Liquid based cytology for primary screening of cervical cancer showed a significantly increased sensitivity for cervical intraepithelial neoplasia of grade 1 but not for lesions of grade 3 or more. We observed a relevant reduction in unsatisfactory slides with liquid based cytology as a result of a decrease in obscuring inflammation. We observed a slight increase of the point estimate for relative sensitivity of liquid based cytology compared with conventional cytology for cervical intraepithelial neoplasia of grade 2 or more (1.17 with atypical cells of undetermined significance as the cut-off point, 1.03 with low grade intraepithelial lesions as the cut-off point) but this was far from significant. Values between 0.87 and 1.56 were included in the 95% confidence interval of relative sensitivity with atypical cells of undetermined significance as the cut-off point. Therefore we cannot exclude increases and decreases of sensitivity in this range. The study had a 80% power to detect as statistically significant a 50% increase in sensitivity and a 41% power to detect a 30% increase. The study size was, however, determined for another objective (long term rates of cervical intraepithelial neoplasia). These power calculations are based on the observed number of women recruited and the detection rate in the liquid based cytology arm.
We carried out a large randomised trial nested in screening programmes, which was representative of routine activity. Colposcopy was carried out in a high proportion of women whose screening results were positive. Colposcopists were not blinded to type of cytology, but the number of biopsies per woman undergoing colposcopy was similar in the two arms. Histology was independently reviewed, with reviewers blinded to trial arm and cytology result. A few centres adopted a different protocol between study arms for the management of women with atypical cells of undetermined significance. However the results were almost unchanged when the analysis was restricted to the centres that applied the same protocol in both arms and when low grade intraepithelial lesions were considered as the cut-off point for cytology.
Several reviews and meta-analyses of the performance of liquid based cytology, based on non-randomised studies, have been published but have reached conflicting conclusions.1 4 5 6 7 8 9
A recent systematic review on liquid based cytology1
found one small randomised controlled trial only.10
The same review1
identified only five “high quality” studies (slides read without knowledge of the others' results, with verification by masked reference standard of at least all positive slide results).11 12 13 14 15
Such studies did not show increased accuracy with liquid based cytology, in agreement with our results. However four of them were split sampled and this could affect the accuracy of liquid based cytology.
We also found that liquid based cytology had a lower positive predictive value than conventional cytology. This reduction was the result of an increased frequency of abnormal findings (usually low grade) without an increase in high grade cervical intraepithelial neoplasia on histology. An increased frequency of low grade lesions with liquid based cytology has already been observed.1
The relative frequency of atypical cells of undetermined significance varied between studies, but overall in high and medium quality studies more slides were classified as atypical cells by liquid based cytology than by conventional cytology.1
Interpretation of cytology is highly subjective. Therefore the effect of moving from conventional to liquid based cytology could vary across laboratories. Our data do not, however, show evidence of heterogeneity between the centres in this study. We also did not observe any difference in the performance of liquid based cytology compared with conventional cytology according to previous experience with liquid based cytology, nor with increasing experience in the study. Although the power of interaction test is usually limited, in this case all P values were far from significant. In addition, point estimates changed little when we restricted the analysis to centres with experience of ThinPrep, or to the second half of enrolment in each centre. It is possible that greater experience could have an effect but, in case of shift from conventional to liquid based cytology, this would mean a long period of decreased accuracy before possible advantages.
On the basis of this analysis, the main advantage of moving to liquid based cytology is a reduction in the rate of unsatisfactory slides. Other established advantages are the shorter time needed for interpretation12 16
and the possibility of using the same sample for testing for human papillomavirus and for other molecular tests.
What is already known on this topic
- Despite the widespread use of liquid based cytology only a few high quality studies and no large randomised trial have examined its diagnostic accuracy
- Systematic reviews have produced conflicting conclusions
What this study adds
- Liquid based cytology shows no significant difference in sensitivity to conventional cytology
- A significant reduction in positive predictive value was, however, apparent