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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5528_Библиотеки_им_академика_М_И_Перельмана.pdf
70 D. Schmolze & V. J. A. Konda
(a) (b) (c) (d)
(e) (f ) (g) (h)
Figure 2. Barrett’s associated neoplasia on probe-based confocal laser endomicroscopy. Probebased confocal images are demonstrated in (a)–(d). There is a disorganized architecture with variable
height of the epithelium, irregular appearing cells, and variable distance between glands in (a) and (b).
These areas were targeted for endoscopic mucosal resection and their corresponding pathology is
demonstrated in (e) and (f), respectively. Both cases demonstrated high-grade dysplasia. In (c) and
(d), there is loss of organization and there are clumps of black cells. These cases demonstrated
intramucosal carcinoma on their corresponding endoscopic mucosal resection specimens in (g) and
(h), respectively.
Given the limited field of view of endomicroscopy ranging between
240 microns (pCLE) and 550 microns (eCLE), these techniques are often
best combined with some other approach that allows the endoscopist to
identify where they want to have imaging of greater details. A multimodal
imaging approach may include a “red flag” technique which alerts the endoscopist to a suspicious area to then target with a detailed assessment. One
multicenter, randomized, control trial investigated the assessment of 101
patients with HGD and early cancer with sequential imaging of High Definition White Light Endoscopy (HD-WLE), Narrow-band imaging (NBI),
4
and pCLE.
Narrow-band imaging is a filtered blue light that allows for
virtual chromoendoscopy to enhance visualization of mucosal patterns and
vascular patterns. Patients were randomized to under HD-WLE and then
NBI imaging or NBI followed by HD-WLE imaging and then a second
endoscopist blinded to the previous assessments carried out the pCLE
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assessments. The addition of pCLE to HD-WLE imaging increased the
sensitivity from 34.2% to 68.3% and the negative predictive value from
89.8% to 94.6% on a per location analysis. A multicenter, randomized
trial with HD-WLE and eCLE of 192 patients demonstrated a significantly
higher yield of 34% for neoplasia with eCLE-targeted biopsies compared to
a 7% yield with random biopsies. Overall, several meta-analyses conclude
that CLE can distinguish between non-dysplastic and dysplastic Barrett’s
esophagus with sensitivity ranging 68–77%and specificity ranging 88–89%
on per lesion analysis and with sensitivity ranging 86–90% and specificity
ranging 83–89% on per patient analysis,
5–7
This ability to identify real-time
suspicious areas and target these areas with biopsy or endoscopic mucosal
resection can be incorporatedinto clinical surveillance and treatment strategies during endoscopy.
8, 9
Optical coherence tomography-based technologies are now commercially available to perform cross-sectional imaging in the esophagus. Volumetric laser endomicroscopy provides a span of 6 cm of visualization
down to a resolution of 7 microns with a depth of 3 mm. The balloon-based
catheter can be introduced through the working channel of the endoscope
10
in a safe and feasible manner.
Squamous epithelium, gastric cardia, and
non-dysplastic Barrett’s esophagus were differentiated from one another
with excellent interobserver variability among 10 observers examining 64
images of these three histology types.
11
Squamous epithelium typically
demonstrates a layered architecture. Gastric cardia can be identified by
rugae and vertical patterns representing gastric pits. A loss of layering and
occasional glands characterize Barrett’s esophagus (see Figure 3). OCT
scoring criteria have been developed based on signal intensity and glandu-
12
lar architecture.
have been proposed,
While additional criteria for the detection of dysplasia
13
the criteria for dysplasia are evolving and continue to
be refined. One-to-one histological correlation is now feasible with a laser
marking feature that allows tissue acquisition to target specific areas identi-
14
fied on imaging.
There has been enthusiasm for OCT-based technologies
to be able to utilize subsurface imaging to identify subsquamous glands
that may be either residual or recurrent disease after Barrett’s endotherapy.
However, there still remain challenges with differentiating disease from
normal submucosal structures.
15
72 D. Schmolze & V. J. A. Konda
(c)(
)
(a) (b)
d
Figure 3. Volumetric laser endomicroscopy. Volumetric laser endomicroscopy is an optical coherence tomography-based technology that provides imaging of the esophagus. Layered epithelium
characteristic in squamous epithelium is demonstrated in (a). Gastric cardia has rounded rugae that
are discernable and a vertical pattern (blue arrows) within the epithelium reflecting the gastric pits
as shown in (b). There is a loss of layering in Barrett’s esophagus as shown in (c). Irregular glands
(yellow arrow) may be seen in areas suspicious of dysplasia in (d).
An OCT-based tethered capsule has been developedand has the potential to screen individuals for Barrett’s esophagus in an office base setting without the need for an endoscopy.
16
Further studies are required for
validation prior to adoption as a widespread screening tool, but the possible
alternative to endoscopy is enticing.
Considerations for endomicroscopy in esophageal neoplasia include
limited ability to distinguish the exact grade of neoplasia. Most of the diagnostic accuracy studies aim to differentiate non-dysplastic BE from HGD
and early cancer, but we are unable to reliably differentiate between lowgrade dysplasia and HGD, exclude cancer, or identify invasive carcinoma.
While endoscopists may be trained to differentiate the endomicroscopic
characteristics, there are still issues with learning curve and competency
that are relevant for widespread practice. These strategies are not currently part of recommended guidelines for surveillance and do not replace
the need for histology for complete diagnosis and staging of neoplasia.
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However, they are becoming increasingly utilized tools in specialized centers during surveillance and treatment of Barrett’s esophagus.
While most of the experience to date for available endomicroscopy
platforms is in Barrett’s esophagus with CLE and OCT, there have been
several platforms and disease states that have other possible areas to utilize
in vivo microscopy in the esophagus. Notably, squamous cell neoplasia is an
area where these previous modalitiesmay have valueand also where another
platform of in vivo microscopy demonstrates promise. Endocytoscopy platforms, initially probe-based and then integrated into the endoscope, have
been developed that allowed for visualization of the tissue with light-based
microscopy. When combined with the staining of methylene blue and cresyl
violet, features of cell arrangements and nuclear–cytoplasmic ratios have
been proposed to classify esophageal squamous atypia.
17
The technologies are rapidly developing to provide in vivo visualization at a microscopic level to identify esophageal diseases. With additional
development,refinement, and validation,these technologies havethe potential to be incorporated into clinical practice to providereal-time information
to improve screening, surveillance, treatment, and post-treatment monitoring in Barrett’s esophagus and other esophageal diseases.
Stomach
Many studies have investigated in vivo imaging of the stomach, although
compared to the esophagus there are less large, robust studies, and the optimal role for in vivo microscopy remains to be defined. A wide range of
neoplastic and non-neoplastic conditions have been characterized, including Helicobacter pylori gastritis, intestinal metaplasia, dysplasia, and gastric carcinoma. In the stomach, the dominant modality so far has been CLE,
both probe-based and endoscope-based.
lies in screening for pre-neoplastic conditions, particularly in high-risk populations. Gastric carcinoma is especially prevalent in Asia, where early
detection and treatment is a public health priority.
screening relies on white light endoscopy with targeted biopsy of endoscopically visible lesions, along with random biopsies from different areas
As in the esophagus, the most obvious potential for in vivo microscopy
18
Currently, endoscopic
74 D. Schmolze & V. J. A. Konda
(a) (b) (c)
Figure 4. CLE appearance of normal stomach. Normal gastric mucosa, as visualized by Zhang et al.
(a) Superficial gastric pits composed of columnar cells with a round opening. (b) Subsurface gastric
pits, showing round lumens and interstitium. (c) Corresponding H&E-stained image of normal gastric
mucosa.
Figure 5. CLE appearance of gastric pathologies. A subset of the seven patterns identified by Zhang
et al. is shown, with the confocal appearance on the top row and the corresponding histopathology
image on the bottom row. Pattern B’ corresponds to chronic active neutrophilic gastritis. The confocal
image shows dilated crypts (blue arrow) and swollen epithelial cells (red arrow). Pattern F is intestinal
metaplasia. Goblet cells (white arrows) are easily seen, and the epithelial cells are more slender and
brighter than normal (red arrows). A villiformappearance is also appreciated. Pattern G
corresponds
1
to diffuse-type (signet ring) adenocarcinoma, with disruption of normal architecture and infiltration of
carcinoma cells visible. Pattern G
corresponds to intestinal-type adenocarcinoma, with architecturally
2
and cytologically malignant gland formation.
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of the stomach. The approach is relatively time-consuming a nd expensive
and depends on the expertise of the endoscopist.Various enhancement techniques such as chromoendoscopy
19
can improve accuracy, but there is still
a need for improved sensitivity.
One early study described the confocal appearance of a variety of gastric lesions.
20
The investigators first identified 7 reproducible patterns in 20
patients and then validated their schema in 132 consecutive patients undergoing endoscopy. The patterns identified corresponded to a wide range of
gastricpathologies, including acuteand chronic gastritis, intestinalmetaplasia, and gastric carcinoma, both diffuse type and intestinal type (Figures 4
and 5). While the study was predominantly descriptive, the investigators
determined that pattern type “E” was able to predict atrophic gastritis with
a sensitivity and specificity of 84% and 97%, respectively. Pattern type “G”
achieved 90% sensitivity and 99% specificity for the prediction of gastric
cancer.
Severalstudies have used in vivo microscopy to specifically imagepre-
21
cancerous gastric lesions. In a representative study, Gut et al.
used CLE
to identify intestinal metaplasia, a well-known risk factor for the development of gastric carcinoma.
identifying areas of intestinal metaplasia.
22
Standard endoscopy has poor sensitivity for
23
First, 28 patients with known
intestinal metaplasia underwent CLE imaging, and diagnostic criteria were
established. Subsequently, these criteria were prospectively validated on 53
patients. Standard histopathology was used as the gold standard.
Intravenous fluorescein was administered as a contrast agent, which
was not absorbed by the mucus-containing goblet cells present in areas
of intestinal metaplasia. These cells were therefore easily visualized as
dark areas and were used as a diagnostic criterion for intestinal metaplasia.
Additional criteria were a villiform appearance of the gastric epithelium,
and alterations of the gastric absorptive cells and brush border (Figure 6).
In the prospective phase of the study, 13,670 CLE images were
obtained from 53 patients. 36 patients were found to have histologically
confirmed intestinal metaplasia. The sensitivity and specificityof CLE were
found to be 98% and 95%, respectively. By comparison, the sensitivity and
specificity for conventional endoscopy were 37% and 92%, respectively.
In a more recent study, a group from the same endoscopy center performed a randomized controlled trial to evaluate the diagnostic yieldof CLE
76 D. Schmolze & V. J. A. Konda
(a) (d) (g)
(b) (e) (h)
Figure 6. CLE appearance of gastric intestinal metaplasia. (a) A region containing an area of
intestinal metaplasia (left side) and normal mucosa (right side). Villiform epithelial changes are
evident, and goblet cells are visualized (green arrow). Absorptive cells in the area of intestinal
metaplasia (purple arrow) are more slender and brighter than normal absorptive cells (blue arrow).
(b) The corresponding standard histopathology image from the same area. (d) A marked villiform
appearance in an area of intestinal metaplasia, and (e) the corresponding histopathology image.
(g) Another representative area of intestinal metaplasia, showing goblet cells (green arrow),absorptive
cells (purple arrow), and the brush border (orange arrow). (h) The corresponding histopathology
image.
versus standard white light endoscopy.24Patients undergoing endoscopy
were randomized to a CLE protocol (85 patients) or standard endoscopic
exam (83 patients). On a per-biopsy basis,CLE-targeted biopsy gave a diagnostic yield of 66%, compared to 16% for standard endoscopy. Moreover,
the CLE protocol decreased by 68% the mean number of biopsies required
per patient.
25
A recent meta-analysis
confirmed the utility of CLE for diagnosing
intestinal metaplasia; the pooled sensitivity and specificity were found to
be 97% and 95%, respectively.
Besides intestinal metaplasia, other precursor lesions and risk factors
have been imaged with in vivo microscopy. One of the more intriguing
is Helicobacter pylori gastritis. Infection with H. pylori is a well-known
risk factor for the development of gastric pathology, including gastric
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(a) (b)
(c)
Figure 7. Acriflavine-aided CLE Imaging of H. pylori organisms. (a) 1,000× magnification CLE image
showing accumulations of brightly fluorescing H. pylori organisms (arrows). (b) 10,000× magnification, showing individual organisms and even flagella (arrows). (c) Immunostain and (d) Warthin–Starry
stains performed on conventional histopathology slides highlight organisms.
(d)
carcinoma.26Infection by the organism commonly precedes more direct
precursor lesions such as intestinal metaplasia and dysplasia, and early
treatment can prevent these more serious developments. Identification and
eradication of H. pylori infection is a major public health goal in many
endemic countries.
Several studies have evaluated the ability of in vivo microscopy to aid
in the diagnosis of H. pylori infection. In the first case report, Kiesslich
27
et al. imaged a single patient with upper gastrointestinal complaints.
In
addition to intravenous fluorescein, topical acriflavine was applied prior to
imaging. The latter stain appeared to be taken up by the organisms, thus
allowing for direct visualization (Figure 7).
Few subsequent studies have attempted to directly visualize organ-
isms, but several have imaged the associated changes in the gastric mucosa
78 D. Schmolze & V. J. A. Konda
(a) (b)
(c) (d)
Figure 8. H. pylori associated CLE features. Individual neutrophils (a) and microabscesses (c)
associated with H. pylori infection are readily visualized using CLE. The corresponding H&E images
are shown in panels (b) and (d).
that commonly accompany infection (e.g. active gastritis, atrophic gastritis, and intestinal metaplasia). In a representative study by Ji et al.,
28
103 consecutive patients undergoing endoscopy were imaged with a CLE
protocol. Three features associated with H. pylori infection were identified: white spots, neutrophils, and microabscesses (Figure 8). The ability
of these features to predict infection was compared to the final histopathologic diagnosis, and a sensitivity and specificity of 89.2% and 95.7% were
achieved.
Besides precursor lesions, gastric carcinoma itself has been imaged
using in vivo microscopy. This is still a worthy clinical goal since early
gastric cancer can often be cured, while advanced disease carries a dismal prognosis.
29
In an early study, Kakeji et al.30performed a combined
ex vivo and in vivo study on 27 patients with gastric cancer. The malignant lesions showed very obvious differences from the background normal
stomach in both the ex vivo and in vivo settings (Figure 9). A software
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Figure 9. CLE imaging of gastric carcinoma. The top row shows ex vivo,acriflavine-stained confocal
images of normal gastric epithelium (left panel) and gastric carcinoma (right panel). The carcinoma
shows highly disorganized architecture and large neoplastic cells. The middle row shows the corresponding histopathology images. The bottom row shows in vivo, fluorescein-enhanced CLE images
of normal gastric epithelium (left panel), and gastric carcinoma (right panel). The carcinoma shows
disrupted architecture, large neoplastic cells, and tortuous blood vessels.