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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5528_Библиотеки_им_академика_М_И_Перельмана.pdf
140 S. G. Krishna
et al.
Differentiation of mucinous and non-mucinous PCLs
There is accumulating evidencein the literature demonstrating an improved
diagnostic accuracy for EUS-nCLE to differentiate between mucinous and
non-mucinous PCLs. The accuracy to diagnose mucinous-PCLs ranges
from 94 to 97% among the 2 largestsurgical series [INDEX and CONTACT
studies].
14,15
The inter- and intra-observeragreement for EUS-nCLE imaging and diagnosis of mucinous PCLs is “substantial”. For differentiating
mucinous PCLs, the following has been demonstrated: (1) gastroenterologists naïve to nCLE imaging can reliably identify nCLE diagnostic image
19
patterns with “substantial” inter- and intra-observer agreement
and (2)
among definitively diagnosed PCLs, the inter- and intra-observer agreement among blinded external EUS experts was “almost perfect”.
15
Future research in EUS-nCLE
Despite all the evidence in published studies, there are limitations to interpretation a nd hurdles to the implementation of EUS-nCLE in routine
practice.
Some of the limitations of current studies include the following:
(1) Fewer surgically resected lesions: Newer revisions of the International
Consensus Guidelines have further stressed the need to avoid unnecessary surgery. To this effect, pancreatobiliary surgeons are more conservative than ever before. This means that benign lesions like SCAs may
not be resected unless clinically deemed aggressive.
(2) Lack of formal training in EUS-nCLE: Learning the technique and
nuances of nCLE image interpretation requires focused training. At
this time, there is the absence of a structured training either during or
after gastroenterology fellowship.
(3) Stringent criteria for high-quality nCLE imaging: In vivo imaging of
PCLs and interpretation of the patterns are challenging since the microscope (CLE miniprobe) and the slide to be examined (epithelium of the
cyst) are not stationary. Bringing the cyst epithelium within a suitable focal length of the CLE probe and acquiring high-quality imaging
during EUS needs training, practice, and validation.
Pancreaticobiliary System 141
(4) There is a paucity of research studies combining EUS-nCLE and cyst
fluid molecular markers in the identification of advanced neoplasia in
mucinous-PCLs.
14
Next-generation s equencing analysis of fluid from
PCLs has revealed highly specific molecular markers for the diagnosis
of advanced neoplasia in mucinous cysts. Whole exome and targeted
sequencing studies of PCL fluid have identified distinct mutational
profiles of the major PCLs as well as those with advanced neoplasia (high-grade dysplasia and pancreatic adenocarcinoma).
20–22
EUSnCLE imaging in combination with cyst fluid molecular analysis can
provide a high degree of diagnostic accuracy for the differentiation of
PCLs.
Conclusion
In conclusion, EUS-guided nCLE and in vivo microscopy of pancreatic
cystic lesions is a minimally invasive procedure that improves the preoperative diagnostic performance of diagnosing mucinous cysts with high
accuracy. This technology is currently limited to a few academic centers;
however, due to the substantial need for improved diagnosis of pancreatic cystic lesions, we anticipate studies to address structured training of
endosonographers in this novel technology and subsequent wider application. Continued research in in vivo microscopy could unravel additional
imaging features which could assist in the risk stratification of mucinous
cystic lesions. Complementary analysis of the cyst fluid molecular markers
can further improvediagnostic accuracy. These investigationsare necessary
to guide the complex decision-making process while managing patients
with pancreatic cysts.
Solid Pancreatic Lesions
Endoscopic ultrasound-guided fine-needle aspiration is the current recommended diagnostic test in solid pancreatic lesions (SPL) with high diagnostic accuracy.
to specimen inadequacy, inconclusive cytopathology, and the potential
need for on-site cytopathology.
23
However, EUS-FNA is not without challenges related
24
Other modalities are being explored
142 S. G. Krishna
et al.
to increase diagnostic accuracy in correctly identifying solid pancreatic
masses including needle-based confocal laser endomicroscopy.
25
EUS-
nCLE image acquisition is accomplished in the same manner as with cystic
pancreatic lesions.
Endomicroscopy characteristics of SPLs
Two initial small studies evaluating nCLE in focal pancreatic masses compared endomicroscopy images to the histopathology of resected speci-
24,26–28
mens.
diagnosis of pancreatic adenocarcinoma were found to have vascular irregularity with fluorescein leakage on nCLE along with dark aggregates of
malignant cells. Glandular structures were noted in a limited number of
malignant cases including a pancreatic neuroendocrine tumor (PNET) and
two non-pancreatic metastases.
in benign lesions. A pancreatic sarcoma appeared as a clump of small circular cells with fibrous thin bands on endomicroscopy without the presence
of dark aggregates.
benign and malignantlesions.
appearance.
The endomicroscopy for the diagnosis of solid pancreatic lesions
(ENES) study sought to establish particular endomicroscopy patterns of
malignant focal pancreatic lesions.
tified that correlated with benign versus malignant SPLs. Dark clumps,
distended vessels, and small mobile black cells were the endomicroscopy
findings associated with malignant focal pancreatic masses (Figure 7).
These initial studies have demonstrated the feasibility of EUS-nCLE
in patients with solid pancreatic masses. Such promising data for this innovative technique may result in endomicroscopy serving as an adjunct to
EUS-FNA or to aid in a final diagnosis of inconclusive FNA results. While
more recent trials have developednCLE image criteria for diagnoses, larger
additional studies are still ongoing to corroborate these findings. Endomicroscopy for solid pancreatic lesions is at its beginning since most of the
research has been on pancreatic cystic lesions. Further, EUS-FNA is a technically easier procedure with high diagnostic yield.
The majority of lesions with a confirmed histopathologic
26,28
Dark aggregates were also visualized
26
Thin gray bands were found in an equal number of
28
26,28
Normal pancreas tissue had a “coffee-bea n”
29
Specific nCLE patterns were iden-
Pancreaticobiliary System 143
Figure 7. In vivo endoscopic ultrasound-guidedneedle-based confocallaser endomicroscopy (nCLE)
of solid pancreatic adenocarcinoma: Dark or black cellular aggregates are observed (Courtesy: Dr.
Bertrand Napoleon, Hospital Jean Mermoz, Lyon, France).
Endomicroscopy of the Bile Duct
Cholangiocarcinoma (CCA), ampullary cancer, and pancreatic cancer are
malignant epithelial tumors that originate in the pancreaticobiliary tract.
Specifically, CCA is often diagnosed in the setting of new painless jaundice
with radiographic evidence of a biliary stricture. There is usually no resulting discernable mass as is often the case in pancreatic adenocarcinoma.
30,31
These tumors present a diagnostic and therapeutic challenge.
Nearly
90% of patients with a final diagnosis of CCA do not presentuntil the malignancy has reached an advanced stage resulting in obstructive jaundice.
32–34
As many as 50% of such cases are unresectable at the time of clinical
diagnosis.
34,35
While the overall survival for CCA remains abysmal, there
remains a stark difference in the 5-year patient survival between resected
(20–40%) and unresected CCA (<7%).
33,34, 36
In light of these data, early
and accurate diagnostic differentiation of biliary strictures is imperative.
Furthermore, some studies have revealed that up to 24% of patients undergoing curative surgical resection for malignant biliary strictures are found
to have benign pathology.
32,35, 37, 38
144 S. G. Krishna
et al.
Endoscopic retrogradecholangiopancreatography(ERCP) is the most
common approach in evaluating biliary stenosis concerning malignant etiology but has severalkey limitations. The most important is that commonly
available diagnostic modalities such as cytologic brushing and/or intraductal biopsies have limited yield. While a few studies have demonstrated
a modestly high sensitivity (75%) for cytologic brushing and intraductal
biopsies combined,
39
more recent meta-analyses have shown much lower
sensitivity: 45% for cytologic brushing, 48.1% for intraductal biopsies, and
32,40
a 59.4% combining brushing and biopsies.
The low yield is a direct
result of only superficially sampling a lesion that typically invades through
the wall of the bile duct.
41
Cholangiocarcinoma often infiltrates and propagates circumferentially and longitudinally along the bile duct wall with
extensivedesmoplasia and inflammation. This is especiallytrue in the nodular sclerosing subtype which is the most common variant. Therefore, from
a diagnostic perspective, cytologic yield is understandably poor. The low
diagnostic accuracy is also affected by the fact that many patients require
multiple procedures for indeterminate biliary strictures and stenosis.
33,35, 42
In patients with Primary Sclerosing Cholangitis (PSC), further diagnostic
challenges are presented. With a CCA incidence rate between 7 and 14%,
early confirmation or exclusion of malignancy in patients with PSC is often
difficult secondary to the chronic inflammation and fibrosis of the bile
43,44
duct.
CLE image acquisition in the bile duct
The probe-based confocal laser endomicroscope (pCLE) (CholangioFlex
probe, Mauna Kea Technologies,Paris, France; Table 1) is utilizedfor imaging the biliary system. To perform biliary pCLE, ERCP is performed as per
standard method, and the confocal miniprobe is advanced via a cholangioscope or hingedcatheter into the biliary tree.
fluorescein is given intravenously at the time of the procedure, which then
distributes through vascular, extracellular, and lymphatic spaces to provide
a real-time microscopic image. Unlike other confocal microscopes, pCLE
cannot adequately resolve strictures at various depths but instead focuses on
a plane, 40–70 μm deep to the surface. The typical CholangioFlex probe
45
For most cases, 2.5 ml of 10%
Pancreaticobiliary System 145
(a) (b)
Figure 8. Panel (a): Confocal endomicroscopy of the bile duct showing classic reticular pattern.
Panel (b): Correlating frozen section at 60μm from epithelial surface showing branching collagen
with open spaces.
also provides a field of view of 325 microns and has a resolution of 3.5
microns. Images are acquired in real time and effort is made to keep the
probe perpendicular to the bile duct wall and to scan the stricture from
proximal to distal. Since its inception, pCLE has played a pivotal role in
the diagnostic evaluation of the bile duct.
46
Probe-based CLE patterns in biliary stenosis
The unique image pattern that came to be associated with biliary pCLE is
comprised of a dark gray reticular pattern, which consists of thin branching
gray bands within a fluorescein-rich background, which appears white or
light gray (Figure 8). Within this pattern, certain abnormalities could be
identified that suggested malignancy. The Miami classification represents
the first consensus on what these commonly observed biliary pCLE patterns
represent.
following (Figure 9)
• irregular and enlarged vessels (>40 μm),
• lack of visible contrast in the bile duct wall,
• large black bands (>40 μm),
• clumps of irregular black cells (Figure 9).
45,47–49
Features seen only in patients with malignant strictures included the
50,51
:
146 S. G. Krishna
Figure 9. Probe-based confocal endomicroscopy of dysplastic biliary epithelium demonstrating dark
disorganized clumps of irregular black cells and large black bands.
et al.
In a review of 89 patients with indeterminate biliary strictures,
Meining et al. were able to show that the sensitivity, specificity, positivepredictive value, and negative-predictive value of pCLE for detecting can-
47
cerous strictures were 98%, 67%, 71%, and 97% respectively.
What was
particularly interesting in these early studies was the exceptionally high
negative predictive value. On the other hand, inflammatory strictures, or
even strictures that had been stented multiple times, yielded mixed results.
Miami classification for pCLE of biliary strictures
Due to similar but varied findings in pCLE image results for indeterminate
biliary strictures, an international group of experts developed descriptive
classification of pCLE findings using a set of criteria titled Miami Classifi-
45,47–49
cation.
indeterminate biliary strictures were randomized and reviewed in a blinded
manner by investigators who underwent abbreviatedtraining in recognizing
endomicroscopy patterns.
nant and benign biliary lesions. Grouping of the following pCLE ch aracteristics improved diagnostic differentiation of malignant from non-malignant
strictures:
(1) Malignant biliary stenoses: Presence of epithelial structures or thick
white bands or thicker dark bands >40μm or “dark clumps”.
(2) Benign strictures (Figure 10): Thin branching bands with or without
flow, with the largest diameter of 31 μm.
In excess of 100 pCLE videos obtained from 45 patients with
48
Individual pCLE criteria were found in malig-
48
Pancreaticobiliary System 147
Figure 10. Probe-based confocal endomicroscopy of bile duct demonstrating thickened collagen
bundles (reticulum) observed in a benign inflammatory stricture.
With the designation of the Miami classification of confocal biliary
images, Caillol et al. correlated pCLE sequences of biliary strictures with
38
definitive histology.
The “dark clumps” observed in this and earlier studies were found to correspond to tumor glands on histology. Thick white
bands correlated histologically with branched blood vessels.
38
There is
currently an ongoing prospective analysis to further validate correlation
between confocal imaging and histologic findings.
Paris criteria for non-malignant inflammatory stenosis
The presence of benign inflammation secondary to prior biliary stenting
appeared to contribute to misdiagnoses of malignancy on confocal imaging
in earlier studies. In addition, chronic strictures are frequently associated
with epithelial changes that can appear as inflamed, thickened, or hyperplastic glands but rarely as dysplastic and unorganized dark clumps which
are the hallmark of malignancy. Many patients had biliary stents removed
immediately preceding pCLE.
did not describe endomicroscopy patterns secondary to benign inflammatory conditions (e.g. PSC or prior stenting).
was developed to reduce false-positive cases secondary to benign inflammatory lesions.
52,53
Endomicroscopy criteria specific to non-neoplastic
inflammatory conditions were characterized to further aid in differentiation
47
The development of the Miami criteria
48
Thus, the Paris Classification
148 S. G. Krishna
et al.
from malignant biliary strictures. These criteria consist of the following
(Figure 10)
52
:
• several thin white bands representing vascular congestion,
• dark granular patterns with scales,
• enlarged spaces (>20 μm) between scales,
• thickened reticular structures.
Further research is ongoing, as the use of the Paris classification continues to be associated with misdiagnoses of benign strictures. In addition,
the FOCUS trial which incorporated the Paris classification along with the
more established Miami classification did not necessarily produce a significant improvement in accuracy for pCLE alone. However, we did see for the
first time that pCLE along with other modalities can produce remarkably
high diagnostic yields.
35
In the FOCUS trial, 112 patients with 71 malignant strictures were reviewed;sensitivity of tissue sampling with pCLE was
89%, and the accuracy was 88%.
Correlation of pCLE imaging of the bile duct with representative histology
Both the Miami and Paris classifications have provided a robust approach
for pCLE imaging of biliary strictures, but both suffer from their use of
descriptive rather than pathological terminology and lack ofhistopathologic
correlations. It was immediately obvious that despite how ubiquitous the
reticular pattern was for the pancreaticobiliary system, it was not a structure
that we had readily observed in the pCLE of other tissues/organ systems.
Hence, early classification schemes relied on descriptive terminology such
as “white bands,” “dark bands,” and “clumps.”
The bile duct is mostly comprised of a simple cuboidal epithelium
and an extensive submucosal space. It lacks the typical 5 layers that are
found throughout the gastrointestinal tract and this is most evident on highresolution ultrasound of the bile duct. As a result, studies into histological
correlates suggest that the reticular pattern (Figure 8) is comprised of the
branched collagen bundles of the submucosal space, while the fluorescein
is in the interstitial fluid. As expected, dysplastic glands in this space are a
sign of infiltrating malignancy. In addition, grossly enlarged blood vessels
and thickened collagen bundles are a sign of the associated desmoplasia.
Pancreaticobiliary System 149
It is important to note that inflammation and chronic obstruction can cause
epithelial changes that are evident on pCLE but do not resemble the dark
and disorganized glandular clumps that are associated with malignancy.
Conclusion
A multitude of studies have demonstrated the feasibility and clinical importance of CLE in the examination of biliary stenosis and strictures. The
current opinion is that pCLE is a valuable adjunct to current endoscopic
technology facilitating the diagnosis of malignant strictures based on its
excellent sensitivity and acceptable specificity. However, some investigators debate that the role of CLE in the bile duct may be best served as a
last step in subjects with inconclusive results following standard of care.
These data have been compounded in recent systemic reviews and metaanalyses.
54,55
Current leaders in this field have supported the use of probebased confocal endomicroscopy for the bile duct, primarily in its enhanced
accuracy relative to ERCP with brush cytology or forceps biopsy, and its
support in clinical decision-making by its heightened ability to exclude
benign biliary lesions otherwise suspicious for malignancy.
56–58
pCLE may be able to overcome the limited sensitivity of available tissue
sampling techniquesfor biliary strictures and objectify patient management
decisions by detecting biliary malignancies earlier and avoiding successive
procedures and surgeries.
53
Notably,
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