Advertisement

Increased detection of high grade CIN, when using electrical impedance spectroscopy as an adjunct to routine colposcopy, is maintained when used across international boundaries: Prospective data from nine European countries

Open AccessPublished:June 01, 2022DOI:https://doi.org/10.1016/j.ejogrb.2022.05.025

      Highlights

      • HPV vaccination and primary HPV screening have been shown to be effective.
      • Women at low risk of high grade CIN are now being referred to colposcopy.
      • Colposcopy performs poorly when there is a low prevalence of high grade CIN.
      • ZedScan increases the detection of high grade CIN across multiple centres.

      Abstract

      Objective

      To evaluate the performance of EIS (ZedScan) with colposcopy in the detection of high grade CIN (HG-CIN) in different health care settings.

      Method

      Pooled analysis of data from 26 colposcopy centres in 9 countries. All women underwent colposcopy and ZedScan examination. Data was recorded prospectively via a proforma. Indications for referral to colposcopy were according to national guidelines. Pathology was reported according to national guidelines.

      Results

      5257 women were examined by 82 colposcopists, median 93 women per centre (range 41 – 2684), 3 users per centre (range 1–8). Referral indications were; 19.3% high grade cytology, 50.4% low grade, 30.3% clinical or HPV positive / cytology negative. The prevalence of HG-CIN was 26.5%; 79.1% in high grade referrals, 16.7% low grade, 9.4% clinical or HPV positive / cytology negative. The use of ZedScan detected an extra 269 cases of high grade CIN (24% increase) (7.5% increase for high grade referrals, 57.9% for low grade and 52% for clinical or HPV positive/cytology negative). Based upon colposcopic impression (CI), the sensitivity of colposcopy for CIN2 + was 74.1% compared with 91.6% for colposcopy with ZedScan (Chi2 p < 0.0001). The PPV for a ZedScan directed biopsy varied according to referral cytology and colposcopic impression (19.5% to 85.7%).
      489 women underwent treatment at first visit, when ZedScan suggested treatment, 95.1% had HG-CIN/HG-CGIN or cervical cancer.
      The pooled results for the whole 26 centres were consistent with the results obtained for the largest centre (Sheffield) alone and also with the results with this largest centre excluded.

      Conclusions

      The addition of EIS (ZedScan) increases detection of HG-CIN with the PPV for a ZedScan directed biopsy consistent with the published literature. Results were similar in multiple healthcare settings. With more women being referred to colposcopy at low risk of HG-CIN, due to HPV vaccination and primary HPV screening, this study confirms the value of a real time adjunctive technology.

      Keywords

      Introduction

      Cervical screening in many countries continues to evolve in response to primary HPV screening and vaccination. Vaccinated women will have a low prevalence of high grade CIN (CIN2+) and many screening programmes, require women with a single or persistent high risk HPV (hrHPV) positive screen to be referred to colposcopy. The net impact of these two major developments will result in more women being referred to colposcopy at low risk of high grade CIN (HG-CIN).
      The performance of colposcopy can be difficult to assess as true sensitivity and specificity requires excision of the transformation zone of all women to ascertain disease status. To overcome this, surrogate markers including directed biopsies and colposcopic impression (CI) can be used [
      • Brown B.H.
      • Tidy J.A.
      The diagnostic accuracy of colposcopy – A review of research methodology and impact on the outcomes of quality assurance.
      ]. The outcome of colposcopy can be measured in two ways, CI reflects the opinion of the colposcopist at the time of the examination and does not always equate to what might happen to the woman, whereas disease presence (DP) indicates HG-CIN has been confirmed regardless of the indication for the biopsy and determines clinical management. The positive predictive value (PPV) of CI to confirm HG-CIN on biopsy can be used within a quality assurance programme to assess performance. However, PPV to detect HG-CIN is dependent on disease prevalence and will fall if prevalence declines [

      Cervical screening: programme and colposcopy management. NHSCSP No20. 20 September 2021. www.gov.uk/government/publications/cervical-screening-programme-and-colposcopy-management. Last accessed 20 January 2022.

      ]. Multiple studies have shown variations in PPV relating to indication for referral, high grade cytology vs low grade, HPV16 associated lesions vs non HPV16. The PPV for CI is best for women with high grade cytology and HPV16 associated lesions [
      • Wentzensen N.
      • Walker J.L.
      • Gold M.A.
      • Smith K.M.
      • Zuna R.E.
      • Mathews C.
      • et al.
      Multiple biopsies and detection of cervical cancer precursors at colposcopy.
      ,
      • Huh W.K.
      • Papagiannakis E.
      • Gold M.A.
      Observed colposcopy practice in US community-based clinic: The retrospective control arm of the IMPROVE-COLPO study.
      ,
      • Macdonald M.C.
      • Brown B.H.
      • Lyon R.E.
      • Healey T.J.
      • Palmer J.E.
      • Tidy J.A.
      Influence of high risk HPV genotype on colposcopic performance: A large prospective study demonstrates improved detection of disease with ZedScan I, particularly in non-HPV 16 patients.
      ,
      • Tidy J.A.
      • Lyon R.
      • Ellis K.
      • Macdonald M.
      • Palmer J.E.
      The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.
      ].
      We previously demonstrated the utility of electrical impedance spectroscopy (EIS) [
      • Brown B.H.
      • Tidy J.
      • Boston K.
      • Blackett A.D.
      • Smallwood R.H.
      • Sharp F.
      The relationship between tissue structure and imposed electrical current flow in cervical neoplasia.
      ]. EIS is sensitive to the cellular structure of the epithelium and offers information that is not available to visual examination. ZedScan incorporates EIS and can be used as a real time adjunct to colposcopy with multiple studies confirming increased detection of HG- CIN [
      • Macdonald M.C.
      • Brown B.H.
      • Lyon R.E.
      • Healey T.J.
      • Palmer J.E.
      • Tidy J.A.
      Influence of high risk HPV genotype on colposcopic performance: A large prospective study demonstrates improved detection of disease with ZedScan I, particularly in non-HPV 16 patients.
      ,
      • Tidy J.A.
      • Lyon R.
      • Ellis K.
      • Macdonald M.
      • Palmer J.E.
      The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.
      ,
      • Brown B.H.
      • Tidy J.
      • Boston K.
      • Blackett A.D.
      • Smallwood R.H.
      • Sharp F.
      The relationship between tissue structure and imposed electrical current flow in cervical neoplasia.
      ,
      • Tidy J.A.
      • Brown B.H.
      • Lyon R.E.
      • Healey T.J.
      • Palmer J.E.
      Are colposcopy and electrical impedance spectroscopy complementary when used to detect high-grade cervical neoplasia?.
      ,
      • Tidy J.
      • Brown B.
      • Healey T.
      • Daayana S.
      • Martin M.
      • Prendiville W.
      • et al.
      Accuracy of detection of high-grade cervical intraepithelial neoplasia using electrical impedance spectroscopy with colposcopy.
      ,
      • Muszynski C.
      • Dupont E.
      • Vaysse B.
      • Lanta S.
      • Tidy J.
      • Sergent F.
      • Gondry J.
      The impact of using electrical impedance spectroscopy (ZedScan) on the performance of colposcopy in diagnosing high grade squamous lesions of the cervix.
      ,
      • Homola W.
      • Fuchs T.
      • Baranski P.
      • Zimmer A.
      • Zimmer M.
      • Pomorski M.
      Use of electrical impedance spectroscopy as an adjunct to colposcopy in a pathway of cervical intraepithelial neoplasia diagnostics.
      ]. However, data from clinical trials and cohort studies are not always confirmed when a technology is implemented across multiple healthcare settings with variations in disease prevalence. The aim of the study was to report routine data for the combination of ZedScan with colposcopy across multiple centres with multiple clinicians in several European countries.

      Method

      A prospective cohort study was performed. Clinicians underwent training in the use of ZedScan. Eight to 12 ZedScan readings were taken around the squamo-columnar junction and associated lesions following application of acetic acid. Positive ZedScan readings could be relocated using a ‘single point function’ to identify the site for a ZedScan directed biopsy. A secondary function of ZedScan identifies women with high grade CI who might be suitable for treatment at first visit (See and Treat, S&T). Cytology, HPV testing, colposcopy and histopathology were performed in accordance with national or local guidelines. Each biopsy was sent separately for reporting. Data was recorded prospectively including; indication for colposcopy, CI, ZedScan data, site and indication for all biopsies – colposcopic directed, ZedScan or both. Biopsy results were added to the data sheet for subsequent analysis. Ethical or audit committee approval was obtained according to institutional guidance. Data was anonymised and pooled for analysis. Statistical analysis was performed using descriptive statistics, Chi square and Fisher’s exact test (two tailed) where appropriate.

      Results

      All 26 centres

      5257 women were examined by colposcopy and ZedScan at 26 colposcopy clinics in 9 European countries (Eire, England, Finland, France, Germany, Israel, Netherlands, Scotland and Sweden) between 2015 and 2021. 82 clinicians took part. The median number of women examined per centre was 93 (41 – 2684), the median number of clinicians per centre was 3 (1 – 8). Indications for referral were; high grade cytology 1013 (19.3%), low grade cytology 2652 (50.4%), non-abnormal cytology referrals 1592 (30.3%) which included clinical indications – symptoms, abnormal cervix, persistent HPV positive / cytology negative referrals and follow-ups. [Fig. 1]. 489 women underwent LLETZ after colposcopic and ZedScan examinations. 1392 women had HG-CIN on biopsy or LLETZ.
      Figure thumbnail gr1
      Fig. 1STARD diagram for outcomes for 5257 women referred to colposcopy.
      1006 cases of HG-CIN were detected by both colposcopy (CI ≥ CIN2) and ZedScan, 269 cases were identified by ZedScan when CI was ≤ CIN1, 26 were negative by ZedScan but CI ≥ CIN2. 91 were negative by both ZedScan and CI ≤ CIN1 but still underwent biopsy. Use of ZedScan increased detection of HG-CIN from 1123 to 1392 (269, 24%). [Table 1].
      Table 1Detection of CIN2 + by ZedScan (*Prevalence calculated for all HG-CIN including extra cases detected by ZedScan).
      All CentresExcluding SheffieldSheffield
      Indication for referralNPrevalence of CIN2+*

      N (%)
      Increased cases of CIN2+

      N (%)
      NPrevalence of CIN2+*

      N (%)
      Increased cases of CIN2+

      N (%)
      NPrevalence of CIN2+*

      N (%)
      Increased cases of CIN2+

      N (%)
      All referrals52571123 (26.5%)269 (24%)2573724 (28.1%)156 (27.5%)2684668 (24.8%)113 (20.4%)
      High grade1013801 (79.1%)56 (7.5%)556412 (74.1)41 (11.1%)457389 (85.1%)18 (4.6%)
      Low grade2652442 (16.7%)162 (57.9%)1640291 (17.7%)109 (60%)1012151 (14.9%)53 (54.1%)
      Non cytology referrals1592149 (9.4%)51 (52%)33721 (5.6%)6 (40%)1215128 (10.5%)45 (54.2%)

      Analysis of Sheffield centre data

      2684 women were examined by colposcopy and ZedScan by 8 clinicians at one centre, Sheffield U.K., representing just over 51% of the evaluation population. Indications for referral were; high grade cytology 457 (17.0%), low grade cytology 1012 (37.7%), non-abnormal cytology referrals 1215 (45.3%). 329 women underwent LLETZ after colposcopic and ZedScan examinations. 311 women had HG-CIN on biopsy or LLETZ.
      524 cases of HG-CIN were detected by both colposcopy (CI ≥ CIN2) and ZedScan, 113 cases were identified by ZedScan when CI was ≤ CIN1, 31 were negative by ZedScan but of these 9 were CI ≥ CIN2 on colposcopy. 22 were negative by ZedScan and CI ≤ CIN1 but still underwent biopsy. Use of ZedScan increased the detection of HG-CIN from 555 to 668 (113, 20.4%). [Table 1].

      Analysis of the other 25 centres

      2573 women were examined by colposcopy and ZedScan by 74 clinicians. The median number of women examined per centre was 89 (41 – 208), the median number of clinicians per centre was 3, (1 – 7). Indication for referral were; high grade cytology 556 (21.6%), low grade cytology 1640 (63.7%), non-abnormal cytology referrals 377 (14.7%). 160 women underwent LLETZ after colposcopic and ZedScan examinations. 724(28.1%) women had HG-CIN on biopsy or LLETZ.
      482 cases of HG-CIN were detected by both colposcopy (CI ≥ CIN2) and ZedScan, 156 cases were identified by ZedScan when CI was ≤ CIN1, 17 were negative by ZedScan but CI ≥ CIN2. 69 were negative by ZedScan and CI ≤ CIN1 but still underwent biopsy. Use of ZedScan increased the detection of HG-CIN from 568 to 724 (156, 27.5%). [Table 1].

      Positive predictive value of ZedScan directed biopsies

      Analysis of 2684 women who underwent a ZedScan examination at Sheffield was undertaken to assess the PPV of a ZedScan directed biopsy. 457 with high grade cytology, 1012 low grade cytology and 1094 persistent hrHPV infection with normal cytology, 126 with clinical indications. All women referred with an abnormal cytology were hrHPV positive. When CI was taken into account there was a higher PPV when CI was abnormal. The highest PPV was associated with a high grade CI and lowest when CI was normal. [Table 2].
      Table 2Positive predictive value for a ZedScan directed biopsy for HG-CIN for different referral indications and colposcopic impressions.
      Referral indication + colposcopic impressionPositive predictive value for CIN2+
      High grade cytology + CI HG-CIN90.0%
      Low grade cytology + CI HG-CIN44.6%
      Low grade cytology + CI CIN125.0%
      Low grade cytology + CI normal6.0%
      hrHPV positive/cytology negative + CI HG-CIN47.4%
      hrHPV positive/cytology negative + CI CIN120.3%
      hrHPV positive/cytology negative + CI normal2.9%

      Performance of colposcopy and comparison across centres

      Results for all 26 centres shows the sensitivity of colposcopy using the CI method was 74.1% but increased to 91.6% with the use of ZedScan (p < 0.0001). Use of ZedScan increased the detection of HG-CIN by 269 (24%) cases, a 7.5% increase in high grade cytology and 57.9% in low grade referrals. [Table 3].
      Table 3Detection of CIN2 + with colposcopy and ZedScan. 95% Confidence intervals are given in brackets.
      All centresExcluding SheffieldSheffield
      Overall increase in detection of CIN2+24.0% (21.5–26.5)27.5% (23.8–31.2)20.4% (17.1–23.8)
      Increased detection in HG referrals7.5% (5.6–9.4)11.1% (7.9–14.3)4.6% (2.5–6.7)
      Increased detection in LG referrals57.9% (52.1–63.7)60% (52.9–67.1)54.1% (44.2–64.0)
      Sensitivity of Colp + ZedScan (CI Method)91.6% (90.1–93.1)90.5% (88.4–92.6)96.7% (95.3–98.1)
      Sensitivity of Colp alone (CI Method)74.1% (71.8–76.4)68.9% (65.5–72.2)79.8% (76.8–82.8)
      To address any potential differences between the groups of centres Table 3 contains the increased sensitivity results, with 95% confidence intervals, for all 26 centres, with Sheffield excluded and Sheffield alone. None of the differences are statistically significant at the p < 0.05 level.

      Women who underwent excisional treatment at first visit (See and Treat, S&T)

      489 women underwent S&T and ZedScan suggested S&T as an option for 428, 87.5% of all S&T, and of those 407 (95.1%) were confirmed as HG-CIN and 10 had CIN1. When the analysis was restricted to only women having S&T after referral with high grade cytology, 460 had LLETZ of which 432 (93.9%) were confirmed as HG-CIN and 15 were CIN1. ZedScan suggested S&T for 421 (91.5%) of which 401 (95.2%) were confirmed as HG-CIN and 9 were CIN1. The outcome for women at the Sheffield centre and the other 25 centres are consistent with a high prevalence of HG-CIN. [Table 4].
      Table 4Performance of ZedScan for See & Treat (S&T).
      All CentresExcluding SheffieldSheffield
      Indication for S&TNZedScan suggests S&T N (%)CIN2+N (%)NZedScan suggests S&T N (%)CIN2+N (%)NZedScan suggests S&T N (%)CIN2+N (%)
      All indications489428 (87.5%)407 (95.1%)160117 (73.0%)110 (94.0%)329311 (94.5%)297 (95.5%)
      High grade cytology460421 (91.5%)401 (95.2%)136111 (81.6%)105 (94.6%)324309 (95.4%)295 (95.4%)

      Discussion

      Colposcopy is becoming more challenging given the impact of HPV vaccination on the prevalence of HG-CIN with fewer young women being referred to colposcopy and treatment [
      • Brotherton J.M.
      • Fridman M.
      • May C.L.
      • Chappell G.
      • Saville A.M.
      • Gertig D.M.
      Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study.
      ,
      • Palmer T.
      • Wallace L.
      • Pollock K.G.
      • Cuschieri K.
      • Robertson C.
      • Kavanagh K.
      • et al.
      Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12–13 in Scotland: retrospective population study.
      ,
      • Lukic A.
      • De Vincenzo R.
      • Ciavattini A.
      • Ricci C.
      • Senatori R.
      • Ruscito I.
      • et al.
      Are We Facing a New Colposcopic Practice in the HPV Vaccination Era? Opportunities, Challenges, and New Perspectives.
      ]. As a consequence many organised screening programme or national guidance documents recommend primary HPV because of the lower prevalence of HG-CIN [

      Cervical screening: programme and colposcopy management. NHSCSP No20. 20 September 2021. www.gov.uk/government/publications/cervical-screening-programme-and-colposcopy-management. Last accessed 20 January 2022.

      ]. Guidelines from Australia and USA also recommend women with certain hrHPV genotypes (HPV16 and 18) are referred immediately to colposcopy whereas guidelines from other countries recommend colposcopy if there is abnormal cytology [

      9 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Perkins, RB, Guido, RS, Castle PE, Chelmow D, Einstein MH, Garcia F, Huh WK, Kim JJ, Moscicki A-B, Nayar R, Saraiya M, Sawaya GF, Wentzensen N, Schiffman M, for the 9 ASCCP Risk-Based Management Consensus Guidelines Committee. Journal of Lower Genital Tract Disease: April 2020 - Volume 24 - Issue 2 - p 102-131.

      ,

      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. 22 November 2021. https://wiki.cancer.org.au/australiawiki/index.php?title=Guidelines:Cervical_cancer/Screening&action=history. Last accessed 20 January 2022.

      ]. Unfortunately, some women develop persistent hrHPV infection with negative cytology and require referral to colposcopy at 12 or 24 months of persistent infection [

      Cervical screening: programme and colposcopy management. NHSCSP No20. 20 September 2021. www.gov.uk/government/publications/cervical-screening-programme-and-colposcopy-management. Last accessed 20 January 2022.

      ]. Previously the UK screening guidelines recommended colposcopy for any cytological abnormalities with or without hrHPV triage, giving a threshold for HG-CIN of between 10 and 15% whereas the recent ASCCP guidelines have recommended immediate referral to colposcopy if the risk of CIN3 + is>4% [

      9 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Perkins, RB, Guido, RS, Castle PE, Chelmow D, Einstein MH, Garcia F, Huh WK, Kim JJ, Moscicki A-B, Nayar R, Saraiya M, Sawaya GF, Wentzensen N, Schiffman M, for the 9 ASCCP Risk-Based Management Consensus Guidelines Committee. Journal of Lower Genital Tract Disease: April 2020 - Volume 24 - Issue 2 - p 102-131.

      ,
      • Kelly R.S.
      • Patnick J.
      • Kitchener H.C.
      • Moss S.M.
      HPV testing as a triage for borderline or mild dyskaryosis on cervical cytology: results from the Sentinel Sites study.
      ]. There is as yet no consensus as to whether all women with very low prevalence of HG-CIN would benefit referral to colposcopy.
      We have reported that women with persistent HPV16 infection, even with negative cytology, have a higher prevalence of HG-CIN (10.7% vs 4.7%) when compared to 13 other hrHPV genotypes and also confirmed the PPV for colposcopy to detect disease by CI was greater for HPV16 lesions (57.2% vs 32.1%) [
      • Tidy J.A.
      • Lyon R.
      • Ellis K.
      • Macdonald M.
      • Palmer J.E.
      The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.
      ]. These observations led to Jeronimo and Schiffman proposing that colposcopy was at a crossroads and required improvement [
      • Jeronimo J.
      • Schiffman M.
      Colposcopy at a crossroads.
      ]. One approach would be to examine the role of adjuvant technologies using optical assessment of the cervix or electrical impedance spectroscopy (EIS) [
      • Brown B.H.
      • Tidy J.
      • Boston K.
      • Blackett A.D.
      • Smallwood R.H.
      • Sharp F.
      The relationship between tissue structure and imposed electrical current flow in cervical neoplasia.
      ,
      • Louwers J.A.
      • Zaal A.
      • Kochen M.
      • ter Harmsel W.A.
      • Graziosi G.M.C.
      • Spruijt J.W.M.
      • et al.
      Dynamic spectral imaging colposcopy: higher sensitivity for the detection of premalignant cervical lesions.
      ,
      • Roensbo M.T.
      • Hammer A.
      • Blaakær
      Can dynamic spectral imaging system colposcopy replace conventional colposcopy in the detection of high-grade cervical lesions?.
      ].
      Prior clinical trials and cohort studies have confirmed the utility of EIS (ZedScan) increasing the detection of HG-CIN across a range of referrals, hrHPV status and aceto-white status. The increased detection ranges from 12.8% for high grade referrals to 81% for low grade referrals and was irrespective of hrHPV genotype [
      • Macdonald M.C.
      • Brown B.H.
      • Lyon R.E.
      • Healey T.J.
      • Palmer J.E.
      • Tidy J.A.
      Influence of high risk HPV genotype on colposcopic performance: A large prospective study demonstrates improved detection of disease with ZedScan I, particularly in non-HPV 16 patients.
      ,
      • Tidy J.A.
      • Lyon R.
      • Ellis K.
      • Macdonald M.
      • Palmer J.E.
      The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.
      ,
      • Balasubramani L.
      • Brown B.H.
      • Healey J.
      • Tidy J.A.
      The detection of Cervical Intraepithelial Neoplasia by electrical impedance spectroscopy: the effects of acetic acid and tissue homogeneity.
      ]. This evaluation has confirmed the use of ZedScan increased detection of HG-CIN irrespective of referral indication with the largest increase seen in women referred with a low prevalence of HG-CIN (57.9%, p > 0.0001). The increase in detection following high grade referral was less (7.5%) but still significant (p > 0.0001). A single colposcopy clinic, Sheffield, examined just over 51% of the study population so to assess for potential bias the data was analysed excluding the Sheffield centre. This analysis showed the increase in detection to be even larger (60% low grade referrals and 11.1% high grade, both p > 0.0001) [Table 1]. The routine use of ZedScan provides clinically relevant improvements across multiple users in multiple European healthcare settings confirming previous findings.
      The sensitivity of colposcopy when measured using colposcopic impression is reported to be 68.5% (95% CI 59.9–77.1%) [
      • Brown B.H.
      • Tidy J.A.
      The diagnostic accuracy of colposcopy – A review of research methodology and impact on the outcomes of quality assurance.
      ]. The sensitivity of colposcopy in this evaluation of real world data was between 68.9 and 74.1%. However, there is a significant improvement in sensitivity to 91.6% (p > 0.0001) when colposcopy is combined with ZedScan. [Table 3] The sensitivity of colposcopy is reported to be increased when multiple biopsies are taken [
      • Roensbo M.T.
      • Hammer A.
      • Blaakær
      Can dynamic spectral imaging system colposcopy replace conventional colposcopy in the detection of high-grade cervical lesions?.
      ,
      • Pretorius R.G.
      • Belinson J.L.
      • Burchette R.J.
      • Hu S.
      • Zhang X.
      • Qiao Y.L.
      Regardless of skill, performing more biopsies increases the sensitivity of colposcopy.
      ]. While this increases the detection of HG-CIN it comes with the consequences of increased cost and time in pathology laboratories and unnecessary morbidity [

      The TOMBOLA (Study Of Management of Borderline and Other Low-grade Abnormal smears) Group. After-effects reported by women following colposcopy, cervical biopsies and LLETZ: results from the TOMBOLA study. BJOG. 2009;116(11): 1506 - 1514.

      ].
      There are currently no data to suggest an appropriate PPV for a biopsy to detect HG-CIN. Colposcopists may take biopsies to exclude HG-CIN, to confirm low grade CIN or normality. Two recent clinical studies have considered this. TOMBOLA examined women referred with low grade cytology, permitting up to 4 biopsies to be taken, and reported a PPV for HG-CIN of 26% at both study entry and exit [

      TOMBOLA Group. Cytological surveillance compared with immediate referral for colposcopy in management of women with low grade cervical abnormalities: multicentre randomised controlled trial. BMJ.2009 Jul 28;339:b2546.10.1136/bmj.b2546.

      ,
      • Cruickshank M.E.
      • Cotton S.C.
      • Sharp L.
      • Smart L.
      • Walker L.G.
      • Little J.
      on behalf of the TOMBOLA Group, Management of women with low grade cytology: how reassuring is a normal colposcopy examination?.
      ]. Wentzensen et al reported a study of 690 women who underwent colposcopy and up to four biopsies [
      • Wentzensen N.
      • Walker J.L.
      • Gold M.A.
      • Smith K.M.
      • Zuna R.E.
      • Mathews C.
      • et al.
      Multiple biopsies and detection of cervical cancer precursors at colposcopy.
      ]. The PPV for high grade CI was 63.2% falling to 28.8% for non-high grade CIN when all biopsies were included but was much lower when only one biopsy was considered (39% for high grade CI to 16.3% for non-high grade). Both referral cytology and HPV genotype had a major influence on the PPV. The IMPROVE-COLP study of 3602 women who underwent colposcopy as part of routine care across the USA [
      • Huh W.K.
      • Papagiannakis E.
      • Gold M.A.
      Observed colposcopy practice in US community-based clinic: The retrospective control arm of the IMPROVE-COLPO study.
      ] reported that high grade cytology had a higher PPV when compared to low grade, 36.1% vs 8.5%. CI also varied according to referral cytology; for women with both high grade cytology and CI the PPV was 77.4% compared with 35.6% for low grade CI. For low grade cytology and high grade CI PPV was 50.0% and 7.7% for low grade CI. The authors concluded that CI was poor in predicting HG-CIN. This may be explained by the finding of 22% of biopsy proven HG-CIN is associated with normal colposcopy [
      • Jespersen M.M.
      • Booth B.B.
      Petersen LK Can biopsies be omitted after normal colposcopy in women referred with low-grade cervical cytology? A prospective cohort study.
      ]. The English Cervical Screening programme reports the PPV for HG-CIN is dependent on the prevalence of HG-CIN, with 76.2–88.5% for high grade cytology and 9.5–26.0% for low grade [

      Cervical Screening Programme, England 2019-20. 26 November 2020. https://digital.nhs.uk/data-and-information/publications/statistical/cervical-screening-annual/england---2019-20. Last accessed 20 January 2022.

      ]. A systematic review and meta-analysis of the accuracy of colposcopically directed biopsies found 91.3% sensitivity for HG-CIN, when comparing punch biopsies with final histology after excisional treatment, but in the studies of low grade CI sensitivity dropped to 50.0% – 87.1% [
      • Underwood M.
      • Arbyn M.
      • Parry-Smith W.
      • De Bellis-Ayres S.
      • Todd R.
      • Redman C.W.E.
      • et al.
      Accuracy of colposcopically-directed punch biopsies: a systematic review and meta-analysis.
      ]. The outcome of colposcopic examination is therefore dependent on the prevalence of disease in the referral population. This evaluation and other publications confirm these findings and demonstrate the impact of women referred with persistent HPV infection but negative cytology [
      • Tidy J.A.
      • Lyon R.
      • Ellis K.
      • Macdonald M.
      • Palmer J.E.
      The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.
      ]. Importantly, the PPV for a ZedScan directed biopsy was within the published range, confirming the increased sensitivity to detect HG-CIN, when using EIS, was not the result of taking extra biopsies.
      Treatment at first visit (S&T) can be helpful in the management of HG-CIN. A study addressing the health psychology of women referred to colposcopy found treatment at first visit was congruent with their personal belief’s as to how best to treat the problem [
      • Balasubramani L.
      • Orbell S.
      • Haggar M.
      • Brown V.
      • Tidy J.
      Do women with high grade CIN prefer a See and Treat option in colposcopy?.
      ]. It is also of help for women who have a history of poor attendance at colposcopy and has the potential to improve clinic capacity by reducing the number of return visits [

      The TOMBOLA (Study Of Management of Borderline and Other Low-grade Abnormal smears) Group. After-effects reported by women following colposcopy, cervical biopsies and LLETZ: results from the TOMBOLA study. BJOG. 2009;116(11): 1506 - 1514.

      ]. A downside is the concern for over treatment especially in young women who have not completed their family with the potential risk of premature delivery [
      • Kyrgiou M.
      • Koliopoulos G.
      • Martin-Hirsch P.
      • Arbyn M.
      • Prendiville W.
      • Paraskevaidis E.
      Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis.
      ,
      • Castanon A.
      • Landy R.
      • Brocklehurst P.
      • Evans H.
      • Peebles D.
      • Singh N.
      • et al.
      PaCT Study Group. Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study.
      ]. To minimise over treatment the English cervical screening programme requires there to be evidence of HG-CIN in over 90% of excised tissue at S&T [

      Cervical screening: programme and colposcopy management. NHSCSP No20. 20 September 2021. www.gov.uk/government/publications/cervical-screening-programme-and-colposcopy-management. Last accessed 20 January 2022.

      ]. However, this programme reported only 72.5% of samples contained HG-CIN [

      Cervical Screening Programme, England 2019-20. 26 November 2020. https://digital.nhs.uk/data-and-information/publications/statistical/cervical-screening-annual/england---2019-20. Last accessed 20 January 2022.

      ]. ZedScan, can be utilised, by applying a higher probability threshold can identify women who might be suitable for S&T. In women referred with high grade cytology, where ZedScan suggested S&T, 95.2% of excised tissue confirmed HG-CIN. [Table 4].

      Weaknesses and strengths

      Colposcopic examinations did not follow a unified approach but were undertaken according to regional and national guidelines. There was no review of the colposcopic imaging, if taken, or histology and may allow variation of practice to potentially bias the results. This evaluation reflects outcomes from routine practice in colposcopy and was performed across multiple European countries, different screening programmes and multiple colposcopists. The data was consistent even when the single largest centre was excluded from the analysis.

      Conclusions

      Colposcopy is fundamental to evaluating an abnormal cervical screening result and these are the groups forming an increasing proportion of the colposcopy population. Routine use of ZedScan increases the sensitivity of colposcopy in all referral groups, especially in low prevalence referrals, with more HG-CIN detected at colposcopy, whilst maintaining an appropriate PPV for a ZedScan directed biopsy and treatment.

      Disclosure

      J A Tidy is the clinical founder of Zilico Ltd., who market ZedScan as an adjunct device to colposcopy.
      B H Brown is the academic founder of Zilico Ltd., who market ZedScan as an adjunct device to colposcopy.

      Source of funding

      Zilico Ltd supplied devices and sensors free of charge. Zilico Ltd supported data collection and analysis.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We would like to thank all the women and colposcopists who participated in the evaluation in the following locations Eire (Dublin), England (Birmingham, Bournemouth, Bradford, Burnley, London, Manchester, Medway, Middlesbrough, Nottingham, Norwich, Preston, Reddich, Sheffield, Stafford, Stoke, Telford, Finland (Helsinki), France (Amiens), Germany (Berlin, Hannover), Israel (Nahariyya), Netherlands (Tilburg, Utrecht), Scotland (Aberdeen) and Sweden (Stockholm). We also thank Dr P. Highfield for his support with the analysis.

      References

        • Brown B.H.
        • Tidy J.A.
        The diagnostic accuracy of colposcopy – A review of research methodology and impact on the outcomes of quality assurance.
        Eur J Obstet Gynecol Repro Biol. 2019; 240: 182-186
      1. Cervical screening: programme and colposcopy management. NHSCSP No20. 20 September 2021. www.gov.uk/government/publications/cervical-screening-programme-and-colposcopy-management. Last accessed 20 January 2022.

        • Wentzensen N.
        • Walker J.L.
        • Gold M.A.
        • Smith K.M.
        • Zuna R.E.
        • Mathews C.
        • et al.
        Multiple biopsies and detection of cervical cancer precursors at colposcopy.
        J Clin Oncol. 2015; 33: 83-89
        • Huh W.K.
        • Papagiannakis E.
        • Gold M.A.
        Observed colposcopy practice in US community-based clinic: The retrospective control arm of the IMPROVE-COLPO study.
        J Low Genit Tract Dis. 2019; 23: 110-115
        • Macdonald M.C.
        • Brown B.H.
        • Lyon R.E.
        • Healey T.J.
        • Palmer J.E.
        • Tidy J.A.
        Influence of high risk HPV genotype on colposcopic performance: A large prospective study demonstrates improved detection of disease with ZedScan I, particularly in non-HPV 16 patients.
        Eur J Obstet Gynecol Reprod Biol. 2017; 211 (Epub 2017 Feb 20): 194-198https://doi.org/10.1016/j.ejogrb.2017.02.020
        • Tidy J.A.
        • Lyon R.
        • Ellis K.
        • Macdonald M.
        • Palmer J.E.
        The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.
        BJOG. 2020; 127: 1260-1267https://doi.org/10.1111/1471-0528.16250
        • Brown B.H.
        • Tidy J.
        • Boston K.
        • Blackett A.D.
        • Smallwood R.H.
        • Sharp F.
        The relationship between tissue structure and imposed electrical current flow in cervical neoplasia.
        Lancet. 2000; 355: 892-985
        • Tidy J.A.
        • Brown B.H.
        • Lyon R.E.
        • Healey T.J.
        • Palmer J.E.
        Are colposcopy and electrical impedance spectroscopy complementary when used to detect high-grade cervical neoplasia?.
        Eur J Gynaecol Oncol. 2018; 49https://doi.org/10.12892/ejgo3882.2018
        • Tidy J.
        • Brown B.
        • Healey T.
        • Daayana S.
        • Martin M.
        • Prendiville W.
        • et al.
        Accuracy of detection of high-grade cervical intraepithelial neoplasia using electrical impedance spectroscopy with colposcopy.
        Br J Obstet Gynaecol. 2013; 120: 400-411
        • Muszynski C.
        • Dupont E.
        • Vaysse B.
        • Lanta S.
        • Tidy J.
        • Sergent F.
        • Gondry J.
        The impact of using electrical impedance spectroscopy (ZedScan) on the performance of colposcopy in diagnosing high grade squamous lesions of the cervix.
        J Gynecol Obstet Hum Reprod. 2017; https://doi.org/10.1016/j.jogoh.2017.08.007
        • Homola W.
        • Fuchs T.
        • Baranski P.
        • Zimmer A.
        • Zimmer M.
        • Pomorski M.
        Use of electrical impedance spectroscopy as an adjunct to colposcopy in a pathway of cervical intraepithelial neoplasia diagnostics.
        Ginekol Pol. 2019; 90: 628-632https://doi.org/10.5603/GP.2019.0107
        • Brotherton J.M.
        • Fridman M.
        • May C.L.
        • Chappell G.
        • Saville A.M.
        • Gertig D.M.
        Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study.
        Lancet. 2011; 377: 2085-2092https://doi.org/10.1016/S0140-6736(11)60551-5
        • Palmer T.
        • Wallace L.
        • Pollock K.G.
        • Cuschieri K.
        • Robertson C.
        • Kavanagh K.
        • et al.
        Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12–13 in Scotland: retrospective population study.
        BMJ. 2019; 3l1161https://doi.org/10.1136/bmj.l1161
        • Lukic A.
        • De Vincenzo R.
        • Ciavattini A.
        • Ricci C.
        • Senatori R.
        • Ruscito I.
        • et al.
        Are We Facing a New Colposcopic Practice in the HPV Vaccination Era? Opportunities, Challenges, and New Perspectives.
        Vaccines. 2021; 9: 1081https://doi.org/10.3390/vaccines9101081
      2. 9 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Perkins, RB, Guido, RS, Castle PE, Chelmow D, Einstein MH, Garcia F, Huh WK, Kim JJ, Moscicki A-B, Nayar R, Saraiya M, Sawaya GF, Wentzensen N, Schiffman M, for the 9 ASCCP Risk-Based Management Consensus Guidelines Committee. Journal of Lower Genital Tract Disease: April 2020 - Volume 24 - Issue 2 - p 102-131.

      3. 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. 22 November 2021. https://wiki.cancer.org.au/australiawiki/index.php?title=Guidelines:Cervical_cancer/Screening&action=history. Last accessed 20 January 2022.

        • Kelly R.S.
        • Patnick J.
        • Kitchener H.C.
        • Moss S.M.
        HPV testing as a triage for borderline or mild dyskaryosis on cervical cytology: results from the Sentinel Sites study.
        Br J Cancer. 2011; 105: 983-988
        • Jeronimo J.
        • Schiffman M.
        Colposcopy at a crossroads.
        Am J Obstet Gynecol. 2006; 195: 349-353
        • Louwers J.A.
        • Zaal A.
        • Kochen M.
        • ter Harmsel W.A.
        • Graziosi G.M.C.
        • Spruijt J.W.M.
        • et al.
        Dynamic spectral imaging colposcopy: higher sensitivity for the detection of premalignant cervical lesions.
        BJOG. 2011; 118: 309-318
        • Roensbo M.T.
        • Hammer A.
        • Blaakær
        Can dynamic spectral imaging system colposcopy replace conventional colposcopy in the detection of high-grade cervical lesions?.
        ACTA Obstet Gynecol Scand. 2015; 94: 781-785
        • Balasubramani L.
        • Brown B.H.
        • Healey J.
        • Tidy J.A.
        The detection of Cervical Intraepithelial Neoplasia by electrical impedance spectroscopy: the effects of acetic acid and tissue homogeneity.
        Gynecol Oncol. 2009; 115: 267-271
        • Pretorius R.G.
        • Belinson J.L.
        • Burchette R.J.
        • Hu S.
        • Zhang X.
        • Qiao Y.L.
        Regardless of skill, performing more biopsies increases the sensitivity of colposcopy.
        J Low Genit Tract Dis. 2011; 15: 180-188
      4. The TOMBOLA (Study Of Management of Borderline and Other Low-grade Abnormal smears) Group. After-effects reported by women following colposcopy, cervical biopsies and LLETZ: results from the TOMBOLA study. BJOG. 2009;116(11): 1506 - 1514.

      5. TOMBOLA Group. Cytological surveillance compared with immediate referral for colposcopy in management of women with low grade cervical abnormalities: multicentre randomised controlled trial. BMJ.2009 Jul 28;339:b2546.10.1136/bmj.b2546.

        • Cruickshank M.E.
        • Cotton S.C.
        • Sharp L.
        • Smart L.
        • Walker L.G.
        • Little J.
        on behalf of the TOMBOLA Group, Management of women with low grade cytology: how reassuring is a normal colposcopy examination?.
        BJOG. 2015; 122: 380-386
        • Jespersen M.M.
        • Booth B.B.
        Petersen LK Can biopsies be omitted after normal colposcopy in women referred with low-grade cervical cytology? A prospective cohort study.
        BMC Womens Health. 2021; 21: 394https://doi.org/10.1186/s12905-021-01537-5
      6. Cervical Screening Programme, England 2019-20. 26 November 2020. https://digital.nhs.uk/data-and-information/publications/statistical/cervical-screening-annual/england---2019-20. Last accessed 20 January 2022.

        • Underwood M.
        • Arbyn M.
        • Parry-Smith W.
        • De Bellis-Ayres S.
        • Todd R.
        • Redman C.W.E.
        • et al.
        Accuracy of colposcopically-directed punch biopsies: a systematic review and meta-analysis.
        BJOG. 2012; 119: 1293-1301
        • Balasubramani L.
        • Orbell S.
        • Haggar M.
        • Brown V.
        • Tidy J.
        Do women with high grade CIN prefer a See and Treat option in colposcopy?.
        Br J Obstet Gynaecol. 2007; 114: 39-45
        • Kyrgiou M.
        • Koliopoulos G.
        • Martin-Hirsch P.
        • Arbyn M.
        • Prendiville W.
        • Paraskevaidis E.
        Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis.
        Lancet. 2006; 367: 489-498
        • Castanon A.
        • Landy R.
        • Brocklehurst P.
        • Evans H.
        • Peebles D.
        • Singh N.
        • et al.
        PaCT Study Group. Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study.
        BMJ. 2014; 349: g6223-g