The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings.

OBJECTIVE: We sought to evaluate the performance of the human papillomavirus high-risk DNA test in patients 30 years and older. MATERIALS AND METHODS: Screening (n=835) and diagnosis (n=518) groups were defined based on prior Papanicolaou smear results as part of a clinical trial for cervical cancer detection. We compared the Hybrid Capture II (HCII) test result with the worst histologic report. We used cervical intraepithelial neoplasia (CIN) 2/3 or worse as the reference of disease. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR-), receiver operating characteristic (ROC) curves, and areas under the ROC curves for the HCII test. We also considered alternative strategies, including Papanicolaou smear, a combination of Papanicolaou smear and the HCII test, a sequence of Papanicolaou smear followed by the HCII test, and a sequence of the HCII test followed by Papanicolaou smear. RESULTS: For the screening group, the sensitivity was 0.69 and the specificity was 0.93; the area under the ROC curve was 0.81. The LR+ and LR- were 10.24 and 0.34, respectively. For the diagnosis group, the sensitivity was 0.88 and the specificity was 0.78; the area under the ROC curve was 0.83. The LR+ and LR- were 4.06 and 0.14, respectively. Sequential testing showed little or no improvement over the combination testing. CONCLUSIONS: The HCII test in the screening group had a greater LR+ for the detection of CIN 2/3 or worse. HCII testing may be an additional screening tool for cervical cancer in women 30 years and older.

The accuracy of the Papanicolaou smear in the screening and diagnostic settings.

OBJECTIVE: We evaluated the performance of the Papanicolaou smear in screening and diagnostic settings. STUDY DESIGN: We analyzed Papanicolaou smear results of 1,850 women recruited into a clinical trial to evaluate an emerging technology for the detection of cervical cancer. Screening and diagnosis groups were based on the history of previous Papanicolaou smear results. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR-), receiver operating characteristic curves, and areas under the receiver operating characteristic curve (AUC). RESULTS: In the screening group, by defining disease as cervical intraepithelial neoplasia (CIN) 2,3/cancer or worse and using high-grade squamous intraepithelial lesion (HSIL) as the test cutpoint, the AUC was 0.689, and the LR+ and LR- were 39.25 and 0.67, respectively. In the diagnosis group, the AUC was 0.764, and the LR+ and LR- were 3.79 and 0.56, respectively. By defining disease as human papillomavirus/CIN 1 or worse and HSIL as the test cutpoint, the AUC was 0.586, and the LR+ and LR- were 17.01 and 0.92 in the screening group; in the diagnosis group, the AUC was 0.686, and the LR+ and LR- were 2.77 and 0.75, respectively. CONCLUSIONS: In a screening setting, a Papanicolaou smear result of HSIL or worse is 39 times more likely in a patient with CIN 2,3/cancer than in a patient without it. This compares to 4 times more likely in the diagnostic setting. The magnitude of the positive likelihood ratio observed in the screening group indicated that abnormal Papanicolaou smear results obtained in the screening setting should have more impact on clinical decision making than those from results obtained in the diagnostic setting.

Accuracy of colposcopy in the diagnostic setting compared with the screening setting.

OBJECTIVE: To estimate the accuracy of colposcopy to identify cervical precancer in screening and diagnostic settings. METHODS: As part of a larger clinical trial to evaluate the diagnostic accuracy of optical spectroscopy, we recruited 1,850 patients into a diagnostic or a screening group depending on their history of abnormal findings on Papanicolaou tests. Colposcopic examinations were performed and biopsies specimens obtained from abnormal and normal colposcopic sites for all patients. The criterion standard of test accuracy was the histologic report of biopsies. We calculated sensitivities, specificities, likelihood ratios, receiver operating characteristic curves, and areas under the receiver operating characteristic curves. RESULTS: The prevalence of high-grade squamous intraepithelial lesions (HSIL) or cancer was 29.0% for the diagnostic group and 2.2% for the screening group. Using a disease threshold of HSIL, colposcopy had a sensitivity of 0.983 and a specificity of 0.451 in the diagnostic group when the test threshold was low-grade squamous intraepithelial lesions (LSIL), and a sensitivity of 0.714 and a specificity of 0.813 when the test threshold was HSIL. Using the same HSIL disease threshold, in the screening group, colposcopy had a sensitivity of 0.286 and a specificity of 0.877 when the test threshold was LSIL, and a sensitivity of 0.191 and a specificity of 0.961 when the threshold was HSIL. The colposcopy area under the receiver operating characteristic curve was 0.821 (95% confidence interval 0.79-0.85) in the diagnostic setting compared with 0.587 (95% confidence interval 0.56-0.62) in the screening setting. Changing the disease threshold to LSIL demonstrated similar patterns in the tradeoff of sensitivity and specificity and measure of accuracy. CONCLUSION: Colposcopy performs well in the diagnostic setting and poorly in the screening setting. Colposcopy should not be used to screen for cervical intraepithelial neoplasia. LEVEL OF EVIDENCE: II.

The clinical effectiveness of optical spectroscopy for the in vivo diagnosis of cervical intraepithelial neoplasia: where are we?

OBJECTIVE: In this review, we evaluate the diagnostic efficacy of optical spectroscopy technologies (fluorescence and reflectance spectroscopy) for the in vivo diagnosis of cervical neoplasia using both point probe and multispectral imaging approaches. METHODS: We searched electronic databases using the following terms: cervical cancer, cervical intraepithelial neoplasia, squamous intraepithelial lesion, and spectroscopy, fluorescence spectroscopy, or reflectance spectroscopy. We included studies that evaluated fluorescence and reflectance spectroscopy devices for in vivo diagnosis, compared those results with biopsy results, and reported on the sensitivity and specificity of the devices tested. RESULTS: Twenty-six studies, including seven phase II trials and one randomized clinical trial, met our acceptability criteria. We found several important differences across the studies including device approach (multispectral versus point probe), study population, disease classification system, and disease threshold. This heterogeneity prevented formal combination of sensitivity and specificity results. CONCLUSION: Optical spectroscopy has similar performance to colposcopy and may help localize lesions and therefore be an effective adjunct to colposcopy. Reports on the diagnostic accuracy of these devices should use common thresholds for the construction of receiver operating characteristic curves to enable comparisons with standard technologies and facilitate their adoption. Optical spectroscopy has also been identified for possible use as ASCUS triage and primary screening, yet neither has been sufficiently evaluated to warrant a conclusion as to their suitability in this role.

The performance of fluorescence and reflectance spectroscopy for the in vivo diagnosis of cervical neoplasia; point probe versus multispectral approaches.

OBJECTIVE: This review evaluates the diagnostic efficacy of fluorescence spectroscopy, reflectance spectroscopy, and their combination that use both point probe and multispectral imaging approaches in diagnosing cervical neoplasia in vivo. METHODS: Articles were selected for this review from a literature search which report the performance of fluorescence and reflectance spectroscopy devices in diagnosing cervical neoplasia in vivo. This analysis focused on the comparison of point probe versus multispectral approaches; the use of fluorescence, reflectance, and their combination; and finally the types of populations that have been studied for in vivo diagnosis of squamous intraepithelial lesions (SIL). RESULTS: Twenty-six studies were included and their heterogeneity precluded formal meta-analysis. Though point probes were expected to have greater specificity and multispectral approaches greater sensitivity, there was considerable overlap in the performance of point probe and multispectral devices. There were few studies that studied fluorescence spectroscopy alone and reflectance spectroscopy alone. Combined fluorescence and reflectance approaches showed considerable overlap among point probe and multispectral devices. The overlap of performance suggests that fluorescence and reflectance may have similar performance. Currently the paucity of data precludes definitive conclusions regarding the additive effect of both approaches. Only two of twenty-six trials have recruited patients with no history of an abnormal Papanicolaou smear (screening populations) and twenty-four trials include patients with a range of cervical abnormalities from atypia to cancer (diagnostic populations). DISCUSSION: Optical spectroscopy using a point probe and multispectral approaches appears to overlap in performance. Fluorescence and reflectance spectroscopies examine different aspects of epithelial-stromal biology and appear to yield similar diagnostic performance. While intuitively appealing, their combination may or may not be additive. There have been few studies of these technologies in screening populations. Better definitions of device trial design and reporting requirements would facilitate combining analyses to formally examine performance.

The clinical effectiveness of fluorescence and reflectance spectroscopy for the in vivo diagnosis of cervical neoplasia: an analysis by phase of trial design.

OBJECTIVE: In this review, we focus on the pilot, Phase I, II, and III clinical trials of fluorescence spectroscopy, reflectance spectroscopy, and their combination for the in vivo diagnosis of cervical neoplasia using both point probe and multi-spectral imaging approaches. Research groups that have progressed from pilot through Phase II/III clinical trials were analyzed. METHODS: A formal search was conducted to identify articles which report the performance of fluorescence and reflectance spectroscopy trials which diagnose cervical neoplasia in vivo. This report focuses on the funding source, prevalence of disease in the trials, type of population (screening versus diagnostic), gold standard criterion for diagnosis (histopathology versus colposcopy alone and histopathology), histopathologic classification (World Health Organization (WHO) 8 categories, Bethesda 5 categories, or both (13 categories)), number of clinical trial sites, number of medical investigators, number of histopathology reviews by histopathologists for a consensus diagnosis, use of acetic acid, explicit sample size calculation in the published report, actual sample size in the trial, ages of patients included in the trial, and the phase of the trial design, as they affect performance and plotted as sensitivity and 1-specificity. RESULTS: Twenty-six studies were included and their heterogeneity precluded formal meta-analytic combination. While most factors inherent in the review were not significant sources of variability; there were three variables that affected performance, i.e., sample size, age of patients, and phase of trial design. DISCUSSION: As with pharmaceutical trials, as the sample size increased, as the heterogeneity of the population increased, as the age of the patients included patients over 50 years old, and as the phase of clinical trial design progressed from pilot through Phase III randomized trial, the performance of all devices decreased.