No dysplasia

1
Presumed neoplastic progression in Barretts
mucosa
Low-grade dysplasia
No dysplasia
Invasive CA in lamina propria
High-grade dysplasia
2
Barretts biopsies Epithelial Changes The old
paradigm few options either esophagectomy or
shorter follow-up
Designation Implications Negative Follow-up?
Ignore? Indefinite Shorten follow-up? Dysplasi
a Low-grade Shorten follow-up?
High-Grade Esophagectomy? Shorten
follow-up mapping? Invasive carcinoma Esophagect
omy
3
A common dysplastic biopsy that the endoscopist
thinks comes from Barretts mucosa, but there is
no Barretts. All
epithelium is either dysplastic or cardiac or
squamous.
4
Do the same guidelines apply to dysplasia at the
GEJ when there is no Barretts? No one has
specifically dealt with this, but our experience
suggests that they are handled as if they were
Barretts biopsies.
5
Barretts and EGJ biopsies Epithelial Changes
The old paradigm few options either
esophagectomy or shorter follow-up
Designation Implications Negative Follow-up?
Ignore? Indefinite Shorten follow-up? Dysplasi
a Low-grade Shorten follow-up?
High-Grade Resect? Shorten follow-up
mapping? Small carcinoma Resect
6
Barretts and EGJ biopsies Epithelial Changes
The new paradigm more options ablation and
endoscopic mucosal resection (EMR)
Designation Implications Negative Follow-up?
Ignore? Ablation? Indefinite Shorten follow-up?
Ablation? Dysplasia Low-grade Shorten
follow-up? Ablation? High-Grade Resect? EMR?
Ablation? Shorten follow-up mapping? Small
carcinoma Resect? EMR? Ablation?
7
Endoscopic mucosal resection
8
Adult male Heartburn in his history, on
PPIs Endoscopic appearance of 1 cm long Barretts
segment Biopsy adenocarcinoma invading lamina
propria Repeat endoscopy 9 mm nodule at GEJ. No
Barretts. No depth by EUS Endoscopic mucosal
resection (EMR) of the nodule and adjacent mucosa
9
1.2 x 0.8 cm
10
Squamous on both sides
Squamous on this side
Columnar on this side
Columnar on both sides
11
Cardiac mucosa with dysplasia on and right below
the surface. No Barretts mucosa
12
Cardiac mucosa with dysplasia on and right
beneath the surface. No Barretts mucosa
13
Was Barretts mucosa originally present, but it
all became dysplastic?
Maybe.. or maybe not!
14
EMR traumatizes the tissue
Lots of artifact shredding on surface
15
Lots of artifact cell dissociation
16
High-grade dysplasia
17
How do I know that this is high grade
dysplasia? I used the criteria!
18
12 Morphologic Criteria forUnequivocally
Neoplastic Epithelium
Cytologic
Architectural
Cellular Crowding Stratification
Pattern Tubular clustering Villous
surface Complexity
Cytoplasmic loss of maturation
19
12 Morphologic Criteria forUnequivocally
Neoplastic Epithelium
If each of these 12 features was graded on a
scale of 0- 3, there would be a series of totals
from 0 to 36.
Cytologic
Architectural
Cellular Crowding Stratification
Pattern Tubular clustering Villous
surface Complexity
Cytoplasmic loss of maturation
20
Cytologic and Architectural Hints
forUnequivocally Neoplastic Epithelium
Architectural Cellular Crowding
Stratification Pattern Tubular
clustering Villous surface Complexity
Cytologic Nuclear Enlargement NC
ratio Hyperchromatism Pleomorphism
Abnormal mitoses Cytoplasmic loss of
maturation
These changes do not occur at the same rate or
with the same weight in every dysplasia!
21
Neg Indef LGD HGD
The standard diagnoses used for biopsies of
Barretts mucosa
22
What are the Minimal Criteria for the
Diagnosis of High-Grade Dysplasia in Barretts
Mucosa?
23
Ideal low-grade dysplasia
Nuclei confined to the basal half Little
pleomorphism Cytoplasmic maturation Uniformity
24
Ideal high-grade dysplasia
Full-thickness nuclear stratification Pleomorphis
m No cytoplasmic maturation No uniformity
25
What do we need to add to this to make it just
barely more than LGD?
What do we need to subtract from this to make it
just barely more than LGD?
26
High side of low? Low side of high?
Low-grade
High-grade
27
What are the published criteria for the 2 grades
of dysplasia?
28
Snell, et al. Long-term nonsurgical management of
Barretts esophagus with high-grade dysplasia.
Gastroenterol 1201607, 2001 (Hines VA and Loyola
University)
The interpretation of the microscopic findings
was based on previously established definitions.
The reference was to the Riddell et al 1983 paper
that dealt with colitis, not Barretts.
This paper does not give hard diagnostic criteria
29
Skacel, et al The diagnosis of low-grade
dysplasia in Barretts esophagus and its
implications for disease progression. Am J
Gastroenterol. 953383, 2000 (Cleveland Clinic)
..each (biopsy) was classified . using
previously published criteria (modified) also
citing the Riddell paper from 1983.
30
Montgomery, et al Reproducibility of the
diagnosis of dysplasia in Barrett esophagus a
reaffirmation. Hum Pathol. 32368, 2001 (12 GI
pathologists from all over the US)
..the participants were familiar with the
criteria proposed in 1988 and used these as a
general basis for their interpretations.
The reference was to the paper by Reid et al on
observer variation in the diagnosis of dysplasia
in Barretts esophagus.
31
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum Pathol.
19166. 1988 (study of multiple cases by GI
pathologists from 4 centers in the US and Canada)
The features were separated into 2 types 1.
Architectural 2. Nuclear (cytologic)
These are features of dysplasia in general, not
specifically any grade.
32
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum
Pathol. 19166. 1988
Architecture 1. budded, branched, crowded, or
irregularly shaped glands

33
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum
Pathol. 19166. 1988
Architecture 2. papillary extensions into gland
lumina
34
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum
Pathol. 19166. 1988
Architecture 3. villiform configuration of the
mucosa
35
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum
Pathol. 19166. 1988
Nuclear 1. marked variation in size and shape
36
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum
Pathol. 19166. 1988
Nuclear 2. nuclear and/or nucleolar enlargement
37
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum
Pathol. 19166. 1988
Nuclear 3. increased nuclear/cytoplasmic ratio
38
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum
Pathol. 19166. 1988
Nuclear 4. hyperchromatism
39
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum
Pathol. 19166. 1988
Nuclear 5. increased numbers of abnormal mitoses
Is there a normal number of abnormal mitoses?
40
Reid, et al Observer variation in the diagnosis
of dysplasia in Barretts esophagus. Hum Pathol.
19166. 1988 (study of multiple cases by GI
pathologists from 4 centers in the US and Canada)
The diagnosis of LGD or HGD is based on the
severity of both architectural and cytologic
criteria Although either architectural or
cytologic abnormalities may predominate, HGD is
diagnosed if either one is sufficiently
prominent.
How prominent is sufficiently prominent in
separating the highest side of LGD from the
lowest side of HGD?
This widely quoted paper does not tell us.
41
Buttar, et al Extent of high-grade dysplasia in
Barretts esophagus correlates with risk of
adenocarcinoma. Gastroenterol. 1201630, 2001
HGD was defined by criteria originally
established by Reid et al
This is all well and good, but the Reid paper did
not establish HGD criteria nor did it tell us how
much of each feature was required to move a
mucosa from LGD to HGD
42
Montgomery, et al Reproducibility of the
diagnosis of dysplasia in Barrett esophagus a
reaffirmation. Hum Pathol. 32368, 2001
HGD No surface maturation. The architecture
may show crowding or be markedly distorted with
glandular crowding and little lamina propria.
43
Montgomery, et al Reproducibility of the
diagnosis of dysplasia in Barrett esophagus a
reaffirmation. Hum Pathol. 32368, 2001
HGD Nuclei may have either delicately clumped
dark heterochromatin and inconspicuous nucleoli
or prominent irregular nuclei with irregularly
clumped chromatin and irregular nucleoli.
Markedly enlarged hyperchromatic nuclei are a
feature of HGD, and these may extend to the
surface. Loss of nuclear polarity is seen.
Mitoses are readily identified
How do we tell marked from less than marked?
Where does regular end and irregular begin?
Anything with the word may is not a criterion!
44
The GI pathology textbooks must have helpful
criteria. After all, people buy them because they
are useful for solving problems, such as
this. Right?
45
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46
Illustrations of Barretts dysplasias in a well
known GI pathology textbook
High-grade
Low-grade
These dont look alike.
Any fool can tell them
apart. No
book tells us where LGD ends and HGD begins.
47
Not one of these fabulous textbooks of GI
pathology, written or edited by giants in our
field, has a useful set of criteria for the
lowest of HGDs.
So much for the giants!!!
48
How do we tell the difference between low-grade
and high-grade dysplasias?
There are no specific rules, just suggestions.
From a practical standpoint, we look at it and
try to determine if it looks bad enough
Or, we show it to other people to see if they
think it looks bad enough
49
We need a high-grade dysplasia stain!!!
50
What are the Minimal Criteria for the Diagnosis
of High-Grade Dysplasia in Barretts Mucosa?
The answer is obvious the minimal criteria for
the diagnosis of HGD exist in our eyeballs and in
our occular-cerebral reflexes.and we have
different eyeballs and reflexes
51
These changes are not defined anywhere!!!!!
52
As far as I know, there are no reproducibility
studies of diagnoses in this intermediate
dysplasia area!
53
Sorry!
54
What changes in biopsies lead us to the diagnosis
of an invasive carcinoma?
55
Single neoplastic cells in the lamina propria
indicating mucosal invasion
56
Adenocarcinoma cells in squamous epithelium
57
Desmoplasia indicating submucosal invasion
58
Back to the EMR specimen It did have some changes
diagnostic of invasive carcinoma
59
Single cells in lamina propria
60
Complex architecture with anastomosing tubules
and desmoplastic stroma
61
Invading the squamous mucosa and beneath it
62
Tumor with desmoplasia invading lamina propria
cardiac mucus gland (in the lamina propria)
63
Columnar margin of resection High grade
dysplasia and maybe carcinoma
64
Is this carcinoma at the resection margin?
It is too fried for me to be sure
The ink only made it blue
65
Diagnosis of the endoscopic mucosal resection
specimen Invasive adenocarcinoma extending only
into lamina propria. High grade dysplasia
involving the columnar mucosal resection
margin. One other margin may be involved by
carcinoma, but that margin is too cauterized for
adequate interpretation. No Barretts mucosa
66
For EMR specimens of superficial carcinomas in
Barretts mucosa, there are new anatomic
complexities.
67
Human Pathology. 221158-61, 1991
This was the first detailed, controlled study of
a peculiar anatomic stromal alteration that
occurs in about 90 of Barretts mucosae, the
appearance of a second muscularis mucosae layer
right beneath the mucosa.
68
(No Transcript)
69
Superficial lamina propria
The inner muscularis mucosae
Deep lamina propria
The outer muscularis mucosae
70
The original or outer MM is continuous with the
MM under the squamous mucosa
71
Diagram by K Takubo
72
This paper was the first to recognize that
Barretts mucosa is more than just a mucosal
change, but it is actually a mucosal-stromal
complex
73
Inner MM
We can see it in EMR specimens
Outer MM
74
Duplicated MM extending into mucosa and filling
the lamina propria
The musculo-fibrous anomaly
75
What is the prognosis when Barretts
adenocarcinoma invades into the deep lamina
propria? It is the same as invasion into the
upper lamina propria, or is it the same as
invasion into the submucosa?
76
In the last year, the importance of this
duplication in terms of invasive carcinoma has
been analyzed
Am J Surg Pathol. 311719-25, 2007
77
Because of the duplicated MM, intramucosal
carcinoma now includes
78
Carcinoma invading into the inner MM
79
CA invading into deeper lamina propria
Inner MM
Outer MM
80
Am J Surg Pathol. 311719-25, 2007
Inner MM
Outer MM
81
Inner MM
Carcinoma invading through the outer MM into the
submucosa
Outer MM
82
The outer muscularis mucosae is sometimes thick
enough to be confused with the muscularis propria.
Inner MM
Outer MM
83
Am J Surg Pathol 32566, 2008
In EMR specimens, pathologists need to be aware
of the duplicated muscularis mucosae for accurate
staging of carcinoma and so as not to confuse the
outer MM with the muscularis propria.
84
In EMR specimens for high-grade dysplasia and
superficially invasive adenocarcinomas at or near
the gastroesophageal junction, what type of
mucosa is the origin? Recent study from Germany
and Japan covering close to 200 EMR specimens
the most common marginal mucosa by far is
cardiac, not Barretts. Todays case is an
example. What does this mean as far as Barretts
surveillance is concerned? We dont know!
85
Summary
86
We have to deal with new endoscopic technics, and
there are many of them We have to adjust our
diagnostic approach to dysplasias and carcinoma
as new criteria emerge Remember that Barretts
mucosa has duplicated stromal layers beneath
it We still are on the upward slope of our
learning curve. Tell me when we hit the top