EUROPEAN UROLOGY 60 (2011)

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1 EUROPEAN UROLOGY 60 (2011) available at journal homepage: Platinum Priority Bladder Cancer Editorial by Simon P. Kim and R. Jeffrey Karnes on pp of this issue Lymph Node Dissection Technique Is More Important Than Lymph Node Count in Identifying Nodal Metastases in Radical Cystectomy Patients: A Comparative Mapping Study Ryan P. Dorin a, Siamak Daneshmand a, Manuel S. Eisenberg a, Shahin Chandrasoma a, Jie Cai a, Gus Miranda a, Peter W. Nichols a,b, Donald G. Skinner a, Eila C. Skinner a, * a USC Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; b USC Institute of Urology, Department of Pathology, University of Southern California, Los Angeles, CA, USA Article info Article history: Accepted July 5, 2011 Published online ahead of print on July 14, 2011 Keywords: Cystectomy Extended lymphadenectomy Bladder cancer Metastases Abstract Background: The value of lymph node dissection (LND) in the treatment of bladder urothelial carcinoma is well established. However, standards for the quality of LND remain controversial. Objective: We compared the distribution of lymph node (LN) metastases in a twoinstitution cohort of patients undergoing radical cystectomy (RC) using a uniformly applied extended LND template. Design, setting, and participants: Patients undergoing RC at the University of Southern California (USC) Institute of Urology and at Oregon Health Sciences University (OHSU) were included if they met the following criteria: (1) no prior pelvic radiotherapy or LND; (2) lymphatic tissue submitted from all nine predesignated regions, including the paracaval and para-aortic LNs; (3) bladder primary; and (4) category M0 disease. The number and location of LN metastases were prospectively entered into corresponding databases. Measurements: LN maps were constructed and correlated with preoperative and pathologic characteristics. Kaplan-Meier curves were constructed to estimate overall survival (OS) and recurrence free survival (RFS) among LN-positive (LN+) patients. Results and limitations: Inclusion criteria were met by 646 patients (439 USC, 207 OHSU), and 23% had LN metastases at time of cystectomy. Although there was a difference in the median per-patient LN count between institutions, there were no significant interinstitutional differences in the incidence or distribution of positive LNs, which were found in 11% of patients with pt2b and in 44% of patients with pt3a tumors. Among LN+ patients, 41% had positive LNs above the common iliac bifurcation. Estimated 5-yr RFS and OS rates for LN+ patients were 45% and 33%, respectively, and did not differ significantly between institutions. Conclusions: LN metastases in regions outside the boundaries of standard LND are common. Adherence to meticulous dissection technique within an extended template is likely more important than total LN count for achieving optimal oncologic outcomes. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. USC Institute of Urology, University of Southern California, Keck School of Medicine, 1441 Eastlake Avenue, NOR 7416, Los Angeles, CA , USA. Tel ; Fax: address: skinner_e@ccnt.usc.edu (E.C. Skinner) /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 60 (2011) [(Fig._1)TD$FIG] 1. Introduction Urothelial carcinoma of the bladder afflicts > new patients and causes > deaths per year in the United States [1]. Up to 40% of patients present with muscle-invasive disease, and approximately 25% will harbor lymph node (LN) metastases at time of cystectomy [2]. Performing an LN dissection (LND) at the time of radical cystectomy (RC) is thus important for both accurate staging and tumor removal. Recent investigations have suggested improved survival with extension of the LND to include the presacral and common iliac LNs [3]. This is based on LN mapping studies showing a significant percentage of metastases in LNpositive (LN+) patients occurring above the common iliac bifurcation [4 8], and multiple reports demonstrating improved survival with an increased number of LNs removed [3,9,10]. In this study, we compare two large experiences with extended LND using a uniformly applied surgical technique. It is our intent to accurately illustrate the incidence and locations of metastatic LNs in RC patients in these two cohorts. 2. Patients and methods 2.1. Patient selection and data collection At the University of Southern California (USC), demographic, clinical, and pathologic data are prospectively collected for patients undergoing RC and maintained in an institutional review board-approved database. In May 2002, the method of pathologic submission of LND specimens transitioned from en bloc to 13 predesignated anatomically defined packets. At Oregon Health Sciences University (OHSU), a similar prospective database has been maintained, and extended LND has been performed using the same surgical technique and submission of LNs in anatomical packets by a single surgeon (SD) since September The current study thus included patients who underwent RC and extended LND with curative intent at USC and OHSU from May 2002 to December Patients were excluded ifthe pathologicspecimen was missing a lymphatictissue sample from any of the predesignated LN packets constituting an extended LND at bothinstitutions, iftheyhad undergoneprior pelvicradiotherapyorlnd for any indication, or had non-ln metastases at time of surgery. Kaplan-Meier curves were constructed to estimate overall survival (OS) and recurrence-free survival (RFS). The log-rank test was used to compare subgroups of patients. All p values are two-sided Clinical staging Preoperative clinical staging was performed using standard radiologic and physical exam criteria, as well as pathology results from the transurethral resection specimen. Clinical staging data were available for the USC cohort only Surgical technique and lymph node packeting Radical cystectomy was performed in a standardized fashion at both institutions as previously described [11]. The boundaries of LND were the inferior mesenteric artery (IMA) takeoff proximally; the genitofemoral nerves laterally; the circumflex iliac vein and LN of Cloquet distally; the internal iliac vessels posteriorly, including the obturator fossa and presciatic (fossa Marcille) LNs; and the presacral LNs overlying the sacral promontory (Fig. 1). LNs were submitted in 13 (USC) or 9 (OHSU) separate Fig. 1 Lymph node packets: (1) paracaval, (2) para-aortic, (3, 4) right (R) and left (L) common iliac, (5) presacral, (6, 7) R and L external iliac, (8, 9) R and L obturator/internal iliac. nodal packets. For analytic purposes, the LND regions were divided into three anatomic levels, as described in previous mapping studies [6]. Those regions usually included in a standard LND were designated level 1. Regions corresponding to those included in what are frequently described as extended LND templates were designated level 2. Regions above the aortic bifurcation were designated level 3. Perivesical LNs were submitted en bloc with the cystectomy specimen Pathologic analysis RC specimens were examined using a standardized protocol. Multiple sections and histologic evaluation were performed on the primary bladder tumor, bladder wall, and all LNs. LNs were identified visually and by palpation without clearing techniques, solvents, or special stains. The definition of a LN differed between institutions, however, with an aggregate of lymphocytes at USC being counted as a LN, while at OHSU the presence of a capsule was required. The total number of LNs and positive LNs in each packet was documented. Histologic grading was according to the method of Bergkvist et al. [12]. Pathologic staging of the primary bladder tumor was according to the American Joint Cancer Committee- Union Internationale Contre le Cancer 1997 TNM classification [13]. Pathologic subgroups of the primary bladder tumor in LN positive cases were defined as organ confined (OC) (pt2b) or extravesical (EV) (pt3a). 3. Results 3.1. Patients Inclusion criteria were met by 646 patients (439 USC, 207 OHSU). Demographic data are summarized in Table 1.

3 948 EUROPEAN UROLOGY 60 (2011) Table 1 Patient demographics University of Southern California Oregon Health Sciences University Combined Age, yr, median (range) 67 (33 88) 67 (40 91) 67 (33 91) Gender (%) Male 339 (77) 161 (78) 500 (77) Female 100 (23) 46 (22) 146 (23) Primary tumor histology (%) Urothelial carcinoma 427 (97) 187 (90) 614 (95) Adenocarcinoma 5 (1.2) 3 (1.4) 8 (1.2) Squamous cell 6 (1.5) 7 (3.4) 13 (2) Neuroendocrine 1 (0.25) 7 (3.4) 8 (1.2) Primary tumor stage (%) Organ confined (pt2b) 280 (64) 130 (63) 410 (63) Extravesical 159 (36) 77 (37) 236 (37) Primary tumor grade (%) Low (grade 1 2) 94 (21) 43 (21) 137 (21) High (grade 3 4) 345 (79) 164 (79) 509 (79) Urinary diversion (%) Orthotopic neobladder 381 (87) 132 (64) 513 (79) Continent cutaneous reservoir 20 (5) 18 (9) 38 (6) Ileal conduit 38 (9) 57 (28) 95 (15) Patients underwent surgery by one of five faculty surgeons at USC and by one surgeon (SD) at OHSU, all specializing in urologic oncology. Preoperatively, 86% of patients (379 of 439) with clinical staging data available were staged as having OC tumors (ct2bn0). [(Fig._2)TD$FIG] 3.2. Distribution of lymph node metastases A median 72 LNs (range: ) and 40 LNs (range: 5 118) were counted per patient at USC and OHSU, respectively ( p < 0.001). The median number of LNs per patient in each packet is illustrated in Fig. 2. Of the 646 patients, 151 (23%) had LN metastases (23% USC, 24% OHSU). The incidence of LN metastasis correlated significantly with primary tumor stage (Table 2). Eleven percent (11% USC, 12% OHSU; p = 0.63) of the 410 patients with OC primary tumors and 44% (44.7% USC, 44.2% OHSU; p = 0.94) of the 236 patients with EV primary tumors had LN metastases. The number of patients with positive LNs in each of the LN packets, and in each of the three levels, is illustrated in Fig. 3. Of note, 18% of all positive LNs were located above the aortic bifurcation. The highest extent of LN metastases in each patient was analyzed. This parameter describes how far proximally positive LNs were identified in a given patient. Of 151 LN+ patients, 28% (30% USC, 24% OHSU) had metastases up to level 3 regions, 13% (14% USC, 12% OHSU) had metastases extending to level 2 regions, and 59% (56% USC, 64% OHSU) Table 2 Lymph node positivity by pathologic stage ( p < 0.001) Stage Patients, no. Patients with positive lymph nodes, no. Patients with positive lymph nodes, % p ptis/pta pt pt pt3a pt3b pt Fig. 2 Median number of lymph nodes (LNs) removed per patient in each location: orange = level 3 LNs; yellow = level 2 LNs; blue = level 1 LNs. Total

4 [(Fig._3)TD$FIG] EUROPEAN UROLOGY 60 (2011) Fig. 3 Number of patients with positive lymph nodes (LN+) in each location. had metastases in level 1 regions only (Table 3). No significant differences were observed in the positive LN distribution between the USC and OHSU cohorts. This same parameter was examined for LN+ patients with OC primary tumors and EV primary tumors, respectively (Table 3). LN positivity was also examined based on preoperative clinical stage, which was available only for the 439 patients from the USC cohort. Of 379 patients with clinical stage T2bN0, 84 (22%) had positive LNs, and 38% of these patients harbored metastases in level 2 or 3 regions (Table 3). In the USC cohort, 31 patients underwent neoadjuvant chemotherapy (7 patients with ct3 tumors and 8 with clinically positive LNs), of whom 8 had pathologically positive LNs. There were 57 patients with a single positive-ln packet, and 93% of these patients had positive LNs in level 1 regions only. There were seven LN+ patients who did not have any metastases in the true pelvis. These patients had positive LNs in level 2 only (n = 4), level 3 only (n = 1), or levels 2 and 3(n = 2), while having pathologically negative level 1 LNs. Table 3 Highest extent of lymph node metastases by primary tumor pathology for patients with positive lymph nodes (LN+) * Organ confined (pt2b) (n = 46) Extravesical (pt3a) (n = 105) Clinically organ confined (ct2b) (n = 84) All LN+ patients (n = 151) Level 3 10 (22) 32 (31) 19 (23) 42 (28) Level 2 4 (9) 16 (15) 13 (15) 20 (13) Level 1 32 (69) 57 (54) 52 (62) 89 (59) * Patients, no. (% of LN+ patients within subgroup) Survival and recurrence The estimated 5-yr OS and RFS rates for LN+ patients were 33% and 45%, respectively, with a median OS of 23.3 mo. The median follow-up interval was 36 mo. RFS and OS by highest level of LN metastases are illustrated in Figs. 4 and 5. Patients with positive LNs above level 1 experienced significantly lower OS compared with patients with positive LNs confined to level 1 regions ( p = 0.04), and a trend towards lower RFS ( p = 0.12). Median OS for patients with positive LNs above the aortic bifurcation (n = 42) was 18 mo. When stratified by institution, there were no significant differences in 5-yr OS (36% OHSU, 33% USC; p = 0.19) or RFS (53% OHSU, 41% USC; p = 0.32) (Fig. 6). In subgroup analyses, there were also no interinstitutional differences in RFS ( p = 0.17) or OS ( p = 0.80) for patients with level 1 LN metastases, or RFS for patients with level 2 and 3 LN metastases ( p = 0.58). 4. Discussion The importance of LND in the treatment of bladder cancer is well documented. Long-term survival rates of 30 40% in patients with LN metastases treated with cystectomy and extended LND have been reported in multiple series [2,14], and removal of more LNs has been significantly associated with improved survival [9,10,15 19]. Significant survival benefits of a more extensive LND have also been demonstrated in LN-negative patients [15,18 20], presumably due to removal of micrometastases not detected on routine pathologic exam. This hypothesis is supported by reverse transcriptase polymerase chain reaction studies for detection of LN metastases in cystectomy specimens, in which

5 950 [(Fig._4)TD$FIG] EUROPEAN UROLOGY 60 (2011) Estimated probability of survival Blue: level 1 (n = 89) Green: level 2 (n = 20) Orange: level 3 (n = 42) Time since surgery, yr Fig. 4 Overall survival of lymph node (LN) positive patients stratified by highest level of positive LNs. standard histopathologic analysis missed 20 30% of positive LNs [21,22]. Extended LND has also been associated with lower positive margin and local recurrence rates, and improved identification of LN+ patients [9,23]. The incidence of LN metastases outside the template of a standard LND is high, occurring in 41% of our LN+ patients. Previous studies have reported similar findings [6,14,23]. The present study also demonstrates a high incidence of metastases specifically in regions above the aortic bifurcation. This was observed in similar proportions in the both the USC and OHSU cohorts. Also very similar were the overall and stage-specific distribution of LN metastases. [(Fig._5)TD$FIG] This is likely attributable to the consistency of the dissection technique used by the involved surgeons, all of whom were USC surgeons by training or appointment. The concordant LN maps also serve to validate the accuracy and reproducibility of the LN distribution in this study, which, to our knowledge, represents the largest reported series of cystectomy patients undergoing extended LND above the aortic bifurcation. The median number of LNs counted per patient was significantly different at the two institutions (72 USC vs 40 OHSU). This is undoubtedly due to differing definitions of a LN between pathology departments, and may also reflect 1.00 Estimated probability of RFS 0.80 Blue: level 1 (n = 89) Green: level 2 (n = 20) Orange: level 3 (n = 42) Time since surgery, yr Fig. 5 Recurrence-free survival (RFS) of lymph node (LN) positive patients stratified by highest level of positive LNs.

6 [(Fig._6)TD$FIG] EUROPEAN UROLOGY 60 (2011) Fig. 6 Overall survival (OS) and recurrence-free survival (RFS) stratified by institution. USC = University of Southern California; OHSU = Oregon Health Sciences University. the submission of the LN specimen divided into four additional packets at USC, as LN packeting has been shown to result in increased LN counts, even when adhering to the same dissection template [24,25]. This is further supported by the observation that the median number of LNs counted per patient for the surgeon from OHSU (SD) since his arrival at USC has increased from 40 to 57 (range: ). This discrepancy, juxtaposed with the consistency of the distribution of LN metastases between institutions and the similar oncologic outcomes, illustrates the relatively greater importance of meticulous dissection within a defined template over achievement of a particular LN count. Stratifying by clinical stage, we found that a similarly high proportion of LN+ patients with preoperatively organconfined (ct2bn0) primary tumors had metastases above the iliac bifurcation (38%). This suggests that current preoperative staging techniques are not accurate enough to justify a more limited LND in apparently lower stage patients. This is not surprising, given the poor sensitivity of current imaging in identifying positive LNs [26,27] and the reported 40% rate of clinical understaging of primary bladder tumors [28,29]. A striking finding was the very low number (1%) of patients who had metastases in regions above the iliac bifurcation without synchronous metastases in the true pelvis, a finding consistent with previous mapping studies [30]. Similarly, only one patient had LN metastases above the aortic bifurcation only. Therefore, if a patient has no LN metastases in level 1 or 2, dissection above the aortic bifurcation would seem unnecessary. To make this determination intraoperatively, however, one would have to await the results of a detailed pathologic examination of all level 1 and 2 LNs, which should be significantly more time consuming than extending the LND proximally by 5 10 cm. Controversy remains regarding the utility of extended LND above the common iliacs, with some authors concluding that patients with metastases in these regions are incurable and that an extended dissection results in increased morbidity or is often not feasible (193 of the 285 patients excluded in this study for missing LN packets did not undergo a level 3 dissection). And while these patients may experience poorer oncologic outcomes compared to those with less advanced disease, we and others have reported significant long-term survival rates in these patients after extended LND, with an estimated 5-yr RFS of 36% in the present study [14]. Furthermore, we have seen neither increased morbidity nor poorer functional outcomes with extended LND in our own experience or the published literature. A limitation of this study is its retrospective nature. The survival data presented are not based on an intent-to-treat study design, and, therefore, although extended LND to the IMA is our routine, a selection bias likely exists regarding which patients underwent a full extended LND and were thus eligible for inclusion. Another limitation is the absence of a control group treated with a more limited LND to better define the effect of our extended template. We cannot conclude from this study, therefore, whether ours represents the optimal LND template. There are two randomized trials currently underway for comparison of standard versus extended LND; these are better designed to answer this question. Our objectives were different: to map the distribution of LN metastases in patients undergoing cystectomy at two different institutions using a uniform technique, thus illustrating the incidence of metastases outside the true pelvis, and to demonstrate the value of a consistently applied template in identifying metastatic LNs, regardless of differences in the number of LNs counted by the pathologist. 5. Conclusions LN metastases in regions outside the boundaries of standard LND are common, occurring in 41% of LN+ patients in this study. The distribution and incidence of LN metastases, and the recurrence and survival rates, were nearly identical between two institutions with different pathologic definitions of a LN and, thus, significantly different LN counts. Adherence to meticulous dissection technique within a consistent, defined template is more important than achieving a minimum LN count. Author contributions: Eila C. Skinner 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.

7 952 EUROPEAN UROLOGY 60 (2011) Study concept and design: Dorin, Daneshmand, E Skinner, D Skinner, Miranda. Acquisition of data: Dorin, Daneshmand, E Skinner, Miranda, Cai, Eisenberg, Nichols. Analysis and interpretation of data: Dorin, Daneshmand, E Skinner, Eisenberg, Nichols. Drafting of the manuscript: Dorin, Daneshmand, Chandrasoma, Eisenberg. Critical revision of the manuscript for important intellectual content: Dorin, Daneshmand, E Skinner, D Skinner. Statistical analysis: Dorin, Daneshmand, E Skinner, Miranda, Cai. Obtaining funding: Skinner. Administrative, technical, or material support: Miranda, Cai. Supervision: Scarpa. 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: S. Daneshmand is a speaker for Endo Pharmaceuticals. Funding/Support and role of the sponsor: None. References [1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, CA Cancer J Clin 2010;60: [2] Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19: [3] Dhar NB, Klein EA, Reuther AM, et al. Outcome after radical cystectomy with limited or extended pelvic lymph node dissection. J Urol 2008;179: [4] Leadbetter WF, Cooper JF. 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