Assessment of Assessment of AdenomasAdenomas

Geraint WilliamsPathology Department

Cardiff University

The great majority of lesions in the Screening Programme are

small adenomas and hyperplastic polyps

Recognising adenomas

Categorising adenomas

Invasion

Completeness of Excision

Serrated lesions

Recognising adenomas

Categorising adenomas

Invasion

Completeness of Excision

Serrated lesions

Size

Villousness Dysplasia

Frequency of Carcinoma in Adenomas

< 1 cm 1479 1.3%

1-2 cm 580 9.5%

> 2 cm 430 46.0%

Muto et al 1975

Frequency of Carcinoma in Adenomas

tubular 1875 4.7%

tubulovillous 380 22.4%

villous 234 41.9%

Muto et al 1975

Frequency of Carcinoma in Adenomas

mild dysplasia 1734 5.7%

moderate dysplasia 549 18.0%

severe dysplasia 223 34.5%

Muto et al 1975

High Risk (‘Advanced’) High Risk (‘Advanced’) AdenomasAdenomas

> 1 cm

villous component

severe dysplasia

As long as there is no invasive malignancy and excision is

complete -

No worries!

Rectosigmoid Adenoma Follow-Rectosigmoid Adenoma Follow-UpUp

1618 patients followed for a mean of 14 years after removal of rectosigmoid adenomas:

49 (3%) developed colorectal cancer:14 rectal SIR 1.2 (CI 0.7-2.1) (11/14 had incompletely excised adenomas)35 colonic SIR 2.1 (CI 1.5-3.0)

Atkin et al 1992

Risk of Subsequent Colon Risk of Subsequent Colon CancerCancer

tubular 1 mild 1.3

tubulovillous 3.8 moderate 3.4

villous 5.0 severe 3.3

<1 cm 1.5 1 tumour 1.7

1-2 cm 2.2 >2 tumours 4.8

>2 cm 5.9

Risk of Subsequent Colon Risk of Subsequent Colon CancerCancer

Patients Cancers SIRLow Risk AdenomasSingle 712 4 0.6Multiple 64 0 0Total 776 4 0.5

High Risk AdenomasSingle 683 20 2.9Multiple 159 11 6.6Total 842 31 3.6

Advanced Adenoma PatientsAdvanced Adenoma Patients

> 1 cm

villous component

severe dysplasia

multiple polyps

Risk of Advanced Neoplasia Risk of Advanced Neoplasia 5.5yrs5.5yrs

Patients Ad Neo RRNo neoplasia 298 7 1Tubular Adenoma <10mm 622 38 2.56

1-2 496 23 1.923+ 126 15 5.01

Tubular Adenoma >10mm 123 19 6.40Villous Adenoma 81 13 6.05High Grade Dysplasia 46 8 6.87Carcinoma 23 8 13.56

Lieberman et al 2007

Even if there is no invasive malignancy and excision is complete -

Grading of dysplasia and assessment of villousness in adenomas that are <10mm will

govern surveillance

So we’ve got to try hard to get it right!

Grading Dysplasia in 2189 Grading Dysplasia in 2189 Adenomas at 13 CentresAdenomas at 13 Centres

min max median

mild 29% 88% 42%

moderate 10% 67%43%

severe 1% 24% 4%

Low grade and high grade

High Grade DysplasiaHigh Grade Dysplasia

Expected in <5% of all adenomas

Equates to ‘intramucosal adenocarcinoma’

Involves more than 1-2 glands

High Grade DysplasiaHigh Grade Dysplasia

Recognition based primarily on ARCHITECTURE:

COMPLEX glandular crowding and irregularity

PROMINENT budding

CRIBRIFORM ‘back-to-back’ glands

INTRALUMINAL papillary tufting

Low power diagnosis - epithelium is thick, blue, disorganised and ‘dirty’

High Grade DysplasiaHigh Grade Dysplasia

CYTOLOGY:

Loss of polarity and nuclear stratification

Markedly enlarged nuclei

Atypical mitoses

Prominent apoptosis

Usually more than one of these

Histology of 2206 Adenomas Histology of 2206 Adenomas at 13 Centresat 13 Centres

min max median

tubular 62% 93% 84%

tubulovillous 6% 37% 15%

villous 0% 6% 1%

Reproducibility of Identifying Reproducibility of Identifying VillousnessVillousness

– 3 observers– Overall agreement 61%

Jensen et al 1995

Tubulovillous AdenomasTubulovillous Adenomas

The 20% Rule

Neoplastic VilliNeoplastic Villi

Classical

Palmate

Foreshortened

May have prominent low grade mucinous epithelium

Flat AdenomasFlat Adenomas

– thickness does not exceed twice that of adjacent mucosa

– more often right sided– usually small (<1cm) with tubular growth

pattern– more often high grade dysplasia– 40% contain carcinoma– uncommon because no chromoendoscopy

Muto et al 1985

National Polyp StudyNational Polyp Study

• 1418 patients• Complete colonoscopy with removal of

adenomas• No special attempt to identify flat

adenomas• Follow up colonoscopy, mean 5.9 years• 97% clinical follow up, 80% colonoscopies• 8401 patient years

National Polyp StudyNational Polyp Study

• 90% reduction in colorectal cancer incidence

• all five colorectal cancers found on follow-up were polypoid

Macroscopic Examination & Macroscopic Examination & Trimming of PolypsTrimming of Polyps

• Size - to nearest millimetre in formalin fixed specimen (whole polyps)

• Polypoid lesions• Fixed intact• Bisect through stalk if <10mm• If larger, trim to leave central intact stalk• At least three levels of stalk

• Sessile lesions pinned out and all-embedded after inking margins

Serrated Lesions

Hyperplastic polypSerrated adenoma

Mixed polypSessile serrated polypSerrated carcinoma

Hyperplastic Polyps

• Formerly metaplastic polyps• Left > right• Male > female • Infolded epithelial tufts and enlarged

goblet cells• No dysplasia• Failure of anoikis (shedding of mature

cells)

Ki-67

Hyperplastic Polyp

Increase in frequency with age

17 times commoner in colons with carcinoma

Similar dietary and lifestyle risk factors to CRC

K-ras mutation common

Clonal

Monocryptal?

Serrated Adenoma

Dysplasia by definition

Eosinophilic cytoplasm

Pseudostratified, ‘pencillate’ nuclei

May be tubular, tubulovillous or villous

Invade to give serrated carcinoma

Longacre & Fenoglio-Preiser 1990

‘Traditional’ Serrated adenoma (TSA)

Mixed Polyps

Collision between hyperplastic polyp and adenoma

Dysplasia in Hyperplastic Polyp

Longacre & Fenoglio-Preiser 1990

Sessile Serrated Polyp (Adenoma)

• Serrated polyps with unusual architectural features

• No conventional dysplasia but may have ‘nuclear atypia’ or ‘hypermucinous’ change

• Right colon

• Females > males

• Large sessile, poorly defined

Torlakovic & Snover 1996

Sessile serrated polyp

Serrated Adenocarcinoma

• Serrated, mucinous or trabecular growth pattern

• Abundant eosinophilic cytoplasm

• Chromatin condensation• Preserved polarity• No necrosis

Tuppurainen K et al 2005 J Pathol 207: 285-94

Tuppurainen K et al 2005 J Pathol 207: 285-94

Serrated Neoplasia

Microsatellite instability

DNA methylation

MLH1 inactivation

BRAF mutation

Baker K et al J Clin Pathol 2004; 57: 1089

BRAF mutation

• Typical adenomas 0%• Typical hyperplastic polyps 19-78%• Sessile serrated adenomas 75-78%• Traditional serrated adenomas 20-66%• Mixed Polyps 57-89%

• HNPCC cancers 0%• All colorectal cancers 15%• MSI-high non-HNPCC cancers 76%

Serrated Neoplasia Pathway

Proximal hyperplastic polyp

Sessile serrated polyp

Serrated adenoma

MSI-high, methylation-rich non-HNPCC “serrated” carcinoma (50% mucinous)

Higuchi T & Jass JR 2004 J Clin Pathol 57: 682

1250 Polyps at Colonoscopy

Polyp Dysplasia %

Adenoma Tubular + 55 Tubulovillous + 15

Villous + 1

Serrated Hyperplastic - 24.5polyps Sessile Serrated Polyp - 2.5

Mixed Polyp + 0.8Serrated Adenoma + 1.2

NBCSP

Hyperplastic polypSerrated adenoma

Mixed polyp

Sessile serrated polypSerrated carcinoma