Sampling, sampling errors and specimen preparation.

To obtain an adequate cervical smear for making a correct cytologic diagnosis, smear taking, laboratory handling and interpretation must be optimal. Many people are involved, and only by a combined effort of all links can this target be seriously approached: the smear takers will have to be open minded about technical improvements and read the morphologic descriptions cautiously; in the laboratory, cytotechnicians and physicians will have to challenge themselves and each other. It is mandatory to discard specimens that do not meet general standards of adequacy. At present a host of new techniques are being implemented. It is not feasible for all laboratories to be engaged in testing these new methods, but we are all requested to follow the development the best we can and switch to new ways when justified. Our working conditions are very different; therefore, it is our professional responsibility and plight to respond at the right time. So far the conclusion is that the conventional Pap smear is the international standard of care for the diagnosis of cervical cancer precursers in cancer screening programs. Certainly, this may change within a very short time. Liquid-based techniques, and in particular HPV technologies, are just around the corner.

Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma.

The prevalence of human papilloma virus (HPV) DNA in different histological subtypes of cervical adenocarcinoma and related tumors was examined using formalin-fixed, paraffin-embedded tissue samples from 105 primary cervical adenocarcinomas and adenosquamous carcinomas. Broad-spectrum HPV DNA amplification and genotyping was performed with the SPF10 primer set and line probe assay (LiPA), respectively. HPV DNA was detected in 82 of 90 (91%) mucinous adenocarcinomas, encompassing endocervical, intestinal, and endometrioid histological subtypes, and in nine of nine adenosquamous tumors (100%). HPV DNA was not detected in any nonmucinous adenocarcinomas including clear cell, serous, and mesonephric carcinomas (0/6). The most common viral types detected in adenocarcinoma were HPV 16 (50%) and HPV 18 (40%), followed by HPV 45 (10%), HPV52 (2%), and HPV 35 (1%). Multiple HPV types were detected in 9.7% of the cases. In conclusion, mucinous adenocarcinomas and adenosquamous carcinomas of the cervix demonstrate a very high prevalence of HPV DNA, similar to that reported for cervical squamous cell carcinoma. Only rare histological variants of cervical adenocarcinoma seem unrelated to HPV infection.

Two-stage cervical cancer screening: an alternative for resource-poor settings.

OBJECTIVE: We sought to introduce 2-stage cervical cancer screening in which 2 screening tests are performed sequentially (the second test is performed only if the first result is positive), followed by treatment if both test results are abnormal. STUDY DESIGN: A total of 1423 women from Cape Town, South Africa, were screened by direct visual inspection, human papillomavirus deoxyribonucleic acid testing, cytologic testing, and cervicography. If an abnormality was identified with any test, women were referred for colposcopy. RESULTS: Direct visual inspection, cytologic testing, human papillomavirus deoxyribonucleic acid testing, and cervicography, when used alone, identified 24, 26, 23, and 23 cases of disease (high-grade squamous intraepithelial lesion or cancer) per 1000 women, respectively, and would classify 182, 71, 137, and 112 women without disease as having abnormal results. Two-stage screening with direct visual inspection first, followed by cytologic testing, human papillomavirus deoxyribonucleic acid testing, or cervicography, would detect 18, 16, and 18 cases per 1000 women, respectively, and would substantially reduce the number of women without disease who were classified as having abnormal results. CONCLUSION: Two-stage screening for cervical cancer provides an attractive alternative to conventional screening for low-resource settings.

Human papillomavirus DNA testing for cervical cancer screening in low-resource settings.

BACKGROUND: In many low-resource settings, there are barriers to cytologic screening for cervical cancer. This study evaluates human papillomavirus (HPV) DNA testing as an alternative screening method. METHODS: Cervical samples from 2944 previously unscreened South African women aged 35-65 years were tested for high-risk types of HPV with the use of the Hybrid Capture I (HCI) assay. Women also had a Pap smear, direct visual inspection of the cervix, and Cervicography(TM). Women positive on any screening test were referred for colposcopy. Samples from women with biopsy-confirmed, low-grade squamous intraepithelial lesions (SILs) (n = 95), high-grade SILs (n = 74), or invasive cervical cancer (n = 12) and a random sample of women with no cervical disease (n = 243) were retested for HPV DNA with the use of the more sensitive Hybrid Capture II (HCII) assay. All P values are two-sided. RESULTS: High-risk HPV DNA was detected in 73.3% and 88.4% of 86 women with high-grade SIL or invasive cancer and in 12.2% of 2680 and 18.1% of 243 women without evidence of cervical disease, with the use of the HCI and HCII assays, respectively. HPV DNA testing with the HCII assay was more sensitive than cytology for detecting high-grade SIL and invasive cancer (McNemar's test, P =.04), and testing with the HCI assay was of equivalent sensitivity (P =.61). Cytology had a statistically significantly better specificity (96.8%) than either the HCI assay (87.8%) or the HCII assay (81.9%) (P<.01). Receiver operating characteristic curves identified test cutoff values that allow HPV DNA testing to identify 57% of women with high-grade SIL or cancer, while classifying less than 5% of women with no cervical disease as HPV DNA positive. CONCLUSIONS: HPV DNA testing has a sensitivity equivalent to, or better than, that of cytology. Since HPV DNA testing programs may be easier to implement than cytologic screening, HPV testing should be considered for primary cervical cancer screening in low-resource settings.

Endometrial precancer diagnosis by histopathology, clonal analysis, and computerized morphometry.

Management of endometrial precancers is compromised by longstanding debate over the natural history of endometrial hyperplasias and inconsistencies in their diagnosis. The recent demonstration that some hyperplasias, like cancers, are phenotypically monoclonal is useful in recognizing biological precancers. A clonal analysis has been undertaken of a series of 93 endometrial tissues and their morphology has been evaluated by subjective diagnostic classification and computerized morphometric analysis. A pathologist's diagnosis of atypical endometrial hyperplasia was highly associated with monoclonal growth. Both microsatellite-stable and microsatellite-unstable precancers were classified as atypical hyperplasias, indicating overlapping morphologies for these two groups. Diagnosis of non-atypical endometrial hyperplasias was not reproducible and identified a group of lesions equally likely to be monoclonal as polyclonal. Computerized morphometry resolved these lesions into monoclonal and polyclonal subgroups with a high degree of accuracy and reproducibility. The predictive value of morphometry was dominated by that fraction of the sample which consisted of stroma (volume percentage stroma). This can be measured manually and used to predict monoclonality when below the threshold value of 55%. This study shows that morphometric analysis reproducibly and precisely identifies monoclonal endometrial precancers from histological sections. It may serve, furthermore, to classify accurately lesions judged by pathologists as indeterminate (non-atypical hyperplasias). The material from this study (available at www.endometrium.org from March 1, 2000) and precisely defined architectural diagnostic criteria provide new tools for diagnostic standardization of endometrial precancers.

Histologic studies of the effects of circulating hot saline on the uterus before hysterectomy.

STUDY OBJECTIVE: To evaluate a new device for endometrial ablation. DESIGN: (Canadian Task Force classification II-1). SETTING: University-affiliated hospital. PATIENTS: Thirty-two women scheduled for hysterectomy. INTERVENTIONS: Endometrial ablation and hysterectomy. MEASUREMENTS AND MAIN RESULTS: The new device for endometrial ablation was evaluated by studying depth of necrosis after staining for the oxidative enzyme NADH. Uniform endomyometrial necrosis was achieved at a depth of 2 to 4 mm with 90 degrees C saline circulated for 10 minutes. CONCLUSION: The procedure was successful in all patients, and there were no adverse clinical sequelae. (J Am Assoc Gynecol Laparosc 6(3):269-273, 1999)

Evaluation of Hydro ThermAblator for endometrial destruction in patients with menorrhagia.

OBJECTIVE: To describe endometrial destruction with the Hydro ThermAblator. DESIGN: (Canadian Task Force classification II-1). SETTING: University-affiliated hospital. PATIENTS: Twenty-six women with uncontrolled menorrhagia. INTERVENTION: Endometrial ablation with saline heated to 90 degrees C and circulated in the uterine cavity for 10 minutes under hysteroscopic control. MEASUREMENTS AND MAIN RESULTS: All patients tolerated the procedure well, all but one was satisfied with the results, and there were no significant side effects or complications. Seventy-seven percent of women were either amenorrheic or hypomenorrheic after 6 months, and 88% were amenorrheic or hypomenorrheic after 1 year, including one patient who was treated a second time; 87.5% were amenorrheic or hypomenorrheic at 18 months. One woman had persistent menorrhagia and was treated by hysterectomy. CONCLUSION: In this study, endometrial ablation was performed successfully with the Hydro ThermAblator in 25 of 26 women. (J Am Assoc Gynecol Laparosc 6(3):275-278, 1999)

Effect of a unique constant-estrogen, pulsed-progestin hormone replacement therapy containing 17beta-estradiol and norgestimate on endometrial histology.

OBJECTIVE: To evaluate the effect of a 17beta-estradiol(E2)/norgestimate (NGM) HRT regimen, which provides constant estrogen in combination with pulsed progestin administration, on endometrial histology in healthy postmenopausal women 40 to 65 years of age who had experienced natural menopause at least 12 months before the start of the study. METHODS: A total of 1,253 postmenopausal women were randomized to receive either continuous 1 mg E2, or constant estrogen, pulsed progestin regimens of 1 mg E2/30 microg NGM, 1 mg E2/90 microg NGM, or 1 mg E2/180 microg NGM (3 days on, 3 days off) in a 12-month, multicenter, double-blind study. Endometrial biopsies were obtained pre- and post-treatment, and were evaluated by at least 2 (if required, by 3) pathologists who were blinded with respect to treatment and to each other's diagnosis. RESULTS: At the end of the study, no cases of endometrial hyperplasia were diagnosed in subjects who received E2 1 mg/NGM 90 microg or E21 mg/NGM 180 microg, whereas 74 (28%) and 16 (6%) cases of endometrial hyperplasia were diagnosed in subjects who received continuous E2 1 mg and E2 1 mg/NGM 30 microg, respectively. A dose-related endometrial response to NGM was apparent (P < .001). The percentage of patients with inactive/atrophic endometrium increased with NGM dose. CONCLUSION: The results of this study support the safety and efficacy of this unique HRT regimen and suggest that the minimal NGM dose required to protect the endometrium from hyperplasia in a pulsed progestin regimen consisting of continuous E2 1 mg is 90 microg.

Reflex human papillomavirus deoxyribonucleic acid testing in women with abnormal Papanicolaou smears.

OBJECTIVE: The study examined interrelationships between sensitivity and specificity of "reflex human papillomavirus deoxyribonucleic acid testing" from liquid-based cervical cytologic specimens by means of receiver operator characteristics curves. STUDY DESIGN: A cohort study was performed on 265 women evaluated by colposcopy because of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion found on Papanicolaou smear. RESULTS: At a positive threshold of 0.2 pg/ml (1000 copies of human papillomavirus per test), human papillomavirus deoxyribonucleic acid testing detected 86% of women with cervical intraepithelial neoplasia and 93% of women with high-grade cervical intraepithelial neoplasia with a specificity of 30%. Decreasing the sensitivity of the human papillomavirus test to 1 pg/ml (5000 copies of human papillomavirus per test) improved the specificity of a positive result to 44% but decreased the clinical sensitivity to 78% for cervical intraepithelial neoplasia grade 2 or 3. Relationships between sensitivity and specificity were influenced by patient age and referral diagnosis. For example, limiting the analysis to only women with a referral for atypical squamous cells of undetermined significance found on Papanicolaou smear and a positive human papillomavirus test threshold of 0.5 pg/ml produced a sensitivity of 90% for cervical intraepithelial neoplasia grade 2 or 3 and a test specificity of 55%. CONCLUSION: Human papillomavirus deoxyribonucleic acid testing of residual cellular material from liquid cytologic specimens appears to be more appropriate for older women (>30 years old) and women with atypical squamous cells of undetermined significance, as opposed to low-grade squamous intraepithelial lesion, on their Papanicolaou smears.

Cigarette smoking and cervical dysplasia among non-Hispanic black women.

This is the first case-control study to determine whether smoking is associated with cervical dysplasia, after adjustment for human papillomavirus (HPV) infection, among a group of non-Hispanic black women. Subjects were interviewed and asked questions about smoking and other risk factors for cervical cancer. HPV infection was determined by hybrid capture. Thirty-two women with histologically confirmed incident dysplasia and 113 control women with normal cytologic smears were enrolled; all women were HIV negative. Smoking was more strongly associated with dysplasia among women with high-grade lesions than among all case women combined. After adjustment, women with high-grade lesions were roughly four times more likely to be ever (odds ratio [OR]: 3.8; 95% confidence interval [CI]: 0.76-18.4) or current (OR: 4.3; 95% CI: 0.83-21.9) smokers, compared with control women. Larger studies among black women that control for HPV infection are needed to confirm these findings and to explore associations among black women with low-grade lesions.

Triage of women with ASCUS and LSIL on Pap smear reports: management by repeat Pap smear, HPV DNA testing, or colposcopy?

BACKGROUND: The purpose of this study was to determine the efficacy of a repeat Papanicolaou (Pap) smear and the Hybrid Capture tube-based (HCT) HPV DNA test for detecting cervical intraepithelial neoplasia (CIN) grade 2 or 3 in women with recent atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) Pap smear reports. METHODS: Women with a recent Pap smear report of ASCUS (n = 169) or LSIL (n = 110) had a repeat Pap smear, sampling of the cervix for HCT HPV DNA assay and a colposcopy examination. Data were evaluated using three different triage thresholds for colposcopy examination: a repeat Pap smear of persistent ASCUS or more severe dysplasia, a finding of persistent LSIL or more severe dysplasia, and a carcinogenic HPV test result. RESULTS: The sensitivity, specificity, and positive and negative predictive values for detecting CIN 2/3 were 70%, 45%, 7%, and 96% for a repeat Pap smear using an ASCUS-positive threshold and 20%, 86%, 8%, and 94% for a repeat Pap smear using an LSIL-positive threshold, respectively, when women with an initial ASCUS Pap smear were considered. HPV testing for carcinogenic viruses alone or in combination with a repeat Pap smear (using ASCUS as a positive threshold) yielded results of 50%, 67%, 9%, and 96%, respectively, and 70%, 37%, 7%, and 95%, respectively, for detecting CIN 2/3. In women with an initial LSIL Pap smear, respective values for detecting CIN 2/3 by a repeat Pap smear with an ASCUS threshold were 92%, 26%, 14%, and 96%, and for an LSIL threshold 23%, 64%, 8%, and 86%, respectively. Hybrid Capture HPV testing alone or in combination with a repeat Pap smear yielded 69%, 43%, 14%, and 91%, respectively, and 100%, 21%, 14%, and 100%, respectively. CONCLUSIONS: A Pap smear triage threshold restricted to LSIL or more severe dysplasia for women with prior ASCUS or LSIL Pap smear results was clearly ineffective for detecting high-grade cervical precancerous lesions. In contrast, when the repeat Pap smear triage threshold was expanded to include persistent ASCUS as abnormal, 83% of the women with CIN 2/3 were detected. Detection of carcinogenic HPV DNA using the HCT test was almost as sensitive for detecting CIN 2/3 as a solitary repeat Pap smear using an ASCUS or more severe positive threshold. Combining the HPV test with a repeat Pap smear did not significantly improve the sensitivity of cytology for detecting high-grade CIN. This study suggests that women with ASCUS and particularly LSIL Pap smears should be referred for a colposcopy examination until better triage methods become available.

Comparison of two tests for detecting carcinogenic HPV in women with Papanicolaou smear reports of ASCUS and LSIL.

BACKGROUND: The detection of cancer-associated types of human papillomavirus (HPV) in cervical specimens predicts the presence and future development of cervical intraepithelial neoplasia (CIN). The purposes of this study were (1) to determine the efficacy of a second-generation assay by hybrid capture (HC II) to detect carcinogenic HPV from residual cervical cells of a liquid-based cervical cytologic specimen, and (2) to compare the performance of this second-generation test with the first-generation hybrid capture (HCT) HPV test of material from direct cervical sampling to detect CIN in women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) Papanicolaou (Pap) smear reports. METHODS: Women with a recent Pap smear report of ASCUS or LSIL had a sampling of the cervix using either an Ayre's spatula and cytobrush or an Accellon device sampling for liquid-based cytologic system HC II HPV testing, followed by a Dacron swab sampling of the cervix for standard HCT HPV testing of the paired specimens. All women received colposcopy examinations including cervical biopsy and endocervical curettage, when indicated, to determine criterion standards for comparison. RESULTS: Paired swabs and liquid-based cervical specimens from 242 women were available for testing by standard HCT and the newer HC II HPV DNA assays. The sensitivity, specificity, and positive and negative predictive values for detecting CIN grade 2 or 3 (CIN 2/3) were 61.9%, 57.0%, 12.0%, and 94.0%, respectively, for the HCT test, and 90.5%, 29.4%, 10.9%, and 97.0%, respectively, for the liquid-based cytology HC II assay. When only women with an initial ASCUS Pap smear report were considered, the HC II test results were 88.9%, 40.3%, 9.1%, and 98.2%, respectively. CONCLUSIONS: Testing for lower genital tract carcinogenic HPV DNA using a cervical cytology liquid transport media residual sample is clinically feasible. The new HC II microplate HPV test achieved a greater test sensitivity for detecting carcinogenic HPV and correspondingly of CIN 2/3 compared with the currently available first-generation HC HPV test. Use of a liquid-based cervical cytology system combined with intermediate triage by HC II testing of residual cells for carcinogenic HPV alone may help to efficiently identify CIN 2/3 in women who have a prior screening Pap smear report of ASCUS.

Colposcopy, cervicography, speculoscopy and endoscopy. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial.

ISSUES: The colposcope was developed in 1925 and is well established in clinical gynecologic practice for defining and delineating cytologically detected lesions mainly of the cervix but also the vagina and vulva. Additionally, various endoscopic procedures in gastroenterology, pulmonary and urologic lesions enhance the cytologic detection and histologic verification of precancerous and cancerous lesions. The cost-effectiveness of all these devices and their applicability, particularly in countries with a limited health budget, is a major issue. This task force considered aspects of the present state of the art and the challenges in the 21st century. CONSENSUS POSITION: Automated cytology can interface with colposcopic examination in a number of significant ways. Automated cytologic analysis of conventional cervical smears can potentially direct colposcopic examination by predicting the nature of a lesion, assist in determining which patients should receive colposcopy and, in some settings, thereby reduce the number of colposcopies. Potentially, various combinations of automated cytology and colposcopy may be used to generate screening protocols that might result in more effective and inexpensive screening. The role of cervicography, or high-resolution cervical photography, as a screening device remains to be defined. Sensitivity for high grade lesions is generally no greater than that in cytology, and specificity appears lower. The interpretation of cervical photographs in triage of mildly abnormal cytology may prove to be useful in countries with established cytology programs. In areas of the world where cytology screening programs are not in place, the interpretation of cervical photographs may have its most dramatic effect. Cost-effectiveness analyses are needed. There are, at present, insufficient data for the evaluation of speculoscopy, a procedure using chemiluminescent illumination of the cervix for visualization of acetowhite areas. Basic training in colposcopy should be integrated into the residency programs of obstetrics and gynecology. Criteria for the adequate training of colposcopists should be developed. Continuing education programs in colposcopy should be developed when they are not already in existence. The cost-effectiveness of integrating colposcopy as a primary screening technique should be evaluated. Following a high-grade squamous intraepithelial lesion (HSIL) cytology result, colposcopically directed punch biopsy should be taken with or without endocervical curettage. This generally should precede the loop electrosurgical excision procedure (LEEP); however, in certain circumstances direct LEEP may be indicated. LEEP under colposcopic vision is an efficient way to treat an HSIL lesion of the cervix because the histologic extent and margins can be determined, unlike with laser surgery or cryosurgery. It is also more cost-effective than cold knife conization because general anesthesia and an operating room are unnecessary. Following LEEP, the endocervical canal should be examined colposcopically for any evidence of involvement. Lesions in the endocervix can then be removed with a different-shaped loop. Further research into Raman spectroscopy as a diagnostic aid in cervical pathology is needed, as is the use of micrococolpohysteroscopy for in vivo cytologic analyses, especially of the endocervical canal and transformation zone. Hysteroscopy is the most direct method for the diagnosis and treatment of intrauterine diseases. Hysteroscopic endometrial biopsy is more accurate than conventional biopsy methods. Cervical invasion of endometrial cancer can be detected by hysteroscopy. The depth of invasion, however, is more accurately determined by magnetic resonance imaging or computed tomography. ONGOING ISSUES: Many topics for ongoing research and/or implementation are mentioned under "Consensus Position," above. (ABSTRACT TRUNCATED)

Computerized screening devices and performance assessment: development of a policy towards automation. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial.

ISSUES: The extension of automation to the diagnostic assessment of clinical materials raises issues of professional responsibility, on the part of both the medical professional and designer of the device. The International Academy of Cytology (IAC) and other professional cytology societies should develop a policy towards automation in the diagnostic assessment of clinical cytologic materials. CONSENSUS POSITION: The following summarizes the discussion of the initial position statement at the International Expert Conference on Diagnostic Cytology Towards the 21st Century, Hawaii, June 1997. 1. The professional in charge of a clinical cytopathology laboratory continues to bear the ultimate medical responsibility for diagnostic decisions made at the facility, whether automated devices are involved or not. 2. The introduction of automated procedures into clinical cytology should under no circumstances lead to a lowering of standards of performance. A prime objective of any guidelines should be to ensure that an automated procedure, in principle, does not expose any patient to new risks, nor should it increase already-existing, inherent risks. 3. Automated devices should provide capabilities for the medical professional to conduct periodic tests of the appropriate performance of the device. 4. Supervisory personnel should continue visual quality control screening of a certain percentage of slides dismissed at primary screening as within normal limits (WNL), even when automated procedures are employed in the laboratory. 5. Specifications for the design of primary screening devices for the detection of cervical cancer issued by the IAC in 1984 were reaffirmed. 6. The setting of numeric performance criteria is the proper charge of regulatory agencies, which also have the power of enforcement. 7. Human expert verification of results represents the "gold standard" at this time. Performance characteristics of computerized cytology devices should be determined by adherence to defined and well-considered protocols. Manufacturers should not claim a new standard of care; this is the responsibility of the medical community and professional groups. 8. Cytology professionals should support the development of procedures that bring about an improvement in diagnostic decision making. Advances in technology should be adopted if they can help solve problems in clinical cytology. The introduction of automated procedures into diagnostic decision making should take place strictly under the supervision and with the active participation and critical evaluation by the professional cytology community. ONGOING ISSUES: Guidelines should be developed for the communication of technical information about the performance of automated screening devices by the IAC to governmental agencies and national societies. Also, guidelines are necessary for the official communication of IAC concerns to industry, medicolegal entities and the media. Procedures and guidelines for the evaluation of studies pertaining to the performance of automated devices, performance metrics and definitions for evaluation criteria should be established.

Human papillomavirus. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial.

ISSUES: Cervical squamous cell carcinomas, adenocarcinomas and their precursors are caused by the human papillomavirus (HPV). Although HPV appears to be essential to the transformation of these epithelial cells, it is not sufficient, and a variety of cofactors and molecular events must take place between when an HPV infection occurs and a cervical cancer or its precursor develops. This review examines the data supporting these contentions, briefly outlines the molecular events that occur, considers the epidemiology and natural history of the disease, and details the implications of using HPV detection and typing in both clinical management and population-based screening programs. CONSENSUS POSITION: 1. Based on the available molecular, clinical and epidemiologic data, a subset of HPVs are unequivocally the etiologic agents for cervical cancers and their precursors. 2. Different mucosotropic HPVs have varying neoplastic potential. However, the great majority of cervical HPVs have oncogenic potential. Since oncogenic HPV-induced epithelial transformation to a high grade lesion or cancer is rare relative to the rate of infection, the term high risk is discouraged. 3. HPV's interaction with host cells has two principal biologic consequences: a) All anogenital HPVs induce low grade squamous lesions, which are the morphologic correlate of a productive infection. b) Rarely, HPVs induce a proliferative epithelial phenotype that pathologists recognize as a high grade lesion and that is the proximate cytohistologic precursor of invasive cervical carcinoma. 4. HPV biology and issues of practical clinical management should be reflected in the classification systems used for cytologic and histologic diagnosis. ONGOING ISSUES: The molecular identification of HPVs (HPV testing) potentially may be very useful for primary screening or secondary triage of patients with certain lesions. However, the technology available to the practicing clinician is still evolving. Optimization of type spectrum, sensitivity, specificity and ease of use is under development. Data regarding these factors as well as a clear cost benefit analysis are sparse or pending in several large trials. Until such data are available, caution in clinical implementation of HPV testing is warranted.

The AutoPap 300 QC System multicenter clinical trials for use in quality control rescreening of cervical smears: I. A prospective intended use study.

BACKGROUND: The AutoPap 300 QC System is an automated device for the analysis of conventionally prepared cervical cytology slides. The AutoPap System selects an enriched population of cases for human quality control (QC) review. The device assigns a score based on the likelihood that a slide is abnormal. Cases are selected for QC rescreening that have scores exceeding a preset threshold corresponding to approximately the top 10% (or greater) of scores. METHODS: AutoPap false-negative detection, compared with a 10% random QC process, was tested in a 6-center clinical evaluation study. At each site, a block of up to 150 consecutive negative slides (including detected false-negative cases) were selected randomly daily. All slides were run on the AutoPap System and rescreened by cytotechnologists for truth determination. The false-negative cases included in the top 10% group selected by AutoPap System then were compared with false-negative detection by the random selection process. RESULTS: Fourteen thousand nine hundred fourteen cases were analyzed. The AutoPap-enriched 10% quality control group contained false-negative cases at rates 3 to 5 times that of the random selection method (P < 0.01). The sensitivity for all false-negative cases was 35% and was 52% for false-negative cases at the level of low grade squamous intraepithelial lesion and higher. CONCLUSIONS: The AutoPap 300 QC System provides the potential for a marked increase in the number of false-negative cervical cytology cases that can be detected on QC rescreening. A significant reduction in laboratory false-negative rates can be expected if this device is utilized in routine practice.

The AutoPap 300 QC System multicenter clinical trials for use in quality control rescreening of cervical smears: II. Prospective and archival sensitivity studies.

BACKGROUND: The AutoPap 300 QC System is an automated device for the analysis of conventional cervical cytology slides. The AutoPap selects an enriched population of cases for quality control review. These studies evaluated the overall sensitivity of AutoPap device to a wider variety of cytologic abnormalities than could be analyzed in the prospective portion of the clinical trials. METHODS: At five clinical trial sites, positive cases were selected from: 1) archives (historic sensitivity study) or 2) current positive cases (current archive sensitivity study). Cases were analyzed by the AutoPap System along with matched negative cases and stratified into detection deciles by instrument score for each diagnostic category. RESULTS: For the historic sensitivity study, the percentages of cases present within the top 10% instrument scores were as follows: atypical glandular cells of undetermined significance (AGUS): 33.7% (n = 243); low grade squamous intraepithelial lesion (LSIL): 57% (n = 412); high grade squamous intraepithelial lesion (HSIL): 81.6% (n = 385); and carcinoma: 77.7% (n = 139). For the current archive sensitivity study, the percentage of cases within the top 10% of instrument scores were as follows: atypical squamous cells of undetermined significance (ASCUS): 37.6% (n = 205); AGUS: 27.3% (n = 22); LSIL: 53.7% (n = 410); HSIL: 80.7% (n = 202); and carcinoma: 62.5% (n = 8). Sensitivities at higher percentiles proportionately were greater. CONCLUSIONS: The AutoPap 300 QC System is detection sensitive, particularly at the level of LSIL and greater. When coupled with the data from the prospective intended use study, these results provided confirmation of the instrument's ability to enhance the false-negative detection rate significantly when compared with a 10% random case selection process. In addition, high sensitivities to all categories of abnormality suggest the possibility of using such instrumentation as a primary screening device for cervical cytology.

Prospects for automated cytology.

Rescreening of Pap smears using automated devices offers the ability to re-examine Paps initially interpreted as within normal limits and to use cell-sorting technology to increase the detection of missed abnormal smears. Only recently has the development of high-resolution imaging techniques and advances in computer sciences and cell classifiers enabled investigators to achieve sensitivity and specificity levels in automated screening and quality control devices.

Conventional cervical cytologic smears vs. ThinPrep smears. A paired comparison study on cervical cytology.

OBJECTIVE: To compare the time required for evaluation, the diagnostic accuracy and quality of conventional glass slide smears vs. ThinPrep smears in 365 women. STUDY DESIGN: Both smears were obtained at the same time using the Accellon Combi cervical biosampler. Histology served as the diagnostic "gold standard." RESULTS: The average screening time was 1 minute, 23 seconds, shorter per smear with the ThinPrep method as compared to the conventional glass slide (P < .001). Direct diagnostic agreement between the two smear methods was obtained in 311 of 364 evaluable smears (85.4%, kappa = .63). Despite the relatively high rate of "adequate but limited by absence of transformation zone components" observed with the ThinPrep method, the sensitivity and specificity of the ThinPrep method was slightly greater but not statistically significantly different than the conventional technique, irrespective of the disease categories (low and high grade squamous intraepithelial lesion and invasive cancer). CONCLUSION: The shorter time required to screen ThinPrep smears compared to conventional smears in this study was not sufficiently important to offset the current unit price for preparing ThinPrep smears.