### Abstract

#### Background

The prognosis for patients with lymph node (LN)–positive bladder cancer (BCa) is likely affected by the extent of lymphadenectomy in radical cystectomy (RC) cases. Specifically, the prognostic significance of the LN density (ratio of positive LNs to the total number removed) has been demonstrated.

#### Objective

To evaluate the prognostic signature of lymphadenectomy variables, including the LN density, for a large, multicentre cohort of RC patients with LN-positive BCa.

#### Design, setting, and participants

The clinical and histopathologic data from 477 patients with LN-positive urothelial BCa (pN1–2) were analysed. The median follow-up period for all living patients was 28 mo.

#### Measurements

Multivariable Cox regression analysis was used to test the effect of various pelvic lymph node dissection (PLND) variables on cancer-specific survival (CSS) based on colinearity in various models.

#### Results and limitations

The median number of LNs removed was 12 (range: 1–66), and the median number of positive LNs was 2 (range: 1–25). Two hundred ninety (60.8%) of the patients presented with stage pN2 disease. The median and mean LN density was 17.6% and 29% (range: 2.3–100), respectively, where 268 (56.2%) and 209 (43.8%) patients exhibited am LN density of ≤20% and >20%, respectively. In separate multivariable Cox regression models adjusted for age, sex, pTN stage, grade, associated Tis, and adjuvant chemotherapy, the interval-scaled LN density (hazard ratio [HR]: 1.01; *p**p*

#### Conclusions

Our results support the prognostic relevance of LN density in patients with LN-positive BCa, where a threshold value of 20% stratifies the population into two prognostically distinct groups. Before LN density is integrated into the clinical decision-making process, these results should be validated by prospective studies with defined LN templates and standardised histopathologic methods.

### Take Home Message

The prognosis for patients with lymph node (LN)–positive bladder cancer (BCa) is likely affected by the extent of lymphadenectomy in radical cystectomy cases. Data from 477 patients with LN-positive urothelial BCa (pN1–2) were analysed, and the results support the prognostic relevance of LN density in patients with LN-positive BCa, where a threshold value of 20% stratifies the population into two prognostically distinct groups.

**Keywords:** Bladder cancer, Urothelial cancer, Radical cystectomy, Lymphadenectomy, Lymph node metastases, Number of lymph nodes, Lymph node density, Prognosis.

### 1. Introduction

The goal of pelvic lymph node dissection (PLND) during radical cystectomy (RC) for invasive bladder cancer (BCa) is to remove the regional lymph nodes (LN), particularly the typically affected LN sites [1] and [2]. The histopathologic results and the extent of LN removal have significance as prognostic criteria and thus as indicators for adjuvant therapy [3], [4], and [5]. Moreover, there is an increasing perception that extensive PLND is an important therapeutic measure associated with improvement in cancer-specific survival (CSS) in both LN-negative and LN-positive patients [3], [4], and [5]. This viewpoint is supported by the observed histories of long-term survival in patients with LN-positive cancers [6], [7], [8], [9], [10], [11], [12], [13], and [14].

The available data on the therapeutic effect of PLND with LN-positive BCa are inconsistent, so that no evidence-based recommendations are presently specified [6], [7], [8], [9], [10], [11], [12], [13], and [14]. Furthermore, the lowest number of LNs to be removed and the necessity for an extensive PLND is debatable, made more confusing by the variety of definitions for standard versus extensive PLND [3] and [4]. Among the results are mostly retrospective patient studies, with only a small number of cases involving the stratification of prognostic criteria in LN-positive BCa. The prognosis criteria described include the pN stage, the number of positive LNs and the number of removed LNs, their derived ratio (LN density), and the initiation of adjuvant chemotherapy [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], and [14]. The significance of LN density was first pointed out in two separate studies in 2003 by Stein et al and by Herr et al, where a prognosis-relevant threshold value of 20% was established [6], [7], [12], [13], and [14]. The goal of our multicentre data analysis study was to evaluate prognosis criteria using a large cohort of RC patients with LN-positive urothelial BCa and to define factors associated with long-term survival.

### 2. Patients and methods

Clinical and pathologic information was gathered from 2556 patients with urothelial BCa who had undergone RC in one of eight German urology clinics (six university clinics, two maximum care clinics) over a 20-yr period (1989–2008); this information was merged into a multi-institutional database. The indication for RC in all participating clinics was consistent with current guideline recommendations. Among the patients in this database, 25.5% (*n**n**n**n*

LN density was calculated using the following formula: number of positive LNs times 100% divided by the total number of removed LNs. In addition to the evaluation of LN density as an interval-scaled continuous variable, an additional analysis was conducted using an ordinal-scaled dichotomised variable with a threshold value of 20% (≤20% vs >20%), a figure previously selected in many publications [6], [7], [12], [13], and [14].

The mean observation period for patients who were still alive at the end of the study was 41.3 mo (range: 2–240; median: 28 mo). The extent of the preoperative staging examination, the histopathologic workup of the RC specimens, as well as the type of follow-up testing were defined through standardised though individual in-house protocols for the respective clinics. All histopathology reports were based on the TNM classification (6th edition) [15]; prior to 2002, TNM classification was made by the study pathologist (S.G.). If problems occurred with an assignment, the original histopathology report was reviewed.

Total survival and CSS were calculated by the Kaplan-Meier method, and group differences were indicated by the log-rank test. Multivariable Cox regression models were developed with the goal of identifying those factors that would enable an independent prognosis of CSS (each model with stepwise backward elimination).

Because of the colinear association of the LN density with the number of positive LNs (*R**R**n**R*

Finally, the analysis of the best threshold value for the LN density with respect to the dichotomised boundary between two prognostically different groups was carried out using the maximal χ^{2} statistic proposed by Boulesteix [16]. Achievement of a significance level of *p*≤ 0.05 was adopted for all statistical tests.

### 3. Results

The clinical and histopathologic criteria for the 477 patients with LN-positive urothelial BCa are shown in Table 1. A tumour stage that extends beyond the muscles (pT3 or higher at 73%) and an LN status of pN2 (*n*

Variable | No. (%) or variable unit |
---|---|

Patient age, yr | |

66.3 | |

65.6 (33–86) | |

Sex, No. (%) | |

101 (21.2) | |

376 (78.8) | |

RC time frame, No. (%) | |

50 (10.5) | |

179 (37.5) | |

248 (52.0) | |

Follow-up, mo | |

16 | |

26.8 | |

28 | |

41.3 (2–240) | |

12 | |

18 (0–142) | |

pT stage, No. (%) | |

24 (5.0) | |

103 (21.6) | |

350 (73.4) | |

pN stage, No. (%) | |

187 (39.2) | |

290 (60.8) | |

Grade, No. (%) | |

79 (16.6) | |

398 (83.4) | |

Associated Tis, No. (%) | 134 (28.1) |

Adjuvant chemotherapy, No. (%) | 159 (33.3) |

Total number of removed LNs: | |

12 | |

14 (1–66) | |

Total number of removed LNs: | |

12 | |

14 (1–66) | |

Total number of positive LNs | |

2 | |

3.2 (1–25) | |

LN density, % | |

17.6 | |

29 (2.3–100) | |

LN density, dichotomised, No. (%) | |

268 (56.2) | |

209 (43.8) |

For the entire study population after 1, 3, and 5 yr, the CSS was 73%, 49%, and 39%, respectively. Patients in tumour stages pT2 or lower and pT3 or higher exhibited a CSS of 49% and 35% (*p**p*

Table 2 shows the results of the univariable and multivariable Cox regression analyses relating to CSS. The pN stage lost its independent effect once the LN density parameter (either interval scaled or ordinal scaled) was included. In contrast, the pT stage (three-fold ordinal scaling) exhibited an independent contribution in each of the three Cox regression models. The total number of removed LNs had an independent effect (interval scaled; hazard ratio [HR]: 0.97; *p**p*

Variable | Univariate analysis HR (95% CI), p value |
Multivariate analysis HR (95% CI), p value Model 1 |
Multivariate analysis HR (95% CI), p value Model 2a^{*} |
Multivariate analysis HR (95% CI), p value Model 2b^{**} |
---|---|---|---|---|

Patient age (continuous) | 1.01 (0.99–1.02), p |
NS | NS | NS |

Sex: female vs male | 1.07 (0.78–1.47), p |
NS | NS | NS |

RC time frame: | ||||

0.94 (0.78–1.13), p |
NS | NS | NS | |

pT stage: >pT2 vs pT2 vs <pT2 | 1.43 (1.11–1.85), p |
1.34 (1.04–1.74), p |
1.38 (1.07–1.79), p |
1.37 (1.06–1.78), p |

pN stage: pN2 vs pN1 | 1.41 (1.07–1.86), p |
1.47 (1.11–1.94), p |
NS | NS |

Grade: G3 vs <G3 | 1.04 (0.72–1.49), p |
NS | NS | NS |

Associated Tis: yes vs no | 0.97 (0.73–1.30), p |
NS | NS | NS |

Adjuvant chemotherapy: yes vs no | 0.89 (0,67–1.17), p |
NS | NS | NS |

Total no. LNs (continuous) | 0.97 (0.96–0.99), p |
0.97 (0.95–0.99), p |
– | – |

Total no. positive LNs (continuous) | 1.02 (0.99–1.06), p |
NS | – | – |

LN density (continuous) | 1.01 (1.00–1.01), p |
– | 1.01 (1.00–1.01), p |
– |

LN density: >20% vs ≤20% | 1.70 (1.31–2.22), p < 0.001 |
– | – | 1.65 (1.27–2.15), p < 0.001 |

^{*}
Model 2a: Exclusion of total number of removed LNs and total number of positive LNs as well as integration of the interval-scaled LN density.

^{**}
Model 2b-1: Exclusion of LN density. Model 2b: Exclusion of total number of removed LNs and total number of positive LNs as well as integration of the ordinal-scaled LN density.

HR

Variable | Multivariate analysis HR (95% CI), p value Model 2b-1^{*} (n |
Multivariate analysis HR (95% CI), p value Model 2b-2^{**} (n |
---|---|---|

Patient age (continuous) | NS | 1.03 (1.01–1.05), p |

Sex: female vs male | NS | NS |

RC time frame: | ||

NS | NS | |

pT stage: >pT2 vs pT2 vs<pT2 | NS | 1.48 (1.02–2.14), p |

pN stage: pN2 vs pN1 | NS | NS |

Grade: G3 vs <G3 | NS | NS |

Associated Tis: yes vs no | NS | NS |

Adjuvant chemotherapy: yes vs no | NS | NS |

LN density: >20% vs ≤20% | 1.83 (1.00–3.33), p |
1.58 (1.02–2.43), p |

^{*}
Model 2b-1: <12 LN.

^{**}
Model 2b-2: ≥12 LN.

HR

In a multivariable Cox regression model (with exclusion of patients undergoing adjuvant chemotherapy), only pT stage (HR: 1.39; 95% CI, 1.03–1.90; *p**p**p*

The inclusion of LN density with a threshold value of 20 led to an approximately 58.7% improvement (*p**p**p**p*

### 4. Discussion

The present RC cohort represents the largest evaluation of patients with LN-positive urothelial BCa with the exception of the Surveillance Epidemiology and End Results population [8]. Consideration of our results and those of the previous studies (Table 4) points to LN density with a threshold value of 20% as a criterion for stratifying the rather heterogeneous prognoses of patients in stage pN+. Our study is the first to document that LN density (threshold value

Study, yr | No. | Total no. of LN, median (range) | Total no. of positive LN, median (range) | Threshold value of the LN density | Results |
---|---|---|---|---|---|

Stein et al, 2003[6] | 244 | 30 (1–96) | 2 (1–63) | ≤20 vs >20 | Significantly poorer RFS and OS above the threshold value (MRA) |

Herr, 2003 [7] | 162 | 13 (2–32) | 3 (1–14) | ≤20 vs >20 | Significantly poorer CSS above the threshold value (MRA) |

Konety et al, 2003 [17] | 361 | N/A | N/A | <25, 26–50, 51–75, >75 | No significantly poorer CSS above the multiple threshold values (MRA) |

Abdel-Latif et al, 2004 [18] | 110 | 17.9 (mean) | 4.1 (mean) | <10, 10–20, >20 | No significantly poorer RFS above the multiple threshold values (MRA) |

Fleischmann et al, 2005 [14] | 101 | 22 (10–43) | N/A | <20 vs ≥20 | No significantly poorer RFS above the threshold value (MRA) |

Kassouf et al, 2006 [19] | 108 | 12 (1–58) | 2 (1–10) | ≤25 vs >25 | Significantly poorer RFS and OS above the threshold value (MRA) |

Steven and Poulsen, 2007 [13] | 64 | 27 (11–49) | N/A | ≤20 vs >20 | Significantly poorer RFS and OS above the threshold value (URA) |

Kassouf et al, 2008 [12] | 248 | 12 (2–58) | 2 (1–14) | ≤20 vs >20 | Significantly poorer CSS above the threshold value (MRA) |

Wright et al, 2008 [8] | 1260 | 9 (1–48) | 2 (1–18) | <12.6, 12.6–25, 25,1–50, >50 | Significantly poorer CSS and OS above the multiple threshold values (MRA) |

Wiesner et al, 2009 [10] | 46 | 33 (15–77) | 3 (1–28) | ≤11 vs >11 | Significantly poorer CSS above the threshold value (MRA) |

Osawa et al, 2009 [11] | 60 | 12 (1–80) | 2 (1–12) | ≤25 vs >25 | Significantly poorer OS above the threshold value (MRA) |

Bruins et al, 2009 [9] | 181^{*} |
N/A | 1 (1–2) | ≤4 vs >4 | Significantly poorer RFS and OS above the threshold value (MRA) |

Present study | 477 | 12 (1–66) | 2 (1–25) | ≤20 vs >20 | Significantly poorer CSS above the threshold value (MRA) |

^{*}
Exclusively evaluations of patients with 1–2 positive LNs.

LN

Before applying these findings to clinical practice, however, one must address whether LN density is superior to pN stage in terms of its prognostic value. The standard TNM classification for LN metastases (N category) is based on an evaluation of the number and size of positive LNs, dependent on the removal of positive LNs by the surgeon. Understaging can occur as a result of a failure to remove a sufficient number of LNs.

Various studies have compared the prognostic value of LN density and pN stage. Herr investigated the 1997/2002*p**p**p**inter alia* for adjuvant chemotherapy having been carried out, only a higher LN density (threshold value of 20%) correlated with a significant worsening of CSS (HR: 2.75; *p**p**p*

In our analysis, LN density exhibited a stronger effect on CSS compared to pN stage according to the 1997/2002 staging system. Whether interval scaled (continuous) or ordinal scaled (threshold value of 20%), LN density crowded the pN stage out of the Cox model (Table 2). The parameters found in our study to have the strongest prognostic signature (LN density and pT stage) can be used to delineate groups characterised by different mortality risks. Patients at tumour stage pT2 or lower with an LN density ≤20% exhibit a CSS of 56% after 5 yr, while patients at tumour stage pT3 or higher with an LN density >20% exhibit a 5-yr CSS of 28% (*p*

To further address the clinical application of using LN density as a prognostic criterion requires an evaluation of the unresolved issues that remain regarding LN density. Previous studies relating to the prognostic value of LN density are summarised in Table 4. The various authors defined different threshold values for LN density, with the most frequently used value being 20%. This threshold value was confirmed through our investigation and was found to be superior when compared to a threshold value of 25% using multivariable Cox analysis.

It is unclear whether the prognostic significance of LN density extends to patients who have undergone adjuvant chemotherapy, while the number of such patients is increasing at the present time. Furthermore, it must be defined what sort of additional procedures will be offered to patients with an LN density above a certain threshold value (eg, 20%). Would they be suitable candidates for adjuvant chemotherapy, while patients below the threshold value would not? Would the prognostic discriminatory power of LN density be maintained if adjuvant chemotherapy were indicated for all patients? All of the Cox regression models developed in our investigation were adjusted for adjuvant chemotherapy, although this was not the case in most of the other previous studies [7], [8], [10], [14], [17], [18], and [19].

A limitation of this study was the retrospective design, with a long timeframe for the investigation, which covered two decades and thus spanned modifications in the staging modalities and necessarily also the further development of surgical techniques, including PLND techniques. This also includes the removed LN range from 1 to 66, suggesting that some patients had an incomplete LN dissection or an inadequate pathologic review. Considering this, one must keep in mind that LN density in a group of patients with a complete LN dissection reflects the volume of metastatic disease, which results in a poor outcome. However, LN density in patients who underwent LN plucking does not reflect volume of disease, and the poor survival might other be the result of an inadequate LN dissection or higher metastatic load. Other limitations include the absence of centralised pathologic reviews and the different, clinic-specific diagnostic protocols, therapies, and follow-up care provided to the patients included in the study. Moreover, no information was available to us regarding patient comorbidities, which could also indirectly influence the surgeon's decision on the extent of the PLND; similarly, no information was available on the extracapsular spread of LN metastases. Finally, consideration must also be given to the fact that 19.6% of the LN-positive patients (128 of 653) were excluded from the total database because of incongruent or missing data.

### 5. Conclusions

Despite its limitations, the results of this large RC cohort of LN-positive patients are important with respect to the heterogeneous prognoses in this patient population. LN density with a threshold value of 20% is presented as an instrument for stratifying these patients on the basis of their distinct oncologic progression. Before LN density can be integrated into the pN classification and the clinical decision-making process, however, the present results should be validated by prospective studies with defined LN dissection areas and standardised histopathologic examination methods. Overall, evidence has emerged from our investigation that patients with LN-positive urothelial BCa will benefit from an extended PLND in the course of an RC [20] and [21].

* Author contributions:* Patrick J. Bastian had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

*Study concept and design:* May, Herrmann, Bolenz, Tiemann, Fritsche, Burger, Buchner, Bastian.

*Acquisition of data:* May, Herrmann, Bolenz, Tiemann, Brookman-May, Fritsche, Burger, Buchner, Gratzke, Wülfing, Trojan, Ellinger, Tilki, Gilfrich, Höfner, Roigas, Zacharias, Gunia, Wieland, Hohenfellner, Michel, Haferkamp, Müller, Stief, Bastian.

*Analysis and interpretation of data:* May, Herrmann, Bolenz, Tiemann, Fritsche, Burger, Buchner, Bastian.

*Drafting of the manuscript:* May, Herrmann, Bolenz, Tiemann, Fritsche, Burger, Buchner, Gratzke, Trojan, Bastian.

*Critical revision of the manuscript for important intellectual content:* May, Herrmann, Bolenz, Tiemann, Brookman-May, Fritsche, Burger, Buchner, Gratzke, Wülfing, Trojan, Ellinger, Tilki, Gilfrich, Höfner, Roigas, Zacharias, Gunia, Wieland, Hohenfellner, Michel, Haferkamp, Müller, Stief, Bastian.

*Statistical analysis:* May, Herrmann, Bolenz, Tiemann, Fritsche, Burger, Buchner, Bastian.

*Obtaining funding:* May, Herrmann, Bolenz, Tiemann, Brookman-May, Fritsche, Burger, Buchner, Gratzke, Wülfing, Trojan, Ellinger, Tilki, Gilfrich, Höfner, Roigas, Zacharias, Gunia, Wieland, Hohenfellner, Michel, Haferkamp, Müller, Stief, Bastian.

*Administrative, technical, or material support:* May, Herrmann, Bolenz, Tiemann, Brookman-May, Fritsche, Burger, Buchner, Gratzke, Wülfing, Trojan, Ellinger, Tilki, Gilfrich, Höfner, Roigas, Zacharias, Gunia, Wieland, Hohenfellner, Michel, Haferkamp, Müller, Stief, Bastian.

*Supervision:* May, Herrmann, Bolenz, Tiemann, Brookman-May, Fritsche, Burger, Buchner, Gratzke, Wülfing, Trojan, Ellinger, Tilki, Gilfrich, Höfner, Roigas, Zacharias, Gunia, Wieland, Hohenfellner, Michel, Haferkamp, Müller, Stief, Bastian.

*Other* (specify): None.

* Financial disclosures:* I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

* Funding/Support and role of the sponsor*: None.

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### Footnotes

^{a}
Klinik für Urologie, St. Elisabeth Klinikum Straubing, Straubing, Germany

^{b}
Urologische Universitätsklinik, Universität Münster, Münster, Germany

^{c}
Universitätsmedizin Mannheim, Mannheim, Germany

^{d}
Klinik für Urologie der Universität Regensburg, Caritas Krankenhaus St. Josef, Regensburg, Germany

^{e}
Klinik und Poliklinik für Urologie und Kinderurologie, Universitätsklinikum Bonn, Bonn, Germany

^{f}
Urologische Universitätsklinik, LMU München, München, Germany

^{g}
Urologische Universitätsklinik, Universität Heidelberg, Heidelberg, Germany

^{h}
Urologische Universitätsklinik, Universität Frankfurt/Main, Frankfurt/Main, Germany

^{i}
Urologische Klinik, Vivantes Kliniken Am Urban und Im Friedrichshain Berlin, Berlin, Germany

^{j}
Urologische Klinik, Vivantes Klinikum AVK Berlin, Berlin, Germany

^{k}
Pathologisches Institut, Helios-Klinikum Bad Saarow, Bad Saarow, Germany

Corresponding author. Department of Urology, Klinikum der Universität München–Campus Großhadern, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 Munich, Germany. Tel. +49 89 7095 0; Fax: +49 89 7095 6720.

^{1}
These authors contributed equally to this study.

### Article information

PII: S0302-2838(11)00051-0

DOI: 10.1016/j.eururo.2011.01.030

© 2011 European Association of Urology, Published by Elsevier B.V.

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