Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02494388 |
| Other study ID # |
CINE-Cyst |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
June 23, 2015 |
| Last updated |
January 15, 2018 |
| Start date |
June 2015 |
| Est. completion date |
June 2017 |
Study information
| Verified date |
July 2015 |
| Source |
University of Medicine and Pharmacy Craiova |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The study is based on a multi-center approach of needle based confocal laser endomicroscopy
(nCLE) combined with endoscopic ultrasound (EUS) and EUS-guided fine needle aspiration (FNA)
to evaluate pancreatic cystic lesions (PCL), in order to obtain a correct histopathological
diagnosis.After detection of PCL, certain morphological EUS features allow the discrimination
of specific cyst types. Additionally, EUS-FNA is recommended as the first-line procedure
whenever pathological diagnosis is required; however the procedure has its drawbacks, mainly
represented by the relatively low negative predictive value in diagnosing pancreatic cancer.
In this case a more precisely diagnostic tool is required; the potential role of CLE has been
explored in gastrointestinal (GI) pathology showing good accuracy for predicting the final
histopathological diagnosis based on immediate evaluation of tissue and vascular patterns.
Although the clinical impact of nCLE for the decision making algorithms in cystic pancreatic
neoplasm has not yet been described, the hypothesis is that EUS-nCLE could allow targeted
tissue sampling of cystic pancreatic neoplasms resulting in more accurate diagnosis. The aim
of the study is to describe the clinical impact of nCLE for the clinical decision management
algorithm based on EUS, EUS-FNA and/or EUS-CLE imaging criteria for cystic pancreatic
neoplasms, while evaluating also the feasibility and safety of nCLE examination.
Description:
Clinical Impact of Needle-based Confocal Laser Endomicroscopy of Cystic Pancreatic Lesions
(CINE-Cyst)
Background The diagnostic evaluation of cystic pancreatic lesions represents a difficult
problem for clinical decision making, due to the increased incidental discovery of such
lesions during cross-sectional imaging (computed tomography or magnetic resonance).
Prevalence of cystic pancreatic lesions is estimated between 2 to 20% in the adult population
(1-3), while autopsy studies show that the prevalence increases with age (4). The WHO
classification (revised in 2010) reported several categories, with serous cystadenoma (SCA),
mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN) and
pseudopapillary neoplasms representing more than 90% (5). Several of these lesions progress
to cystadenocarcinoma (with the notable exception of SCA), hence the differential diagnosis
is extremely important for the clinical decisions that currently involve either imaging
follow-up (usually based on EUS and magnetic resonance imaging [MRI]) or referral to surgery
with a final pathological diagnosis established after resection.
Nevertheless, there is considerable overlap in the imaging characteristics of benign,
premalignant or malignant pancreatic cysts which leads to unclear clinical management
algorithms. Several international guidelines addressed the diagnosis and management of cystic
pancreatic lesions (6-8). The most comprehensive guideline reported a clinical decision
algorithm which included clinical and imaging criteria, like pancreatitis / jaundice or cyst
size > 3 cm, thickening / enhancing cyst walls, main pancreatic duct (MPD) size 5-9 mm,
non-enhancing mural nodules and abrupt changes in the caliber of pancreatic duct with distal
pancreatic atrophy [8]. If any of these clinical / imaging characteristics are present then
EUS is considered mandatory to assess a definite mural nodule, main duct features suspicious
for involvement, as well as to perform EUS-guided fine needle aspiration (FNA) with
cytopathology exam in order to exclude malignancy.
Endoscopic ultrasound (EUS) represents a highly valuable tool in the management of patients
with focal pancreatic masses, either solid or cystic. As a minimally invasive technique that
enables high-resolution imaging of the pancreatic parenchyma and surrounding structures it is
considered the method of choice for the detection of clinically suspected pancreatic lesions,
with a negative predictive value close to 100% [9]. Its diagnostic sensitivity was shown by
previous studies to be superior compared to other imaging techniques, especially in the case
of smaller tumors [10, 11]. After detection of cystic pancreatic lesions, certain
morphological features allow the discrimination of specific types [12]:
- pseudocysts - parenchymal changes , without septation or nodules
- serous cystadenomas - multiple microcysts and honeycomb appearance
- mucinous cystadenoma - thickened septations and wall, with calcifications
- intrapapillary mucinous neoplasia (IPMN) - communication with the MPD There aren't
universally accepted morphological parameters to predict either the type or the risk of
malignancy by EUS [8]. "Worrisome features" on imaging include cyst size (above 3 cm),
thickened cyst walls, MPD size of 5-9 mm, non-enhanced mural nodules, abrupt changes in
MPD caliber with distal pancreatic atrophy, and lymphadenopathy. "High risk stigmata"
include obstructive jaundice in a cystic pancreatic head mass, enhanced solid component
or MPD size of over 10 mm, thus warranting an indication for surgery, if clinically
feasible. Generally, all cysts with "worrisome features" and cysts over 3 cm, without
worrisome features, should undergo EUS, while all cysts with "high-risk stigmata" should
undergo surgical resection [8].
Additionally, EUS enables guided fine needle aspiration (EUS-FNA) which is currently
recommended as the first-line procedure whenever pathological diagnosis is required [13].
However, EUS-FNA as a sampling technique has its drawbacks, mainly represented by the
relatively low negative predictive value in diagnosing pancreatic cancer. It thus cannot
reliably rule out a diagnosis of malignancy and patients with high clinical suspicion usually
need repeated FNA [14]. The role of EUS-FNA for the differential diagnosis of focal cystic
lesions is still controversial, as CEA and amylase levels as well as cytology are often
useful to differentiate various lesions, but not all of them [8]. Thus, SCA have low levels
of both CEA and amylase. For CEA, values over 192-200 ng/ml have 80% diagnostic accuracy for
mucinous cysts [15]. Likewise, amylase levels might be increased in both IPMN and MCN, making
the differential diagnosis difficult [16]. Cytology has a limited sensitivity, as the
aspirates yield a low number of cells, being most useful if it detects atypical epithelial
cells which can highly predict malignancy, again with an 80% accuracy [17].
Confocal laser endomicroscopy (CLE) has emerged in recent years as a novel technique that
actually enables in vivo microscopic analysis during ongoing endoscopy. Endomicroscopy can be
performed either with dedicated (eCLE) or with miniprobe-based systems (pCLE) [18]. It is a
contrast based technique, the most widely used agent being the intravenously administered
fluorescein [19]. The probe-based endomicroscopy system consists of a flexible catheter probe
representing a bundle of optical fibers linked to a micro-objective, a laser scanning unit
and the control and acquisition software (Cellvizio; Mauna Kea Technology, Paris, France).
The flexible confocal miniprobes were specifically designed to be passed through the working
channels of standard endoscopes, biliary catheters or cholangioscopes and thus the pCLE
system can be easily integrated in any endoscopy unit. The principle of the technique is
based on a laser beam of defined wavelength being focused towards the targeted tissue and the
recaptured signal is displayed as 'optical biopsies' in a single horizontal plane.
The potential role of CLE has been explored in pathology of both upper and lower
gastrointestinal tract, showing good accuracy for predicting the final histopathological
diagnosis based on immediate evaluation of tissue and vascular patterns [20]. Recently CLE
has gone beyond the superficial luminal indications with the development of a new microprobe,
i.e. a flexible probe thin enough that it can be passed through a 19-gauge needle. Thus under
EUS guidance solid organs can be accessed for real-time microscopic information. nCLE imaging
of abdominal organs has been so far achieved in animal models [21, 22]. The feasibility of
the technique was also proved in a clinical study [23] and descriptive criteria for the
diagnosis of pancreatic cystic neoplasms were developed from a multicentre trial [24].
However, the clinical impact of nCLE for the decision making algorithms in cystic pancreatic
neoplasm has not yet been described. The hypothesis is that EUS-nCLE could allow targeted
tissue sampling of cystic pancreatic neoplasms resulting in more accurate diagnosis. With
further validation of the technique real-time pathological diagnosis could be obtained with
immediate initiation of an adequate therapy after a single investigation.
Aim The aim of the proposed study is to describe the clinical impact of nCLE for the clinical
decision management algorithm based on EUS, EUS-FNA and/or EUS-CLE imaging criteria for
cystic pancreatic neoplasms, while evaluating also the feasibility and safety of nCLE
examination.
Imaging tests All patients with a suspicion (clinical, US, CT/MRI) of cystic pancreatic
lesions will be evaluated by EUS, EUS-FNA and EUS-nCLE and compared with the final
pathological diagnosis.
- For EUS examination linear instruments will be used to perform complete examination of
the pancreas.
- Lesion characteristics (echogenicity, echostructure, size, wall, mural nodules,
septations, etc.) will be described.
- The presence of regional lymph nodes will be reported with their maximal size,
echogenicity, shape and margins.
- Identification of liver metastasis will also be looked upon.
- EUS-nCLE will be performed after EUS identification of the cystic pancreatic lesion /
lymph node / liver metastasis:
- The confocal microprobe will be preloaded in a 19G FNA needle as previously
described [13] and advanced into the lesion under EUS guidance.
- nCLE examination will follow after the intravenous administration of the contrast
agent (2.5 ml fluorescein 10%).
- Image data will be stored digitally for offline analysis (at least 2 suggestive
images and 2 suggestive movies of 10 seconds, each).
- EUS-FNA will be performed after image acquisition for cytology smears and cell blocks to
enable a final pathological diagnosis. CEA, CA19-9 and amylase levels will be measured
in the aspirate. Molecular analyses like KRAS and GNAS will be performed, if available.
- nCLE images will be analyzed during the examination by the principal investigator, with
clinical and other procedural information in mind. In a second step offline analysis,
the correlations between representative CLE images and classical hematoxylin and eosin
sections will be identified.
