Assessment of Adenomas Geraint Williams Pathology 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 % 1-2 cm5809.5% > 2 cm % Muto et al 1975

Frequency of Carcinoma in Adenomas tubular % tubulovillous % villous % Muto et al 1975

Frequency of Carcinoma in Adenomas mild dysplasia % moderate dysplasia % severe dysplasia % Muto et al 1975

High Risk (‘Advanced’) Adenomas > 1 cm villous component severe dysplasia

As long as there is no invasive malignancy and excision is complete - No worries!

Rectosigmoid Adenoma Follow-Up 1618 patients followed for a mean of 14 years after removal of rectosigmoid adenomas: 49 (3%) developed colorectal cancer: 14 rectalSIR 1.2 (CI ) (11/14 had incompletely excised adenomas) 35 colonic SIR 2.1 (CI ) Atkin et al 1992

Risk of Subsequent Colon Cancer tubular1mild1.3 tubulovillous3.8moderate3.4 villous5.0severe3.3 <1 cm1.5 1 tumour cm2.2>2 tumours 4.8 >2 cm5.9

Risk of Subsequent Colon Cancer PatientsCancersSIR Low Risk Adenomas Single Multiple6400 Total High Risk Adenomas Single Multiple Total

Advanced Adenoma Patients > 1 cm villous component severe dysplasia multiple polyps

Risk of Advanced Neoplasia 5.5yrs PatientsAd NeoRR No neoplasia29871 Tubular Adenoma <10mm Tubular Adenoma >10mm Villous Adenoma High Grade Dysplasia Carcinoma 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 Adenomas at 13 Centres minmaxmedian mild 29%88%42% moderate 10%67%43% severe 1%24%4%

Low grade and high grade

High Grade Dysplasia Expected in <5% of all adenomas Equates to ‘intramucosal adenocarcinoma’ Involves more than 1-2 glands

High 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 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 at 13 Centres minmaxmedian tubular 62%93%84% tubulovillous 6%37%15% villous 0%6%1%

Reproducibility of Identifying Villousness –3 observers –Overall agreement61% Jensen et al 1995

Tubulovillous Adenomas The 20% Rule

Neoplastic Villi Classical Palmate Foreshortened May have prominent low grade mucinous epithelium

Flat 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 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 Study 90% reduction in colorectal cancer incidence all five colorectal cancers found on follow-up were polypoid

Macroscopic Examination & Trimming 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 polyp Serrated adenoma Mixed polyp Sessile serrated polyp Serrated 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:

Serrated Neoplasia Microsatellite instability DNA methylation MLH1 inactivation BRAF mutation Baker K et al J Clin Pathol 2004; 57: 1089

BRAF mutation Typical adenomas0% Typical hyperplastic polyps19-78% Sessile serrated adenomas75-78% Traditional serrated adenomas20-66% Mixed Polyps57-89% HNPCC cancers0% All colorectal cancers15% MSI-high non-HNPCC cancers76%

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 PolypDysplasia% AdenomaTubular+55 Tubulovillous+15 Villous+1 Serrated Hyperplastic-24.5 polypsSessile Serrated Polyp-2.5 Mixed Polyp+0.8 Serrated Adenoma+1.2

NBCSP Hyperplastic polyp Serrated adenoma Mixed polyp Sessile serrated polyp Serrated carcinoma