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RCPath Colorectal Cancer Pathology Standards and Datasets Professor Geraint Williams Cardiff University NBCSP Pathology PowerPoint Presentation
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RCPath Colorectal Cancer Pathology Standards and Datasets Professor Geraint Williams Cardiff University NBCSP Pathology Meeting 22 November 2007. Variable. Prognostically significant?. p value. Variable. Prognostically significant?. p value. Specimen/ operation type. YES. p<0.001.

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slide1
RCPath Colorectal Cancer Pathology Standards and Datasets

Professor Geraint Williams

Cardiff University

NBCSP Pathology Meeting

22 November 2007

slide4

Variable

Prognostically significant?

p value

Variable

Prognostically significant?

p value

Specimen/

operation type

YES

p<0.001

CRM involvement

YES

p<0.001

Local invasion (pT)

YES

p<0.001

Distance to CRM

YES

p<0.001

No. lymph nodes examined

YES

p<0.001

Peritoneal involvement

YES

p<0.001

No. of positive nodes (pN)

YES

p<0.001

Extramural vascular inv.

YES

p<0.001

Validation of Minimum Dataset variables

NYCRIS, 5604 cases, 7 years

slide5
New Information
  • Population data from Registries
    • Northern & Yorkshire
  • Large single centre studies
    • Gloucester
  • Multicentre randomised trials
    • CLASSIC
    • Dutch Rectal Cancer Study
    • CR07
changes
Changes
  • Clarify features of therapeutic importance
    • Lymph nodes
    • Non-peritonealised surgical resection margins
    • Tumour perforation
    • Serosal involvement
    • Extramural venous invasion
changes7
Changes
  • Clarify features of therapeutic importance
  • Introduce new data items of proven prognostic importance
    • Measure the depth of extramural spread
    • Grade the quality of the resection plane in rectal cancer
    • Record complete or marked regression following neoadjuvant therapy for rectal cancer
changes8
Changes
  • Clarify features of therapeutic importance
  • Introduce new data items of proven prognostic importance
  • Introduce quality standards
changes9
Changes
  • Clarify features of therapeutic importance
  • Introduce new data items of proven prognostic importance
  • Introduce quality standards
  • Include recommendations for reporting local excisions
changes10
Changes
  • Clarify features of therapeutic importance
  • Introduce new data items of proven prognostic importance
  • Introduce quality standards
  • Include recommendations for reporting local excisions
  • Streamline the proforma
slide11
Features of Therapeutic Importance
  • Lymph node metastases
    • ALL nodes examined
    • care with those close to non-peritonealised margin
    • consider whether to embed whole nodes
    • count number of positive nodes
    • fat clearance, serial sections, immunostaining or molecular investigation for “micrometastases”, recording of extracapsular spread, not recommended
lymph node sampling
Lymph Node Sampling

Pheby et al.J Clin Pathol 2004; 57: 43-47

slide13
Lymph Node Sampling
  • National Cancer Data Base, American College of Surgeons
  • 35,787 cases T3N0, 1985-91
  • 5 year survival:
    • 64% if 1-2 nodes examined
    • 86% if >25 nodes examined
  • Significant differences in survival between
    • 1-7
    • 8-12
    • 13+

Swanson et alAnn Surg Oncol 2003; 10: 65-71

slide15
NICE 2004

“There is no consensus on the precise number of lymph nodes that need to be examined, but the research evidence suggests that it should be in double figures”

RCPath STANDARD

In a series of at least 50 cases of symptomatic colorectal cancer the mean number of lymph nodes examined is 12

slide17
Revised N Staging
  • Isolated Tumour Cells or Clusters (ITCs)
    • Single cells, or small clusters <0.2mm in lymph nodes detected by ICC or H&E do NOT affect pN stage.
    • They may be coded as pN0 (i+)
      • or pN0 (mol+) if detected by flow cytometry or molecular techniques
      • or pN0 (i+) (sn) in a sentinel node
slide19
5th edition TNM
  • A tumour nodule greater than 3mm in diameter in perirectal or pericolic adipose tissue without histological evidence of residual lymph node is classified as a regional lymph node metastasis.
  • However, a tumour nodule up to 3mm in diameter is classified in the T category as discontinuous extension, i.e. T3
slide20
6th edition TNM
  • “A tumour nodule in the pericolic/perirectal adipose tissue without histologic evidence of residual lymph node is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node.
  • If the nodule has an irregular contour, it should be classified in the pT category, and also coded as V1 (microscopic venous invasion) or V2, if it was grossly evident, because there is a strong likelihood that it represents venous invasion”
  • An objective assessment (size) has been replaced by a subjective one (form and contour)
slide21
Impact of Changes
  • 80 cases pT3 colorectal cancer
  • Extramural nodules categorised into smooth and round or irregular by 23 pathologists
  • Agreement assessed by kappa statistics
slide22

7/16

13/10

slide24
Impact of Changes
  • 80 cases pT3 colorectal cancer
  • Extramural nodules categorised into smooth and round or irregular by 23 pathologists
  • Agreement assessed by kappa statistics
  • Kappa = 0.36 (2:1 or worse in 10 nodules)
  • No difference between consultants and trainees
  • No difference between specialists and non-specialists
slide25
Impact of Changes
  • Using majority opinion for each nodule:
  • 5/80 cases upstaged from N0 to N1
  • 4 more upstaged from N1 to N2

Howarth SM et al. Gut 2004; 53:A21

slide26

RCPath Recommendations

  • Retain 5th edition of TNM staging for colorectal cancer
slide27
Features of Therapeutic Importance
  • Non-peritonealised “Circumferential” margin positivity
slide28
Non-peritonealised Margin
  • “Bare” surgical margin
  • Completely different from the serosal surface
slide31
Non-peritonealised Margin Involvement (53/210 patients)

Anterior 74%

Lateral 13%

Posterior 13%

Direct spread 73.6%

Nodes 20.8%

Vascular 5.6%

Boyle et al 2004

slide32
Non-peritonealised Margin

Margin Local Recurrence

Primary tumour 22.1%

Lymph node 12.4%

Nagtegaal et alAm. J. Surg. Pathol. 2002; 26; 350–357.

slide33
Non-peritonealised Margin

Margin Local Recurrence

> 2mm 5.8%

1-2mm 14.9%

0 16.4%

Nagtegaal et alAm. J. Surg. Pathol. 2002; 26; 350–357.

slide35
Prognosis in Dukes B Colonic Carcinoma
  • Variable - good Bs and bad Bs
  • Many possible reasons:
    • encompasses T3 and T4 tumours
    • quality of lymph node sampling
  • Uncertainty with regard to adjuvant therapy
slide36
Prognosis in Dukes B Colonic Carcinoma
  • 268 cases, continuous, unselected
  • Single pathologist (mean LNs 21, tumour blocks 5.7)
  • 5 year survival rate 76% (95% CI 70-81%)
  • Logrank & Cox multivariate regression:
    • Tumour perforation
    • Serosal involvement
    • Venous invasion
    • Circumferential margin involvement

Petersen VC et alGut 2002; 51: 65-9

slide37
Prognosis in Dukes B Colonic Carcinoma
  • Tumour perforation 2
  • Serosal involvement 1
  • Venous invasion 1
  • Circumferential margin involvement 1

HIGH RISK = 2 or more

slide39
Tumour Perforation
  • Automatically pT4b
  • Assessed macroscopically and confirmed microscopically
  • Excludes perforation of the colon proximal to an obstructing cancer
  • May be serosal or retro/infra-peritoneal
slide40
Serosal Involvement
  • Different from omental or mesenteric deposits (pM1)
  • Independent prognostic factor in rectal and colonic cancer
  • Predicts intraperitoneal and/or pelvic recurrence

Shepherd et al 1995, 1997

Petersen et al 2002

slide41

Serosal involvement in Colon Cancer

No %

Lennon et al 118 30

Shepherd et al 173 43

Burdy et al 107 15

Merkel et al 611 12

Petersen et al 268 42

Morris 1306 22

slide42
RCPath STANDARD

The frequency of cases with serosal involvement is at least 10% for rectal cancer and 20% for colon cancer

slide43
Serosal involvement (pT4)
  • Tumour cells visible on peritoneal surface or free in peritoneum with ulceration of visceral peritoneum
  • Tumour close to serosal surface with inflammatory reaction or mesothelial hyperplasia - examine more levels
slide44

Serosal involvement (pT4)

  • Blocks from areas of peritoneal irregularity, pallor, dulling or inflammation
  • At least two sections with levels if close or inflamed
  • Reflections, crevices, clefts
slide48
Features of Therapeutic Importance
  • Extramural venous invasion
slide49
Venous invasion (706 cases)
  • Definite in 52%, thick walled veins 15%
  • 5 yr survival:

no VI 79% possible 70% definite 43%

no VI 79% intramural 66% extramural thin 41% extramural thick 19%

Talbot et al 1981

venous invasion
Venous Invasion

“tumour within extramural endothelium-lined space that is either surrounded by a rim of muscle or contains red blood cells”

Talbot et al 52%

NYCRIS 29%

Sternberg 52%

slide51

Venous Invasion in Colorectal Cancer

No %

Newland et al 467 16

Merkel et al 611 9

Petersen et al 268 34

Meguerdichian et al 256 28

Messerini et al 395 24

Morris 1306 12

slide52
RCPath STANDARD

The frequency of colorectal cancer cases with extramural venous invasion is at least 25%

slide54
Extramural venous invasion
  • Look for areas where veins emerge through muscularis propria
  • Worm-like structure at base of tumour
  • Sections tangential to base of tumour

Sternberg et al J Clin Pathol 2006; 59: 207-10

slide55
Extramural venous invasion
  • ‘Naked’ arteries
  • Levels and elastin stains when suspicion
slide57
Non-peritonealised margin involvement in colon cancer - the Cinderella surgical margin
  • Regions of the colon where a significant proportion of the circumference is retroperitoneal
    • caecum
    • ascending colon
    • descending colon
    • distal sigmoid
slide61
Features of Prognostic Importance
  • Measurement of extramural spread
slide62

Variable

Prognostically significant?

p value

Variable

Prognostically significant?

p value

Specimen/

operation type

YES

p<0.001

CRM involvement

YES

p<0.001

Local invasion (pT)

YES

p<0.001

Distance to CRM

YES

p<0.001

No. lymph nodes examined

YES

p<0.001

Peritoneal involvement

YES

p<0.001

No. of positive nodes (pN)

YES

p<0.001

Distance beyond muscularis propria (pT3)

YES

p<0.001

Extramural vascular inv.

YES

p<0.001

Validation of Minimum Dataset variables

NYCRIS, 5604 cases, 7 years

slide66
Plane of Surgical Resection

3 Mesorectal fascial plane

2 Intramesorectal plane

1 Muscularis propria plane

slide67

CR07

Local Recurrence

3 yr 5 yr

Mesorectal fascial plane 4% 8%

Intramesorectal plane 8% 9%

Muscularis propria plane 15% 21%

P=0.0019

slide68
Mesorectal fascial plane
  • Smooth mesorectal surface or minor irregularities only; no defect deeper than 5mm.
  • The mesorectum itself is of good bulk anteriorly and posteriorly
  • No ‘coning’ near the tumour
slide69
Intramesorectal plane
  • Irregular mesorectal surface; muscularis propria not visible except at insertion of levators
  • The mesorectum of moderate bulk anteriorly and posteriorly
  • Significant ‘coning’ distally
slide70
Muscularis propria plane
  • Mesorectal surface irregular with deep cuts and tears
  • Muscularis propria visible on surface
  • The mesorectum itself is of little bulk
  • Marked ‘coning’ near the tumour
slide72
yp TNM
  • Categorises the extent of tumour actually present in the specimen
  • NOT an estimate of disease prior to neoadjuvant therapy
  • Ignore residual acellular elements
  • At least 5 blocks of tumour site
slide73

Dworak Grading of Regression

Grade 0 No regression detectable.

Grade 1 Minimal regression : dominant tumour mass with obvious fibrosis and/or vasculopathy.

Grade 2 Moderate regression : dominantly fibrotic changes with few tumour cells or groups (easy to find).

Grade 3 Good regression : very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucin

Grade 4 Total regression : no tumour cells, only fibrotic mass or mucin

Dworak O et al Int J Colorectal Dis 1997; 12: 19-23

slide74

Relation to Outcome

  • Relapse-free survival when margins are clear
  • Grade 0-2 28%
  • Grade 3-4 72%
    • Rodel et al J Clin Oncol 2005; 23: 8688-96
slide75

Grading Regression

Grade 0 No regression detectable.

Grade 1 Minimal regression : dominant tumour mass with obvious fibrosis and/or vasculopathy.

Grade 2 Moderate regression : dominantly fibrotic changes with few tumour cells or groups (easy to find).

Grade 3 Good regression : very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucin

Grade 4 Total regression : no tumour cells, only fibrotic mass or mucin

slide76

Relation to Outcome

  • 66 rectal carcinomas
  • 4500 cGy RT + 5-FU based chemotherapy
  • 25.3% had >95% response
  • Improved recurrence-free survival (P = 0.05)
    • Shia J et alAm J Surg Pathol 2004; 28: 215-223
slide77
Regression Categories
  • No residual tumour and/or mucous lakes only
  • Minimal residual tumour, i.e. only occasional microscopic tumour foci are identified with difficulty
  • No marked regression
slide78
Non Core Items
  • Anatomical location of positive non-peritonealised margins
  • Quality of resection planes in A-P resections
    • Levator
    • Sphincteric
    • Intrasphincteric / submucosal
slide79
Non Core Items
  • Separate identification of mucinous tumours
  • Advancing margin (infiltrative vs expansive)
  • Tumour infiltrating lymphocytes
  • Tumour budding
  • Extramural nodules <3mm diameter
  • Intramural venous invasion
  • Immunohistochemical data
  • Molecular data
slide80
Reporting Local Excisions
  • Polypectomy
  • Endoscopic mucosal resections
  • Transanal endoscopic microsurgical excision of rectal tumours
slide81
Indications for Formal Resection
  • Incomplete excision
    • including tumours <1 mm from margin
  • Poor differentiation (? worst area)
  • Lymphatic or vascular invasion
  • Invasion of deep submucosa
slide83
“Adverse outcome” in relation to Haggitt levels

0-3 1/101

4 7/28

Haggitt et al 1995

1-2 0/42

3 6/24

4 27/185

Ueno et al 2004

slide84

Kikuchi Levels and LN involvement

2%

8%

23%

Kikuchi et al Dis Colon Rectum 1995; 38: 1286

slide86
Lymph Node Metastasis and Dimensions of Invasive Tumour

Width of submucosal invasion

<4mm 2.5%

>4mm 18.2%

Depth of submucosal invasion

<2mm 3.9%

>2mm 17.1%

Ueno et al Gastroenterology 2004; 127: 385

slide89

Acknowledgements

Phil Quirke

Neil Shepherd

Bowel Cancer Screening Programme Pathology Advisory Panel

Royal College of Pathologists

BSG Pathology Section