# Laparoscopic Nephroureterectomy: Oncologic Outcomes and Management of Distal Ureter; Review of the Literature

Authors: Andre Berger; Amr Fergany
Journal: Advances in Urology
 (2009)

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## Abstract

Introduction. Laparoscopic radical nephroureterectomy (LNU) is being increasingly performed at several centers across the world. We review oncologic outcomes after LNU procedure and the techniques for the management of distal ureter. Materials and Methods. A comprehensive review of the literature was performed on the oncological outcomes and management of distal ureter associated with LNU for upper tract transitional cell carcinoma (TCC). Results and Discussion. LNU for upper tract TCC is performed pure laparoscopically (LNU) or hand-assisted (HALNU). The management of the distal ureter is still debated. LNU appears to have superior perioperative outcomes when compared to open surgery. Intermediate term oncologic outcomes after LNU are comparable to open nephroureterectomy (ONU). Conclusions. Excision of the distal ureter and bladder cuff during nephroureterectomy remains controversial. Intermediate term oncologic outcomes for LNU compare well with ONU. Initial long-term oncologic outcomes are encouraging. Prospective randomized comparison between LNU and open surgery is needed to define the role of these modalities in the current context.


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## Body

## 1. Introduction

Upper tract TCC accounts for 5% of all urothelial tumors [1]. It usually occurs in
patients older than 60. Compared to bladder cancer, upper tract TCC is
diagnosed more frequently at advanced stages. In most series, in almost half
the patients, tumor stages at diagnosis have been described as pT2 or higher. Stage is the main predictor for survival. Delay
in diagnosis and treatment is related to worse prognosis. Standard management consists of open
radical nephroureterectomy (ONU), which usually requires one large or two
separate abdominal incisions. Since LNU was first reported by the Washington University Group in 1991 [2],
the benefits of this procedure regarding perioperative morbidity, cosmesis, and
convalescence have been established [3–5]. Mainly, there are 2 laparoscopic
approaches: pure laparoscopic nephroureterectomy (LNU) and hand-assisted
nephroureterectomy (HALNU). Despite the perioperative advantages, some
oncological issues remain unclear, mainly management of the distal ureter and
the role of lymphadenectomy.


## 2. Materials and Methods

We performed an extensive National Library of Medicine
database search with no date restriction using the keywords upper tract
transitional cell carcinoma, nephroureterectomy, and laparoscopic nephroureterectomy.
Of the over 100 papers identified, 25 of each were selected for this review on
the basis of their contribution in advancing the field with regards to (1)
evolution of concepts (2) development and refinement of techniques, and (3)
intermediate oncological outcomes.


## 3. Results and Discussion

### 3.1. Management of Distal Ureter

The management of the distal ureter
is still controversial. The open extravesical or transvesical approach is
accepted as the most oncologically safe. However, patient factors as obesity
and previous history of pelvic surgery or radiotherapy can make ureteral
excision more difficult. In 1952, McDonald et al. first reported an endoscopic
method to handle the distal ureter [6]. In the laparoscopic era, many attempts
have been made to avoid the open approach to the distal ureter, which is still
commonly used. Shalhav et al. [4] described the laparoscopic stapling of the
distal ureter and bladder cuff and positive margins were associated with the
method. Matin et al.   compared the outcomes (median follow-up 23 months)
using the two different techniques of en bloc excision of bladder cuff: 36
patients underwent technique of cystoscopic intravesical secured
detachment of en bloc bladder cuff and juxtavesical ureter using needlescopic instruments
percutaneouslly [7] and 12 underwent laparoscopic extravesical stapling. The
stapling technique was associated with a decreased overall survival, decreased
recurrence free survival, and higher positive surgical margin rate. Kurzer et
al. (2006) evaluated 49 patients on a mean follow-up of 10.6 months and
reported their results after cystoscopic circumferential excision of the distal
ureter without primary closure of the bladder cuff with simultaneous ureteral
ligation during HALNU [8]. No cases of local pelvic or peritoneal recurrences
were reported. Vardi et al. (2006) reported a new technique to manage the
distal ureter [9]. They proposed an en bloc excision of the bladder cuff and
juxtavesical ureter during HALNU using a flexible cystoscope and a 5F electrode
without repositioning the patient. Mean follow-up was 31 months (range 5–44) and none of
the 6 patients presented with local recurrence. Recently, Nanigan et al. (2006)
reported using robotic assistance in an attempt to decrease the technical
challenge of excision of distal ureter in 11 patients [10]. As part of the
procedure, they filled the bladder with a saline solution before opening it and
aspirated all the fluid to avoid dissemination of cancer cells. In addition to
the disadvantage of increased cost, the 6-month follow-up is not enough to
evaluate local recurrence. Agarwall et al. (2008) modified the Cleveland Clinic
technique. They performed a circumscribed incision in the ureteric orifice with
a bladder cuff using a Collins knife. The ureter stump was ligated with an
endoloop via cystoscope to avoid urine leak from the upper tract. Complete
excision was achieved in all 13 patients. Five patients had bladder recurrence,
2 close to the ureteral scar [11].Since most studies do not show any difference between
different methods of handling the distal ureter, the best option is to follow
individual surgeon's preference as long as the fundamental oncological concepts
are preserved: having a complete resection of the distal ureter with bladder
cuff and avoiding tumor spillage.


### 3.2. Oncological Outcomes after LNU

Laparoscopic nephroureterectomy is performed utilizing the
same surgical principles as laparoscopic radical nephrectomy. A transperitoneal
or retroperitoneal approach can be chosen. Most surgeons are familiar with the
transperitoneal approach, which has the advantage of allowing dissection of the
ureter all the way to the bladder. This is essential if endoscopic management
of the distal ureter (as previously described) is planned. Surgeons familiar
with the retroperitoneal approach to radical nephrectomy can perform the renal
part of the operation retroperitoneally, although access to the distal ureter
is difficult with this approach. This is best suited to cases where the distal ureter
will be managed through an open approach. In either case the ureter is not
divided and left in continuity. A clip placed on the ureter will minimize the
risk of tumor seeding resulting from manipulation of the kidney. In cases of
ureteric tumors, careful attention to wide dissection of the ureter is
essential to avoid a positive margin or entry into the ureter with tumor
spillage.Long-term follow-up after ONU is well
documented in some large series. Charbit et al. (1991) reported the first big
follow-up series with upper tract TCC in 108 patients [17]. Survival rates
after 5 and 10 years were 67% and 65%, respectively. Hall et al. (1998)
reviewed 252 patients after ONU (median follow-up 64 months). Recurrence
occurred in 67 (27%) patients and urothelial recurrences represented 69% of
total [18]. Median time to recurrence was 12 months. Actuarial 5-year
cancer-specific survival rates by primary tumor stage were 100% for Ta/Cis, 92%
for T1, 73% for T2, and 41% for T3. Median survival for pT4 patients was 6
months. On multivariate analysis, tumor stage was a significant predictor for
recurrence, whereas patient age and stage were significant predictors for
survival. In contrast, a multicenter study by Ozsahin et al. (1999) evaluated
126 patients with upper tract TCC (median follow-up 39 months) and reported
poor oncological outcomes of ONU [19]. In a median period of 9 months, 66% of
the patients recurred. The 5- and 10-year overall survivals were 29% and 19%,
respectively. Multivariate analysis revealed that independent prognostic
factors influencing outcome were T staging, positive surgical margin, and tumor
in the ureter. Lower survival rates in this study may be explained by high
proportions of high grade (76%), nonorgan confined disease (59%), and positive
surgical margin (26%).Long-term follow-up studies after LNU are still sparse. El
Fettouh et al. (2002) reported the results of 116 patients who underwent LNU on
a multicenter basis with a median follow-up of 25 months [12]. Positive margins
were identified in 4.5% of patients, local recurrence in 1.7%, bladder
recurrence in 24%, and mean time to recurrence was 13.9 months. Distant
metastasis rate was 9%; mean time to metastasis was 13 months. Two-year
cancer-specific survival was 87%. According to T stage, 2-year cancer specific
survival was 89% for pT1, 86% for pT2, 77% for pT3, and 0% for pT4. Muntener et
al. (2007) reported the outcomes of 39 patients after LNU (median follow-up 74
months). Five-year cancer specific survival was 68%. Tumor stage was the only
factor related to cancer death and ureteral tumor was the only factor
associated with recurrence [13].Cohorts comparing perioperative and
short/intermedi-ate oncological outcomes between ONU and LNU have been
published. Bariol et al. (2004) evaluated 25 patients who underwent LNU and 42
who underwent ONU for TCC in a median follow-up of 101 and 96 months,
respectively [14]. Local and bladder recurrence rates were 28% (7 patients)
for LNU and 42% (15 patients) for ONU, while more ureteral tumors were
described in ONU. One and 5-year metastases-free survivals were 80% and 72% for
LNU and 87% and 82% for ONU, while no statistical difference between the two
surgical treatments was found. Rouprêt et al. (2007) compared 20 patients who
underwent LNU (median follow-up 68.5 months) to 26 who underwent ONU (median
follow-up 78 months). Recurrence occurred in 20% of cases of LNU and 53% of ONU
[15]. Median time to recurrence was 15 and 18 months, respectively. Five-year
cancer-specific survival was 90% and 61% and 5-year recurrence-free survival
was 71% and 51%, respectively. Okegawa et al. (2006) compared 25 LNU (mean
follow-up 24 months) and 23 ONU (mean follow-up 29 months). In LNU and ONU
groups, recurrence rates were 20% and 17% and mean time to recurrence were 9.5
and 23.4 months  [20].
Distant metastasis rate was 8%  for LNUX and 13% for ONUX. Two-year
cancer-specific survival was 91% for LNU and 89% for ONU. No significant
difference was detected in recurrence-free survival and cancer-specific
survival. Manabe et al. (2007) evaluated 58 patients after LNU (mean follow-up
13.6 months) and 166 after ONU (mean follow-up 28 months). Bladder recurrence
was reported in 33% of patients after LNU and in 38% after ONU [16]. Distant
metastases were reported in 17% and 20% of the patients, respectively. The
2-year recurrence-free survivals were 76% and 82%. No difference was found in
cancer-specific survival.Some recent series report results
after hand-assisted LNU (HALNU), but oncologic outcomes are limited. Wolf et al. evaluated 54 patients who underwent HALNU with median follow-up of 25
months [21]. Urothelial recurrences occurred in 66% patients. History of
bladder tumors was associated with urothelial recurrence. Nonurothelial
recurrences were found in 25% of the patients at a mean 10.4 months follow-up.
Age and grade correlated with nonurothelial recurrence. The 2 and 3-year
cancer-specific survival were 86% and 80%, respectively. Organ-confined disease
and nonorgan-confined disease were associated with a 3-year survival of 100%
and 36%, respectively. High-grade disease correlated with poorer 3-year
cancer-specific survival. Chung et al. (2007) also described comparable
recurrence free, 3-year cancer-specific and overall survivals in 39 patients
after HALNU (median follow-up 48 months) and 41 patients after ONU (median
follow-up 62 months) [22].The propensity for dissemination of high-grade TCC is well
known. An important concern with laparoscopic approach is port site metastasis.
Seven cases have been published so far. No surgical bag was used in six cases
and the surgical bag was torn during retrieval of the specimen in one case [22].Recently, the importance of
extended lymph node dissection for bladder cancer regarding staging and
prognosis has been established. Given the histological similarity between
bladder cancer and upper tract TCC, lymphadenectomy should also be important
for the management of upper tract TCC. Kondo et al. (2007) evaluated 169
patients that underwent open nephroureterectomy divided in 3 different groups:
complete lymphadenectomy, incomplete lymphadenectomy, and no lymphadenectomy
[23].  Extended lymphadenectomy improved
survival in patients with pT3 stage or higher. On multivariate analysis,
complete lymphadenectomy, T stage and grade were significant prognostic factors
for cancer-specific survival. Brausi et al. (2007) reported retroperitoneal
lymph node dissection and T stage as the only independent significant
prognostic factors on overall survival [24].  Busby et al. (2006) found no difference
between ONU and LNU concerning number of lymph nodes retrieved, median number
of positive nodes retrieved, and median density of positive nodes, showing that
lymphadenectomy can be performed in the laparoscopic approach as adequately as
in open approach [25].Intermediate oncological outcomes after LNU are similar to
ONU. Series combining long follow-up and large number of patients are lacking.
Finally, to confirm these previous encouraging findings, prospective randomized
trials are still needed Table1 summarizes the oncological outcomes after LNU.Table 1
LNU series and comparative studies.
Patients (n) LNU/ONUMedian follow-up (mo)Recurrence (%)Local recurrence (%)Bladder recurrence (%)Distant metastasis (%)Overall survival (%)Cancer-specific survival (%)Risk factor associated to survival (%)LNU X SeriesEl Fettouh11625Not statedNot stated249Not stated87Not stated(2002) [12](2 year)Muntner3974465Not stated1859 (5 year)68Tumor stage(2007) [13](5 year)LNU versus open surgeryBariol58 26/22101/96Not stated8/1528/ 4228/1856/5972/82Not stated(2004) [14](5 year)Rouprêt46 20/ 2668/ 7819 (urothelial)Not statedNot stated10/35Not stated90/61Tumor stage and grade(2006)  [15](5 year)Manabe224 58/16614/ 28 (mean)33/381 case port/ 2 casesNot stated17/2084/84 (2 year)85/82Tumor stage and grade(2007) [16](2 year)


## 3.1. Management of Distal Ureter

The management of the distal ureter
is still controversial. The open extravesical or transvesical approach is
accepted as the most oncologically safe. However, patient factors as obesity
and previous history of pelvic surgery or radiotherapy can make ureteral
excision more difficult. In 1952, McDonald et al. first reported an endoscopic
method to handle the distal ureter [6]. In the laparoscopic era, many attempts
have been made to avoid the open approach to the distal ureter, which is still
commonly used. Shalhav et al. [4] described the laparoscopic stapling of the
distal ureter and bladder cuff and positive margins were associated with the
method. Matin et al.   compared the outcomes (median follow-up 23 months)
using the two different techniques of en bloc excision of bladder cuff: 36
patients underwent technique of cystoscopic intravesical secured
detachment of en bloc bladder cuff and juxtavesical ureter using needlescopic instruments
percutaneouslly [7] and 12 underwent laparoscopic extravesical stapling. The
stapling technique was associated with a decreased overall survival, decreased
recurrence free survival, and higher positive surgical margin rate. Kurzer et
al. (2006) evaluated 49 patients on a mean follow-up of 10.6 months and
reported their results after cystoscopic circumferential excision of the distal
ureter without primary closure of the bladder cuff with simultaneous ureteral
ligation during HALNU [8]. No cases of local pelvic or peritoneal recurrences
were reported. Vardi et al. (2006) reported a new technique to manage the
distal ureter [9]. They proposed an en bloc excision of the bladder cuff and
juxtavesical ureter during HALNU using a flexible cystoscope and a 5F electrode
without repositioning the patient. Mean follow-up was 31 months (range 5–44) and none of
the 6 patients presented with local recurrence. Recently, Nanigan et al. (2006)
reported using robotic assistance in an attempt to decrease the technical
challenge of excision of distal ureter in 11 patients [10]. As part of the
procedure, they filled the bladder with a saline solution before opening it and
aspirated all the fluid to avoid dissemination of cancer cells. In addition to
the disadvantage of increased cost, the 6-month follow-up is not enough to
evaluate local recurrence. Agarwall et al. (2008) modified the Cleveland Clinic
technique. They performed a circumscribed incision in the ureteric orifice with
a bladder cuff using a Collins knife. The ureter stump was ligated with an
endoloop via cystoscope to avoid urine leak from the upper tract. Complete
excision was achieved in all 13 patients. Five patients had bladder recurrence,
2 close to the ureteral scar [11].Since most studies do not show any difference between
different methods of handling the distal ureter, the best option is to follow
individual surgeon's preference as long as the fundamental oncological concepts
are preserved: having a complete resection of the distal ureter with bladder
cuff and avoiding tumor spillage.


## 3.2. Oncological Outcomes after LNU

Laparoscopic nephroureterectomy is performed utilizing the
same surgical principles as laparoscopic radical nephrectomy. A transperitoneal
or retroperitoneal approach can be chosen. Most surgeons are familiar with the
transperitoneal approach, which has the advantage of allowing dissection of the
ureter all the way to the bladder. This is essential if endoscopic management
of the distal ureter (as previously described) is planned. Surgeons familiar
with the retroperitoneal approach to radical nephrectomy can perform the renal
part of the operation retroperitoneally, although access to the distal ureter
is difficult with this approach. This is best suited to cases where the distal ureter
will be managed through an open approach. In either case the ureter is not
divided and left in continuity. A clip placed on the ureter will minimize the
risk of tumor seeding resulting from manipulation of the kidney. In cases of
ureteric tumors, careful attention to wide dissection of the ureter is
essential to avoid a positive margin or entry into the ureter with tumor
spillage.Long-term follow-up after ONU is well
documented in some large series. Charbit et al. (1991) reported the first big
follow-up series with upper tract TCC in 108 patients [17]. Survival rates
after 5 and 10 years were 67% and 65%, respectively. Hall et al. (1998)
reviewed 252 patients after ONU (median follow-up 64 months). Recurrence
occurred in 67 (27%) patients and urothelial recurrences represented 69% of
total [18]. Median time to recurrence was 12 months. Actuarial 5-year
cancer-specific survival rates by primary tumor stage were 100% for Ta/Cis, 92%
for T1, 73% for T2, and 41% for T3. Median survival for pT4 patients was 6
months. On multivariate analysis, tumor stage was a significant predictor for
recurrence, whereas patient age and stage were significant predictors for
survival. In contrast, a multicenter study by Ozsahin et al. (1999) evaluated
126 patients with upper tract TCC (median follow-up 39 months) and reported
poor oncological outcomes of ONU [19]. In a median period of 9 months, 66% of
the patients recurred. The 5- and 10-year overall survivals were 29% and 19%,
respectively. Multivariate analysis revealed that independent prognostic
factors influencing outcome were T staging, positive surgical margin, and tumor
in the ureter. Lower survival rates in this study may be explained by high
proportions of high grade (76%), nonorgan confined disease (59%), and positive
surgical margin (26%).Long-term follow-up studies after LNU are still sparse. El
Fettouh et al. (2002) reported the results of 116 patients who underwent LNU on
a multicenter basis with a median follow-up of 25 months [12]. Positive margins
were identified in 4.5% of patients, local recurrence in 1.7%, bladder
recurrence in 24%, and mean time to recurrence was 13.9 months. Distant
metastasis rate was 9%; mean time to metastasis was 13 months. Two-year
cancer-specific survival was 87%. According to T stage, 2-year cancer specific
survival was 89% for pT1, 86% for pT2, 77% for pT3, and 0% for pT4. Muntener et
al. (2007) reported the outcomes of 39 patients after LNU (median follow-up 74
months). Five-year cancer specific survival was 68%. Tumor stage was the only
factor related to cancer death and ureteral tumor was the only factor
associated with recurrence [13].Cohorts comparing perioperative and
short/intermedi-ate oncological outcomes between ONU and LNU have been
published. Bariol et al. (2004) evaluated 25 patients who underwent LNU and 42
who underwent ONU for TCC in a median follow-up of 101 and 96 months,
respectively [14]. Local and bladder recurrence rates were 28% (7 patients)
for LNU and 42% (15 patients) for ONU, while more ureteral tumors were
described in ONU. One and 5-year metastases-free survivals were 80% and 72% for
LNU and 87% and 82% for ONU, while no statistical difference between the two
surgical treatments was found. Rouprêt et al. (2007) compared 20 patients who
underwent LNU (median follow-up 68.5 months) to 26 who underwent ONU (median
follow-up 78 months). Recurrence occurred in 20% of cases of LNU and 53% of ONU
[15]. Median time to recurrence was 15 and 18 months, respectively. Five-year
cancer-specific survival was 90% and 61% and 5-year recurrence-free survival
was 71% and 51%, respectively. Okegawa et al. (2006) compared 25 LNU (mean
follow-up 24 months) and 23 ONU (mean follow-up 29 months). In LNU and ONU
groups, recurrence rates were 20% and 17% and mean time to recurrence were 9.5
and 23.4 months  [20].
Distant metastasis rate was 8%  for LNUX and 13% for ONUX. Two-year
cancer-specific survival was 91% for LNU and 89% for ONU. No significant
difference was detected in recurrence-free survival and cancer-specific
survival. Manabe et al. (2007) evaluated 58 patients after LNU (mean follow-up
13.6 months) and 166 after ONU (mean follow-up 28 months). Bladder recurrence
was reported in 33% of patients after LNU and in 38% after ONU [16]. Distant
metastases were reported in 17% and 20% of the patients, respectively. The
2-year recurrence-free survivals were 76% and 82%. No difference was found in
cancer-specific survival.Some recent series report results
after hand-assisted LNU (HALNU), but oncologic outcomes are limited. Wolf et al. evaluated 54 patients who underwent HALNU with median follow-up of 25
months [21]. Urothelial recurrences occurred in 66% patients. History of
bladder tumors was associated with urothelial recurrence. Nonurothelial
recurrences were found in 25% of the patients at a mean 10.4 months follow-up.
Age and grade correlated with nonurothelial recurrence. The 2 and 3-year
cancer-specific survival were 86% and 80%, respectively. Organ-confined disease
and nonorgan-confined disease were associated with a 3-year survival of 100%
and 36%, respectively. High-grade disease correlated with poorer 3-year
cancer-specific survival. Chung et al. (2007) also described comparable
recurrence free, 3-year cancer-specific and overall survivals in 39 patients
after HALNU (median follow-up 48 months) and 41 patients after ONU (median
follow-up 62 months) [22].The propensity for dissemination of high-grade TCC is well
known. An important concern with laparoscopic approach is port site metastasis.
Seven cases have been published so far. No surgical bag was used in six cases
and the surgical bag was torn during retrieval of the specimen in one case [22].Recently, the importance of
extended lymph node dissection for bladder cancer regarding staging and
prognosis has been established. Given the histological similarity between
bladder cancer and upper tract TCC, lymphadenectomy should also be important
for the management of upper tract TCC. Kondo et al. (2007) evaluated 169
patients that underwent open nephroureterectomy divided in 3 different groups:
complete lymphadenectomy, incomplete lymphadenectomy, and no lymphadenectomy
[23].  Extended lymphadenectomy improved
survival in patients with pT3 stage or higher. On multivariate analysis,
complete lymphadenectomy, T stage and grade were significant prognostic factors
for cancer-specific survival. Brausi et al. (2007) reported retroperitoneal
lymph node dissection and T stage as the only independent significant
prognostic factors on overall survival [24].  Busby et al. (2006) found no difference
between ONU and LNU concerning number of lymph nodes retrieved, median number
of positive nodes retrieved, and median density of positive nodes, showing that
lymphadenectomy can be performed in the laparoscopic approach as adequately as
in open approach [25].Intermediate oncological outcomes after LNU are similar to
ONU. Series combining long follow-up and large number of patients are lacking.
Finally, to confirm these previous encouraging findings, prospective randomized
trials are still needed Table1 summarizes the oncological outcomes after LNU.Table 1
LNU series and comparative studies.
Patients (n) LNU/ONUMedian follow-up (mo)Recurrence (%)Local recurrence (%)Bladder recurrence (%)Distant metastasis (%)Overall survival (%)Cancer-specific survival (%)Risk factor associated to survival (%)LNU X SeriesEl Fettouh11625Not statedNot stated249Not stated87Not stated(2002) [12](2 year)Muntner3974465Not stated1859 (5 year)68Tumor stage(2007) [13](5 year)LNU versus open surgeryBariol58 26/22101/96Not stated8/1528/ 4228/1856/5972/82Not stated(2004) [14](5 year)Rouprêt46 20/ 2668/ 7819 (urothelial)Not statedNot stated10/35Not stated90/61Tumor stage and grade(2006)  [15](5 year)Manabe224 58/16614/ 28 (mean)33/381 case port/ 2 casesNot stated17/2084/84 (2 year)85/82Tumor stage and grade(2007) [16](2 year)


## 4. Conclusion

Many centers worldwide are now performing LNU. Contemporary
series have demonstrated technical feasibility and safety. The management of
distal ureter is still debated. Although large series of 5-year oncologic data are
not yet available in the LNU literature, reports indicate that intermediate and
long-term oncological outcomes are similar to ORC. Carefully designed
prospective randomized trials comparing LNU and ONU are necessary to define the
role of these modalities in the current and future management of upper tract
TCC.



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*Source: 826725-2008-11-05.xml*