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Keywords:

  • bladder neoplasm;
  • kidney pelvis;
  • lymph node excision;
  • transitional cell carcinoma;
  • ureteral neoplasms

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lymphadenectomy in bladder cancer
  5. Lymphadenectomy in UCUUT
  6. Acknowledgments
  7. Conflict of interest
  8. References

The role of lymphadenectomy has been controversial in urological malignancies. Urothelial carcinoma of the bladder and upper urinary tract has a high potential to spread through the lymphatic network compared with other malignancies, including renal cell carcinoma or prostate cancer. In urothelial carcinoma of the bladder, lymphadenectomy of pelvic nodes had been considered as the standard procedure when radical cystectomy was carried out. Recently, many investigators have examined the influence of its extent, and the majority of the studies have supported the beneficial role of extended lymphadenectomy in accurate staging or in improving patient survival. Although randomized controlled trials are required to establish a greater level of evidence, more urological surgeons have already noticed the necessity for extended lymphadenectomy in bladder cancer. In contrast to bladder cancer, there have been far fewer studies on urothelial carcinoma of the upper urinary tract. This might be because of the smaller number of the patients with urothelial carcinoma of the upper urinary tract and the lack of understanding of regional nodes. However, studies of lymph node mapping and the retrospective analyses with respect to the benefit of lymphadenectomy have been carried out in urothelial carcinoma of the upper urinary tract by some investigators, although the results are still controversial. However, the results from multi-institutional studies by high volume centers have supported the beneficial role of lymphadenectomy in urothelial carcinoma of the upper urinary tract, as it has been proposed in bladder cancer. Thus, lymphadenectomy for urothelial carcinoma of the bladder and the upper urinary tract might have a potential role in staging and improving the oncological outcomes.


Abbreviations & Acronyms
Ao =

aorta

CompLND =

complete lymphadenectomy

CSS =

cancer-specific survival

DFS =

disease-free survival

EAU =

European Association of Urology

Exd =

extended

IMA =

inferior mesenteric artery

IncompLND =

incomplete lymphadenectomy

IVC =

inferior vena cava

LN =

lymph nodes

L-LU =

left lower ureter

L-MU =

left middle ureter

L-RP =

left renal pelvis

L-UU =

left upper ureter

NoLND =

no lymphadenectomy

NS =

not significant

OS =

overall survival

pN+ =

patients with lymph node metastasis

pN0 =

patients without lymph node metastases

pNx =

patients whom lymphadenectomy was not carried out

Pros =

prospectively

Retro =

retrospectively

R-LU =

right lower ureter

R-MU =

right middle ureter

R-RP =

right renal pelvis

R-UU =

right upper ureter

Std =

standard

TNM =

tumor–nodes–metastasis

UCUUT =

urothelial carcinoma of the upper urinary tract

UICC =

Union for International Cancer Control

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lymphadenectomy in bladder cancer
  5. Lymphadenectomy in UCUUT
  6. Acknowledgments
  7. Conflict of interest
  8. References

Lymphadenectomy has recently attracted considerable interest from urological surgeons, as extended lymphadenectomy might have a role in accurate staging or improving patient survival in those patients with urological malignancies, including renal cell carcinoma,1 prostate cancer,2 and urothelial carcinoma of the bladder3 and the upper urinary tract.4 Extended lymphadenectomy in renal cell carcinoma might have some benefit in accurate staging in the patients with locally advanced disease, but their therapeutic benefit remains undetermined.5 In prostate cancer, the therapeutic benefit of extended lymphadenectomy is controversial, despite some advantage in accurate pathological staging.6,7 Failure to show the survival benefit of extended lymphadenectomy in renal cell carcinoma or prostate cancer might result from the low incidence of lymphatic metastases of these diseases.7,8

Urothelial carcinoma has been known for tumors developing lymphatic metastases at a relatively high incidence of 20–30% compared with those of other urological malignancies.9,10 Thus, lymphadenectomy might have a potential role in improving the oncological outcome in patients with urothelial carcinoma compared with those with renal cell carcinoma or prostate cancer.

In the present review article, we summarized the current understanding of the role of regional lymphadenectomy in urothelial carcinoma of the bladder and the upper urinary tract from the published literature and the results from our department. There are many questions outstanding about lymphadenectomy, but in the present review article we focused on topics including the boundary of regional LN, its staging benefit and its therapeutic benefit. We discusses these points in both urothelial carcinoma of the bladder and in the upper urinary tract, so that the similarities and differences between two diseases can be understood more comprehensively.

We state that in lieu of a formal ethics committee, the principles of the Helsinki Declaration have been followed.

Lymphadenectomy in bladder cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lymphadenectomy in bladder cancer
  5. Lymphadenectomy in UCUUT
  6. Acknowledgments
  7. Conflict of interest
  8. References

History of lymphadenectomy in bladder cancer

Bladder cancer is known to show a high incidence of nodal involvement at approximately 25%.9,11 Radical cystectomy with the removal of associated LN has been an established standard surgical procedure for locally-advanced bladder cancer.12 In the 1970s, Dretler et al. reported the benefit of lymphadenectomy.13 In their report, survival of node-positive patients was improved by lymphadenectomy without increasing the morbidity and mortality. In the 1980s, Skinner et al. reported that “meticulous” lymphadenectomy provided 36% of 5-year survival in those patients with lymphatic involvement.14 Since then, pelvic lymphadenectomy has been considered as beneficial in both node-positive and node-negative patients with bladder cancer who were candidates for radical cystectomy. However, pelvic node dissection with the superior boundary at the bifurcation of the common iliac artery has been advocated based on the results in which nodal metastases were rarely observed above this level in patients with a few microscopic pelvic lymphatic metastases.15

In the early 1990s, two large studies showed that extended pelvic lymph node dissection provided long-term recurrence-free survival in some patients with pelvic lymph node metastasis.16,17 However, the extent of lymphadenectomy has not been determined, as the additional benefit by extending the boundary of lymphadenectomy from the bifurcation of the common iliac arteries to the aortic bifurcation (extended dissection) was unclear.18 Thus, the analysis of the sentinel nodes or lymph node mapping had been required to determine the regional nodes.

Boundary of regional LN

There have been several studies into detecting sentinel nodes by injecting a radioactive tracer. Sherif et al. examined the sentinel nodes detected by lymphoscintigraphy and visual inspection.19 They found that three of four metastatic sentinel nodes were located outside the normally-excised LN of the obturator fossa. Liedberg et al. also examined the sentinel nodes with a similar procedure to that of Sherif.20 In their results, 41% of patients showed that all lymph node metastases were located only outside the obturator regions. Roth et al. also analyzed the sentinel nodes by using single-photon emission computed tomography, and found that 19% of patients had primary drainage nodes at the common iliac and presacral nodes and 8% at the superior to the uretero-iliac junction.21 These studies showed that the boundary of regional nodes should be extended more cranially.

The results detecting the sentinel nodes were confirmed by lymph node mapping studies from the node-positive patients who underwent radical cystectomy with lymphadenectomy. Leissner et al. found that the incidence of lymph node metastasis was 21.0% at nodes inferior to the bifurcation of the common iliac artery, and 18.6% at the common iliac and presacral nodes.11 They also showed that 10% of primary sites of lymphatic spread were at the common iliac nodes, and tumor spread to the contralateral side of the pelvic nodes was also found. Jensen et al. also reported that approximately 10% of patients had a single positive node at the common iliac or presacral sites.22

Leissner also reported that 16.5% of LN positive for metastases were found between the level of the IMA and the aortic bifurcation, suggesting the necessity for dissection of this region especially for the purpose of staging.11 Vazina et al. reported similar results in which the incidence of metastasis to the nodes between the IMA and aortic bifurcation was approximately 8% in the tumors of pT3 or higher.23 These results have shown the necessity for dissecting more cranial nodes than aortic bifurcation nodes for the complete removal of the disease and accurate staging. However, Zehnder et al. compared the templates of the University of Southern California in which the superior boundary was the IMA, and that of the University of Bern in which the uretero-iliac crossing was the upper limit.24 Patient survival was almost equal between these two large institutions, suggesting no survival benefit from dissecting more cranial than the level of the uretero-iliac crossing. In addition, there is concern about the increased risk of complications, such as lymphocele, lymphedema or incontinence, by disrupting the sympathetic nerve in more extensive lymphadenectomy.25 Thus, whether extending the cranial boundary to the level of the IMA from that of the aortic bifurcation improves the patient survival remains unclear.

To summarize, the commonly accepted template of lymphadenectomy for bladder cancer was the genitofemoral nerve and pelvic side wall laterally, the circumflex iliac vein and Cloquet's node distally, and the aortic bifurcation cranially.25 The latest edition of TNM classification states that regional nodes includes presacral and common iliac nodes, although the common iliac nodes are considered as the secondary drainage nodes.26 Thus, as Kitamura et al. proposed, the extent of standard lymphadenectomy used to be the dissection below the bifurcation of the common iliac, but is currently extended to the aortic bifurcation as the cranial boundary3 (Fig. 1). Extended lymphadenectomy is currently considered as the dissection of the para-aortic and para-caval nodes below the IMA.

image

Figure 1. Recognition of the extent of standard and extended lymphadenectomy in bladder cancer (adapted from Kitamura et al.,3 with permission).

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Staging benefits of extended lymphadenectomy

Staging benefit is a possible favorable aspect of lymphadenectomy. It might provide more accurate information for the need for adjuvant chemotherapy or the prediction of patient prognosis. As many investigators report, the larger template of lymphadenectomy results in the higher yields of LN11,22,23,27–34 (Table 1). The incidence of patients with node-positive disease is likely to increase as the total number of lymph nodes removed increases, as shown in the aforementioned reports. In contrast, the other reports did not show a positive correlation between the number of LN removed and the incidence of node-positive disease.29,31,33 Miocinovic et al. recently reported unfavorable patient survival with metastases to the presacral and/or retroperitoneal nodes compared with those with metastasis limited to true pelvic nodes.34 Bochner and Jensen reported that the removal of LN located between the IMA and the aortic bifurcation did not improve nodal staging, as all of their patients with positive nodes above the aortic bifurcation also had metastatic nodes more distally.22,29

Table 1.  Reports of staging benefits according to the extent of lymphadenectomy in bladder cancer
AuthorsYearCranial boundary of LND templateMedian or mean number of LN removedIncidence of pN+Reference
Poulsen1998Aortic bifurcation2512.9% (≤pT3a), 50% (≥pT3b)27
Common iliac bifurcation148.9% (≤pT3a), 47.8% (≥pT3b)
Herr2002Distal common iliac arterypN0; 8, pN+; 1120%28
Bouchner2004Standard (common iliac bifurcation)821%29
Extended (aortic bifurcation)22.521%
Abdel-Latif2004Distal common iliac artery17.926.3%30
Leisnner2004IMA43.127.9%11
Vazina2004Aortic bifurcation2524.4%s23
Stein2007IMAen bloc3123%31
separate6825%
Dhar2008Limited (common iliac bifurcation)128% (≤pT2), 21% (≥pT3)35
Extended (crossing of the ureter)2216% (≤pT2), 34% (≥pT3)
Dangle2010Aortic bifurcation36.930%32
Jensen2010IMA2425.3%22
Abol-Enein2010Standard (common iliac bifurcation)1624%33
Extended (IMA)4924%
Miocinovic2011IMA3736%34
Zehnder2011Extended (crossing of the ureter)2215% (≤pT2), 37% (≥pT3)24
Super-extended (IMA)3823% (≤pT2), 46% (≥pT3)

Thus, standard lymphadenectomy below the bifurcation of the common iliac artery appears to be at least insufficient to make an accurate lymphatic staging. In the aspect of staging benefit, the regional nodes described in the 2009 TNM classification in which LN below the aortic bifurcation are included is reasonable,26 and all regional nodes should be dissected to determine an accurate nodal stage.

Therapeutic benefits of extended lymphadenectomy

The staging benefit of lymphadenectomy has been supported by many reports, as described in the previous section. However, there have been a few reports suggesting a therapeutic benefit from extended lymphadenectomy (Table 2). Poulsen et al. originally reported the therapeutic benefit of extended lymphadenectomy below the aortic bifurcation compared with limited lymphadenectomy below the bifurcation of the common iliac vessels in the subgroups with tumors confined to the bladder wall (pT3a or less; 85% vs 64%, P < 0.02) and in those without lymph node metastasis (pT3a or less and pN0; 90% vs 71%, P < 0.02).27 Dhar et al. compared two large series at the Cleveland Clinic and the University of Bern.35 The extent of lymphadenectomy was limited to below the bifurcation of the common iliac artery in the results from the Cleveland Clinic, and extended to the crossing of the ureters with the common iliac artery in those from the University of Bern. They showed the superiority of extended lymphadenectomy compared with limited lymphadenectomy in those patients with highly advanced disease, since 5-year recurrence-free survival in the patients with pT3pN0-2 was 19% in the limited and 49% in the extended lymphadenectomy groups. The recent reports by Abol-Enein et al. also showed that extended lymphadenectomy below the IMA provided better disease-free and cancer-specific survival compared with the standard lymphadenectomy below the bifurcation of the common iliac artery.33 Thus, most reports have shown the therapeutic benefit of extended lymphadenectomy in muscle-invasive bladder cancer.

Table 2.  Reports of therapeutic benefits according to the extent of lymphadenectomy in bladder cancer
AuthorsYearCranial boundary of LND templateMedian number of LN removedStage and Lymph node statusSurvivalRef
Poulsen1998Aortic bifurcation25≤pT3a and pN05 years DFS: 90%27
Common iliac bifurcation145 years DFS: 71%
Mills2001Common iliac bifurcation20pTany pN+3 years OS: 39%36
5 years OS: 29%
Herr2002Distal common iliac arterypN0: 8, pN+: 11pN0 (LN 0–3, 4–7, ≥8)5 years CSS: 23% vs 63% vs 82%28
pN0 (LN <11, LN ≥11)5 years CSS: 20% vs 44%
Abdel-Latif2004Distal common iliac artery17.9pN03 years DFS: 78.3%30
pN+3 years DFS: 37.8%
Dhar2008Limited (common iliac bifurcation)12pT2pN0, pT3pN0, pN+5 years DFS: 67%, 27%, 7%35
Extended (crossing of the ureter)225 years DFS: 77%, 57%, 35%
Abol-Enein2010Standard (common iliac bifurcation)16pT any54.7%33
Extended (IMA)4966.6%
Zehnder2011Extended (crossing of the ureter)22pN0, pN+5 years DFS: 69%, 42%24
Super-extended (IMA)385 years DFS: 71%, 40%

However, whether extending the cranial boundary to the level of the IMA from the aortic bifurcation is beneficial still remains unclear. Zehnder et al. compared the results from the two large series from the University of Southern California and the University of Bern.24 The upper extent of lymphadenectomy was at the level of IMA, which was called “super extended” in the results from the University of Southern California, and at the mid-upper third of the common iliac artery, which was described as “extended” in those from University of Bern. They showed a similar 5-year recurrence-free survival between the University of Southern California and the University of Bern in the patients with pT2pN0-2 (57% vs 67%) and in those with pT3pN0-2 (32% vs 34%). Thus, lymphadenectomy limited to below the bifurcation of the common iliac arteries might not be enough to obtain the maximum chance to survive, but the upper extent still remains undetermined with respect to the therapeutic benefit of lymphadenectomy.

Lymphadenectomy for patients with pN+ has been reported to provide long-term survival in some patients.36 Herr et al. reported that the survival of patients with pN+ improved as the number of the LN removed increased.28 In the reports from the two high-volume institutions comparing the limited lymphadenectomy of the Cleveland Clinic with the extended lymphadenectomy of the University of Bern, 5-year recurrence-free survival of the patients with pN+ was significantly higher in the patients with extended lymphadenectomy than that with the limited lymphadenectomy (35% vs 7%).35 Abol-Enein et al. reported similar results of extended lymphadenectomy in those patients with pN+.33 Thus, according to these reports, the therapeutic benefit of lymphadenectomy was found in patients with pN+, and this effect is likely to depend on the extent of the lymphadenectomy.

However, we have to be aware of the fact that most of the results described here were based on retrospective analyses. In other words, none of these studies prospectively compared the two different types of lymphadenectomy, such as limited or extended. Thus, one should notice that these favorable results of extended lymphadenectomy have not been supported at a high evidence level.12

Minimum number of LN removed influencing the patient survival

The number of the LN increases as the template of lymphadenectomy is extended.18 Several studies examined the influence of the number of LN on patient survival to identify the minimum number of nodes required for improving survival. Herr et al. reported that patients in whom nine or more LN were removed had better survival than those in whom four to seven LN or zero to three LN were dissected.28 Konety et al. also reported that 10 LN should be removed.37 Koppie et al. found that the dose–response curve for the number of LN compared with survival showed that, when adjusted for covariates, the probability of survival did not plateau, but instead continued to rise as the number of LN removed increased.38 Current understanding from a current literature review3 is that more than 30 nodes should be removed on the basis of recent studies.32,39

The ratio of the number of LN positive for metastasis to the total number of nodes removed (lymph node density) has been reported to be a good indicator for predicting the survival of patients with pN+. Lymph node density lower than 20% is likely to be associated with better survival of these patients.40,41 Thus, this value can be used to stratify patients with pN+.

Disadvantages of lymphadenectomy in bladder cancer

Thurairaja et al. stated that there is concern about the increased risk of complications, such as lymphocele, lymphedema or incontinence, by disrupting the sympathetic nerve in more extensive lymphadenectomy.25 Brossner et al. compared the incidence of complications between limited and extended lymphadenectomy, and showed the incidence of complications requiring surgical intervention was similar between limited (9%) and extended (11%) lymphadenectomy.42 Thus, they concluded that extended lymphadenectomy did not increase the surgical morbidity within 30 days after surgery, although the operation time was extended by 63 min in the extended lymphadenectomy group.42 These results are similar to the other reports showing no influence of the extent of lymphadenectomy despite the longer operation time in extended lymphadenectomy.11,27,43 Thus, these studies suggested that high-risk patients with comorbidity for whom longer operation time should be avoided are likely to be unfit for extended lymphadenectomy. Surgeons have to determine the indication for extended lymphadenectomy on an individual patient basis, as there is no guideline for the indication of extended lymphadenectomy.12,44

Summary and future prospects of lymphadenectomy in bladder cancer

Recent reports support the staging and therapeutic benefit of extended lymphadenectomy including the common iliac and presacral nodes in patients with urothelial carcinoma of the bladder. However, prospective randomized studies are still lacking. Thus, the evidence level to support extended lymphadenectomy remains low (level 3), as the curative value of lymphadenectomy is still unknown and a standardized lymphadenectomy has yet to be defined.12

In the future, the role of extended lymphadenectomy will be supported by a prospective randomized trial with a larger number of patients. In contrast, a nomogram that can predict the risk of lymphatic metastases or the survival rate with or without lymphadenectomy might help to determine the indication or the extent of lymphadenectomy. We are still in the process of establishing the sophisticated decision making regarding lymphadenectomy for bladder cancer.

Lymphadenectomy in UCUUT

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lymphadenectomy in bladder cancer
  5. Lymphadenectomy in UCUUT
  6. Acknowledgments
  7. Conflict of interest
  8. References

History of lymphadenectomy in UCUUT

Lymphatic metastases are also commonly found in UCUUT with an incidence of 30–40%.45,46 Early mapping studies carried out in the 1980s showed that lymphatic spread from tumors of the renal pelvis and upper ureter was primarily to the para-aortic and para-caval nodes, and that from the distal ureter, spread was to the pelvic nodes.45,47,48 Thus, nephroureterectomy with lymphadenectomy was advocated as the standard surgical procedure.49 However, it has not been well examined whether lymphadenectomy has any role in improving the staging accuracy or patient survival or what an optimal extent of lymphadenectomy is. This might be because of a lack of understanding about the regional nodes, and a very low incidence of UCUUT compared with that of bladder cancer.

However, in the 1990s, two Japanese studies were published examining the role of lymphadenectomy. Komatsu et al. reported superior patient survival in pN0, and suggested that lymphadenectomy provided accurate staging of these patients, but the therapeutic benefit is only applicable to selected patients.50 Miyake et al. showed that lymphadenectomy might provide a therapeutic benefit in patients with no lymphovascular invasion.51 However, a definitive conclusion could not be drawn from these studies because of the small number of patients. Thus, there have been no suggestions or recommendations as to whether routine lymphadenectomy is beneficial to patients with UCUUT.

Boundary of regional LN

The UICC TNM classification states that the regional lymph nodes for UCUUT are the hilar, abdominal para-aortic and para-caval nodes, and for the ureter, the intrapelvic nodes.52 This description is likely to have been based on the early studies of the 1980s.45,47,48 However, the influence of the laterality or the location of primary tumors on the regional nodes was not clearly shown until we examined a detailed mapping study from 42 patients with lymphatic metastases by using surgical specimens or radiological findings.53 The upper ureter was designated as the upper third of the ureter, which is superior to the IMA, the middle ureter as the middle third, from the level of the IMA to the crossing with the common iliac artery, and the lower ureter, as being below the crossing.

What we found in this study was that primary metastatic sites encompassed a wider area for the tumors of the right renal pelvis and the upper two-thirds of the right ureter when compared with the conventional understanding.53 We recently re-analyzed the mapping with 75 patients with nodes positive for metastases who were treated until October 2011. These results were very similar to those from the previous studies (Table 3). However, these recent results also showed the spread of metastases to the interaortocaval nodes from the tumor of the right renal pelvis and the presacral nodes from those of the lower ureter. These results were supported by those from Assouad et al. in which they examined the lymphatic spread from the kidneys by using adult cadavers.54

Table 3.  Summary of the primary sites of nodal involvement according to the location of the tumor (with 75 patients until October 2011)
Location of the primary tumor (No patients with nodal metastasis)SuprahilarHilarPara-cavalRetro-cavalInteraorto-cavalPara-aorticCommon iliacExternal iliacObturatorInternal iliacPresacral
RightRP (22)14 (84%)8 (36%)9 (41%)3 (14%) 
UU (3)1 (33%)1 (33%)2 (66%) 
MU (5)1 (20%)4 (80%) 
LU (7)4 (57%)1 (14%)5 (71%)2 (29%)1 (14%)
LeftRP (25)20 (80%)1 (4%)11 (44%) 
UU (0) 
MU (5)5 (100%) 
LU (8)4 (50%)2 (25%)3 (38%)1 (13%) 

The results of our mapping study led us to determine the regional lymph node. We have proposed that nodal sites where the incidence of metastasis was 30% or more were considered as the regional lymph nodes.55 However, our recent results suggest that the interaortocaval nodes should be added for the tumors from the right renal pelvis, and the presacral nodes for those of lower ureters. Diagrams of the anatomic regions of lymphadenectomy we currently propose are described in Figure 2 according to our latest mapping study.

image

Figure 2. Current recognition of the regional lymph node in UCUUT according to the location of the primary tumors in our department.

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Staging benefits of lymphadenectomy in UCUUT

In the tumors of bladder cancer, extended lymphadenectomy is likely to improve the staging accuracy.29,31,33,34 In UCUUT, Komatsu et al. reported that patients who were found to have pathological lymphatic metastases by lymphadenectomy showed worse survival that those who did not have the lymph node involvement, and suggested that lymphadenectomy might provide accurate staging, which might be used to select patients for adjuvant chemotherapy.50 We summarized the previous reports that examined the benefits of lymphadenectomy in UCUUT (Table 4). Several studies also showed that lymphadenectomy could provide a staging benefit for patients by classifying the patients according to the prognosis. Two large multi-institutional studies and one single center study showed that the patients with no metastases to LN (pN0) confirmed by lymphadenectomy showed a better survival than pNx.57,58,61 In contrast, the results from two population-based studies and one multi-institutional study demonstrated that pN+ showed worse survival than pNx.58,62,63 Identifying the patients with pathological lymphatic metastases might enable us to consider adjuvant chemotherapy for patients with poor prognosis.

Table 4.  Reports on staging and therapeutic benefit of lymphadenectomy in UCUUT
AuthorsYearNo. patientsInstituteTemplate of LNDStaging benefitsTherapeutic benefitsSubject benefiting form LNDMinimum no. LN requiredRef
Kondo2007169SingleClearly describedNot determinedYes: CompLND as an independent for CSSpT3 or higherNot determined55
Brausi200783SingleDescribedNot determinedYes: RPLD as an independent for OSpT2 or higherNot determined56
Roscigno2008132SingleDescribeYes: CSS is pN0 > pNxYes; LN ≥ 6 as an independent for CSSpT2 or higher657
Roscigno20091130MulticenterNot well describedYes: CSS is pN0 > pNx, pN+ < pNxNot determinedpT2 or higherNot determined58
Roscigno2009552MulticenterNot well describedNot determinedYes: LN ≥ 8 as an independent for CSSpN0859
Kondo2010209SingleClearly describedNot determinedYes: CompLND as an independent for CSSpT2 or higherNot a significant factor60
Abe2010293MulticenterNot well describedYes: DFS is pN0 > pNxYes; NoLND as independent for recurrencepT2 or higherNot determined61
Lughezzani20102824MulticenterNot describedYes; CSS is pN+ < pNxNo; CSS is pN0 = pNxAny TNot determined62
Burger2011785MulticenterNot well describedYes; CSS is pN+ < pNxNo; CSS is pN0 = pNxAny TNot determined63

In addition, our results also showed that the total number of LN resected increased when the template of lymphadenectomy was extended (Fig. 3). In the complete lymphadenectomy, in which all regional sites were resected, the total number of LN was higher than that of incomplete lymphadenectomy, in which lymphadenectomy did not include all regional sites. The number of LN was even higher in complete lymphadenectomy carried out prospectively. Thus, most studies supported the staging benefit of lymphadenectomy. The statement of the guidelines currently to supports the role of lymphadenectomy in optimal staging of the disease.64,65

image

Figure 3. The number of lymph nodes removed according to the type of lymphadenectomy. (inline image) IncompLND; (inline image) CompLND (Retro); (inline image) CompLND (Pros).

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Therapeutic benefits of lymphadenectomy in UCUUT

In contrast to the role of lymphadenectomy in accurate staging, its role in the therapeutic benefit has not been well determined. Based on our mapping study,53 we had determined the optimal template for lymphadenectomy in which the nodes with 30% or more chance to have metastases were included.55 Then, we retrospectively analyzed the influence of the extent of lymphadenectomy on patient survival in UCUUT. When the regional nodes were all dissected (complete lymphadenectomy), the survival of the patients with the advanced stage was significantly higher than those who did not undergo lymphadenectomy.55 The patients with incomplete lymphadenectomy in which the extent of lymphadenectomy did not include all the regional sites showed lower survival than those with complete lymphadenectomy, but there was no statistical significance. However, we made the same analysis by increasing the number of the patients for whom the surgery was carried out until October 2011, and showed that the patient survival between complete and incomplete lymphadenectomy reached statistical significance (Fig. 4). Five-year cancer-specific survival in the patients with pT2 or higher and pT3 or higher was 77.9% and 73.2% in the patients with complete lymphadenectomy, but just 54.0% and 43.7% in those with incomplete lymphadenectomy and 59.0% and 47.3% in those with no lymphadenectomy (Fig. 4).

image

Figure 4. The influence of the extent of lymphadenectomy was analyzed by comparing cancer-specific survival between (a) pT2 or higher (191 patients) and (b) pT3 or higher (140 patients). Patient survival was calculated using the Kaplan–Meier method, and the statistical significance was compared using the log–rank test. (inline image) CompLND (pT2 78 patients and pT3 56 patients); (inline image) IncompLND (pT2 30 patients and pT3 22 patients); (inline image) NoLND (pT2 83 patients and pT3 62 patients).

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Other investigators have also examined the therapeutic benefit of lymphadenectomy (Table 4). Roscigno, Brausi and Abe also showed that lymphadenectomy was an independent factor to improving patient survival.56,57,61 Contrary to our results, the results of two population-based studies showed no therapeutic benefit from lymphadenectomy in which the survival of the patients with pN0 did not differ from those with pNx,62,63 although the extent of lymphadenectomy in these two studies was not clearly described. Thus, the therapeutic benefit of lymphadenectomy was controversial, although some studies favored the benefit of lymphadenectomy in improving the oncological outcome of UCUUT as it is in bladder cancer. The current EAU guideline states the following, “However, these data are retrospective; it is not possible to standardize either indication or the extent of lymphadenectomy”.65

Minimum number of LN removed influencing patient survival

In bladder cancer, the number of LN removed has been reported to be a good indicator to optimize lymphadenectomy.18,32,39 In UCUUT, the multi-institutional study showed that cancer-specific survival continued to increase as the number of LN resected increased,59 as reported by Koppie et al. in bladder cancer.38 They also reported that the minimum number of LN required to improve the survival of patients with pN0 was eight in UCUUT.59 However, we have previously reported that the template-based lymphadenectomy (the complete lymphadenectomy vs the incomplete lymphadenectomy) significantly influenced patient survival, but the number of the LN did not.60 This might show that lymphadenectomy should be carried out on the basis of the anatomical template, and that the total number of LN excised might be used for assessing the quality of lymphadenectomy.

The ratio of the number of LN positive for metastasis to the total number of nodes removed (lymph node density) lower than 20% is likely to predict better survival of patients with bladder cancer who had lymph node involvement.40,41 There has only been one multi-institutional study addressing lymph node density in UCUUT. Bolenz et al. showed that the patients with lymph node density of 30% or more were at greater risk of disease recurrence and cancer-specific mortality.66 However, the accumulation of more results is required to discuss this issue in UCUUT.

Disadvantage of lymphadenectomy in UCUUT

In contrast to bladder cancer, the disadvantage of lymphadenectomy or the adverse influence of the extending of lymphadenectomy have not been well examined so far. We examined the results of nephroureterectomy in patients who underwent surgery in our department according to the type of lymphadenectomy (Fig. 5). CompLND indicates “complete lymphadenectomy”, in which all regional sites were dissected. IncompLND indicates “incomplete lymphadenectomy”, in which lymphadenectomy was carried out, but did not include all regional sites. As shown in Figure 5, operation time, intraoperative bleeding and the day of hospital discharge did not differ between groups. The incidence of overall complications was highest in the CompLND group, but the major complication of Clavien grade 3 or higher was found at a very low incidence. Thus, CompLND resulted in the increase of minor complications including wound infection, but did not influence the surgery. In the study of renal cell carcinoma, lymphadenectomy with a relatively wide template did not increase the complication rate compared with patients without lymphadenectomy.67 Thus, carrying out lymphadenectomy for UCUUT is unlikely to be a time-consuming procedure, and is unlikely to increase the risk of major complications. Nevertheless, we think that high-risk patients with comorbidity are unfit for lymphadenectomy, similar to bladder cancer.

image

Figure 5. The results of nephroureterectomy according to the types of lymphadenectomy are shown. CompLND indicates “complete lymphadenectomy” in which all regional sites were dissected. IncompLND indicates “incomplete lymphadenectomy” in which lymphadenectomy was carried out, but did not include all regional sites. (inline image) Overall; (inline image) Clavien ≥G3.

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Summary and future prospects of lymphadenectomy in UCUUT

There have been insufficient studies examining the role of lymphadenectomy in UCUUT to establish the level of evidence in the guidelines compared with those for bladder cancer.65 However, the majority of the results from bladder cancer support the benefit of extended lymphadenectomy, although the level of evidence in the guideline is still low.12 It might suggest that the role of lymphadenectomy in UCUUT is also important, as UCUUT is likely to simulate the biological behavior of bladder cancer because of the same histology among the two diseases.

In the future, the importance of lymphadenectomy in UCUUT should be further examined by validating templates of regional lymph nodes from other investigators, and by prospective studies with larger numbers of patients. Then, we will discuss whether lymphadenectomy can be a standard treatment for UCUUT.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Lymphadenectomy in bladder cancer
  5. Lymphadenectomy in UCUUT
  6. Acknowledgments
  7. Conflict of interest
  8. References

The authors thank Ms Clare Dover for English correction of this manuscript. We also thank Ms Yukiko Hirane and Ms Noriko Hata for secretarial work.

References

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  2. Abstract
  3. Introduction
  4. Lymphadenectomy in bladder cancer
  5. Lymphadenectomy in UCUUT
  6. Acknowledgments
  7. Conflict of interest
  8. References
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