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
12 Pathology Make a diagnosis Plan treatment and follow up Collect accurate dataAudit of service developmentFacilitate high quality research
13 Quality Measures in Bowel Screening Key Performance Indicators (KPI)High level overview of programme performanceEndoscopy (“JAG” accreditation)Pathology
14 Key Performance Indicators (KPIs) Uptakeoverallby deprivation categoryresponse rate to first invitationresponse rate to remindersTime to colonoscopyProportion of +ves undergoing colonoscopyColonoscopy completion rateColonoscopy complication rateadmissionsperforationsbleedingdeathsPositivity rateCancer Detection RateStage at diagnosis (incl. polyp cancers)Adenoma detection ratehigh riskPPVfor cancerfor adenomafor high risk adenomafor any neoplasia14
15 KPI 4 Positive screening test result rate, by NHS Board
16 Close links with other UK jurisdictions Pathology QAAdherence to RCPath standards in reporting of colorectal cancersParticipation in web-based EQACentral 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) EQAAdministered by Dr Nic Mapstone, hosted by University of Leeds
18 EQA Slides accessed online http://www.gieqa.org.uk/ 4 possible answers for each slideLow grade dysplasiaHigh grade dysplasiaAdenocarcinomaOtherIt is possible to enter a comment
19 EQAA case is valid only if the diagnosis is agreed by 80% of the regional lead pathologistsScores per case:2 points for same diagnosis as consensus1 point for one category removed (e.g. high grade dysplasia/carcinoma)0 points otherwise
22 Case E8 Result 13 12 288 Other Low Grade Dysplasia High Grade DysplasiaCarcinomaLeads13Participants12288
23 Scottish participation in EQA 43 registeredLimited data on actual participation (July 2012 review of circulations G,H)1/3 participated in both1/3 in one of the two circulations1/3 in neitherUpdated data awaited.
24 Slide referralRecognised difficulty in distinguishing epithelial misplacement from invasive cancer in adenomatous polyps
26 Case D9 Result 11 238 2 Other Low Grade Dysplasia High Grade Dysplasia CarcinomaLeads11Participants2382
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 panel10 cases (4.2%) submitted as probably benign were upgraded to cancerThere 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.
33 Case F7 Result 1 3 7 4 64 227 Other Low Grade Dysplasia High Grade DysplasiaCarcinomaLeads137Participants464227
34 The programme is almost as much about adenomas as cancer Adenomas in ScreeningAdenomas much more common than cancersAdenomas are the precursors of most cancersAdenomas (even when removed) are a marker of cancer riskThe programme is almost as much about adenomas as cancerIt 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 ACS34
40 Risk of Advanced Neoplasia at 5.5 yrs in a Colonoscopic Series Finding at first exam Patients Ad Neo RRNo neoplasiaTubular Adenoma <10mmTubular Adenoma >10mmVillous AdenomaHigh Grade DysplasiaCarcinomaLieberman et al 200740
41 Grading Dysplasia in 2189 Adenomas at 13 Centres min max medianmild 29% 88% 42%moderate 10% 67% 43%severe 1% 24% 4%41
42 Histology of 2206 Adenomas at 13 Centres min max mediantubular 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 polypsvillous component*severe dysplasia**in selected series only44
46 OPTICAL PROJECTION TOMOGRAPHY Original prototype was invented by James Sharpe whilst at MRC Human Genetics in 20021Whole mount, in vitro, imaging technology for small biological specimens (1-15mm)Optical equivalent of an X-ray CT scannerGenerates 3D images and 2D virtual sections through three orthogonal planesVisualises 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 1mm1cm10 cmOPTCONFOCAL MICROSCOPYMRI/CTORGANSEMBRYOSORGANISMSCELLSTISSUES
48 FEATURES OF OPTProduces 3D images & virtual sections in 3 orthogonal planesWholemount technologyNon-destructive – analysis post OPT possible (e.g. IHC)Visualise unstained anatomy with autofluorescence*Visualise fluorescent labels & coloured stainsInvestigate gene & protein expression in context of 3D anatomyProduces quantifiable and digital data – archiveDigital 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 UsesVery little work done on human tissueLymph Nodes
52 OBJECTIVETO IDENTIFY IF OPT HAS DIAGNOSTIC PROPERTIES IN EARLY COLORECTAL CANCERUsing paraffin blocks of existing screen-detected polypsCompare OPT generated images with traditional techniquesCurrent Gold Standard: Haematoxylin & Eosin (H&E) stained sections
53 PROJECT DESIGN PHASE TWO PHASE THREE PHASE ONE Training optimise techniqueArchived polypsPHASE ONEBlindedPHASE TWOClinical IntegrationWhole PolypsPHASE 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 9.6mmSagittal(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 diagnosisVillous morphologyThe 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 featuresDYSPLASIAMORPHOLOGYOTHER FEATURESLow Grade Dysplasia (LGD)Tubular Adenoma (TA)VasculatureHigh Grade Dysplasia (HGD)Tubulovillous Adenoma (TVA)Epithelial Displacement (EPD)Invasive Cancer (ICA)Villous Adenoma (VA)Ulceration/Mucous.
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 pitType II: Stellar or Asteroid pitType 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 pitType V: Amorphous or non-structured pit
67 Next StepsSeries of images analysed blindly by 5 consultant pathologistsCompare 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 MitchellUniversity of DundeeR Steele (Dept of Clinical & Population Science & Education)NHS Tayside and Tayside Tissue BankF Carey; J WilsonUniversity of CambridgeR KeoghCentre for Genomic Regulation, BarcelonaJ Sharpe