Original Article

Yonago Acta medica 2016;59:143–148

Transurethral En Bloc Resection of Bladder Tumor Using an Endoscopic 		
Submucosal Dissection Technique: Preliminary Results in an Animal Model
Shuichi Morizane,* Takehiro Sejima,* Hideto Iwamoto,* Toshihiko Masago,* Masashi Honda,* Yuichiro
Ikebuchi,† Kazuya Matsumoto,† Masaru Ueki‡ and Atsushi Takenaka**Division of Urology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan,†Department of Gastroenterology, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan and ‡Center
for Promoting Next-Generation Highly Advanced Medicine, Tottori University Hospital, Yonago 683-8504, Japan

ABSTRACTthe laser resection and the wire loop resection. This
technique is considered the routine method for removing
most bladder tumors for several decades, and it aims toensure accurate histological diagnosis and remove allvisible lesions. However, TURBT is not ideal to obtaintumor samples for pathological evaluation because of
inaccuracies in determining the exact orientation of thetumor and tissue fragmentation. The presence of bladdermuscularis propria within the tumor is used to discriminate between NMIBC and muscle invasive bladder cancer.2, 3 Maruniak et al. reported that bladder muscularis
propria is absent in up to 51% of bladder cancers treatedwith conventional TURBT.4 Richterstetter et al. also reported relatively high residual tumor rates, reaching 16%
in patients with pTa tumors and 38% in patients with
NMIBC. In addition, they concluded that an extended
TURBT provides detailed information about the horizontal and vertical extent of the bladder tumor lesion.5
The failure to detect bladder muscularis propria within
the tumor tissue is likely to lead to understaging or a redundant second TURBT.
Over the last decades, several studies have focusedon the development of new techniques based on transurethral en bloc resection of bladder tumors.6–11 In thegastrointestinal tract, endoscopic mucosal resection andendoscopic submucosal dissection (ESD) have become
the standard procedures for the treatment of superficial
tumors.12, 13 In the present study, we evaluated the application of this technique and the use of a Dual Knife toresect bladder tumors in an animal model.

Background

Transurethral resection of bladder tumor(TURBT) technique has been considered the routine
method for removing most bladder tumors for decades.
In contrast, endoscopic submucosal dissection (ESD) isthe gold-standard treatment for gastrointestinal superficial tumors. We investigated the effectiveness and applicability of a new technique for en bloc bladder tumor
resection using ESD procedure.
Methods Four Landrace Large White Duroc female
pigs were anesthetized with isoflurane prior endoscopic
resection using a large-caliber prototype fiber bronchoscope. After local infiltration of the submucosa withsodium hyaluronate using an injector needle, a section of
the target area (1.0–2.0 cm diameter circular area) was
cut with the Dual Knife.
Results In total, seven target sections were resectedfrom the pigs. The median size of the resected sections
was 1.8 cm (range 1.0–2.5 cm) and the median time taken to perform the resection of one section was 20 min(range 4–35 min). These target sections were completely
resected en bloc. Although the small bladder perforations occurred on two occasions, no other short-term
complications such as uncontrollable bleeding were observed.
Conclusion This procedure is a slightly difficult in thepigs with thin bladder walls. However, this procedure
with the slim flexible cystoscope may allow us to beable to remove bladder tumors using only light sedation,
especially for cases when small tumor recurrence isobserved during routine cystoscopy for the patients with
non-muscle invasive bladder cancer.

MATERIALS AND METHODS
Ethics

Key words endoscopic surgical procedure; carcinoma;

This study was approved by the Tottori University Animal Ethics Committee (12-Y-57), and the animals received human care throughout the experiment.

transurethral resection; urinary bladder
Bladder cancer is the fourth most common cancer inmen, and accounts for 10,410 cancer-related deaths per
year.1 Approximately, 70% are presented as non-muscle
invasive bladder cancer (NMIBC). Most Ta and T1 bladder tumors are treated with the transurethral resectionof bladder tumor (TURBT) technique, which involves

Corresponding author: Shuichi Morizane, MD, PhD
morizane@med.tottori-u.ac.jp
Received 2016 March 11
Accepted 2016 April 11
Abbreviations: ESD, endoscopic submucosal dissection; NMIBC,
non-muscle invasive bladder cancer; TURBT, Transurethral resection of bladder tumor

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Animals

penetrate the surrounding non-target tissue during resection. An ERBOTOM ICC 200 (Erbe ElektromedizinGmbH, Tübingen, Germany) was used as an electrosurgical generator.

Four Landrace Large White Duroc female pigs (35–40kg) were used in this study. The animals were fed regularly until 24 h before the surgical procedure; thereafter
they were starved with free access to water. After the experiment was completed, the animals were killed using
a lethal dose of potassium chloride, after which necropsy
was performed.

Surgical procedure

The endoscopic resection procedure was performed asfollows:i) The fiber bronchoscope was introduced through theurethra allowing for visual inspection of the bladder. Using the endoscope, all the urine was collected from the
bladder and 100–150 mL of ambient air was introduced
into the bladder using an injector.
ii) A circular area of 1.0–2.0-cm diameter was definedin the bladder with the Dual Knife using an electrosurgical current (Forced coagulation mode 20 W) and identified as the target area for resection. This procedure wasomitted in some cases.
iii) After locally infiltrating the submucosa with a solution of sodium hyaluronate (MucoUp; Johnson andJohnson, Tokyo, Japan) or glycerol (Fig. 2a), we madean incision around the target area using the Dual Knife(Endo Cut mode 120 W: Fig. 2b).
iv) Through the proximal incision, we injected MucoUp
into the muscle layer around the target area to lift thelesion.
v) A section of the target area was cut using the Dual
Knife (Swift Coag mode 25 W) excising the target following a procedure similar to that of ESD (Fig. 2c).
vi) The resected section was retrieved using a Roth Net
through the urethra (Figs. 2d and e).
vii) After the animal was euthanized, the bladder was
extracted via laparotomy and dissected for macroscopic
examination.

Anesthesia

The pigs were premedicated with an intramuscular doseof ketamine hydrochloride (10 mg/kg) and xylazine hydrochloride (2 mg/kg). Subsequently, they were intubated with a 6.5-mm endotracheal tube cuffed, inflated toprevent air leaks and mechanically ventilated, and anesthetized with isoflurane. The animals remained anesthetized throughout the study with doses ranging from 2.0%
to 3.0%.
Equipment

A large-caliber prototype fiber bronchoscope (FB-19TX;
PENTAX, Tokyo, Japan) was used to perform the endoscopic resections (Fig. 1a). This tool is a large-caliber
endoscope with a 6.2-mm diameter insertion tube anda 3.2-mm diameter instrument channel. An injector
needle (Impactflow H type 25 gauge, insertion tube 2.6mm diameter, needle length 4 mm; TOP, Tokyo, Japan),an electrosurgical knife (Dual Knife, insertion tube 2.7mm diameter, needle length 2.0 mm; Olympus Medical
Systems, Tokyo, Japan), and a tissue recovery bag (RothNet; Olympus Medical Systems, Tokyo, Japan) werethe list of endoscopic instruments used. Dual Knife is a
novel single-use electrosurgical knife with a 2-mm razor
blade, commonly used for gastrointestinal tract ESD (Fig.
1b). It has a knob-shaped tip and a non-adjustable-knife
length, which makes the needle less likely to slip and

RESULTS
Endoscopy of the bladder using a fiber bronchoscope
was technically feasible in all the animals. Seven of theeight target sections were successfully resected from thefour pigs. However, because we took 60 min or morein the 2nd procedure, we gave up the one excision outof the eight target sections. In the seven procedures,the median size of the resected pieces ex vivo was 1.8
cm (range 1.0–2.5 cm), and the median time taken tosurgically resect each target piece was 20 min (range
4–35 min). The time required to perform a resection
decreased as the surgeon became familiarized with theprocedure. The first four resections took approximately
26.5 min each whereas the time taken for the last threeresections averaged 9 min.
All the seven target sections could be completely
resected en bloc; however, because the pieces contained

Fig. 1. Photograph of (a) the Large-caliber prototype fiber bronchoscope, and (b) the Dual Knife.

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Transurethral en bloc resection by ESD method

DISCUSSION
In this animal model experiment, we demonstrated thefeasibility of a new transurethral ESD-like en bloc resection, using the Dual Knife based on the ESD procedurecommonly used to extract superficial tumors from thegastrointestinal tract. Using this method, the target lesions can be resected in one piece and the resection canbe performed endoscopically. Although we can resect
the bladder tumors at all locations of the bladder by thea considerable portion of muscular tissue, the complications from the small bladder perforation developed in
two of the seven operations performed. No other shortterm complications, such as uncontrollable bleeding
were observed. Figure 3 shows the presence of muscular
tissue both in the target section and in the corresponding
section of the bladder. The depth of the dissection wasalmost controlled by injecting MucoUp into the muscle
layer around the target section.

Fig. 2. Endoscopic findings. (a) Local infiltration of the submucosa with a solution of sodium hyaluronate or glycerol. (b) Incision
around the target lesion with the Dual Knife (c) Excision madefollowing an endoscopic submucosal dissection-like procedure (d)View of the area following the excision the target section (e) Retrieval of the resected section with the Roth Net.

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required to become sufficiently skilled to perform thisprocedure within a reduced time frame.
Transurethral ESD-like en bloc resection is a slightly difficult procedure, particularly during muscularincision with the Dual Knife, and it carries a risk of perforation if the muscle is not injected with a solution suchas MucoUp in this animal model. In the present study,
MucoUp administration created a prominent long-lasting muscular elevation, which allowed the safe placement of circumferential and bottom incisions aroundthe target region except for two cases. Although there
is no evidence about the injection with solution into themuscle layer, we considered that these small perforations
could be prevented by injecting MucoUp into the muscle
layer repeatedly. On the other hand, the organs outsideof the bladder may be protected by injecting MucoUp
under the target sections, even when small bladder perforation occurred. Previously, Nieder et al. reported thecomplication rates about the bleeding and the bladderperforations associated with TURBT.15 They concluded
that the transfusion was required in 0.9 to 13% and the
bladder perforation was occurred in 1.3 to 5%. However
we usually experience some bleeding at TURBT, we terminate the operations after carefully stopping the bleeding by cauterization. Therefore, we have not frequently
experienced the hemorrhage requiring transfusions. We
consider that the bleeding is not a problem except for thelarge or multiple bladder tumors. Hypothetically speaking, if we experienced a small bladder perforation, we
would manage it conservatively with urethral catheter
drainage a little longer than the patients without bladderperforations. Therefore, we consider that the ESD procedure can be applied similar to TURBT for the patientswith small bladder tumors.
Yamamoto et al. reported on the use of MucoUp asa submucosal injection in colorectal and gastric endoscopic resections.16, 17 The bladder wall is thicker than
the gastrointestinal wall and decreases with increasing
bladder volume.18 Although the mean wall thickness ofthe gastric antrum and rectum are 2.9 (± 0.8) mm and2.1 (± 0.5) mm, respectively,19 that of the bladder of ahealthy adult human is approximately 3.35 mm.18 Therefore, we propose that performing ESD in the bladder(of an adult human bladder of approximately 100 mL involume) is comparatively safer than performing ESD in
the gastrointestinal tract.
The en bloc TUR technique was first described in
1997, and it has been acknowledged to improve pathological staging;6–8, 20 however, this procedure is suitableto retrieve small tumors, because they are retrieved using a resectoscope with a standard evacuator. Naselli etal. reported a technical modification that allows retrieval

Fig. 3. Histological image showing (a) a resected target section,and (b) a resected bladder (hematoxylin and eosin staining; Bar =900 μm).

conventional TURBT after obtaining enough skills, it isdifficult to resect the tumors near the dome of the bladder where a loop electrode touches perpendicularly. The
resection near the dome of the bladder was also difficultin this study, and we were not able to resect completely
in the 2nd procedure.
It has been confirmed that the absence of detrusor
muscle in the specimen is associated with a significantly higher risk of residual disease, early recurrence andtumor understaging.14 Although deep resection can potentially result in bladder perforations, urologists have toobtain a certain detrusor muscle with the bladder tumor
for the purpose of diagnosis and treatment. Therefore,
as Nieder et al. have previously described, the surgeonsmust take into consideration the tumor appearance andthe need to obtain muscle, the bladder thickness, and thedepth of penetration of the loop into the wall as the current is applied.15 We also consider that it is very important for the ESD procedure as well as for the TURBT.
The Dual Knife used in our study enabled us to obtaina reasonable amount of tissue from the muscle layer. Its
knob-shaped tip and non-adjustable length (2 mm) makethe needle less likely to slip and enables easy penetration
into the surrounding non-target tissue during the resection of the lesion. This procedure allowed the retrievalof the target tissue, containing a minor section of themuscle layer at its base and without bladder perforation,even in those cases when the bladder was not sufficiently
dilated and injected MucoUp into the muscle layer sufficiently. In addition, we found that the time required toperform this surgery decreased as the surgeon becamefamiliarized with the slim flexible cystoscope and theDual Knife, suggesting that some training would be146

Transurethral en bloc resection by ESD methodof tissue sections of up to 4.5 cm using laparoscopic
forceps.10 On the other hand, Lodde et al. reported thelimitations of using en bloc techniques for tumors larger
than 2.5 cm in diameter.9 Considering that the diameterof the urethra is approximately 1.0 cm, the size of thetumor which can be retrieved in one piece through theurethra is limited. We also acknowledge the difficulties
associated with the retrieval of tumors larger than 2.5
cm in one piece using this technique, and therefore, suggest that conventional TURBT is unavoidable for larger
tumors. Furthermore, although endoscopic cold cup biopsy forceps and hot cup forceps can be used to retrieve
tumor specimens for pathological evaluation, thesemethods are limited to those specimens whose sizes
are below those of the inner diameter of the cystoscopic
working channel and the cup size.21, 22 These methods
are highly efficient for small tumors, and it is thus difficult to perform an en bloc resection for tumors larger
than 5 mm. Although our technique also presents some
limitations to perform en bloc resections for big tumors,this method is useful to resect tumors up to 2.5 cm andis more effective than cup biopsy.
Despite TURBT being the routine method for bothprimary and repeated treatment of bladder tumors, thistechnique is prone to tissue fragmentation, possibly
causing an early recurrence of NMIBC because of theimplantation of detached cancer cells into the bladderurothelium following resection.23 The use of conventional TURBT led to a larger number of tumor fragments,
necessitating the use of an evacuator for complete
retrieval. Consequently, a high intravesical pressure
may be created during the process of tumor retrieval.
El-Abbady et al. showed that some malignant cells penetrate through the denuded urothelium during TURBT
because of the presence of high intravesical pressure,which may result in tumor recurrence at later stages.24
One-piece resection is considered the gold standard forgastrointestinal endoscopic mucosal resection, because
it allows for an accurate histological assessment andreduces the risk of recurrence.25, 26 In addition, ESD
reportedly improves the rate of successful en bloc resection in the gastrointestinal tract;27, 28 therefore, we would
expect that these en bloc procedures may also decrease
the risk of recurrence in the case of NMIBC.
We believe that the pain associated with the transurethral procedure can be reduced with a slim endoscope. With this procedure, we may be able to remove
bladder tumors using only light sedation, especially forcases when small tumor recurrence is observed during
routine cystoscopy for the patients with NMIBC. For thereasons discussed above, this method is primarily recommended for small and non-multiple bladder cancer.

We also consider that this method would help reduce themedical costs and the waiting period associated with thetreatment of this type of tumors. Furthermore, we expect
it to lead to improvements in histological assessments,
and to reduce the risk of recurrence by maintaining tissue integrity, thereby limiting tumor seeding. Because of
its potential to replace current bladder cancer treatment,
further investigations are warranted.
As previously reported, a main advantage of air overwater cystoscopy is its lower costs associated.29 Ciudin
et al. showed a lack of statistical differences between
water cystoscopy and air cystoscopy in patients without
hematuria, whereas the latter presented a higher diagnostic sensitivity and specificity in such patients.30 In
the present study, the endoscopic view during air cystoscopy was not particularly good due to the discharge ofurine, the smoke from the electorotome, and the use ofan older type of fiber bronchoscope. At the time of theexperiment, a slim flexible cystoscope with a large instrument channel, which allowed the insertion of a large
instrument such as the Dual Knife, was not available.
New instruments combining a slim insertion tool and achannel diameter, allowing the insertion of larger instruments while allowing for the adjustment of air injectionand evacuation, should be developed to provide easy use
and high stability for transurethral ESD-like en bloc resection.
This pilot study was conducted in a small numberof Landrace Large White Duroc pigs. In the present
study, the small bladder perforations occurred in two of
the seven operations performed. The thickness of the
bladder wall of a pig is less than half of that of a human,creating an additional difficulty; however, because thebladder wall is thicker in humans, we consider the possibility of bladder perforation to be even lower in humans,
more so if the resection is performed more carefully andusing injection MucoUp into the muscle layer repeatedly.
Despite this limitation, we have confirmed that transurethral ESD-like en bloc resection could be performed relatively safely and correctly. The present findings can be
regarded as a significant step in the field. We are hoping
to apply this technique to treat bladder tumors in human.
In conclusion, transurethral ESD-like en bloc resection using the Dual Knife is a slightly difficult procedurein the pigs with thin bladder walls in this study. However, this procedure with the slim flexible cystoscope may
allow us to be able to remove bladder tumors using only
light sedation, especially for cases when small tumor
recurrence is observed during routine cystoscopy for thepatients with NMIBC.
The authors declare no conflict of interest.

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S. Morizane et al.

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