1. Pathologist and Prognosis in Colorectal Cancer Surgery. Dr Bryan F Warren Consultant Gastrointestinal Pathologist Oxford M62 Course 2004

2. Pathology of the formal colorectal cancer resection specimen.  Staging and prognosis  What is the significance of the“radial margin”?  How should I look for lymph nodes?  What is a ‘bad Dukes B cancer’?

3. Cuthbert E Dukes Consultant Pathologist St Mark’s Hospital 1926-1956

4. Evolution of pathological staging. UICC TNM 6 th Edition 2002 Major changes or minor changes? Likely that RCPath will recommend staying with TNM 5 th edition.

5. Reproduced from Schiller KFR, Cockel R, Hunt RH, Warren BF 2001.

6. Rectal cancer-How I do it The specimen is received fresh, and inspected by me +/- surgeon +/- trainee pathologists and surgeons. I/we inspect: Mesorectal margin Close distal margin Tumour on peritoneal surface/mesorectal margin

8. Mesorectal margin and local recurrence in rectal cancer Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision Lancet 1986;8514:996  14/52 LRM +  12/14 local recurrence  Specificity 92%  Sensitivity 95%  Positive predictive value 85%

9. How many slices for histology?

10. Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision Lancet 1986;8514:996 Single slice chosen macroscopically: 6/52 (12%) LRM + On embedding and sectioning the whole tumour using large blocks: (10u H&E stained sections cut on a sledge microtome) 14/52 (27%) LRM +

11. Adam IJ, Mohamdee MO, Martin IG, Scott NA, Finan PJ, Johnston D, Dixon MF, Quirke P. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994; 344(8924):707-711. 190 patients CRM + in 25%(35/141) potentially curative resections CRM + in 36%(69/190) of all cases Local recurrence after potentially curative resection in 25% CRM+ independently influenced both local recurrence and survival Confirms the need to examine CRM carefully

12. Hall NR, Finan PJ, Al-Jaberi T, Tsang CS, Brown SR, Dixon MF, Quirke P. Circumferential margin involvement after mesorectal excision of rectal cancer with curative intent. Predictor of survival but not local recurrence? Dis Colon Rectum 1998;979-983. 218 patients 152 potentially curative resections.  20 (13%) tumour within 1mm CRM  50% disease recurrence CRM+ at 41 months  Local recurrence in 15%  24% disease recurrence CRM- at 41 months  Local recurrence in 11%(p=0.38)  Disease free survival (p=0.01) and mortality (p=0.005) were related to CRM+ Patients with an involved CRM may die of distant disease before local recurrence is apparent.

13. Birbeck KF, Macklin CP, Tiffin NJ, Parsons W, Dixon MF, Mapstone NP, Abbott CR, Scott NA, Finan PJ, Johnston D, Quirke P. Rates of circumferential resection margin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Ann Surg 2002;235:449-457. 608 patients 1986-1997  586 clinical follow up available  105 (17.9%) developed local recurrence  165 CRM positive 38.2% local recurrence  421 CRM negative 10% local recurrence.  CRM – had improved (75%) 5 year survival over CRM+ (29%) CRM+ immediate post surgical predictor of survival (CR07) Useful indicator of the quality of surgery-Audit

14. Pathologists’ assessment of the mesorectum macroscopically. Nagtegaal ID, van de Velde CJ, van der Worp E, Kapiteijn E, Quirke P, van Krieken JH; Cooperative Clinical Investigators of the Dutch Colorectal Cancer Group. Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control. J Clin Oncol 2002; 20: 1714-5. 180 patients  24% (43) incomplete mesorectum  36.1% local and distant recurrence vs 20.3% in the group with a complete mesorectum  2mm margin  Survival is predicted by proper assessment of the mesorectum, and judgement of the quality of TME.

15. Trials – CR07 quality of surgery P Quirke et al

16. Mode of CRM involvement Birbeck et al  6 types of CRM involvement  Direct tumour spread 46 pts52.17% local recurrence  Discontinuous tumour spread 110pts 45%  Tumour within a lymph node19pts10.53%(caution pt. no. small)  Tumour within a blood vessel23pts30.43%  Tumour within lymphatics14pts71.43%  Perineural tumour11pts54.55%

17. Lymph nodes  Find all that are there  Three contributors to lymph node numbers: patient, surgeon and pathologist  Sampling method must not compromise assessment of CRM  Fat clearance? or  30 minutes, hard seat, bright light, sharp knife?

18. Serosal Involvement in Colon Cancer l found in 242/412 (58.7%) l most powerful independent prognostic marker (greater than extent of spread or LN involvement) l present in 45/46 patients who developed intraperitoneal recurrence l present in all 6 patients who developed pelvic recurrence Shepherd et al 1997

19. Serosal Involvement in Rectal Cancer –anterior and lateral walls of mid and upper rectum –found in 54/209 (25.8%) –independent prognostic marker –in 12 cases of local recurrence following complete resection (CRM-), 6 had LPI Shepherd et al 1995

21. Prognosis in Dukes B Colonic Carcinoma –268 cases, continuous, unselected –Single pathologist (mean LNs 21, tumour blocks 5.7) –5 year survival rate 76% (95% CI 70-81%) –Logrank & Cox multivariate regression analysis: Serosal involvement Venous invasion (intramural or extramural) Circumferential Margin involvement Tumour perforation

22. Prognosis in Dukes B Colonic Carcinoma –Serosal involvement1 –Venous invasion (intramural or 1 extramural) –Circumferential margin involvement (or inflamed in association with tumour)1 –Tumour perforation2 HIGH RISK = 2 or more

24. Non-peritonealised “circumferential” margin involvement in colon cancer l Regions of the colon where a significant proportion of the circumference is retroperitoneal –caecum –ascending colon –descending colon –distal sigmoid

27. Right hemicolectomy specimen

28. Retroperitoneal Margin Involvement in Caecal Cancer –37 right hemicolectomies –Retroperitoneal surgical margin involved in 4/37 (11%) –Local recurrence approximately 10% Bateman & Warren 2001

29. Guidelines Changes (Courtesy of Professor GT Williams) l Highlight the features that are of therapeutic importance l Clarify the definitions of important prognostic features and conventions for TNM staging l Include recommendations for reporting local excisions l Streamline the proforma

30. Features of Therapeutic Importance l Tumour perforation l Lymph node metastases l Circumferential margin positivity (rectal cancer) l Serosal involvement l Extramural vascular invasion l Poor differentiation

31. Problems with regression  Complete or partial  Quantitation if partial  Significance of mucus pools  Poor relationship to TNM stage

32. Rectal Cancer Regression Grade 1Tumour ‘sterilised’ or only microscopic foci, marked fibrosis 2Marked fibrosis with macroscopic tumour 3Little or no fibrosis, abundant macroscopic disease Wheeler et al Dis Colon Rectum 2002;45:1051-6

33. Change l Multidisciplinary teams l Sub-specialisation l Improved preoperative staging (MRI) l Better surgery for rectal cancer l Better evidence for the efficacy of adjuvant and neoadjuvant chemotherapy and radiotherapy

34. Summary The pathologist and prognosis in colorectal cancer surgery: To stage the tumour accurately To assess the surgical margins of the resected specimen accurately To assess the quality of the surgery To sample lymph nodes adequately To be aware of features of a ‘bad’ Dukes B tumour To communicate effectively with the multidisciplinary team