MCC 2011 - Slide 7

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MCC 2011 - Slide 7

  1. 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. 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. 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. 4. TOTAL MESORECTAL EXCISION TME line Blunt dissection line Mesorectal fascia
  5. 5. PATHOLOGICAL EXAMINATION OF THE CRM
  6. 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 & 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
  7. 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
  8. 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 < 0.0001 Quirke et al. 2009
  9. 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>
  10. 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
  11. 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
  12. 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<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 < 0.0001 </li></ul><ul><li>N stage* : p < 0.0001 </li></ul>Quirke et al. 2009 * = independent predictors of CRMI
  13. 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%
  14. 20. 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%
  15. 22. TME and the low rectal cancer
  16. 23. TME and the low rectal cancer
  17. 24. CRM and the low rectal cancer
  18. 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>
  19. 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
  20. 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 %
  21. 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>
  22. 34. MESORECTAL EXCISION
  23. 35. 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%
  24. 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 %
  25. 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 %**
  26. 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
  27. 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
  28. 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>
  29. 41. Why bother assessing regression after pre-operative treatment ? <ul><li>prognosis : survival , local recurrence & 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>
  30. 42. Who should get adjuvant chemotherapy after pre-operative chemo-radiotherapy and surgery ? Collette et al 2007 ( EORTC trial 22921 )
  31. 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>
  32. 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>
  33. 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>
  34. 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>
  35. 48. MANDARD GRADE 1
  36. 49. MANDARD GRADE 1
  37. 50. MANDARD GRADE 2
  38. 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>
  39. 52. TRG & 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 & 2 = TRG 1 </li></ul><ul><li>mandard 3 = TRG 2 </li></ul><ul><li>mandard 4 & 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
  40. 53. Beddy et al 2008
  41. 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 % & < 86 % response ) </li></ul><ul><li>pCR : 20 % </li></ul><ul><li>TRG : 100 % - 20 % ; 86 – 99 % - 21 % ; < 86 % - 59 %. </li></ul>Quah et al 2008
  42. 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
  43. 56. CRM involvement after multi-modality treatment for locally advanced rectal cancer <ul><li>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 </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 & 2.6 for ypN2 and by CRMI : HR 1.68. </li></ul>Gosens et al 2007
  44. 57. SURVIVAL AFTER CHEMORADIOTHERAPY IN LOCALLY ADVANCED RECTAL CARCINOMA Rullier et al 2010
  45. 58. PRE – OPERATIVE CHEMORADIOTHERAPY
  46. 59. MANDARD GRADE 1
  47. 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
  48. 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&E : 3 further levels from an area of mucin or fibrosis </li></ul><ul><li>Cytokeratin immunocytochemistry at discretion of pathologist </li></ul>
  49. 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
  50. 63. LYMPH NODE HARVEST & PROGNOSIS IN STAGE II RECTAL CANCER. <ul><li>527 stage II & 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>> 13 nodes 19 % 82 %* </li></ul>* P < 0.02. NB No difference in survival for stage III disease. Tepper et al 2001
  51. 64. LYMPH NODE HARVEST & PROGNOSIS IN STAGE II RECTAL CANCER. <ul><li>527 stage II & 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>> 13 nodes 19 % 82 %* </li></ul>* P < 0.02. NB No difference in survival for stage III disease. Tepper et al 2001
  52. 65. Rullier et al 2008
  53. 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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