Longitudinal Evaluation of Interobserver and Intraobserver Agreement of Cervical Intraepithelial Neoplasia Diagnosis Among an Experienced Panel of Gynecologic Pathologists
Department of Epidemiology, Merck and Co., Inc., North Wales, PA 19454-1099, USA.American Journal of Surgical Pathology (Impact Factor: 5.15). 01/2008; 31(12):1854-60. DOI: 10.1097/PAS.0b013e318058a544
Histologic diagnoses of cervical intraepithelial neoplasia grades 2 and 3 (CIN 2/3) are the key end points in clinical trials that evaluate the efficacy of a prophylactic quadrivalent human papillomavirus vaccine against cervical cancer. Adjudication of end points uses a panel of 4 pathologists. Quality control slides (n=185) from a nonclinical trial study with preestablished gold standard CIN diagnoses were used to characterize the panel's agreement on CIN diagnoses and monitor performance longitudinally. At 3-month intervals over 2 years, 1 of 6 different batches of quality control slides (n=30-31) was included with clinical trial slides for independent review by each of the 4 panelists. Unweighted kappas (kappa) were estimated within each panelist pair by dichotomizing the diagnoses as CIN+ versus non-CIN+ (including normal, unsatisfactory, and atypical immature metaplasia) or CIN 2/3+ versus non-CIN 2/3+ (including normal, unsatisfactory, atypical immature metaplasia, and CIN 1). Quadratic weighted kappa was calculated within each panelist pair using 4 diagnostic categories: normal, CIN 1, CIN 2, and CIN 3 or worse. Substantial interobserver agreement was observed (weighted kappa=0.765 to 0.865). Agreement with weighted kappa=0.779 to 0.887 was observed between the individual panelists and the gold standard, which is almost perfect agreement by Landis-defined categories. Intraobserver agreement was very high (weighted kappa=0.756 to 0.883). Some fluctuation in intraobserver and interobserver agreement was observed over the study period but there was no decreasing time trend. These data indicate that the interpretation of histologic end points used in the quadrivalent vaccine clinical trial program is highly valid and reliable.
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ABSTRACT: On the basis of the unique subset of our database comprising patients who received a Papanicolaou test and a cervical biopsy during the same clinic visit, clinicopathologic factors potentially associated with cytohistologic diagnostic noncorrelation in these concurrently collected samples is investigated. In the first analysis, a selected group of variables potentially associated with noncorrelation relative to the diagnosis of high-grade dysplasia were examined, whereas the second analysis was centered on the effect of varying levels of Papanicolaou test inflammation (below the Bethesda 2001 threshold, ie, partially obscuring inflammation) on noncorrelation regarding the overall diagnosis of dysplasia. For the latter, the overall density of neutrophilic infiltrate on each Papanicolaou test slide was graded in a blinded fashion on a 4-tiered scale (no significant amount, mild, moderate, and severe), followed by a comparison of correlating and noncorrelating cases at each tier. There was no overrepresentation of noncorrelating cases in severe inflammation group. Indeed, correlating and noncorrelating cases did not significantly differ at any level of inflammation. In the first analysis, correlating (n = 17) and noncorrelating (n = 17) cases did not significantly differ in patient age, number of biopsies obtained, endocervical curettage status, glandular involvement by high-grade dysplasia, or frequency of background grade 1 cervical intraepithelial neoplasia. Noncorrelating cases were more likely than correlating cases to be grade 2 cervical intraepithelial neoplasia rather than grade 3 or worse (82% vs 41%, respectively, P = .02), which is probably attributable to the absence of a basaloid proliferation in the most superficial layers of grade 2 lesions. Furthermore, noncorrelating cases showed a comparatively smaller percentage of submitted biopsies involved by high-grade dysplasia (52% vs 75%, respectively, P = .03), consistent with smaller extent of disease. These findings further illustrate that lesional factors are important potential contributors to the false-negative rate of the Papanicolaou test.International Journal of Surgical Pathology 06/2008; 17(1):31-7. DOI:10.1177/1066896908315818 · 0.95 Impact Factor
- American Journal of Clinical Pathology 08/2008; 130(2):162-4. DOI:10.1309/GCVB5C4KFV7TFC7F · 2.51 Impact Factor
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ABSTRACT: Human Papillomavirus (HPV) infection causes cervical cancer, a significant portion of anal, vulvar, vaginal, and oropharyngeal cancers, genital warts, and recurrent respiratory papillomatosis (RRP). HPV 16 and 18 cause 70-90% of HPV-related cancers whereas HPV 6 and 11 cause 90% of RRP and genital wart cases. Together these four types cause 30-50% of all cervical intraepithelial neoplasia such as those detected by Papinicalou screening. In June 2006, a quadrivalent HPV (6, 11, 16, 18) vaccine was licensed in the United States, and subsequently in the European Union (September 2006), both following expedited review. We describe the primary objectives of the quadrivalent HPV vaccine clinical trial program including studies in females aged 9-45 and males aged 9-26. Planned long-term efficacy and safety evaluations, as well as programs to evaluate vaccine impact on oropharyngeal cancer are also described.Vaccine 09/2008; 26(49):6244-57. DOI:10.1016/j.vaccine.2008.07.056 · 3.62 Impact Factor
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