The Kamal Ishak Lecture. The pathology of bowel cancer screening

Transcription

1 The Kamal Ishak Lecture The pathology of bowel cancer screening Professor Neil A Shepherd Gloucester & Cheltenham, UK 27 th IAP-AD Congress 2 nd Emirates Surgical Pathology Conference Dubai, 26 November 2015

2 Kamal G Ishak,

3 The Kamal Ishak Lecture Established 1998 Mohammad Akhtar Samir Amr Alastair Burt Francoise Galateau-Salle Zachary Goodman Najib Haboubi Kristin Henry Hala Makhlouf Florabel Mullick Nour Sneige Ghazi Zaatari

4 Cancer screening: what s it all about? Cervical cancer detection of pre-malignant change cervical smear detection of high risk patients HPV testing Breast cancer detection of early stage cancer mammography detection of pre-malignant change mammography Colorectal cancer detection of early stage cancer FOB, FIT, etc detection of pre-malignant change FOB, FIT, etc

5 What colorectal cancer screening is all about. detecting cancer earlier Dukes staging for symptomatic CRC versus screen-detected CRC in the English BCSP D 25% A C D true A 8% 26% 1% 26% C 34% B 33% until you have survival data, excellent pathological staging is all you have it s the most important surrogate marker for the success of the programme B 25% polyp cancers 22% detecting and removing pre-malignant pathology

6 Gut 2015; 64:

7 Bowel cancer screening in Europe, 2015

8 Bowel cancer screening in Asia & Australasia, 2015

9 Bowel cancer screening in England universal screening (60-70) by FOB first introduced in 2006 full roll-out not until 2011 then age extension to 75 then one-off sigmoidoscopy screening at age 55 introduced independent of FOB screening in 2013 now considering conversion from FOB to FIT

10 Bowel cancer screening: the subconscious musings of a Gloucestershire pathologist, circa 2006 most of it is a pathological doddle 130 extra polyps a year mainly adenomas and HPs piffle! a few more cancer resections but lots of easy Dukes A/stage 1 and Julietta is going to give us a whole wad of dosh to do it..

11 In the UK, it s not just England s BCSP..

12 The first 10,000 Northern Ireland BCSP specimens 0.7% 2.1% 0.3% 0.3% 4.1% 2.9% 15.3% 16.9% 4.8% 0.8% 0.4% 2.8% 48.7% Diagnosis Total Adenocarcinoma 2.8% Adenocarcinoma (in polyp) 0.8% Suspicion of malignancy 0.4% Tubular adenoma 48.7% Tubulovillous adenoma 16.9% Hyperplastic polyp 15.3% Sessile serrated lesion 2.9% Traditional serrated adenoma 0.3% Villous adenoma 0.3% Inflammatory polyp 0.7% Inflammation 4.1% Other 2.1% Normal 4.8% Grand Total 100%

13 BCSS polyp pathology screenshot

14 Cairns SR, et al; BSG guidelines 2010 (after Atkin WS, Saunders BP; Gut 2002)

15 Reliability of pathological assessment of villosity and dysplasia grade

16 Reliability of pathological assessment of villosity and dysplasia grade

17 Variability in polyp type, BCSP South West

18 Three big issues in bowel cancer screening pathology (and all very relevant to routine colorectal pathology practice.) serrated pathology & what do we do about it expected but not the amount nor the diagnostic difficulties polyp cancers (pt1 disease) & what we do about it expected but not he management difficulties the large adenomatous polyp of the sigmoid colon expected but not the amount nor the diagnostic difficulties

19 What is serrated pathology? a distinctive morphological appearance in the large intestinal mucosa with specific molecular fingerprints but varied endoscopic and macroscopic features and a variable but highly significant neoplastic potential representing the most important advance in our understanding of colorectal cancer development in the last decade

20 Terminology of sessile serrated pathology sessile serrated adenoma Torlakovic and Snover, 1996 sessile serrated polyp/adenoma USA; WHO, 2010 sessile serrated polyp sessile serrated lesion UK; European CR screening guidelines

21 Bateman AC, Shepherd NA. J Clin Pathol 2015.

22 Bateman & Shepherd, 2015 Approved by BSG Pathology Section, BCSP National Pathology Committee, RCPath, European CRC Screening Pathology Group & BSG Serrated Pathology Working Party

23 Sessile serrated lesions

24 Sessile serrated lesion:? dysplasia

25 Traditional serrated adenoma disruption of signalling pathways of stem cell control expansion of progenitor cell population in ectopic crypt foci/lateral buds these lateral bud cells proliferate and gain somatic mutations leading to dysplasia arising outside the stem cell niche and more rapid malignant transformation Davis H et al, 2014

26 Mixed polyps collision between hyperplastic polyp and adenoma dysplasia in a hyperplastic polyp or SSL traditional serrated adenoma and standard adenoma more than two phenotypes with one or more showing serration Longacre TA & Fenoglio-Preiser CM, 1990; Bateman AC & Shepherd NA, 2015

27 Mixed polyp HP and TSA

28 Colorectal cancer molecular pathogenesis

29 Prevalence of serrated lesions in Western populations hyperplastic polyp sessile serrated lesion SSL with dysplasia traditional serrated adenoma serrated adenocarcinoma 25-30% of all colorectal polyps 1.7-9% of all colorectal polyps 13% of SSLs % of all colorectal polyps 10-25% of all colorectal cancers Bettington M et al. Histopathology 2013; 62:

30 Number of diagnosed SSAs Oxford audit 2013 Total number SSLs diagnosed SNOMED search for term serrated

31 Endoscopic appearances of SSLs difficult to spot at endoscopy predilection for right side where the prep is usually worse flat and often draped over a fold adherent mucus often the only clue

32 Three big issues in bowel cancer screening pathology serrated pathology & what do we do about it expected but not the amount nor the diagnostic difficulties polyp cancers (pt1 disease) & what we do about it expected but not he management difficulties the large adenomatous polyp of the sigmoid colon expected but not the amount nor the diagnostic difficulties

33 Polyp cancer issues is it cancer? double reporting recommendation in BCSP since 2012 the phenomenon of epithelial misplacement and the Expert Board other diagnostic issues and mimics what do we do about polyp cancer? measurement and budding are king

34 What colorectal cancer screening is all about. detecting early stage cancer Dukes staging for symptomatic CRC versus screen-detected CRC in the English BCSP D 25% A C D true A 8% 26% 1% 26% B C 34% 33% B 25% polyp cancers 22%

35 Management of polyp cancers Resection No resection reduce recurrence risk risk of positive lymph nodes sub stage pt1 site rectum > colon complications of surgery mortality: surgical team, age, co-morbidity, country morbidity quality of life colostomy, anterior resection syndrome

36 The adenoma harbouring malignancy: the big three criteria is it poorly differentiated? does it show vascular invasion? does it reach the margin? i.e. within 1 mm (or 2mms?) Cooper et al. Gastroenterology 1995; 108:

37 Is this vascular invasion?

38 Is this vascular invasion?

39 A bit of Thursday in Dubai philosophy You can have all the fancy immunohistochemistry and molecular biology you like, but what s the two most important adjunctive tests we do in Histopathology? The deeper level and the peer at the computer to get the patient s history.

40 Is this vascular invasion?

41 Adenoma in an LGC: much commoner in the right colon

42 What do we do with the adenoma harbouring malignancy? The big three parameters we can understand vascular invasion and poor differentiation what about margin involvement? many papers have attested (25 versus 5) that this is the most predictive parameter for ADVERSE PROGNOSIS, notwithstanding the lack of logic Cooper et al, 1995; Geraghty, Williams and Talbot, 1991

43 Geboes K, Ectors N & Geboes KP, 2005

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46 Selecting patients for resection a careful balance between risks of metastatic disease & risks of surgery happy about poorly differentiated and vascular invasion: difficulty is margin involvement age and co-morbidity are important crucial MDTM discussion

47 Margin involvement by cancer in malignant polyps commonest adverse prognostic parameter commonest isolated adverse prognostic parameter definition historically the single most important predictor of adverse prognosis but not, apparently, lymph node metastatic disease do we really believe that margin involvement should be an indicator for resection if it is not a good predictor of lymph node metastatic disease - in the current day practice of excellent polypectomy??

48 Classification of early colorectal cancer in polyps: Haggitt et al, 1986

49 margin involvement Issues with pathological assessment lacks logic: is evidence good enough? definitions poor differentiation & lymphovascular invasion sm3 (Kikuchi) Haggitt 4 differences in polyp type budding measuring: depth, width less problems but still subjective need muscularis mucosae & propria only for sessile lesions? sessile v polypoid subjective pedunculated sub-pedunculated sessile subjective; definitions inter-observer variation

50 Measuring depth and width of invasion: Japanese methodology Assessment of depth of invasion (if completely excised) direct measurement from muscularis mucosae depth > 2mm 20% nodal +ve (vs. 5%) width of invasive front > 4mm 20% nodal +ve (vs 4%) Ueno et al: Gastroenterology 2004; 127:

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52 What about tumour budding? detachment of single tumour cells or in small aggregates (< 5 cells) = dedifferentiation now known to be adverse prognostic marker abnormalities in EMT (epithelialmesenchymal transition)

53 Where are we with tumour budding? independent prognostic significance in polyp cancers Ueno et al, 2004 independent significance in Dukes B/stage II colon cancers Wang et al, 2009 less powerful in Dukes C/stage III issues: varying methods of assessment heterogeneity reproducibility more data required

54 BCSP polyp cancer inter-observer study Leeds, February 2013: poor levels of agreement with differentiation, lymphatic spread, vascular spread, margin positivity good levels of agreement with margin positivity once definitions of margin had been established best levels of agreement with MEASURING depth of spread, width of cancer, distance from margin. measuring is the future..

55 The most useful tool in BCSP.

56 Three big issues in bowel cancer screening pathology serrated pathology & what do we do about it expected but not the amount nor the diagnostic difficulties polyp cancers (pt1 disease) & what we do about it expected but not he management difficulties the large adenomatous polyp of the sigmoid colon expected but not the amount nor the diagnostic difficulties

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58 Epithelial misplacement in adenomas 85% in sigmoid colon unusual in rectum (unless there has been previous intervention) same epithelium as surface, accompanied by lamina propria, haemosiderin deposition what about misplaced epithelium at the diathermy margin? intense pathological mimicry of invasive cancer

59 The question Is this cancer in the submucosa or is it the benign phenomenon of epithelial misplacement?

60 Epithelial misplacement vs invasive carcinoma There is a very important adage in pathology: why make two diagnoses when one will do?

61 Pathological conundra in BCSP epithelial misplacement mimicking cancer 85% in sigmoid colon selected into BSCP as these are large prolapsing adenomatous polyps that bleed can be very difficult and some almost impossible require Expert Board and BCSP-funded research but some are more straight forward and yet may be miscalled by pathologists.

62 Loughrey & Shepherd, Histopathology ARI, January 2015

63 BCSP Expert Board three pathologists you need a majority for this highly subjective and difficult assessment N A Shepherd, D S A Sanders & M R Novelli funded (IT, postage, secretarial support) in England by BCSP (thanks, Julietta) opportunity for education and research into difficult EM v Ca cases

64 Expert Board: the fun continues cases: 20 cases in 2009; 72 in 2014 EB three-way agreement of 80.3%: kappa score of 0.67 (substantial agreement) originating pathologist(s) v EB: benign diagnosis 30.6% v 80.2% (originator(s) v EB) in 50%, final diagnosis changed from originating pathologist(s) to EB double diagnosis (ie EM and carcinoma) in 26 cases (10.5%)

65 Epithelial misplacement vs carcinoma: a seedbed for research an almost unique phenomenon where pathologists get it badly wrong and experts can t agree as to whether it s cancer or not... what to do? immunohistochemistry? Yantiss RK, Bosenberg MW, Antonioli DA, Odze RD. Utility of MMP-1, p53, e- cadherin and collagen IV immunohistochemical stains in the differential diagnosis of adenomas with misplaced epithelium versus adenomas with invasive adenocarcinoma. Am J Surg Pathol 2002; 26: D reconstruction? clever spectroscopic analysis? optical coherence tomography analysis?

66 Epithelial misplacement: 3D reconstruction

67 Epithelial misplacement: 3D reconstruction Epithelial misplacement

68 Epithelial misplacement in sigmoid colonic polyps: a major conundrum in BCSP epithelial misplacement mimicking cancer: 85% in sigmoid colon selected into BSCP as these are large prolapsing adenomatous polyps that bleed detected by FOB screening can be very difficult and some almost impossible, a phenomenon not really seen before in UK GI pathology Shepherd NA, Griggs RKS. Epithelial misplacement in sigmoid colonic adenomatous polyps: bowel cancer screening-generated diagnostic conundrum of the century. Modern Pathology 2015 require Expert Board and BCSP-funded research a major source of diagnostic error, especially detected through rigid QA procedures will it be as prevalent or as problematic in FIT screening? has this phenomenon been seen in other screening programmes?!?

69 Setting bowel cancer screening pathology standards

70 CRC screening as a driver for enhanced overall colorectal pathology service quality adenoma pathology: classification and grading of dysplasia; villosity serrated pathology : sensible reclassification use of performance indicators and quality measures to drive up colorectal cancer reporting quality, especially through BCS QA Loughrey MB, Quirke P, Shepherd NA. RCPath guidelines for the reporting of colorectal cancer, 2014

71 Histopathology Annual Review Issue, January 2015 O Brien MJ, Zhao Q, Yang S. Colorectal serrated pathology cancers and precursors. Histopathology 2015; 66: Loughrey MB, Shepherd NA. The pathology of colorectal cancer screening. Histopathology 2015; 66: Novelli MR. The pathology of hereditary polyposis syndromes. Histopathology 2015; 66: Voltaggio L, Montgomery E. Polypoid stromal lesions of the intestines. Histopathology 2015; 66:

72 Take home messages bowel cancer screening and its QA continues to improve the overall quality of colorectal pathology we really must make ourselves be more useful for surveillance by ensuring good agreement levels with high grade dysplasia and villosity, in particular our knowledge of serrated pathology is increasing exponentially but we have still got a lot to learn we have real management problems with polyp cancers measurement may be the answer in the future. epithelial misplacement v cancer the diagnostic conundrum of the century (in the UK at least ) bowel cancer screening, with its quality induced by comprehensive quality assurance, will ultimately give us the answers to many of these vexatious questions..

73 Acknowledgements Dr Adrian Bateman The late Professor Jeremy Jass Dr Simon Leedham Professor Marco Novelli The late Professor Bryan Warren Professor Geraint Williams

74 Thank you for listening!