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 cm
> 2 cm
1479 1.3%
580 9.5%
430 46.0%
Muto et al 1975

Frequency of Carcinoma in
Adenomas tubular tubulovillous villous
1875 4.7%
380 22.4%
234 41.9%
Muto et al 1975

Frequency of Carcinoma in
Adenomas mild dysplasia moderate dysplasia severe dysplasia
1734 5.7%
549 18.0%
223 34.5%
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 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 Cancer tubular 1 tubulovillous 3.8
villous 5.0
mild 1.3
moderate 3.4
severe 3.3
<1 cm
1-2 cm
>2 cm
1.5
2.2
5.9
1 tumour 1.7
>2 tumours 4.8

Risk of Subsequent Colon Cancer
Patients Cancers SIR
Low Risk Adenomas
Single
Multiple
Total
712
64
776
4
0
4
0.6
0
0.5
High Risk Adenomas
Single
Multiple
Total
683
159
842
20
11
31
2.9
6.6
3.6

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

Risk of Advanced Neoplasia 5.5yrs
No neoplasia
Tubular Adenoma <10mm
1-2
3+
Tubular Adenoma >10mm
Villous Adenoma
High Grade Dysplasia
Carcinoma
Patients Ad Neo
298 7
622
496
38
23
126
123
81
46
23
15
19
13
8
8
Lieberman et al 2007
RR
1
2.56
1.92
5.01
6.40
6.05
6.87
13.56

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 mild moderate severe min max median
29% 88% 42%
10% 67% 43%
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 tubular tubulovillous villous min max median
62% 93% 84%
6%
0%
37%
6%
15%
1%

Reproducibility of Identifying
Villousness
– 3 observers
– Overall agreement 61%
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

Hyperplastic polyp
Serrated adenoma
Mixed polyp
Sessile serrated polyp
Serrated carcinoma

• 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

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?

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)

Collision between hyperplastic polyp and adenoma
Dysplasia in Hyperplastic Polyp
Longacre & Fenoglio-Preiser 1990

• 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

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

• Typical adenomas 0%
• Typical hyperplastic polyps
• Sessile serrated adenomas
19-78%
75-78%
• Traditional serrated adenomas 20-66%
• Mixed Polyps
• HNPCC cancers
• All colorectal cancers
57-89%
0%
15%
• MSI-high non-HNPCC cancers 76%

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

Polyp Dysplasia %
Adenoma Tubular
Tubulovillous
Villous
Serrated Hyperplastic polyps
-
Sessile Serrated Polyp -
Mixed Polyp
Serrated Adenoma
+
+
+
+
+
55
15
1
24.5
2.5
0.8
1.2

Hyperplastic polyp
Serrated adenoma
Mixed polyp
Sessile serrated polyp
Serrated carcinoma