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Pathology Issues in Bowel Screening
Frank Carey
SPAN
Lead-time Bias
Time
TumourGrowth
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
Disease-Specific Mortality in gFOBT Randomised Trials
(Relative Risks)
• Minnesota– Annual 0.67 (CI 0.51-0.83)– Biennial 0.79 (CI 0.62 - 0.97)
• Nottingham– Biennial 0.85 (CI 0.74 - 0.98)
• Funen– Biennial 0.82 (CI 0.68 - 0.99)
• Göteborg– Biennial 0.84 (CI 0.71-0.99)
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.
Scottish Pilot 2000-07
• Fife, Grampian, Tayside
• FOB kits posted out and returned to Dundee
• +ve tests lead to colonoscopy performed locally
0
1
2
3
4
5
CR
C m
orta
lity/
100
0 pe
rson
s
0 1 2 3 4 5 6 7 8 9 10Years since screening/matched date
Invited for screening Controls
Rate and 95% CI (Nelson-Aalen estimates)Cumulative Mortality from Colorectal Cancer
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%
Single Centre
Investigation and treatment devolvedto health boards (n=14)
Age range 50 - 74
Organisation of the bowel cancer screening programme - Scotland
Uptake- Gender and Deprivation
%
SIMD
Pathology
• Make a diagnosis• Plan treatment and
follow up• Collect accurate data• Audit of service
development• Facilitate high quality
research
Quality Measures in Bowel Screening
• Key Performance Indicators (KPI)– High level overview of programme
performance
• Endoscopy (“JAG” accreditation)
• Pathology
Key Performance Indicators (KPIs)
1. Uptake– overall– by deprivation category– response rate to first invitation– response rate to reminders
2. Time to colonoscopy3. Proportion of +ves undergoing colonoscopy4. Colonoscopy completion rate5. Colonoscopy complication rate
– admissions– perforations– bleeding– deaths
6. Positivity rate7. Cancer Detection Rate8. 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
KPI 4 Positive screening test result rate, by NHS Board
0
1
2
3
4
Argyll andClyde
Ayrshireand Arran
Borders Dumfriesand
Galloway
Fife ForthValley
Grampian GreaterGlasgow
Highland Lanarkshire Lothian Orkney Shetland Tayside WesternIsles
Scotland*
%
males females
Ayrshire and Arran
Fife
Forth Valley
Lothian
Orkney Tayside
Western Isles
Dumfries and Galloway
Greater Glasgow
Lanarkshire
Argyll and Clyde
Grampian
0
1
2
3
4
0 20000 40000 60000 80000 100000 120000
Completed kits with final results
%
95% Confidence Intervals Scotland
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
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
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
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
Case E8
Case E8
• Result
Other Low Grade Dysplasia
High Grade Dysplasia
Carcinoma
Leads 13
Participants 12 288
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.
Slide referral
• Recognised difficulty in distinguishing epithelial misplacement from invasive cancer in adenomatous polyps
Case D9
Case D9
• Result
Other Low Grade Dysplasia
High Grade Dysplasia
Carcinoma
Leads 11
Participants 11 238 2
Referral Panel
• Dr M Balsitis
• Prof F Carey
• Dr P Fineron
• Prof G Murray
• (Dr A Lessels)
Referral review
• Started April 2009. 240 cases received by March 2012
• Participation not even across Boards.
• 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.
Can anyone diagnose these things?
Case F7
Case F7
• Result
Other Low Grade Dysplasia
High Grade Dysplasia
Carcinoma
Leads 1 3 7
Participants 4 64 227
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
Issues in adenomas
Recognising adenomas
Categorising adenomas
Serrated lesions
Tubular adenoma
Villous adenoma
Severe dysplasia
Risk of Advanced Neoplasia atRisk of Advanced Neoplasia at5.5 yrs in a Colonoscopic Series5.5 yrs in a Colonoscopic Series
Finding at first exam Patients Ad Neo RR
No neoplasia 298 7 1
Tubular Adenoma <10mm 622 38 2.56
1-2 496 23 1.92
3+ 126 15 5.01
Tubular Adenoma >10mm 123 19 6.40
Villous Adenoma 81 13 6.05
High Grade Dysplasia 46 8 6.87
Carcinoma 23 8 13.56
Lieberman et al 2007
Grading Dysplasia in 2189 Grading Dysplasia in 2189 Adenomas at 13 CentresAdenomas at 13 Centres
min max median
mild 29% 88% 42%
moderate 10% 67% 43%
severe 1% 24% 4%
Histology of 2206 Adenomas at 13 Histology of 2206 Adenomas at 13 CentresCentres
min max median
tubular 62% 93% 84%
tubulovillous 6% 37% 15%
villous 0% 6% 1%
Tubulovillous AdenomasTubulovillous Adenomas
The 20% Rule(for intact excised lesions):
The minor component comprises at least
20% of the lesion.
““AdvancedAdvanced”” Adenoma Patients Adenoma Patients
– > 1 cm (measured for smaller lesions on
microscope slide)
– multiple polyps
– villous component*
– severe dysplasia*
*in selected series only
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 2002 296, 541-545
The Imaging Gap100 μm 1mm 1cm 10 cm10 μm
CONFOCAL MICROSCOPY MRI/CT
OPTOPT
CELLS TISSUES ORGANISMS
EMBRYOSORGANS
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 2002 296, 541-545
How does OPT work
Two Imaging Modes:
1. Transmission i.e.Brightfield
2. Emission i.e.Fluorescent
How does OPT work
Two Imaging Modes:
1. Transmission i.e.Brightfield
2. Emission i.e.Fluorescent
OPT Uses• Very little work done on human tissue• Lymph Nodes
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 techniquesCurrent Gold Standard: Haematoxylin & Eosin (H&E) stained sections
PROJECT DESIGN
IMAGE PROJECTION
Raw ImageB&W Cross Section
3D B&W
3D MIP
3D Merged MIP
IMAGE PROJECTION9
.6m
m
Sagittal(X axis)
Coronal(Y axis)
Trans Axial(Z axis)
• Virtual 2D sections through three orthogonal planes
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 featuresDYSPLASIA 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
.
LGD
Discrete ArchitectureClearTubulesOrganised
HGD
CrowdedMore DenseArchitecture not clear
OTHER FEATURES: Misplacement
EPM
Epithelial Misplacement (EPM)
Invasive Cancer
Very DenseHomogenousDifficult to distinguish boundaries
TUBULAR ADENOMA
Pits
Uniform Pattern
Organised
TUBULOVILLOUS ADENOMA
Elongated Crypts
Few Pits
Projections
VILLOUSNESS
SPECTRUM OF CHANGESPECTRUM OF CHANGETubular Villous
TUBULOVILLOUS VILLOUSTUBULAR
0% 20% 80% 100%
OTHER FEATURES: VESSELS
OTHER FEATURES: ULCERATION
• What the pathologist can’t see
• 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
Next Steps
• Series of images analysed blindly by 5 consultant pathologists
• Compare interobserver variation with assessment of H&E sections from the same polyps
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