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130 S. G. Krishna
Table 1. Confocal laser endomicroscopy probes utilized in imaging pancreatobiliary epithelium. The
features are compared to standard microscopy.
Channel Field of Confocal
Device size view Resolution depth
et al.
Aq-FlexTM19 Needle based ≥ 0.91 mm 325μm3.5μm 40–70μm
Cholangioflex
Standard Microscope NA NA 0.70μmNA
Microscopy 20X
Standard Microscope NA NA 0.45μmNA
Microscopy 40X
TM
Probe based ≥ 1.0 mm 325μm3.5μm 40–70μm
via the working channel of a duodenoscope. The AQ-Flex miniprobe
(Cellvizio, Mauna Kea Technologies, Paris, France) is used for imaging
pancreatic lesions and is introduced into the lesion of interest via a 19gauge fine needle aspiration (FNA) needle during endoscopic ultrasound
(EUS).
Pancreatic Cystic Lesions
Pancreatic cystic lesions (PCLs) are increasingly detected with advances
in abdominal imaging.
Mucinous PCLs [intraductal papillary mucinous neoplasms (IPMNs)
and mucinous cystic neoplasms (MCNs)] have the potential for malignant
transformation. The most common non-mucinous lesions are serous cystadenomas (SCAs) and pseudocysts. In the absence of a known history of
pancreatitis, SCAs account for 32–39%, MCNs 10–45%, and BD/Mixed
IPMNs 21–33% of PCLs encountered in practice.
neoplasms, although representing 10% of neoplastic PCLs, are common in
young women.
3
To evaluate PCLs, a combination of clinical history, demographics,
imaging and EUS features, cytology, cyst fluid carcinoembryonic antigen (CEA), and amylase is used to identify mucinous cysts.
distinguishing benign non-mucinous from pre-malignant mucinous PCLs
remains difficult with the current diagnostic strategy. Unusual cysts like
1,2
The classification of PCLs is shown in Table 2.
3
Solid pseudopapillary
4
However,
Pancreaticobiliary System 131
Table 2. Classification of pancreatic cystic lesions (PCLs) encountered in endoscopic management of patients with incidental lesions.
Mucinous PCLs
Intraductal Papillary Mucinous Neoplasm (IPMN)
Branch Duct IPMN
Mixed Duct IPMN
Mucinous Cystic Neoplasm (MCN)
Non-mucinous PCLs
Serous Cystadenoma (SCA)
Solid Pseudopapillary Neoplasm
Cystic Neuroendocrine Tumor (Cystic-NET)
Squamous lined cysts
Epidermoid cysts
Lymphoepithelial cysts
Pseudocysts
Other malignant PCLs
Ductal adenocarcinoma with cystic degeneration
Acinar-cell cystadenocarcinoma
Cystic degeneration of metastatic lesions to the pancreas
macrocystic SCA, atypical pseudocysts, and lymphoepithelial cysts can
5
pose additionalchallenges.
A solitaryPCL begins as a diagnosticchallenge
and sometimes remains so after the completion of available investigations.
Evaluation of surgically resected PCLs in two larger high-volume centers
found that 20–30% were benign. Similarly, 42–75% of resected mucinous
PCLs have low to intermediate-grade dysplasia.
6–9
Current guidelines rec-
ommend surgical resection for all large (>4 cm) MCNs (malignancy risk:
17.5%), all patients with MD-IPMN (malignancy risk: 61%), and BDIPMNs with high-risk features (obstructive jaundice, dilated main pancreatic duct >1cm, solid enhancing intracystic nodule, and malignancy risk:
10
25%).
Endoscopic ultrasound-guided needle-basedConfocal Laser Endomicroscopy (nCLE) is an emerging technological advance that provides
in vivo, real-time, microscopic imaging of PCLs. More than 500 patients
have been enrolled worldwide since 2011 in various studies involving EUSnCLE for the evaluation of PCLs. Recent major trials have established the
132 S. G. Krishna
et al.
safety profile and feasibility of diagnostic capabilities of EUS-guided nCLE
in patients with PCLs.
11–16
EUS-nCLE image acquisition
All EUS examinations are performed using a standard linear echoendoscope. Fluorescein(5 ml; 10% fluorescein sodium) is intravenouslyinjected
2–3 min prior to CLE imaging. The AQ-Flex nCLE miniprobe (Cellvizio,
Mauna Kea Technologies, Paris, France) is then advanced through a proprietary locking device into the 19-gauge (g) needle. The preloaded 19-g
needle is advanced under EUS guidance into the PCL (Figure 1). The tip
Figure 1. Endoscopic Ultrasound (EUS)-guided needle-based confocal laser endomicroscopy
(nCLE) of pancreatic cystic lesions (PCL) located in the head of pancreas: In vivo imaging of
the epithelium of the PCL.
Pancreaticobiliary System 133
of the nCLE probe is negotiated until it opposes the intracystic epithelium.
Intracystic endomicroscopic images (video) are then captured for a maximum of 10 minutes with permissible angulation of the 19g needle using the
elevator of the echoendoscope. After image acquisition, the nCLE probe is
withdrawn and the PCL is aspirated.
Characteristics of in vivo microscopy of PCLs
The nCLE images are broadly classified into epithelial and vascular pat-
14,15
terns.
nCLE image patterns are detailed in Tables 2 and 3.
Table 2. Classification, images, description, and associated cyst type of epithelial EUS-nCLE image
patterns.
Variable Figures Explanation of patterns PCL type
Epithelial patterns
The classification, description, and cyst-type association of EUS-
Papillae A papilla is a finger-like
projection of variable
length consisting of an
overlying epithelium
and underlying vascular
core
Epithelial
bands
Epithelial bands are either
single or multiple layers
of epithelium without a
papillary configuration.
These bands
demonstrated layering
or a horizon-type
configuration
IPMN
MCN
134 S. G. Krishna
Ta b le 2 . ( Continued)
Variable Figures Explanation of patterns PCL type
et al.
Dark
background
with bright
particles
Trabecular
pattern
Notes: PCL: Pancreatic cystic lesion; EUS: Endoscopic Ultrasound; nCLE: needle-based
Confocal Laser Endomicroscopy; IPMN: Intraductal papillary mucinous neoplasm; MCN:
Mucinous cystic neoplasm; Cystic-NET: Cystic neuroendocrine tumor.
Adapted from Krishna SG et al. Gastrointestinal Endoscopy 2017 March.
Inflammatory cells
(macrophages) with
autofluorescence are
observed as “bright
particles”. Lack of
vascularity generates a
dark background
Nests of cells separated by
blood vessels of fibrous
bands
Pseudocyst
MCNs with
chronic
inflammation
Cystic-NET
15
While ongoing research continues to evaluate therole of EUS-nCLE in
the management of PCLs, published studies have established the following
image pattern interpretations for specific PCLs.
Serous cystadenomas
For the identification of SCAs (Figure 2), a characteristic vascular pattern
has been observed duringin vivo microscopy using EUS-nCLE. This unique
pattern has been described as a “superficial vascular network” or “fern pattern” of vascularity (Figure 2(a)).
a concentratedparallel or interconnectednetwork ofvessels emanatingfrom
a larger vessel (similar to a fern leaf). Further, studies have demonstrated
13,15,17,18
This pattern is best described as
Pancreaticobiliary System 135
Table 3. Classification, images,description, and associatedcyst type of vascular EUS-nCLE image
patterns.
Variable Figures Explanation of patterns PCL type
Vasc u l ar
patterns
Branched
pattern
Rope-ladder
pattern
Fern pattern
The “branched” pattern is
similar to a tree where
ensuing branches are of
smaller diameter than
the preceding one
The “rope-ladder” pattern
consists of blood vessels
of similar diameter
running in parallel with
interconnecting rungs
There is a concentrated
network of parallel
vessels emanating from
a central vessel similar
to a fern-leaf
MCN
IPMN
Cystic-NET
IPMN
MCN
SCA
Notes: PCL: Pancreatic cystic lesion; EUS: Endoscopic Ultrasound; nCLE: Needle-based
Confocal Laser Endomicroscopy; IPMN: Intraductal papillarymucinous neoplasm; MCN:
Mucinous cystic neoplasm; Cystic-NET: Cystic neuroendocrine tumor; SCA: Serous cystadenoma. Adapted from Krishna SG et al. Gastrointestinal Endoscopy 2017 March.
15
136 S. G. Krishna
(a) (b) (c)
Figure 2. In vivo endoscopic ultrasound-guided needle-based confocal laser endomicroscopy
(nCLE), ex vivo CLE, and histopathology of serous cystadenoma: CLE images, panels a (in vivo) and
b(ex vivo) depict “fern pattern” of vascularity. Histopathology (panel c; H & E, 40x) reveals cuboidal
to flat epithelial cells with clear cytoplasm lining some cystic spaces. Adapted from Ref. [17].
et al.
an “almost perfect” inter- and intraobserver agreement (Landis and Koch
interpretation of κ values) for the “fern pattern” among externally blinded
15,19
experts in endosonography (INDEX study).
Probe-based ex vivo CLE
imaging in surgically resected SCAs (Figure 2(b)) has also depicted a “fern
pattern” of vascularity. The characteristic histopathology of SCAs includes
multiple cystic spaces lined by cuboidal/flat epithelial cells. The correlative pathology image in Figure 2(c) revealed flattened cystic spaces lined
by cuboidal epithelial cells.
Intraductal papillary mucinous neoplasm
These PCLs are characterized by the presence of papillary-type epithelium
in an incomplete or completefrond-like conformation.A “rope-ladder” type
vascular pattern has also been described which is more frequently observed
than the “branched pattern” in the context of vascularity (Table 2).
14,15
Complete “finger-like” papillary projections are observed on both in vivo
and ex vivo CLE imaging in IPMNs (Figures 3(a) and 3(b)).
17
The CLE
images resemble correlative histopathology as shown in Figure 3(c).
Mucinous cystic neoplasms
These lesions are observed to have epithelial bands without a papillary or
frond-like conformation (Figure 4). These epithelial bands, either single
Pancreaticobiliary System 137
(a) (b) (c)
(d) (e) (f)
Figure 3. In vivo endoscopic ultrasound-guided needle-based confocal laser endomicroscopy
(nCLE), ex vivo CLE, and histopathology of Intraductal Papillary Mucinous Neoplasms: Panels a,
b, & c are from a patient with gastric subtype of IPMN with high-grade dysplasia. Panels d, e, & f are
from a patient with intestinal subtype with high-grade dysplasia. Complete “fingerlike” papillae are
observed in both in vivo and ex vi vo CLE. Histopathology (panels c, f): 40x magnification; H&E stain.
Adapted from Ref. [17].
or multiple, are observed in a horizon-type configuration. The presence
of inflammatory cells in MCNs is detected by imaging isolated bright and
reflectiveheterogeneous particles.
14,15
The vascularity in MCNs is predom-
inantly of the “branched” pattern, but the “rope-ladder” vascular pattern is
15
also observed occasionally (Table 2).
Ex vivo imaging (Figure 4) also
reveals epithelial bands with improved definition. While the histopathology of MCNs revealsthe characteristic “ovarian stroma”, no corresponding
in vivo or ex vivo features have been observed.
17
Pseudocysts
The presence of inflammatory cells is imaged as multiple clusters of bright
reflective heterogeneous particles on a dark background (Table 2). Pseudocysts generally do not have any detectable vascular patterns.
15
138 S. G. Krishna
(a) (b) (c)
(d) (e) (f)
et al.
(g) (h) (i)
Figure 4. In vivo endoscopic ultrasound-guided needle-based confocal laser endomicroscopy
(nCLE), ex vivo CLE, and histopathology of Mucinous Cystic Neoplasms: Epithelial bands with
incomplete papillary formation are observed in CLE. Thein vivo CLE demonstrates horizon-like bands
whereas ex vivo CLE demonstrates better-defined epithelial bands. Corresponding histopathology
(panels c, f, and i): 40x magnification; H&E stain. Adapted from Ref. [17].
Cystic neuroendocrine tumor
In vivo and ex vivo imaging of cystic-NETs demonstrate dark clusters
or trabeculae of cells separated by bright vascular spaces or fibrous tissue (Figure 5). These findings match microscopic imaging from surgical
histopathology.
14,15, 17
Pancreaticobiliary System 139
(a) (b) (c)
Figure 5. In vivo endoscopic ultrasound-guided needle-based confocal laser endomicroscopy
(nCLE), ex vi vo CLE, and histopathology of cystic neuroendocrine tumor: Circumscribed clusters
of cells in a trabecular growth pattern separated by vascular or fibrous cords are observed on CLE
examination (panels a and b). Histopathology (panel c, 40x; panel f, 20x) revealed characteristic
uniform tumor cells arranged in cords or trabecular fashion. (Ref. [17]).
(a) (b) (c) (d)
Figure 6. In vivo endoscopic ultrasound-guided needle-based confocal laser endomicroscopy
(nCLE), ex vivo CLE, and histopathology of lymphoepithelial cyst: CLE images, a (in vivo) and b
(ex vivo ) reveal clusters of bright particles representing keratin flakes. Macroscopicallythe lesion was
filled with yellowish pasty material which by microscopy (panel c) demonstrated keratin flakes. The
cyst was lined by squamous epithelium surrounded by abundant lymphoid tissue (panel d; H & E,
40x). (Ref. [17]).
Squamous lined cysts (Lymphoepithelial cyst)
When lymphoepithelial cysts have keratinous debris, these can appear
as clusters of bright particles (Figure 6). The cyst wall is lined
by squamous epithelium bordered by abundant lymphoid tissue on
histopathology.
17