# Comprehensive Management of Upper Tract  Urothelial Carcinoma

Authors: Georgios Koukourakis; Georgios Zacharias; Michael Koukourakis; Kiriaki Pistevou-Gobaki; Christos Papaloukas; Athanasios Kostakopoulos; Vassilios Kouloulias
Journal: Advances in Urology
 (2009)

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## Abstract

Urothelial carcinoma of the upper urinary tract represents only 5% of all urothelial cancers. The 5-year cancer-specific survival in the United States is roughly 75% with grade and stage being the most powerful predictors of survival. Nephroureterectomy with excision of the ipsilateral ureteral orifice and bladder cuff en bloc remains the gold standard treatment of the upper urinary tract urothelial cancers, while endoscopic and laparoscopic approaches are rapidly evolving as reasonable alternatives of care depending on grade and stage of disease. Several controversies remain in their management, including a selection of endoscopic versus laparoscopic approaches, management strategies on the distal ureter, the role of lymphadenectomy, and the value of chemotherapy in upper tract disease. Aims of this paper are to critically review the management of such tumors, including endoscopic management, laparoscopic nephroureterectomy and management of the distal ureter, the role of lymphadenectomy, and the emerging role of chemotherapy in their treatment.


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## Body

## 1. Introduction

Primary urothelial carcinoma of the upper tract is a rare urological
disease and has a propensity for multifocality, local recurrence, and
development of metastases. Almost 5% of all urothelial neoplasms occur in the
kidney and ureters. The vast majority of upper tract tumors arise in the kidney, comprising 4% to
15% of all primary kidney neoplasms in the United States,
whereas ureteral tumors represent only 1% [1].As a result, urothelial carcinoma of the bladder has been examined to a
greater extent than urothelial tumors elsewhere.The main treatment for patients with upper tract urothelial neoplasms and a normal
contralateral kidney is a complete nephroureterectomy with removal of a cuff of
urinary bladder. Due to
the high rate of ureteral stump recurrence, which has been reported to be
between 30% and 75%, it is important to complete the nephroureterectomy with a
cuff of urinary bladder [2–10]. Hall et
al. [11] reported in one of the largest series in the literature on 252
patients who were treated for upper tract urothelial tumors with a median
follow-up of 64 months. One hundred ninety-four (76.6%) patients underwent open
radical nephroureterectomy with removal of bladder cuff, 42 (16.7%) patients
underwent parenchymal-sparing surgery, 14 (5.6%) patients underwent nephrectomy
alone, and 2 (0.8%) had exploration only for nonresectable disease. Overall, patients undergoing parenchymal-sparing surgery had a lower actuarial 5-year disease-free survival
rate than those treated with initial aggressive surgical resection (23% versus 45%, P<.0009).
Patients with grades 1 and
2 tumors were equally distributed in these 2 groups. This study
supported the use of aggressive open surgical
resection for initial treatment of upper tract urothelial tumors, with a 5-year disease-free survival rate of 45%.Nevertheless, the gold standard of open radical nephroureterectomy with
resection of a bladder cuff is being challenged by minimally invasive
approaches to the managing
of upper tract transitional cell carcinoma (TCC). For upper tract
urothelial carcinoma, laparoscopic nephroureterectomy has been used as an
alternative to an open procedure. Since the first laparoscopic nephroureterectomy, performed by Clayman in
May 1991 at Washington University (St. Louis, Mo, USA), numerous reports regarding
the safety and efficacy of that procedure have been published [12, 14–23]. This
paper will cover the therapeutic approaches to upper
tract TCC, including laparoscopic nephroureterectomy,
endoscopic approaches, and the prognostic value of lymphadenectomy in patients with muscle
invasion. Topical immunotherapy, adjuvant
chemotherapy, and adjuvant radiation therapy will also be discussed.


## 2. Surgical Treatment

### 2.1. Laparoscopic Treatment

Recently, Gill et al. published on their experience of 42 patients who
underwent laparoscopic retroperitoneal nephroureterectomy with a mean follow-up
of 11.1 months [12]. The distal ureter
was treated with a combination of laparoscopic and endoscopic transvesical approaches [23]. A
comparable research was performed between those patients and another 35, who
underwent open nephroureterectomy at their department. In the laparoscopic
group, the blood lost was significantly less (242 versus 696 mL). Postsurgically,
patients in the laparoscopic group had a significantly more rapid
recommencement of ambulation (1.4 versus 2.5 days), oral intake (1.6 versus 3.2
days), shorter hospital stay (2.3 versus 6.6 days), decreased analgesic
necessities (26 mg morphine sulfate equivalent versus 228 mg), and a more rapid
period of recovery (8 versus 14.1 weeks). Complications occurred in 5 (12%) and 10 (29%) patients in the
laparoscopic and open groups, respectively. These complications integrated 1 renal vein injury, 1 patient with fluid extravasations from
mobilization of the bladder cuff, and 3 patients with atelectasis in the
laparoscopic group. The open group had 4 patients with atelectasis, 5
patients with postoperative ileus, and 1 patient with a pneumothorax. Two cases required
an open conversion because of a renal
injury and an elective conversion secondary to local tumor infiltration with obliteration of tissue planes near the hilum.The mean pathologic grade was 2.3 for both of the groups, with the laparoscopic
group having 9, 10, and 23 patients with grades 1, 2, and 3 tumors and the open
group having 6, 10, and 16 patients with grades 1, 2, and 3 tumors,
respectively. Surgical margins were positive in 3 (7%) patients in the
laparoscopic group and 5 (15%) patients in the open group. All 3 patients in
the laparoscopic group received systemic chemotherapy postoperatively, and
pulmonary metastases developed in 1 patient during follow-up. For comparable
stage and grade of primary tumor, the negative surgical margin rate was similar
between the 2 groups. The
two groups of laparoscopic and open surgeries have no difference as
regarding the bladder recurrence (23 versus 37%), retroperitoneal or port
site/incisional recurrence (0 versus 0%), or distant metastases (8,6 versus
13%). There was no difference in either cancer-specific survival (97% versus
87%) or crude survival (97% versus 94%) after adjusting for the shorter
follow-up period (11 versus 34 months) between the laparoscopic and open
groups, respectively, during follow-up. Mortality occurred in 2 patients (6%) of
the laparoscopic group and in 6 of the open group (30%). The authors cannot
estimate whether these mortality rates are significantly different or equivalent
[12]. The results of the trails that compare laparoscopic treatment with open
surgery are summarized in Table 1. The techniques of laparoscopic retroperitoneal nephroureterectomy and partial nephrectomy are
shown in Figures 1(a), 1(b), and 1(c) and in Figure 2, respectively. Patients are
placed in the full flank position. Usually, the operating table is
flexed and the kidney rest is elevated, thereby increasing the space
between the iliac crest and the lower ribs. Retroperitoneal access is
obtained through a small 10- to 15-mm incision just below and medial to the tip
of the 12th rib (Figure 1(a)). The muscle and fascia are separated using
a blunt instrument that allows one finger to develop a working space posterior to the kidney above the psoas muscle (Figure
1(b)). Often the lower pole of the kidney is immediately palpated. The colon
is separated away from the anterolateral abdominal wall with the index
finger. Additional trocars are placed below the 12th rib just above the psoas
muscle posteriorly, and then more anteriorly through the lateral abdominal wall
under direct vision using the laparoscope (Figure 1(c)). Laparoscopic
partial nephrectomy is ideal for a patient with an exophytic, small, and
peripherally located renal tumor (Figure 2).Table 1
Studies that compare laparoscopic nephroureterectomy with open surgery.
StudyNo. of patientsTumor gradeFollow-upOutcomesGill et al. [12]42 in LT, 35 in OS34 patients in LT arm and 28 in OS arm III tumors11.1 months in LT,34.4 in OSLT significantly decreasing morbidity with comparable oncological and survival data to OSShalhav et al. [13]25 in LT 17 in OS21 patients in LT arm and 14 in OS arm grade II2 years in both armsLT has longer operating time but the same efficacy and is better toleratedLT: laparoscopic treatment, OS: open surgery.(a) Access for a right retroperitoneal laparoscopic radical
nephrectomy (LRN). A 10- to 15-mm incision is made below and medial to the
tip of the 12th rib. (b) The flank muscles are pierced with a blunt-tipped
instrument followed by finger dissection and development of the retroperitoneum
space to permit trocar placement. (c) Trocar placement for a right
retroperitoneal LRN.
(a)(b)(c)Figure 2
Retroperitoneal laparoscopic left partial nephrectomy.The literature research discovered similar effects
in transperitoneal laparoscopic nephroureterectomy [13, 24]. The familiarity
with anatomic landmarks and a larger working space are some advantages of
transperitoneal approach compared to retroperitoneal one. The retroperitoneal approach,
however, has distinct advantages, for example, permittance of early control of the renal
artery and vein, no manipulation of the bowel leading to less incidence of
ileus and possibly a shorter hospital stay, and confinement of possible
urinomas or seromas to the retroperitoneal space [12, 25].


### 2.2. Hand-Assisted Laparoscopic Nephroureterectomy

Apart from standard
laparoscopic nephroureterectomy among urologists, hand-assisted laparoscopic
nephroureterectomy is also an acceptable technique [18, 20]. Patient
preparation and positioning is identical to that described for transperitoneal
LRN (laparoscopic nephroureterectomy). The hand-assisted
LRN technique usually begins with a 6 cm to 8 cm incision for hand-port
placement through a lower quadrant Gibson-type incision (Figure 3(a)) or
through the lower midline abdomen (Figure 3(b)).
The Kawauchi et al.'s [18] experience was
described in 34 consecutive patients who
underwent hand-assisted laparoscopic nephroureterectomy using a Lap Disc (Hakko Shoji, Tokyo, Japan). Those 34 patients were compared with the
previous group of 34 patients who underwent open nephroureterectomy. Mean
follow-up was 13.1 months in the hand-assisted group and 48.8 months in the
open group [18]. In the hand-assisted
group, there was observed a similar operative time (233 versus 236 minutes),
decreased analgesia frequency (2.1 versus 4.1 days), decreased blood loss (236
versus 427 mL), quicker return to ambulation (1.5 versus 2.5 days), and shorter
hospital stay (13 versus 21.1 days). In the Japanese series compared with the American ones, the
lengthy stay is a social issue and not reflective of actual patient recovery. There were 4 (12%) complications in both groups, with 1 open conversion
in the hand-assisted group. The 4 complications in the hand-assisted group
include 1 conversion due to bleeding from the left adrenal gland, 2 wound
infections, and 1 pulmonary infarction in a patient who recovered with
conservative treatment [18]. As
regarding the histological tumor grade, the pathologic studies have revealed
that in the hand-assisted group there were 5, 20, and 9 patients with grades 1,
2, and 3 tumors, whereas in the open group there were 4, 17, and 13 patients
with grades 1, 2, and 3 tumors, respectively. Recurrence rate was 12% (4
patients) in the hand-assisted group, with a mean time to recurrence of 9.5
months. Patients in the open group had a longer mean time to recurrence at 14.4
months, with a 47% (16 patients) recurrence rate [18].(a) Right lower quadrant hand-port placement for hand-assisted right
radical nephrectomy, and (b) Lower midline hand-port placement for hand-assisted
right radical nephrectomy.
(a)(b)Seifman et al. [26] completed a prospective study comparing 16 patients
(mean follow-up, 19 months) who underwent hand-assisted laparoscopic
nephroureterectomy to 11 patients (mean follow-up 16 months) who underwent the
open technique. Despite the fact that the operative time was longer in the
hand-assisted group (320 versus 199 minutes), there was a decrease in the
length of hospital stay (3.9 versus 5.2 days), time to oral intake (33 versus
38 hours), analgesic requirements (20 versus 31 tablets), and return to normal
activity (18 versus 38 days). Tumor
recurrence appeared in 3 of 16 laparoscopic cases and in 7 of 11 open cases.
However, the open series had a higher number of patients with grade 3 (6 of 11)
and T3 disease (5 of 11) compared with the laparoscopic group (5 of 16 with
grade 3, 3 of 16 with T3 disease).Landman et al. [20] compared 16 patients
who underwent hand-assisted laparoscopic nephroureterectomy to 11
patients who underwent a
standard one. In the standard group, the mean follow-up was 27.4 months,
whereas in the hand-assisted group it was 9.6 months. Compared with the
standard technique, patients who underwent the hand-assisted technique had a
decreased operative time (4.4 versus 5.3 hours), similar blood loss (201 versus
190 mL), longer time to oral intake (20 versus 13 hours), similar analgesic use
(33 versus 29.3 mg of morphine), longer hospital stay (4.5 versus 3.3 days),
and longer time to complete recovery (8 versus 5.2 weeks).Complications occurred in 5 patients in
both groups, with 1 open conversion in the hand-assisted group due to failure
to progress. Myocardial infarction and respiratory failure was the cause of death postoperatively for a
patient in the hand-assisted group. Pathologic stage and grade were similar in the 2 groups, with the
majority of patients having low-grade and low-stage tumors. Metastatic disease
developed in 3 out of 15 hand-assisted cases and in 2 patients of the standard
group [20].The results of the trails that compare hand-assisted laparoscopic nephroureterectomy
with other techniques are summarized in Table2. Thereafter, these studies
sustain the utility of both hand-assisted and pure laparoscopic techniques for
nephroureterectomy. The hand-assisted technique has the advantage of the
tactile sensation and blunt-manual dissection. The probability of cancer control
is similar to open techniques. However, due to the fact that most of the
studies were current, long-term action—a five-year period—is required for
definitive results.Table 2
Studies that compare hand-assisted laparoscopic nephroureterectomy with other techniques.
StudyNo. of patientsTumor gradeFollow-upOutcomesKawauchi et al. [18]34 in HALN 34 in OS24 patients in HALN arm and 25 in OS arm grade II13.1 months in HALN,48.8 in OSTTR for HALN 9.5 months with RR 12% TTR for OS 14.4 months with RR 47%Seifman et al. [26]16 in HALN 11 in OS12 patients in HALN arm and 9 in OS grade II tumors19 months in HALN,16 in OSTR for HALN in 3 patients and for OS in 7 patientsLandman et al. [20]16 in HALN 11 in LN13 patients in HALN arm and 8 in LN arm grade III tumors9.6 months in HALN,27.4 in LNHALN decreases operative time without significantly altering short-term parameters of convalescenceHALN: hand-assisted laparoscopic nephroureterectomy, LN:
laparoscopic nephroureterectomy, OS: open surgery, TTR: time to recurrence, RR:
recurrence rate, TR: tumor recurrence.


### 2.3. Robotic-Assisted Laparoscopic Management of Upper Urothelial Tract TCC

The daVinci robotic surgical system has
revolutionized minimally invasive urologic laparoscopy as applied to
prostatectomy. By providing a three-dimensional operating environment and
instrumentation with two additional degrees of freedom, the daVinci surgical system
appears to have dramatically reduced the learning curve for complex-laparoscopic procedures. Even laparoscopically inexperienced open surgeons can
become remarkably talented in a technically challenging procedure such as
robotic radical prostatectomy in as few as 12 patients [27].Since there are not any studies regarding
the robotic-assisted laparoscopic management of upper urothelial tract
carcinoma, we analyze the papers of robot-assisted laparoscopic partial
nephrectomy and we believe that the technique will be soon applicable for small
lesions of renal pelvis and upper ureter.The first series of robot-assisted
laparoscopic partial nephrectomy (RLPN) for small renal masses was reported by
Gettman et al. [28]. Since then, there have been five other reports, three of
which detail the New York University experience
[29–33]. The results of the last trail
conducted by Deane et al. [33] as regarding the mean tumor size, the mean total procedure time, the
mean estimated blood loss, and the mean warm
ischemia time are similar to those analyzed in the previously reported series,
and by comparing them with laparoscopic partial nephrectomy (LPN), there were
no differences. Moreover, in this cohort there were no conversions, while in
the New York University series, among 12 patients,
there were two conversions: one to a hand-assisted approach and one to an open
approach [30]. In the series of Kaul et
al. [32], like in that of Deane et al. [33], there were no conversions; however,
a patient had urgent re-exploration and nephrectomy. These studies are summarized
in Table 3.Table 3
Studies for robotic-assisted laparoscopic nephrectomy.
StudyNo. of patientsConversionsFollow-upOutcomesGettman et al. [28]131 to LN13 monthsRALN is feasible and safely performedPhillips et al. [30]122 one to HALN and 1 to OS12 monthsRALN is safe, feasible, and reproducibleCaruso et al. [31]101 to LN12 monthsRALN safe and feasible procedure in patients with small exophytic massesKaul et al. [32]10No conversions15 monthsRALN is a viable alternative to LN for patients with small exophytic massesDeane et al. [33]10No conversions16 monthsNo difference between RALN and LN as regarding PT,IBL and MWITRALN: robotic-assisted laparoscopic nephrectomy,
LN: laparoscopic nephrectomy, OS: open surgery, PT: procedure time,
IBL: intraoperative blood loss, MWIT: mean warm ischemia time.RLPN using the daVinci surgical system can be performed by a fellowship of
trained urologic oncologists with extensive experience in robotic radical
prostatectomy; early results mirror those achieved by experienced laparoscopic
surgeons performing standard LPN. These results can further support the
assumption of introducing a robotic interface which provides surgeons with
extensive experience in open and other robotic procedures (in this instance,
open partial nephrectomy and robot-assisted radical prostatectomy), with the
successful incorporation of advanced robotic procedures, such as partial
nephrectomy, into their clinical practice.


### 2.4. Management of Distal Ureter and Bladder Cuff

While there is a negligible disagreement about
the role of laparoscopic nephroureterectomy, the management of the distal
ureter and bladder cuff with laparoscopy varies among the surgeons. Techniques
include (1) open excision, (2) transvesical laparoscopic detachment and
ligation technique, (3) laparoscopic stapling of the distal ureter and bladder,
and (4) the “pluck” technique. Steinberg and Matin have recently reviewed these
techniques [21].


#### 2.4.1. Open Technique

An open technique involves initial
dissection of the renal unit laparoscopically. After its completion, the ureter
is clipped but not ligated to avert potential downstream seeding of tumor
cells. Once the laparoscopic ports are separated, either a midline, Gibson, or
Pfannenstiel incision is performed. The distal ureter is identified and
dissected towards the bladder. The specimen is then isolated en bloc with a
border of bladder cuff. The bladder may be opened and the ureter dissected
intravesically and extravesically, or secured and the full dissection performed
extravesically.Matsui et al. [22] reported their results in
17 patients who underwent laparoscopic nephroureterectomy using an open
technique to remove the distal ureter and bladder cuff. A comparison with another
17-patient group who underwent standard nephroureterectomy was performed. The
mean follow-up was 8.8 months in the laparoscopic group and 23.0 months in the
standard group. Patients who were in high risk and had good performance status
had received adjuvant chemotherapy postoperatively. In the laparoscopic group,
1, 6, and 10 patients had grades 1, 2, and 3 diseases on final pathologic
examination. The standard group had 0, 6, and 11 patients with grades 1, 2, and
3 diseases on final pathologic examination. T3 disease was found in 5 patients
in both groups with the rest of patients having T2 or lower disease. Three patients in the
laparoscopic group and four in the standard group, respectively, had
received adjuvant chemotherapy. The
recurrence was observed only in a patient in the laparoscopic group, in comparison
to six in the standard group, but that could be attributed to the shorter
follow-up of the laparoscopic group. After adjusting to that difference in
follow-up, there were no significant differences in the disease-free survival
rate between the 2 groups [22].Klingler et al. [16] also reported on 19
patients who underwent laparoscopic nephroureterectomy; mean follow-up 22.1
months, with an open approach to remove the distal ureter and bladder cuff. The
comparison was made to 15 patients who underwent standard nephroureterectomy,
mean follow-up 23.1 months. According to the T stage, there were 12 patients
with T1 versus 10, 2 patients with T2 versus 2, and 5 with T3 versus 3 in the laparoscopic and
standard groups, respectively. Tumor recurrence was observed in a patient in
both groups who had grade 3 and T3 disease. This study also concluded that the
risk for tumor recurrence and cancer control rates was similar between the
standard technique and the laparoscopic group with an open technique of
handling the distal ureter and bladder cuff.


#### 2.4.2. Transvesical Laparoscopic Technique

Gill et al. [23] have used a transvesical
laparoscopic technique to remove the distal ureter and bladder cuff. That was
performed by using 2 needlescopic ports placed suprapubically into the bladder
under cystoscopic guidance. The patient was repositioned into the dorsal
lithotomy position before placing the bladder ports. A ureteral catheter was then placed in the ipsilateral orifice through an
endoloop that was passed through the laparoscopic bladder ports. A grasper was
used to tent the ureter anteriorly and a Collins knife to dissect the bladder
cuff and ureter. The intramural ureter and bladder cuff were completely
detached en bloc from the bladder. The dissection continued with the Collins
knife into the pelvic extraperitoneal fatty tissues.Gill et al. [12] compared 42 patients who
underwent that technique to 35 patients who underwent the standard open
nephroureterectomy. That study-case was discussed earlier in this study and as a
conclusion the patients had comparable cancer-specific survival and tumor
recurrence. The follow-up, however, was shorter for patients who underwent the
transvesical laparoscopic technique.Stifelman et al. [34] have also reported using
a combined transvesical laparoscopic and endourologic technique on 22 patients
with an average follow-up of 13 months. The pathologic examination has revealed
that 3, 10, and 9 patients had grades 1, 2, and 3 tumors. Five lesions were Ta,
8 were T1, 2 were T2, and 7 were T3 disease. In all cases, the margins were
negative. Disease recurrence was observed in six patients: four with low grade,
low-stage bladder tumors, not involving the resection site, and two with grade
III T3 tumors who presented later with metastatic lesions. All patients were alive at 18 months. This technique simulates established open principles for upper tract
urothelial tumors. Potential criticisms of this technique are the risk of fluid
extravasation and subsequent potential tumor seeding. This is minimized, however, by continuous suction from the
transvesical ports. Furthermore, a meta-analysis of the literature reveals no
reports of tumor seeding in over 50 patients to date [12, 21, 23, 34, 35]. In
cases in which tumor is presented in the distal and intramural ureter, active
bladder disease exists, and in patients who have received prior pelvic
radiation therapy this technique is contraindicated.


#### 2.4.3. Laparoscopic Stapling Technique

Laparoscopic stapling of the distal ureter
and bladder cuff has been combined with cystoscopic unroofing [13, 21]. With
this procedure, ureteral unroofing is performed initially via cystoscopy and
placement of a balloon catheter in the intramural ureter. The distal ureter and
bladder cuff are then stapled laparoscopically during the distal dissection,
using an Endo-GIA (US Surgical, Norwalk, Conn, USA) stapler.Shalhav et al. [13] reported their
experience using the laparoscopic stapling technique in 25 patients who
underwent laparoscopic nephroureterectomy and compared them with 17 patients
who underwent open radical nephroureterectomy. A patient in the laparoscopic
group underwent the “pluck” technique, which will be discussed later in this
review. Mean follow-up was shorter in the laparoscopic group (24 versus 43
months). Thirteen patients in both groups had grade 2 disease or greater.
Distal metastases developed in 4 patients (31%) in the laparoscopic group and 3
patients (23%) in the open group. In the laparoscopic group, local recurrence
rate was lower, 3 versus 7, but this could be attributed to a shorter
follow-up. All patients with recurrence
in the laparoscopic group had tumors that recurred in the bladder and were
treated with transurethral resection. The authors argue in this series that the
stapling technique minimizes the risk of tumor spillage, since the bladder cuff
just caudal to the ureter is secured and occluded with six rows of titanium
staples before it is incised.Yoshino et al. [37] also reported their
experience with 23 patients using flexible endoscopic gastrointestinal
automatic stapler (Ethicon Endosurgery, Cincinnati, Ohio, USA)
in their laparoscopic series. At a mean follow-up period of 15 months, 4
patients had bladder recurrence which was successfully treated by transurethral
resection. Three of those patients had no evidence of disease at greater than a
20-month-follow-up, whereas 1 died of other medical comorbidities.While the previous studies support the use
of the stapling technique for distal ureteral and bladder cuff management,
Matin and Gill [35] evaluated outcome and patterns of recurrence based on the
form of bladder cuff control. They concluded that positive margins were higher
with a laparoscopic stapling approach than either the open or the transvesical
technique. Additionally, the stabling technique was associated with poorer
recurrence-free survival.The theoretical risk of stone formation, secondary to the migration of
staples into the bladder mucosa, could be an additional animadversion of this
technique. Chandhoke et al. [38] reported that there was neither stone
formation nor visible staples in the bladder after using the stapling
technique. A recent case report revealed the presence of a nearly complete
intravesical titanium staple line on surveillance cystoscopy at a follow-up of
6 months [39]. However, there was no identifiable
encrustation in that patient, and a successful transurethral resection of the
staple line was performed without sequela.


#### 2.4.4. The “Pluck” Technique

The “pluck” technique involves an aggressive transurethral resection of
the ipsilateral ureteral orifice with a simultaneous “plucking” of the distal
ureteral during the laparoscopic procedure. Before the resection of the renal unit and ureter, this
resection is performed initially via a resectoscope. McNeil et al. [36] treated
25 patients using that technique and compared them with 42 patients who
underwent open nephroureterectomy. In the laparoscopic group, the follow-up was
shorter mean 32.9 versus 42.3 months. According to tumor grade, in the
laparoscopic group, there were 4, 6, and 9 patients with grades 1 and 2, while
in the open group there were 2, 8, and 6 patients with grade 3. Pathologic
examination also revealed T1, T2, and T3 diseases in 0, 1, and 9 patients in the
laparoscopic group and 0, 3, and 6 patients in the open group. Four deaths in
the laparoscopic group and nine in the open group were observed. The authors concluded that there was no increase in local recurrence within the laparoscopic group during the follow-up, but the exact incidence of recurrence was not reported. The studies that compare the techniques of the management
of distal ureter and bladder cuff with
other methods of treatment are summarized in
Table 4.Table 4
Studies that compare techniques for the management of distal
ureter end bladder cuff with other methods of treatment.
StudyNo. of patientsTumor gradeFollow-upOutcomesOpen techniqueMatsui et al.
[22]17 in OT 17 in
SN14 patients OT arm and 13 in SN arm grade III8.8 months in OT and 23 months in SNNo difference in
DFSKlingler et al. [16]19 in OT 15 in SN15 patients in OT
and 13 in SN arm grade II21.1 months in OT and 23.1
months in SNCCR and RTR similar in both armsTransvesical laparoscopic
techniqueGill et al. [12]42
in LT 35 in SN34 patients in LT arm and 28 in OS arm III
tumors11.1 in LT and 34.4 months in SNCSS and
TR comparable in both armsLaparoscopic stapling techniqueShalhav et al. [13]25 in LT 17 in SN21 patients in LT arm and 14 in OS arm grade II24
months LT 43 months SNRTR lower in LTThe
“pluck” techniqueMcNeill et al. [36]25 in PT 42 in SN18 patients in PT arm grade II and 36 patients in SN arm grade
III32.9 months PT 42.3 months SNNo difference
in TRSN: standard nephroureterectomy,
OT: open technique, CCR: cancer control rate, RTR: risk of tumor
recurrence, CSS: cancer specific survival, TR: tumor recurrence,
ORN: open radical nephroureterectomy, PT: “pluck” technique.The major criticism of that technique is tumor
seeding and the potential to leave behind a segment of an incompletely resected
ureter [21, 40–42]. Arango et al.
[40] described a case of a fatal recurrence at the resection site after
endoscopic resection of the intramural ureter. The patient had stage 1 grade 2
transitional cell carcinoma with a normal lower ureter and bladder.
Nevertheless, seven months later, the patient presented with pelvic pain and
urgency. Computed tomography revealed a large vesical mass at the site of the
resected lower ureter. The biopsy showed a grade 3 tumor stage IV and the
patient underwent salvage cystectomy with adjuvant chemotherapy. Three months
after cystectomy the patient died. The exact incidence of tumor seeding is
unknown and difficult to assess. On the other hand, the theoretical potential
combined with the above reports has led some authors to abandon this technique
[40–42].To summarize, laparoscopic nephroureterectomy with open distal
ureterectomy is a safe and acceptable alternative to open nephroureterectomy.
Cancer control rates seem to be similar with superior convalescence. In terms
of managing the distal ureter and bladder cuff, the open technique is the most
efficacious so as to achieve negative margins and decreased risk of cancer
seeding. However, because of the relatively small series in the literature (due
to the low incidence and prevalence of the disease) and because most literature
is fairly recent (due to recent advances), long-term follow-up and larger
series are necessary to assess cancer-specific survival and recurrence rates.


## 2.1. Laparoscopic Treatment

Recently, Gill et al. published on their experience of 42 patients who
underwent laparoscopic retroperitoneal nephroureterectomy with a mean follow-up
of 11.1 months [12]. The distal ureter
was treated with a combination of laparoscopic and endoscopic transvesical approaches [23]. A
comparable research was performed between those patients and another 35, who
underwent open nephroureterectomy at their department. In the laparoscopic
group, the blood lost was significantly less (242 versus 696 mL). Postsurgically,
patients in the laparoscopic group had a significantly more rapid
recommencement of ambulation (1.4 versus 2.5 days), oral intake (1.6 versus 3.2
days), shorter hospital stay (2.3 versus 6.6 days), decreased analgesic
necessities (26 mg morphine sulfate equivalent versus 228 mg), and a more rapid
period of recovery (8 versus 14.1 weeks). Complications occurred in 5 (12%) and 10 (29%) patients in the
laparoscopic and open groups, respectively. These complications integrated 1 renal vein injury, 1 patient with fluid extravasations from
mobilization of the bladder cuff, and 3 patients with atelectasis in the
laparoscopic group. The open group had 4 patients with atelectasis, 5
patients with postoperative ileus, and 1 patient with a pneumothorax. Two cases required
an open conversion because of a renal
injury and an elective conversion secondary to local tumor infiltration with obliteration of tissue planes near the hilum.The mean pathologic grade was 2.3 for both of the groups, with the laparoscopic
group having 9, 10, and 23 patients with grades 1, 2, and 3 tumors and the open
group having 6, 10, and 16 patients with grades 1, 2, and 3 tumors,
respectively. Surgical margins were positive in 3 (7%) patients in the
laparoscopic group and 5 (15%) patients in the open group. All 3 patients in
the laparoscopic group received systemic chemotherapy postoperatively, and
pulmonary metastases developed in 1 patient during follow-up. For comparable
stage and grade of primary tumor, the negative surgical margin rate was similar
between the 2 groups. The
two groups of laparoscopic and open surgeries have no difference as
regarding the bladder recurrence (23 versus 37%), retroperitoneal or port
site/incisional recurrence (0 versus 0%), or distant metastases (8,6 versus
13%). There was no difference in either cancer-specific survival (97% versus
87%) or crude survival (97% versus 94%) after adjusting for the shorter
follow-up period (11 versus 34 months) between the laparoscopic and open
groups, respectively, during follow-up. Mortality occurred in 2 patients (6%) of
the laparoscopic group and in 6 of the open group (30%). The authors cannot
estimate whether these mortality rates are significantly different or equivalent
[12]. The results of the trails that compare laparoscopic treatment with open
surgery are summarized in Table 1. The techniques of laparoscopic retroperitoneal nephroureterectomy and partial nephrectomy are
shown in Figures 1(a), 1(b), and 1(c) and in Figure 2, respectively. Patients are
placed in the full flank position. Usually, the operating table is
flexed and the kidney rest is elevated, thereby increasing the space
between the iliac crest and the lower ribs. Retroperitoneal access is
obtained through a small 10- to 15-mm incision just below and medial to the tip
of the 12th rib (Figure 1(a)). The muscle and fascia are separated using
a blunt instrument that allows one finger to develop a working space posterior to the kidney above the psoas muscle (Figure
1(b)). Often the lower pole of the kidney is immediately palpated. The colon
is separated away from the anterolateral abdominal wall with the index
finger. Additional trocars are placed below the 12th rib just above the psoas
muscle posteriorly, and then more anteriorly through the lateral abdominal wall
under direct vision using the laparoscope (Figure 1(c)). Laparoscopic
partial nephrectomy is ideal for a patient with an exophytic, small, and
peripherally located renal tumor (Figure 2).Table 1
Studies that compare laparoscopic nephroureterectomy with open surgery.
StudyNo. of patientsTumor gradeFollow-upOutcomesGill et al. [12]42 in LT, 35 in OS34 patients in LT arm and 28 in OS arm III tumors11.1 months in LT,34.4 in OSLT significantly decreasing morbidity with comparable oncological and survival data to OSShalhav et al. [13]25 in LT 17 in OS21 patients in LT arm and 14 in OS arm grade II2 years in both armsLT has longer operating time but the same efficacy and is better toleratedLT: laparoscopic treatment, OS: open surgery.(a) Access for a right retroperitoneal laparoscopic radical
nephrectomy (LRN). A 10- to 15-mm incision is made below and medial to the
tip of the 12th rib. (b) The flank muscles are pierced with a blunt-tipped
instrument followed by finger dissection and development of the retroperitoneum
space to permit trocar placement. (c) Trocar placement for a right
retroperitoneal LRN.
(a)(b)(c)Figure 2
Retroperitoneal laparoscopic left partial nephrectomy.The literature research discovered similar effects
in transperitoneal laparoscopic nephroureterectomy [13, 24]. The familiarity
with anatomic landmarks and a larger working space are some advantages of
transperitoneal approach compared to retroperitoneal one. The retroperitoneal approach,
however, has distinct advantages, for example, permittance of early control of the renal
artery and vein, no manipulation of the bowel leading to less incidence of
ileus and possibly a shorter hospital stay, and confinement of possible
urinomas or seromas to the retroperitoneal space [12, 25].


## 2.2. Hand-Assisted Laparoscopic Nephroureterectomy

Apart from standard
laparoscopic nephroureterectomy among urologists, hand-assisted laparoscopic
nephroureterectomy is also an acceptable technique [18, 20]. Patient
preparation and positioning is identical to that described for transperitoneal
LRN (laparoscopic nephroureterectomy). The hand-assisted
LRN technique usually begins with a 6 cm to 8 cm incision for hand-port
placement through a lower quadrant Gibson-type incision (Figure 3(a)) or
through the lower midline abdomen (Figure 3(b)).
The Kawauchi et al.'s [18] experience was
described in 34 consecutive patients who
underwent hand-assisted laparoscopic nephroureterectomy using a Lap Disc (Hakko Shoji, Tokyo, Japan). Those 34 patients were compared with the
previous group of 34 patients who underwent open nephroureterectomy. Mean
follow-up was 13.1 months in the hand-assisted group and 48.8 months in the
open group [18]. In the hand-assisted
group, there was observed a similar operative time (233 versus 236 minutes),
decreased analgesia frequency (2.1 versus 4.1 days), decreased blood loss (236
versus 427 mL), quicker return to ambulation (1.5 versus 2.5 days), and shorter
hospital stay (13 versus 21.1 days). In the Japanese series compared with the American ones, the
lengthy stay is a social issue and not reflective of actual patient recovery. There were 4 (12%) complications in both groups, with 1 open conversion
in the hand-assisted group. The 4 complications in the hand-assisted group
include 1 conversion due to bleeding from the left adrenal gland, 2 wound
infections, and 1 pulmonary infarction in a patient who recovered with
conservative treatment [18]. As
regarding the histological tumor grade, the pathologic studies have revealed
that in the hand-assisted group there were 5, 20, and 9 patients with grades 1,
2, and 3 tumors, whereas in the open group there were 4, 17, and 13 patients
with grades 1, 2, and 3 tumors, respectively. Recurrence rate was 12% (4
patients) in the hand-assisted group, with a mean time to recurrence of 9.5
months. Patients in the open group had a longer mean time to recurrence at 14.4
months, with a 47% (16 patients) recurrence rate [18].(a) Right lower quadrant hand-port placement for hand-assisted right
radical nephrectomy, and (b) Lower midline hand-port placement for hand-assisted
right radical nephrectomy.
(a)(b)Seifman et al. [26] completed a prospective study comparing 16 patients
(mean follow-up, 19 months) who underwent hand-assisted laparoscopic
nephroureterectomy to 11 patients (mean follow-up 16 months) who underwent the
open technique. Despite the fact that the operative time was longer in the
hand-assisted group (320 versus 199 minutes), there was a decrease in the
length of hospital stay (3.9 versus 5.2 days), time to oral intake (33 versus
38 hours), analgesic requirements (20 versus 31 tablets), and return to normal
activity (18 versus 38 days). Tumor
recurrence appeared in 3 of 16 laparoscopic cases and in 7 of 11 open cases.
However, the open series had a higher number of patients with grade 3 (6 of 11)
and T3 disease (5 of 11) compared with the laparoscopic group (5 of 16 with
grade 3, 3 of 16 with T3 disease).Landman et al. [20] compared 16 patients
who underwent hand-assisted laparoscopic nephroureterectomy to 11
patients who underwent a
standard one. In the standard group, the mean follow-up was 27.4 months,
whereas in the hand-assisted group it was 9.6 months. Compared with the
standard technique, patients who underwent the hand-assisted technique had a
decreased operative time (4.4 versus 5.3 hours), similar blood loss (201 versus
190 mL), longer time to oral intake (20 versus 13 hours), similar analgesic use
(33 versus 29.3 mg of morphine), longer hospital stay (4.5 versus 3.3 days),
and longer time to complete recovery (8 versus 5.2 weeks).Complications occurred in 5 patients in
both groups, with 1 open conversion in the hand-assisted group due to failure
to progress. Myocardial infarction and respiratory failure was the cause of death postoperatively for a
patient in the hand-assisted group. Pathologic stage and grade were similar in the 2 groups, with the
majority of patients having low-grade and low-stage tumors. Metastatic disease
developed in 3 out of 15 hand-assisted cases and in 2 patients of the standard
group [20].The results of the trails that compare hand-assisted laparoscopic nephroureterectomy
with other techniques are summarized in Table2. Thereafter, these studies
sustain the utility of both hand-assisted and pure laparoscopic techniques for
nephroureterectomy. The hand-assisted technique has the advantage of the
tactile sensation and blunt-manual dissection. The probability of cancer control
is similar to open techniques. However, due to the fact that most of the
studies were current, long-term action—a five-year period—is required for
definitive results.Table 2
Studies that compare hand-assisted laparoscopic nephroureterectomy with other techniques.
StudyNo. of patientsTumor gradeFollow-upOutcomesKawauchi et al. [18]34 in HALN 34 in OS24 patients in HALN arm and 25 in OS arm grade II13.1 months in HALN,48.8 in OSTTR for HALN 9.5 months with RR 12% TTR for OS 14.4 months with RR 47%Seifman et al. [26]16 in HALN 11 in OS12 patients in HALN arm and 9 in OS grade II tumors19 months in HALN,16 in OSTR for HALN in 3 patients and for OS in 7 patientsLandman et al. [20]16 in HALN 11 in LN13 patients in HALN arm and 8 in LN arm grade III tumors9.6 months in HALN,27.4 in LNHALN decreases operative time without significantly altering short-term parameters of convalescenceHALN: hand-assisted laparoscopic nephroureterectomy, LN:
laparoscopic nephroureterectomy, OS: open surgery, TTR: time to recurrence, RR:
recurrence rate, TR: tumor recurrence.


## 2.3. Robotic-Assisted Laparoscopic Management of Upper Urothelial Tract TCC

The daVinci robotic surgical system has
revolutionized minimally invasive urologic laparoscopy as applied to
prostatectomy. By providing a three-dimensional operating environment and
instrumentation with two additional degrees of freedom, the daVinci surgical system
appears to have dramatically reduced the learning curve for complex-laparoscopic procedures. Even laparoscopically inexperienced open surgeons can
become remarkably talented in a technically challenging procedure such as
robotic radical prostatectomy in as few as 12 patients [27].Since there are not any studies regarding
the robotic-assisted laparoscopic management of upper urothelial tract
carcinoma, we analyze the papers of robot-assisted laparoscopic partial
nephrectomy and we believe that the technique will be soon applicable for small
lesions of renal pelvis and upper ureter.The first series of robot-assisted
laparoscopic partial nephrectomy (RLPN) for small renal masses was reported by
Gettman et al. [28]. Since then, there have been five other reports, three of
which detail the New York University experience
[29–33]. The results of the last trail
conducted by Deane et al. [33] as regarding the mean tumor size, the mean total procedure time, the
mean estimated blood loss, and the mean warm
ischemia time are similar to those analyzed in the previously reported series,
and by comparing them with laparoscopic partial nephrectomy (LPN), there were
no differences. Moreover, in this cohort there were no conversions, while in
the New York University series, among 12 patients,
there were two conversions: one to a hand-assisted approach and one to an open
approach [30]. In the series of Kaul et
al. [32], like in that of Deane et al. [33], there were no conversions; however,
a patient had urgent re-exploration and nephrectomy. These studies are summarized
in Table 3.Table 3
Studies for robotic-assisted laparoscopic nephrectomy.
StudyNo. of patientsConversionsFollow-upOutcomesGettman et al. [28]131 to LN13 monthsRALN is feasible and safely performedPhillips et al. [30]122 one to HALN and 1 to OS12 monthsRALN is safe, feasible, and reproducibleCaruso et al. [31]101 to LN12 monthsRALN safe and feasible procedure in patients with small exophytic massesKaul et al. [32]10No conversions15 monthsRALN is a viable alternative to LN for patients with small exophytic massesDeane et al. [33]10No conversions16 monthsNo difference between RALN and LN as regarding PT,IBL and MWITRALN: robotic-assisted laparoscopic nephrectomy,
LN: laparoscopic nephrectomy, OS: open surgery, PT: procedure time,
IBL: intraoperative blood loss, MWIT: mean warm ischemia time.RLPN using the daVinci surgical system can be performed by a fellowship of
trained urologic oncologists with extensive experience in robotic radical
prostatectomy; early results mirror those achieved by experienced laparoscopic
surgeons performing standard LPN. These results can further support the
assumption of introducing a robotic interface which provides surgeons with
extensive experience in open and other robotic procedures (in this instance,
open partial nephrectomy and robot-assisted radical prostatectomy), with the
successful incorporation of advanced robotic procedures, such as partial
nephrectomy, into their clinical practice.


## 2.4. Management of Distal Ureter and Bladder Cuff

While there is a negligible disagreement about
the role of laparoscopic nephroureterectomy, the management of the distal
ureter and bladder cuff with laparoscopy varies among the surgeons. Techniques
include (1) open excision, (2) transvesical laparoscopic detachment and
ligation technique, (3) laparoscopic stapling of the distal ureter and bladder,
and (4) the “pluck” technique. Steinberg and Matin have recently reviewed these
techniques [21].


### 2.4.1. Open Technique

An open technique involves initial
dissection of the renal unit laparoscopically. After its completion, the ureter
is clipped but not ligated to avert potential downstream seeding of tumor
cells. Once the laparoscopic ports are separated, either a midline, Gibson, or
Pfannenstiel incision is performed. The distal ureter is identified and
dissected towards the bladder. The specimen is then isolated en bloc with a
border of bladder cuff. The bladder may be opened and the ureter dissected
intravesically and extravesically, or secured and the full dissection performed
extravesically.Matsui et al. [22] reported their results in
17 patients who underwent laparoscopic nephroureterectomy using an open
technique to remove the distal ureter and bladder cuff. A comparison with another
17-patient group who underwent standard nephroureterectomy was performed. The
mean follow-up was 8.8 months in the laparoscopic group and 23.0 months in the
standard group. Patients who were in high risk and had good performance status
had received adjuvant chemotherapy postoperatively. In the laparoscopic group,
1, 6, and 10 patients had grades 1, 2, and 3 diseases on final pathologic
examination. The standard group had 0, 6, and 11 patients with grades 1, 2, and
3 diseases on final pathologic examination. T3 disease was found in 5 patients
in both groups with the rest of patients having T2 or lower disease. Three patients in the
laparoscopic group and four in the standard group, respectively, had
received adjuvant chemotherapy. The
recurrence was observed only in a patient in the laparoscopic group, in comparison
to six in the standard group, but that could be attributed to the shorter
follow-up of the laparoscopic group. After adjusting to that difference in
follow-up, there were no significant differences in the disease-free survival
rate between the 2 groups [22].Klingler et al. [16] also reported on 19
patients who underwent laparoscopic nephroureterectomy; mean follow-up 22.1
months, with an open approach to remove the distal ureter and bladder cuff. The
comparison was made to 15 patients who underwent standard nephroureterectomy,
mean follow-up 23.1 months. According to the T stage, there were 12 patients
with T1 versus 10, 2 patients with T2 versus 2, and 5 with T3 versus 3 in the laparoscopic and
standard groups, respectively. Tumor recurrence was observed in a patient in
both groups who had grade 3 and T3 disease. This study also concluded that the
risk for tumor recurrence and cancer control rates was similar between the
standard technique and the laparoscopic group with an open technique of
handling the distal ureter and bladder cuff.


### 2.4.2. Transvesical Laparoscopic Technique

Gill et al. [23] have used a transvesical
laparoscopic technique to remove the distal ureter and bladder cuff. That was
performed by using 2 needlescopic ports placed suprapubically into the bladder
under cystoscopic guidance. The patient was repositioned into the dorsal
lithotomy position before placing the bladder ports. A ureteral catheter was then placed in the ipsilateral orifice through an
endoloop that was passed through the laparoscopic bladder ports. A grasper was
used to tent the ureter anteriorly and a Collins knife to dissect the bladder
cuff and ureter. The intramural ureter and bladder cuff were completely
detached en bloc from the bladder. The dissection continued with the Collins
knife into the pelvic extraperitoneal fatty tissues.Gill et al. [12] compared 42 patients who
underwent that technique to 35 patients who underwent the standard open
nephroureterectomy. That study-case was discussed earlier in this study and as a
conclusion the patients had comparable cancer-specific survival and tumor
recurrence. The follow-up, however, was shorter for patients who underwent the
transvesical laparoscopic technique.Stifelman et al. [34] have also reported using
a combined transvesical laparoscopic and endourologic technique on 22 patients
with an average follow-up of 13 months. The pathologic examination has revealed
that 3, 10, and 9 patients had grades 1, 2, and 3 tumors. Five lesions were Ta,
8 were T1, 2 were T2, and 7 were T3 disease. In all cases, the margins were
negative. Disease recurrence was observed in six patients: four with low grade,
low-stage bladder tumors, not involving the resection site, and two with grade
III T3 tumors who presented later with metastatic lesions. All patients were alive at 18 months. This technique simulates established open principles for upper tract
urothelial tumors. Potential criticisms of this technique are the risk of fluid
extravasation and subsequent potential tumor seeding. This is minimized, however, by continuous suction from the
transvesical ports. Furthermore, a meta-analysis of the literature reveals no
reports of tumor seeding in over 50 patients to date [12, 21, 23, 34, 35]. In
cases in which tumor is presented in the distal and intramural ureter, active
bladder disease exists, and in patients who have received prior pelvic
radiation therapy this technique is contraindicated.


### 2.4.3. Laparoscopic Stapling Technique

Laparoscopic stapling of the distal ureter
and bladder cuff has been combined with cystoscopic unroofing [13, 21]. With
this procedure, ureteral unroofing is performed initially via cystoscopy and
placement of a balloon catheter in the intramural ureter. The distal ureter and
bladder cuff are then stapled laparoscopically during the distal dissection,
using an Endo-GIA (US Surgical, Norwalk, Conn, USA) stapler.Shalhav et al. [13] reported their
experience using the laparoscopic stapling technique in 25 patients who
underwent laparoscopic nephroureterectomy and compared them with 17 patients
who underwent open radical nephroureterectomy. A patient in the laparoscopic
group underwent the “pluck” technique, which will be discussed later in this
review. Mean follow-up was shorter in the laparoscopic group (24 versus 43
months). Thirteen patients in both groups had grade 2 disease or greater.
Distal metastases developed in 4 patients (31%) in the laparoscopic group and 3
patients (23%) in the open group. In the laparoscopic group, local recurrence
rate was lower, 3 versus 7, but this could be attributed to a shorter
follow-up. All patients with recurrence
in the laparoscopic group had tumors that recurred in the bladder and were
treated with transurethral resection. The authors argue in this series that the
stapling technique minimizes the risk of tumor spillage, since the bladder cuff
just caudal to the ureter is secured and occluded with six rows of titanium
staples before it is incised.Yoshino et al. [37] also reported their
experience with 23 patients using flexible endoscopic gastrointestinal
automatic stapler (Ethicon Endosurgery, Cincinnati, Ohio, USA)
in their laparoscopic series. At a mean follow-up period of 15 months, 4
patients had bladder recurrence which was successfully treated by transurethral
resection. Three of those patients had no evidence of disease at greater than a
20-month-follow-up, whereas 1 died of other medical comorbidities.While the previous studies support the use
of the stapling technique for distal ureteral and bladder cuff management,
Matin and Gill [35] evaluated outcome and patterns of recurrence based on the
form of bladder cuff control. They concluded that positive margins were higher
with a laparoscopic stapling approach than either the open or the transvesical
technique. Additionally, the stabling technique was associated with poorer
recurrence-free survival.The theoretical risk of stone formation, secondary to the migration of
staples into the bladder mucosa, could be an additional animadversion of this
technique. Chandhoke et al. [38] reported that there was neither stone
formation nor visible staples in the bladder after using the stapling
technique. A recent case report revealed the presence of a nearly complete
intravesical titanium staple line on surveillance cystoscopy at a follow-up of
6 months [39]. However, there was no identifiable
encrustation in that patient, and a successful transurethral resection of the
staple line was performed without sequela.


### 2.4.4. The “Pluck” Technique

The “pluck” technique involves an aggressive transurethral resection of
the ipsilateral ureteral orifice with a simultaneous “plucking” of the distal
ureteral during the laparoscopic procedure. Before the resection of the renal unit and ureter, this
resection is performed initially via a resectoscope. McNeil et al. [36] treated
25 patients using that technique and compared them with 42 patients who
underwent open nephroureterectomy. In the laparoscopic group, the follow-up was
shorter mean 32.9 versus 42.3 months. According to tumor grade, in the
laparoscopic group, there were 4, 6, and 9 patients with grades 1 and 2, while
in the open group there were 2, 8, and 6 patients with grade 3. Pathologic
examination also revealed T1, T2, and T3 diseases in 0, 1, and 9 patients in the
laparoscopic group and 0, 3, and 6 patients in the open group. Four deaths in
the laparoscopic group and nine in the open group were observed. The authors concluded that there was no increase in local recurrence within the laparoscopic group during the follow-up, but the exact incidence of recurrence was not reported. The studies that compare the techniques of the management
of distal ureter and bladder cuff with
other methods of treatment are summarized in
Table 4.Table 4
Studies that compare techniques for the management of distal
ureter end bladder cuff with other methods of treatment.
StudyNo. of patientsTumor gradeFollow-upOutcomesOpen techniqueMatsui et al.
[22]17 in OT 17 in
SN14 patients OT arm and 13 in SN arm grade III8.8 months in OT and 23 months in SNNo difference in
DFSKlingler et al. [16]19 in OT 15 in SN15 patients in OT
and 13 in SN arm grade II21.1 months in OT and 23.1
months in SNCCR and RTR similar in both armsTransvesical laparoscopic
techniqueGill et al. [12]42
in LT 35 in SN34 patients in LT arm and 28 in OS arm III
tumors11.1 in LT and 34.4 months in SNCSS and
TR comparable in both armsLaparoscopic stapling techniqueShalhav et al. [13]25 in LT 17 in SN21 patients in LT arm and 14 in OS arm grade II24
months LT 43 months SNRTR lower in LTThe
“pluck” techniqueMcNeill et al. [36]25 in PT 42 in SN18 patients in PT arm grade II and 36 patients in SN arm grade
III32.9 months PT 42.3 months SNNo difference
in TRSN: standard nephroureterectomy,
OT: open technique, CCR: cancer control rate, RTR: risk of tumor
recurrence, CSS: cancer specific survival, TR: tumor recurrence,
ORN: open radical nephroureterectomy, PT: “pluck” technique.The major criticism of that technique is tumor
seeding and the potential to leave behind a segment of an incompletely resected
ureter [21, 40–42]. Arango et al.
[40] described a case of a fatal recurrence at the resection site after
endoscopic resection of the intramural ureter. The patient had stage 1 grade 2
transitional cell carcinoma with a normal lower ureter and bladder.
Nevertheless, seven months later, the patient presented with pelvic pain and
urgency. Computed tomography revealed a large vesical mass at the site of the
resected lower ureter. The biopsy showed a grade 3 tumor stage IV and the
patient underwent salvage cystectomy with adjuvant chemotherapy. Three months
after cystectomy the patient died. The exact incidence of tumor seeding is
unknown and difficult to assess. On the other hand, the theoretical potential
combined with the above reports has led some authors to abandon this technique
[40–42].To summarize, laparoscopic nephroureterectomy with open distal
ureterectomy is a safe and acceptable alternative to open nephroureterectomy.
Cancer control rates seem to be similar with superior convalescence. In terms
of managing the distal ureter and bladder cuff, the open technique is the most
efficacious so as to achieve negative margins and decreased risk of cancer
seeding. However, because of the relatively small series in the literature (due
to the low incidence and prevalence of the disease) and because most literature
is fairly recent (due to recent advances), long-term follow-up and larger
series are necessary to assess cancer-specific survival and recurrence rates.


## 2.4.1. Open Technique

An open technique involves initial
dissection of the renal unit laparoscopically. After its completion, the ureter
is clipped but not ligated to avert potential downstream seeding of tumor
cells. Once the laparoscopic ports are separated, either a midline, Gibson, or
Pfannenstiel incision is performed. The distal ureter is identified and
dissected towards the bladder. The specimen is then isolated en bloc with a
border of bladder cuff. The bladder may be opened and the ureter dissected
intravesically and extravesically, or secured and the full dissection performed
extravesically.Matsui et al. [22] reported their results in
17 patients who underwent laparoscopic nephroureterectomy using an open
technique to remove the distal ureter and bladder cuff. A comparison with another
17-patient group who underwent standard nephroureterectomy was performed. The
mean follow-up was 8.8 months in the laparoscopic group and 23.0 months in the
standard group. Patients who were in high risk and had good performance status
had received adjuvant chemotherapy postoperatively. In the laparoscopic group,
1, 6, and 10 patients had grades 1, 2, and 3 diseases on final pathologic
examination. The standard group had 0, 6, and 11 patients with grades 1, 2, and
3 diseases on final pathologic examination. T3 disease was found in 5 patients
in both groups with the rest of patients having T2 or lower disease. Three patients in the
laparoscopic group and four in the standard group, respectively, had
received adjuvant chemotherapy. The
recurrence was observed only in a patient in the laparoscopic group, in comparison
to six in the standard group, but that could be attributed to the shorter
follow-up of the laparoscopic group. After adjusting to that difference in
follow-up, there were no significant differences in the disease-free survival
rate between the 2 groups [22].Klingler et al. [16] also reported on 19
patients who underwent laparoscopic nephroureterectomy; mean follow-up 22.1
months, with an open approach to remove the distal ureter and bladder cuff. The
comparison was made to 15 patients who underwent standard nephroureterectomy,
mean follow-up 23.1 months. According to the T stage, there were 12 patients
with T1 versus 10, 2 patients with T2 versus 2, and 5 with T3 versus 3 in the laparoscopic and
standard groups, respectively. Tumor recurrence was observed in a patient in
both groups who had grade 3 and T3 disease. This study also concluded that the
risk for tumor recurrence and cancer control rates was similar between the
standard technique and the laparoscopic group with an open technique of
handling the distal ureter and bladder cuff.


## 2.4.2. Transvesical Laparoscopic Technique

Gill et al. [23] have used a transvesical
laparoscopic technique to remove the distal ureter and bladder cuff. That was
performed by using 2 needlescopic ports placed suprapubically into the bladder
under cystoscopic guidance. The patient was repositioned into the dorsal
lithotomy position before placing the bladder ports. A ureteral catheter was then placed in the ipsilateral orifice through an
endoloop that was passed through the laparoscopic bladder ports. A grasper was
used to tent the ureter anteriorly and a Collins knife to dissect the bladder
cuff and ureter. The intramural ureter and bladder cuff were completely
detached en bloc from the bladder. The dissection continued with the Collins
knife into the pelvic extraperitoneal fatty tissues.Gill et al. [12] compared 42 patients who
underwent that technique to 35 patients who underwent the standard open
nephroureterectomy. That study-case was discussed earlier in this study and as a
conclusion the patients had comparable cancer-specific survival and tumor
recurrence. The follow-up, however, was shorter for patients who underwent the
transvesical laparoscopic technique.Stifelman et al. [34] have also reported using
a combined transvesical laparoscopic and endourologic technique on 22 patients
with an average follow-up of 13 months. The pathologic examination has revealed
that 3, 10, and 9 patients had grades 1, 2, and 3 tumors. Five lesions were Ta,
8 were T1, 2 were T2, and 7 were T3 disease. In all cases, the margins were
negative. Disease recurrence was observed in six patients: four with low grade,
low-stage bladder tumors, not involving the resection site, and two with grade
III T3 tumors who presented later with metastatic lesions. All patients were alive at 18 months. This technique simulates established open principles for upper tract
urothelial tumors. Potential criticisms of this technique are the risk of fluid
extravasation and subsequent potential tumor seeding. This is minimized, however, by continuous suction from the
transvesical ports. Furthermore, a meta-analysis of the literature reveals no
reports of tumor seeding in over 50 patients to date [12, 21, 23, 34, 35]. In
cases in which tumor is presented in the distal and intramural ureter, active
bladder disease exists, and in patients who have received prior pelvic
radiation therapy this technique is contraindicated.


## 2.4.3. Laparoscopic Stapling Technique

Laparoscopic stapling of the distal ureter
and bladder cuff has been combined with cystoscopic unroofing [13, 21]. With
this procedure, ureteral unroofing is performed initially via cystoscopy and
placement of a balloon catheter in the intramural ureter. The distal ureter and
bladder cuff are then stapled laparoscopically during the distal dissection,
using an Endo-GIA (US Surgical, Norwalk, Conn, USA) stapler.Shalhav et al. [13] reported their
experience using the laparoscopic stapling technique in 25 patients who
underwent laparoscopic nephroureterectomy and compared them with 17 patients
who underwent open radical nephroureterectomy. A patient in the laparoscopic
group underwent the “pluck” technique, which will be discussed later in this
review. Mean follow-up was shorter in the laparoscopic group (24 versus 43
months). Thirteen patients in both groups had grade 2 disease or greater.
Distal metastases developed in 4 patients (31%) in the laparoscopic group and 3
patients (23%) in the open group. In the laparoscopic group, local recurrence
rate was lower, 3 versus 7, but this could be attributed to a shorter
follow-up. All patients with recurrence
in the laparoscopic group had tumors that recurred in the bladder and were
treated with transurethral resection. The authors argue in this series that the
stapling technique minimizes the risk of tumor spillage, since the bladder cuff
just caudal to the ureter is secured and occluded with six rows of titanium
staples before it is incised.Yoshino et al. [37] also reported their
experience with 23 patients using flexible endoscopic gastrointestinal
automatic stapler (Ethicon Endosurgery, Cincinnati, Ohio, USA)
in their laparoscopic series. At a mean follow-up period of 15 months, 4
patients had bladder recurrence which was successfully treated by transurethral
resection. Three of those patients had no evidence of disease at greater than a
20-month-follow-up, whereas 1 died of other medical comorbidities.While the previous studies support the use
of the stapling technique for distal ureteral and bladder cuff management,
Matin and Gill [35] evaluated outcome and patterns of recurrence based on the
form of bladder cuff control. They concluded that positive margins were higher
with a laparoscopic stapling approach than either the open or the transvesical
technique. Additionally, the stabling technique was associated with poorer
recurrence-free survival.The theoretical risk of stone formation, secondary to the migration of
staples into the bladder mucosa, could be an additional animadversion of this
technique. Chandhoke et al. [38] reported that there was neither stone
formation nor visible staples in the bladder after using the stapling
technique. A recent case report revealed the presence of a nearly complete
intravesical titanium staple line on surveillance cystoscopy at a follow-up of
6 months [39]. However, there was no identifiable
encrustation in that patient, and a successful transurethral resection of the
staple line was performed without sequela.


## 2.4.4. The “Pluck” Technique

The “pluck” technique involves an aggressive transurethral resection of
the ipsilateral ureteral orifice with a simultaneous “plucking” of the distal
ureteral during the laparoscopic procedure. Before the resection of the renal unit and ureter, this
resection is performed initially via a resectoscope. McNeil et al. [36] treated
25 patients using that technique and compared them with 42 patients who
underwent open nephroureterectomy. In the laparoscopic group, the follow-up was
shorter mean 32.9 versus 42.3 months. According to tumor grade, in the
laparoscopic group, there were 4, 6, and 9 patients with grades 1 and 2, while
in the open group there were 2, 8, and 6 patients with grade 3. Pathologic
examination also revealed T1, T2, and T3 diseases in 0, 1, and 9 patients in the
laparoscopic group and 0, 3, and 6 patients in the open group. Four deaths in
the laparoscopic group and nine in the open group were observed. The authors concluded that there was no increase in local recurrence within the laparoscopic group during the follow-up, but the exact incidence of recurrence was not reported. The studies that compare the techniques of the management
of distal ureter and bladder cuff with
other methods of treatment are summarized in
Table 4.Table 4
Studies that compare techniques for the management of distal
ureter end bladder cuff with other methods of treatment.
StudyNo. of patientsTumor gradeFollow-upOutcomesOpen techniqueMatsui et al.
[22]17 in OT 17 in
SN14 patients OT arm and 13 in SN arm grade III8.8 months in OT and 23 months in SNNo difference in
DFSKlingler et al. [16]19 in OT 15 in SN15 patients in OT
and 13 in SN arm grade II21.1 months in OT and 23.1
months in SNCCR and RTR similar in both armsTransvesical laparoscopic
techniqueGill et al. [12]42
in LT 35 in SN34 patients in LT arm and 28 in OS arm III
tumors11.1 in LT and 34.4 months in SNCSS and
TR comparable in both armsLaparoscopic stapling techniqueShalhav et al. [13]25 in LT 17 in SN21 patients in LT arm and 14 in OS arm grade II24
months LT 43 months SNRTR lower in LTThe
“pluck” techniqueMcNeill et al. [36]25 in PT 42 in SN18 patients in PT arm grade II and 36 patients in SN arm grade
III32.9 months PT 42.3 months SNNo difference
in TRSN: standard nephroureterectomy,
OT: open technique, CCR: cancer control rate, RTR: risk of tumor
recurrence, CSS: cancer specific survival, TR: tumor recurrence,
ORN: open radical nephroureterectomy, PT: “pluck” technique.The major criticism of that technique is tumor
seeding and the potential to leave behind a segment of an incompletely resected
ureter [21, 40–42]. Arango et al.
[40] described a case of a fatal recurrence at the resection site after
endoscopic resection of the intramural ureter. The patient had stage 1 grade 2
transitional cell carcinoma with a normal lower ureter and bladder.
Nevertheless, seven months later, the patient presented with pelvic pain and
urgency. Computed tomography revealed a large vesical mass at the site of the
resected lower ureter. The biopsy showed a grade 3 tumor stage IV and the
patient underwent salvage cystectomy with adjuvant chemotherapy. Three months
after cystectomy the patient died. The exact incidence of tumor seeding is
unknown and difficult to assess. On the other hand, the theoretical potential
combined with the above reports has led some authors to abandon this technique
[40–42].To summarize, laparoscopic nephroureterectomy with open distal
ureterectomy is a safe and acceptable alternative to open nephroureterectomy.
Cancer control rates seem to be similar with superior convalescence. In terms
of managing the distal ureter and bladder cuff, the open technique is the most
efficacious so as to achieve negative margins and decreased risk of cancer
seeding. However, because of the relatively small series in the literature (due
to the low incidence and prevalence of the disease) and because most literature
is fairly recent (due to recent advances), long-term follow-up and larger
series are necessary to assess cancer-specific survival and recurrence rates.


## 3. Endoscopic Management

Generally, recommendations for endoscopic
management of upper-tract TCC include patients with anatomic or functional
solitary kidneys, bilateral upper-tract TCC, base line renal insufficiency, or
significant comorbid diseases that preclude abdominal surgery [43]. Patients
with a normal contralateral kidney who have small, low-grade
lesions can also be reasonable candidates for conservative management [44].
Endoscopic treatment of the upper urinary tract can be performed via either a
retrograde ureteroscopic or a percutaneous antegrade approach.As regarding the retrograde ureteroscopic, an
approach can be used for low-volume ureteral and renal pelvic tumors. Proximal
ureter and renal pelvic lesions require flexible ureteroscopes, while tumors
localized in the intramural and distal ureter are best managed by rigid
ureteroscopy [45]. Low morbidity in association with maintenance of urothelial
integrity is the principal advantage of retrograde endoscopy [43, 45, 46]. This
technique is limited, however, by the size of instruments that can be
accommodated in the ureter, which in turn limits the size of tumor that can be
adequately treated. Some portions of the upper urinary tract, such as the lower
pole calyces, are less accessible by a retrograde approach. Furthermore,
retrograde ureteroscopy differs in patients who have undergone a prior urinary
diversion.An initial biopsy of the lesion is required
for the ureteroscopic method followed by a debulkment to its base using
cold-cup forceps (3 Fr or 5 Fr) or a stone basket (1.9 Fr or 2.4 Fr) [45]. Due
to the fact that the wall of the proximal ureter and renal pelvis is thin, no
attempt should be made to resect these regions deeply. The base of the lesion
is subsequently addressed by monopolar electrocautery or laser ablation
(neodymium: yttriumaluminum-garnet [Nd:YAG] or
holmium [Ho]: YAG laser) [47]. With a tissue penetration of less than 0.5 mm, the Ho:YAG laser is
well suited for use in the ureter, allowing for excellent hemostasis with
minimal transmural thermal damage. Conversely, the Nd:YAG laser has a deeper
penetration (5-6 mm) making it
better suited for coagulative necrosis of large lesions, particularly in the
renal pelvis [46].Ureteral perforation and postoperative
strictures are the principal complications associated with retrograde
ureteroscopy. The incidence of perforation in most series is below 10% and is
readily managed by ureteral stenting or percutaneous nephrostomy drainage [48, 49]. The reported stricture rate following retrograde management of upper-tract
TCC ranges from 4.9% to 13.6% [48–50]. Literature
data indicate that a lower incidence of strictures is associated with lesions
managed by laser ablation, rather than with
electrocoagulation [51]. Most postoperative strictures are successfully managed
by endoscopic stenting, laser incision, or balloon dilatation. Ultimately, all
ureteroscopic interventions should be followed with short-term ureteral
stenting to prevent postoperative obstructive sequelae.Nevertheless, being more invasive than
retrograde ureteroscopy, the percutaneous antegrade approach is preferred in
larger tumors of the renal pelvis and proximal ureter. Antegrade nephroscopy
offers better visualization of the renal pelvis whereas accommodating larger
caliber working instruments, being able to handle a larger tumor burden. The
percutaneous approach also allows for superior access to the lower pole
calyces, as well as to renal units with complicated calyceal anatomy. The
principal disadvantage of this approach is violation of urothelial integrity
with reports of tumor seeding of nonurothelial surfaces around the kidney or in
the nephrostomy tract [52, 53]. Larger series, however, fail to note such tract
recurrences, confirming that this phenomenon is uncommon [54–56].After a percutaneous tract that can accommodate a 30 Fr access sheath is subsequently established, the lesion is initially biopsied and
consequently debulked. Due to the larger access tract, antegrade techniques
permit the use of cold-cup biopsy forceps through a standard nephroscope or a
cutting loop from a resectoscope. The base of the lesion is resected and sent
separately for staging purposes, and haemostasis is achieved by electrocautery
or laser ablation as previously described. The established nephrostomy tract can be maintained, allowing for
repeated treatment or administration of topical adjuvant therapy [45, 46].Away from tumor tract seeding, complications of percutaneous management
of upper-tract TCC are similar to those of percutaneous stone procedures and
include bleeding, infection, electrolyte abnormalities, adjacent organ injury,
and pleural injury [45, 46].The safety and efficacy of ureteroscopic
management of upper-tract TCC are confirmed by multiple studies. In 1997,
Tawfiek and Bagley reported on the outcomes of 205 patients summarized from 14
modern series and found a recurrence rate of 33% for 61 renal pelvic tumors and
31% for 144 ureteral tumors [57]. More
recent reviews demonstrate similar findings, with recurrence rates ranging from
31% to 65% and disease-free rates of 35% to 86% [47, 49, 58–62]. The bladder
was the most frequent site of recurrence in these series. Tumor recurrence was
most dependent upon pathologic grade with recurrence rates of 25% for grade I
tumors and almost 50% for higher-grade lesions [48]. It is important to note
that initial endoscopic management does not predict a worse outcome if disease
progression occurs. Boorjian and colleagues reported that ureteroscopic tumor
ablation before nephroureterectomy did not adversely affect postoperative
disease status [63].As regarding the percutaneous approaches, they have promising results
when taking into consideration that these lesions are more substantial than
those managed by retrograde ureteroscopy. Okada et al. performed a review in 84 patients and found an overall
recurrence rate of 27%, with tumor grade strongly predicting outcomes [64].
Additionally, Rouprêt et al. reported a similar recurrence rate of
approximately 30%, with 5-year disease specific survival of almost 80% [65].
Moreover, Lee et al. reviewed their 13-year experience with percutaneous management
of upper-tract TCC patients and found no significant differences in overall
survival compared with those patients who underwent a nephroureterectomy
[66]. Regardless of treatment modality,
patients with low-grade lesions did well, while those with high-grade tumors
were predisposed to tumor recurrence and progression.The recommended follow-up of patients treated for upper-tract TCC should
consist of interval history and physical examination, urinary cytology, and
surveillance cystoscopy every 3 months for the first 2 years after treatment,
every 6 months for the next 2 years and yearly thereafter if the patient is
free from disease recurrence [46, 67]. Radiographic studies including chest X-ray
and abdominopelvic CT should be performed every 6 months for the first 2 years
and yearly thereafter. Ipsilateral endoscopy for patients who undergo
organ-sparing treatment should occur every 6 months for the first 2-3 years and
yearly thereafter, provided that the patient is disease free. Bone scans should
only be performed for symptoms of bone pain or for an elevated alkaline
phosphatase level.


## 4. The Prognostic Value of Lymphadenectomy in Patients with Muscle Invasion

Patients with muscle-invasive transitional
cell carcinoma of the upper urinary tract are at high risk of nodal metastasis,
and the prognosis may be extremely poor in the case of nodal involvement [68, 69].The impact of lymph node dissection on
clinical outcomes is reported only in few papers. Komatsu et al. [68] evaluated
a limited cohort of 36 patients and suggested that lymph node dissection may
provide a therapeutic benefit by selecting patients with lymph node metastasis
as candidates for adjuvant therapy. Miyake et al. [70] reported on 72 patients
with transitional cell carcinoma of the upper urinary tract. 35 of those had
undergone total nephroureterectomy and regional lymphadenectomy. Lymph node
dissection was associated with an increased cancer-specific survival in
patients with no evidence of lymph-vascular invasion. On the other hand, in
patients with evidence of lymph-vascular invasion who were considered at higher
risk of micrometastatic disease, no additional prognostic advantages were
provided by lymph node dissection.In contrast, no data is available on the
extent of lymph node dissection in patients with invasive transitional cell
carcinoma of the upper urinary tract.Recently, Brausi et al. [71] showed that in
patients with muscle-invasive transitional cell carcinoma of the upper urinary
tract, disease-free survival and cancer-specific survival were significantly
higher in patients who had retroperitoneal lymph node dissection in conjunction
with nephroureterectomy than in patients who did not undergo lymph node
dissection. They recommended that an accurate and extended lymph node
dissection can be curative in patients with advanced transitional cell
carcinoma of the upper urinary tract. Nevertheless, they did not analyze the
impact of the number of removed lymph nodes on clinical outcome.Roscigno et al. [72] first tested the role of lymph node dissection on disease-free survival
and cancer-specific survival. They observed 132 consecutive patients with
muscle-invasive transitional cell carcinoma of the upper urinary tract who
underwent radical surgery. Lymph node dissection was performed in 95 cases.
Patients were stratified according to the presence of lymph node dissection and
lymph node status.They concluded that patients undergoing
lymph node dissection at the time of radical surgery had a significantly better
prognosis, contrary to those managed with tumor
excision only, even though, in the group of patients
undergoing lymph node dissection, about 1/4 (26
patients) had nodal metastases. Then, they
analyzed the clinical outcome, according to
nodal status. They observed that the prognosis
of patients who did not receive lymph node
dissection (pNx) was significantly worse than that of pN0 patients, whereas, interestingly, both disease-free
survival (DFS) and cancer-specific survival (CSS) of pNx patients were comparable to those of pN+ patients. This was confirmed at multivariable analysis, where lymph node status emerged as a significant
predictor of DFS and CSS after accounting for age at
diagnosis, T stage, G grade, CIS (cancer in situ),
LVI (lymph-vascular invasion), year of surgery and
postoperative chemotherapy.These data are in contrast with those presented by a recent paper of Brown et al.
[73], showing that survival of Nx and N0 patients is similar and significantly
higher than N+ patients. On the other hand, the M. D. Anderson series evaluated
superficial tumor also, whereas in this series only muscle-invasive
transitional cell carcinomas were considered. Probably in their population a
higher percentage of pNx patients could have had positive nodes if lymph node
dissections were performed.Finally, these results suggest for the first time that the number of
lymph nodes removed and examined, related to the extent of lymph node
dissection, seems to play a significant role in predicting clinical outcome
after radical surgery. In fact, even when only the subset of patients managed
with lymph node dissection was analyzed, the number of lymph nodes removed and
examined emerged, both in invariable and multivariable analyses, as a significant
predictor of DFS and CSS, independently from the evidence of nodal metastases.
A better clinical outcome was observed in those patients in whom at least six
lymph nodes had been removed and examined [74].


## 5. Adjuvant Therapy

### 5.1. Immunotherapy

More than one third of the patients with
endoscopically treated upper tract TCC will develop tumor recurrence [46]. In
order to reduce recurrence rates, adjuvant topical immunotherapy or
chemotherapy can be used. There are several methods to perform an instillation:
by infusion through a percutaneous nephrostomy tube, via a retrograde ureteral
catheter, or by retrograde reflux from the bladder with an indwelling double-J
stent, or by surgical creation of ureteral reflux. The aim of the treatment is a
continued exposure of the urothelium to the topical agent while maintaining a
low-pressure system that is free of infection. These approaches minimize major
complications such as sepsis, although granulomatous changes in the kidney and
systemic adverse effects relating to bacillus Calmette-Guerin (BCG) infection
can occur [75, 76].The same agents used to treat urothelial
carcinoma of the bladder can be used to treat tumorsof the upper
tracts. The most common agents instilled are BCG or mitomycin-C.As regarding the specific role of upper
tract immunotherapy and topical chemotherapy, there are few reports in the
literature. Thalmann et al. [77] reported on 41 renal units treated in 37
patients with BCG (Bacillus Chalmette-Guerin) via percutaneous nephrostomy tube
with a mean follow-up of 44 months. For carcinoma in situ (CIS), there were
treated 25 renal units and another 16 received adjuvant BCG therapy for
superficial tumors in 15 patients. In this study no tumor seeding occurred
along the nephrostomy tract. Indications for treatment in this study included
solitary renal units, renal insufficiency, bilateral disease, and inoperable
disease. Among the patients with
CIS, 9 died of disease (41%), 6 died of other causes (27%), and 7 are alive at
a median follow-up of 50 months (32%). Median overall survival and time to
recurrence were 44 and 25 months, respectively. Fifteen patients with papillary
disease of the urinary tract in 16 renal units were treated (TaG1 in 2, TaG2 in
6, TaG3 in 2, T1G3 in 2, and Tx in 4). Overall survival was 40 months (range of
1–59). Thirteen
patients (87%) had recurrence after a median interval of 10 months (range of 1–69) and
progression after a median interval of 11 months (range of 5–27). Among the 15
patients, 4 are alive, 6 died of disease, and 5 died of other causes with tumor
present in the upper urinary tract.The authors concluded that papillary and
solid tumor recurrences of the upper urinary tract could not be prevented with
BCG therapy. However, BCG therapy did provide cure in approximately 50% of
renal units with CIS. Several other studies also support the use of BCG for
upper tract CIS [78–83].Vasavada et al. [84] also
reported on the use of BCG in the adjuvant setting for upper tract urothelial tumor.
After surgical resection for upper tract transitional cell carcinoma in eight
patients, they received adjuvant BCG therapy. Grades 1, 2, and 3 diseases were present in 2,
5, and 1 patients,
and Ta, T1, and T2 diseases
occurred in 5, 2, and 1 patients
in this cohort. At a mean follow-up of 23.8 months, 5 out of 8 patients (62.5%)
were disease free, 2 out of 8 patients (25%) died of disease, and 1 out of 8
(12.5%) was alive with metastatic disease and receiving systemic chemotherapy.Although the study number was small, the
authors concluded that the application of BCG after definitive resection of the
primary tumor may result in a decreased incidence of local tumor recurrence.To our knowledge, there has not been any
randomized, prospective, placebo-controlled trial specifically addressing the
effectiveness of topical immunotherapy or chemotherapy for adjuvant treatment
of upper tract urothelial tumors [77–85]. Until such studies become available,
adjuvant therapy may be used in patients undergoing nephron-sparing management
of upper tract transitional cell carcinoma with their consent and the addition
of a strict surveillance protocol.


### 5.2. Radiation Therapy and Systemic Chemotherapy

The fact that the transitional cell carcinoma of the upper urinary tract
is relatively rare has led to a scarcity of studies that analyze adjuvant
radiation therapy and chemotherapy for locally advanced but completely resected
upper tract urothelial tumors. When the tumor extents beyond the muscular, the 5-year-survival
rates will be between
0% and 34% [5, 9, 86, 87]. The loco-regional recurrence at 5 years after treatment
with definitive surgery, when no adjuvant chemotherapy was given, has been
reported at several studies between 45% and 60% [88–90]. This high recurrence
rate has been a strong argument for adjuvant therapy for all patients with
locally advanced disease even after complete resection.However, all recent studies count on limited
numbers of patients because of the rarity of this disease. Some researches have
supported [88, 89, 91] the role of adjuvant radiation treatment on upper tract
urothelial malignancies and others have rejected it [92, 93]. The role of
adjuvant chemotherapy alone for transitional cell carcinoma also remains
controversial [94].Maulard-Durdux et al. [92]
reported their experience on postsurgical irradiation in 26 patients with upper
tract tumors after complete resection. 11 patients had stage B disease
(muscular invasion) 42% and 15 patients had stage C disease (periureteral fat
invasion) 58%. According to tumor grade, 10 patients had grade 2, 40%, 15 had
grade 3, 60%, and it was unknown in a patient. The radiation therapy dose was
45 Gy in all patients. After a mean follow-up of 45 months, 13 patients (50%) were
alive, with 11 patients being disease free. Disease metastasized in 14 patients
to the bone, liver, and lungs. The overall 5-year-survival rates and 5-year survival
with no evidence of disease were 49% and 30%, respectively. The authors
concluded that adjuvant radiation therapy did not improve long-term survival
and is only recommended for prospective randomized studies.A recent review of selected
series of surgery with or without adjuvant radiation therapy for
carcinoma of the upper urinary tract revealed some improvement in percent loco-regional
failure [88–90, 92, 93, 94]. Six series of patients who received adjuvant radiation revealed a failure rate between 9% and 38%. The number of patients ranged from 9 to 45, with 1 series having 86 patients. The 5-year-survival rate was 21% to 49%. The series of patients who had surgery only (the
number of patients in these series ranged from 11 to 81) without adjuvant
treatment had a crude loco-regional failure rate of 45% to 65% and a 5-year-survival
rate of 17% to 33%. These studies might conclude that with radiation, there
seems to be some improvement in the failure and survival rate, but large
studies need to be performed.The urothelial tumors of the upper urinary
tract are considered to be chemosensitive tumors [43–45]. Most of the data
regarding the clinical efficacy of chemotherapy in the neoadjuvant and adjuvant
settings are based on experience from bladder TCC. Advantages of neoadjuvant
chemotherapy include eradication of subclinical metastatic disease, better
tolerability before surgical extirpation, and ability to deliver higher doses
than in the adjuvant setting [45]. Both the Advanced Bladder Cancer
Meta-analysis Collaboration and the Southwest Oncology group have presented
compelling data for the use of neoadjuvant platinum-based chemotherapy regimens
before radical cystectomy [95, 96]. Regimens comprised of gemcitabine and
cisplatin that provide a similar survival advantage to methotrexate-vinblastine-doxorubicin-cisplatin (MVAC),
with a better safety profile and tolerability, increase the attractiveness of
neoadjuvant chemotherapy [97]. Similar management strategies are likely to be
beneficial for upper-tract TCC, particularly in the setting of large, bulky
tumors.The role of adjuvant systemic chemotherapy to patients with locally
advanced upper urinary tract tumors is not well defined, because of the
scarcity of controlled trials due to the low prevalence and incidence of
disease. Nevertheless, a recent study by Brown et al. [73] reported on their
experience with both adjuvant radiation therapy and concurrent chemotherapy for
locally advanced disease. After surgery, 31 patients have received adjuvant
radiation therapy. All patients had grade 2 and even 84% of the group were
found to have a pathologic stage of T3 or higher. Nine patients received
methotrexate, cisplatin, and vinblastine chemotherapy for 2 to 4 cycles. Univariate analysis revealed that
patients had improved 5-year actuarial overall and disease-specific survival
with the administration of concurrent chemotherapy when compared with patients
receiving adjuvant radiation alone (27% versus 67%, P=.01; 41% versus
76%, P=.06, resp.).


## 5.1. Immunotherapy

More than one third of the patients with
endoscopically treated upper tract TCC will develop tumor recurrence [46]. In
order to reduce recurrence rates, adjuvant topical immunotherapy or
chemotherapy can be used. There are several methods to perform an instillation:
by infusion through a percutaneous nephrostomy tube, via a retrograde ureteral
catheter, or by retrograde reflux from the bladder with an indwelling double-J
stent, or by surgical creation of ureteral reflux. The aim of the treatment is a
continued exposure of the urothelium to the topical agent while maintaining a
low-pressure system that is free of infection. These approaches minimize major
complications such as sepsis, although granulomatous changes in the kidney and
systemic adverse effects relating to bacillus Calmette-Guerin (BCG) infection
can occur [75, 76].The same agents used to treat urothelial
carcinoma of the bladder can be used to treat tumorsof the upper
tracts. The most common agents instilled are BCG or mitomycin-C.As regarding the specific role of upper
tract immunotherapy and topical chemotherapy, there are few reports in the
literature. Thalmann et al. [77] reported on 41 renal units treated in 37
patients with BCG (Bacillus Chalmette-Guerin) via percutaneous nephrostomy tube
with a mean follow-up of 44 months. For carcinoma in situ (CIS), there were
treated 25 renal units and another 16 received adjuvant BCG therapy for
superficial tumors in 15 patients. In this study no tumor seeding occurred
along the nephrostomy tract. Indications for treatment in this study included
solitary renal units, renal insufficiency, bilateral disease, and inoperable
disease. Among the patients with
CIS, 9 died of disease (41%), 6 died of other causes (27%), and 7 are alive at
a median follow-up of 50 months (32%). Median overall survival and time to
recurrence were 44 and 25 months, respectively. Fifteen patients with papillary
disease of the urinary tract in 16 renal units were treated (TaG1 in 2, TaG2 in
6, TaG3 in 2, T1G3 in 2, and Tx in 4). Overall survival was 40 months (range of
1–59). Thirteen
patients (87%) had recurrence after a median interval of 10 months (range of 1–69) and
progression after a median interval of 11 months (range of 5–27). Among the 15
patients, 4 are alive, 6 died of disease, and 5 died of other causes with tumor
present in the upper urinary tract.The authors concluded that papillary and
solid tumor recurrences of the upper urinary tract could not be prevented with
BCG therapy. However, BCG therapy did provide cure in approximately 50% of
renal units with CIS. Several other studies also support the use of BCG for
upper tract CIS [78–83].Vasavada et al. [84] also
reported on the use of BCG in the adjuvant setting for upper tract urothelial tumor.
After surgical resection for upper tract transitional cell carcinoma in eight
patients, they received adjuvant BCG therapy. Grades 1, 2, and 3 diseases were present in 2,
5, and 1 patients,
and Ta, T1, and T2 diseases
occurred in 5, 2, and 1 patients
in this cohort. At a mean follow-up of 23.8 months, 5 out of 8 patients (62.5%)
were disease free, 2 out of 8 patients (25%) died of disease, and 1 out of 8
(12.5%) was alive with metastatic disease and receiving systemic chemotherapy.Although the study number was small, the
authors concluded that the application of BCG after definitive resection of the
primary tumor may result in a decreased incidence of local tumor recurrence.To our knowledge, there has not been any
randomized, prospective, placebo-controlled trial specifically addressing the
effectiveness of topical immunotherapy or chemotherapy for adjuvant treatment
of upper tract urothelial tumors [77–85]. Until such studies become available,
adjuvant therapy may be used in patients undergoing nephron-sparing management
of upper tract transitional cell carcinoma with their consent and the addition
of a strict surveillance protocol.


## 5.2. Radiation Therapy and Systemic Chemotherapy

The fact that the transitional cell carcinoma of the upper urinary tract
is relatively rare has led to a scarcity of studies that analyze adjuvant
radiation therapy and chemotherapy for locally advanced but completely resected
upper tract urothelial tumors. When the tumor extents beyond the muscular, the 5-year-survival
rates will be between
0% and 34% [5, 9, 86, 87]. The loco-regional recurrence at 5 years after treatment
with definitive surgery, when no adjuvant chemotherapy was given, has been
reported at several studies between 45% and 60% [88–90]. This high recurrence
rate has been a strong argument for adjuvant therapy for all patients with
locally advanced disease even after complete resection.However, all recent studies count on limited
numbers of patients because of the rarity of this disease. Some researches have
supported [88, 89, 91] the role of adjuvant radiation treatment on upper tract
urothelial malignancies and others have rejected it [92, 93]. The role of
adjuvant chemotherapy alone for transitional cell carcinoma also remains
controversial [94].Maulard-Durdux et al. [92]
reported their experience on postsurgical irradiation in 26 patients with upper
tract tumors after complete resection. 11 patients had stage B disease
(muscular invasion) 42% and 15 patients had stage C disease (periureteral fat
invasion) 58%. According to tumor grade, 10 patients had grade 2, 40%, 15 had
grade 3, 60%, and it was unknown in a patient. The radiation therapy dose was
45 Gy in all patients. After a mean follow-up of 45 months, 13 patients (50%) were
alive, with 11 patients being disease free. Disease metastasized in 14 patients
to the bone, liver, and lungs. The overall 5-year-survival rates and 5-year survival
with no evidence of disease were 49% and 30%, respectively. The authors
concluded that adjuvant radiation therapy did not improve long-term survival
and is only recommended for prospective randomized studies.A recent review of selected
series of surgery with or without adjuvant radiation therapy for
carcinoma of the upper urinary tract revealed some improvement in percent loco-regional
failure [88–90, 92, 93, 94]. Six series of patients who received adjuvant radiation revealed a failure rate between 9% and 38%. The number of patients ranged from 9 to 45, with 1 series having 86 patients. The 5-year-survival rate was 21% to 49%. The series of patients who had surgery only (the
number of patients in these series ranged from 11 to 81) without adjuvant
treatment had a crude loco-regional failure rate of 45% to 65% and a 5-year-survival
rate of 17% to 33%. These studies might conclude that with radiation, there
seems to be some improvement in the failure and survival rate, but large
studies need to be performed.The urothelial tumors of the upper urinary
tract are considered to be chemosensitive tumors [43–45]. Most of the data
regarding the clinical efficacy of chemotherapy in the neoadjuvant and adjuvant
settings are based on experience from bladder TCC. Advantages of neoadjuvant
chemotherapy include eradication of subclinical metastatic disease, better
tolerability before surgical extirpation, and ability to deliver higher doses
than in the adjuvant setting [45]. Both the Advanced Bladder Cancer
Meta-analysis Collaboration and the Southwest Oncology group have presented
compelling data for the use of neoadjuvant platinum-based chemotherapy regimens
before radical cystectomy [95, 96]. Regimens comprised of gemcitabine and
cisplatin that provide a similar survival advantage to methotrexate-vinblastine-doxorubicin-cisplatin (MVAC),
with a better safety profile and tolerability, increase the attractiveness of
neoadjuvant chemotherapy [97]. Similar management strategies are likely to be
beneficial for upper-tract TCC, particularly in the setting of large, bulky
tumors.The role of adjuvant systemic chemotherapy to patients with locally
advanced upper urinary tract tumors is not well defined, because of the
scarcity of controlled trials due to the low prevalence and incidence of
disease. Nevertheless, a recent study by Brown et al. [73] reported on their
experience with both adjuvant radiation therapy and concurrent chemotherapy for
locally advanced disease. After surgery, 31 patients have received adjuvant
radiation therapy. All patients had grade 2 and even 84% of the group were
found to have a pathologic stage of T3 or higher. Nine patients received
methotrexate, cisplatin, and vinblastine chemotherapy for 2 to 4 cycles. Univariate analysis revealed that
patients had improved 5-year actuarial overall and disease-specific survival
with the administration of concurrent chemotherapy when compared with patients
receiving adjuvant radiation alone (27% versus 67%, P=.01; 41% versus
76%, P=.06, resp.).


## 6. Conclusions

Treatment of upper-tract urothelial
carcinoma has developed and changed with advances in technology. Treatment has
evolved from open radical nephroureterectomy to percutaneous resection to
ureteroscopic treatment. Adjuvant treatments are also evolving with topical
immunotherapy, radiation, and chemotherapy. Before any decision for optimal treatment, the specifics
of each individual patient with regard to renal function, medical
comorbidities, location of disease, tumor stage, and tumor grade must be taken into account.Due to the fact that the incidence and
prevalence of this tumor is low, the majority of series in the literature are
of limited number. What is clear from the literature with regard to
surgical outcomes for upper-tract TCC is that this is a potentially lethal
disease if not treated appropriately. Due to its relative rarity, many
decisions regarding treatment are extrapolated from our experience in managing
bladder urothelial carcinoma (such as node dissections, topical chemotherapies,
immunotherapies, and adjuvant treatments). The problem about the studies
utilizing minimally invasive techniques is that they lack long-term follow-up. Almost
all of the studies are retrospective in nature and therefore flawed with
selection biases.As a result, the standard way still remains to be surgical removal
with radical nephroureterectomy, and for selected patients segmental
ureterectomy may be performed. Endoscopic management is also reasonable in
patients with low-grade and low-stage disease as long as they adhere to a
strict follow-up protocol that includes frequent cytology and endoscopy. The
benefits of adjuvant radiation and chemotherapy are still debated, but the
literature does reveal some improvement in disease-specific survival using both
forms of treatment.



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*Source: 656521-2008-12-10.xml*