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Pathology Issues in Bowel Screening Frank Carey SPAN.

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Presentation on theme: "Pathology Issues in Bowel Screening Frank Carey SPAN."— Presentation transcript:

1 Pathology Issues in Bowel Screening Frank Carey SPAN

2 Lead-time Bias Time Tumour Growth

3 Proving Screening Works Population-based randomised trials in which the whole group offered screening (including refusers and interval cancers) is compared with the control group


5 Disease-Specific Mortality in gFOBT Randomised Trials (Relative Risks) Minnesota –Annual0.67 (CI ) –Biennial0.79 (CI ) Nottingham –Biennial0.85 (CI ) Funen –Biennial0.82 (CI ) Göteborg –Biennial0.84 (CI )

6 A Scottish Tradition….. Robert Burns Death and Dr Hornbrook (1785) "Ev'n them he canna get attended, Altho' their face he ne'er had kent it, Just shite in a kail- blade, an' sent it, As soon's he smells 't, Baith their disease, and what will mend it, At once he tells 't.

7 Scottish Pilot Fife, Grampian, Tayside FOB kits posted out and returned to Dundee +ve tests lead to colonoscopy performed locally


9 Rate ratio of Colorectal Cancer invited vs controls Overall 0.90 (0.830 – 0.989) Relative reduction in CRC mortality 10% Participants only 0.73 (0.653 – 0.824) Relative reduction in CRC mortality 27%

10 Single Centre Investigation and treatment devolved to health boards (n=14) Age range Organisation of the bowel cancer screening programme - Scotland

11 Uptake - Gender and Deprivation % SIMD

12 Pathology Make a diagnosis Plan treatment and follow up Collect accurate data Audit of service development Facilitate high quality research

13 Quality Measures in Bowel Screening Key Performance Indicators (KPI) –High level overview of programme performance Endoscopy (JAG accreditation) Pathology

14 Key Performance Indicators (KPIs) 1.Uptake –overall –by deprivation category –response rate to first invitation –response rate to reminders 2.Time to colonoscopy 3.Proportion of +ves undergoing colonoscopy 4.Colonoscopy completion rate 5.Colonoscopy complication rate –admissions –perforations –bleeding –deaths 6.Positivity rate 7.Cancer Detection Rate 8.Stage at diagnosis (incl. polyp cancers) 9.Adenoma detection rate –overall –high risk 10.PPV –for cancer –for adenoma –for high risk adenoma –for any neoplasia

15 KPI 4 Positive screening test result rate, by NHS Board

16 Pathology QA Adherence to RCPath standards in reporting of colorectal cancers Participation in web-based EQA Central referral of cases suspected/diagnosed as polypoid cancer (T1Nx) Close links with other UK jurisdictions

17 EQA An essential part of quality assurance for the programme All UK countries participate (+ Irish Republic, Slovenia) Our first experience of electronic (web based) EQA Administered by Dr Nic Mapstone, hosted by University of Leeds

18 EQA Slides accessed online 4 possible answers for each slide –Low grade dysplasia –High grade dysplasia –Adenocarcinoma –Other It is possible to enter a comment

19 EQA A case is valid only if the diagnosis is agreed by 80% of the regional lead pathologists Scores per case: –2 points for same diagnosis as consensus –1 point for one category removed (e.g. high grade dysplasia/carcinoma) –0 points otherwise

20 Case E8


22 Result OtherLow Grade Dysplasia High Grade Dysplasia Carcinoma Leads 13 Participants 12288

23 Scottish participation in EQA 43 registered Limited data on actual participation (July 2012 review of circulations G,H) –1/3 participated in both –1/3 in one of the two circulations –1/3 in neither Updated data awaited.

24 Slide referral Recognised difficulty in distinguishing epithelial misplacement from invasive cancer in adenomatous polyps

25 Case D9

26 Result OtherLow Grade Dysplasia High Grade Dysplasia Carcinoma Leads 11 Participants

27 Referral Panel Dr M Balsitis Prof F Carey Dr P Fineron Prof G Murray (Dr A Lessels)

28 Referral review Started April cases received by March 2012 Participation not even across Boards.

29 30 cases (12.5% of total) submitted with a favoured diagnosis of cancer were assessed as benign by the panel 10 cases (4.2%) submitted as probably benign were upgraded to cancer There was disagreement among panel members as to the final diagnosis in 22 cases (9.2%). All cases were seen in the first instance by 2 pathologists. In the cases where discrepant diagnoses were made a third panel member was involved and the majority diagnosis was registered as final. 4 cases (1.6%) were referred to the English/Welsh Expert Panel. These were difficult, complex cases. 3 were finally diagnosed as benign and one as cancer.

30 Can anyone diagnose these things?

31 Case F7


33 Result OtherLow Grade Dysplasia High Grade Dysplasia Carcinoma Leads 137 Participants

34 Adenomas in Screening Adenomas much more common than cancers Adenomas are the precursors of most cancers Adenomas (even when removed) are a marker of cancer risk The programme is almost as much about adenomas as cancer

35 Issues in adenomas Recognising adenomas Categorising adenomas Serrated lesions

36 Tubular adenoma

37 Villous adenoma

38 Severe dysplasia


40 Risk of Advanced Neoplasia at 5.5 yrs in a Colonoscopic Series Finding at first exam PatientsAd NeoRR No neoplasia29871 Tubular Adenoma <10mm Tubular Adenoma >10mm Villous Adenoma High Grade Dysplasia Carcinoma Lieberman et al 2007

41 Grading Dysplasia in 2189 Adenomas at 13 Centres minmaxmedian mild 29%88%42% moderate 10%67%43% severe 1%24%4%

42 Histology of 2206 Adenomas at 13 Centres minmaxmedian tubular 62%93%84% tubulovillous 6%37%15% villous 0%6%1%

43 Tubulovillous Adenomas The 20% Rule (for intact excised lesions): The minor component comprises at least 20% of the lesion.

44 Advanced Adenoma PatientsAdvanced Adenoma Patients –> 1 cm (measured for smaller lesions on microscope slide) –multiple polyps –villous component* –severe dysplasia* * in selected series only


46 OPTICAL PROJECTION TOMOGRAPHY Original prototype was invented by James Sharpe whilst at MRC Human Genetics in Whole mount, in vitro, imaging technology for small biological specimens (1-15mm) Optical equivalent of an X-ray CT scanner Generates 3D images and 2D virtual sections through three orthogonal planes Visualises unstained tissue as well as fluorescent labels (emission mode) and coloured stains (transmission mode). Ideal for analysis of gene and protein expression. 1 Sharpe et al ,


48 FEATURES OF OPT Produces 3D images & virtual sections in 3 orthogonal planes Wholemount technology Non-destructive – analysis post OPT possible (e.g. IHC) Visualise unstained anatomy with autofluorescence* Visualise fluorescent labels & coloured stains Investigate gene & protein expression in context of 3D anatomy Produces quantifiable and digital data – archive Digital images to scroll through, send for opinions or as teaching tools *Unstained sections used for the purposes of this study. 1 Sharpe et al ,

49 How does OPT work Two Imaging Modes: 1.Transmission i.e.Brightfield 2.Emission i.e.Fluorescent

50 How does OPT work Two Imaging Modes: 1.Transmission i.e.Brightfield 2.Emission i.e.Fluorescent

51 OPT Uses Very little work done on human tissue Lymph Nodes

52 TO IDENTIFY IF OPT HAS DIAGNOSTIC PROPERTIES IN EARLY COLORECTAL CANCER Using paraffin blocks of existing screen-detected polyps TO IDENTIFY IF OPT HAS DIAGNOSTIC PROPERTIES IN EARLY COLORECTAL CANCER Using paraffin blocks of existing screen-detected polyps OBJECTIVE Compare OPT generated images with traditional techniques Current Gold Standard: Haematoxylin & Eosin (H&E) stained sections

53 PROJECT DESIGN Training optimise technique Archived polyps PHASE ONE Blinded Archived polyps PHASE TWO Clinical Integration Whole Polyps PHASE THREE

54 IMAGE PROJECTION Raw Image B&W Cross Section 3D B&W 3D MIP 3D Merged MIP

55 IMAGE PROJECTION 9.6mm Sagittal (X axis) Coronal (Y axis) Trans Axial (Z axis) Virtual 2D sections through three orthogonal planes

56 IMAGE ANALYSIS & DIAGNOSTIC CRITERIA In accordance with the NHS bowel cancer screening diagnostic guidelines: Dysplasia diagnosis Villous morphology –The polyp must have >20% or >80% villous component to classify it as tubulovillous or villous respectively and those <20% villousness are tubular (WHO Classification) Other Anatomical features DYSPLASIAMORPHOLOGYOTHER FEATURES Low Grade Dysplasia (LGD)Tubular Adenoma (TA)Vasculature High Grade Dysplasia (HGD)Tubulovillous Adenoma (TVA)Epithelial Displacement (EPD) Invasive Cancer (ICA)Villous Adenoma (VA)Ulceration/Mucous.

57 LGD Discrete Architecture Clear Tubules Organised

58 HGD Crowded More Dense Architecture not clear

59 OTHER FEATURES: Misplacement EPM Epithelial Misplacement (EPM)

60 Invasive Cancer Very Dense Homogenous Difficult to distinguish boundaries

61 TUBULAR ADENOMA Pits Uniform Pattern Organised

62 TUBULOVILLOUS ADENOMA Elongated Crypts Few Pits Projections



65 OTHER FEATURES: ULCERATION What the pathologist cant see

66 An endoscopic classification method used to help identify suspicious lesions in vivo. Type I: Round pit Type II: Stellar or Asteroid pit Type IIIS: Small round or tubular pit (smaller than I) Type IIIL: Large round or tubular pit (larger than I) Type IV: Dendritic or gyrus-like pit Type V: Amorphous or non-structured pit PIT PATTERN CLASSIFICATION

67 Next Steps Series of images analysed blindly by 5 consultant pathologists Compare interobserver variation with assessment of H&E sections from the same polyps

68 ACKNOWLEDGEMENTS Medical Research Council Technology, Edinburgh S Wedden; G Cranston; J Farrell; L Mitchell University of Dundee R Steele (Dept of Clinical & Population Science & Education) NHS Tayside and Tayside Tissue Bank F Carey; J Wilson University of Cambridge R Keogh Centre for Genomic Regulation, Barcelona J Sharpe

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