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MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
MCC 2011 - Slide 7
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MCC 2011 - Slide 7

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  • 1. THE PATHOLOGY OF TOTAL MESORECTAL EXCISION <ul><li>Prognosis and predicting recurrence </li></ul><ul><li>Pathological audit of surgical technique </li></ul><ul><li>Pathological audit of pre-operative imaging </li></ul><ul><li>Measuring the efficacy of neo-adjuvant therapy </li></ul>
  • 2. COLORECTAL CANCER : PATTERNS OF RECURRENCE AFTER CURATIVE SURGERY <ul><li>Loco-regional eg.rectal 4 – 40 % </li></ul><ul><li>Intra-peritoneal ( 20 % ) </li></ul><ul><li>Lymphatic eg.retroperitoneal nodes </li></ul><ul><li>Haematogenous eg.liver,lungs (20 – 40%) </li></ul>
  • 3. LOCAL RECURRENCE AND THE ANATOMY OF THE MESORECTUM <ul><li>Mechanisms of local recurrence </li></ul><ul><li>1.incomplete excision at the distal surgical resection margin </li></ul><ul><li>2.incomplete excision at the circumferential surgical resection margin </li></ul><ul><li>3.intra-lumenal seeding at the line of anastomosis </li></ul><ul><li>4.extra-lumenal seeding from spontaneous or iatrogenic tumour perforation </li></ul><ul><li>5.new metachronous tumour development at the anastomosis </li></ul>
  • 4. TOTAL MESORECTAL EXCISION TME line Blunt dissection line Mesorectal fascia
  • 5. PATHOLOGICAL EXAMINATION OF THE CRM
  • 6. &nbsp;
  • 7. &nbsp;
  • 8. &nbsp;
  • 9. &nbsp;
  • 10. &nbsp;
  • 11. &nbsp;
  • 12. A Uniform Residual Tumor ( R ) Classification <ul><li>TNM : </li></ul><ul><li>R1 = microscopic residual tumor </li></ul><ul><li>R2 = macroscopic residual tumor </li></ul><ul><li>“ demonstration of tumor directly at the resection margin ( tumor transected )” </li></ul><ul><li>includes continuous and discontinuous tumour spread and distant metastasis !! </li></ul><ul><li>Quirke : </li></ul><ul><li>CRM positive = tumor 1mm or less from the radial margin of the rectal cancer excision </li></ul><ul><li>R1/2 &amp; CRM positive rectal cancers are NOT synonymous or directly comparable </li></ul><ul><li>R1/2 status may be due either to local disease at a surgical margin OR distant metastasis </li></ul>Wittekind et al 2009
  • 13. 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
  • 14. MRC – CRO7 TRIAL : CRMI and LOCAL RECURRENCE <ul><li>3 year LR 3 year DFS </li></ul><ul><li>CRM positive 17 % 50 % </li></ul><ul><li>CRM negative 6 %* 79 %** </li></ul>* p = 0.0011 ** p &lt; 0.0001 Quirke et al. 2009
  • 15. Mode of Circumferential Margin Involvement <ul><li>number % LR </li></ul><ul><li>Direct spread 46 52.2% </li></ul><ul><li>Discontinuous spread 110 40.9% </li></ul><ul><li>Lymph node 19 10.5% </li></ul><ul><li>Blood vessel 23 30.4% </li></ul><ul><li>Lymphatic vessel 14 71.4% </li></ul><ul><li>Perineural 11 54.6% </li></ul><ul><li>No CRMI 421 10% </li></ul><ul><li>Birbeck et al 2002. </li></ul>
  • 16. CRMI IN RECTAL CANCER : A MULTI – CENTRE AUDIT <ul><li>1999 – 2002 </li></ul><ul><li>1036 patients </li></ul><ul><li>39 hospitals </li></ul><ul><li>Overall CRMI 12.5 % ( 0 - 33 % ) </li></ul><ul><li>Anterior resection 7.5 % </li></ul><ul><li>APER 16.7 % </li></ul><ul><li>Hartmanns procedure 31.7 % </li></ul>Tekkis et al 2005
  • 17. CRMI IN RECTAL CANCER : A MULTI - CENTRE AUDIT <ul><li>Curative surgery 7.1 % </li></ul><ul><li>Palliative surgery 37.3 % </li></ul><ul><li>No difference between consultant surgeons, nonconsultant staff or trainees </li></ul><ul><li>Correlation with Dukes Stage, operative intent and type of operation </li></ul><ul><li>CRMI not recorded in 26.2 % cases </li></ul>Tekkis et al. ACPGBI 2005
  • 18. MRC CRO-7 TRIAL : RISK FACTORS FOR CRM INVOLVEMENT <ul><li>SCRT versus Selective Post-Operative chemoradiotherapy : 10% v. 12 % </li></ul><ul><li>APR versus AR : 16% v. 7 % ( p&lt;0.0001 ) </li></ul><ul><li>Tumour height* : 0 – 5 cm : 15 % </li></ul><ul><li>5.1 – 10 cm : 9 % </li></ul><ul><li>10.1 – 15 cm : 9 % ( p = 0.004 ) </li></ul><ul><li>Anterior tumour : present : 13 % </li></ul><ul><li>absent : 7 % ( p = 0.001 ) </li></ul><ul><li>T stage* : p &lt; 0.0001 </li></ul><ul><li>N stage* : p &lt; 0.0001 </li></ul>Quirke et al. 2009 * = independent predictors of CRMI
  • 19. 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%
  • 20. APR for LOW RECTAL CANCER * Only tumours &lt; 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%
  • 21. &nbsp;
  • 22. TME and the low rectal cancer
  • 23. TME and the low rectal cancer
  • 24. CRM and the low rectal cancer
  • 25. Reducing CRM involvement and Local Recurrence following APR for Low Rectal Cancer. <ul><li>more radical surgery </li></ul><ul><li>pre-operative radiotherapy or </li></ul><ul><li>chemoradiotherapy </li></ul>
  • 26. &nbsp;
  • 27. &nbsp;
  • 28. APER WITH EXTENDED PERINEAL EXCISION <ul><li>Study of 99 standard and 27 “cylindrical” APER specimens from UK and Sweden </li></ul><ul><li>73.4 % received pre-operative radiotherapy ( standard APER 67.3 % ; extended APER 96.3 % ) </li></ul><ul><li>CRM positive : 40.6 % with standard APER </li></ul><ul><li>14.8 % with extended APER ( p 0.013 ) </li></ul><ul><li>Surgical perforation : 22.8 % with standard APER </li></ul><ul><li>3.7 % with extended APER ( p 0.03 ) </li></ul>West et al 2008
  • 29. 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 %
  • 30. Macroscopic assessment of Mesorectal excision <ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>INCOMPLETE - little bulk to mesorectum with defects down onto muscularis propria and/or very irregular CRM. </li></ul>
  • 31. &nbsp;
  • 32. &nbsp;
  • 33. &nbsp;
  • 34. MESORECTAL EXCISION
  • 35. Mesorectum Excision Grading * non-irradiated ; curative ; TME. ** 54% radiotherapy ; curative ; TME. *** 27% radiotherapy ; curative &amp; 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%
  • 36. 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 %
  • 37. 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 %**
  • 38. MRC CRO-7 TRIAL : Predicting Local Recurrence. <ul><li>Multivariate analysis : </li></ul><ul><li>Independent risk factors for local recurrence : </li></ul><ul><li>N stage </li></ul><ul><li>T stage </li></ul><ul><li>Tumour involving anterior quadrant </li></ul><ul><li>Plane of surgery </li></ul><ul><li>Treatment allocation ie. pre-op SCRT </li></ul><ul><li>NB CRM status, type of operation and height of tumour did not predict </li></ul><ul><li>recurrence in multivariate analysis. </li></ul>Quirke et al 2009
  • 39. 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
  • 40. Examining the Rectal Cancer Specimen after Chemo-Radiotherapy <ul><li>Determine prognosis : predict local recurrence and distant metastasis </li></ul><ul><li>Assess response of the tumour to radiotherapy / chemotherapy </li></ul><ul><li>Audit surgical technique </li></ul><ul><li>Audit the quality of imaging </li></ul>
  • 41. Why bother assessing regression after pre-operative treatment ? <ul><li>prognosis : survival , local recurrence &amp; distant metastasis </li></ul><ul><li>as a measure of tumour radiosensitivity and chemosensitivity </li></ul><ul><li>surrogate end point when comparing different radiotherapy and chemotherapy protocols </li></ul><ul><li>predictive factor for response to post-operative adjuvant chemotherapy </li></ul>
  • 42. Who should get adjuvant chemotherapy after pre-operative chemo-radiotherapy and surgery ? Collette et al 2007 ( EORTC trial 22921 )
  • 43. Measuring Tumour Response to Neoadjuvant therapy <ul><li>Tumour downstaging : comparison of pre-treatment clinical stage ( cT cN ) with post-treatment pathological stage ( ypT ypN ) </li></ul><ul><li>pCR rate : frequency of ypT0 ypN0 </li></ul><ul><li>Regression Grading </li></ul>
  • 44. Tumour Regression after Neoadjuvant Therapy <ul><li>ypT0 N0 </li></ul><ul><li>“ Scandinavian Style” short </li></ul><ul><li>course radiotherapy ( surgery ? 0 % </li></ul><ul><li>within 1 week ). </li></ul><ul><li>Long course radiotherapy. 0 – 14 % </li></ul><ul><li>Long course combined 10 – 30 % </li></ul><ul><li>chemo-radiotherapy. </li></ul>
  • 45. TUMOUR REGRESSION GRADING <ul><li>Mandard et al. 1994 </li></ul><ul><li>Dworak et al. 1997 </li></ul><ul><li>Wheeler et al. 2002 </li></ul><ul><li>Royal College of Pathologists 2007 </li></ul><ul><li>Beddy et al. 2008 </li></ul>
  • 46. &nbsp;
  • 47. Royal College of Pathologists : Colorectal Cancer Dataset 2007 ( 2 nd Edition ) <ul><li>No residual tumour cells and / or mucus lakes only ( Mandard 1 ) </li></ul><ul><li>Minimal residual tumour ie. only occasional microscopic tumour foci are identified with difficulty ( ? Mandard 2 ) </li></ul><ul><li>No marked regression ( ? Mandard 3 – 5 ) </li></ul>
  • 48. MANDARD GRADE 1
  • 49. MANDARD GRADE 1
  • 50. MANDARD GRADE 2
  • 51. Mandard Grade : A Study of Interobserver Agreement <ul><li>97 slides assessed by 3 dedicated GI pathologists </li></ul><ul><li>complete agreement seen in 56 / 97 cases ( 58 % ) </li></ul><ul><li>Kappa statistic 0.61 – 0.65 ( substantial agreement ) </li></ul><ul><li>when mandard grade is collapsed agreement increases </li></ul><ul><li>MG 1 and 2 vs MG 3 vs MG 4 and 5 : 80% agreement </li></ul><ul><li>MG 1 and 2 vs MG 3, 4 and 5 : 97% agreement </li></ul>
  • 52. TRG &amp; SURVIVAL AFTER CHEMORADIOTHERAPY <ul><li>126 patients 1997 – 2007 with cT3-4 or cN1/2 disease treated with 45-50 Gy plus 5FU prior to surgery </li></ul><ul><li>Mandard grades used with simplification to 3 categories : mandard 1 &amp; 2 = TRG 1 </li></ul><ul><li>mandard 3 = TRG 2 </li></ul><ul><li>mandard 4 &amp; 5 = TRG 3 </li></ul><ul><li>Tumour downstaged in 60 % cases </li></ul><ul><li>TRG 1 : 21 % TRG 2 : 39 % TRG 3 : 40 % </li></ul><ul><li>Local recurrence rate all cases : 7 % </li></ul><ul><li>5 yr disease free and overall survival all cases : 72 % and 63 % </li></ul>Beddy et al 2008
  • 53. Beddy et al 2008
  • 54. Pathological Stage and Survival after Pre-Operative Chemoradiotherapy for Rectal Cancer <ul><li>342 patients 1998 – 2004 with uT3 – 4 or uN1 / N2 tumours receiving 50.4 Gy radiotherapy with 5FU based chemotherapy </li></ul><ul><li>Surgery followed by adjuvant chemotherapy in most cases </li></ul><ul><li>TRG scored as a continuous variable from 0 % to 100 % regression ( subsequently categorized into 100 % response ; 86 % - 99 % &amp; &lt; 86 % response ) </li></ul><ul><li>pCR : 20 % </li></ul><ul><li>TRG : 100 % - 20 % ; 86 – 99 % - 21 % ; &lt; 86 % - 59 %. </li></ul>Quah et al 2008
  • 55. Pathological stage and survival after pre-Operative Chemoradiotherapy for rectal cancer <ul><li>CRM positive in 4 % </li></ul><ul><li>LR rate : 3 % ; distant metastases : 20 %. </li></ul><ul><li>5 yr disease free survival : 74 % </li></ul><ul><li>Best predictor of DFS was pathological stage : </li></ul><ul><li>concordance index* </li></ul><ul><li>Pre-treatment clinical stage 0.5 </li></ul><ul><li>Pathological stage 0.75 </li></ul><ul><li>% tumour response 0.65 </li></ul>* ability to predict disease recurrence Quah et al 2008
  • 56. CRM involvement after multi-modality treatment for locally advanced rectal cancer <ul><li>Local recurrence : in multivariate analysis of ypT, ypN, CRM &amp; Rodel TRG : CRMI was the only significant predictor of LR with a HR of 4.44 </li></ul><ul><li>( 95% CI 1.83-10.81 ). </li></ul><ul><li>Overall survival was predicted by ypN stage : HR 1.75 for ypN1 &amp; 2.6 for ypN2 and by CRMI : HR 1.68. </li></ul>Gosens et al 2007
  • 57. SURVIVAL AFTER CHEMORADIOTHERAPY IN LOCALLY ADVANCED RECTAL CARCINOMA Rullier et al 2010
  • 58. PRE – OPERATIVE CHEMORADIOTHERAPY
  • 59. MANDARD GRADE 1
  • 60. 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
  • 61. CORE STUDY <ul><li>Minimum of 5 tumour blocks </li></ul><ul><li>At least 1 large block </li></ul><ul><li>If no tumour found on initial H&amp;E : 3 further levels from an area of mucin or fibrosis </li></ul><ul><li>Cytokeratin immunocytochemistry at discretion of pathologist </li></ul>
  • 62. 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
  • 63. LYMPH NODE HARVEST &amp; PROGNOSIS IN STAGE II RECTAL CANCER. <ul><li>527 stage II &amp; 1,137 stage III rectal cancer patients undergoing radical surgery with post-operative chemo-radiotherapy </li></ul><ul><li>5 year relapse rate 5 year O.S. </li></ul><ul><li>Stage II : </li></ul><ul><li>0 – 4 nodes 37 % 68 % </li></ul><ul><li>5 – 8 nodes 34 % 73 % </li></ul><ul><li>9 – 13 nodes 26 % 72 % </li></ul><ul><li>&gt; 13 nodes 19 % 82 %* </li></ul>* P &lt; 0.02. NB No difference in survival for stage III disease. Tepper et al 2001
  • 64. LYMPH NODE HARVEST &amp; PROGNOSIS IN STAGE II RECTAL CANCER. <ul><li>527 stage II &amp; 1,137 stage III rectal cancer patients undergoing radical surgery with post-operative chemo-radiotherapy </li></ul><ul><li>5 year relapse rate 5 year O.S. </li></ul><ul><li>Stage II : </li></ul><ul><li>0 – 4 nodes 37 % 68 % </li></ul><ul><li>5 – 8 nodes 34 % 73 % </li></ul><ul><li>9 – 13 nodes 26 % 72 % </li></ul><ul><li>&gt; 13 nodes 19 % 82 %* </li></ul>* P &lt; 0.02. NB No difference in survival for stage III disease. Tepper et al 2001
  • 65. Rullier et al 2008
  • 66. 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 %

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