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

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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