detection by LBCC was not due to a reduced specificity. Also, the favorable test results demonstrated for LBCC are not entirely dissimilar from those of other studies that used a split sample technique, a more biased study design for LBCC.^6-9 Studies by Vassilakos and colleagues¹⁶ and Papillo and coworkers¹⁰ demonstrated that a liquid-based thin layer cytologic report of LSIL or more severe disease correlated better with histologic results of CIN 1 or greater (80.5% and 80.2%, respectively) than CPTs (71.7% and 72.2%, respectively). Finally, because of the limited number of women with cervical caner in this study population, we were unable to determine if there were any differences between LBCC and the CPT in their ability to detect cervical cancer.

Conclusions

Compared with the CPT, LBCC detected a significantly greater percentage of satisfactory Pap tests and significantly reduced the number of unsatisfactory and SBLB tests. These findings demonstrate that LBCC significantly improves the adequacy of Pap tests and may increase the rate of detection of cervical neoplasia compared with CPT. Further study is necessary and warranted, since failure to detect cancer in a timely fashion affects ultimate cure rates, medical costs, quality of life, and perhaps medicolegal expenses. Although liquid-based thin layer cervical cytology is rapidly replacing the glass slide method throughout the United States, additional studies are also necessary to determine whether LBCC reduces the incidence of cervical cancer.

Acknowledgments

We appreciate the assistance of Cytyc Corporation in providing the supplies and grant support necessary for completion of this study.

We would like to thank the faculty and residents in the Family Medicine Center and OB/GYN Clinic who assisted with specimen collection, Jim Best for processing and interpreting cytologic specimens, Aisha Lavin for data management assistance, and April Dean for manuscript preparation.

The Papanicolaou (Pap) test is one of the most common and effective cancer screening tests used by primary care clinicians. However, a recent study conducted through the Agency for Health Care Policy and Research¹ estimated that the true sensitivity of the Pap test is only 51%. Two thirds of the false-negative results occur because of sampling error. The first liquid-based cervical cytology (LBCC) test was approved for clinical use by the United States Food and Drug Administration in 1996.² With LBCC, standard cervical cytology sampling devices are used to obtain a sample from the cervix. The sampling devices are then rinsed in a buffered alcohol transport and preservative solution instead of immediately transferring the cells to a glass slide. Sampling error is reduced, since all the cells are transferred into solution, in contrast with the conventional Pap test (CPT), in which only 20% of the cells are actually transferred to the glass slide.³ The cytologic specimen in solution is then sent to the laboratory where most of the debris, leukocytes, and erythrocytes are filtered from the specimen and a thin layer Pap test is prepared using a special processor. The cells are dispersed evenly with relatively little clumping or overlapping or obscuring debris (Figures 1A and B). The resulting clean smear is circular and contains approximately half the number of representative cells of a CPT. Residual cervical cells in solution that are not initially used for the Pap test may be tested at a later date for lower genital tract pathogens, such as carcinogenic human papillomavirus.^4,5

Liquid-based thin layer cervical cytology has performed favorably in studies using split sample collection techniques.^6-9 With the split sample technique, the cytologic specimen is first transferred to a glass slide for the CPT before transferring the remaining cervical cells to the liquid transport fluid. Evaluation of the LBCC Pap test using this nonrandom study design may be biased, since it is based solely on cells normally discarded. The CPT slides receive the first and perhaps better cellular sample; thus, the quality of that specimen may be vastly different than that available for LBCC. Currently, there are minimal data available in which LBCC was evaluated as it was intended to be used, for a primary cytologic specimen.^10,11 Thus, the full diagnostic potential of this new Pap test technique has not been fully realized. The purpose of our trial was to determine the rates of specimen adequacy and cervical cytologic and histologically confirmed diagnoses obtained with LBCC using a direct-to-vial collection technique and compare these results with those obtained using the CPT.

Methods

Subjects

In our clinical study one group of women was enrolled prospectively, and a second group was considered retrospectively. The first group (LBCC) consisted of 1004 nonpregnant women aged 18 years or older with an intact cervix. The second group consisted of 2110 women with a similar patient profile who had a CPT collected at the same clinics during the 2 years immediately preceding the initiation of the trial.

To ensure an enriched sample of women with cervical neoplasia, approximately 20% of the subjects in both cohorts were included from women presenting consecutively for a colposcopy examination following an abnormal CPT result. The remaining 80% of the subjects represented a general screening population of women presenting for a routine Pap test. All subjects were seen at 1 of 3 clinics: the Family Medicine Center, the Obstetrics and Gynecology Clinic, or the Comprehensive Cancer Center at the Medical College of Georgia in Augusta.

Equipment and Materials

Samples for CPTs and LBCC (ThinPrep Pap Test, Cytyc Corporation, Boxborough, Mass) were collected using a plastic Ayre spatula and cytobrush (Medscand, North Hollywood, Fla). Cervical cells from the second group were processed by CPT methods. Cervical cells from the prospectively enrolled group were preserved and transferred in LBCC solution (PreservCyt, Cytyc Corporation). Cervical samples for the LBCC test were processed using the ThinPrep 2000 Processor (Cytyc Corporation).¹²

Study Design

Eligible prospectively enrolled women presenting consecutively for a routine Pap test or colposcopy examination at any of the 3 designated clinics signed an internal review board-approved informed consent form before participating. After properly visualizing the cervix, a plastic Ayre spatula was used to collect an ectocervical sample. Another sample was collected using a cytobrush rotated 90° to 180° within the endocervical canal. The spatula and cytobrush were then immediately rinsed vigorously in the LBCC solution. The container was sealed, labeled, and sent to the cytology laboratory for processing according to the manufacturer’s instructions.¹² Cytotechnicians or pathologists in the Department of Pathology, Medical College of Georgia (MCG), evaluated all cytology and histology specimens. Cervical cytology was reported using the Bethesda System.

Computerized records from the MCG Cytology Laboratory were used to establish the second group. CPT records with similar patient profiles and clinic affiliation were selected chronologically beginning the day before the initiation of the trial and working backward in time until 2110 records were obtained (approximately 2 years). Cervical specimens were collected previously from this group using the same types of collection devices and technique as that for the LBCC group. However, immediately following sample collection these endocervical and ectocervical cells were plated on a glass slide, fixed, and sent to the cytology laboratory for Pap staining and diagnosis.

Statistical Analysis

The proportion of subjects in each of the Pap test adequacy groups (satisfactory, unsatisfactory, and satisfactory but limited by [SBLB]) were compared between the sample and control groups for the total study group, the colposcopy and general screening cohorts, and the 3 age groups (18-30 years, 31-40 years, 41 years or older). The chi-square statistic was used to compare the proportions unless the tables included cells with expected counts less than 5; for those cases we used the Fisher exact test as extended to tables larger than 2×2. A summary comparison controlling for age group was made using the Cohran-Mantel-Haenszel chi-square statistic. Average age was compared between the groups using the Student t test. At the given sample size the power was calculated to be 80% or greater for detecting a difference in positive rates of 3.5% between the LBCC and the CPT.

Results

Subjects in both groups were comparable by type of clinical visit. Consequently, 1004 LBCC subjects and 2110 CPT subjects were included in the data analysis. The routine Pap test screening group consisted of 796 and 1585 subjects in the LBCC and CPT groups, respectively, representing 79.0% of each population. Approximately 21.0% of the LBCC and CPT subjects (208 and 425, respectively) were represented by women presenting for colposcopy examination following an abnormal Pap test result. Subjects were also stratified into 1 of 3 age ranges for analytic purposes. Thus, 423 and 602 subjects were aged between 18 and 30 years; 287 and 523 subjects were aged 31 to 40 years; and 294 and 885 subjects were aged 41 years or older for the LBCC and CPT populations, respectively. A statistically significant difference between the age distributions was noted (P <.001) with a greater proportion of younger subjects in the LBCC group (mean age=35.0 years) than in the CPT cohort (mean age=39.8 years).

A greater percentage of satisfactory Pap tests were obtained when using LBCC (84.0%) compared with the CPT (60.5%), P ".001 (Figure 1). Also, significantly fewer unsatisfactory and SBLB Pap tests were reported using LBCC (1.2% and 14.8%) compared with the CPT (3.8% and 35.7%). For the colposcopy group, significantly more satisfactory Pap tests were reported for LBCC compared with the CPT (81.7% and 55.3%, respectively; P <.001). Similar results were also noted for the screening group. These significant results were maintained when the data were adjusted for the 3 age groups (Table 1).

The frequencies of cytologic diagnoses for LBCC and the CPT are seen in Table 2. The LBCC method detected a significantly greater percentage of women with low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) Pap tests results (7.4% and 3.7%, respectively) compared with the CPT (1.7% and 1.7%, respectively). Similar significant results were noted when the LBCC and CPT groups were stratified into the screening and colposcopy populations. When both groups were adjusted for age, a greater percentage of LSIL and HSIL diagnoses were noted for LBCC in all 3 age ranges compared with the CPT (Table 4). The classification of atypical squamous cells of undetermined significance (ASCUS) cases was not modified by LBCC compared with the CPT. Because of the limited number of squamous cell carcinoma diagnoses reported, a comparison between the 2 groups was not possible.

The frequency of histologic diagnoses in the 2 groups closely paralleled Pap test diagnoses in the same populations. The LBCC and CPT groups had 5.4% and 1.0% cervical intraepithelial neoplasia 1 (CIN 1) histologic diagnoses, respectively, while 5.9% and 1.7% of the women had histologic diagnoses of CIN 2 and 3, respectively. These results were also maintained consistently across all 3 age ranges. The predictive value of a positive LBCC test (93.9%) was similar to that for the predictive value of a positive CPT (87.8%) when based on available histology results (Table 5). The sensitivity and specificity were equivalent for each test. Of all women with an LSIL or more severe Pap test result in each group, 1.9% of women in the CPT group and 6.5% of women in the LBCC group had cervical biopsies indicating CIN 1 or more severe disease.

Discussion

Pap test specimen adequacy results reflect whether the most likely site for neoplasia of the cervix—the transformation zone—has been sampled properly. LBCC provided significantly greater rates of satisfactory specimen adequacy than the CPT. Also, compared with the CPT, LBCC effectively reduced the number of SBLB and unsatisfactory specimen adequacy reports. Our findings are consistent with those of studies published previously that used split sample collection techniques.^6,7 The improvement of Pap test adequacy using LBCC may be because a clearer inspection of pertinent normal and abnormal cells is achieved by eliminating or minimizing obscuring inflammatory cells, red blood cells, other debris, and clumped or overlapped cells.¹³ A significant decrease in unsatisfactory Pap tests reduces the extra cost, time, and patient and clinician inconvenience incurred from the necessity of repeating a nonrepresentative Pap test. These advantages may be of particular importance to patients, clinicians, and third-party payers.

Also, in regard to specimen adequacy, LBCC performed better than the CPT for women of all age ranges. This is especially important for older women who typically have a greater frequency of unsatisfactory Pap tests because their active transformation zones are positioned deeply within the endocervical canal and are often inaccessible to comprehensive sampling. In addition, a thin atrophic epithelium (commonly seen in the older age group) is more easily traumatized during sampling, which causes potentially obscuring bleeding. Yet, LBCC reduced the rate of unsatisfactory Pap tests by approximately 50% for women older than 40 years. Other than the advantage of filtering unwanted cells, the difference may be explained by the fact that 80% of cervical cells are discarded with the collection devices and not transferred to a glass slide using the CPT method.³ In contrast, nearly all cells are transferred to solution with LBCC. Thus, the larger specimen obtained with the sampling method used in LBCC increases the availability of a typically limited number of endocervical cells retrieved from post-treatment and postmenopausal women who are routinely more difficult to sample.

The ability of the Pap test to detect cytologic changes consistent with neoplasia, when present, is critically important. In our trial, the LBCC method detected a greater percentage of women with LSIL and HSIL compared with the CPT. Approximately 4 times the number of women with LSIL and twice the number of cases of HSIL were detected by LBCC compared with the CPT. These results replicate or surpass those found in studies that evaluated LBCC using a split sample method.^6-9 Twice the rate of neoplasia detection by LBCC has been reported in studies using the split sample method. Our results, based on a direct-to-vial study design, may portray the true potential for LBCC to detect cervical neoplasia. A cleaner monolayer Pap test with a more comprehensive cellular specimen likely accounts for these remarkable differences. Similarly, the reduced number of unsatisfactory and SBLB Pap tests using LBCC may contribute to the greater yield of SILs. Of note, LBCC did not detect a significantly greater rate of ASCUS Pap test results; this may create problematic management decisions for some clinicians.¹⁴ The ability of LBCC to detect a greater percentage of women with SILs was maintained for the general screening population, the colposcopy cohort, and across the 3 age ranges. LBCC may be better able to detect women with HSIL, a lesion unlikely to resolve spontaneously. Women with HSIL (Figures 2A and B) and a comparable histologic diagnosis deserve prompt therapy for this true cancer precursor. Although many women with LSIL have disease that may regress to normal, as many as 20% to 40% of these women will have histologically confirmed CIN 2 or 3 that deserves treatment as well.¹⁵

Limitations

Our study is subject to several limitations. Most important, the observed differences in Pap test performance may have been because of actual differences of cervical neoplasia prevalences between the 2 groups, rather than a difference between Pap tests. Our subjects were selected from comparable patient populations by a study design that other researchers^10,11,16-20 have used to evaluate the direct-to-vial technique. Other than sampling a population of women with LBCC and then having them return for a CPT 1 month later, which risks compliance failure and spectrum of cervical disease changes or acquisition of new disease, there is no other study design to evaluate a direct-to-vial technique. One may question whether our increased rate of neoplasia detection demonstrated by LBCC is due to a substantial number of LBCC false-positive results.²¹ Yet, because the positive predictive values for the LBCC and CPT were similar and there were 3 times as many women with biopsy results of CIN 1 or greater in the LBCC group compared with the CPT group when only women with LSIL or greater Pap test results were considered, the increased rates of SIL detection using LBCC appear to represent an increased detection of true disease and not false-positive results, further validating our findings.²¹ The equivalent results for LBCC and CPT specificity (99%) indicate that the increased rate of SIL detection by LBCC was not due to a reduced specificity. Also, the favorable test results demonstrated for LBCC are not entirely dissimilar from those of other studies that used a split sample technique, a more biased study design for LBCC.^6-9 Studies by Vassilakos and colleagues¹⁶ and Papillo and coworkers¹⁰ demonstrated that a liquid-based thin layer cytologic report of LSIL or more severe disease correlated better with histologic results of CIN 1 or greater (80.5% and 80.2%, respectively) than CPTs (71.7% and 72.2%, respectively). Finally, because of the limited number of women with cervical caner in this study population, we were unable to determine if there were any differences between LBCC and the CPT in their ability to detect cervical cancer.

Conclusions

Compared with the CPT, LBCC detected a significantly greater percentage of satisfactory Pap tests and significantly reduced the number of unsatisfactory and SBLB tests. These findings demonstrate that LBCC significantly improves the adequacy of Pap tests and may increase the rate of detection of cervical neoplasia compared with CPT. Further study is necessary and warranted, since failure to detect cancer in a timely fashion affects ultimate cure rates, medical costs, quality of life, and perhaps medicolegal expenses. Although liquid-based thin layer cervical cytology is rapidly replacing the glass slide method throughout the United States, additional studies are also necessary to determine whether LBCC reduces the incidence of cervical cancer.

Acknowledgments

We appreciate the assistance of Cytyc Corporation in providing the supplies and grant support necessary for completion of this study.

We would like to thank the faculty and residents in the Family Medicine Center and OB/GYN Clinic who assisted with specimen collection, Jim Best for processing and interpreting cytologic specimens, Aisha Lavin for data management assistance, and April Dean for manuscript preparation.