Comparing SurePath, ThinPrep, and conventional cytology as primary test method: SurePath is associated with increased CIN II⁺ detection rates

Using SurePath versus conventional cytology as primary test method resulted in a 12 % increase in the rate of primary smears classified as >BMD. The rate of primary smears classified as BMD decreased by 4 % and women with a primary BMD smear were more often diagnosed with CIN I or II. Combined this led to increased fractions of primary smears both classified as BMD and resulting in the detection of a CIN I or CIN II lesion and to increased fractions of primary smears both classified as >BMD and resulting in the detection of a CIN II or CIN III lesion detected. Altogether, the detection of CIN II⁺ increased by 8 % accompanied by a 14 % increase in the detection of CIN I. Cervical cancer rates were unaffected. The comparison of using ThinPrep versus conventional cytology did not result in such findings, although the sensitivity to detect cervical cancers might be lower.

Given the differences in preparation between both LBC methods, it is possible that the sensitivity for CIN II⁺ differs between them as well. For instance, it was shown that the cell yield is larger when the collecting device was retained instead of discarded from the vial with preservative fluid [30, 31], meaning that if the protocol is followed, the cell yield is larger when using SurePath (i.e., collecting device is retained) than when using ThinPrep (i.e., collecting device is discarded). Therefore, the probability of transferring abnormal cells from the cervical specimen (if present) to the slide is probably larger when using SurePath. The study of Rask et al. [16] seems to confirm this, since they found that replacing conventional cytology by SurePath resulted in a significant 31 % increase in cytological abnormalities within 23–29 aged women, while replacing conventional cytology by ThinPrep resulted in a nonsignificant 11 % decrease [16].

Our research demonstrated that CIN II⁺ detection rates are similar between ThinPrep and conventional cytology, which is compatible with results of previous studies. For instance, the observed CIN II⁺ detection rate ratio of 0.99 (95% CI 0.96–1.02) fits with the pooled relative CIN II⁺ sensitivity of 1.03 (0.97–1.09) as reported in the meta-analysis of Arbyn et al. (i.e., our point estimate lies within the 95% CI) [18]. However, that ratio was based on seven studies comparing LBC with conventional cytology of which two did not use ThinPrep as LBC test method. When only focusing on the included ThinPrep studies, we found and calculated (i.e., using data provided in the study) CIN II⁺ detection rate ratios of 1.17 (95% CI 0.87–1.56) [22], 0.97 (95% CI 0.61–1.55) [20], 0.95 (95% CI 0.62–1.48) [5], and 1.09 (95% CI 0.80–1.48) [21], which were all compatible to the detection rates as observed in the present study. The CIN II⁺ detection rate ratio of the fifth included ThinPrep study was not provided nor could be calculated [11]. Furthermore, the largest randomized controlled trial performed so far, including almost 90,000 participants, found a CIN II⁺ detection rate ratio of 1.00 (95% CI 0.84–1.20) [2] which also fits our data. When focusing on studies comparing SurePath with conventional cytology, only one previous study matched our criteria (i.e., providing a CIN II⁺ detection rate ratio, or data needed to calculate it, at a cutoff of ASCUS or BMD) [23]. Again, their data [i.e., a CIN II⁺ detection rate of 1.01 (95% CI 0.76–1.33)] fitted with ours [i.e., a ratio of 1.08 (95% CI 1.05–1.12)] (i.e., our point estimate lies within the reported 95% CI).

It is expected that from 2016 onwards, primary cytology screening will be replaced by primary HPV screening in the Dutch cervical cancer screening program. If high-risk HPV is present, a reflex cytology triage test will be carried out on the same sample followed by another triage test 6 months later, if the reflex cytology triage test shows no abnormalities. If one of these smears is classified as ≥BMD, the woman will be referred to the gynecologist for colposcopy, otherwise she will be referred to routine screening. Whether our results can be extended from a primary screening to a triage population depends on the performance of the cytology tests on (a) fluid remnant after primary HPV testing in HPV-positive women (in case of reflex triage testing) and (b) directly taken material in (previously) HPV-positive women (in case of triage testing at 6 months). Although prior knowledge of the HPV status influences the interpretation of cytological smears [32, 33], we assume this effect to be similar for the three types of cytology tests. If true, we expect the differences in sensitivity between Surepath, ThinPrep, and conventional cytology in a triage population to be equivalent to the differences in a primary screening population. However, this assumption has not been tested yet. In addition, because conventional cytology cannot be performed on fluid remnant after primary HPV testing [3, 18], our results of comparing SurePath and ThinPrep with conventional cytology cannot be extended to reflex triage testing. As data of Cuzick et al. [34] suggested that the performance of HPV assays depends on the type of LBC test used, it is also possible that the performance of LBC tests on fluid remaining after HPV testing depends on the type of HPV assay used. Thus, more research is needed to assess which combination of primary HPV test and secondary reflex LBC test has the highest CIN II⁺ sensitivity.

We were the first who compared CIN and cervical cancer detection rates between Surepath, ThinPrep, and conventional cytology. Furthermore, we included more than 6 million primary smears, and we showed its effect in real practice instead of in a strictly controlled setting.

At the same time, the lack of a more controlled setting is one of the limitations of our study. As ThinPrep and SurePath were used in different women, differences in demographic factors were inevitable. Although we were able to correct for the confounders age, screen region, SES, and calendar time, we were not able to correct for other potential confounding factors such as screening history or compliance with the given advice. Both could have resulted in biased effect estimates if their distribution differed between the types of cytology tests. In addition, no data are present on whether cytology triage testing at 6 months was combined with HPV testing. Because of the possibility of co-testing, it is likely that the use of HPV triage is correlated with the use of primary LBC testing. As it is known that more CIN I and CIN II lesions are detected when cytology triage is combined with HPV [35], it is probable that the increased sensitivity of SurePath to detect CIN I and CIN II was partly caused by the simultaneous use of HPV testing. However, the entire increase in CIN III detection rates when comparing Surepath with conventional cytology, and for a large part also the increase in CIN II detection rates, is caused by an increase in primary smears being classified as >BMD. Therefore, we still believe that SurePath results in increased CIN II⁺ detection rates, although it might be accompanied by a smaller increase in CIN I detection than estimated. Also, we did not have individual data on which type of primary test was used. Therefore, we combined the date of the primary smear and the quarter of the year within which the laboratory introduced the LBC test as proxy for the type of cytology test that was used. This means that primary screening smears taken during this quarter could have been misclassified, resulting in slightly underestimated effects. Another shortcoming of the study was that we were not able to correct for the use of automated reading, although this has only been introduced in relatively few Dutch laboratories. As study results on the effect of automated screening are heterogeneous, it is unknown how this affected our effect estimates. If automated reading does not affect the sensitivity for CIN II⁺, as shown by Klug and Palmer et al. [36, 37], our estimates are not biased. If automated reading results in a decreased sensitivity for CIN II⁺, as shown in the MAVARIC study [38], we might have underestimated the effect of using SurePath and ThinPrep on CIN II⁺ detection rates. If it results in an increased sensitivity, we might have overestimated the effects. At last, we did not correct for possible learning curve effects, since the aim of our study was to examine the effect of using SurePath and ThinPrep in routine practice, which also includes a possible learning effect.

Our results indicate that the widespread use of SurePath as primary test method has led to an increased probability to detect both CIN I and CIN II⁺ lesions. As only a small fraction of CIN I lesions progress to cancer, increased CIN I detection is often regarded as increased overdiagnosis. In contrast, CIN II⁺ lesions are associated with a substantial cancer risk and are therefore often considered as clinically relevant. However, whether the increased probability to detect CIN II⁺ lesions indeed corresponds with an increased sensitivity for progressive lesions remains to be investigated. If this is the case, using SurePath would in due time result in a decrease in the incidence and mortality of cervical cancer, thereby increasing the health benefits of the screening program. If not, it would only lead to increased burden and harms through overdiagnosis (and treatment) of regressive CIN lesions. The widespread use of ThinPrep as primary test method did not lead to changes in CIN II⁺ detection rates, although cervical cancer detection was nonsignificantly lower. Whether these results imply a decreased sensitivity for progressive CIN II⁺ lesions is unknown. For evidence as to whether the detection of progressive CIN II⁺ lesions is higher with any of the LBC systems than with conventional cytology, cervical interval carcinoma rates have to be compared.