Update on Colonic Serrated (and Conventional) Adenomatous ... · Longitudinal Outcome Study of...
Transcript of Update on Colonic Serrated (and Conventional) Adenomatous ... · Longitudinal Outcome Study of...
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Update on Colonic Serrated
(and Conventional)
Adenomatous Polyps
Robert D. Odze, MD, FRCPC
Chief, Division of GI Pathology
Professor of Pathology
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
Maui, HI 2018
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Serrated Pathway of Colon Carcinogenesis
Silencing of DNA mismatch repair genesby methylation of promoter region of genes
MSI-High colorectal cancer
Lack of APC, Kras and p53 mutations
Serrated morphologic phenotype
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Serrated Pathway of Colon Cancer:
Normal HP SSP
MSI-H
Invasive
CRC
The Hypothesis
BRAF
MSICIMP
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Classification of Serrated Colonic Polyps(WHO 2010 Modified)
1. Non-Dysplastic Serrated Polyps
Normal architecture, normal proliferation
Microvesicular hyperplastic polyp
Goblet cell hyperplastic polyp
Mucin-poor hyperplastic polyp
Abnormal Architecture, abnormal proliferation
Sessile serrated adenoma/polyp
2. Dysplastic Serrated Polyps
Sessile serrated polyp with dysplasia
Serrated adenoma (traditional)
Conventional adenoma with serrated architecture
3. Unclassifiable serrated polyp (either with or without dysplasia)
Hornick et al, In Odze RD, Goldblum J, ed. Surgical Pathology of the GI
Tract, Liver, Biliary Tract, and Pancreas. Second Edition, Philadelphia:
Elsevier Science; 2008.
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Microvesicular HP
• Sessile
• Microvesicular
mucin
• Left>right colon
• Generally<0.5 cm
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Goblet Cell Rich HP
• Sessile
• Minimal
serration
• Elongated
crypts
• ↑ goblet cells
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Mucin Poor HP
• Sessile
• No mucin
• ↑ serration
• Small cells with ↓
cytoplasm
• Dilated crypts
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Molecular
Features
Microvesicular Goblet Cell
Braf 80% Rare
Kras Rare 54%
CIMP-high 68% Rare
P53 - -
Hyperplastic Polyps
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Sessile Serrated PolypSynonyms
Sessile serrated Adenoma
Giant (large) hyperplastic polyp
HP with dysmaturation
HP with increased proliferation
HP with altered proliferation
Atypical HP
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SSP Clinical Features
• More often located in the right colon
• Sessile, broad
• Usually >0.5 cm
• Up to 9% of all polyps (Spring et al, 2006)
– Account for ~1/3 to 1/4 of the serrated polyps
HP
SSP
Adenoma
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Courtesy of
Dr. Douglas
Sessile Serrated Polyp
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• Flat, broad, sessile
• Distorted crypts
• Aberrant diff/prolif
• Rt>left colon
• Generally >0.5 cm
• 9% of all colonic polyps
Sessile Serrated Adenoma/Polyp
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SSA/P
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SSA/P
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Sessile Serrated Polyp
With Dysplasia
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Left colon
0.3 cm
“Small” SSA/P
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Molecular Abnormalities of Colon
Polyps and Cancer
Polyp/cancer CIMP
high
MLH1
methylation
MSI Braf Kras
Conventional Ad + - - - ++
Cancer CIN +/- - - +/- ++
Cancer Lynch - - +++ - ++
Cancer CIMP-high +++ +++ +++ +++ -
HP + - - + +
SSA/P +++ - - +++ -
SSA/P with dys +++ ++ ++ +++ -
TSA ++ - - + +
Rex et al, Am J Gastroterol 2012 (In Press)
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Molecular Features of Colorectal
Hyperplastic Polyps and Sessile Serrated
Adenoma/Polyps from Korea
Kim et al, Am J Surg Pathol 2011;35(9):1274--1286
HP SSA/P
Without Dysplasia With Dysplasia
Feature Right (N=21) Left (N=23) Right (N=13) Left (N=7) Right (N=22) Left (N=15)
Mutations
KRAS 14.3% 47.8% 0% 28.6% 4.5% 26.7%
BRAF 76.2% 17.4% 69.2% 14.3% 68.2% 66.7%
Methylation
MGMT 47.6% 34.8% 61.5% 57.1% 77.3% 73.3%
hMLH1* 81% 47.8% 92.3% 42.9% 77.3% 66.7%
hMLH1† 33.3% 13% 30.8% 14.3% 22.7% 26.7%
APC 28.6% 47.8% 30.8% 14.3% 40.9% 46.7%
p16 66.7% 52.2% 92.3% 42.9% 77.3% 80%
CIMP high 76.2% 43.5% 92.3% 42.9% 77.3% 80%
*Primers by Herman et al†Primers by Park et al
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SSP and Risk of Cancer
• SSP and MSI-H cancers have similar clinical features
– Right sided, older female patients
• SSP precede MSI-H colorectal cancer
– Goldstein, et al, Am J Clin Path 2003
• Associated with hyperplastic polyposis syndrome
– Heterogenous disorder
– Familial clustering, underlying hereditary defect unknown
– Some risk of colon cancer
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Longitudinal Outcome Study of Sessile Serrated
Adenomas of the Colorectum: An Increased Risk for
Subsequent Right-sided Colorectal Carcinoma
Subjects with High-grade
Lesions
N Subjects with
subsequent
AP with LGD
All High-
grade
Lesions
AP with
HGD
CRC Time from
Diagnosis of
Polyp to
Subsequent
High-grade
Lesions (y)
SSA 40 18 6 (15%) 1 5 (13%) 8.3 (1-15)
HP 55 7 2 (4%) 1 1 (2%) 2.8 (2-3.6)
AP 55 26 3 (5%) 2 1 (2%) 3.2 (1.1-5.4)
AP indicates adenomatous polyp; CRC, colorectal carcinoma;
HGD, high-grade dysplasia; HP, hyperplastic polyp; LGD, low-
grade dysplasia; N, number of subjects without prior high-grade
lesions; SSA, sessile serrated adenoma
Lu et al, Am J Surg Pathol 2010;34(7):927-934
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Longitudinal Outcome Study of Sessile Serrated
Adenomas of the Colorectum: An Increased Risk for
Subsequent Right-sided Colorectal Carcinoma
Subjects with High-grade
Lesions
N Subjects with
subsequent
AP with LGD
All High-
grade
Lesions
AP with
HGD
CRC Time from
Diagnosis of
Polyp to
Subsequent
High-grade
Lesions (y)
SSA 40 18 6 (15%) 1 5 (13%) 8.3 (1-15)
HP 55 7 2 (4%) 1 1 (2%) 2.8 (2-3.6)
AP 55 26 3 (5%) 2 1 (2%) 3.2 (1.1-5.4)
AP indicates adenomatous polyp; CRC, colorectal carcinoma;
HGD, high-grade dysplasia; HP, hyperplastic polyp; LGD, low-
grade dysplasia; N, number of subjects without prior high-grade
lesions; SSA, sessile serrated adenoma
Lu et al, Am J Surg Pathol 2010;34(7):927-934
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Traditional Serrated Adenoma
• Pedunculated or sessile
• Eosinophilic cytoplasm
(↓ mucin)
• Left > right colon
• Any size
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Traditional Serrated Adenoma
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TSALow-Grade High-Grade Adenocarcinoma
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TSA with HP/SSP
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Traditional Serrated AdenomasMolecular Features
Braf 30-60%
Kras 10-27%*
APC 5-28%
MGMT 17-26%
P53 10-20%
*Associated with HGD & Carcinoma
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Adenoma with Serrated Architecture
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Serrated PolypsManagement
Hyperplastic Polyp Biopsy/Polypectomy
SSA/P -polypectomy (complete)
-adenoma-like surveillance?
SSA/P with Dysplasia
Traditional SA
-polypectomy (complete)
-advanced adenoma surveillance?
-colectomy for non-complete
excisions?
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Serrated Polyposis Syndrome*(Formerly Hyperplastic Polyposis)
• ≥5 serrated polyps proximal to sigmoid
● ≥2 at least 10 mm in size
• ≥1 serrated polyp proximal to sigmoid
● First degree relative with SPS
• >20 serrated polyps (any size) throughout colon
*No definitive gene mutation
identified
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Serrated Polyposis SyndromeHallmarks of Genetic Disease
• Phenotype diversity
• Multiple lesions (HP, SSP, Adenomas)
• Young age of onset
• Strong family history (50% have CRC)
• Restricted ethnicity
• 25-50% synchronous cancer in case series
• 7% risk at 5 years in surveillance
• “Methylator mileu” (Inherited? Acquired?)
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Serrated Polyposis SyndromeTreatment
• Screening at ≥40 years or 10 years younger than affected relative, 5 year intervals
• Surgery (extended Rt hemi or subtotal colectomy)
• Annual surveillance residual colon
• Endoscopic management is an option
– Clear all proximal serrated polyps
– Clear all >5 mm in size
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Colonic Neoplastic Precursor
Lesions
1. Benign conventional adenomas
– Non-advanced (tubular, LGD, <1 cm)
– Advanced (villous, HGD, >1 cm)
2. Malignant Colon Polyps
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Advanced vs Non-Advanced
Adenoma
• Criteria differ between studies
• No uniform/validated criteria for villi
or HGD
• Can endoscopy discriminate 0.9 from 1.1 cm accurately?
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Conventional AdenomasVillous
Tubular
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Tubular or Villous?
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High-Grade Dysplasia?
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“Advanced” Adenomas:
Pathologists Don’t Agree
19 GI Pathologists*1
11 General Pathologists
21 Adenomas
Villous *2 HGD
90% agreement 48% 62%
80% agreement 67% 71%
Kappa 0.49 0.43
*1GI pathologists agreed less than general pathologists
*2range of percent villosity; 2-100%
Golembeski et al, Mod Pathol 2007;120(S2):115A
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“Advanced” Adenomas:
Pathologists Don’t Agree
19 GI Pathologists*1
11 General Pathologists
21 Adenomas
Villous *2 HGD
90% agreement 48% 62%
80% agreement 67% 71%
Kappa 0.49 0.43
*1GI pathologists agreed less than general pathologists
*2range of percent villosity; 2-100%
Golembeski et al, Mod Pathol 2007;120(S2):115A
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Conventional AdenomasReporting Issues
• Status of margins
• Size
• Dysplasia (if <1 cm)
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Malignant Colorectal Polyp
Pathology
1. Definition/Terminology
2. Tissue Handling: Endoscopy/ Pathology
3. Pathology Assessment
- Prognostication
- Reporting
4. Summary
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Malignant Colorectal Polyp
Definition
Adenoma with submucosal
invasive adenocarcinoma
≠ High grade dysplasia
≠ Intramucosal adenocarcinoma
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Adenomas Terminology
WHO
Dysplasia/Intraepithelial neoplasia
-No BM invasion
Intramucosal adenocarcinoma
-LP or MM invasion
Submucosal adenocarcinoma
-Invasion beyond MM
pTis
pTis
pT1
“HGD”
“Invasive
Adenoca”
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Malignant Colon Polyp
Invasive Adenocarcinoma
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Information Pathologists Need
to Know
• Shape of Polyp (pedunculated, sessile)?
• Excised in total vs. piecemeal?
• Deepest (stalk) tissue margin
Do not pin, cut, or ink anything
Place in formalin ASAP!
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Polypectomy vs. Colectomy
Factors
1. Patient factors
– Age, co-morbidities, resectability, genetics (lynch), cancer phobia
1. Pathologic factors
– Gross (sessile vs. pedunculated)
– Microscopic
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Unfavorable (High Risk) Features*
Summary• Poor differentiation (high grade)
• LVI
• Positive margin (or <1 or 2 mm?)
• Tumor budding/ dedifferentiation
• Mucinous, cribriform morphology
• Sessile morphology (SM>1 cm)
(Tumor depth and width)
* Indications for colectomy due to risk of LNM, recurrence, metastasis and mortality
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Frequency of Carcinoma at colectomy or
Followup Post Polypectomy for
MCP
Studies # Polyps Unfavorable Outcome Unfavorable Outcome
(Total) (Low Risk* Polyps)
21 1227 135 (11%) 0 (0%)
Low Risk= Margin>2 mm, low grade
Tumor, no LVI
Seitz et al Dis Colon Rectm 2004;47: 1789-1797
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Poor differentiation
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Poor tumour differentiation
• 6-9% malignant polyps (should be <20%)
• Poor differentiation in any part of tumour but
particularly at invasive edge (some studies required 50%
of polyp)
• Patterns:o <50% gland lumina
o mucinous
o signet ring
o tumour ‘buds’ with >5 cells
o Gleeson pattern 4 like cribriform arrangements
o Undifferentiated carcinoma
o NOT true tumour budding (<5 cells)
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– Risk:
– Problem = Interobserver agreement is not good
• Kappa - 64-70% Cooper et al Gastroenterology. 1995;108:1657-65
- 0.14 Terris et al Mod Path 2012;25(2)182A
Residual disease Metastasis Mortality
% (average) 18% 23% 15%
Odds ratio - Hassan 2 4 9**
%/Odds ratio - Ueno 29%/3
(multivariate)
Hassan et al Dis Colon Rectum 2005;48:1588-96 Ueno et al
Gastroenterology 2004;127:385-94
Tumor Differentiation
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LVI
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Vascular invasion
Residual disease Metastasis Mortality
% (average) 18% 35%(LN)/5% (H) 3%
Odds ratio - Hassan 1 7/2** 1.5
%/Odds ratio - Ueno 31%/3
(multivariate)
Hassan et al Dis Colon Rectum 2005;48:1588-96
Ueno et al Gastroenterology 2004;127:385-94
• usually associated with another adverse prognostic
factor
• Vascular invasion does not add to risk when other
adverse factors are already present
• Interobserver agreement is poor/moderate – 37-77%
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> 2mm - clear POSITIVE
Tumor Margin
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Margin of resection
• positive variously defined
o In diathermy artefact
o 1 HP field
o <1mm
o <2mm
• Ueno et al Gastroenterology 2004;127:385-94 only diathermy artefact involvement significant
• ≥1 mm clearance Butte et al Dis Colon Rectum 2012;55:122-127
• general agreement that ≥ 2mm is definitely clear
• positive margin -33% (using all definitions)
Deep Margin
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Unfavorable Histology/ Outcome
Author # Cases Margin “Unfavorable” Adverse
Histology Outcome
Cooper
(1995)
Volk
(1995)
Seitz
(2004)
140
47
114
<1 mm
<2 mm
Clear
71 (50%)
30 (66%)
60 (52%)
20%
33%
27%
Poor diff, LVI, Margin <1 mm or <2 mm or clear
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Tumor Budding
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Tumour budding
• Identified as a significant prognostic factor in several papers
• Ueno et al Gastroenterology 2004;127:385-94
• Tateishi et al Mod Path 2010;1:1-5
• Sohn et al J Clin Pathol 2007;60:912-15
• Katajima et al J Gastroenterol 2004;39:534-43
• Yasuda et al Dis Colon Rectum 2007;50:1370-76
• Choi et al Dis Colon Rectum 2009; 52: 438-445
• Uniform definition lacking – range from any budding to strict definition
– Ueno paper = >5 buds (of <5 cells) in any one 20X field (FD = 0.785mm2);
– Sohn paper = >10 buds
• Reproducibility?
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Polyp morphology
• Pedunculated vs sessile
• Sessile - overall mortality 8x pedunculatedpolyps
• By definition all sessile polyps are Haggittlevel IV (but this over estimates risk based on Haggitt data)
• Reason sessile is worse = increased adverse factors are usually present:
• poor differentiation
• vascular invasion
• positive resection margin**
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Polyp morphology
Residual/recurrent
disease
Metastasis Mortality
% (average) - S 11%/6% 10%(LN)/4% (H) 5%
% (average) - P 3%/0.5% 10%(LN)/1% (H) 0.5%
Odds ratio - Hassan 4 1/4 10
- Risk for sessile polyp Vs pedunculated polyp – pooled
analysis*
Hassan et al Dis Colon Rectum 2005;48:1588-96
*approximation (multivariate)
? not an independent risk factorfor LN metastasis
However, most (85%) of sessile polyps had surgery
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Pathologic Factors
Tumor size/depth of invasion
(Haggitt, Kichuki/Kudo
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Haggitt levels
Haggitt et al Gastroenterology 1985;89:328-36
Depth of invasion
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Haggitt levels
• Haggitt paper Gastroenterology 1985;89:328-36
– 8/64 (12.5%) submucosal invasive carcinoma had an adverse
outcome (LN mets/tumour related death). These were:
• Levels 0-2 = 0 cases (0%)
• Level 3 = 1 case (12.5%)
• Level 4 = 7 cases (87.5%)**
– Level 4 is the significant factor
– 7/28 polyps were level 4 = PPV for adverse behaviour = 25%
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Haggitt Levels
Limitations
1. Not clear # level 4 were pedunculated
2. 59 sessile polyps, by def’n level 4
3. Difficult to apply in practice
-Poor orientation
-Piecemeal specimens
-Pedunculated vs sessile
-Hard to distinguish levels
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Kikuchi/Kudo levels
Kikuchi R et al Dis Colon Rectum 1995;38:1286-1295
Kudo S. Endoscopy 1993;25:455–61.
Sessile polypsLN metastasis risk
Nascimbeni R et al Dis Colon Rectum 2002;45:200–
206.
3%
8%
23%
Overall pT1 – 6-12%
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Rectal location
• Rectal location, in particular, the distal 1/3 of
rectum is an adverse factor for:
1. LN metastases (up to 1/3)
2. Recurrent/Residual disease (5-28%)Haggitt et al Gastroenterology 1985;89:328-36
Nascimbeni R et al Dis Colon Rectum 2002;45:200–206
Nivatvongs S. Surg Clin N Am 2002;82:959–966
Butte et al Dis Colon Rectum 2012;55:122-127
• Reason is not clear from the literature
• Surgical resection favoured for rectal site
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Pathology Reporting
Mandatory Highly recommended
Invasion vs. No invasion
Type of Cancer
Tumor Differentiation
LVI
Distance to deep margin (mm)
Status of mucosal margins
Leading Edge characteristics
- Tumor budding
- Dedifferentiation
Desmoplasia
Mucinous or cribriform
Haggitt level (pedunculated)
Kikuchi level (sessile)
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Piecemeal Polypectomy
Words of Caution
•Invasion vs no invasion difficult to evaluate
Desmoplasia
MM breach Presume invasion
LVI
•Cannot assess: Deep margin (unless excised separately)
mucosal margins, leading edge, Haggitt or Kikuchi level
•Can assess: Type of tumor, differentiation, and status of
cauterized tissue edges
Review with Pathologist at microscope!
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Surgical Resection Recommendations
*N=70 cases Nivatrong S et al Surg Clin N Am 2002;82:959-966
Site Pedunculated Sessile
Colon
Rectum
(Upper 2/3)
Rectum
(Lower 1/3)
Unfavorable features
Haggitt 4
Same
Same
Unfavorable features
SM2, 3 (or >1 mm)
Piecemeal Excision
Same
All
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Summary1. Direct communication between
endoscopist and pathologist is vital
2. Understand the terminology, staging
and meaning of unfavorable features
3. Make sure polyps are evaluated in total
(Don’t leave cancer in the tissue block!)
4. Don’t ever make false assumptions!
Assume the worse