Research Article
Pathological Evaluation of Horizontal Extension in Non-Muscle Invasive Bladder Cancer Resected using TURBO (Transurethral Resection of Bladder Tumor in One Piece) Technique
Ueda Y1, Zozumi M2, Suzuki T1, Kanematsu A1, Nojima M1, Hirota S2 and Yamamoto S1*
1Department of Urology, Hyogo College of Medicine, Japan
2Department of Surgical Pathology, Hyogo College of Medicine, Japan
*Corresponding author: Shingo Yamamoto, Department of Urology, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo, 663-8501, Japan
Published: 13 Sep, 2016
Cite this article as: Ueda Y, Zozumi M, Suzuki T,
Kanematsu A, Nojima M, Hirota
S, et al. Pathological Evaluation of
Horizontal Extension in Non-Muscle
Invasive Bladder Cancer Resected
using TURBO (Transurethral Resection
of Bladder Tumor in One Piece)
Technique. Clin Oncol. 2016; 1: 1093.
Abstract
Using TURBO technique, we accurately evaluated horizontal extension of non-muscle invasive
bladder tumors in relation to clinical and pathological parameters. Non-muscle invasive bladder
tumors sized less than 20 mm were resected with an approximately 5-mm margin from the stalk
using the TURBO technique. Specimens from 52 cases were pathologically examined to determine
the amount of horizontal extension, which was analyzed for correlations with several clinical and
pathological parameters, including tumor size and stalk diameter.
Twenty cases (38.5%) were found to have horizontal extension of cancer, ranging from 0.6 to 6.1
mm (median 2.8 mm). The existence of horizontal extension was significantly more often associated
with primary (17/32: 53.1%) than recurrent (3/20; 15.0%) tumors (p=0.014) and likely to be
associated with high grade tumors (p=0.053). Tumors with a stalk greater than 2 mm were more
significantly associated with horizontal extension (18/37; 48.6%) in contrast to those with a smaller
stalk (2/15; 13.3%) (p=0.040), though no such trend was observed in terms of tumor size (p=0.202).
Furthermore, horizontal extension length was significantly correlated with stalk diameter/tumor
size ratio (r=0.5060), but not with tumor size (r= -0.2203) or stalk diameter (r=0.1847).
Our findings showed that resection with a wider surgical margin are required in cases with a tumor
stalk diameter thicker than 2 mm, especially in those with a stalk diameter/tumor size ratio of 0.4 or
more. Our results are considered to be the first useful evidence showing the need for horizontally
complete resection of non-muscle invasive bladder cancer.
Keywords: En bloc resection technique; Horizontal extension; Non-muscle invasive bladder tumors; Stalk diameter/tumor size ratio; TURBO
Introduction
A transurethral resection of bladder tumor (TURBT) procedure is the gold standard diagnostic
tool as well as treatment method for bladder cancer, especially in cases of non-muscle invasive tumors.
However, that method occasionally results in insufficient tumor specimens for accurate pathological
examination results, because of fragmentation into pieces and/or degeneration by thermal damage.
Therefore, conventional TURBT may sometimes lead to pathological under-diagnosis by neglecting
micro-stromal invasion, or vertically and/or horizontally incomplete excision in cases requiring a
second transurethral resection.
A new technique for en bloc resection of bladder tumors without fragmentation, termed TURBO
(transurethral resection of bladder tumor in one piece), has been recently reported [1,2]. While a
similar technique using a laser has also been presented [3]. These methods for en bloc resection of
bladder tumors are considered more likely to contribute to improvements in accurate pathological
diagnosis by avoiding fragmentation of and direct thermal damage to bladder tumors during the
procedure. As reported by Ukai et al. [4] as well as others [1-3], use of TURBO or a similar method
provides for more accurate histological diagnosis, especially regarding the depth of lamina propria
invasion, as compared to conventional TURBT, because specimens obtained by TURBO were found
to be well oriented with a well maintained 3-D architecture. However, the usefulness of TURBO for
evaluating resected bladder tumors in regard to horizontal extension
has yet to be reported.
In the present study, we examined both horizontal extension
and vertical invasion of specimens obtained by TURBO, and then
analyzed the correlation between horizontal extension and several
clinical and pathological parameters, including tumor size and stalk
diameter, in non-muscle invasive bladder tumors.
Table 1
Materials and Methods
Materials
Between September 2009 and December 2013, 68 patients
underwent TURBO at our institution for bladder tumors sized less
than 20 mm suspected to be non-muscle invasive cancer without
carcinoma in situ based on preoperative endoscopic findings and
clinical information. Of those surgical specimens, 52 showed adequate
quality for a detailed pathological examination to evaluate horizontal
extension and vertical invasion, and were analyzed for the present
study. Median patient age was 73 years old (30 to 95 years) and males
were predominant (n=45, 86.5%). The analyzed specimens included
32 primary (61.5%) and 28 solitary (53.8%) tumors (Table 1).
TURBO technique: As previously reported [1,2,4]. TURBO was
performed using a 26-Fr resectoscope equipped with a 45˚ needle
electrode (TURis, Olympus Medical Systems, Japan). Briefly, with
this method, the tumor is initially carefully investigated in terms
of size, stalk shape, and visible horizontal extension of disease
around the mass. Using the 45˚ needle electrode, marks are made
circumferentially at approximately 5 mm from the edge of the stalk.
After connecting the marks circularly with the electrode, the tumor
is then resected horizontally through the superficial muscular layer
by electric cutting with a loop electrode while pushing the bottom
with the tip of the sheath. The tumor specimen is thus obtained
with surrounding normal tissue and a superficial muscular layer. In
each of the present cases, the main tumor was resected by TURBO,
while other daughter tumors and apparent low-grade lesions were
incised using conventional TURBT or a cold cup biopsy technique
to reduce operation time. There were no complications encountered,
such as perforation of the bladder wall or postoperative urinary tract
infection.
Tissue processing for pathological examination: Following
resection of the tumor specimen, the bottom was immediately
stretched and pinned onto a piece of paper. After fixing with 20%
buffered formalin overnight, the specimen was embedded in agarose
using a double embedding technique [5] (Figure 1). Next, serially
sectioning was performed, and the pathological diagnosis was
determined and confirmed by two pathologists. Parameters such as
tumor size and stalk diameter, and horizontal extension length were
evaluated by a single pathologist using a virtual slide system (Scan
Scope XT, Aperio, USA) (Figure 2).
Statistical analysis: Statistical analysis was performed using
StatMate (ATMS Co. Ltd, Japan), with p values <0.05 shown by a chisquare
test and r values >0.4 shown by a correlation coefficient test
considered to indicate significance.
Results and Discussion
All tumors were diagnosed as urothelial carcinoma, while 47
cases (90.4%) were pathologically defined as pTa and 5 (9.6%) as pT1.
Among the pT1 tumors, micro-stromal invasion was observed in 3
(5.8% of all cases), which was considered to have been neglected and
diagnosed as pTa if the specimen had been obtained by conventional
TURBT.
Microscopic examinations were performed to determine tumor
horizontal extension, which indicated that 43 (82.7%) tumors were
completely resected, while 9 (17.3%) showed a horizontal surgical
margin positive for cancer. Of the 52 present tumors, 20 (38.5%) were
found to have a horizontal extension of cancer ranging from 0.6 to
6.1 mm (median 2.8 mm), which was significantly more associated
with primary (17/32, 53.1%) as compared to recurrent (3/20, 15.0%)
tumors (p=0.014), and also more likely to be associated with high
grade tumors (p=0.053), whereas age, gender, urine cytology, and
pT stage showed no such associations. Median tumor size and stalk
diameter of tumors showing horizontal extension were 6.4 mm (2.6-
17 mm) and 3.2 mm (0.7-9.2 mm), respectively, while those of tumors
without horizontal extension were 4.8 mm (0.8-13.2 mm) and 2.6
mm (0.5-10 mm), respectively, with no significant differences noted
(Table 1).
Conversely, when the existence or absence of horizontal extension
was overlooked for determining the relationship with tumor size and
stalk diameter, larger tumor size or thicker stalk diameter seemed to be
associated with horizontal extension of cancer (Figure 3). Therefore,
several cutoff points for tumor size and stalk diameter were applied
for determining the relationship of presence of horizontal extension.
Tumors with a stalk greater than 2 mm in diameter were significantly
associated with horizontal extension (18/37; 48.6%) in contrast to
those with a smaller stalk (2/15; 13.3%) (p=0.040). However, that
trend was not observed in terms of tumor size (p=0.202) (Table 2).
When the correlations of horizontal extension length with tumor
size and stalk diameter were analyzed, no significant association
was observed (r= -0.2203 and r=0.1847, respectively) (Figure 4A
and B). On other hand, we found that horizontal extension length
was significantly correlated with the stalk diameter/tumor size ratio
(r=0.5060), suggesting that resection with a wider surgical margin
is required in cases with a stalk diameter/tumor size ratio of 0.4 or
greater (Figure 4C).
A previous study reported that a residual tumor is found in 20-
78% of patients who undergo a second transurethral resection and
whose initial diagnosis was pT1 [6]. While others have reported
pathological findings of specimens obtained in a second transurethral
resection showing that 2-28% of such patients were pT2 [7,8]. A
second transurethral resection is strongly recommended in cases with
a pathological diagnosis of high grade or pT1 tumor initially treated
by TURBT [9]. Thus, particularly for non-muscle invasive cancer,
an important role of transurethral surgery is not only complete
resection of the tumor, but also harvest of a high quality specimen for
accurate pathological diagnosis. However, specimens obtained with
conventional TURBT are occasionally insufficient for an accurate
pathological examination, because of fragmentation into pieces or
degeneration from thermal damage.
Several recent studies have noted that the depth of tumor invasion
is significantly correlated with progression in patients with T1 cancer
[10-12]. Younes et al. [10] reported that patents with a tumor that has
invaded to the level of the muscularis mucosae had a 5-year survival
rate of 75%, whereas that was only 11% in those with tumors invading
through the level of the muscular is mucosae. Orsola et al. [11] also
reported that the depth of invasion noted with TURBT specimens
is an independent prognostic factor for T1 bladder cancer, because
the rate of progression in cases with a tumor showing deep invasion
of the lamina propria was significantly higher as compared to those
without such deep invasion.
In this regard, TURBO can provide specimens more optimal for
pathological diagnosis, because the tumor is resected en bloc with
surrounding normal tissue including normal epithelium, lamina
propriae, and a superficial muscular layer without direct thermal
damage. Ukai et al. [4] reported that definite pathological staging
was possible in 93% of their TURBO specimens, including 30 pTa, 58
pT1, and 2 pTa cases, while 7 cases (7%) had a deep resection positive
margin for cancer and were ambiguously staged. Similarly, in our
study, 5 pT1 cases (9.6%) were found among 52 superficial bladder
tumors, of which micro-stromal invasion was observed in 3 (5.8%),
which may have been neglected and diagnosed as pTa if the specimen
had been obtained by conventional TURBT.
Another advantage of TURBO for pathological diagnosis of
bladder tumors is the possibility for accurate evaluation of horizontal
extension. Urologists use empirical means to determine the surgical
margin prior to resecting a bladder tumor, as there are no reported
methods for accurate evaluation of horizontal extension in cases of
non-muscle invasive bladder cancer. In the present cases, 9 of 52
tumors (17.3%) resected with an approximately 5-mm margin from
the stalk showed a horizontal surgical margin positive for cancer,
suggesting that at least a 10-mm margin from the stalk may be required
for complete resection of a superficial bladder tumor, even those sized
20 mm or less. We found that horizontal extension was significantly
associated with a stalk diameter greater than 2 mm, but did not find
an association with larger tumor size. Another interesting finding
is that even though horizontal extension length was not associated
with tumor size or stalk diameter, it was significantly correlated
with the stalk diameter/tumor size ratio. These results indicate that a
larger tumor or thicker stalk alone is not always indicative of longer
horizontal extension, whereas the stalk diameter/tumor size ratio
may be an important indicator to determine surgical margin from
the stalk.
Taken together, for achievement of complete resection as well
as obtaining a sufficient specimen for pathological examination
in cases of non-muscle invasive bladder cancer, stalk diameter as
well as stalk diameter/tumor size ratio should be carefully observed
before performing the procedure. Resection with a wider surgical
margin should also be required in cases with a stalk diameter thicker
than 2 mm, especially when the stalk diameter/tumor size ratio is
0.4 or greater, as observed in the present study. To the best of our
knowledge, the present findings provide the first useful evidence for
the need of horizontally complete resection of non-muscle invasive
bladder cancer. Along this line, the effectiveness of narrow band
imaging (NBI) in conjunction with TURBT has been reported for
visualization of minute bladder tumors [13,14]. For assessment of the
usefulness of NBI for complete resection of a horizontally extended
bladder tumor, we are now conducting an assessment of TURBO
with NBI.
Finally, complete resection of a bladder tumor may contribute to
control sympatric tumor recurrence. As for cases with deep resection,
of 5 patients shown to have pT1 disease based on TURBO specimen
finings, 1 underwent a radical cystectomy and 2 suffered from
heterotopic pTa-recurrence, whereas none of our patients developed
invasive disease during the follow-up period (data not shown). On the
other hand, in regard to horizontal resection, sympatric recurrence
was observed in 1 (12.5%) of the patients with a horizontal surgical
margin positive and in 2 (4.7%) of those without such a margin
positive, which was not a significant difference (p=0.89) (data not
shown), though this result may have been due to the small number
of cases as well as modification caused by postoperative intravesical
instillation.
Figure 1
Figure 1
The bottom of the tumor was immediately stretched and pinned
onto a piece of paper. After fixing overnight with 20% buffered formalin,
the specimens were (A) embedded in agarose using a double embedding
technique and (B) serially sectioned.
Figure 2
Figure 2
TURBO specimen parameters.We measured (A) tumor size, (B)
stalk diameter, and (C) length of horizontal extension using a virtual slide
system (Scan Scope XT, Aperio, USA).
Figure 3
Figure 3
Relationship of existence or absence of horizontal extension with
tumor size and stalk diameter.
Figure 4
Figure 4
Correlation of horizontal extension length with (A) tumor size, (B)
stalk diameter, and (C) stalk diameter/tumor size ratio.
Table 2
Conclusion
Our findings showed that resection with a wider surgical margin is required in cases with a tumor stalk diameter thicker than 2 mm, especially in those with a stalk diameter/tumor size ratio of 0.4 or more. To the best of our knowledge, the present findings provide the first useful evidence for the need of horizontally complete resection of non-muscle invasive bladder cancer. However, the present study was performed in a retrospective manner and the sample size was small, thus larger prospective studies are needed to investigate factors that contribute to better clinical outcomes.
Acknowledgement
The present study was supported by a grant from the Hyogo Clinical Urologists Association in 2013. In lieu of formal ethics committee approval for this retrospective study, the principles of the Helsinki Declaration were followed. In addition, all patients provided written informed consent after receiving a guarantee of confidentiality.
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