RCPath Colorectal Cancer Pathology Standards and Datasets

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• RCPath Colorectal Cancer Pathology Standards and
  Datasets
• Professor Geraint Williams
• Cardiff University
• NBCSP Pathology Meeting
• 22 November 2007

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Validation of Minimum Dataset variables
NYCRIS, 5604 cases, 7 years
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• New Information
• Population data from Registries
• Northern Yorkshire
• Large single centre studies
• Gloucester
• Multicentre randomised trials
• CLASSIC
• Dutch Rectal Cancer Study
• CR07

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Changes

• Clarify features of therapeutic importance
• Lymph nodes
• Non-peritonealised surgical resection margins
• Tumour perforation
• Serosal involvement
• Extramural venous invasion

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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

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Changes

• Clarify features of therapeutic importance
• Introduce new data items of proven prognostic
  importance
• Introduce quality standards

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Changes

• Clarify features of therapeutic importance
• Introduce new data items of proven prognostic
  importance
• Introduce quality standards
• Include recommendations for reporting local
  excisions

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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

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• 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

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Lymph Node Sampling
Pheby et al. J Clin Pathol 2004 57 43-47
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• 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 gt25 nodes examined
• Significant differences in survival between
• 1-7
• 8-12
• 13

Swanson et al Ann Surg Oncol 2003 10 65-71
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plt0.001
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• 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

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• Revised N Staging
• Isolated Tumour Cells or Clusters (ITCs)
• Single cells, or small clusters lt0.2mm in lymph
  nodes detected by ICC or HE 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

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• 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

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• 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)

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• 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

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7/16
13/10
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21/2
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• 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 (21 or worse in 10 nodules)
• No difference between consultants and trainees
• No difference between specialists and
  non-specialists

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• 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 53A21
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RCPath Recommendations

• Retain 5th edition of TNM staging for colorectal
  cancer

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• Features of Therapeutic Importance
• Non-peritonealised Circumferential margin
  positivity

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• Non-peritonealised Margin
• Bare surgical margin
• Completely different from the serosal surface

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• 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

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• Non-peritonealised Margin
• Margin Local Recurrence
• Primary tumour 22.1
• Lymph node 12.4
• Nagtegaal et al Am. J. Surg. Pathol. 2002 26
  350357.

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• Non-peritonealised Margin
• Margin Local Recurrence
• gt 2mm 5.8
• 1-2mm 14.9
• 0 16.4
• Nagtegaal et al Am. J. Surg. Pathol. 2002 26
  350357.

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• 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

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• 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 al Gut 2002 51 65-9
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• Prognosis in Dukes B Colonic Carcinoma
• Tumour perforation 2
• Serosal involvement 1
• Venous invasion 1
• Circumferential margin involvement 1
• HIGH RISK 2 or more

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• 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

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• 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

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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

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

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• 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

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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

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• Features of Therapeutic Importance
• Extramural venous invasion

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• 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

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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

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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

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• RCPath STANDARD
• The frequency of colorectal cancer cases with
  extramural venous invasion is at least 25

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Quality
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• 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

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• Extramural venous invasion
• Naked arteries
• Levels and elastin stains when suspicion

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• 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

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• Features of Prognostic Importance
• Measurement of extramural spread

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Validation of Minimum Dataset variables
NYCRIS, 5604 cases, 7 years
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plt0.001
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MRI Validation
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Quality of TME Specimens
1
2
3
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• Plane of Surgical Resection
• 3 Mesorectal fascial plane
• 2 Intramesorectal plane
• 1 Muscularis propria plane

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CR07

• Local Recurrence
• 3 yr 5 yr
• Mesorectal fascial plane 4 8
• Intramesorectal plane 8 9
• Muscularis propria plane 15 21
• P0.0019

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• 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

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• 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

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• 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

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• 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

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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
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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
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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

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Relation to Outcome 66 rectal
carcinomas 4500 cGy RT 5-FU based
chemotherapy 25.3 had gt95 response Improved
recurrence-free survival (P 0.05) Shia J et
al Am J Surg Pathol 2004 28 215-223
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• 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

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• Non Core Items
• Anatomical location of positive
  non-peritonealised margins
• Quality of resection planes in A-P resections
• Levator
• Sphincteric
• Intrasphincteric / submucosal

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• Non Core Items
• Separate identification of mucinous tumours
• Advancing margin (infiltrative vs expansive)
• Tumour infiltrating lymphocytes
• Tumour budding
• Extramural nodules lt3mm diameter
• Intramural venous invasion
• Immunohistochemical data
• Molecular data

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• Reporting Local Excisions
• Polypectomy
• Endoscopic mucosal resections
• Transanal endoscopic microsurgical excision of
  rectal tumours

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• Indications for Formal Resection
• Incomplete excision
• including tumours lt1 mm from margin
• Poor differentiation (? worst area)
• Lymphatic or vascular invasion
• Invasion of deep submucosa

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Haggitt RC et al Gastroenterology 198589328-36
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• 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

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Kikuchi Levels and LN involvement
2
8
23
Kikuchi et al Dis Colon Rectum 1995 38 1286
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Ueno et al Gastroenterology 2004 127 385
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• Lymph Node Metastasis and Dimensions of Invasive
  Tumour
• Width of submucosal invasion
• lt4mm 2.5
• gt4mm 18.2
• Depth of submucosal invasion
• lt2mm 3.9
• gt2mm 17.1

Ueno et al Gastroenterology 2004 127 385
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Acknowledgements

• Phil Quirke
• Neil Shepherd
• Bowel Cancer Screening Programme Pathology
  Advisory Panel
• Royal College of Pathologists
• BSG Pathology Section