Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial

Abstract

Objective To compare the accuracy of conventional cytology with liquid based cytology for primary screening of cervical cancer. Design Randomised controlled trial. Setting Nine screening programmes in Italy. Participants Women aged 25-60 attending for a new screening round: 22 466 were assigned to the conventional arm and 22 708 were assigned to the experimental arm. Interventions Conventional cytology compared with liquid based cytology and testing for human papillomavirus. Main outcome measure Relative sensitivity for cervical intraepithelial neoplasia of grade 2 or more at blindly reviewed histology, with atypical cells of undetermined significance or more severe cytology considered a positive result. Results In an intention to screen analysis liquid based cytology showed no significant increase in sensitivity for cervical intraepithelial neoplasia of grade 2 or more (relative sensitivity 1.17, 95% confidence interval 0.87 to 1.56) whereas the positive predictive value was reduced (relative positive predictive value v conventional cytology 0.58, 0.44 to 0.77). Liquid based cytology detected more lesions of grade 1 or more (relative sensitivity 1.68, 1.40 to 2.02), with a larger increase among women aged 25-34 (P for heterogeneity 0.0006), but did not detect more lesions of grade 3 or more (relative sensitivity 0.84, 0.56 to 1.25). Results were similar when only low grade intraepithelial lesions or more severe cytology were considered a positive result. No evidence was found of heterogeneity between centres or of improvement with increasing time from start of the study. The relative frequency of women with at least one unsatisfactory result was lower with liquid based cytology (0.62, 0.56 to 0.69).Conclusion Liquid based cytology showed no statistically significant difference in sensitivity to conventional cytology for detection of cervical intraepithelial neoplasia of grade 2 or more. More positive results were found, however, leading to a lower positive predictive value. A large reduction in unsatisfactory smears was evident. Trial registration Current Controlled Trials ISRCTN81678807. INTRODUCTIONLiquid based cytology is used widely for primary screening of cervical cancer but high quality studies on its accuracy are limited. Indeed almost all published studies are based either on the comparison of non-randomly assigned populations or on double testing the same women. With the double testing design, cells used for diagnosis could be removed with the conventional sample, which is taken first, leading to an underestimation of the accuracy of liquid based cytology. In addition only some of the published studies, in a primary screening setting, considered histologically confirmed cervical intraepithelial neoplasia as the end point and only a few verified the diagnosis by colpohistology in the large majority of women with abnormal cytology results. A recent review identified one small randomised trial only and concluded that large randomised trials were needed.

A randomized trial comparing conventional cytology to liquid‐based cytology and computer assistance

“…Additionally, two recent large randomized studies, which were situated within organized screening programs did not observe a higher relative sensitivity of LBC for histologically confirmed CIN compared with CC. 9,10,25 However, in one of these studies, the detection rate of invasive cervical cancer with LBC was twice as high compared with CC. 9 There are differences between our study and the previous trials.…”

“…26,27 Large randomized trials which did not find differences in relative sensitivity between CC and LBC were situated within a well-organized screening program 9 or at existing cervical screening centres. 10 The degree of experience with reading of LBC may be in part responsible for different results between studies. In contrary to other trials 9,10 all cytotechnicians and cytologists reading LBC or CC had broad experience with the respective technique already at the beginning of our study.…”

“…[5][6][7] Health technology assessments (HTA) and meta-analysis reviews as well as two recent, large randomized trials which were conducted in the context of organized screening programs did not find a higher sensitivity of LBC for the detection of cervical intraepithelial neoplasia grade 2 and higher (CIN2þ). [8][9][10][11][12] LBC has advantages such as faster reading of slides, fewer unsatisfactory specimens, and the possibility to use residual liquid sample for testing of Human Papillomavirus (HPV) and other molecular markers. 9,11,13,14 A disadvantage is the higher cost of LBC.…”

Cervical cancer patterns with automation‐assisted and conventional cytological screening: A randomized study

“…Often the first results have suggested high cross-sectional sensitivity while using nonrandomized studies and surrogate markers like cytology and any CIN, but little or no information has been available for the main outcome, cervical cancer. 2,15,16 …”

A randomised comparison of SurePath liquid‐based cytology and conventional smear cytology in a colposcopy clinic setting

“…Despite a plethora of studies suggesting improved sensitivity in LBC, 2,18 it is notable that a recent large randomised screening study, 19 a smaller randomised study with colposcopic verification 20 and two recent meta-analyses 1,17 did not identify increased sensitivity for high-grade abnormalities from LBC. In this study, when all randomised cases are included, there was a nonsignificant trend towards improved sensitivity in the LBC arm.…”