advances in the detection and evaluation of barrett's ......advances in the detection and...
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Advances in the Detection and Evaluation of Barrett's Esophagus:
Has a paradigm shift occurred?
New York Society for Gastrointestinal Endoscopy
December 18, 2015
Dr. Seth Gross
Overview of WATS3D
The Problem
Adenocarcinoma – A Disease with a Rapidly Increasing Incidence
AdenoCa Esoph
Melanoma
Prostate
Lung/Breast
Colon
Pohl H et al. J Natl Cancer Inst 2005;97:142-6.
Not Much Progress Being Made…
Incidence
Mortality
Pohl H et al. J Natl Cancer Inst 2005;97:142-6.
Trends in EAC
Kong CY et al, CEBP, 2014.
We are Losing the Battle Against Esophageal Adenocarcinoma
Most Presentation is Late-Stage
Schlansky B et al. Aliment Pharmacol Therap, 2006.
• Case-control study in the KP Bay Area population
• Cases: Pts with known BE who died of EAC, 1995-2009• Controls: Pts from the pop with BE who did not die of EAC
• Matched for age, sex, and duration of f/u
• Exposure: Surveillance endoscopy in 3 yrs prior to index date
• Basic idea is that those dying of CA should be less likely to have surveillance exam than those who did not die
“Since dysplasia has no distinctive gross features, endoscopists collect random samples of esophageal tissue for biopsy; thus sampling error is a major problem.
By the time biopsy specimens show high-grade dysplasia in patients with Barrett’s esophagus, approximately one third of patients have an invasive cancer. Extensive sampling can reduce this problem but cannot eliminate it…Despite its shortcomings, endoscopy with random sampling for dysplasia remains the clinical standard for managing Barrett’s esophagus.”
Spechler SJ. Clinical practice. Barrett's Esophagus. N Engl J Med 2002; 346
“Sampling error is a major problem”
Invasive cancerIntramucosal cancer
Dysplasia
Limitations of the Random Biopsy
in the Detection of Barrett’s Esophagus
“The distribution of goblet cells is patchy within the columnar lined distal esophagus. The yield of intestinal metaplasia on biopsies obtained from the columnar lined esophagus will depend on the length of columnar mucosa as well as the number of biopsies obtained.”
Prateek Sharma, Barrett’s Esophagus and Esophageal Adenocarcinoma, 2001
• Random biopsy yield of IM in VSSBE of less than 1cm (evidenced as an irregular Z-line) = 15%
• Random biopsy yield of IM in SSBE of less than 3cm = 58%
Wallner et al, Scan. J of Gastroenterology 2000
Limitations of the Random Biopsy
in the Detection of Barrett’s Esophagus
Dysplastic Very Short Segment Barrett’s Esophagus
15
Forceps biopsies were negative for both BE and dysplasia
Unlike Cytology, the WATS3D Biopsy Obtains a
Complete Transepithelial Tissue Sample of the
Entire Thickness of the Esophageal Mucosa
16
The wider surface area sampled by the transepithelial WATS
biopsy addresses this problem
Forceps biopsy has a significant
potential for sampling error
Why didn’t anyone think of this before?
• WATS transepithelial tissue samples are routinely over 100μ thick, 50X thicker than the 2μ thick cytology or histology sample.
• This uniquely thick specimen consists of a complex mixture of disaggregated 3D tissue fragments which needs to be exhaustively searched by the pathologist for evidence of abnormality.
Neural Network Based 3D Imaging Analyzes the 100µ Thick WATS3D Tissue Sample by Synthesizing 100, 1 Micron Optical Slices.
Three Dimensional Image Capture and Computer
Analysis – U.S. Pat. No. 8,199,997
EDF Image
Images captured at
different z-planes
EDF Processing
Limited DOF
XYBoth X+Y
objects are in
focus
A
B
C
X
Y
• Extended Depth of Field WATS3D computer analysis keeps all objects within the microscopic field of view in focus in 1 µ slices.
• Every 1 µ focal plane is captured up to a 100 μspecimen.
20
• Computer Analysis presents to the pathologist a 3D Image Synthesized from Multiple 1μ Optical Slices.
• 196 areas/sample in the 3D display image are highlighted for the pathologist by the neural network.
Detailed Scanner Architecture
Low
40X
Medium
10X
High
20X
Centroid
Coordinates
Slide Map ReAcquire
selected cells
DSP:
- Coverslip,
- Bubble,
- Empty
~10,000
centroids/
slide
~1000 med.
res. fields
Bayesian
Classifier:
Cell level
Slide level
DSP:
Preprocess
Math Morph.
Cluster NN
- Base
- Geometric
Color
Grouping
Color - HSI
K-means
Feature
Extraction
Segment
Nucleus size,
Nuc. IOD,
N/C ratio,
Moments,
Texture,
Curvature
Abnormality
Score
Neural Nets:
Single NN
- Base
- Specialized
Cell Selection
Focus Map Focus Map
Cluster
Geometry
Focus
21 743 5 6
Neural Net
• Training by back-propagation
• Iteratively adjust connection weights in the direction that moves the outputs towards the desired values
f1 f2 f3 f4 f5
h1 h2
o1
f6
h3 h4
w1 w2 w3 w4 w5 w6
o1
25
HG - Individual cells separating from the edge of the cluster
02-01-KC
HG- Pleomorphic cells
02-06-B-G
Carcinoma - Clusters of pleomorphic cells within lymphatic spaces
02-17-RM
HG - Multiple variations
02-23-PC
02 25-RM
HG - Multiple variations
Introduction to WATS3D Data
• Unless testing a specific, identified lesion or performing a complete microscopic analysis of an entire tissue specimen, “test sensitivity” is not a relevant metric.
• For techniques designed to increase the detection of additional occult abnormality, the primary statistical metric is “Added Yield”
• Added Yield = Additional detection of disease resulting from addition of adjunctive test /Detection without addition of the adjunctive test
WATS3D is an Adjunctive Test
• In all studies clinicians are advised to continue to use their FB to test those areas of the esophagus which appear most suspicious endoscopically and to use WATS3D to test additional tissue.
• WATS3D and FB results are expected to differ because the two biopsy techniques are being used to test different tissue areas.
• Contingency table/Confusion matrix therefore has limited value.
Dr. Nicholas J. Shaheen
DDW 2014 Presidential Plenary Session:
Esophageal Brush Biopsy With Computer-
Assisted Tissue Analysis Increases Detection
of Barrett’s Esophagus and Dysplasia In A
Multi-Site Community-Based Setting
Seth A. Gross1, Vivek Kaul2; Anthony Infantolino3; Michael S. Smith4
1.Medicine/Gastroenterology, New York University Medical Center, New York, NY, United States.
2.Medicine/Gastroenterology, University of Rochester School of Medicine, Rochester, NY, United States.
3.Medicine/Gastroenterology, Thomas Jefferson University, Philadelphia, PA, United States.
4.Medicine/Gastroenterology, Temple University School of Medicine, Philadelphia, PA, United States.
Aim
• The goal of this study of 2,559 patients was to assess the benefits of WATS3D in routine community practice.
Methods
• Retrospective review of prospectively collected data
• Multi-site: 28 community based gastroenterologists
• Patients had both FB and WATS3D
• FB and WATS3D samples were sent to a central laboratory (CDx DiagnosticsTM, Suffern, NY).
• Absolute yield of BE using FB alone = 15%
• Absolute yield of BE after addition of WATS3D = 25%
• Added yield of BE resulting from addition of WATS3D = 68.4% (95% CI 58%-80%)
• NNT = 9.6
BE FB + FB - Total
WATS3D + 194 258 462
WATS3D - 183 1863 2046
Total 377 2121 2498
Dysplasia FB + FB - Total
WATS3D + 11 11 22
WATS3D - 6 2470 2476
Total 17 2481 2498
• Absolute yield of dysplasia on FB alone = 0.24%• Absolute yield of dysplasia after adding WATS3D = 0.68%• Added yield of dysplasia resulting from the addition of
WATS3D = 64.7% (95% CI 25%-142%)
ACG 2014
Increased Detection of Barrett’s Esophagus and Dysplasia in Community Gastroenterology Practices Resulting From the Addition of Computer-Assisted Transepithelial Brush Biopsy to Forceps Biopsy
Seth Gross1, Vivek Kaul2, Michael S. Smith3
1.Medicine/Gastroenterology, New York Univ. Medical Center, New York, NY
2.Medicine/Gastroenterology, Univ. of Rochester School of Medicine, Rochester, NY
3.Medicine/Gastroenterology, Temple Univ. School of Medicine, Philadelphia, PA,
• A prospective registry with 19 New Community Practices undergoing screening or surveillance endoscopy with both FB and WATS3D
• 1655 patients, average age was 59 years (43% male)
• The indication for endoscopy was GERD in over 75% of patients
• In cases with suspected BE, segment length was less than 3 cm
• FB alone identified BE in 203 cases (12%), and dysplasia in 9 cases (0.54%)
• WATS3D identified an additional 203 cases of BE, increasing the absolute yield for BE to 25%.
• WATS3D also detected an additional 12 cases of dysplasia, increasing the absolute yield for dysplasia to 1.26%.
• Added Yields of 110% for BE and 133% for dysplasia.
ACG 2015
• Study of over 12,000 patients in community-based settings
• WATS3D Biopsy Oral Presentation
• Wednesday, October 21, 7:00 – 7:10 AM
• Kalakaua Ballroom A
• First author is Dr. Erkanda P. Ikonomi, Department of Internal Medicine, Temple University Hospital, Philadelphia, PA
• All adults with a history of BE undergoing surveillance upper endoscopy between June 2012 and October 2014 at two tertiary-care, high-volume Barrett’s centers
• Cases were included in the analysis if they had:
• Prior RFA or SCT for treatment of BE• No visual evidence of BE during surveillance endoscopy• WATS3D and FB both performed during the same session
with results available for review
WATS3D Is Beneficial When Used For Post-Ablation Surveillance
Iorio et al. DDW 2015 Presentation 345
IM/Dysplasia/ Neoplasia
Forceps BiopsyPositive
Forceps Biopsy Negative
Total
WATS3D Positive 15 24 39
WATS3D Negative 24 145 169
Total 39 (18.8%) 169 208
Dysplasia/ NeoplasiaForceps Biopsy
PositiveForceps Biopsy
NegativeTotal
WATS3D Positive 0 4 4
WATS3D Negative 7 197 204
Total 7 (3.4%) 201 208
• With the addition of WATS3D to FB, the rate of detecting any metaplasia or dysplasia increases by 11.5% (from 18.8 to 30.3%) with a relative yield increase of 61.5%
• For dysplasia alone, the incremental yield of adding WATS3D to FB is 1.9% (from 3.4 to 5.3%); the augmented yield is 57.1%
• NNT for any metaplasia or dysplasia is 8.7, and 52.6 for dysplasia alone
Adjunctive Benefit of WATS3D
following Barrett’s Ablation
42%
57.10%
39.8%42%
68.4%64.7%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Anandasabapathy S et al. Kataria RD et al. Johanson JF et al. Gross S et al. Gross S et al. Gerson L et al.
Barr
ett
’s E
sophagus
Barr
ett
’s E
sophagus
Dyspla
sia
Dyspla
sia
Post-
Abla
tion B
arr
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’s E
sophagus
Barr
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’s E
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nd
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Cross-Sectional Data - Added Yield of Barrett’s Esophagus and Dysplasia
Incre
ased D
iagnostic Y
ield
with
Ad
junctive U
se
of
WA
TS
3D
N = 1,266 N = 2,559 N = 2,559 N = 151 N = 31 N = 1,699
Meta-analysisSurveillance Screening
1. Anandasabapathy et al. Dig Dis Sci, e-pub
2. Kataria et al. American College of Gastroenterology Annual Meeting; October 11-16, 2013; San Diego, California. Abstract P23.
3. Johanson et al. Dig Dis Sci, e-pub
4. Gross et al. Digestive Disease Week; May 18-21, 2014; Chicago. Abstract Su1452.
5. Gerson et al. Digestive Disease Week; May 18-21, 2014; Chicago. Abstract Sa1833.
Summary of Cross-Sectional Data
• Adjunctive use of WATS3D has been shown in large studies to markedly increase the detection of both BE and dysplasia in both community screening and academic surveillance settings.
• While substitutive use was not directly tested in any study and is not recommended, contingency tables suggest an advantage to WATS3D for this use.
What’s Next: WATS3D Clinical Registry
• The efficacy of WATS3D in addressing the intrinsic sampling error of random esophageal biopsy has been well established by cross-sectional data.
• As a result WATS3D is now being incorporated as part of the routine standard of care in both community and academic GI practices.
• Collecting longitudinal data from this routine clinical use may determine if WATS3D can not only provide greater detection of disease, but also a more prognostically useful detection of disease.
WATS3D Clinical Registry
• Participation open to community and academic settings
• Goals:
• 1) Understand the utilization of WATS3D in real world settings
• 2) Understand the longitudinal outcomes of patients assessed with WATS3D
• 3) Understand the significance of pathologic findings detected by WATS3D
• Crypt Dysplasia - To of effacement of the normal honeycomb pattern of the non-dysplastic gland
• Non-goblet cell Intestinal Metaplasia – CDX2
Crypt dysplasia with surface maturation: a
clinical, pathologic, and molecular study
of a Barrett's esophagus cohort.
Lomo LC, Blount PL, Sanchez CA, Li X, Galipeau PC, Cowan DS, Ayub K, Rabinovitch PS, Reid BJ, Odze RD.
The aim of this study was to evaluate the clinical, pathologic, immunohistochemical, and molecular characteristics of basal crypt dysplasia-like atypia (BCDA) with surface maturation. BCDA with surface maturation, in mucosal biopsies from patients with BE, is an uncommon but significant pathologic change that shows a variety of proliferative and molecular abnormalities and has a high association with conventional dysplasia and/or adenocarcinoma.
Standard Anatomic Pathology Practice - Fundamentally unchanged
since 1850 - An approx. 5mm deep tissue sample is cut into a few thin
(2μ) sections which are stained with H&E to show tissue architecture
Standard microscopy requires 2μsectioning, destroying the natural appearance of the glandular surface
The surface of the gland, not the histologic section,
may hold the most definitive evidence of LGD
The non- dysplastic glandular surface is a cellular honeycomb
WATS3D preserves and presents the en face view of the gland, allowing for appreciation of the normal honeycomb arrangement of cells and its dysplastic effacement. May allow elimination of “Indefinite for Dysplasia”
WATS3D en face view of non dysplastic BE cf. confocal microscopy
“Indefinite for dysplasia ” on H&E
03-13-RCB
WATS3D en face view of same case shows dysplastic effacement
03-13-RCB
Does CDX2 expression predict Barrett's metaplasia in oesophageal columnar epithelium without goblet cells?
Kerkhof M, Bax DA, Moons LM, van Vuuren AJ, van Dekken H, Steyerberg
EW, Kuipers EJ, Kusters JG, Siersema PD; Cybar Study
CDX2 expression in cardiac-type mucosa might be able to predict the presence of undetected intestinal metaplasia in columnar-lined oesophagus, and thus may be a putative marker for the presence of intestinal metaplasia in the absence of goblet cells.
WATS3D Detection of Non-goblet cell IM
WATS3D Registry Requirements
• Open to qualified endoscopists who are using WATS3D as part of their clinical standard of care.
• Single consent of patient required to utilize de-identified data
• Data submission with each endoscopy along with all path reports and a photograph of the most proximal area of BE or of the z-line.
• $125 for the enrollment endoscopy , $100 for each subsequent endoscopic or surgical intervention
Thank you