Lymphadenectomy with Cystectomy: Is It Necessary

European Urology European Urology 46 (2004) 457 461 Lymphadenectomy with Cystectomy: Is It Necessary and What Is Its Extent? Mohamed A. Ghoneim *, Hassan Abol-Enein Urology & Nephrology Center, Gomhouria Street, Mansoura, Dakahlia 35516, Egypt Accepted 16 June 2004 Available online 2 July 2004 Keywords: Bladder cancer; Cystectomy; Lympadenectomy * Corresponding author. Tel. þ20 50 223 45 45; Fax: þ20 50 223 52 52. E-mail address: unc@mum.mans.edu.eg (M.A. Ghoneim). The results of management of invasive bladder cancer need substantial improvement. The 5-year diseasefree survival following radical cystectomy ranges from 50 60% [1 6]. Evidence has been provided that node positivity is a significant and independent prognostic factor [1,4]. The relative risk for the development of a treatment failure among node positive patients was computed to be 1.8 [4]. In this regard, two questions impose themselves and need to be answered: (1) Is a lymphadenectomy with cystectomy worthwhile? (2) If the answer is affirmative what would be the optimal field for lymphadenectomy?. There are some investigators who would argue that a simple cystectomy without a formal lymphadenectomy is sufficient. On one hand, if the disease is organ confined, a lymphadenectomy is not necessary. On the other, if the lymph nodes are involved, the disease can be considered as systemic and a node dissection is an exercise in futility. This is supported by the fact that earlier reports of the 5-year survival of radical cystectomy for node positive cases were dismal [1,7]. A second important argument, is that there are no prospective trials which demonstrate the superiority of radical versus simple cystectomy, in terms of oncological outcomes. In addition, with simple cystectomy, some lymph nodes are inadvertently removed without a formal lymphadenectomy (nodes on the bladder surface and those related to some of the visceral branches of the anterior division of the internal iliac artery). As early as 1982, Skinner pointed out that a meticulous pelvic node dissection can make a difference [8]. Since then, several reports indicated that a diseasefree survival can be achieved in an important proportion of node positive cases treated by radical cystectomy (Table 1). Nevertheless, controversies do exist relative to the required extent of lymphadenectomy, the number of nodes that have to be retrieved, and the prognostic factors affecting survival following node dissection for node positive cases. A critical review of recent relevant literature would be imperative to indicate what we have achieved and to identify areas which need a further inquiry. 1. Incidence of regional node involvement The reported incidence of regional lymph node involvement following radical cystectomy for bladder cancer is between 14% and 28% (Table 2). It is universally acknowledged that this incidence correlates with the stage of the primary tumour: the higher the stage the greater is the incidence of node involvement [10,13,14]. In a recent study, Abdel-Latif et al. [15] studied the incidence of nodal involvement relative to several of the patient s and tumour characteristics by univariate as well as multivariate analysis. They confirmed the influence of the primary stage as an independent factor. Two additional factors were identified: the tumour grade and lymphovascular invasion. Herr, reported that the more lymph nodes removed, the higher the number of patients detected with positive nodes [16]. A Spearman rank correlation coefficient of 0.17 was determined. Contrary to his conclusion, such a value reflects only a weak correlation. A poor correlation between the total number of removed nodes and positive nodes, was also noted a study carried out in our center [15]. 0302-2838/$ see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2004.06.010

458 M.A. Ghoneim, H. Abol-Enein / European Urology 46 (2004) 457 461 Table 1 Survival of patients with nodal disease treated by radical cystectomy Author(s), year 5-year survival (%) Smith and Whitmore, 1981 [7] Pagano et al., 1991 [1] Ghoneim et al., 1997 [4] Vieweg et al., 1999 [9] Mills et al., 2001 [10] Stein et al., 2003 [11] 7.0 (Disease-free) 4.0 (Overall) 23.0 (Disease-free) 31.2 (Cancer-specific) 29.0 (Overall) 31.0 (Overall) Table 4 pn stage among cases with nodal disease Author(s), year pn1 pn2 pn3 pn stage (%) Vieweg et al., 1999 [9] 38.9 54.9 6.0 Mills et al., 2001 [10] 27.7 68 3.6 Stein et al., 2003 [11] 33.0 32.0 35 Abdel-Latif et al., 2004 [15] 38.2 43.6 18.2 Abol-Enein et al., 2004 [20] 45.8 27.1 27.1 Table 2 Incidence of nodal disease among bladder cancer cases treated by radical cystectomy Author(s), year Total no. of cases Cases with nodal disease, n (%) Smith and Whitmore, 1981 [7] 662 134 (20.0) Frazier et al., 1993 [2] 407 59 (14.5) Ghoneim et al., 1997 [4] 1026 188 (19.5) Vieweg et al., 1999 [9] 682 193 (28.1) Herr and Donat, 2001 [12] 763 193 (25.0) Mills et al., 2001 [10] 452 83 (18.0) Stein et al., 2003 [6] 1054 246 (24.0) 2. Prognosis following radical cystectomy for patients with node positive disease Many factors can influence the oncologic outcome among cases with nodal involvement treated by radical cystectomy: The pt stage, the N stage, the total number of retrieved lymph nodes and the extent of lymphadenectomy. As for back as 1992, Lerner et al. pointed out the significant impact of the tumour s pt stage on survival in cases with nodal metastasis [17]. They discriminated between tumours confined to the bladder wall and those with extravesical extention. They reported a 5- year survival of 50% for the former and only 18% for the latter. Similar findings were later reported by several investigators [6,9]. These findings are summarized in Table 3. In general, extravesical spread of the primary would reduce the survival probability by one half. Our findings confirm these data and provide Table 3 Survival relative to the pt stage Author(s), year 5-year disease specific survival, % Organ confined (pt2b) Lerner et al., 1992 [17] 50 18 Vieweg et al., 1999 [9] 57.5 22.4 Stein et al., 2003 [6] 46.0 30.0 Non-organ confined (pt3) evidence that extravesical extension acts as an independent variable with a hazard ratio of 2.1 for pt3 cases and of 6.7 for pt4 cases [15]. The distribution of nodal metastasis relative to the pn stage is outlined in Table 4. The prognostic impact of the pn category (number of positive nodes) was the subject matter of several reports. Lerner et al. [17] observed that the 5-year survival probality in cases with 5 or fewer involved nodes was almost double that of those with cases with 6 or greater involved nodes: 35% and 17% respectively. Vieweg et al. [9] reported that in cases of organ confined disease there was no survival difference between N0 and N1 cases but rather a consistently decreasing survival benefit as we go from N1 to N3 disease. Mills and associates [10] reported that survival in patients with fewer than 5 positive nodes was significantly better than in those with 5 or more positive nodes. Nevertheless, this significance was not maintained when multivariate analysis was carried out. Using multivariate analysis, Herr [16] observed that the number of positive nodes stratified as 4 or fewer and 5 or more did not have an independent impact on survival. In a recent study by Stein et al. [11], the impact of the number of positive nodes on survival was verified by univariate as well as multivariate analysis. A prognostic cutoff of 8 positive nodes was computed. Results from our center confirm the significance of the number of involved nodes as an independent factor [14]. The 3-year disease free survival for the N1 category was 58.6% approximitalety similar to that of an organ confined node negative disease. Hazard ratios of 2.1 and 4.8 were determined for N2 and N3 categories respectively. 3. The extent of lymphadenectomy In 1998, Poulsen and associates [18] studied the influence of the extent of node dissection on survival following radical cystectomy for bladder cancer. They compared the results of 126 cases with an extended

M.A. Ghoneim, H. Abol-Enein / European Urology 46 (2004) 457 461 459 dissection up to the aortic bifurcation and those of 68 patients who had an endopelvic dissection only. They concluded that the extended dissection improved recurrence free survival for pt3 but not for >pt3 cases. This study was retrospective and nonrandomized. Univariate analysis was only used for statistical analysis. Anatomical mapping of the retrieved nodes was not carried out or the number of retrieved nodes in each category was specified. Leissner et al. [13] tried to standardize the number and location of lymph nodes to be removed during radical cystectomy. They reviewed their experience with 447 radical cystectomy cases. The planned field of dissection was up to the aortic bifurcation. The number of retrieved nodes was correlated to the cancer specific survival. The mean number of removed nodes was 14.7/case. A significant survival advantage was noted when 16 nodes were removed. Again, this was a retrospective study, in which 1/3 of their cases were unfollowed. No anatomical mapping of the retrieved nodes was carried out. Mills et al. [10] reported their experience with 83 patients with nodal disease treated by cystectomy and a meticulous pelvic dissection up to the bifurcation of the common iliac arteries. Anatomical mapping of individual groups of the harvested nodes was performed. The median number of retrieved nodes/case was 20. Bilateral nodal disease was noted in 40% of their cases. Survival was correlated to some of the tumour s characteristics. With multivariate analysis, only capsular infiltration achieved independent significance with a hazard ratio of 2.6. This study entailed a meticulous dissection, anatomical mapping and a careful statistical analysis. Nevertheless it was a retrospective study and dissection was limited to the pelvic nodes. Furthermore, the status of the more proximal groups was undetermined. Herr [16], introduced the concept of a ratio based lymph node staging for bladder cancer. This ratio was defined as the number of positive nodes/total number of retrieved nodes. He studied the results of 162 cystectomy cases with positive nodes. The lymphadenecomy was only endopelvic. The median number of removed nodes was 13/case. The author proposed that cases with a ratio of 20% had a significantly better survival than those with a ratio of >20%. This study may be legitimately criticized since it was retrospective, with only endopelvic dissection and without an attempt for anatomical mapping. Stein et al. [11] reviewed their results with 224 bladder cancer cases with nodal disease treated by radical cystectomy and an extended lymphadenectomy up to the aortic bifurcation. They reported that the median number of retrieved nodes was 30/case. They had also Table 5 The extent of lympadenectomy and the mean number of retrieved nodes Author(s), year Extent of dissection Mean no. of retrieved nodes Leissner et al., 2000 [13] Common iliac 14.6 Mills et al., 2001 [10] Pelvic 20.0 Stein et al., 2003 [11] Aortic bifurcation 30.0 Herr et al., 2003 [12] Pelvic 13.0 Vazina et al., 2004 [19] Aortic bifurcation 25.0 Abdel-Latif et al., 2004 [14] Pelvic 17.9 Abol-Enein et al., 2004 [20] Distal aortic 50.0 employed the concept of a ratio based lymph node staging but the term density was utilized. It must be noted that a ratio of 20% was proposed by the 2 previously mentioned studies in spite of a difference in the total number of harvested nodes (the denominator): 13 in the former and 30 in the latter. In our opinion determination and potential usefulness of a ratio based node staging requires a unified definition of the required extent of lymphadenectomy and an agreement on the optimal number of nodes that should be harvested. Currently, the potential usefullness of this parameter is undermined by the wide variation in the number of retrieved nodes as reported by different investigators (Table 5). 4. The patho-anatomic study It is abundantly evident that the above-mentioned studies were retrospective and the derived data inconsistent. There is no agreement on the limits of lymphadenectomy with cystectomy. The mean number of retrieved nodes was different. Furthermore, lymph node mapping of the individual anatomic groups was lacking. To circumvent these shortcomings, a prospective study was carried out in our center [20]. Two hundred patients with invasive bladder cancer were treated by radical cystectomy and an extended lymphadenectomy. The proximal extent of node dissection was at the level of origin of the inferior mesenteric artery. The field of dissection is diagrammatically represented in Fig. 1. The procedure was carried by 2 surgeons only to minimize as much as possible an operator dependent variation. The nodes retrieved from each anatomic region was sent separately on a template for pathologic evaluation. The mean number of harvested nodes/case was 50.6 14.4. Positive nodes were encountered in 48 cases (24%). Bilateral involvement was observed in 40% of node positive cases. The number of positive nodes/ involved case was 8.08 13.2.

460 M.A. Ghoneim, H. Abol-Enein / European Urology 46 (2004) 457 461 Fig. 1. The field of dissection: Region 1, paracaval; Region 2, interaortocaval; Region 3, paraaortic; Regions 4 & 5, common iliac; Regions 6 & 7, external iliac; Region 8, intercommon iliac (presacral); Regions 9 & 10, obturator; Regions 11 & 12, internal iliac. Table 6 The frequency distribution of the number of positive nodes and their anatomic location No. of þve nodes Pelvic only Pelvic/extrapelvic Single 21 a 1 b 2 5 10 3 >5 1 12 a 16 between ext-iliac vein and obturator nerve, 5 between obturator nerve and bladder wall. b 1 common iliac node...? sampling error. Fig. 2. Location of the single positive nodes. Note: (a) Only one node was outside the pelvis (left common iliac). (b) No definitive sentinel node. The distribution of involved nodes relative to their number/case as well as their anatomical location is outlined in Table 6. Out of the 48 patients with nodal disease 22 (45.6%) had an involvement of only a single node (pn1); all of which except one were in the pelvic region (Fig. 2). 13 patients had 2 5 involved nodes (pn2), 10 of which were again within the pelvis. The majority of cases with more than 5 involved nodes (N3) were endopelvic with extensions to the extrapelvic regions. Involvement of extrapelvic nodes was invariably associated with endopelvic nodal disease. These finding point out that there are no skipped lesions. Involvement of the endopelvic nodes is the first step in nodal metastasis. 5. Conclusions What could be learnt from previous and current validated information? 1. With radical cystectomy, the incidence of nodal disease is in the order of 25%. The pt category is an independent factors that influence this incidence 2. The pn stage among node positive cases indicates that 30 40% are of the pn1 category. 3. All the involved nodes of the pn1 category are within the pelvis and there are no skipped lesions. 4. Meticulous pelvic node dissection will clear all involved nodes of pn1 and most of pn2 categories. 5. The prognosis of pn1 cases treated by radical cystectomy is good and approximates that of organ confined pathology (N0). 6. Bilateral dissection is mandatory.

M.A. Ghoneim, H. Abol-Enein / European Urology 46 (2004) 457 461 461 7. If the pelvic nodes are negative by frozen section; more extensive proximal dissections are not usefull. 8. The prognosis of cases with extrapelvic nodal disease is very poor. The usefulness of an extensive dissection is questionable. Nevertheless, it may be argued that such a dissection can reduce the bulk of the disease and render adjuvant therapies more effective. This contension remains to be verified. References [1] Pagano F, Bassi P, Galetti TP, Meneghini A, Milani C, Artibani W, et al. Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumour, nodes and metastasis classification. J Urol 1991;145:45 50. [2] Frazier HA, Robertson JE, Doge RK, Paulson DF. The value of pathologic factors in predicting cancer-specific survival among patients treated with radical cystectomy for transitional cell carcinoma of the bladder and prostate. Cancer 1993;71:3993 4001. [3] Soloway MS, Lopez AE, Patel J, Lu Y. Results of radical cystectomy for transitional cell carcinoma of the bladder and the effect of chemotherapy. Cancer 1994;73:1926 31. [4] Ghoneim MA, El-Mekresh MM, El-Baz MA, El-Attar IA, Ashamallah A. Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1026 cases. J Urol 1997;158:393 9. [5] Dalbagni G, Genega E, Hashibe M, Zhang ZF, Russo P, Herr H, et al. Cystectomy for bladder cancer: A contemporary series. J Urol 2001;165:1111 6. [6] Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al. Radical cystectomy in the treatment of invasive bladder cancer: longterm results in 1054 patients. J Clin Oncol 2001;19:666 75. [7] Smith JA, Whitmore Jr WF. Regional lymph node metastasis from bladder cancer. J Urol 1981;126:591 3. [8] Skinner DG. Management of invasive bladder cancer: a meticulous pelvic node dissection can make a difference. J Urol 1982;128:34 6. [9] Vieweg K, Gschwend JE, Herr HW, Fair WR. Pelvic lymph node dissection can be curative in patients with node positive bladder cancer. J Urol 1999;161:449 54. [10] Mills RD, Turner WH, Fleischmann A, Markwalder R, Thalmann GN, Studer UE. Pelvic lymph node metastases from bladder cancer: outcome in 83 patients after radical cystectomy and pelvic lymphadenectomy. J Urol 2001;166:19 23. [11] Stein JP, Cai J, Groshen S, Skinner DG. Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en block pelvic lymphadenectomy: the concept of lymph node density. J Urol 2003;170:35 41. [12] Herr HW, Donat SM. Outcome of patients with grossly node positive bladder cancer after pelvic lymph node dissection and radical cystectomy. J Urol 2001;165:62 4. [13] Leissner J, Hohenfellner R, Thuroff JW, Wolf HK. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU Int 2000;85:817 23. [14] Wishnow KI, Johnson DE, Ro JY, Swanson DA, Babaian RJ, Von Eschenbach AC. Incidence, extent and location of unsuspected pelvic lymph node metastasis in patients undergoing radical cystectomy for the bladder cancer. J Urol 1987;137:408 10. [15] Abdel-Latif M, Abol-Enein H, El-Baz M, Ghoneim MA. Nodal involvement in bladder cancer cases treated with radical cystectomy: Incidence and prognosis. J Urol 2004;172:85 9. [16] Herr HW. Superiority of ratio based lymph node staging for bladder cancer. J Urol 2003;169:943 5. [17] Lerner SP, Skinner E, Skinner DG. Radical cystectomy in regionally advanced bladder cancer. Urol Clin North Am 1992;19:713 23. [18] Poulsen AL, Horn T, Steven K. Radical cystectomy: extending the limits of pelvic lymph node dissection improved survival for patients with bladder cancer confined to the bladder wall. J Urol 1998;160: 2015 20. [19] Vazina A, Dugi D, Shariat SF, Evans J, Link R, Lerner SP. Stage specific lymph node metastasis mapping in radical cystectomy speciment. J Urol 2004;171:1830 4. [20] Abol-Enein H, El-Baz M, Abdel-Hamed MA, Abdel-Latif M, Ghoneim MA. Lymph node involvement in bladder cancer patients treated by radical cystectomy: a patho-anatomic study; a single center experience. J Urol (in press).