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Endocervical sampling in women with suspected cervical neoplasia: a systematic review and meta-analysis of diagnostic test accuracy studies

Open AccessPublished:August 04, 2022DOI:https://doi.org/10.1016/j.ajog.2022.07.036

      Objective

      Endocervical sampling in women with suspected cervical neoplasia can be performed by either endocervical brush or endocervical curettage. This study aimed to estimate the diagnostic accuracy, discomfort, and number of inadequate samples with either test.

      Data Sources

      Four bibliographic databases were searched on June 9, 2022, with no date or language restrictions.

      Study Eligibility Criteria

      We included all diagnostic studies and randomized clinical trials that compared the endocervical brush with endocervical curettage in women with an indication for colposcopy.

      Methods

      The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406). Two authors independently screened studies, extracted data, performed the risk-of-bias assessment (Quality Assessment of Diagnostic Accuracy Studies-2), and rated the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. A meta-analysis of diagnostic test accuracy was performed using a bivariate random-effects model.

      Results

      We included 7 studies: 4 diagnostic cohort studies and 3 randomized clinical trials. The reference standard was conization or hysterectomy. Risk of bias and concern about applicability were high for some of the studies in patient selection and flow and timing. Overall pooled sensitivity was 81% (95% confidence interval, 48–95; 799 women; 7 studies; low quality of evidence) for endocervical brush and 70% (95% confidence interval, 42–89; 761 women; 7 studies; low quality of evidence) for endocervical curettage. Overall pooled specificity was 73% (95% confidence interval, 36–93; 799 women; 7 studies; low quality of evidence) for endocervical brush and 81% (95% confidence interval, 56–94; 761 women; 7 studies; low quality of evidence) for endocervical curettage. The risk ratio for inadequate samples with endocervical curettage compared with endocervical brush was 2.53 (95% confidence interval, 0.58–11.0; P=.215; low-certainty evidence). Two studies reported on patient discomfort; one found less discomfort in the endocervical brush group, and the other found no difference.

      Conclusion

      No difference was found between endocervical brush and endocervical curettage in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited.

      Key words

      Why was this study conducted?

      In suspected cervical neoplasia the cervical canal can either be sampled by endocervical brush or endocervical curettage. There is clinical variation in the diagnostic approach, and no previous review has compared the 2 modalities.

      Key findings

      We included 7 studies and found no statistical difference between the endocervical brush and curettage in sensitivity (81% vs 70%) and specificity (73% vs 81%). The studies had risk of bias and were small. No statistical difference was found in inadequate sample rate or adverse effects either.

      What does this add to what is known?

      Endocervical brush might be an alternative to cervical curretage in women with suspected cervical dysplasia but due to low quality evidence our findings were not conclusive.

      Introduction

      Cervical cancer is the fourth most frequent cancer in women
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      and is a major cause of death worldwide, especially in low-income countries.
      • World Health Organization
      WHO cervix cancer.
      It is well-established that cervical cancer is caused by infection with human papillomavirus (HPV) in epithelial cells, and the virus is found in approximately 99.7% of reported cervical cancers.
      • Walboomers J.M.
      • Jacobs M.V.
      • Manos M.M.
      • et al.
      Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.
      HPV-induced cervical neoplasia is a precursor to cancer, gradually developing from mild cervical intraepithelial neoplasia (CIN1) to severe degrees (CIN3) and eventually to invasive cancer.
      • Holowaty P.
      • Miller A.B.
      • Rohan T.
      • To T.
      Natural history of dysplasia of the uterine cervix.
      This natural history of the disease has led to the implementation of primary prevention with HPV vaccines and secondary prevention with screening programs.
      Cervical neoplasia is mostly asymptomatic, but women may present with postcoital bleeding. The strategy for diagnosing cervical neoplasia is most commonly colposcopy, biopsies from the transformation zone, and endocervical sampling. Indication for these diagnostic tests may be abnormal cytology, positive HPV DNA testing, or symptoms (eg, postcoital bleeding). A positive finding (indicating high-grade neoplasia) on biopsies or endocervical sampling will result in further diagnostics, for example a colposcopy-guided conization. Two commonly used methods for obtaining an endocervical or cervical canal sample are the endocervical brush (EB) and endocervical curettage (ECC).
      The EB is a collection device with a brush made of flexible plastic hairs that follow the contours of the endocervical canal, which provides a cytologic sample (single cells) from the endocervical surface.
      • Vooijs G.P.
      Endocervical brush device.
      Different EB sampling devices exist, with a combined brush and spatula device being the most effective for collecting endocervical cells.
      • Martin-Hirsch P.P.L.
      • Jarvis G.G.
      • Kitchener H.C.
      • Lilford R.
      Collection devices for obtaining cervical cytology samples.
      ECC, on the other hand, is performed using a metal curette device that provides a histologic (tissue) sample.
      There is considerable variation in choice of test method and therefore it is relevant to conduct a review.

      Objective

      We aimed to systematically review the existing literature and perform a meta-analysis of diagnostic test accuracy (DTA) to provide estimates of the diagnostic accuracy of the EB and ECC, respectively, for the detection of cervical neoplasia in women with any indication for colposcopy, biopsies, and endocervical sampling. Furthermore, we investigated patient discomfort and inadequate sampling.

      Materials and Methods

      Eligibility criteria, information sources, search strategy

      All diagnostic studies and randomized clinical trials (RCTs), regardless of setting, including women with abnormal cytology in cervical cancer screening and women with possible symptoms of cervical cancer undergoing colposcopy, biopsy, EB, or ECC sampling were included. The target condition was cervical neoplasia, and the reference standard was the final histologic result of either conization or hysterectomy. Furthermore, we also addressed the possible discomfort caused by either method.
      We conducted a systematic search in the following 4 bibliographic databases on June 9, 2022, with no restrictions regarding language or date of publication: MEDLINE (Ovid), Embase (Ovid), the Cochrane Library, and CINAHL (EBSCO). The search strategy was originally developed by a medical librarian (H.S.L.) in collaboration with a subject advisor (L.K.P.) for a Danish national clinical guideline and was updated for the current review. To accommodate peer review, the original search strategy published in the protocol was modified to include studies without “colposkopy” as an obligatory search term, and >1000 more studies were screened with the search performed on June 9, 2022.
      The modified search was a combination of “cervical” AND “neoplasia” AND “curettage,” with the corresponding synonyms in subject headings and title or abstract. The full search strategy can be found in Appendix 1. The search results were imported into Covidence
      • Kellermeyer L.
      • Harnke B.
      • Knight S.
      Covidence and Rayyan.
      for removal of duplicates and abstract screening.

      Study selection

      All studies were screened by 2 authors independently, and any disagreement was resolved through discussion.

      Data synthesis

      Two authors (B.B.B. and J.B.S.) extracted information about year, time period, author, country, funding, and threshold for treatment, and enough information was collected to create a 2-by-2 table (true positive, false positive, true negative, false negative).

      Assessment of risk of bias

      The same authors also individually performed bias assessment using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool
      • Whiting P.F.
      • Rutjes A.W.S.
      • Westwood M.E.
      • et al.
      QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.
      and individually rated the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      A full review protocol was published on February 24, 2021 on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021222406) before conducting this review.
      • Laursen J.B.
      • Schroll J.B.
      • Petersen L.K.
      • et al.
      Choice of method for endocervical sampling in women with suspected neoplasia - a systematic review. 2021.
      We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for DTA
      • McInnes M.D.F.
      • Moher D.
      • Thombs B.D.
      • et al.
      Preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: the PRISMA-DTA statement.
      and the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy.
      Cochrane Methods Screening and Diagnostics Tests
      Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. 2021.

      Data synthesis

      Meta-analysis was conducted using metadiag package
      • Verde E.
      bamdit: an R package for Bayesian Meta-Analysis of Diagnostic Test Data. 2018.
      and meta package
      • Balduzzi S.
      • Rücker G.
      • Schwarzer G.
      How to perform a meta-analysis with R: a practical tutorial.
      in R, version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). In accordance with the recommendations from the Cochrane DTA handbook, we conducted a meta-analysis if ≥3 studies without substantial clinical heterogeneity were available. We chose a bivariate random-effects model to determine summary estimates of sensitivity and specificity with 95% confidence intervals (CIs), and a univariate random-effects model to estimate risk ratios (RRs) for inadequate samples with 95% CI and P value with a significance level of α=0.05.
      A sensitivity analysis was performed to validate the credibility of the results, excluding studies at high risk of bias in QUADAS-2 domains, as described in our protocol. A separate analysis was done for each domain in turn. Furthermore, a separate analysis stratifying by chosen study design was performed.

      Results

      Study selection

      We identified 2636 studies, and after removal of 1014 duplicates, 2 authors screened 1622 studies. We excluded 1506 studies after title and abstract screening and obtained 116 studies for full-text screening, 4 of which were from additional sources. Seven studies
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      • Hoffman M.S.
      • Sterghos S.
      • Gordy L.W.
      • Gunasekaran S.
      • Cavanagh D.
      Evaluation of the cervical canal with the endocervical brush.
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      • Frost L.
      Cytobrush in evaluation of cervical dysplasia. Is cervical curettage necessary?.
      were ultimately included in the meta-analysis. The studies were conducted from 1988 to 2013, with a total of 1097 women included in the final analysis. The study characteristics are shown in Table 1.
      Table 1Characteristics of the included studies in the quantitative analysis
      Study nameCountryStudy designParticipants (number of women with histology present)Inclusion criteriaCriteria for conization/hysterectomyNumber of inadequate samples for diagnosis (curettage/cytobrush)Women discomfortDefinition of positive resultFunding
      Andersen et al,
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      1988
      United StatesCohort87 (87)All women who underwent conization in 1986 at that hospitalInadequate colposcopy, positive ECC, suspension of microinvasion, earlier treatment failure, other7/NRNREndocervical dysplastic processNR
      Hoffman et al,
      • Hoffman M.S.
      • Sterghos S.
      • Gordy L.W.
      • Gunasekaran S.
      • Cavanagh D.
      Evaluation of the cervical canal with the endocervical brush.
      1993
      United StatesCohort388 (101
      Only 101 included in the final analysis.
      )
      Abnormal cytologyInadequate colposcopy, CIN3, positive ECC, or cytobrush11/2NREndocervical involvement (single pathologist)NR
      Mogensen et al,
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      1997
      DenmarkRCT173 (88)Abnormal cytology≥CIN210/0NR≥CIN2NR
      Klam et al,
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      2000
      CanadaRCT315 (147)Abnormal cytologyBiopsy-verified neoplasia (severity not specified)0/1No differenceJudgment of both tests by pathologistNR
      Boardman et al,
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      2003
      United StatesCohort62 (60)Indication for conization or hysterectomyBenign and (pre)malign13/1NRAny degree of dysplasia, CIN, or malignancyNIH (government)
      Goksedef et al,
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      2013
      TurkeyRCT208 (33)LSILBiopsy-verified neoplasia (severity not specified)0/4More pain with ECC≥CIN1NR
      Frost,
      • Frost L.
      Cytobrush in evaluation of cervical dysplasia. Is cervical curettage necessary?.


      1990
      DenmarkCohort203Abnormal cytology≥CIN2 (or suspicion-based on clinical findings)22/10NR≥CIN2NR
      CIN, cervical intraepithelial neoplasia; ECC, endocervical curettage; LSIL, low-grade intraepithelial lesion; NIH, National Institutes of Health; NR, not reported; RCT, randomized clinical trial.
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.
      a Only 101 included in the final analysis.
      We excluded 109 studies for the following reasons: wrong study design (n=58), wrong intervention (n=27), wrong comparator (n=10), not available (n=6), wrong setting (n=4), ongoing trials (n=2), and wrong outcomes (n=2) (Figure 1).
      Figure thumbnail gr1
      Figure 1Flow chart illustrating the search and the study selection
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.

      Study characteristics

      The 7 studies were performed in the United States, Denmark, Turkey, and Canada and included between 62 and 388 women. Three studies were RCTs
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      ,
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      ,
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      and 4 were cohort studies,
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      ,
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      ,
      • Hoffman M.S.
      • Sterghos S.
      • Gordy L.W.
      • Gunasekaran S.
      • Cavanagh D.
      Evaluation of the cervical canal with the endocervical brush.
      where the study by Boardman et al
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      had the sequence of index tests randomized (table–envelope).
      In the RCT by Mogensen et al,
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      women undergoing colposcopy-directed biopsies were randomized to either EB or ECC. Women with ≥CIN2 underwent conization, and 131 of 180 women were included in the final analysis. Women with ≤CIN1 or an inadequate sample underwent follow-up with biopsies in a crossover design where previous EB changed to ECC and vice versa. The RCT by Klam et al
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      randomized women to either EB or ECC, and both index tests were assessed by a single pathologist. Only 147 of 315 women with biopsy-verified disease underwent conization. In addition, in the RCT by Goksedef et al
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      women were randomized to either EB or ECC, and both index tests were assessed by a single pathologist. However, in this study only 33 of 208 women with biopsy-verified disease underwent cone biopsy.
      In all 4 cohort studies participants had both index tests done and were compared with either conization or hysterectomy. One of the cohort studies included women with conization performed at a single center,
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      and the other included women with any indication for conization or hysterectomy.
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      In 3 RCTs and 1 cohort study, women with an abnormal cytology were included.
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      • Hoffman M.S.
      • Sterghos S.
      • Gordy L.W.
      • Gunasekaran S.
      • Cavanagh D.
      Evaluation of the cervical canal with the endocervical brush.
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      A considerable variation in the prevalence of cervical neoplasia was present in these studies, ranging from 6%
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      to 90%.
      • Frost L.
      Cytobrush in evaluation of cervical dysplasia. Is cervical curettage necessary?.
      The results of sensitivity and specificity for the individual included studies are shown in Figure 2. Detection of ≥CIN 2 was chosen as the cutoff value; however, some studies did use other cutoffs (Table 1). The highest sensitivity reported was 97% for the EB and 94% for ECC.
      • Frost L.
      Cytobrush in evaluation of cervical dysplasia. Is cervical curettage necessary?.
      The highest specificity was 97% for the EB
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      and 97% for ECC.
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      Figure thumbnail gr2
      Figure 2Summary findings on sensitivity of endocervical brush and endocervical curettage
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.

      Risk of bias of included studies

      The QUADAS-2 scores are shown in Table 2. All studies were rated as having unclear risk of bias in patient selection because the index tests were assessed in 2 settings—one where women were undergoing conization (2 of the cohort studies
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      ,
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      ) and one based on abnormal cytology referral (3 RCTs and 1 cohort study
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      • Hoffman M.S.
      • Sterghos S.
      • Gordy L.W.
      • Gunasekaran S.
      • Cavanagh D.
      Evaluation of the cervical canal with the endocervical brush.
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      ). However, in both settings only women who underwent conization (reference standard) were included in the final analysis. Four studies
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      ,
      • Frost L.
      Cytobrush in evaluation of cervical dysplasia. Is cervical curettage necessary?.
      were rated to have concerns of applicability because of a more selected patient group than our predefined target population, which included all women with an indication for colposcopy, biopsies, and endocervical sampling (patient selection; QUADAS-2, domain 1). The index tests were generally assessed to have low risk of bias, but there were some applicability issues related to our research question. Klam et al and Goksedef et al
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      ,
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      were rated to have high risk of concerns regarding applicability because they used the same criteria for both ECC and EB (interpretation by a pathologist), which does not correspond to clinical practice (index test; QUADAS-2, domain 2). Most studies had insufficient details on the reference standard. Klam et al,
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      Mogensen et al,
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      and Goksedef et al
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      were RCTs in a clinical setup, and therefore not all women had a conization or hysterectomy done. Klam et al
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      was rated as having high risk of bias and applicability concerns regarding the reference standard because women without a reference test conducted were classified as true negatives. The rest of the included studies were rated as having unclear risk of bias and applicability concerns regarding the reference standard because different diagnostic criteria were used for conization and hysterectomy across the studies (QUADAS-2, domain 3). The criteria are shown in Table 1. The following 3 studies were rated as having high risk of bias in flow and timing. Firstly, in Mogensen et al
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      only 88 of 173 women had conization done, and 49 women were excluded from analysis after randomization. Secondly, in Klam et al
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      only 147 of 308 women underwent conization, but women without a reference standard were still included in the analysis and coded as true negatives. Thirdly, in Goksedef et al
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      only 33 of 208 women underwent conization, and 40 of 248 women were excluded from the study (QUADAS-2, domain 4).
      Table 2QUADAS-2 scores for the included studies
      StudyRisk of biasApplicability concerns
      Patient selectionIndex testReference standardFlow and timingPatient selectionIndex testReference standard
      Andersen et al,
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      1988
      ULULHLU
      Hoffman et al,
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      1993
      ULULUUU
      Mogensen et al,
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      1997
      ULUHUUU
      Klam et al,
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      2000
      ULHHUHH
      Boardman et al,
      • Boardman L.A.
      • Meinz H.
      • Steinhoff M.M.
      • Heber W.W.
      • Blume J.
      A randomized trial of the sleeved cytobrush and the endocervical curette.
      2003
      ULULHUU
      Goksedef et al,
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      2013
      ULUHHHU
      Frost,
      • Frost L.
      Cytobrush in evaluation of cervical dysplasia. Is cervical curettage necessary?.
      990
      ULULHUU
      L Low risk H High risk U Unclear risk
      QUADAS-2, Quality Assessment of Diagnostic Accuracy Studies-2.
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.

      Synthesis of results

      We performed a DTA meta-analysis for summary sensitivity and specificity for all 7 included studies. The forest plots for our main analysis are shown in Figures 2 and 3. The sensitivity analysis and the Bayesian receiver-operating characteristics curves are shown in the supplied Appendix 2 and 3.
      Figure thumbnail gr3
      Figure 3Summary findings on specificity of endocervical brush and endocervical curettage
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.
      The overall pooled sensitivity was 81% (95% CI, 48–95; 799 women; 7 studies) for EB and 70% (95% CI, 42–89; 761 women) for ECC.
      The overall pooled specificity was 73% (95% CI, 36–93; 799 women) for EB and 81% (95% CI, 56–94; 761 women) for ECC.
      The sensitivity analysis did not alter the interpretation of the results; however, in the analysis sorted by study design, the sensitivities of the 2 methods were equivalent. In the sensitivity analysis on risk of bias, no studies were excluded in QUADAS-2 domain 1 (all studies had unclear risk of bias) and in domain 2 (all studies had low risk of bias). One study
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      was omitted in QUADAS-2, domain 3 because it was found to have high risk of bias given that women without a reference standard were assigned to the true negative category. Three included studies
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      ,
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      ,
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      were omitted in QUADAS-2, domain 4 because not all included women had the reference standard assigned. When sorted by study design, the 3 RCTs reported equivalent sensitivity for both EB and ECC (Appendix 2).
      We also performed a meta-analysis of summary RRs for risk of inadequate samples. The overall RR was 2.53 (95% CI, 0.58–11.0; P=.215) for ECC compared with EB for inadequate samples (Figure 4) .
      Figure thumbnail gr4
      Figure 4Forest plot over inadequate samples
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.
      Two studies reported on discomfort,
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      ,
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      and only the study by Goksedef et al
      • Goksedef B.P.
      • Api M.
      • Kaya O.
      • Gorgen H.
      • Tarlaci A.
      • Cetin A.
      Diagnostic accuracy of two endocervical sampling method: randomized controlled trial.
      reported a significant difference between ECC (mean [standard deviation] visual analog scale [VAS] score, 2.55 [1.12]) and EB (mean [standard deviation] VAS, 1.99 [0.87]).
      We rated the evidence using the GRADE tool for diagnostic testing.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      We downgraded the quality of evidence from high to low: one level because of inconsistency in study designs because studies had different criteria for conducting either hysterectomy or conization, and another level because of indirectness because of differences in included study population and because of imprecision in the estimates with wide CIs. The main results and the gradings are shown in Tables 3 and 4.
      Table 3Overview of GRADE profile for endocervical cytobrush
      Endocervical cytobrush

      Population: women where there was an indication for endocervical diagnostic procedure

      Index test: endocervical cytobrush

      Reference standard: conization specimen or hysterectomy

      Pooled sensitivity: 0.81 (0.48–0.95); and specificity: 0.73 (0.36–0.93)
      Test resultNumber of women if 100 were testedNumber of participants (studies)Certainty of evidence GRADE:
      True positives (correctly detected)41 (24–48)799 (7)Low (●●○○)
      False positives (test positive, but not cervical neoplasia)13 (3–32)
      True negatives (correctly excluded)37 (18–47)
      False negatives (missed)9 (2–26)
      The prevalence of 50% was chosen as the mean prevalence of cervical neoplasia in the studies.
      GRADE, Grading of Recommendations, Assessment, Development, and Evaluation.
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.
      Table 4Overview of GRADE profile for endocervical curettage
      Endocervical curettage

      Population: women where there was an indication for endocervical diagnostic procedure

      Index test: endocervical curettage

      Reference standard: conization specimen or hysterectomy

      Pooled sensitivity: 0.70 (0.42–0.89); and specificity: 0.81 (0.56–0.94)
      Test resultNumber of women if 100 were testedNumber of participants (studies)Certainty of evidence GRADE:
      True positives (correctly detected)35 (21–45)761 (7)Low (●●○○)
      False positives (test positive, but not cervical neoplasia)9 (3–22)
      True negatives (correctly excluded)41 (28–47)
      False negatives (missed)15 (5–29)
      The prevalence of 50% was chosen as the mean prevalence of cervical neoplasia in the studies.
      GRADE, Grading of Recommendations, Assessment, Development, and Evaluation.
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.

      Comment

      Main findings

      We analyzed the results of 7 studies reporting the DTA of EB and ECC, and including data for 799 women undergoing EB and 761 women undergoing ECC.
      The overall sensitivity was found to be slightly higher for EB than for ECC (low-certainty evidence), and vice versa, specificity was found to be slightly higher for ECC than for EB (low-certainty evidence). The results, however, were nonsignificant.
      Furthermore, a nonsignificant increased risk of inadequate samples with ECC compared with EB was found, and no clinical difference in discomfort of the women between the tests were found.
      As reported, EB was found to have a nonsignificant higher sensitivity, but lower specificity than ECC. It has been argued that because of this lower specificity EB is not as valuable as ECC as a diagnostic test, but is rather a superior screening tool.
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      If assuming a cervical neoplasia prevalence of 50% for women undergoing endocervical sampling, and using our pooled sensitivity and specificity estimates for EB and ECC, EB would detect 6 more cases of cervical neoplasia relative to ECC for every 100 women undergoing endocervical sampling (Tables 3 and 4). However, EB would also lead to 4 more false-positives compared with ECC. Although conization is considered safe, it is still associated with side effects such as increased perinatal mortality owing to preterm delivery, stenosis, and a very small risk of excessive bleeding.
      • Kuroki L.M.
      • Bergeron L.M.
      • Gao F.
      • Thaker P.H.
      • Massad L.S.
      See-and-treat loop electrosurgical excision procedure for high-grade cervical cytology: are we overtreating?.
      • Tanaka Y.
      • Ueda Y.
      • Kakuda M.
      • et al.
      Predictors for recurrent/persistent high-grade intraepithelial lesions and cervical stenosis after therapeutic conization: a retrospective analysis of 522 cases.
      • Ørtoft G.
      • Henriksen T.B.
      • Hansen E.S.
      • Petersen L.K.
      After conisation of the cervix, the perinatal mortality as a result of preterm delivery increases in subsequent pregnancy.
      • Santesso N.
      • Mustafa R.A.
      • Wiercioch W.
      • et al.
      Systematic reviews and meta-analyses of benefits and harms of cryotherapy, LEEP, and cold knife conization to treat cervical intraepithelial neoplasia.
      The above estimates are based on previous testing and chosen populations in the included studies. The diagnostic accuracy may differ in a population with, for instance, only endocervical high-grade squamous intraepithelial lesion (HSIL) cytology and negative biopsies. A concern of too many false-positives (too low specificity) may limit the use of EB as a sole diagnostic test in this population for referral to a diagnostic conization. Accuracy in this situation must be addressed empirically because it was only in the study by Hoffman et al
      • Hoffman M.S.
      • Sterghos S.
      • Gordy L.W.
      • Gunasekaran S.
      • Cavanagh D.
      Evaluation of the cervical canal with the endocervical brush.
      that endocervical HSIL in itself elicited a diagnostic conization. The diagnostic pathway for these women differs globally. In the Australian and Canadian guidelines, for women with negative colposcopy-guided biopsies but with HSIL-positive cytobrush samples (and HPV-DNA–positive samples in Australia), a diagnostic excisional procedure should be considered.

      Cancer Council Australia. National cervical screening program: guidelines for the management of screen-detected abnormalities, screening in specific populations and investigation of abnormal vaginal bleeding. 2022. Available at: https://www.cancer.org.au/clinical-guidelines/cervical-cancer-screening. Accessed August 17, 2022.

      ,
      • Bentley J.
      EXECUTIVE COUNCIL OF THE SOCIETY OF CANADIAN COLPOSCOPISTS, SPECIAL CONTRIBUTORS
      Colposcopic management of abnormal cervical cytology and histology.
      However, in other countries, Denmark included, this is not the case, and isolated HSIL only warrants a follow-up examination.
      It has been suggested that ECC may be more sensitive for disease in the endocervical canal because its sampling technique is more precise than EB, and the high sensitivity and lower specificity of EB could be related to ectocervical disease (contamination). Modified sleeve technique has been proposed to increase the specificity of the EB by guiding and shielding the EB into the endocervical canal, thereby minimizing ectocervical contamination.
      • Gosewehr J.A.
      • Julian T.M.
      • O’Connell B.J.
      Improving the cytobrush as an aid in the evaluation of the abnormal Papanicolaou test.
      However, in the studies by Hoffman et al,
      • Hoffman M.S.
      • Sterghos S.
      • Gordy L.W.
      • Gunasekaran S.
      • Cavanagh D.
      Evaluation of the cervical canal with the endocervical brush.
      Mogensen et al,
      • Mogensen S.T.
      • Bak M.
      • Dueholm M.
      • Frost L.
      • Knoblauch N.O.
      • Praest J.
      • Svanholm H.
      Cvtobrush and endocervical curettarre in the diagnosis of dysplasia and malignancy of the uterine cervix.
      and Klam et al
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      looking at verified endocervical disease, EB was still reported to have higher sensitivity for endocervical disease than ECC. In a study by Zahn et al,
      • Zahn C.M.
      • Rao L.K.F.
      • Olsen C.
      • Whitworth S.A.
      • Washington A.
      • Crothers B.A.
      Reproducibility of endocervical curettage diagnoses.
      the interobserver agreement in the interpretation of ECC by blinded pathologists was only moderate, which could be considered slightly concerning.
      In 2 of the included studies,
      • Andersen W.
      • Frierson H.
      • Barber S.
      • Tabbarah S.
      • Taylor P.
      • Underwood P.
      Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal.
      ,
      • Klam S.
      • Arseneau J.
      • Mansour N.
      • Franco E.
      • Ferenczy A.
      Comparison of endocervical curettage and endocervical brushing.
      1 and 7 inadequate samples, respectively, have been registered as true-negatives instead of being excluded in analysis as seen in the other studies. This could lead to a false lower sensitivity but higher specificity for ECC because of misclassification. Yet, because of few inadequate samples in the 2 studies and because the rest of the included 5 studies excluded inadequate samples, this is not likely to be the reason for the diverging sensitivities of EB and ECC. In light of these findings, a recent study by Mihaljevic et al
      • Rubeša-Mihaljević R.
      • Vrdoljak-Mozetič D.
      • Dinter M.
      • Verša Ostojić D.
      • Štemberger-Papić S.
      • Klarić M.
      Diagnostic three slides Pap test compared to punch biopsy and endocervical curettage in confirmed HSIL+ diagnosis.
      has reported in a subanalysis that ECC samples with abundant material had higher sensitivity than those with scant material. We would have liked to have included this study, but some errors and inconsistencies were found in their 2×2 tables, and the corresponding author did not reply to our e-mail. Another study found but not yet published was a RCT by Gonzalez et al
      • González C.A.
      • Pérez M.O.
      • Ontoria M.H.
      • Segarra A.C.
      • Bel C.B.
      • Violeta V.B.
      EP1058 Efficacy of the endocervical curettage vs endocervical brushing for the detection of high grade endocervical dysplasia.
      that was presented in a conference paper in 2019 and has not undergone peer review. They did not publish the 2×2 tables, and we have not been able to contact the authors by e-mail.
      Only 2 studies reported women’s discomfort. One study did not find any difference, and the other found a small association with slightly higher VAS score for ECC, but VAS of 2.55 vs VAS of 1.99 is not considered clinically relevant.
      • McCormack H.M.
      • Horne D.J.
      • Sheather S.
      Clinical applications of visual analogue scales: a critical review.
      Our results are in accordance with the RCT from Undurraga et al,
      • Undurraga M.
      • Catarino R.
      • Navarria I.
      • et al.
      User perception of endocervical sampling: a randomized comparison of endocervical evaluation with the curette vs cytobrush.
      reporting no difference in women’s preference for the 2 procedures.

      Strengths and limitations

      The strengths of this review include a prespecified protocol, comprehensive bias assessment using the QUADAS-2 tool, and a thorough literature search conducted by an expert research librarian.
      This review had some limitations, including a low number of studies and participants. DTA studies vary in study design because no clear superior study design has been proposed. Therefore, the included studies varied in design between RCT and diagnostic cohort studies, which caused heterogeneity. Another limitation is potential selection bias because only women who underwent a conization and/or hysterectomy were included in the final analysis of all but 1 study. However, these diagnostic procedures are considered the gold standard and as such are necessary for proper diagnostic accuracy measurements. As mentioned, the diagnostic pathway for women varies globally, leading to variable prevalence of cervical neoplasia in the included studies. This variation needs to be addressed in future studies. Furthermore, some of the studies were >20 years old, and although no major technical breakthrough regarding endocervical samples has emerged, a liquid-based analysis of cytology is now, for instance, the most used type of analysis, and HPV-DNA status is now also used in adjunction to colposcopy referral.

      Comparison with existing literature

      Our results are in accordance with the European Guidelines for Quality Assurance in Cervical Cancer Screening, Second Edition,
      • Arbyn M.
      • Anttila A.
      • Jordan J.
      • et al.
      European Guidelines for Quality Assurance in Cervical Cancer Screening. Second edition--summary document.
      and a review focusing on ECC by Driggers et al,
      • Driggers R.W.
      • Zahn C.M.
      To ECC or not to ECC: the question remains.
      reporting higher sensitivity for EB than for ECC, although also nonsignificant, leading to a higher detection rate for EB.
      A real-life evidence study
      • Shepherd J.P.
      • Guido R.
      • Lowder J.L.
      Should endocervical curettage routinely be performed at the time of colposcopy? A cost-effectiveness analysis.
      supported the use of ECC, especially in women aged >50 years. The finding that ECC may be more useful in older women is also supported by Gage et al.
      • Gage J.C.
      • Duggan M.A.
      • Nation J.G.
      • Gao S.
      • Castle P.E.
      Detection of cervical cancer and its precursors by endocervical curettage in 13,115 colposcopically guided biopsy examinations.
      This may be because of a higher risk of inadequate biopsies in elderly women because the transformation zone is retracted with age into the cervical canal. ECC then might be more useful because it gives a histologic evaluation of the endocervical canal. However, these studies did not compare ECC with EB. A study also examined combining EB and ECC for endocervical sampling,
      • Gibson C.A.
      • Trask C.E.
      • House P.
      • Smith S.F.
      • Foley M.
      • Nicholas C.
      Endocervical sampling: a comparison of endocervical brush, endocervical curette, and combined brush with curette techniques.
      reporting no difference in the amount of material attained from using both sampling techniques. However, their finding was in direct contrast to the findings by the newer RCT by Undurraga et al.
      • Undurraga M.
      • Catarino R.
      • Navarria I.
      • et al.
      User perception of endocervical sampling: a randomized comparison of endocervical evaluation with the curette vs cytobrush.
      More high-quality studies are needed to further address this idea of combined sampling.
      Our results are in accordance with the RCT by Undurraga et al,
      • Undurraga M.
      • Catarino R.
      • Navarria I.
      • et al.
      User perception of endocervical sampling: a randomized comparison of endocervical evaluation with the curette vs cytobrush.
      which reported a higher risk of inadequate samples with ECC than with EB (14.3% vs 2.0%; P=.002), and we also reported a higher, albeit nonsignificant, risk of inadequate samples using ECC. The finding of an inadequate sample rate of 14.3% in the study by Undurraga et al
      • Undurraga M.
      • Catarino R.
      • Navarria I.
      • et al.
      User perception of endocervical sampling: a randomized comparison of endocervical evaluation with the curette vs cytobrush.
      may be considered high. A study by Gage et al
      • Gage J.C.
      • Duggan M.A.
      • Nation J.G.
      • Gao S.
      • Castle P.E.
      Detection of cervical cancer and its precursors by endocervical curettage in 13,115 colposcopically guided biopsy examinations.
      with >13,000 ECC samples only reported an inadequate sample rate of 4%. However, no clear definition of inadequate sampling was given in the studies.

      Conclusion and implications

      No difference was found between EB and ECC in diagnostic accuracy, inadequate sampling rate, and adverse effects based on low-quality of evidence. Variation in the characteristics of women and the resulting diagnostic pathways make the external validity limited.

      Appendix 1

      MEDLINE

      (Cervix Uteri/ or (cervix or cervical or vaginal or cervicovaginal or endocervi∗ or ectocervi∗).ab,kf,ti.) and (exp Uterine Cervical Dysplasia/ or Cervical Intraepithelial Neoplasia/ or (dysplas∗ or neoplas∗).ab,kf,ti.) and (exp Curettage/ or (curettage or ((cervi∗ or endocervi∗) adj3 (abras∗ or abrad∗ or scrap∗)) or cytobrush∗ or uterobrush∗ or endocervical sampler∗ or cervex-brush∗ or cyto-brush∗).ab,kf,ti.)

      EMBASE

      ((exp uterine cervix/ or (cervix or cervical or vaginal or cervicovaginal or endocervi∗ or ectocervi∗).ab,kw,ti.) and (exp uterine cervix dysplasia/ or uterine cervix carcinoma in situ/ or (dysplas∗ or neoplas∗).ab,kw,ti.) and (exp curettage/ or (curettage or ((cervi∗ or endocervi∗) adj3 (abras∗ or abrad∗ or scrap∗)) or cytobrush∗ or uterobrush∗ or endocervical sampler∗ or cervex-brush∗ or cyto-brush∗).ab,kw,ti.)) not (conference abstract or conference paper or “conference review” or editorial or letter).pt.

      CINAHL

      (((MH “Cervix”)) OR (cervix OR cervical OR vaginal OR cervicovaginal OR endocervi∗ OR ectocervi∗)) AND (((MH “Cervix Dysplasia”)) OR ((MH “Cervical Intraepithelial Neoplasia”)) OR (dysplas∗ OR neoplas∗)) AND (((MH “Curettage+”)) OR (curettage OR ((cervi∗ OR endocervi∗) N3 (abras∗ OR abrad∗ OR scrap∗)) OR cytobrush∗ OR uterobrush∗ OR endocervical sampler∗ OR cervex-brush∗ OR cyto-brush∗))
      Supplemental Table 1Search strategy
      TitleEndocervical sampling in women with suspected cervical neoplasia: a systematic review and meta-analysis of diagnostic test accuracy studies
      Search specialistHenrik Laursen, Fagbibliotek, Regional Hospital Central Jutland

      Mail: [email protected]
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.
      Supplemental Table 2Revised search strategy
      DatabasesInterfaceHitsDate of search
      MEDLINEOvid MEDLINE(R) ALL <1946 to June 08, 2022>1099Sept 6, 2022
      EmbaseOVID Embase 1974 to 2022 June 081179Sept 6, 2022
      The Cochrane Libraryhttps://www.cochranelibrary.com/advanced-search/82Sept 6, 2022
      CINAHLEBSCO CINAHL with Full Text274Sept 6, 2022
      Total number of references: 2634.
      Number of references after deduplication in Covidence: 1620.
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.
      Supplemental Table 3COCHRANE Library
      #1MeSH descriptor: [Cervix Uteri] explode all trees1102
      #2(cervix or cervical or vaginal or cervicovaginal or endocervi∗ or ectocervi∗):ti,ab,kw39,719
      #3#1 or #239,719
      #4MeSH descriptor: [Uterine Cervical Dysplasia] explode all trees218
      #5MeSH descriptor: [Cervical Intraepithelial Neoplasia] explode all trees609
      #6(dysplas∗ or neoplas∗):ti,ab,kw93,981
      #7#4 or #5 or #693,990
      #8MeSH descriptor: [Curettage] explode all trees570
      #9(curettage or ((cervi∗ or endocervi∗) near/3 (abras∗ or abrad∗ or scrap∗)) or cytobrush∗ or uterobrush∗ or endocervical sampler∗ or cervex-brush∗ or cyto-brush∗):ti,ab,kw1920
      #10#8 or #91920
      #11#3 and #7 and #1082
      -Cochrane reviews1
      -CENTRAL81
      -Cochrane Library search total82
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.

      Appendix 2

      Sensitivity analysis

      Supplemental Table 4Sensitivity analysis for endocervical brush and curettage
      Reason for exclusionNumber of studies analyzedEndocervical brushEndocervical curettage
      Pooled sensitivity in % (95% CI)Pooled specificity in % (95% CI)Pooled sensitivity in % (95% CI)Pooled specificity in % (95% CI)
      All studies781 (48–95)73 (36–93)70 (43–89)81 (56–94)
      QUADAS-2 assessmentHigh risk in domain 17Same result (all studies included)Same result (all studies included)Same result (all studies included)Same result (all studies included)
      High risk in domain 27Same result (all studies included)Same result (all studies included)Same result (all studies included)Same result (all studies included)
      High risk in domain 3679 (43–96)66 (27–91)69 (40–89)77 (48–93)
      High risk in domain 4471 (30–94)59 (19–90)64 (30–89)71 (37–92)
      Study designRandomized clinical trials471 (30–94)59 (19–90)64 (30–89)71 (37–92)
      Cohort design368 (25–97)73 (25–97)0.69 (23–94)81 (38–97)
      CI, confidence interval; QUADAS-2, Quality Assessment of Diagnostic Accuracy Studies-2.
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.

      Appendix 3

      Bayesian SROC curve

      Figure thumbnail fx1
      Supplemental Figure 1Bayesian SROC curve for endocervical brush
      FPR, false positive rate; SROC, summary receiver operator characteristic; TPR, true positive rate.
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.
      Figure thumbnail fx2
      Supplemental Figure 2Bayesian SROC curve for endocervical curettage
      FPR, false positive rate; SROC, summary receiver operator characteristic; TPR, true positive rate.
      Damkjær. Endocervical sampling in suspected cervical neoplasia. Am J Obstet Gynecol 2022.

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