Lymph node yield in node-negative patients predicts cancer specific survival following radical cystectomy for transitional cell carcinoma

Bladder cancer is among the most common newly diagnosed cancer in the Western population, with an estimated 77,000 new cases diagnosed in the US in 2016 [1]. Following progression to muscle-invasive bladder cancer (pT2), curative treatment of choice is radical cystectomy including regional lymph node dissection [2]. From time of diagnosis Australian bladder cancer patients have a 5-year survival rate of approximately 58% [3, 4, 5]. Accordingly, there is an inherent need for improved treatment regimens for these patients. Organ-confined muscle-invasive bladder tumours are often complex with up to 25% having lymph node metastasis [6]. There is mounting evidence suggesting the addition of pelvic lymph node dissection (PLND) to radical cystectomy provides superior oncological outcomes compared to non-PLND cohorts. Specifically, lymphadenectomy provides improved cancer staging, prolongs time to disease recurrence and cancer-specific survival [7, 8, 9, 10, 11, 12, 13]. As such, contemporary European Urological Association guidelines support radical cystectomy and regional lymph node dissection for curative treatment of muscle invasive bladder cancer [2].

The improved oncological outcomes following PLND have prompted changes to dissection practices, with clinicians adopting more extensive dissection templates [14]. The precise oncological benefits of varying dissection templates are unclear and this is reflected by uncertain guidelines. Current data suggests that more extensive dissection results in improved oncological outcomes [15]. However there may be no added oncological benefit to superextended dissection above the mid-upper third of the common iliac vessels [10]. There is still no consensus regarding the boundaries or nomenclature of a standard set of PLND templates [15]. We aim to investigate the impact of lymph node yield and dissection extent on oncological outcomes in an Australian cohort treated surgically for primary bladder cancer.

In total 353 patients were identified, of which 71 did not have any nodes taken and 62 were node positive, leaving a study cohort of 220 node-negative patients (62% of total). The greater proportion of patients were male patients (80%) and received cystoprostatectomy surgery. Of the female patients, a majority (63%) also had concurrent hysterectomy. Of the included patients, 131 recorded a time on study of 2 years or more and 55 were followed for at least 5 years. Over the entire study period, 49 (22%) suffered cancer-specific mortality, 26 of which occurred within 2 years of surgery, with a further 14 (6.4%) dying of another cause. Demographic, surgical, and pathological data are summarized in Table 1.

Table 1
Demographic, surgical, and pathological characteristics of the study cohort (n=220)

• Click for larger image
• Click for full table
• Download as Excel file

1. Trends in node dissection

The proportion of surgeries with concomitant PLND to sPLND or ePLND steadily increased throughout the study period from 5.3% in 2005–2006 to 59% in 2013–2014 (Fig. 2). The number of nodes harvested in a cystectomy for our node-negative cohort similarly increased from a mean of 7.4 in the first 2 years to 17 in the latter 2 years (Fig. 3).

Fig. 2
Populations of highest dissection level over time.

• Click for larger image
• Download as PowerPoint slide

Fig. 3
Populations of number of nodes taken over time.

• Click for larger image
• Download as PowerPoint slide

2. Effect of PLND in node-negative disease

The number of nodes harvested from PLND was associated with time to cancer specific mortality. A Kaplan-Meier plot is shown in Fig. 4 with the log-rank test of overall difference between the groups reaching conventional significance (p=0.045). In a Cox proportional-hazards model with adjustment for pathological T stage, margin status, age at surgery, and year of surgery, node harvest independently predicted survival. Compared to cases where 1 to 5 nodes were taken, the hazard ratio (HR) for 6 to 15 nodes harvested was 0.78 (95% confidence interval [CI], 0.43–1.39; p=0.39) and for greater than 15 nodes the HR was 0.31 (95% CI, 0.17–0.57; p<0.001) (Table 2). Analysing node harvest as a continuous variable in a multivariable logistic model yielded a predicted probability of bladder cancer death in 2 years of 16% (95% CI, 13%–19%) for 10 nodes taken, decreasing to 5.5% (95% CI, 0%–12%) with 30 nodes taken (Fig. 5). Increasing node harvest in each dissection template was observed to decrease the chance of 2-year cancer-specific mortality (Fig. 6).

Fig. 4
Kaplan-Meier plots of bladder cancer specific survival grouped by number of nodes harvested with log-rank test.

• Click for larger image
• Download as PowerPoint slide

Fig. 5
Predicted probability (red line) of bladder cancer death within 2 years of cystectomy and 95% confidence interval. Black dots are patients who died of bladder cancer and blue dots are patients alive at 2. One patient alive at 2 years with 68 nodes harvested not shown.

• Click for larger image
• Download as PowerPoint slide

Fig. 6
Predicted probability of bladder cancer death within 2 years of cystectomy versus number of nodes taken at each dissection level.

• Click for larger image
• Download as PowerPoint slide

Table 2
Multivariable Cox regression mode

• Click for larger image
• Click for full table
• Download as Excel file

To our knowledge we present the largest Australian series investigating lymphadenectomy and disease specific survival in the surgical management of bladder cancer. The results of the current study highlight the increasing trend of aggressive node dissection in radical cystectomy patients. Further, the current study has identified improved cancer-specific survival with increased lymph node yield in nodenegative patients.

Our study identified the significant trend of increasing use of standard and extended lymph node dissection across the study period [14]. Such trends are consistent with a growing body of evidence highlighting improved oncological outcomes with more extensive lymph node dissections. Bi et al. [15] performed a meta-analysis comparing ePLND versus sPLND. Despite heterogeneity of definitions, this group defined ePLND included dissection of all lymph nodes between the aortic bifurcation and common iliac vessels (proximally), the genitofemoral nerve (laterally), and the circumflex iliac vessel (inferiorly) – consistent with ePLND in our cohort. Super-ePLND extended cranially to the level of the inferior mesenteric artery – representing a level of dissection that was not performed in our study. The pooled data analysis produced highlighted the superiority of ePLND and super-ePLND compared to sPLND, irrespective of nodal positivity status. Additionally, recent literature has directly compared the effect of ePLND and super-ePLND. Intuitively, the principles of accurate nodal staging and local cancer control would support a super extended PLND. However, such aggressive management regimes may expose patients to significant morbidity and longer operating times. Accordingly, the potential oncological benefit must be considered against to potential morbidity. Oncologically, multiple groups have reported that super-ePLND has comparable disease free survival to PLND limited to below the aortic bifurcation [10, 17]. Therefore, a dissection template limited to the aortic bifurcation proximally is reasonable – represented by the extended PLND cohort in our study.

Lymphadenectomy improves survival in both nodepositive and node-negative cohorts. In our cohort of nodenegative patients, we identified that increasing lymph node yield during PLND correlated with an improved oncological outcome. In the current cohort, increasing nodal harvest categorically from less than five nodes, to greater than five and greater than 15 nodes progressively improved cancer-specific survival. Our findings are corroborated by recent reports in contemporary literature [18]. May et al. [19] assessed 1,291 node-negative patients following radical cystectomy and PLND. Converse to our study, this group did not identify the continuous number of lymph nodes as significant independent predictor of cancer-specific survival (HR, 0.98; 95% CI, 0.96–1.01; p=0.140). However, utilizing a cutoff value of greater than 16 nodes resulted in a decreased probability of cancer mortality.

Further, in our cohort, improved cancer-specific survival with increased nodal yield occurred independent of dissection template. For limited, standard, or extended PLND, the risk of mortality reduced with more meticulous dissections (Fig. 5). Accordingly, it has been proposed that total lymph node yield may act as a quantitative measure of PLND quality [20]. Several groups have addressed whether a minimum number of lymph nodes should be assessed following radical cystectomy with PLND. Previous groups have proposed minimal nodal counts between 4 to 16 [9, 19, 21, 22]. Conversely, other groups recommend thorough anatomical PLND without minimum nodal counts [11].

The precise mechanism for increased nodal yield and resulting improved survival in node-negative patients is uncertain. It is likely that in this setting, the benefit of PLND is removal of underdetected micrometastases [23]. Removal of lymph nodes with micrometastatic deposit may improve survival by reducing overall tumour burden and allowing the immune system and chemotherapeutics to target a smaller number of cancer cells [24]. New techniques employing immunohistochemical analysis and reverse transcription real-time polymerase chain reaction can aid in detection of micrometastases [25, 26]. It has been demonstrated that patients with micrometastases who are otherwise node-negative on routine analysis have a trend toward worse cancer specific survival and recurrence free survival than truly node-negative patients [25]. The observed predictive value of the lymph node yield may be a result of confounding patient, surgeon or institutional factors that may contribute to improved outcomes [19]. Specifically, high-risk patients may have a limited dissection while a more aggressive approach is employed in patients with superior premorbid function. Similarly, increased surgeon experience may improve quality of performing an aggressive PLND. Lastly, as highlighted by May et al. [19], this association may be the result of the Will-Rogers stage-migration phenomenon. In this setting, the examination of increased lymph nodes results in the upstaging due to more extensive nodal sampling. Accordingly, these patients are reclassified as N1 that would have otherwise been classified as N0 with high nodal yield. Subsequently, patients that underwent more extensive PLND are likely to have superior oncologic outcomes as these patients are more likely to be truly node-negative [27, 28].

There are several limitations to the current study. Firstly, there are inherent limitations with the retrospective nature of the current study, given data is reliant of accurate documentation. Further, several pertinent treatment details were not available for data collection. Specifically, data pertaining to neo-adjuvant, adjuvant, salvage or palliative chemotherapy or radiotherapy were not available. Our study did not assess the impact of reviewing pathologist on lymph node yield. However prior study has shown the reviewing pathologist does not alter the reported lymph node yield [29]. Despite these limitations, as highlighted, this represents the most comprehensive Australian radical cystectomy database to-date.

The findings of the current study highlight the increased uptake in more extensive, meticulous PLND during cystectomy for node-negative patients. Our study highlights the improved oncological outcomes with increasing LNY, irrespective of the extent of dissection. Further, robust prospective clinical research is needed to aid interpretation of lymph node dissection data.