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

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