Colorectal polyps and

Adenoma-Carcinoma Sequence

C.S. Ho MB,BS, FRCPC

Professor of Radiology
University of Toronto
 Objectives of presentation

Definitions of terms:
Pathology
Evidence for Adenoma-carcinoma sequence
Polyps – Morphology & Histology

• Non-neoplastic
– Mucosal, juvenile polyp,
– inflammatory polyp,
– Hyperplastic
• Neoplastic
– Sessile Serrated Adenoma
– Adenomatous
- lipomas, GIST, carcinoid
 Hyperplastic Polyps
• Represents 50% of all colonic polyps
• Majority are Small, < 5mm, left colon.
• Half found in the recto-sigmoid
• Some, the sessile serrated polyps – sessile
serrated adenoma (SSA) can become
malignant
 Serrated Sessile Polyps

Hyperplastic Polyp
Serrated
sessile
Sessile serrated polyp adenoma
Sessile Serrated Adenoma
 Colonic Adenoma
• Neoplastic polyps
• 20% - 30% occurs below age 40
• 40% - 50% after age 60
• Types: tubular (85%) , tubulovillous (10%),
villous (5%)
• Advanced Adenoma –High Risk
– Size > 1cm
– High grade dysplasia
– Villous component (10x potential to
malignancy vs tubular)
 Flat Adenoma

Matsui et al. World J Surg 2000

 Evidence for Adenoma
Carcinoma sequence
• Indirect – Epidemiology
Pathology

• Direct – DNA evidence

 Indirect Evidence
• Age – peak age for polyps precedes cancers
by 7-8 years
• Populations with high incidence of adenoma
have high incidence of CRC
• Comparable Distribution in colon
• Pathology – adenoma association with
carcinoma
• Removal of adenomas reduces incidence of
carcinoma
 Pathologic Evidence for Polyp-
Cancer sequence
.
Adenoma Carcinoma Sequence

 Stepwise pathologic progression over many

years.
 Studies in patients with FAP and HNPCC
(Lynch syndrome) have led to understanding
the molecular changes causing CRC
Hallmarks of Cancer: achieved
through mutation of genes
Molecular pathways to CRC
Adenoma-carcinoma Pathway APC /ß catenin Pathway

Serrated Polyp Carcinoma Pathway / Microsatellite instability (MSI)

 DNA Stool testing
• Multi-target DNA or APC – PCR to detect
minute amount.
• APC, K-ras and p53 genes, mutations
on Bat-26 ,long DNA Analyzable.
• sensitivity for cancer 91%,
• large adenomas 82%
• large series (Mayo 2008)– less sensitive
than expected – 63% CRC; 57% Adenoma
• Expensive, handling difficulty
Stool DNA testing vs FIT
(n=9989)
Cancer Advanced polyps

Sensitivity
Stool DNA 92.3% 42.4%
(Cologuard)
FIT 73.8% 23% (p<0.001)
(p=0.004)

Specificity
Stool DNA 86.6%
FIT 94.9%

Imperiale TF et al. NEJM 2014; 370:1287

Emerging Blood tests for
screening CRC
 Blood tests for CRC screening
• Biomarkers, tumor antigen CA11-19
(BDP Biotech, ASCO, 2014)
• Colon sentry – 7-gene panel biomarker
miRNA
GTA 446 (Cologic –Phenominome Inc)
Significance: Game changer.
Stratify risk profile; lowers cost ; improve patient
acceptance and screening uptake
 Sensitivity & Specificity

Cologic Colon- CA11-19 FOBT

sentry

Sensitivity 86% 70 -78% 95% 35%

Specificity 90% ?? 66-70% 80% 87%

Monoclonal antibody against EGFR
ineffective in mutated Kras
 Risk according to polyp size
• Prediction of polyp risk based on historic
data obtained from studies on high risk
patients – now considered invalid
• Histology from polypectomy does not
predict past or future growth of the polyp
removed.
• Cancer risk for polyp ≥ 1 cm is estimated to
be 1%, much less than 10% as often quoted.
Findings re polyps in the average
risk screening population
Screening prevalence of Typical Reported
value
All colorectal polyps ≥ 6 mm 14% 13 -16%

Small 6 -9 mm polyps 8% 8 -9%

Large ≥ 10mm polyps 6% 5-7%
Advanced neoplasm (any size) 3 -4% 3.3 – 6.9%
Small (6 – 9) mm advanced adenoma 0.3% 0.17 -0.46%
High Grade Dysplasia (HGD) in small polyp 0.05% 0.048 -0.064%
Invasive carcinoma in small polyps 0.01% 0 – 0.039%
Rate of HGD in 6 -9 mm adenomas 0.7% 0.5 – 0.8%
Rate of invasive carcinoma 6 -9 mm adenomas 0.1% 0.5 -2.4%
Rate of invasive carcinoma in 1 -2 cm adenomas 1% 0.5 -2.4%
 Screening CT Colonography

Advanced Adenoma
• > 10 mm
• Villous component
• High Grade Dysplasia
 Summary
• The adenoma carcinoma sequence is a
long progress due to a number of stepwise
genetic changes leading to clonal
proliferation of cells which become
uncontrolled and self-sustaining cancer.
• More sensitive tests based on Genetic
changes are now available with favourable
prospects
• .Polyp size and histology are risk factors
that predicts malignant changes.
 POLYP
Adenoma Hyperplastic

Target = Advanced adenoma &

high risk serrated lesions