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- MATERIALS AND METHODS
The results of ThinPrep® cytology agreed with the final case diagnoses in 85.4% of cases in this study, comparable to the 88.8% agreement of smear cytology. However, analysis of abnormal final diagnoses showed important differences in the two methods. Using ASCUS as the threshold for colposcopy referral, ThinPrep® cytology would have resulted in the referral of 12.7% of women as well as the detection of 92.9% of patients with a final diagnosis of HSIL and 100% of those with carcinoma. In comparison, conventional cytology would have resulted in the referral of 6.7% of women, detecting 77.8% with HSIL and 90.9% with carcinoma. Thus, the sensitivity of ThinPrep® cytology was higher than conventional cytology in this study, but the proportion of women referred for colposcopy was greater. The performance achieved with both the conventional smear and the ThinPrep® was superior to the 50% (95% confidence interval, 49–67%) sensitivity and 69%(95% confidence interval, 62–77%) specificity reported in the meta-analysis by Fahey et al.12
Based on the reference standards that were employed, many of the additional referrals based on the ThinPrep® method represented SIL. Based on the final case diagnoses, 29 (63%) of 46 women with ThinPrep® preparations diagnosed as HSIL paired with negative smears were considered to have SIL. In contrast, a final diagnosis of SIL was established in only 2 (11%) of 18 women with smears diagnosed as HSIL and negative ThinPrep® preparations. Similarly, HPV detection in women with abnormal ThinPrep® slides and negative smears was higher than that in women with abnormal smears and negative ThinPrep® slides. This probably, in part, reflects different criteria for the category of LSIL, but the comparison still reflects well on the specificity of the ThinPrep® method.
An important function of cervical cytology is to stratify patients according to cancer risk. Given that nearly all carcinoma is related to HPV, the rate of detection of oncogenic types of HPV should be higher among women with SIL than among women with ASCUS smears and lowest among women with negative cytology. This correlation has been demonstrated in a previous study in which the cytologic diagnoses of five pathologists using TBS was compared with HPV DNA detection.13 In the current study, HPV was detected in 4.9% of women with negative ThinPrep® cytology, 13.4% with ASCUS, 66.1% with SIL, and 81.8% with carcinoma. These results demonstrate that the severity of ThinPrep® cytologic diagnoses is strongly associated with HPV detection. The association between smear diagnoses and HPV detection were similar, but smear diagnoses of LSIL were associated with nearly a 50% lower level of HPV detection, suggesting that many reactive smears were misclassified as LSIL. Results from recent U.S. studies using HPV testing methods similar to the one used in this study have consistently detected HPV DNA in approximately 60–80% of women with LSIL diagnosed by different pathologists.13 Thus, in the U.S., cytologic diagnoses of LSIL are nearly synonymous with HPV infection. However, in this study this suggests that different diagnostic criteria for LSIL may have been applied.
Although not part of the study design, a referral threshold of LSIL could be theoretically applied to the data. This would result in similar rates of referral to colposcopy: 5.2% for the ThinPrep® method and 4.9% for the smear. Of the cases with a final diagnosis of HSIL or carcinoma, the ThinPrep® method would pick up significantly more cases (115) than the smear method (103; P < 0.05). It is noteworthy that for the three cases with a final diagnosis of carcinoma that were diagnosed as ASCUS by the ThinPrep® method, two of the ThinPrep® slides were signed out “AGUS can't rule out AIS or malignancy,” and one was signed out “ASCUS can't rule out HSIL.” It is possible that a refined referral threshold, including ASCUS smears, where the differential is with HSIL, may preserve most of the sensitivity while reducing the number of referrals. This needs to be further investigated by both the ThinPrep® method and the conventional smear.
The “gold standard” final case diagnoses in this study reflect the results of an intensive screening effort coupled with comprehensive workup, including colposcopy and histologic studies. Based on the absence of significant pathology in a random sample of 150 subjects in this study with negative screening results who were examined colposcopically, we believe that nearly all of the disease in the population under study was detected. Therefore, we think that the detection of SIL using ThinPrep® cytology in this study represents an accurate estimate of the sensitivity of the method. Previous studies demonstrating close to 90% diagnostic agreement between smears and ThinPrep® slides prepared from split samples demonstrated the comparability of these two methods but did not permit the sensitivity determinations that have been presented in this report.
Although the intense screening effort presented in this study permitted the assignment of a “gold standard” diagnosis for most subjects, extrapolation of our results to other populations has certain limitations. First, the cervical carcinoma incidence in the population studied is approximately five times that in most U.S. populations. Therefore, the predictive values of cytologic techniques in well-screened groups may be different. Second, direct comparisons between smear and ThinPrep® diagnoses is difficult because the slides were interpreted in different laboratories. This can be seen in the ASCUS:LSIL ratios and in the unsatisfactory rates in the two laboratories, suggesting different adherence to the criteria of TBS. Although the ASCUS:LSIL ratio with the ThinPrep® was 2.2:1 and the ratio with the conventional smear was 0.6:1, the respective LSIL:HSIL ratios were virtually identical (2.0:1 and 2.1:1, respectively). ThinPrep® ASCUS:LSIL ratios and the unsatisfactory rate were both consistent with those from most U.S. laboratories. Third, it is noteworthy that the quality of the Papanicolaou stain that was applied to the smears was not optimal. Similarly, the ThinPrep® processor that was used in this study has subsequently been updated and improved. Use of the new ThinPrep® 2000 model, which presents 40% more cells, with Costa Rica follow-up cases has resulted in a decrease in the number of unsatisfactory slides. Finally, the ThinPrep® slides were prepared from rinses of the samplers after the conventional smear was made rather than from the entire specimen, perhaps in some cases resulting in a reduction in the number of diagnostic cells that reached the vial. Despite these limitations, our data suggest that the performance of ThinPrep® cytology was more sensitive in detecting HSIL than smears, albeit with a substantial increase in referral of patients for colposcopy.
In summary, this study extends previous work suggesting that the ThinPrep® method is at least as good as conventional cytology in detecting SIL and carcinoma. In this population-based study, the clinical effectiveness, particularly regarding detection of HSIL, is demonstrated. The clinical utility of the ThinPrep® method, and its cost-effectiveness in particular, are now being evaluated as more experience is gained with the technique in clinical practice.