MCC 2011 - Slide 7

THE PATHOLOGY OF TOTAL MESORECTAL EXCISION Prognosis and predicting recurrence Pathological audit of surgical technique Pathological audit of pre-operative imaging Measuring the efficacy of neo-adjuvant therapy

COLORECTAL CANCER : PATTERNS OF RECURRENCE AFTER CURATIVE SURGERY Loco-regional eg.rectal 4 – 40 % Intra-peritoneal ( 20 % ) Lymphatic eg.retroperitoneal nodes Haematogenous eg.liver,lungs (20 – 40%)

LOCAL RECURRENCE AND THE ANATOMY OF THE MESORECTUM Mechanisms of local recurrence 1.incomplete excision at the distal surgical resection margin 2.incomplete excision at the circumferential surgical resection margin 3.intra-lumenal seeding at the line of anastomosis 4.extra-lumenal seeding from spontaneous or iatrogenic tumour perforation 5.new metachronous tumour development at the anastomosis

TOTAL MESORECTAL EXCISION TME line Blunt dissection line Mesorectal fascia

PATHOLOGICAL EXAMINATION OF THE CRM

A Uniform Residual Tumor ( R ) Classification TNM : R1 = microscopic residual tumor R2 = macroscopic residual tumor “ demonstration of tumor directly at the resection margin ( tumor transected )” includes continuous and discontinuous tumour spread and distant metastasis !! Quirke : CRM positive = tumor 1mm or less from the radial margin of the rectal cancer excision R1/2 & CRM positive rectal cancers are NOT synonymous or directly comparable R1/2 status may be due either to local disease at a surgical margin OR distant metastasis Wittekind et al 2009

LOCAL RECURRENCE AFTER CURATIVE RESECTION author n. CRM- CRM+ total Follow-up ( median ) Ng et al (1993) 80 17 % 60 % 20 % 26.6 Adam et al (1994) 190 8 % 66 % 23 % 63 HaasKock et al(1996) 253 8 % 29 % 11 % 29

MRC – CRO7 TRIAL : CRMI and LOCAL RECURRENCE 3 year LR 3 year DFS CRM positive 17 % 50 % CRM negative 6 %* 79 %** * p = 0.0011 ** p < 0.0001 Quirke et al. 2009

Mode of Circumferential Margin Involvement number % LR Direct spread 46 52.2% Discontinuous spread 110 40.9% Lymph node 19 10.5% Blood vessel 23 30.4% Lymphatic vessel 14 71.4% Perineural 11 54.6% No CRMI 421 10% Birbeck et al 2002.

CRMI IN RECTAL CANCER : A MULTI – CENTRE AUDIT 1999 – 2002 1036 patients 39 hospitals Overall CRMI 12.5 % ( 0 - 33 % ) Anterior resection 7.5 % APER 16.7 % Hartmanns procedure 31.7 % Tekkis et al 2005

CRMI IN RECTAL CANCER : A MULTI - CENTRE AUDIT Curative surgery 7.1 % Palliative surgery 37.3 % No difference between consultant surgeons, nonconsultant staff or trainees Correlation with Dukes Stage, operative intent and type of operation CRMI not recorded in 26.2 % cases Tekkis et al. ACPGBI 2005

MRC CRO-7 TRIAL : RISK FACTORS FOR CRM INVOLVEMENT SCRT versus Selective Post-Operative chemoradiotherapy : 10% v. 12 % APR versus AR : 16% v. 7 % ( p<0.0001 ) Tumour height* : 0 – 5 cm : 15 % 5.1 – 10 cm : 9 % 10.1 – 15 cm : 9 % ( p = 0.004 ) Anterior tumour : present : 13 % absent : 7 % ( p = 0.001 ) T stage* : p < 0.0001 N stage* : p < 0.0001 Quirke et al. 2009 * = independent predictors of CRMI

CRM involvement AP’s and AR’s The frequency of involvement of the CRM is 1.5-2X higher in AP than AR APR’s AR’s Leeds 1986-1997 all cases n=686 36.5% 22.3% Classic trial Curative n=400 21% 10% Dutch TME trial Curative n=1586 29% 13%

APR for LOW RECTAL CANCER * Only tumours < 5cm from anal verge N. LR. 5 year LR. 5 year Survival 5 year Survival 5 year AR APR AR APR Marr et al. 2005 561 13.5% 24% 66% 52% Wibe et al. 2003 2136 10 % 15% 68% 55% Heald et al. 1997 136* 4 % 47% 68% 29%

Reducing CRM involvement and Local Recurrence following APR for Low Rectal Cancer. more radical surgery pre-operative radiotherapy or chemoradiotherapy

APER WITH EXTENDED PERINEAL EXCISION Study of 99 standard and 27 “cylindrical” APER specimens from UK and Sweden 73.4 % received pre-operative radiotherapy ( standard APER 67.3 % ; extended APER 96.3 % ) CRM positive : 40.6 % with standard APER 14.8 % with extended APER ( p 0.013 ) Surgical perforation : 22.8 % with standard APER 3.7 % with extended APER ( p 0.03 ) West et al 2008

CRM involvement after neoadjuvant therapy. CRMI surgery Short course RT Long course RT CRT Marjnen et al ( 2003 ) 1mm 18 % 16 % CRO-7 (preliminary) 1mm 14 % 12 % Sauer et al ( 2004 ) 0 mm 3 % 2 % Bujko et al ( 2006 ) 1mm 12.9 % 4.4 %* Den Dulk et al ( 2007 ) 0 mm 6.5 % 4.9 %

Macroscopic assessment of Mesorectal excision COMPLETE - intact mesorectum with only minor irregularities of an otherwise smooth mesorectal surface. No defect deeper than 5mm and no coning towards the distal margin. NEARLY COMPLETE - moderate bulk to mesorectum but irregularity of mesorectal surface. Moderate coning allowed. Muscularis propria not visible except for area of insertion of levator muscles. INCOMPLETE - little bulk to mesorectum with defects down onto muscularis propria and/or very irregular CRM.

Mesorectum Excision Grading * non-irradiated ; curative ; TME. ** 54% radiotherapy ; curative ; TME. *** 27% radiotherapy ; curative & palliative ; TME. No. Mesorectal plane Intra-mesorectal plane Muscularis propria plane Nagtegaal et al. ( 2002 )* 180 56.6% 19.4% 23.9% Maslekar et al. ( 2006 )** 130 47% 40% 13% Jeyorajah et al.(2007)*** 287 53.7% 33.1% 13.2%

Macroscopic assessment of Mesorectal excision Dutch TME study CRM negative cases 2 year local recurrence rate 2 year distant recurrence Overall recurrence rate Complete or nearly complete 5.5 % 12.2 % 14.9 % incomplete 11.4 % 19.2 % 28.6 %

MRC CRO-7 TRIAL : MESORECTAL GRADING * P = 0.0039 ** P = 0.14 Quirke et al. 2009 frequency 3 year LR 3 year DFS Mesorectal fascial plane 52 % 4 % 79 % Intramesorectal plane 34 % 7 % 75 % Muscularis propria plane 13 % 13 %* 70 %**

MRC CRO-7 TRIAL : Predicting Local Recurrence. Multivariate analysis : Independent risk factors for local recurrence : N stage T stage Tumour involving anterior quadrant Plane of surgery Treatment allocation ie. pre-op SCRT NB CRM status, type of operation and height of tumour did not predict recurrence in multivariate analysis. Quirke et al 2009

CRO-7 : IMPACT OF PLANE OF SURGERY ON LOCAL RECURRENCE AT 3 YEARS. Quirke et al. 2006. No. PRE POST HR Muscularis propria plane 141 9 % 29 % 2.76 Intra mesorectal plane 382 6 % 12 % 2.02 Mesorectal plane 596 1 % 6 % 4.47

Examining the Rectal Cancer Specimen after Chemo-Radiotherapy Determine prognosis : predict local recurrence and distant metastasis Assess response of the tumour to radiotherapy / chemotherapy Audit surgical technique Audit the quality of imaging

Why bother assessing regression after pre-operative treatment ? prognosis : survival , local recurrence & distant metastasis as a measure of tumour radiosensitivity and chemosensitivity surrogate end point when comparing different radiotherapy and chemotherapy protocols predictive factor for response to post-operative adjuvant chemotherapy

Who should get adjuvant chemotherapy after pre-operative chemo-radiotherapy and surgery ? Collette et al 2007 ( EORTC trial 22921 )

Measuring Tumour Response to Neoadjuvant therapy Tumour downstaging : comparison of pre-treatment clinical stage ( cT cN ) with post-treatment pathological stage ( ypT ypN ) pCR rate : frequency of ypT0 ypN0 Regression Grading

Tumour Regression after Neoadjuvant Therapy ypT0 N0 “ Scandinavian Style” short course radiotherapy ( surgery ? 0 % within 1 week ). Long course radiotherapy. 0 – 14 % Long course combined 10 – 30 % chemo-radiotherapy.

TUMOUR REGRESSION GRADING Mandard et al. 1994 Dworak et al. 1997 Wheeler et al. 2002 Royal College of Pathologists 2007 Beddy et al. 2008

Royal College of Pathologists : Colorectal Cancer Dataset 2007 ( 2 nd Edition ) No residual tumour cells and / or mucus lakes only ( Mandard 1 ) Minimal residual tumour ie. only occasional microscopic tumour foci are identified with difficulty ( ? Mandard 2 ) No marked regression ( ? Mandard 3 – 5 )

Mandard Grade : A Study of Interobserver Agreement 97 slides assessed by 3 dedicated GI pathologists complete agreement seen in 56 / 97 cases ( 58 % ) Kappa statistic 0.61 – 0.65 ( substantial agreement ) when mandard grade is collapsed agreement increases MG 1 and 2 vs MG 3 vs MG 4 and 5 : 80% agreement MG 1 and 2 vs MG 3, 4 and 5 : 97% agreement

TRG & SURVIVAL AFTER CHEMORADIOTHERAPY 126 patients 1997 – 2007 with cT3-4 or cN1/2 disease treated with 45-50 Gy plus 5FU prior to surgery Mandard grades used with simplification to 3 categories : mandard 1 & 2 = TRG 1 mandard 3 = TRG 2 mandard 4 & 5 = TRG 3 Tumour downstaged in 60 % cases TRG 1 : 21 % TRG 2 : 39 % TRG 3 : 40 % Local recurrence rate all cases : 7 % 5 yr disease free and overall survival all cases : 72 % and 63 % Beddy et al 2008

Pathological Stage and Survival after Pre-Operative Chemoradiotherapy for Rectal Cancer 342 patients 1998 – 2004 with uT3 – 4 or uN1 / N2 tumours receiving 50.4 Gy radiotherapy with 5FU based chemotherapy Surgery followed by adjuvant chemotherapy in most cases TRG scored as a continuous variable from 0 % to 100 % regression ( subsequently categorized into 100 % response ; 86 % - 99 % & < 86 % response ) pCR : 20 % TRG : 100 % - 20 % ; 86 – 99 % - 21 % ; < 86 % - 59 %. Quah et al 2008

Pathological stage and survival after pre-Operative Chemoradiotherapy for rectal cancer CRM positive in 4 % LR rate : 3 % ; distant metastases : 20 %. 5 yr disease free survival : 74 % Best predictor of DFS was pathological stage : concordance index* Pre-treatment clinical stage 0.5 Pathological stage 0.75 % tumour response 0.65 * ability to predict disease recurrence Quah et al 2008

CRM involvement after multi-modality treatment for locally advanced rectal cancer Local recurrence : in multivariate analysis of ypT, ypN, CRM & Rodel TRG : CRMI was the only significant predictor of LR with a HR of 4.44 ( 95% CI 1.83-10.81 ). Overall survival was predicted by ypN stage : HR 1.75 for ypN1 & 2.6 for ypN2 and by CRMI : HR 1.68. Gosens et al 2007

SURVIVAL AFTER CHEMORADIOTHERAPY IN LOCALLY ADVANCED RECTAL CARCINOMA Rullier et al 2010

PRE – OPERATIVE CHEMORADIOTHERAPY

ASSESSING TUMOUR REGRESSION AFTER CHEMORADIOTHERAPY Bedrossian et al 2004. No. Gross residual disease Microscopic disease No residual disease Ulcer or Tumour 184 (85%) 61 % 26 % 13 % Ulcer scar or induration 29 (13%) 3 % 38 % 59 % No visible abnormality 3 (2%) 0 / 3 1 / 3 2 / 3

CORE STUDY Minimum of 5 tumour blocks At least 1 large block If no tumour found on initial H&E : 3 further levels from an area of mucin or fibrosis Cytokeratin immunocytochemistry at discretion of pathologist

Lymph node harvest after neoadjuvant therapy ( Numbers represent median or average no of nodes. ) Surgery only Short course RT Long course RT Marijnen et al.2001 9.7 7.7 Wichmann et al 2002 19 13 Wijesuriya et al 2005 9 4 Baxter et al 2004 10 7

LYMPH NODE HARVEST & PROGNOSIS IN STAGE II RECTAL CANCER. 527 stage II & 1,137 stage III rectal cancer patients undergoing radical surgery with post-operative chemo-radiotherapy 5 year relapse rate 5 year O.S. Stage II : 0 – 4 nodes 37 % 68 % 5 – 8 nodes 34 % 73 % 9 – 13 nodes 26 % 72 % > 13 nodes 19 % 82 %* * P < 0.02. NB No difference in survival for stage III disease. Tepper et al 2001

pNX after chemoradiotherapy for rectal cancer : what does it mean ? ( ypNX v. ypN0 = N.S. ; ypN0 v. ypN1 = 0.001 ) Habr-Gama et al 2007 5yr overall survival 5yr disease free survival yp NX 91 % 74 % yp N0 91 % 59 % yp N1 or 2 66 % 30 %

MCC 2011 - Slide 7

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MCC 2011 - Slide 7