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Results of the HTA Adequacy Study

This study aims to determine the minimum cellularity required for reliable assessment of Liquid Based Cervical (LBC) cytology samples. It includes a survey of current practice, evaluation of cytotechnologists' ability to detect abnormalities, and analysis of cellularity thresholds for detecting abnormal cells.

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Results of the HTA Adequacy Study

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  1. Results of the HTA Adequacy Study BAC Scientific Meeting 2013 JHF Smith Royal Hallamshire Hospital, Sheffield

  2. Previous publications on cervical LBC adequacy (1) • Most cases with HSIL have more than one abnormal cell among 4000 normal cells. Geyer 2000 • The Bethesda system requires a minimum of 5,000 well preserved and well visualised squamous cells for a liquid based preparation to be deemed ‘satisfactory’. Bethesda 2001

  3. Previous publications on cervical LBC adequacy (2) • One study reported a higher detection rate of high grade lesions when cellularity of SurePath [SP] LBC preparations exceeded 20,000 cells. Bolick 2002 • SP preparations with < 10000 cells should be designated less than adequate. Bishop 2002 • Clear demarcation in sensitivity between SP specimens with < 5000 and > 5000 cells. Studeman 2003

  4. Previous publications on cervical LBC adequacy (3) • Minimum cellularity ThinPrep [TP] samples cannot be defined in practical terms, but value somewhere between 5000 – 10000 cells would give acceptable inadequacy rates whilst maximising detection of dyskaryosis. McQueen & Duvall 2006 • TP slides reported as unsatisfactory or SBLB shown to contain < 20000 cells. Siebers 2013

  5. LBC Adequacy in UK Most UK laboratories have adopted an interim figure of up to15,000 cells, based on manufacturers’ guidance and the LBC pilot experience

  6. Adequacy of LBC samples • An adequate liquid-based sample is defined as one that contains the minimum level of squamous epithelial cellularity necessary to ensure a squamous abnormality detection rate equivalent to that offered by conventional smears. Achievable standards, Benchmarks for Reporting, and Criteria for Evaluating Cervical Cytopathology. 3rdedn. NHSCSP 2012.

  7. A multistranded study to determine the minimum cellularity required for the reliable assessment of Liquid Based Cervical (LBC) cytology samples • Survey current practice in UK laboratories using LBC to establish the cellularity of a large cohort of inadequate, negative and abnormal slides • Evaluate the ability of cytotechnologists in a large number of laboratories to detect abnormalities of differing type and relative abundance by preparing sets of slides which vary in their total cellularity and in the total number, type and relative proportion of abnormal cells http://www.hta.ac.uk/project/1600.asp

  8. Objectives 1: Survey of Cellularity • To assess current standards and practice for the reporting of LBC preparations across England, Scotland and Wales • To determine the cellularity of samples deemed inadequate, negative or abnormal by a range of laboratories across the country. • To determine the cellularity of samples deemed negative, HPV+ in the ARTISTIC/MCM trial.

  9. Objectives 2: Ability to Detect Abnormality • To assess the impact of varying the overall cellularity; relative proportion of abnormal cells and the type and presentation of dyskaryotic cells on their likelihood of detection. • To determine the threshold of cellularity of LBC preparations which allow the majority of samples containing abnormal cells to be detected by routine screening.

  10. Survey of Cellularity Slide Survey • 56 (28 TP & 28 SP) laboratories submitted 20 consecutive inadequate, low grade and high grade dyskaryosis plus 50 consecutive negative LBC cases. • Slides relabelled with an anonymised code, placed in transport boxes in a pre-determined randomised order, so boxes contained a mixture of different diagnostic groupings from different originating laboratories. • Boxes were sent in sets of 5 to each of the participating laboratories via courier.

  11. Survey of Cellularity Cell Counting • Nominated primary screening staff • All slides assessed for presence of TZ indicators and had a formal cell count by protocols agreed with the manufacturers • Similar proportions of slides from each laboratory and of each cytological type sent to each laboratory

  12. AA – 4 - 15 AA – 4 - 15 Cell Count HTA LBC Adequacy Study MM – 3 - 15 Cell Count HTA LBC Adequacy Study ThinPrep SurePath Total cell count = mean cell count of 10 counts x area of cell deposit x area of ocular Adjacent SP counts starting at edge of cell deposit Alternate TP counts starting at edge of cell deposit, weighted to allow for cell distribution

  13. Summary Statistics for each field (Thinprep)

  14. Summary Statistics for each field (Surepath)

  15. Weighted v Unweighted Specimen Cellularity (TP & SP)

  16. Weighted vs Un-weighted Specimen Cellularity split by Slide Diagnosis (TP)

  17. Weighted vs Un-weighted Specimen Cellularity split by Slide Diagnosis (SP)

  18. Relative Frequency Histograms of Specimen Cellularity Score (TP & SP)

  19. Relative Frequency Histograms split by Slide Diagnosis (TP)

  20. Relative Frequency Histograms split by Slide Diagnosis (SP)

  21. Ability to Detect Abnormality 180 Routine TP & SP samples LSIL & HSIL Scanty, numerous, pale & HCCG 50% 50% Serial dilutions 5-10K, 10-15K, 15-20K, 20-25K, 25-30K, 35-45K, 45-55K, 55K+ Mixed dilution with known negative cases <25, 25-49, 50-99, 100-149, 150-199, 200-399, 400-799, 800-1600, 1600+

  22. Slide evaluation • Total cell count and total abnormal cell count determined for each slide by two members of a four member expert cytology group • HSIL or LSIL observed in all but one SP and all but two TP slides • Slides randomised into batches of 308 (88 serial dilution, 88 mixed dilution, 66 negative, 66 inadequate) • Each batch circulated to 3 of 24 laboratories using either SP or TP giving three independent assessments for each slide

  23. Percentage of assessments in each cytological category by cellularity and LBC system

  24. Percentage of assessments in each cytological category by cellularity and LBC system OR=0.56 95% CI 0.34,0.94, p=0.019 OR=0.51 95% CI 0.30,0.88, p=0.016 p<0.001 p<0.001 p<0.017 p<0.195

  25. Conclusions • Low cellularityreduces the likelihood that dyskaryotic cells will be detected by about 7% in both the SP and TP LBC systems. • The Bethesda system requirement for a minimum of 5000 cells is appropriate only for the ThinPrep system. • A minimum cellularity of 15,000 cells is appropriate for the SP system.

  26. Acknowledgement This study was funded by the National Institute for Health Research Health Technology Assessment Programme. http://www.hta.ac.uk/project/1600.asp

  27. Acknowledgement G Cook MS Desai M Gittins HC Kitchener C Roberts P Sasieni LS Turnbull

  28. Any Questions ?

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