Uma Mahadevan, MD
Recognition of Flat Dysplasia
American College of Gastroenterology
Western Regional Course
January 26, 2013
Uma Mahadevan MD
Associate Professor of Medicine
Co-Medical Director
UCSF Center for Colitis and Crohn’s Disease
Slides courtesy of Fernando Velayos MD MPH
Risk of CRC in IBD is elevated
Inflammation of the colon is the key factor
• Risk
of CRC in IBD is 7-18 % in newer studies
Site
RR
95% CI
All CD
2.5
1.3-4.7
Colon
4.5
1.3-14.9
Ileum
1.1
0.8-1.5
0.8
1.5
Canavan C et. al.Aliment Pharmacol Ther 2006: 23; 1097
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Uma Mahadevan, MD
Known risk factors are almost all non-modifiable
• Non-modifiable risk factors:
–
–
–
–
–
Duration (increases after 10 years)
Extent (15X greater in pancolitis)
PSC (5X greater)2
Family history of CRC (2.5X greater) 1
Inflammatory polyps (“pseudopolyps”-2.5X) 3,4
• Potentially modifiable risk factor:
– Histologic inflammation at surveillance colonoscopy3
1Askling
J, et al. Gastroenterology. 2001
BU, et al. Dis Colon Rectum. 2001
3Rutter, et al. Gastroenterology. 2004. Bansal, et al. Presented at ACG 2005, Honolulu. Rubin et al. Presented at DDW
2006, Los Angeles.
4Velayos et. al . Gastroenterology. 2006
2Lindberg
Role of Chromoendoscopy in
Surveillance
• Two main uses in IBD Surveillance
– Improve detection of subtle colonic lesions
(increase sensitivity of surveillance)
– Once lesion detected-to aid in differentiating
between neoplastic and non-neoplastic based on
crypt architecture and modified pit pattern
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Uma Mahadevan, MD
Difference Between Chromoendoscopy and
Virtual chromoendoscopy
• Chromoendoscopy
– Dye spray through catheter
– Ab
Absorptive
ti d
dye: ((stain
t i ttaken
k up b
by noninflammed
i fl
d mucosa but
b t poorly
l ttaken
k
up by active inflammation and dysplasia): methylene blue
– Contrast dye (coats surface to highlight subtle disruptions of normal
contours): indigo carmine
• Virtual chromoendoscopy
– Rotating color filters the R-G-B bands while increasing the relative intensity
of blue bands
– Post-processing techniques (i-Scan/Fujinon) to achieve pseudocolored
image
– Enhance tissue vasculature (differential optical absorption of light by Hb
associated with dysplasia (blue band)) or mucosal contours
Chromoendoscopy Finds More Dysplasia than
Conventional Exams
Number of Dysplastic Lesions
Author
(Year)
Institution
# of UC
Patients
Type of
Imaging
Chromo
Conventional
Sensitivity /
Specificity
Kiesslich
(2003)
University of
Mainz, Germany
263
Methylene
blue
32
10
93% sens.
93% spec.
Rutter
(2004)
St. Mark’s
Hospital,
Harrow, UK
100
Indigo
carmine
7
0
Not given
Hurlstone
(2005)
The Royal
Hallamshire
Hospital,
Sheffield, UK
350
Indigo
Carmine-and
Magnification
69
24
93% sens.
88% spec.
Kiesslich
(2007)
University of
Mainz, Germany
161
Confocal
endomicrosco
py
19
4
9 % se
94.7%
sens.
s
98.3% spec.
97.8%
accuracy
Dekker
(2007)
Academic
Medical Center,
Amsterdam, The
Netherlands
42
Narrow-band
imaging
8
7
Not given
Marion
(2008)
Mount Sinai,
New York, USA
102
Methylene
Blue
17
9
Not given
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Uma Mahadevan, MD
Significance of Pit Patterns
Type I/II predict non-neoplastic
lesions
Type III/IV/V predict neoplastic lesions
Kudo S et al. Endoscopy 1993
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Uma Mahadevan, MD
SURFACE guidelines for
chromoendoscopy
• Strict patient selection
– Avoid active disease
• Unmask the mucosal surface
– Excellent bowel prep; remove mucus and debris
• Reduce peristaltic waves
• Full-staining length of the colon
• Augmented detection with dyes
– 0.4%
0 4% indigo carmine; 0
0.1%
1% methylene blue
• Crypt architecture analysis
– Pit pattern III/IV of concern
• Endoscopic targeted biopsies
– Biopsy all mucosal alterations, especially pit pattern III/IV
Role of chromoendoscopy in surveillance
• Not yet standard of care
• Chromoendoscopy
Ch
d
((nott virtual
i t l chromo)-is
h
) i an
alternative surveillance technique mentioned in
guidelines from Crohn’s and Colitis Foundation
of America (2006) and British Society of
Gastroenterology Guidelines (2010)
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Uma Mahadevan, MD
Chromoendoscopy does not change the principles of
“flat” dysplasia management in 2013
• If flat or invisible dysplasia now becomes
“
“subtle”
” dysplasia
– Still need to resect the dysplastic tissue
• Miss rate of chromoendoscopy is unknown
(not much follow-up)
– If too many subtle areas-feasible to examine them
all?
– Pit pattern examination of the entire colon not
practical
What to do when when dysplasia is found?
Normal
Epithelium
Inflamed
Epithelium
Indefinite
Dysplasia
Low-Grade
Dysplasia
Colectomy?
Polypectomy?
High-Grade
Dysplasia
Cancer
Secondary
y
Prevention
Watch closely?
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Uma Mahadevan, MD
First, let’s define dysplasia types and start with
a common vocabulary
• Macroscopic classification
“Flat”
Flat”
• Microscopic classification
Normal
Indefinite
“Elevated”
Elevated”
Low
Low--Grade
High
High--Grade
• How detected
– Non-targeted vs. targeted biopsies
Itzkowitz S. and Harpaz N.
Gastroenterology 126:1634, 2004
Does all dysplasia mandate colectomy?
Recommendations from a recent guideline
are mostly grade A
Farraye Gastroenterology 2010; 138: 738
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Uma Mahadevan, MD
Perspective: What proportion of dysplasia fall into
the “flat” category
• Rutter 2006
– 25/110 (22.7%) LGD “invisible” or flat
• Rubin 2007
– 29/75 LGD invisible (38.7%)
• Velayos 2009
– 16/61 (26.2%) LGD invisible
• Marion
M i 2008
– 3/12 LGD invisible (25%)
Rutter MD et. al.. GI Endoscopy 2004: 60(3):334
Rubin DT et. al.. GI Endoscopy 2007: 65 (7): 998
Velayos FS et al ACG 2009
Marion JF et al AJG 2008: 103: 2342
Perspective: What proportion of dysplasia
fall into this category
~25%
~75%
Gastroenterology 2010; 138: 738
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Uma Mahadevan, MD
Now let’s define the three parameters relevant for
preventing CRC and CRC mortality in IBD once any
type of dysplasia is detectedNOTE: it is what you are already doing in non-IBD
patients
1. Rate of progression of dysplasia to
advanced dysplasia or CRC (metachronous)
2. Rate of occult cancer in patients diagnosed
with dysplasia (synchronous)
3. Resectability of the dysplastic lesion
Can I
see it?
Is it
discreet?
Can I
resect it?
Case example for flat LGD
A 43 year-old
ld man with
i h 16 years off extensive
i ulcerative
l
i
colitis found to have low-grade dysplasia in the
sigmoid (30 cm from the anal verge)
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Uma Mahadevan, MD
ENDOSCOPY
3 questions to ask in this case
1. Rate of progression of
dysplasia to advanced
dysplasia or CRC
(metachronous)
2. Rate of occult cancer
in patients diagnosed
with dysplasia
(synchronous)
3. Resectability of the
dysplastic lesion
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Uma Mahadevan, MD
Controversy in the agreement of
dysplasia
GI Pathologists
Kappa statistic indicates how
much greater observer
agreementt exists
i t than
th would
ld be
b
expected by chance
Range -1.0 to +1.0
Value 0= pure chance only
Value 1.0= perfect agreement
Value >0.75 =excellent agreement
Value 0.4-0.74= fair to good agreement
Value <0.4= poor agreement
- Eaden J J of Pathol 2001; 194:152
P1
P1 P2
P3
P4
P5
P6
P7
P8
P9
P10
P11
P12
P13
General Pathologists
P2 P3 P4 P5
0.43 0.25 0.12 0.15
0.12 0.16 0.24
0.44 0.38
0.44
-
P6
0.59
0.40
0.27
0.18
0.27
-
P7
0.48
0.36
0.39
0.17
0.26
0.51
-
P8
0.2
0.24
0.18
0.25
0.29
0.14
0.13
-
P9
0.22
0.15
0.24
0.17
0.14
0.35
0.32
0.13
-
P10
0.37
0.28
0.47
0.20
0.29
0.36
0.39
0.21
0.32
-
P11
0.19
0.19
0.33
0.27
0.2
0.24
0.34
0.13
0.28
0 21
0.21
-
P12
0.23
0.27
0.52
0.31
0.48
0.38
0.43
0.33
0.25
0 48
0.48
0.39
-
P13
0.33
0.26
0.35
0.17
0.12
0.43
0.40
0.11
0.26
03
0.3
0.43
0.29
-
Very few kappa values over 0.5
All pathologists agreed only on 4 of 51 (7.8% agreement (all HGD))
GI pathologists agreed only on 6 slides (11.7% agreement (4 HGD, 2 reactive atypia))
General pathologists agreed on 8 slides ( 15.7 % agreement (5HGD,2LGD,1 atypia))
Controversy is in the progression of
“flat” LGD to HGD or Cancer
Study
Setting
LGD (n)
Rate
Connell
Co
e 1994
99
St Mark’s
Mark s
9
54%
5
% @5y
Ullman 2002
Mayo Clinic
18
33% @5y
Ullman 2003
Mount Sinai
46
53% @5y
Rutter 2006
St Mark’s
36
25% @5y
Van Schaik 2010
6 Dutch centers
21
37% @5y
Lindberg 1996
Huddinge
37
35% @20y
Befrits 2002
Karolinska
60
2% @10y
Lim 2003
Leeds, UK
29
10% @10y
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Uma Mahadevan, MD
3 questions to ask in this case
1. Rate of progression of
dysplasia to advanced
dysplasia or CRC
(metachronous)
2. Rate of occult cancer
in patients diagnosed
with dysplasia
(synchronous)
3. Resectability of the
dysplastic lesion
What is the probability of finding
occult (synchronous) cancer after a
diagnosis fLGD?
Study
If colectomy done
immediately
Bernstein 1994
3/16 (19%)
Ullman 2003
2/11 (19%)
Rutter 2006
2/10 (20%)
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Uma Mahadevan, MD
3 questions to ask in this case
1. Rate of progression of
dysplasia to advanced
dysplasia or CRC
(metachronous)
2. Rate of occult cancer
in patients diagnosed
with dysplasia
(synchronous)
3. Resectability of the
dysplastic lesion
Characteristics to resectability
You already ask yourself this when you do screening
and surveillance in patients without IBD
Can I
see it?
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Is it
discreet?
Can I
resect it?
13
Uma Mahadevan, MD
Fact: Non-resectable colonic
dysplasia is managed with surgery
• Concern in IBD is typically the type of surgery
– Colectomy in IBD vs. limited resection in non-IBD
With these 3 principles let’s review
the guidelines for dysplasia and ask
if all dysplasia mandates colectomy
~25%
~75%
Gastroenterology 2010; 138: 738
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Uma Mahadevan, MD
Does all dysplasia mandate
colectomy?
Questions and
parameters to
decide
“nonadenoma like
dysplasia
lesion or
mass”
Progression
No info
Occult Cancer
43%
Resectable
No
Colectomy?
Yes
(grade A)
* Further adenoma 50%-need close surveillance
Farraye F Gastroenterology 2010; 138: 738
Bernstein C Lancet 1994
Does all dysplasia mandate
colectomy?
Questions and
parameters to
decide
“nonadenoma like
dysplasia
lesion or
mass”
“adenoma-like
lesion or mass
and no flat
dysplasia
elsewhere”
Progression
No info
<5%*
Occult Cancer
43%
<5%
Resectable
No
Yes
Colectomy?
Yes
(grade A)
No
(grade A)
* Further adenoma 50%-need close surveillance
Farraye F Gastroenterology 2010; 138: 738
Bernstein C Lancet 1994
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Uma Mahadevan, MD
Does all dysplasia mandate
colectomy?
Questions and
parameters to
decide
“nonadenoma like
dysplasia
lesion or
mass”
“adenoma-like “flat highlesion or mass grade
and no flat
dysplasia”
dysplasia
elsewhere”
Progression
No info
<5%*
High
Occult Cancer
43%
<5%
42%
Resectable
No
Yes
No
Colectomy?
Yes
(grade A)
No
(grade A)
Yes
(grade A)
* Further adenoma 50%-need close surveillance
Farraye F Gastroenterology 2010; 138: 738
Bernstein C Lancet 1994
Does all dysplasia mandate
colectomy?
Questions and
parameters to
decide
“nonadenoma like
dysplasia
lesion or
mass”
“adenoma-like “flat highlesion or mass grade
and no flat
dysplasia”
dysplasia
elsewhere”
“flat lowgrade
dysplasia”
Progression
No info
<5%*
High
1-12% vs 2555%
Occult Cancer
43%
<5%
42%
19%
Resectable
No
Yes
No
No
Colectomy?
Yes
(grade A)
No
(grade A)
Yes
(grade A)
Insufficient
(grade I)
* Further adenoma 50%-need close surveillance
Farraye F Gastroenterology 2010; 138: 738
Bernstein C Lancet 1994
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Uma Mahadevan, MD
Rates of colectomy for dysplasia in a large
community-based population
Colectomy after dysplasia diagnosis
Velayos et al. Gastroenterology 2010
Velayos et al DDW 2008
Problem with data for current guidelines
• Available IBD data retrospective, conflicting,
smallll numbers
b
• No prospective and modern data regarding
rates of progression, occult cancer
• Not account for evolving concepts and
techniques (chromoendoscopy)
• Not tested if can use endpoint endoscopic
resection regardless of dysplasia type as in
non-IBD dysplasia (polyps)
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Uma Mahadevan, MD
Summary: Does all dysplasia
mandate colectomy?
Questions and
parameters to
decide
“nonadenoma like
dysplasia
lesion or
mass”
“adenoma-like “flat highlesion or mass grade
and no flat
dysplasia”
dysplasia
elsewhere”
“flat lowgrade
dysplasia”
Progression
No info
<5%*
1-12% vs 2555%
High
Occult Cancer
43%
<5%
42%
19%
Resectabilityy
No
Yes
No
No
Colectomy?
Yes
(grade A)
No
(grade A)
Yes
(grade A)
Insufficient
(grade I)
* Further adenoma 50%-need close surveillance
Farraye F Gastroenterology 2010; 138: 738
Bernstein C Lancet 1994
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