pathogenesis of colorectal cancer in serrated polyposis syndrome · 2019-04-16 · pathogenesis of...

Pathogenesis of Colorectal Cancer in Serrated Polyposis Syndrome

Christophe Rosty

Brisbane, QLD, Australia

F 78 – Positive FOBT – Extended right hemicolectomy

Tumour 3

Tumour 2Tumour 1

Tumour 3Tumour 2Tumour 1

Tumour 3Tumour 2Tumour 1MLH1 MLH1 MLH1

18 polyps up to 21 mm in size

Sessile serrated polyp/lesion (SSP)

Sessile serrated polyp/lesion with dysplasia (SSPD)

Risk of CRC in serrated polyposis patients?

Risk of CRC in serrated polyposis patients?

• Two large retrospective studies from Europe

• CRC in 16-29% of SPosis patients

• Majority of CRC at or before the diagnosis of SPosis

• Nearly 50% are from rectosigmoid

• Risk factors for CRC:• Phenotype 1 + 2

• > 2 SSPs proximal to splenic flexure

• 1 SSP with dysplasia

• 1 advanced conventional adenoma

Carballal et al. Gut 2016; 65:1829-1837Ijspeert JEG et al. Gut 2017; 66:278-284

Serrated neoplasia pathway CRC

Microvesicular HP

SSP

Normal colonic mucosa

BRAF mutation

BRAF serrated pathway

Microvesicular HP

SSP BRAF-mutated TSA


BRAF mutation

BRAF mutationCIMP


Microvesicular HP

SSP BRAF-mutated TSA


Goblet cell HP

KRAS-mutated TSA

BRAF mutation

BRAF mutationCIMP

KRAS mutation

BRAF serrated pathway KRAS serrated pathway

Microvesicular HP

SSP

MLH1-deficient SSP with dysplasia

BRAF-mutated MMR-deficient CRC


BRAF mutation

CIMP-H

MLH1 methylationWNT activation


75%

SSP

SSPD

Carcinoma

SSPSSPD

Carcinoma – 6mm lesion

Microvesicular HP

SSP

BRAF-mutated MMR-proficient CRC


MLH1-proficient SSP with dysplasia

BRAF mutation

CIMP-H


WNT activationTP53 mutation

25%

Microvesicular HP

SSP




BRAF mutation

CIMP-H




BRAF-mutated TSA

BRAF-mutated TSA with high grade dysplasia

BRAF mutationCIMP


SSP

SSPD

Carcinoma

Carcinoma

MLH1 retained

Carcinoma

SSP SSPD

Compared with SSP with MLH1-deficient dysplasia/carcinoma, MLH1-proficient dysplasia/carcinoma:

➢ More frequent in men (64% vs 30%)

➢ In younger patients (71 y vs 76.7 y)

➢ Less often in proximal colon (72% vs 91%)

➢ Less often CIMP-high (80% vs 98%)

➢ More p53 aberrant expression (34% vs 7%)

Bettington et al. Gut 2017;66:97-106.

KRAS-mutated MMR-proficient CRC

KRAS-mutated TSA with high grade dysplasia


Goblet cell HP

KRAS-mutated TSA

KRAS mutation

KRAS serrated pathway

CIMP-L


TSA

Carcinoma

TSA HGD

Carcinoma

Microvesicular HP

SSP

MLH1-deficient SSP with dysplasia

BRAF-mutated MMR-deficient CRC


KRAS-mutated MMR-proficient CRC

BRAF-mutated TSA

BRAF-mutated TSA with high grade dysplasia

KRAS-mutated TSA with high grade dysplasia


Goblet cell HP


KRAS-mutated TSA

BRAF mutation

BRAF mutationCIMP

KRAS mutation

CIMP-H

MLH1 methylationWNT activation

BRAF serrated pathway KRAS serrated pathway


CIMP-L



15% 5% 10%

Are all CRCs in serrated polyposis serrated neoplasia pathway CRCs?

45 CRCs in serrated polyposis patients

• Median age 58.5 y (18 – 76)

• Females 71%

• 46% BRAF mutation

• 5% KRAS mutation

• 38% MLH1-deficient

Rosty et al. Am J Surg Pathol 2013;37:434-442.

Polyp subtypes in 100 serrated polyposis patients

• CRC more frequent when conventional adenomas present

17%

Rosty et al. Am J Surg Pathol 2012;36:876-882.

2019 WHO criteria

WHO 2010 criteria

Criterion 1At least 5 serrated polyps proximal to the sigmoid colon with at least two ≥ 10 mm

Criterion 2Any number of serrated polyps proximal to the sigmoid colon in an individual who had a first-degree relative with SP

Criterion 3More than 20 serrated polyps of any size but distributed throughout the colon

WHO 2019 revision

• 2010 criterion 2 discarded

• Criteria 1 and 2 in line with phenotypes 1 and 2

WHO 2019 revision

• 2010 criterion 2 discarded

• Criteria 1 and 2 in line with phenotypes 1 and 2

• Distal polyps included in the definition with some restriction for size and number of rectal polyps

WHO 2019 revision

• Polyp count is cumulative over multiple colonoscopies

• Any histological subtype of serrated polyp is included in the final polyp count

Criterion 1At least 5 serrated polyps proximal to the rectum all ≥ 5 mm, with at least two ≥ 10 mm

Criterion 2More than 20 serrated polyps of any size but distributed throughout the large bowel, with at least 5 proximal to the rectum

Summary

• CRC in serrated polyposis are heterogeneous• Within the serrated neoplasia pathway

• Half not from serrated polyps – canonical adenoma carcinoma pathway

Summary



• No firm line between criteria fulfilled or not – continuum

Summary



• No firm line between criteria fulfilled or not – continuum

• CRC risk stratification needed for recommendation on tailored surveillance intervals• Role of conventional adenomas and advanced polyps

pathogenesis of colorectal cancer in serrated polyposis syndrome · 2019-04-16 · pathogenesis of...

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