David Driman

Serrated Colorectal Polyps
A Practical Approach
David Driman MBChB FRCPC
Conflict of Interest Disclosure
Dr. David Driman
I have not had in the past 3 years, a financial interest,
arrangement or affiliation with one or more organizations that
could be perceived as a direct or indirect conflict of interest in
the content of this presentation.
1950s, 1960s, 1970s
hyperplastic polyp
villous adenoma
do not  CRC
do  CRC
“Welcome to the 1980s!”
Trouble brewing…
1980s
• several reports (~13)…
• hyperplastic polyps commoner in populations at risk for
•
•
•
•
developing CRC
hyperplastic polyp at the margin of adenomas
hyperplastic polyposis
giant/atypical hyperplastic polyps with dysplasia/cancer
adenocarcinoma arising in mixed adenomatous-hyperplastic
polyp
1990s
• a new polyp appears
(Longacre TA, Fenoglio-Preiser CF. Am J Surg Pathol 90;14:524)
• analyzed 110 polyps with mixed features of hyperplastic polyp
and adenoma
• suggested that instead of being mixed polyps, these were
adenomas with a serrated configuration
 “serrated adenoma”
1990s
• Torlakovic and Snover analysed a series of 6
“hyperplastic polyposis” cases
(Torlakovic E, Snover DC. Gastroenterology 96;110:748)
• 4/6 had associated CRC
• morphology of polyps not hyperplastic but more akin to (sessile)
serrated adenomas
 coined the term “serrated adenomatous polyposis”
Image courtesy Dr. J.R. Jass
2000s
• sporadic serrated adenomas linked to CRC - adjacent to tumor in 5.8% of 466 CRCs
(Makinen MJ et al. J Pathol 01;193:286)
• hyperplastic polyps are precursors to MSI+ CRC
(Hawkins NJ, Ward RL. J Natl Cancer Inst 01;93:1307)
• Torlakovic and Snover “sessile serrated adenoma” and “traditional serrated adenoma”
(Torlakovic E et al. Am J Surg Pathol 03;27:65)
• CRCs preceded by SSAs – 91 “HPs” found at sites where MSI-H CRCs later diagnosed
(Goldstein NS et al. Am J Clin Pathol 03;119:778)
• SSAs evolve to CRC quicker than other polyps
(Lazarus R et al. Am J Clin Pathol 05;123:349)
• SSAs caught in the act - reports of colectomy series with adenocarcinomas arising in SSAs
(Goldstein NS. Am J Clin Pathol 06;125:132; Sheridan TB et al. Am J Clin Pathol 06;126:564)
Summary… by 2006
• there are more than 2 types of colorectal polyp
• some polyps have features of both “adenoma” and
“hyperplastic polyp”
• new terms: sessile serrated adenoma, traditional serrated
adenoma
• multiple serrated adenomas may be associated with colorectal
cancer
• single serrated adenomas associated with colorectal cancer,
especially MSI cancer
serrated neoplasia pathway
Consensus Meeting 2011
Canadian Classification of Serrated Polyps
2011-2014
Hyperplastic polyp
cytological
dysplasia
Sessile serrated adenoma*
± dysplasia
Traditional serrated adenoma
± high-grade dysplasia
Serrated polyp, unclassified
*some US pathologists: sessile serrated polyp
*UK pathologists: sessile serrated lesion
conventional
dysplasia
No they
don’t.
Because they’re
premalignant like
other adenomas.
Do SSAs have
dysplasia like
other
adenomas?
And calling them sessile
serrated polyps or lesions
might confuse you and you
may not want to remove them.
And they have architectural
dysplasia so we pathologists
feel OK calling them
adenomas.
Oh.
The pathologist and the endoscopist
Then why do
you call them
adenomas?
Oh.
UNOfficial Canadian Classification of
Serrated Polyps
Hyperplastic polyp
Sessile serrated adenoma
± dysplasia
Traditional serrated adenoma
± high-grade dysplasia
Serrated polyp, unclassified
Weird serrated polyp with features of HP, SSA, TSA and regular adenoma in
various combinations (WSPWFHPSSATSARA)
Pathogenesis: SSA and TSA
• abnormal crypt cell compartmentalization / landscaping
 abnormal organization of cells within crypts
 abnormal crypt relationship to stroma, m. mucosae, surface epithelium
TSA
SSA
abnormal spatial positioning of crypts  loss of
crypt anchoring to m. mucosae  ectopically
budded crypts, piled up epithelium  serration
inhibition of apoptosis  piling up of
epithelium  serration
KRAS
BRAF
What is the distribution of serrated polyps?
Evaluated 6,340 colorectal polyps from a high-volume
community-based GI pathology practice
Right
Left
HP
331 (15%)
1810
SSA
615 (81%)
142
TSA
18 (32%)
39
Bettington M et al. Am J Surg Pathol 2014;38:158-166
2 Pathologists, LHSC, Jan-Mar 2014
Right
Left
HP
0
125
SSA
51
4
Unclassified
7
0
LHSC
S14-2234
Hyperplastic Polyp
Hyperplastic Polyp
• serrations in luminal half
• straight crypts
• narrow bases
• immature proliferative cells in
lower third–half of crypts
• mitoses restricted to lower
half of crypts
Hyperplastic Polyps
reporting subtypes
not recommended
microvesicular
goblet cell rich
predominantly microvesicular mucin
goblet cells predominate
little microvesicular mucin
LHSC
S14-3876
Sessile Serrated Adenoma
SSA
horizontally spreading
and bizarre crypt bases
sessile
dilated crypt bases
abnormally located
differentiated cells
(goblet, gastric)
submucosal fat
exaggerated deep
crypt serration
SSA – Deep Crypt Abnormalities
•
•
•
dilated crypts
complex serrated crypts with lateral extensions
serrated crypts with upward lateral serrations
SSA – Upper Crypt Abnormalities
• enlarged vesicular nuclei
• prominent nucleoli
• mitoses
SSA – Diagnostic Criteria
> 2 or 3 contiguous crypts demonstrate features of SSA (crypts that are dilated
and assume abnormal shapes including L-shapes and inverted T-shapes;
prominent serrations at the base of crypts)
WHO Classification of Tumors of the Digestive System, 4th ed. 2010
1 unequivocal architecturally distorted, dilated and/or horizontally branched
crypts, especially with inverted maturation
Rex D et al. Am J Gastroenterol 2012;107:1315
R-sided polyp
think twice about
diagnosing a HP on
the R side, especially
if it’s >1cm or it’s in
any way unusual
endoscopically
SSA
• most have a mixture of deep
serrated and dilated crypts
• most have foci of “HP” within
them
SSA
HP foci can be present
eosinophilic, pencillate (TSA-like) cells can be present
HP with prolapse
changes
6 mm polyp, sigmoid
Serrated Polyp – Cancer Pathway
SSA
SSA+D
adenoca
SSA with dysplasia
NOT a “mixed hyperplastic
polyp – tubular adenoma”
SSA with dysplasia
SSA with dysplasia
3 mm polyp, sigmoid
SSA+D
SP, unclassified +D
HP +D(TA)
7
2
2
SSA with dysplasia
Dysplasia in SSAs
tubular adenoma – like
“conventional”
TSA – like
“serrated”
LHSC
S14-2688
SSA with dysplasia
and
invasive adenocarcinoma
LHSC
S14-2477
Traditional Serrated Adenoma
TSA Features
4 pencillate cells
1
ectopic crypt buds
3 rigid, sharp serrations
2 dysplasia
TSA vs TVA
• classic TSA features (e.g. ECFs) become less recognizable as
dysplasia increases
increasing grades of dysplasia
number of recognizable ECFs
more easily recognized as TSA
looks like a TVA/VA
TSA: Variable Dysplasia
Proliferation in TSAs
Ki67
TSA
HP with Prolapse
TSA with HGD and Adenocarcinoma
Clinical Significance
of SSAs
• SSAs  CRC (20-30%)
• increased risk with multiple
and/or large SSAs
• some  CRC quickly and while
small
Serrated Polyp – Cancer Pathway
normal
MVHP
SSA
MLH1 promoter methylation
 loss of MLH1  MSI
SSA+D
MLH1
Goldstein NS. Am J Clin Pathol 2006;125:132
Sheridan TB et al. Am J Clin Pathol 2006;126:564
Li D et al. Am J Gastroenterol 2009;104:695
Lu FI et al. Am J Surg Pathol 2010;34:927
adenoca
Serrated Adenocarcinoma
Putative Molecular Pathways to CRC
SERRATED PATHWAYS
FAMILIAL PATHWAYS
Normal mucosa
Lynch
germline mutation
MMR gene
FAP
germline mutation
APC gene
CONVENTIONAL PATHWAYS
Normal mucosa
BRAF CIMP-H
KRAS
APC
APC allele loss
APC
APC
SSA
TSA ± sTVA
TA
TAs++
TA
TVA
MLH1 loss
p16 loss
MGMT loss
Wnt
MMR allele loss
p53
Hypomethylation
Hypomethylation
KRAS
SSAD
SSAD
TSA-HGD
TA-HGD
TA-HGD
TA-HGD
TVA-HGD
frameshift mutations
e.g. TGFRb
SMAD4
p53
SMAD4
p53
p53
frameshift mutations
e.g. TGFRb
BRAF CIMP-H
MSI CRC
BRAF CIMP-H
MSS CRC
KRAS CIMP-L
MSS CRC
CIMPMSI CRC
CIMPMSS CRC
CIMPMSS CRC
CIMP-L
MSS CRC
good
poor
poor
good
standard
standard
standard
5-FU
resistant
sensitive
sensitive
resistant
sensitive
sensitive
sensitive
Anti-EGFR
resistant
resistant
resistant
sensitive
sensitive
sensitive
resistant
Prognosis
Rates of Progression to Cancer
Adenomatous Polyp
Sessile Serrated Adenoma
SSA with Dysplasia
Interval CRCs
• due to missed polyps (70-80%) or
incompletely resected polyps (10-20%)
Pohl H, Robertson DJ. Clin Gastroenterol Hepatol 2010;8:858
Leung K et al. Gastrointest Endosc 2010;71:111
Robertson DJ et al. Gastroenterology 2008;134:A-111
Farrar WD et al. Clin Gastroenterol Hepatol 2006;4:1259
• often R-sided, MSI-H, CIMP-H
Sawhney MS et al. Gastroenterology 2006;131:1700
Arain MA et al. Am J Gastroenterol 2010;105:1189
• 77% risk reduction in CRC incidence for colonoscopy but primarily for left
sided cancers
Brenner H et al. Ann Int Med 2011;154:22
Baxter NN et al. Ann Int Med 2009;150:1
Singh H et al. Gastroenterology 2010;139:1128
• relative failure of colonoscopy to protect against right-sided colon cancer
due to missed SSAs
Endoscopic Detection of SSAs
• detection rates of serrated lesions vary dramatically among endoscopists
• substantial numbers of endoscopists miss more than half of the serrated
polyps in the proximal colon
Kahi CJ et al. Clin Gastroenterol Hepatol 2011;9:42
Hetzel JT et al. Am J Gastroenterol 2010;105:2656
• difficult to completely excise
subtle nodularity
+NBI: abrupt cutoff of
submucosal vein, reddish
mucous cap
subtly nodular and swollen
crest of fold
debris-stained mucous cap
(“egg-drop soup”)
Images from Tadepalli US et al. Gastrointest Endosc 2011;74:1360
Serrated Polyps:
Initial Management
complete endoscopic removal
except: multiple, diminutive (≤5mm) polyps
 random biopsies
re-endoscopy in 3-6m
• if piecemeal removal or potential incomplete removal
surgery
• if lesion cannot be removed endoscopically
• multiple large lesions
Surveillance Intervals Following Endoscopic
Resection of Serrated Lesions (consensus)
HP
SSA/TSA
SSA+D
Size
Number
Location
Interval (years)
<10mm
any
Rectosigmoid
10
≤5mm
≤3
Proximal to sigmoid
10
Any
≥4
Proximal to sigmoid
5
>5mm
≥1
Proximal to sigmoid
5
<10mm
<3
Any
5
≥10mm
1
Any
3
<10mm
≥3
Any
3
≥10mm
≥2
Any
1-3
Any
Any
Any
1-3
Beware the right-sided “hyperplastic polyp” >1 cm
Rex DK et al. Am J Gastroenterol 2012;107:1315
SSA and TSA: Reporting
• SSA
• negative for dysplasia
• with dysplasia (low or high-grade) ≡ advanced adenoma
COMMENT
“Sessile serrated adenomas with dysplasia are advanced lesions
that have an increased propensity to transform to adenocarcinoma.
Complete endoscopic removal is recommended. If complete
endoscopic removal cannot be achieved, surgical resection should
be considered.”
• TSA
• negative for high-grade dysplasia
• with high-grade dysplasia
Take Home Messages - I
• SSAs are much commoner in the right colon.
• SSAs can be missed by endoscopists and account for increasingly
recognized interval colon cancers.
• An SSA with dysplasia of any grade is an advanced SSA with an
increased propensity to become malignant. These polyps must be
completely removed.
• Mixed polyps (TA-SSA/HP) “don’t” exist; these are advanced SSAs.
• HPs are unusual in the right colon.
• If you’re considering a diagnosis of HP in the right colon, think again
and consider ordering deeper levels and check the endoscopic
findings; if it’s bigger than 5 mm, it’s probably an SSA.
Take Home Messages - II
• TSAs are left sided lesions and may be misdiagnosed as TVAs or
•
•
•
•
VAs.
The most characteristic feature of a TSA is the ectopic crypt
bud, which should be present in all TSAs but can occur
occasionally in other adenomas.
TSAs may have SSA-like or HP-like foci within them.
HPs with prolapse can be confused with TSAs.
We don’t know that much about TSAs in terms of their
malignant potential but they’re probably similar to
conventional adenomas.
Acknowledgements
• GI pathologist colleagues at LHSC
• Dr. Runjan Chetty
• Dr. Jeremy Jass

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