Introduction
Differentiating benign from malignant gallbladder disease is difficult by imaging
diagnosis alone. Pathological evaluation is ideal for treatment decision making, but
it is not easy for anatomical reasons. As a potential pathologic diagnostic method,
the usefulness of gallbladder bile cytology using a drainage tube placed transpapillary
into the gallbladder has been reported [1]
[2]. In addition, transpapillary gallbladder biopsy has also been described. However,
this procedure requires specially designed biopsy forceps, a large-diameter pusher
catheter, or a cholangioscope [3]
[4]
[5]
[6]
[7]. Recently, a novel device delivery system has been developed and reported to be
useful for bile duct biopsy during endoscopic retrograde cholangiopancreatography
(ERCP) [8]. Gallbladder biopsies applying this method have also been reported [9]
[10]. The aim of the present study was to evaluate the feasibility of transpapillary
gallbladder biopsy using this novel device delivery system in consecutive patients
for the diagnosis of gallbladder disease.
Patients and methods
Study design
This retrospective observational study was conducted at Tonan Hospital, Sapporo,
Hokkaido, Japan. The study protocol was approved by the ethics committee of our hospital
(institutional ID: 22022-1-2-1). All participants provided written informed consent
before
undergoing the procedure.
Patients
Eleven consecutive patients who underwent transpapillary gallbladder biopsy using
a newly designed device delivery system at our institution from June 2021 to July
2022 were evaluated.
Age, sex, indications of gallbladder biopsy, presence of pancreaticobiliary maljunction,
main target sites (gallbladder neck/body/fundus), presence of sphincterotomy, gallbladder
cannulation success rate, device delivery system insertion success rate, target lesion
biopsy success rate, adequate specimen collection rate, gallbladder bile juice cytology
results, biopsy procedure time, total procedure time, and adverse event (AE) rates
were analyzed. Data associated with the endoscopic procedure were evaluated using
ERCP database, endoscopy reports, and video records.
Definitions
Gallbladder cannulation success was defined as successful insertion of a guidewire
and an ERCP catheter into the gallbladder. System insertion success was defined as
successful insertion of a device delivery system into the gallbladder. Target biopsy
success was defined as successful biopsy of a targeted gallbladder lesion (e.g., lesion
in the gallbladder fundus, body, or neck). Biopsy procedure time was defined as the
time to completion of biopsy after successful guidewire placement in the gallbladder.
Total procedure time was defined as the time from scope insertion to removal.
Equipment and endoscopic procedures
Endoscopic procedures were performed or supervised by physicians with extensive
experience in ERCP using a side-viewing duodenoscope (TJF-260V or TJF-290V; Olympus
Medical
Systems, Tokyo, Japan) and a catheter (ERCP-Katheter; MTW Endoskopie, Wesel, Germany).
Biliary sphincterotomy was performed in necessary cases. Following cholangiography,
a
0.032-inch hydrophilic guidewire (Radifocus; Terumo, Tokyo, Japan) was advanced into
the
gallbladder via the cystic duct. Subsequently, the catheter was advanced to the cystic
duct
following the guidewire. Following successful gallbladder cannulation, the hydrophilic
guidewire was replaced with a stiff type guidewire (EndoSelector, Boston Scientific,
Natick,
Massachusetts, United States; or VisiGlide2, Olympus Medical Systems). After withdrawing
the
catheter, a device delivery system (Endosheather; Piolax Medical Device, Kanagawa,
Japan)
was inserted into the gallbladder. This delivery system has a 2.44-mm (7.2F) diameter
outer
sheath and allows the insertion of devices up to 1.9 mm (5.7F) in diameter ([Fig. 1]). After the delivery system was inserted into the target site, multiple biopsies
were performed using 1.8-mm-diameter pediatric biopsy forceps (Radial Jaw 4P; Boston
Scientific). Combinations of pushing and pulling of the biopsy forceps, and opening
and
closing of the tip were performed to guide the forceps to the target site ([Video 1]). In
principle, the number of biopsies was at least five. Additional biopsies were performed
if
the specimen was deemed grossly inadequate. Finally, a pigtail-shaped nasogallbladder
drainage tube was placed in the gallbladder for bile juice cytology ([Fig. 2]). Clinical symptoms and physical findings were recorded after the procedure.
Laboratory data were also assessed the following day. After the planned number of
cytology
specimens was collected (6 times in principle), the drainage tube was removed. After
the
endoscopic procedures, surgery was performed in all 11 cases, and the biopsy results
and
final pathological diagnosis were compared.
Fig. 1 Device delivery system and biopsy forceps. a Novel device delivery system (Endosheather; Piolax Medical Device, Kanagawa, Japan)
composed of an inner catheter and an outer sheath. b Outer sheath. c Biopsy forceps inserted into the outer sheath of the device delivery
system.
Fig. 2 Fluoroscopic images of the gallbladder biopsy procedure. a After bile duct cannulation, the guidewire was coiled in the gallbladder. b The device delivery system was then inserted into the gallbladder (arrows). c Thereafter, biopsy forceps was inserted into the delivery system and biopsy was performed.
The procedure was repeated until grossly sufficient specimens have been obtained.
d Finally, a nasobiliary drainage tube was placed into the gallbladder.
Results
The clinical characteristics of the assessed 11 patients are summarized in [Table 1]. The indications for gallbladder biopsy were gallbladder wall thickness (10/11,
90.9%) and a gallbladder protruding lesion (1/11, 9.1%). The main target sites were
the gallbladder fundus (9/11, 81.8%), body (1/11, 9.1%), and neck (1/11, 9.1%). Gallbladder
cannulation success and system insertion success were achieved in 10 patients (90.9%).
In one patient with a protruding lesion in the gallbladder body, guidewire insertion
into the gallbladder was unsuccessful, owing to cystic duct deformation. In one patient,
the delivery system did not follow the 0.025-inch guidewire initially used and had
to be replaced with a 0.035-inch hard-type guidewire. Target biopsy success was achieved
in seven patients (63.6%). In two patients, insertion of the system into the target
site (i.e., gallbladder fundus) was difficult and the biopsy was performed in the
gallbladder body. In one patient with gallbladder neck wall thickness, the gallbladder
anatomy made it difficult to accurately assess whether a biopsy could be performed
from the target site. The median number of biopsies was 5.5 (range, 3–8). Appropriate
evaluable specimens were obtained in all 10 patients in which biopsies were taken
from the gallbladder. Gallbladder bile juice cytology was performed in nine patients
(81.8%). The biopsy procedure time was 8.7 minutes (range, 5.4–32.7). The total procedure
time was 47 minutes (range, 28–89). Details of the endoscopic procedures are summarized
in [Table 2]. Biopsy results, cytology results, and final diagnosis are shown in [Table 3]. In one patient in whom all six gallbladder bile juice cytology results were benign,
the biopsy result was suspicious of adenocarcinoma ([Fig. 3]). The patient’s final diagnosis was gallbladder cancer.
Table 1 Clinical characteristics of the 11 assessed patients.
|
Age, median (range), years
|
71 (28–85)
|
|
Sex (male/female)
|
3/8
|
|
Indications of gallbladder biopsy, n (%)
|
|
|
10 (90.9)
|
|
|
1 (9.1)
|
|
|
2 (18.2)
|
|
Main target sites, n (%)
|
|
|
9 (81.8)
|
|
|
1 (9.1)
|
|
|
1 (9.1)
|
Table 2 Details of the endoscopic procedures.
|
Sphincterotomy, n (%)
|
8 (1 prior) (72.7)
|
|
Gallbladder cannulation success, n (%)
|
10 (90.9)
|
|
Device insertion success, n (%)
|
10 (90.9)
|
|
Adequate specimen collection, n (%)
|
10 (90.9)
|
|
Target lesion biopsy success, n (%)
|
7 (63.6)
|
|
Number of biopsies, median, n (range)
|
5.5 (3–8)
|
|
Performing gallbladder bile cytology, n (%)
|
9 (81.8)
|
|
Cytology results
|
|
|
1
|
|
|
1
|
|
|
7
|
|
Biopsy time, min (range)
|
8.7 (5.4–32.7)
|
|
Total procedure time, min (range)
|
47 (28–89)
|
Table 3 Biopsy results and surgical outcomes.
|
No.
|
Biopsy result
|
Cytology result
|
Final diagnosis
|
|
1
|
No neoplastic lesion
|
Benign (6/6)
|
No neoplastic lesion
|
|
2
|
No neoplastic lesion
|
Benign (6/6)
|
Chronic cholecystitis
|
|
3
|
No neoplastic lesion
|
Benign (6/6)
|
Adenomyomatosis
|
|
4
|
No neoplastic lesion
|
Benign (6/6)
|
Adenomyomatosis
|
|
5
|
No neoplastic lesion
|
Cytology not performed
|
Atypical epithelium (BilIN2)
|
|
6
|
Granuloma
|
Benign (7/7)
|
Chronic cholecystitis
|
|
7
|
Xanthogranulomatous reaction
|
Suspicious (1/6), Indeterminate (5/6)
|
Xanthogranulomatous cholecystitis
|
|
8
|
Atypical glands
|
Indeterminate (6/6)
|
Gallbladder cancer (Tis, Stage 0)
|
|
9
|
Atypical glands
|
Malignant (6/6)
|
Gallbladder cancer (T2bN2M0, Stage IVb)
|
|
10
|
Suspicious of adenocarcinoma
|
Benign (6/6)
|
Gallbladder cancer (T3aN0M0, Stage IIIa)
|
Fig. 3 Biopsy and excised specimens. a An atypical epithelium is confirmed suggestive of adenocarcinoma (arrowheads). b The excised specimen showed SS depth, Stage IIIa (UICC 7th) gallbladder cancer (arrowheads).
c Adenocarcinoma was histopathologically confirmed from the microscopic image.
AEs occurred in two patients (i.e., cholecystitis 1, self-limiting hematoma 1). In
the patient with cholecystitis, there was stenosis in the cystic duct that appeared
to be due to inflammation; after balloon dilation, a delivery system was inserted
and a gallbladder biopsy was performed. The patient was fine the day after the procedure,
but developed acute cholecystitis after removal of the drainage tube placed for bile
cytology. An emergency cholecystectomy was performed in this patient.
Discussion
Of the 11 patients in whom transpapillary gallbladder biopsy was attempted during
the study period using a newly designed device delivery system, 10 patients in whom
guidewire placement into the gallbladder was possible had successful device insertion.
When delivery system insertion into the gallbladder is difficult, replacement with
a 0.035-inch hard-type guidewire or the use of a double guidewire technique may be
effective. In one patient, the delivery system could be introduced by changing the
0.025-inch guidewire to a 0.035-inch hard-type guidewire. However, two of these 10
patients had unsuccessful advancement of the device delivery system to the target
site (i.e., gallbladder fundus). In one patient with gallbladder neck wall thickness,
it was difficult to rigorously assess whether a biopsy could be taken from this site.
Therefore, seven cases (63.6%) had successful targeted biopsies from the main target
site.
In terms of advantages, transpapillary gallbladder biopsy using a newly designed device
delivery system can be performed using commercially available devices, and multiple
specimens can be easily collected once the delivery system is inserted. In addition,
device insertion and biopsy could be performed in all cases in which guidewire insertion
into the gallbladder was possible. Transpapillary gallbladder biopsy is simpler than
previously reported gallbladder biopsy methods that require specially developed devices
and complex procedures [4]
[5]
[6]
[7]. The usefulness of gallbladder bile cytology using a nasogallbladder drainage tube
has already been reported [1]
[2]. Because transpapillary gallbladder biopsy can be performed in addition to gallbladder
bile cytology, its use in close examination of gallbladder lesions is worth considering.
In cases of a tortuous, thin cystic duct and failed cases of gallbladder cannulation,
this method is either not possible or very difficult. For anatomical reasons, it was
difficult to rigorously assess whether a biopsy from the target site could be obtained
from lesions in the neck or body of the gallbladder, or in elevated lesions of the
gallbladder. For this reason, a good indication for this technique is considered to
be wall thickening at the fundus of the gallbladder, where it is difficult to differentiate
between benign and malignant lesions by imaging diagnosis such as ultrasonography
or endoscopic ultrasonography. Furthermore, a problem we encountered was that in some
patients, the delivery system could not be inserted into the gallbladder fundus. If
a more flexible and smaller outer diameter delivery system with the same inner diameter
and controllable biopsy forceps with the same specimen collection performance are
developed, transpapillary gallbladder biopsy could become even more useful. In terms
of risks, AEs such as perforation of the cystic duct or gallbladder, and bleeding
and infection may occur during the procedure, which requires careful attention and
delicate manipulation. When we performed transpapillary gallbladder biopsy after balloon
dilation in a patient with a stenosed cystic duct, we experienced acute cholecystitis
possibly caused by cystic duct edema after removal of the gallbladder drainage tube.
In such a situation, we should have considered not inserting the delivery system or
leaving a stent in place for gallbladder drainage.
For study limitations, this was a single-center retrospective study with a small number
of cases. At this stage, the small number of patients with gallbladder cancer included
in this cohort limits any definitive statements regarding the diagnostic accuracy
of transpapillary gallbladder biopsy. Larger studies should allow the selection of
patients who would benefit from this procedure.
Conclusions
Transpapillary gallbladder biopsy using a newly designed device delivery system is
a potential option for the diagnosis of gallbladder disease. The addition of transpapillary
gallbladder biopsy may be advantageous when performing bile juice cytology using a
nasogallbladder drainage tube for the diagnosis of gallbladder disease.
A guidewire was initially placed in the gallbladder, then the device delivery system
was inserted into the gallbladder using an over the wire method, and finally biopsy
was performed. To perform adequate biopsy of the target site, the forceps tip position
was changed by pushing and pulling the delivery system and opening and closing the
forceps tip as necessary.Video 1
