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Pathology Issues in Bowel Screening

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Presentation on theme: "Pathology Issues in Bowel Screening"— Presentation transcript:

1 Pathology Issues in Bowel Screening
Frank Carey SPAN

2 Lead-time Bias Tumour Growth Time

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

4

5 Disease-Specific Mortality in gFOBT Randomised Trials (Relative Risks)
Minnesota Annual 0.67 (CI ) Biennial 0.79 (CI ) Nottingham Biennial 0.85 (CI ) Funen Biennial 0.82 (CI ) Göteborg Biennial 0.84 (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 2000-07 Fife, Grampian, Tayside
FOB kits posted out and returned to Dundee +ve tests lead to colonoscopy performed locally

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

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)
Uptake overall by deprivation category response rate to first invitation response rate to reminders Time to colonoscopy Proportion of +ves undergoing colonoscopy Colonoscopy completion rate Colonoscopy complication rate admissions perforations bleeding deaths Positivity rate Cancer Detection Rate Stage at diagnosis (incl. polyp cancers) Adenoma detection rate high risk PPV for cancer for adenoma for high risk adenoma for any neoplasia 14

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

16 Close links with other UK jurisdictions
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 http://www.gieqa.org.uk/
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

21

22 Case E8 Result 13 12 288 Other Low Grade Dysplasia
High Grade Dysplasia Carcinoma Leads 13 Participants 12 288

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 Case D9 Result 11 238 2 Other Low Grade Dysplasia High Grade Dysplasia
Carcinoma Leads 11 Participants 238 2

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

28 Referral review Started April 2009. 240 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 31

32

33 Case F7 Result 1 3 7 4 64 227 Other Low Grade Dysplasia
High Grade Dysplasia Carcinoma Leads 1 3 7 Participants 4 64 227

34 The programme is almost as much about adenomas as cancer
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 It is widely accepted that mutations of specific genes such as APC/K-ras and /or p53 are of fundamental importance in colorectal tumorigenesis. The reported frequencies of these mutations vary but in cancers APC and K-ras occur in approx half the tumours and p53 mutation or overexpression has been reported in up to 3/4 of cases. Reports of APC and K-ras mutations in adenomas are similar to those in cancers but the notable exception is p53 which has been reported in as few as 4% of cases. This observation has led to the belief that p53 mutation is a late event in the ACS 34

35 Recognising adenomas Categorising adenomas Serrated lesions
Issues in adenomas Recognising adenomas Categorising adenomas Serrated lesions 35

36 Tubular adenoma

37 Villous adenoma

38 Severe dysplasia

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40 Risk of Advanced Neoplasia at 5.5 yrs in a Colonoscopic Series
Finding at first exam Patients Ad Neo RR No neoplasia Tubular Adenoma <10mm Tubular Adenoma >10mm Villous Adenoma High Grade Dysplasia Carcinoma Lieberman et al 2007 40

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

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

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

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

45 45

46 OPTICAL PROJECTION TOMOGRAPHY
Original prototype was invented by James Sharpe whilst at MRC Human Genetics in 20021 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. 1Sharpe et al ,

47 The Imaging Gap CONFOCAL MICROSCOPY MRI/CT OPT ORGANS EMBRYOS
1mm 1cm 10 cm OPT CONFOCAL MICROSCOPY MRI/CT ORGANS EMBRYOS ORGANISMS CELLS TISSUES

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. 1Sharpe et al ,

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

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

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

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

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

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

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

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 DYSPLASIA MORPHOLOGY OTHER 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

63 VILLOUSNESS SPECTRUM OF CHANGE 0% 20% 80% 100% TUBULAR TUBULOVILLOUS

64 OTHER FEATURES: VESSELS

65 OTHER FEATURES: ULCERATION
What the pathologist can’t see

66 PIT PATTERN CLASSIFICATION
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

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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