4 Serrated Lesions of the Colon ACG 2012gi.org/wp-content/uploads/2012/08/12ACG_Midwest_Kahi_Serrated... · SERRATED LESIONS OF THE COLON Charles J. Kahi, MD, MSc, FACG Indiana University

ACG Regional Course- IndianapolisCopyright ACG 2012

August 2012 1

SERRATED LESIONS OF THE COLON

Charles J. Kahi, MD, MSc, FACGIndiana University School of Medicine

Richard L. Roudebush VA Medical CenterIndianapolis, Indianap

DISCLOSURE

Speaker Relationship with Industry includingSpeaker Relationship with Industry, includingConsultantSpeaker Ownership/ PartnershipPrincipal Research Institutional, Organizational or Other Financial Benefit:

NONE


August 2012 2

PATHOLOGY: BASIC FEATURES

• Heterogeneous group of lesions• Heterogeneous group of lesions

• Serrated (sawtooth) architecture of the epithelial compartment

• Subtypes defined by architectural features, and location/extent of the proliferative zone

E l i d t i l th l i l• Evolving and controversial pathological definitions.

WHO Classification (2010)

• Hyperplastic Polyp- Microvesicular HP (MVHP)- Microvesicular HP (MVHP)- Goblet-cell rich HP (GCHP)- Mucin-poor HP (MPHP)

• Sessile Serrated Adenoma/Polyp (SSA/P)- SSA/P without cytological dysplasia- SSA/P with cytological dysplasia

• Traditional Serrated Adenoma (TSA)

-Snover D, et al. WHO classification of tumours. Pathology and genetics. Tumours of the digestive system. 4th edition. Berlin: Springer-Verlag. 2010.


August 2012 3

Serrated polyposis (formerly hyperplastic polyposis)

• 5 serrated polyps proximal to the sigmoid, of which 2 are > 10 mm in size

• 20 or more serrated polyps throughout the colon

• Serrated polyp in FDR of patient with serrated polyposis

Snover D, et al. WHO classification of tumours. Pathology and genetics. Tumours of the digestive system. 4th edition. Berlin: Springer-Verlag. 2010.

HYPERPLASTIC POLYPS

• All 3 subtypes characterized by crypt elongation

• Crypts are straight with narrow bases

• Proliferation in the lower third of the crypt, serration in the luminal aspect

• MVHP have microvesicular mucin

- Mostly left colon, 15% right colon

• GCHP have mostly goblet cells less serration• GCHP have mostly goblet cells, less serration

- Nearly always left colon, small size

• Pathological and molecular differences between subtypes: No known clinical implications.


August 2012 4

HYPERPLASTIC POLYP

SSA/P

• 15-25% of all serrated polyps

• Distorted architecture due to altered proliferative zone• Distorted architecture due to altered proliferative zone

• Proliferative zone often displaced from base to side

• Crypts are dilated and branched, L- or inverted T-shaped

• Crypts may be filled with mucin (endoscopic mucus cap)

• Crypts may herniate through muscularis mucosae(inverted growth pattern)

• SSA/P with cytologic dysplasia: Usually abrupt transition to area with dysplasia similar to conventional adenoma.


August 2012 5

MVHP versus SSA/P

• Controversial issue

• Many serrated polyps have features of both MVHP and SSA/P, however minimum criteria needed to distinguish are unclear

• There is considerable inter-observer variation in differentiating MVHP from SSA/P, even among experts.

- Khalid O, Radaideh S, Cummings OW, et al. World J Gastroenterol 2009;15:3767-70.- Wong NA, Hunt LP, Novelli MR, et al. Histopathology 2009;55: 63-6.- Farris A et al. Am J Surg Path 2008; 32: 30-5.

SSA/P with inverted T-shaped crypt


August 2012 6

SSA/P with mucin-filled crypts

SSA/P: Inverted growth pattern


August 2012 7

SSA/P with dysplasia

TSA

• Uncommon subtype of serrated polyps

• Usually located in the distal colon• Usually located in the distal colon

• Complex and distorted architecture with villous elements (“filiform”)

• Recent studies suggest that best defining feature may be ectopic crypts due to loss of anchoring to muscularismucosae

• Dysplasia may occur and progress to cancer, but molecular pathways are poorly defined.


August 2012 8

Molecular Pathways in CRC

• Chromosomal instability (CIN)---60%-70%- Adenoma-carcinoma sequence

• Defective DNA mismatch repair, leading to microsatellite instability (MSI)---5% - Lynch syndrome

• Serrated pathway---25%-35%- BRAF oncogene mutations- Epigenetic DNA promoter hypermethylation leading to the CpG island methylator phenotype (CIMP).

Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011;42(1):1-10.

The Serrated Pathway

• Leads to sporadic CRC with MSI, and some MSS CRCs with CIMPwith CIMP

• Activating mutation of BRAF (anti-apoptotic)

- BRAF mutations present in SSA/P, and many MVHP

- BRAF mutations are associated with CIMP+ CRCs

• Some CIMP+ CRCs have MSI, associated with hypermethylation of MLH1.

Snover D, et al. WHO classification of tumours. Pathology and genetics. Tumours of the digestive system. 4th edition. Berlin: Springer-Verlag. 2010.


August 2012 9

Normal Mucosa

BRAF mutation

MicrovesicularHyperplastic Polyp

SSA/P with

Cancer

Promoter hypermethylation

Sessile Serrated Adenoma/Polyp

SSA/P with cytological dysplasia

MSI, MLH1 methylation

Variable progression rate Rapid progression (HNPCC-like)

Snover D, et al. WHO classification of tumours. 2010.

Clinical Implications

• Close links between serrated pathway and interval (post-colonoscopy) CRC:

- Interval CRC 4 times more likely than non-interval CRC to have MSI

- More likely to be located in the proximal colon

- More likely to be associated with CIMP- More likely to be associated with CIMP.

- Sawhney et al. Gastroenterology 2006; 131: 1700-5

- Arain et al. Am J Gastroenterol 2010; 105: 1189-95.


August 2012 10

Colonoscopy is less protective against right-sided CRC

Author, year Outcome Left-sided CRC(95% CI)

Right-sided CRC(95% CI)

Baxter, 2009 CRC Mortality(Adj OR)

0.33 (0.28-0.39)

0.99 (0.86-1.14)

Singh, 2010 CRC Mortality(SMR)

0.53(0.42-0.67)

0.94(0.77-1.17)

Brenner, 2010 AdvancedNeoplasm

0.33 (0 21 0 53)

1.05 (0 63 1 76)Neoplasm

Prevalence(0.21-0.53) (0.63-1.76)

Brenner, 2011 CRC Prevalence(OR)

0.16 (0.12- 0.20)

0.44 (0.35-0.55)

Why is colonoscopy protection less in the right colon?

• REVERSIBLE:B lBowel prepOperator Dependent

- Cecal Intubation- Withdrawal time and technique- Adenoma detection- Detection of flat and depressed (non-polypoid) neoplasms- Detection of serrated polyps

• IRREVERSIBLE:Tumor Biology

Rex, D. Gastroenterology 2011; 140: 19-21.


August 2012 11

HP: Endoscopic features

• Usually sessile and 1-5 mm, rarely > 10 mm

• Typically distal (rectosigmoid), can be multiple

• Pearl-colored pale may disappear with insufflationPearl colored, pale, may disappear with insufflation

SSA/P: Endoscopic features

• Often flat, subtle appearance

• Larger than HP 20% 50% > 10 mm• Larger than HP, 20%-50% > 10 mm

• Typically proximal colon

• Mucus cap

• Washing off the mucus cap: Polyp similar in color to surrounding mucosa, indistinct edges

• Surface similar to HP under NBI

- Vu et al. Dis Colon Rectum 2011; 54:1216-23

- Jaramillo et al. Endoscopy 2005; 37: 254-60.


August 2012 12

Large proximal colon serrated lesion

Courtesy Douglas Rex, MD

SSA/P with typical mucus cap


August 2012 13

SSA/P: Beyond the mucus cap

• Retrospective analysis of high-resolution videos of 158Retrospective analysis of high resolution videos of 158 SSA/Ps

• Most prevalent visual descriptors:

- Mucus cap (64%)

- Rim of debris or bubbles (52%)

- Alteration of the contour of a fold (37%)

- Interruption of underlying mucosal vascular pattern (32%)

Tadepalli et al. Gastrointestinal Endoscopy 2011; 74: 1360-8.

COLONOSCOPY IS OPERATOR-DEPENDENT

• Adenoma detection rate (ADR) is a validated predictor of ( ) pCRC risk after screening colonoscopy

10-fold increase risk of interval CRC if ADR <20%, compared to ≥ 20%

Kaminski et al. NEJM 2010; 362: 1795-1803.

• Colonoscopy performed by endoscopists with high• Colonoscopy performed by endoscopists with high completion and polypectomy rates more protective against proximal CRC

Baxter et al. Gastro 2011; 140: 65-72.


August 2012 14

VARIABLE DETECTION OF PROXIMAL SERRATED LESIONS

1. Hetzel et al. Am J Gastroenterol. 2010;105:2656-64.

• 7192 average-risk screening colonoscopies by 13 endoscopists• Patients: Mean age 59, 44% male• 4535 polyps• Proximal serrated polyp detection range: 1.4%-7.6%

(adenoma: 13.5%-36.4%)

2. Kahi et al. Clin Gastroenterol Hepatol. 2011;9(1):42-6.p ; ( )

• 6681 average-risk screening colonoscopies by 15 endoscopists• Patients: Mean age 59, 49% male• 11,049 polyps• Proximal serrated polyp detection range: 1%-18%

(adenoma: 17%-47%).

CORRELATION BETWEEN ADENOMA AND PROXIMAL SERRATED POLYP DETECTION

• Reanalysis of two colonoscopic databases

• Average-risk screening patients

• Significant correlation between ADR and proximal serrated polyp detection rate for men (R=0.71; P =0.003) and women (R=0.73; P=0.002).

ADRs of 25% for men and 15% for women both• ADRs of 25% for men and 15% for women both corresponded to a proximal serrated polyp detection rate of 4.5%.

Kahi et al. Gastrointestinal Endoscopy 2012; 75: 515-20.


August 2012 15

Risk Stratification

LOWER CRC RISK HIGHER CRC RISK

NUMBER None/few ManyNUMBER None/few Many

SIZE Small Large

TYPE HP SSA/P or TSA, dysplasia

ANATOMIC LOCATION Left colon Right colon

Rex et al. Serrated lesions of the Colorectum: Review and Recommendations from an Expert Panel.Am J Gastroenterol advance online publication 19 June 2012; doi: 10.1038/ajg.2012.161

Surveillance intervalsFinding Interval (years)

HP < 10 mm, rectosigmoid, any number 10

HP ≤ 5 mm, proximal to sigmoid, ≤ 3 in 10HP ≤ 5 mm, proximal to sigmoid, ≤ 3 in number

10

HP ≥ 4 in number, proximal to sigmoid 5

HP > 5 mm proximal to sigmoid 5

SSA/P or TSA < 10 mm 5

SSA/P or TSA ≥ 10 mm, or at least 3 SSA/P or TSA

3

SSA/P with dysplasia 1-3

Serrated polyposis 1

Rex et al. Serrated lesions of the Colorectum: Review and Recommendations from an Expert Panel. Am J Gastroenterol advance online publication 19 June 2012; doi: 10.1038/ajg.2012.161


August 2012 16

Serrated lesions: take home points

• Important and clinically relevant

Hi h i d f f d i d• High index of awareness for endoscopic appearance and clues, search deliberately especially in the right colon

• Remove all serrated lesions proximal to the sigmoid and all those > 5 mm in distal colon

• Communicate with your pathologist

• Shorten surveillance interval for SSA/P or TSA, larger size, higher number of proximal lesions.

Documents

4 Serrated Lesions of the Colon ACG 2012gi.org/wp-content/uploads/2012/08/12ACG_Midwest_Kahi_Serrated... · SERRATED LESIONS OF THE COLON Charles J. Kahi, MD, MSc, FACG Indiana University