Lymph node density affects cancer-specific survival in patients with lymph node-positive urothelial bladder cancer following radical cystectomy

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 = 0.002) and the LN density, ordinal-scaled by 20% (HR: 1.65; p < 0.001) exhibit independent effects on CSS. In addition, an independent contribution appears from the pT but not the pN stage. Limitations include surgeon selection bias when determining the extent of lymphadenectomy.

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.     

Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ‐confined (OC) to non‐organ‐confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0–8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6–4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome.

OBJECTIVES

• ? To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres.
• ? To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC.

PATIENTS AND METHODS

• ? Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992–2010) and University of Turku, Turku, Finland (1986–2005) were analysed.

RESULTS

• ? Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ‐confined (OC) to non‐organ‐confined (nOC) disease.
• ? During the study period, upstaging became more common in both centres.
• ? In multivariate analyses, T2 disease at initial presentation (P= 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44–4.77), high grade disease (P= 0.01, OR = 2.85, 95% CI: 1.21–6.7), lymphovascular invasion (LVI) (P < 0.001, OR = 5.17, 95% CI: 3.48–7.68), female gender (P= 0.038, OR = 0.6, 95% CI: 0.38–0.97, and histological variants (P < 0.001, OR = 2.77, 95% CI: 1.6–4.8) were associated with a risk of upstaging from OC to nOC disease.
• ? Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10‐year disease‐specific mortality, P < 0.001).

CONCLUSIONS

• ? Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades.
• ? LVI and the presence of histological variants are strong predictors of upstaging at the time of RC.
• ? Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.

     

Lymph node mapping in patients with bladder cancer undergoing radical cystectomy and lymph node dissection to the level of the inferior mesenteric artery

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To evaluate extended lymph node dissection (LND) as a nodal staging tool in the treatment of invasive carcinoma of the urinary bladder and to suggest a reasonable proximal limit of the dissection.

PATIENTS AND METHODS

In all, 170 patients underwent radical cystectomy with extended LND up to the level of the inferior mesenteric artery. Specimens were evaluated as 13 separate packages from pre‐designated anatomical locations. The number of LNs and presence of positive LNs (LN+) at each location was prospectively registered.

RESULTS

The median (range) number of LNs removed was 24 (6–62). In all, 25.3% of the patients had LN+. The median (range) number of LN+ was 2 (1–20). Advanced T‐stage was correlated with a higher risk of LN+ but not to the specific location of the LN+. Two patients had LN+ above the common iliac bifurcation with no LN+ more distally located within the pelvic region. All other patients with LN+ above the common iliac bifurcation had more distally located LN+. There were no skip lesions to LNs above the aortic bifurcation.

CONCLUSIONS

Extended LND above the common iliac bifurcation including the presacral area provides a more accurate LN staging compared with a standard pelvic LND. Extending the limits above the aortic bifurcation is not necessary from a staging perspective.     

Standardization of radical cystectomy and pelvic lymph node dissection for bladder cancer: a collaborative group report

PURPOSE: We propose standards for radical cystectomy and pelvic lymph node dissection in the surgical treatment of patients with invasive bladder cancer. MATERIALS AND METHODS: We compiled the consecutive cystectomy experience of 16 experienced surgeons during the last 3 years (2000 to 2002) from 4 institutions. We evaluated patient, tumor and surgical variables of margin status, extent of pelvic node dissection, number of nodes examined and surgeon volume associated with bladder cancer outcomes. RESULTS: A total of 1,091 cystectomy cases were evaluated. Surgical margins and number of nodes retrieved correlated with patient age, prior treatments, pathological tumor stage and extent of node dissection, but not surgeon volume. CONCLUSIONS: Standards for radical cystectomy can be established and achieved by experienced surgeons operating on patients presenting with diverse clinical situations.     

Assessing the minimum number of lymph nodes needed at radical cystectomy in patients with bladder cancer

OBJECTIVE

To identify the likelihood of finding one or more positive lymph nodes (LNs) according to the number of LNs removed at radical cystectomy (RC), as the number of LNs removed affects disease progression and survival after RC.

PATIENTS AND METHODS

Between 1984 and 2003, 731 assessable patients had RC and bilateral pelvic lymphadenectomy at three different institutions. ROC curve coordinates were used to determine the probability of identifying one or more positive LNs according to the total number of removed LNs.

RESULTS

Of the 731 patients, 174 (23.8%) had LNs metastases. The mean (median, range) number of LNs removed was 18.7 (17, 1–80). The ROC coordinate‐based plots of the number of removed LNs and the probability of finding one or more LNs metastases indicated that removing 45 LNs yielded a 90% probability. Conversely, removing either 15 or 25 LNs indicated, respectively, 50% and 75% probability of detecting one or more LNs metastases.

CONCLUSIONS

These data indicate that removing 25 LNs might represent the lowest threshold for the extent of lymphadenectomy at RC. Our findings confirm the importance of an extended lymph node dissection.     

Role of lymph node density in predicting survival of patients with lymph node metastases after radical cystectomy: A multi-institutional study

Objectives:   To evaluate the prognostic role of different clinico-pathological parameters in node-positive patients treated by radical cystectomy.
Methods:   A retrospective multi-institutional study of 435 patients who underwent radical cystectomy between 1990 and 2005 was carried out. Of them, pathological lymph node (LN) metastases were found in 83 patients. Sixty of these 83 patients, whose clinical information and follow-up data were available, were included in the analysis. Twenty-five patients had undergone adjuvant chemotherapy, whereas 35 had not. A Cox proportional hazards model was used to determine the impact of the following clinico-pathological parameters on patient survival: number of resected LNs, number of positive LNs, LN density (defined as the ratio of the number of positive LNs divided by the total number of resected LNs) and adjuvant chemotherapy.
Results:   Median follow-up for surviving patients was 41 months (range 4–138) after surgery. The median survival time for all patients was 22 months (95% confidence interval, 15–42 months). At multivariate analysis, LN density of 25% or less, adjuvant chemotherapy and pure urothelial carcinoma were independently significant predictors of survival.
Conclusions:   Lymph node density predicts survival in patients with node-positive bladder cancer.     

Prognostic significance of adjuvant cisplatin-based combination chemotherapy following radical cystectomy in patients with invasive bladder cancer

Objectives: The objectives of this study were to retrospectively examine the outcomes of adjuvant cisplatin‐based combination chemotherapy following radical cystectomy in patients with invasive bladder cancer in order to identify parameters predicting the prognosis of these patients. Methods: This study included a total of 51 patients with muscle invasive bladder cancer who underwent radical cystectomy between January 1995 and December 2004, and subsequently received at least two cycles of either MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) or MVP‐CAB (methotrexate, doxorubicin, vincristine, cyclophosphamide, bleomycin and cisplatin) chemotherapy in an adjuvant setting because of the presence of diseases corresponding to pT3/4 and/or pN1/2 without clinical evidence of metastasis. The significance of several clinicopathological factors as predictors of disease recurrence and cancer‐specific death was evaluated using univariate and multivariate analyses. Results: During the observation period of this study (median, 26.5 months), disease‐recurrence and cancer‐specific death were observed in 21 and 16 patients, respectively. The 5‐year recurrence‐free and cancer‐specific survival rates were 48.6% and 54.1%, respectively. Among several factors examined in this series, lymph node metastasis and concomitant carcinoma in situ (CIS) were identified as significant predictors of both disease‐recurrence and cancer‐specific death, and these were also independently associated with disease‐recurrence and cancer‐specific death. Conclusions: Adjuvant cisplatin‐based combination chemotherapy for patients with extravesically extended bladder cancer following radical cystectomy resulted in comparatively unsatisfactory outcome concerning cancer‐control; accordingly, it would be necessary to develop a more efficacious therapeutic strategy for such patients, particularly for those with lymph node metastasis and/or concomitant CIS.     

Clinical outcome of radical cystectomy for patients with pT4 bladder cancer

Objective:   The objective of this study was to analyze the outcomes of radical cystectomy for patients with pT4 bladder cancer.
Methods:   Between 1995 and 2003, 583 patients underwent radical cystectomy for bladder cancer at our institution and related hospitals, including 76 pathologically diagnosed as having pT4 disease. Of these 76, this study included 60 patients after excluding 16 with pT4Tis disease, and a retrospective review of their records was carried out.
Results:   Pathological examinations demonstrated that seven (11.6%) and 53 (88.4%) patients were Grades 2 and 3, respectively, and 48 (80.0%), 38 (63.4%), 10 (16.7%) and 30 (50.0%) were positive for lymphatic invasion, microvenous invasion, surgical margin and lymph node metastasis, respectively. During the observation period of this study (median, 24.5 months; range, 2–89 months), disease recurrence occurred in 38 (63.3%), and the median time to recurrence after radical cystectomy was 7.0 months (range, 1–38 months). One-, 3- and 5-year cancer-specific survival rates of the 60 patients were 68.8%, 48.5% and 23.9%, respectively. Univariate analysis identified lymph node metastasis, lymphatic invasion, microvenous invasion and positive surgical margin as significant predictors for cancer-specific survival; however, only lymph node metastasis was shown to be independently associated with cancer-specific survival by multivariate analysis.
Conclusions:   The prognosis of patients with pT4 bladder cancer is generally poor, particularly for those with nodal involvement. Therefore, it would be potentially important to carry out careful follow-up for such patients following radical cystectomy and, if necessary, to consider a multimodal therapeutic approach in an adjuvant setting.     

二次电切在降低非肌层浸润性膀胱癌初次电切术后复发率中的临床价值

目的探讨经尿道膀胱肿瘤二次电切术（Re-TURBT）在降低T_a和T₁期非肌层浸润性膀胱癌（NMIBC）电切术后肿瘤复发率的临床价值。 方法回顾性分析2015年2月至2018年11月我院86例诊断为T_a和T₁期的NMIBC患者。患者接受单次经尿道膀胱肿瘤电切术为对照组（40例）,接受二次经尿道膀胱肿瘤切除术为观察组（46例）,两组患者首次电切术中均联合了吉西他滨即刻膀胱灌注化疗。统计观察组二次电切的阳性率及肿瘤分期分级变化情况,同时比较两组患者术后2年内的肿瘤复发及进展情况。 结果两组患者年龄、性别、吸烟史、肿瘤最大径、肿瘤个数、首次电切病理分期比较差异无统计学意义（P>0.05）。观察组二次电切术后的病理结果显示,11例（23.91%）检出残余癌,5例出现临床分期升级,4例病理分级升级。观察组术后2年总复发率低于对照组（P<0.05）。两组术后2年总进展率差异无统计学意义（P>0.05）。 结论Re-TURBT可明显降低T_a和T₁期NMIBC电切术后肿瘤复发率,同时可获得更准确的肿瘤分期,具有一定的临床价值。     

Stage-specific impact of pelvic lymph node dissection on survival in patients with non-metastatic bladder cancer treated with radical cystectomy

Study Type – Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? In patients treated with radical cystectomy, pelvic lymph node dissection may have a beneficial effect on cancer control outcomes. We examined the effect of pelvic lymph node dissection on stage‐specific cancer control outcomes.

OBJECTIVE

• ? To examine the effect of stage‐specific pelvic lymph node dissection (PLND) on cancer‐specific (CSM) and overall mortality (OM) rates at radical cystectomy (RC) for bladder cancer.

METHODS

• ? Overall, 11 183 patients were treated with RC within the Surveillance, Epidemiology, and End Results database.
• ? Univariable and multivariable Cox regression analyses tested the effect of PLND on CSM and OM rates, after stratifying according to pathological tumour stage.

RESULTS

• ? Overall, PLND was omitted in 25% of patients, and in 50, 35, 27, 16 and 23% of patients with respectively pTa/is, pT1, pT2, pT3 and pT4 disease (P < 0.001).
• ? For the same stages, the 10‐year CSM‐free rates for patients undergoing PLND compared with those with no PLND were, respectively, 80 vs 71.9% (P = 0.02), 81.7 vs 70.0% (P < 0.001), 71.5 vs 56.1% (P = 0.001), 43.7 vs 38.8% (P = 0.006), and 35.1 vs 32.0% (P = 0.1).
• ? In multivariable analyses, PLND omission was associated with a higher CSM in patients with pTa/is, pT1 and pT2 disease (all P ≤ 0.01), but failed to achieve independent predictor status in patients with pT3 and pT4 disease (both P ≥ 0.05).
• ? Omitting PLND predisposed to a higher OM across all tumour stages (all P ≤ 0.03).

CONCLUSIONS

• ? Our results indicate that PLND was more frequently omitted in patients with organ‐confined disease.
• ? The beneficial effect of PLND on cancer control outcomes was more evident in these patients than in those with pT3 or pT4 disease.
• ? PLND at RC should always be considered, regardless of tumour stage.

     

Cancer‐specific survival after radical cystectomy and standardized extended lymphadenectomy for node‐positive bladder cancer: prediction by lymph node positivity and density

OBJECTIVE

To investigate the associations between different overall or topographically restricted lymph node (LN) variables and cancer‐specific survival (CSS) after radical cystectomy (RC) and extended LN dissection (LND) with curative intent in patients with LN‐positive bladder cancer.

PATIENTS AND METHODS

Between 2001 and 2006, 152 patients had RC with standardized extended LND for bladder cancer with curative intent. Patients with positive LNs were stratified according to the median of the LN variables (LNs removed, number of positive LNs, LN density). CSS was related to overall and topographically restricted LN variables, e.g. different levels of LND, and relationships were tested by univariate and multivariate analyses. Level 1 LND comprised the regions of the external and internal iliac LNs and of the obturator LNs, level 2 the templates of common iliac and presacral LNs, and level 3 the para‐aortic and paracaval LNs up to the inferior mesenteric artery. The mean (range) follow‐up was 22 (1–84) months.

RESULTS

LN metastases were diagnosed in 46 of the 152 patients (30%) with extended LND. In these 46 patients, the median number of removed LNs was 33 (level 1, 15.5; level 2, 9.0; level 3, 7.0), the median number of positive LNs was 3 (1.5, 0.5 and 0.0, respectively) and the median LN density was 0.11 (0.10, 0.02 and 0.0, respectively). The CSS was 76% at 1 year and 23% at 3 years. There were significant correlations between the 3‐year CSS and the overall LN density (≤0.11 vs >0.11; 34% vs 8%, P = 0.008), and the total number of positive LNs (≤3 vs >3; 33% vs 8%; P = 0.05). Overall LN density (hazard ratio 0.33, 95% confidence interval 0.15–0.72; P = 0.006) was an independent predictor for CSS in multivariate analysis.

CONCLUSIONS

Overall LN density is an independent predictor of survival after RC and extended LND with curative intent. Evaluation of topographically restricted LN positivity and density for different regions and levels of LND does not improve the prediction of CSS compared with overall LN positivity and density. A low incidence of level 3 LN positivity questions the clinical relevance of removing para‐aortic and paracaval LNs. However, our data need to be confirmed by a prospective randomized trial.     

Outcome of patients with grossly node positive bladder cancer after pelvic lymph node dissection and radical cystectomy

PURPOSE: Should the surgeon proceed with surgery when grossly positive nodes are found at cystectomy? To answer this question, we determine the outcome of patients after radical surgery alone for grossly node positive bladder cancer. MATERIALS AND METHODS: A total of 84 patients with grossly node positive (N2-3) bladder cancer found at cystectomy underwent extended pelvic lymph node dissection and have been followed for up to 10 years. The end point of study was disease specific survival. RESULTS: Of the 84 patients 20 (24%) survived and 64 (76%) died of disease. Median survival time was 19 months for all patients and 10 years for surviving patients. Of 53 patients with clinical stage T2 (organ confined) tumors 17 (32%) survived versus 3 of 31 (9.7%) with stage T3 (extravesical) tumors. CONCLUSIONS: A proportion of patients with grossly node positive bladder cancer can be cured with radical cystectomy and thorough pelvic lymph node dissection.     

膀胱癌淋巴结转移特点及对合理施行盆腔淋巴结清扫术的临床意义

目的 探讨膀胱癌淋巴结转移特点及其在根治手术中合理施行盆腔淋巴结清扫术的临床意义. 方法收集1990年1月至2008年9月因膀胱癌行全膀胱切除术77例患者的临床病理资料.男58例,女19例.平均年龄57岁.术后TNM分期:T1 9例,T2 24例,T3 39例,T4 5例.常规将盆腔淋巴结分5组,比较各组转移率和阳性淋巴结检出率.转移率为发生淋巴结转移患者的例数占全部患者的百分比.阳性淋巴结检出率为转移淋巴结枚数占全部检取淋巴结总枚数的百分比. 结果全组淋巴结总转移率和阳性淋巴结检出率分别为27.3%(21/77)和14.8%(233/1576).各组转移率由高到低依次为闭孔、髂内、髂外、髂总和骶前,分别为19.5%(15/77)、19.3%(11/57)、13.7%(10/73)、5.3%(3/57)和3.8%(1/26),差异有统计学意义(P<0.01).各组阳性淋巴结检出率由高到低依次为髂外、闭孔、髂总、髂内和骶前,分别为23.0%(83/361)、22.1%(103/467)、9.5%(17/179)、6.8%(28/411)和1.3%(2/158),差异有统计学意义(P<0.01).9例T1患者均无淋巴结转移. 结论膀胱癌行根治术时,对淋巴结转移率高的闭孔和髂内区域必须清扫,对阳性淋巴结检出率高的髂外和闭孔区域要完整清扫.根据术中闭孔、骶前的可疑淋巴结活检是否阳性,确定盆腔淋巴清扫范围.对非肌层浸润性膀胱癌患者不建议行淋巴结清扫术.