Colorectal cancer (CRC) epidemiology and pathology Gábor Cserni, MD, PhD, DSc Bács-Kiskun County Teaching Hospital Kecskem...
Incidence estimates ‘06 <ul><li>Europe </li></ul><ul><ul><li>217.4 thousand (men) </li></ul></ul><ul><ul><li>195.4 thousan...
Mortality ‘06 <ul><li>Europe </li></ul><ul><ul><li>107.6 thousand (men) </li></ul></ul><ul><ul><li>99.9 thousand (women) <...
ACS 2010 n=72090 n=70480 Estimated deaths: 26580 Estimated deaths: 24790
Risk factors <ul><li>Age (>90% of CRC  ≥ 50y) </li></ul><ul><li>Obesity </li></ul><ul><li>Inactivity </li></ul><ul><li>Die...
Molecular pathways <ul><li>Chromosome instability  (85%) </li></ul><ul><ul><li>Aneuploidy, gains and losses, translocation...
Different pathways <ul><li>Adenoma - carcinoma pathway </li></ul><ul><li>Serrated pathway  </li></ul><ul><ul><li>MSI-H - s...
Based on:  Jass JR. Histopathology 2007;50:113-130. MS: microsatellite; CIMP: CpG island methylator phenotype; TSA: tradit...
Phenotype of MSI-H tumors <ul><li>Right  / left colon (9:1) </li></ul><ul><li>More often  exophytic   </li></ul><ul><li>Mu...
An example NOS   Mucinous Signet ring cells MSH2 MLH1 TIL
Histological types <ul><li>Adenocarcinoma   NOS (usual type) </li></ul><ul><ul><li>dirty (intraglandular necrosis), CK20+,...
Grade <ul><li>For  adenocarcinoma NOS </li></ul><ul><ul><li>LG : >50% gland formation </li></ul></ul><ul><ul><li>HG : <50%...
Medullary carcinoma MLH1 MSH2
Prognostic factors  (cat I – IIA) <ul><li>Stage (pT, pN, M) </li></ul><ul><li>Lymphatic or venous invasion (L, V) </li></u...
Primary tumor: (c)T & pT ( TNM7 ) <ul><li>T & pT  </li></ul><ul><ul><li>TX: Not assessable  (to be minimized) </li></ul></...
pT3:  pT3a  (up to 5 mm from the muscularis propria) &  pT3b  (over 5 mm from the muscularis propria) <ul><li>pT3a tumors ...
Assessment of peritoneal involvement Higher pT4 ration as a result of more precise pathological work-up
Lymph nodes: pN <ul><li>pNX :  Not assessable  (eg: removed earlier / not removed / no LNs identified) </li></ul><ul><li>p...
Lymph node metastasis vs TD <ul><li>Tumor nodule lacking elements of a LN </li></ul><ul><li>TNM5 </li></ul><ul><ul><li>>3 ...
Lymph node metastasis vs TD V1 V1 – orcein stain
Lymph node metastasis vs  TD <ul><li>Tumor nodule lacking elements of a LN </li></ul><ul><li>TNM7 </li></ul><ul><ul><li>Ca...
The suggested number of LNs to be assessed for a reliable pN0 <ul><li>6   Hernanz F et al. Dis Colon Rectum 1994;37:373-6....
How many LNs? As many as possible ! 8574 T3N0M0 CRC from the SEER database Cserni G,  et al . Is there a minimum number of...
Distribution of pN categories at BKMK <ul><li>1997 </li></ul><ul><li>Mean (SD): 9,2 (6,1) </li></ul><ul><li>Median: 8 </li...
Distance from the tumour as qualitative feature Cserni G,  et al .  Distance of lymph nodes from the tumor, an important f...
An example A B A B B C C C No fraction D in this specific case
Results <ul><li>53 pN1 or pN2 </li></ul><ul><li>All but 1 staged correctly as pN+ on the basis of LNs from fraction A </li...
Further testing <ul><li>762 further CRCs studied  - sections A & B (3cm) vs C & D (>3cm) till end 2008 </li></ul><ul><li>O...
Sentinel nodes and lymphatic mapping in CRCs <ul><li>85/86 successfull SN identifications </li></ul><ul><li>29 N+ cases ; ...
Unexpected lymph drainage <ul><li>Lymphatic mapping studies have demonstrated that  direct drainage may occur from a tumor...
Less success in other series   (11-50 pts, mean 24 pts / series) <ul><li>False negative rates  (false negatives / all posi...
Distant metastasis (M –pM) <ul><li>cM0   N o distant metastasis . </li></ul><ul><li>M1/pM1   Distant metastasis. </li></ul...
Venous invasion <ul><li>HE detected VI in 18%  </li></ul><ul><li>Orcein (elastica stain) detected VI in 71% </li></ul><ul>...
Suspected VI in muscularis pr NOT VI! Unsuspected VI in submucosa VI!
 
Resection margins <ul><li>Longitudinal: rarely (1-2%) involved; to be assessed if <3 cm. </li></ul><ul><li>Circumferential...
Quality of surgery  (TME) <ul><li>Quirke's graded assessment of completeness of mesorectal excision  (MRC trial) : </li></...
<ul><li>Once the mesorectum has been violated the risk for spillage of tumor from lymphatics exists.   A  ragged specimen ...
G 3 – Good quality - mesorectal plane (complete TME)
G 1 – Poor quality - muscular plane (incomplete TME)
Tumor regression  grade (TRG) <ul><li>Example ( Dworak 1997 ) </li></ul><ul><li>A: G0 – no regression </li></ul><ul><li>B:...
Predictive factors <ul><li>MSI-H : better prognosis, but  less effect expected from 5FU therapy ? </li></ul><ul><ul><li>Ri...
Predictive factors <ul><li>K-RAS wild type  (vs activating mutation) is predictive of response to  anti-EGFR  therpapies <...
THE END
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BALKAN MCO 2011 - V. Gregorc - Epidemiology, pathology and molecular biology

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BALKAN MCO 2011 - V. Gregorc - Epidemiology, pathology and molecular biology

  1. 1. Colorectal cancer (CRC) epidemiology and pathology Gábor Cserni, MD, PhD, DSc Bács-Kiskun County Teaching Hospital Kecskemét, Hungary
  2. 2. Incidence estimates ‘06 <ul><li>Europe </li></ul><ul><ul><li>217.4 thousand (men) </li></ul></ul><ul><ul><li>195.4 thousand (women) </li></ul></ul><ul><ul><li>412.9 thousand cases </li></ul></ul><ul><ul><li>approx. 12.9% of all cancer cases </li></ul></ul>EUROPE EU Ann Oncol 2007;18:531
  3. 3. Mortality ‘06 <ul><li>Europe </li></ul><ul><ul><li>107.6 thousand (men) </li></ul></ul><ul><ul><li>99.9 thousand (women) </li></ul></ul><ul><ul><li>207.4 thousand cases </li></ul></ul><ul><ul><li>approx. 12.2% of all cancer deaths </li></ul></ul>EUROPE EU Ann Oncol 2007;18:531
  4. 4. ACS 2010 n=72090 n=70480 Estimated deaths: 26580 Estimated deaths: 24790
  5. 5. Risk factors <ul><li>Age (>90% of CRC ≥ 50y) </li></ul><ul><li>Obesity </li></ul><ul><li>Inactivity </li></ul><ul><li>Diet (red and processed meat) </li></ul><ul><li>Heavy alcohol consumption </li></ul><ul><li>Long term smoking </li></ul><ul><li>? Low fiber diet </li></ul><ul><li>Inflammatory bowel disease </li></ul><ul><li>Family history </li></ul><ul><li>Hereditary syndromes: FAP (APC), juvenile polyposis syndrome (SMAD4), HNPCC (MMR genes), Cowden sydrome (PTEN) </li></ul>
  6. 6. Molecular pathways <ul><li>Chromosome instability (85%) </li></ul><ul><ul><li>Aneuploidy, gains and losses, translocations </li></ul></ul><ul><li>Microsatellite instability (15%) – due to mismatch repair gene dysfunction </li></ul><ul><ul><li>Mutation (if germline: HNPCC) </li></ul></ul><ul><ul><li>Methylation (sporadic MSI-H CRCs) </li></ul></ul>
  7. 7. Different pathways <ul><li>Adenoma - carcinoma pathway </li></ul><ul><li>Serrated pathway </li></ul><ul><ul><li>MSI-H - sessile serrated polyp/adenoma as precursor lesion (more often right sided) </li></ul></ul><ul><ul><li>Distal, MSI-L / MSS - traditional serrated adenoma (more often left sided) </li></ul></ul>
  8. 8. Based on: Jass JR. Histopathology 2007;50:113-130. MS: microsatellite; CIMP: CpG island methylator phenotype; TSA: traditional serrated adenoma Ex adenoma, TIL R>L F>M Neg MSI-H (HNPCC) Ex adenoma, dirty necrosis, tumor budding L>R M>F APC TP53 (KRAS) Neg MSS Ex villous adenoma (kras+) or serrated adenoma L>R M>F KRAS+ Low MSI- L or MSS Ex serrated polyps (TSA), serrated, mucinous, HG non-circumscribed, (TIL) R>L F>M BRAF+ High MSI- L or MSS Ex serrated polyps (sessile), serrated, mucinous , HG circumscribed, TIL R>L F>M BRAF+ High MSI-H (sporadic) Morphology Loc M / F Other CIMP MSI / MSS
  9. 9. Phenotype of MSI-H tumors <ul><li>Right / left colon (9:1) </li></ul><ul><li>More often exophytic </li></ul><ul><li>Mucinous type or component (>10%) or medullary type or component (>10%) or signet ring cell type or microglandular pattern </li></ul><ul><li>Tumor infiltrating lymphocytes ( TIL ) </li></ul><ul><li>(minimum of 5 lymphocytes / 1 out 10 HPF) </li></ul>
  10. 10. An example NOS Mucinous Signet ring cells MSH2 MLH1 TIL
  11. 11. Histological types <ul><li>Adenocarcinoma NOS (usual type) </li></ul><ul><ul><li>dirty (intraglandular necrosis), CK20+, CK7-, cdx2+ </li></ul></ul><ul><li>Mucinous ( ≥ 50% component) </li></ul><ul><li>Signet ring cell ( ≥ 50% composed of such cells) </li></ul><ul><li>Medullary (no gland formation, tumor-infiltrating lymphocytes) </li></ul><ul><ul><li>can be CK20- CK7- (or CK7+) cdx2+/- (or cdx2-) </li></ul></ul><ul><li>Undifferentiated (no or at most 5% glands) </li></ul><ul><li>Other rare types: anenosquamous, squamous, WD or poorly differentiated neuroendocrine… etc </li></ul>
  12. 12. Grade <ul><li>For adenocarcinoma NOS </li></ul><ul><ul><li>LG : >50% gland formation </li></ul></ul><ul><ul><li>HG : <50% gland formation </li></ul></ul><ul><ul><li>Three-tiered system: G1 - >95% gland forming & >75% of glands are smooth and regular & no significant component with high grade nuclei; G2 – 50-95% gland forming; G3 - <50% gland forming; ( G4 – undifferentiated tumours) </li></ul></ul><ul><li>Signet ring cell carcinoma and small cell carcinoma are HG by definition </li></ul><ul><li>Medullary carcinoma should not be graded </li></ul><ul><li>Mucinous carcinomas : unsure whether they should be gr a ded or considered high grade. </li></ul>
  13. 13. Medullary carcinoma MLH1 MSH2
  14. 14. Prognostic factors (cat I – IIA) <ul><li>Stage (pT, pN, M) </li></ul><ul><li>Lymphatic or venous invasion (L, V) </li></ul><ul><li>Completeness of excision with curative intent (R) </li></ul><ul><li>Grade </li></ul><ul><li>Type </li></ul><ul><li>Regression </li></ul>Based on Compton C et al. Arch Pathol Lab Med 2000
  15. 15. Primary tumor: (c)T & pT ( TNM7 ) <ul><li>T & pT </li></ul><ul><ul><li>TX: Not assessable (to be minimized) </li></ul></ul><ul><ul><li>T0 : No tumor </li></ul></ul><ul><ul><li>Tis : carcinoma in situ: intraepithelial tumor or involving the lamina propria ( intramucosal ) </li></ul></ul><ul><ul><li>T1 : Tumor invading into submucosa . </li></ul></ul><ul><ul><li>T2 : Tumor invading into muscularis propria . </li></ul></ul><ul><ul><li>T3 : Tumor invading into pericolorectal tissues . </li></ul></ul><ul><ul><li>T4a: Tumor penetrating through visceral peritoneum. </li></ul></ul><ul><ul><li>T4b: Tumor invading into adjacent organs or structures (through the peritoneum or over the m. propria for retro- or infraperitoneal locali z ations) </li></ul></ul>
  16. 16. pT3: pT3a (up to 5 mm from the muscularis propria) & pT3b (over 5 mm from the muscularis propria) <ul><li>pT3a tumors have a better prognostic profile than pT3b. </li></ul>Bori R et al. Pathol Oncol Res 2009;15:527-32.
  17. 17. Assessment of peritoneal involvement Higher pT4 ration as a result of more precise pathological work-up
  18. 18. Lymph nodes: pN <ul><li>pNX : Not assessable (eg: removed earlier / not removed / no LNs identified) </li></ul><ul><li>pN0 : No regional LN metastasis (including isolated tumor cell clusters) </li></ul><ul><li>pN1 : Metastasis to 1-3 regional LNs </li></ul><ul><ul><li>pN1mi Micrometastasis (>0.2 mm and/or >200 cells , but none > 2.0 mm) </li></ul></ul><ul><ul><li>pN1a Metastasis to 1 LN (>2 mm) </li></ul></ul><ul><ul><li>pN1b Metastasis to 2-3 LN (at least one metastasis >2 mm) </li></ul></ul><ul><ul><li>pN1c Tumor deposit(s) (TD) in the subserosa, mesocolon, pericolic, perirectal tissues, without LN structure, if there is no LN metastasis </li></ul></ul><ul><li>pN2 : Metastasis to 4 or more regional LNs </li></ul><ul><ul><li>pN2a Metastasis to 4-6 LNs (at least one metastasis >2 mm) </li></ul></ul><ul><ul><li>pN2b Metastasis to 7 or more LNs (at least one metastasis >2 mm) </li></ul></ul>
  19. 19. Lymph node metastasis vs TD <ul><li>Tumor nodule lacking elements of a LN </li></ul><ul><li>TNM5 </li></ul><ul><ul><li>>3 mm: LN metastasis -> pN </li></ul></ul><ul><ul><li>≤ 3 mm: discontinuous tumor spread -> pT </li></ul></ul><ul><li>TNM6 </li></ul><ul><ul><li>Regular outline: LN metastasis -> pN </li></ul></ul><ul><ul><li>irregular outline: venous invasion: -> V1 </li></ul></ul>
  20. 20. Lymph node metastasis vs TD V1 V1 – orcein stain
  21. 21. Lymph node metastasis vs TD <ul><li>Tumor nodule lacking elements of a LN </li></ul><ul><li>TNM7 </li></ul><ul><ul><li>Can be: discontinuous tumor spread, completely destroyed LN (N1/2), venous invasion (V1/2), </li></ul></ul><ul><ul><li>If destroyed LN: -> pN category </li></ul></ul><ul><ul><li>Discontinuous spread, venous invasion (V1/2) -> TD ( pN1c, if no LN metastasis, for T1-2 tumors) </li></ul></ul><ul><li>TD and V1 on the basis of the orcein (elastica) stain </li></ul>
  22. 22. The suggested number of LNs to be assessed for a reliable pN0 <ul><li>6 Hernanz F et al. Dis Colon Rectum 1994;37:373-6. </li></ul><ul><li>7 Caplin S et al. Cancer 1998;83:666-72. - Mainprize KS et al. J Clin Pathol 1998;51:165-6. - Cserni G. J Clin Pathol 2002;55:386-90. </li></ul><ul><li>8 Maurel J et al. Cancer 1998;82:1482-6. </li></ul><ul><li>9 Cianchi F et al. World J Surg 2002;26:384-9. </li></ul><ul><li>12 TNM Supplement 3rd Ed </li></ul><ul><li>13 Scott KWM et al. Br J Surg 1989;76:1165-7. </li></ul><ul><li>14 Wong JH et al. J Clin Oncol 1999;17:2896-900. - Tepper JE et al. J Clin Oncol 2001;19:157-63. </li></ul><ul><li>16 Cserni G et al. Pathol Oncol Res 1999;5:291-6. </li></ul><ul><li>17 Goldstein NS. Am J Surg Pathol 2002;26:179-89. </li></ul><ul><li>20 Greco P et al. Virchows Arch 2006;449:647-651. </li></ul>
  23. 23. How many LNs? As many as possible ! 8574 T3N0M0 CRC from the SEER database Cserni G, et al . Is there a minimum number of lymph nodes that should be histologically assessed for a reliable nodal staging of T3N0M0 colorectal carcinomas? J Surg Oncol 2002; 81:63-69.
  24. 24. Distribution of pN categories at BKMK <ul><li>1997 </li></ul><ul><li>Mean (SD): 9,2 (6,1) </li></ul><ul><li>Median: 8 </li></ul><ul><li>Range: 0-31 </li></ul><ul><li>2006 </li></ul><ul><li>Mean (SD): 19 (11) </li></ul><ul><li>Median: 17 </li></ul><ul><li>Range: 3-57 </li></ul>Number of LNs assessed More
  25. 25. Distance from the tumour as qualitative feature Cserni G, et al . Distance of lymph nodes from the tumor, an important feature in colorectal cancer specimens. Arch Pathol Lab Med 2001; 125:246-249. Tumour + 1-1 cm 2 cm 2 cm 3 cm 3 cm D C B A B C D 100 cases of CRC Mean: 17 LN / case
  26. 26. An example A B A B B C C C No fraction D in this specific case
  27. 27. Results <ul><li>53 pN1 or pN2 </li></ul><ul><li>All but 1 staged correctly as pN+ on the basis of LNs from fraction A </li></ul><ul><li>All staged correctly on the basis of A and B (3 cms from the tumor in each direction </li></ul><ul><li>SUGGESTION: </li></ul><ul><li>LNs from below the tumor and its 3 cm-wide perimetry should be evaluated for reliable staging. </li></ul><ul><li>Look for further LNs if <7, or if pN1 with 3 LNs + ! </li></ul>Cserni G, et al . Arch Pathol Lab Med 2001; 125:246-249.
  28. 28. Further testing <ul><li>762 further CRCs studied - sections A & B (3cm) vs C & D (>3cm) till end 2008 </li></ul><ul><li>Only 4/369 N+ cases had metastasis in a LN from segment CD without having metastasis in the AB segment. </li></ul><ul><li>14 further cases would have been wrongly classified as pN1 instead of pN2 </li></ul><ul><li>This error rate is LOWER than the FNR of lymphatic mapping </li></ul>Cserni G et al. J Clin Pathol 2011
  29. 29. Sentinel nodes and lymphatic mapping in CRCs <ul><li>85/86 successfull SN identifications </li></ul><ul><li>29 N+ cases ; 15 only SN+ (7 only micrometastatic; 2 only IHC) </li></ul><ul><li>3 false negative cases </li></ul><ul><li>(3.6% FNR as reported - 10.3 % FNR as I understand it ) </li></ul><ul><li>The aim would be a more reliable and improved staging (detailed pathology of SLNs). </li></ul><ul><li>Saha S et al. Ann Surg Oncol 2000;7:120-4 . </li></ul>
  30. 30. Unexpected lymph drainage <ul><li>Lymphatic mapping studies have demonstrated that direct drainage may occur from a tumor site to apical or even paraaortic LNs . </li></ul><ul><li>Merrie AE, et al. Dis Colon Rectum 2001; 44 :410-7. </li></ul><ul><li>T his LN proved to be the only positive LN resected with the colon, but was outside the margins of a standard right hemicolectomy , the operation usually performed for a primary carcinoma at the given location. </li></ul><ul><li>Ts i oulias GJ, et al. Arch Surg 2000; 135 :926-32. </li></ul><ul><li>Bilchik AJ, et al. J Clin Oncol 2001; 19 :1128-36. </li></ul>The only positive (only CK+) / 18 LN Same 2 cases reported in 2 papers
  31. 31. Less success in other series (11-50 pts, mean 24 pts / series) <ul><li>False negative rates (false negatives / all positives) & upstaging rates: </li></ul><ul><li>1/3 (33%) & NA Evangelista W et al. Tumori 2002 ; 88 :37-40 . </li></ul><ul><li>1/3 (33%) & 2/13 (15%) Tsoulias GJ et al. Am Surg 2002; 68 :561-5. </li></ul><ul><li>5/13 (38%) & NA Cserni G et al. Pathol Oncol Res 1999; 5 :291-6. </li></ul><ul><li>3/7 (43%) & 2/16 (13%) Merrie AE et al. Dis Colon Rectum 2001; 44 :410-7. </li></ul><ul><li>2/7 (29%) & 2/20 (10%) F i tzg e rald TL et al. J Surg Oncol 2002; 80 :27-33. </li></ul><ul><li>1/3 (33%) & NA Esser S et al. Dis Colon Rectum 2001; 44 :850-6 </li></ul><ul><li>2/8 (25%) & NA K i tagawa Y et al. Surg Clin North Am 2000; 80 :1799-809. </li></ul><ul><li>12/20 (60%) & 2/15 (13%) Joosten JJA et al. Br J Surg 1999; 86 :482-6. </li></ul>
  32. 32. Distant metastasis (M –pM) <ul><li>cM0 N o distant metastasis . </li></ul><ul><li>M1/pM1 Distant metastasis. </li></ul><ul><ul><li>- M1a: metastasis limited to one organ or localization (eg.: liver, lung, ovary, non regional LN…) </li></ul></ul><ul><ul><li>- M1b: multiple organs or localizations involved </li></ul></ul>
  33. 33. Venous invasion <ul><li>HE detected VI in 18% </li></ul><ul><li>Orcein (elastica stain) detected VI in 71% </li></ul><ul><li>11/89 CRCs had synchronous metastasis (M1) </li></ul><ul><ul><li>9 N+ (pN1 or pN2) </li></ul></ul><ul><ul><li>all VI+ i.e. V1 </li></ul></ul><ul><li>Median follow-up of 17 months 9 further cases were diagnosed with metachronous distant metastasis </li></ul><ul><ul><li>6 N+ </li></ul></ul><ul><ul><li>and VI+ </li></ul></ul><ul><li>S pecificity and sensitivity for predicting distant metastasis : </li></ul><ul><ul><li>LN metastasis : 0.56 and 0.75 , respectively </li></ul></ul><ul><ul><li>O rcein detected VI : 0.39 and 1 , respectively </li></ul></ul><ul><li>Elastic stains enable the detection of clinically relevant VI in greater frequency than HE stained histological slides. If nodal involvement is an indication for systemic chemotherapy , our data suggest that VI detected by the orcein stain should also be an indication for that . </li></ul>Cserni G et al., JCP 2010;63(7):575-8.
  34. 34. Suspected VI in muscularis pr NOT VI! Unsuspected VI in submucosa VI!
  35. 36. Resection margins <ul><li>Longitudinal: rarely (1-2%) involved; to be assessed if <3 cm. </li></ul><ul><li>Circumferential (CRM) : involved in 5-36%; especially in rectum, whatever the mode of involvement </li></ul>Quirke P, Morris E. Histopathology 2007;50:103-12. Mucinous carcinoma CRM involvement: Local R1 resection (R2 if identified macroscopically
  36. 37. Quality of surgery (TME) <ul><li>Quirke's graded assessment of completeness of mesorectal excision (MRC trial) : </li></ul><ul><li>3-Good: Intact mesorectum with only minor irregularities of a smooth mesorectal surface.  No defect is deeper then 5 mm.  No coning on the specimen.  Smooth CRM on slicing . </li></ul><ul><li>2-Moderate: moderate bulk to the mesorectum but irregularity of the mesorectal su r face.   Moderate coning of the specimen towards the distal margin.  At no site is the m.propria visible with the exception of the insertion of levator muscles.  Moderate irregularity of CRM. </li></ul><ul><li>1-Poor: Little bulk to mesorectum with defects down onto m.propria and/or very irregular cir c umferential resection margin. </li></ul>
  37. 38. <ul><li>Once the mesorectum has been violated the risk for spillage of tumor from lymphatics exists.   A ragged specimen without a smooth surface must therefore be a grade 2 . </li></ul>
  38. 39. G 3 – Good quality - mesorectal plane (complete TME)
  39. 40. G 1 – Poor quality - muscular plane (incomplete TME)
  40. 41. Tumor regression grade (TRG) <ul><li>Example ( Dworak 1997 ) </li></ul><ul><li>A: G0 – no regression </li></ul><ul><li>B: G1 – dominant tumor with fibrosis </li></ul><ul><li>C: G2 – significant fibrosis with groups of tumor cells </li></ul><ul><li>D/E: G3 – dominant fibrosis or mucin with very few tumor cells </li></ul><ul><li>F: G4 – complete pathological regression </li></ul>Jacob C et al. J Pathol 2004;204:562-8.
  41. 42. Predictive factors <ul><li>MSI-H : better prognosis, but less effect expected from 5FU therapy ? </li></ul><ul><ul><li>Ribic CM et al. NEJM 2003;349:247-57. </li></ul></ul><ul><ul><li>? Meta-analysis of M1 CRC studies: no ( Des Guetz G et al. Eur J Cancer 2009;45:1890 ) </li></ul></ul><ul><ul><li>As 5-FU mainly acts through the inhibition of TS… </li></ul></ul><ul><li>Low tymidylate synthase ( TS ) expression in biopsy: predictive for response to neoadjuvant 5FU based chemoradiotherapy </li></ul><ul><li>Lower expression of TS and thymidine phosphorylase (TP) genes in post treatment tumor specimens of responders (vs non-responders). </li></ul><ul><ul><li>Jacob C. J Pathol 2004;204:562-8. </li></ul></ul>
  42. 43. Predictive factors <ul><li>K-RAS wild type (vs activating mutation) is predictive of response to anti-EGFR therpapies </li></ul>K-ras plays a central role in the downstream regulatory processes of the EGFR signaling pathway. Activating mutations abolish the GTP-ase activity required for inactivation.
  43. 44. THE END

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