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The evolving role of pelvic lymphadenectomy in the treatment of bladder cancer
Urologic Oncology: Seminars and Original Investigations 22 (2004) 205–213
Seminar article
The evolving role of pelvic lymphadenectomy in the treatment of bladder cancer Kristin M. Sanderson, M.D., M.P.H.*, John P. Stein, M.D., F.A.C.S., Donald G. Skinner, M.D. Department of Urology, USC Norris Cancer Center, Los Angeles, CA, USA
Abstract Regional lymphadenectomy is integral to the surgical management of high-grade invasive bladder cancer. A growing body of evidence suggests that a lymph node dissection may provide not only improved prognostic information, but also a clinically significant therapeutic benefit for both lymph node positive and negative patients undergoing radical cystectomy. While the inclusion of lymph node resection in conjunction with radical cystectomy for patients with clinically negative nodes is well accepted, the extent of the nodal dissection remains highly contentious. Similarly, the benefit of node dissection for patients with advanced disease and gross adenopathy or for those with superficial disease (Ta, T1 or TIS) remains a topic of heated debate. This review describes the historical evolution of lymphadenectomy in the surgical treatment of bladder cancer and provides a comprehensive review of the current literature addressing the role of lymph node dissection in the treatment of bladder cancer. © 2004 Elsevier Inc. All rights reserved. Keywords: Bladder neoplasm; Transitional cell carcinoma; Lymphadenectomy; Cystectomy; Lymph node dissection; Lymph node metastasis; Lymph node density; Bladder cancer
Introduction
Historic perspective
It was more than 50 yrs ago that the first reports of pelvic lymph node dissection as an adjunct to radical cystectomy surfaced in the American medical journals. Invasive bladder cancer at the time carried a dismal prognosis. The operative treatment itself, simple cystectomy, was associated with a 30% to 40% peri-operative mortality rate and exceedingly high rates of pelvic and distant recurrences [1,2]. The presence of gross pelvic adenopathy encountered at surgery was associated with 5-yr survival rate approaching zero [1]. It was at this point that the astute observations of some of the pioneers in Urology led to a paradigm shift in the treatment of bladder cancer, the addition of lymph node resection. With the advent of the pelvic lymph node dissection (LND) as an adjunct to cystectomy, surgeons were finally able to make a meaningful impact on survival outcomes. Today, lymphadenectomy is recognized as an integral part of the treatment of bladder cancer, providing both therapeutic benefit and valuable diagnostic information.
Regional lymph node dissection as an essential part of radical surgery was first introduced by Halstead in 1886. As a surgeon treating carcinoma of the breast, Halstead noted improved survival in advanced breast cancer patients following the addition of a regional lymph node dissection (LND) to the mastectomy, thus was born the Halsteadian philosophy: primary tumors metastasize through lymphatics to regional lymph nodes [3]. Several decades later, interest in the role of lymphadenectomy for the treatment of bladder cancer was growing. The prevailing belief regarding advanced bladder carcinoma with gross adenopathy was that it was uniformly fatal as a result of systemic spread and, therefore, beyond the limits of surgical intervention. In 1936, Drs. Colston and Leadbetter completed an autopsy series on 98 patients with bladder cancer, and the results would challenge the wisdom of the day. They identified a significant number of cadavers in whom limited metastatic disease was restricted to the pelvic lymph nodes and thus, potentially amenable to surgical resection [4]. These findings were confirmed and expanded by Dr. H.J. Jewett one decade later. In 1946, Dr. Jewett published his
* Corresponding author. Tel.: ⫹1-323-865-3700; fax: ⫹1-323-8650120. E-mail address: [email protected] (K.M. Sanderson). 1078-1439/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2004.04.030
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important autopsy series of 107 patients in which he identified a small percentage of patients with extravesical carcinoma who had metastatic involvement limited to the pelvic lymph nodes, “a cardinal site of metastasis” [5]. He also definitively correlated the depth of invasion of the primary tumor with the incidence and extent of lymphatic involvement. This “index of curability” [5] would form the basis of the first widely accepted staging system, the Jewett-Marshall staging system. The correlation between primary tumor stage and lymph node metastasis, first described by Jewett, is now well accepted and has been confirmed in numerous studies [6 –10]. In contemporary series, lymph node metastases increase relative to the invasiveness of the primary tumor. Nodal metastases have been identified in 6% of P1, 9% to 30% of P2, 23% to 31% of P3a, 43% to 60% of P3b and 47% of P4 patients [6,10]. In another series, patients with organ confined (OC) disease comprised only 22.8% of the total node-positive cohort, whereas EV disease accounted for the remaining 77.2% [7]. Even in low-stage disease (Pa, PIS, P0 and P1), up to 7% of patients with will have positive nodes identified by lymphadenectomy [8,11]. The first correlation of pelvic LND with improved prognosis among bladder cancer patients was described in 1950. Drs. Kerr and Colby are credited with the first report of long-term survival in two node-positive patients undergoing radical cystectomy with pelvic LND. In their original manuscript, the authors state that they were “considerably disturbed” over the high incidence of pelvic recurrence after simple cystectomy and this prompted their routine inclusion of lymphadenectomy with radical cystectomy [2]. As a result of this change, they noted a decreased pelvic recurrence rate as well as increased overall survival, prompting them to advocate the routine. These findings led them to advocate the routine completion of a pelvic node dissection during cystectomy to “increase the curability” of carcinoma of the bladder. In that same year, Leadbetter and Cooper [12] published a comprehensive work that detailed his technique of extended pelvic lymph node dissection and defined the boundaries of dissection (i.e., proximal– distal aorta; lateral– genitofemoral nerve; distal– circumflex iliac vein and lymph node of Cloquet) that remain in use today. The authors concluded “it seems possible that . . . a more radical cystectomy combined with pelvic gland dissection may be expected to extend the limits of palliative and curative treatment of infiltrating cancer of the bladder.” [12] More than a decade later, Whitmore and Marshall reported their promising early success with this new treatment modality. Of 55 stage D1 patients (lymph node involvement confined to the pelvis by the Jewett-Marshall system) undergoing radical cystectomy and pelvic node dissection, 4% survived for 5 yrs, a significant improvement over this otherwise uniformly fatal stage of disease. The observation that each of the 2 surviving patients had fewer than 3 involved nodes led them to conclude that “in patients with only limited nodal metastases, radical
cystectomy has provided some 5-yr successful results—the only such of which we are aware” [1]. Improved survival in patients with nodal metastases was replicated in later studies, particularly in OC disease and, importantly, no increased morbidity or mortality was attributed to the extended lymph node dissection [13]. In contrast to Leadbetter, Wishnow became a proponent of a more limited dissection (cephalad limit of dissection–iliac bifurcation) based upon his observation that, in the absence of gross adenopathy, metastatic nodal disease was never present above the level of the iliac bifurcation [10]. This dissection is now commonly referred to as the “standard” LND. The aggregate experience from these early leaders in Urology has formed the cornerstone of our current understanding of the treatment of bladder carcinoma. The pelvic lymphadenectomy is now an integral part of radical cystectomy for bladder cancer. When meticulously completed, the procedure offers not only curative potential, but also valuable staging information. However, ongoing controversy exists to this day regarding the optimal boundaries of lymph node dissection necessary to accurately diagnose metastases and to provide maximal therapeutic benefit without increasing peri-operative morbidities.
Why is accurate staging important for prognosis? Staging allows for the standardized comparison of patient risk factors and the evaluation of treatment results based on a universally accepted system [15]. Accurate staging of bladder cancer is essential to correctly identify those at high-risk for recurrence, particularly node-positive patients, who would potentially benefit from adjuvant therapy and/or a more aggressive surveillance regimen. Determining which patients should receive adjuvant chemotherapy is generally based upon the probability of death from the cancer. The presence of regional metastasis, therefore, plays a critical role in this analysis, as most patients will require subsequent systemic treatment. An inadequate resection of the lymphatics, risking misclassification of the nodal status, would preclude high-risk node-positive patients from receiving this potentially beneficial therapy. Evidence to support the role of adjuvant chemotherapy in the treatment of node-positive bladder cancer is mounting, though it has yet to be definitively proven in a prospective, randomized trial. Previous prospective trials have shown trends in disease-free and overall survival but failed to show statistical significance because of design errors and inadequate power [16 –18]. However, retrospective studies of lymph node-positive patients have provided evidence for the efficacy of adjuvant chemotherapy in this high-risk group. In one study, addition of adjuvant chemotherapy following the surgical treatment of 83 node-positive patients resulted in a statistically significant survival advantage that was maintained when controlled for age, pT stage, pN stage and number of nodes [19]. In another series, adjuvant chemotherapy resulted in a near doubling of disease-free survival (21.5 vs. 13.1 months) [20].
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In addition, the use of chemotherapy was significantly associated with increased survival in a retrospective review of 1,923 population based patients undergoing cystectomy, though the total number of nodes resected during cystectomy was more significant in predicting survival [21]. Though not all retrospective studies have confirmed the benefit of chemotherapy in extending overall survival of node-positive patients [7,22], evidence seems to support the role of adjuvant chemotherapy in this population.
Preoperative staging alternatives—noninvasive identification and localization of metastatic nodes Occult metastatic disease involving grossly normal-appearing nodes is a well-described phenomenon. Dr. Kerr, in 1950, reported unsuspected micrometastases in 40% of his clinically node-negative patients [2]. Despite modern imaging modalities [computed tomography (CT) scan and magnetic resonance imaging (MRI)], efforts to preoperatively diagnose occult nodal disease have been largely unsuccessful and reported rates of occult lymph node metastasis remain substantial, ranging from 14% up to 27% [9,19 –23]. CT scan and MRI fail to accurately identify pelvic nodal micrometastases in 21% and 15% of patients, respectively [24,25]. Positron emission tomography (PET) scan, the newest addition to the imaging armamentarium, has also proven to be disappointing in this capacity. In a recent study, eight patients completed both CT and PET scans prior to radical cystectomy and standard pelvic LND. No false positives were noted and the PET scan was able to correctly detect nodal metastases in 2 patients, 1 of whom was negative by CT scan. However, the false negative rate was 33% [26]. These data are consistent with the results from the largest study to date in which one-third of the patients with pathologically confirmed nodal metastases were missed [27]. An alternative attempt to better localize lymphatic spread from the primary tumor is the sentinel lymph node biopsy (SLN). Proven to be successful and accurate in predicting the lymphatic drainage in both melanoma and breast cancer, SLN has provided confirmation of the orderly anatomic progression of tumor cells from primary site to regional lymph nodes in these cancers [28]. Preoperative injection of either lymphophilic dye or radiolabeled tracer around the neoplastic lesion allows for localization of the primary nodal drainage of the tumor. During surgery, a handheld detection tube is used to localize the concentration of tracer, and nodes are visually assessed for the concentration of blue dye. Once this nodal packet is excised and examined, wider dissection of lymph nodes is then completed only if the primary packet is determined to be positive for metastatic disease. When used in the surgical treatment of melanoma, approximately 80% of patients have been spared the morbidity of an extensive lymph node dissection [29]. Because of the difficulty in accurately predicting the presence and location of lymph node metastases in bladder cancer, the utility of sentinel node biopsy has been investigated pro-
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spectively in 2 small studies [30,31]. Patients underwent preoperative endoscopic injection of tracer before cystectomy. In all cases, a standard lymphadenectomy was completed. Intraoperatively, no distinct SNL could be identified in 15% to 20% of these patients. In those in whom a SLN was localized, the node lay outside the obturator lymph node packet in 33% of the patients. Of 12 patients with metastatic tumors involving the nodes, a positive sentinel node was identified in eleven, with one false-negative (8.6%). Thus, based upon the intraoperative findings, one patient would have been denied a more extensive, possibly curative, node resection had the SLN methodology been employed. Of interest, in a majority of patients (63–75%) the sentinel node was located above the bifurcation of the common iliacs and outside the boundaries of a standard LND [30,31]. Although preliminary, these reports are promising. In the future, the use of sentinel node technology may prove to be valuable in determining the primary drainage site of bladder tumors. Currently, however, the accuracy of this technology is unacceptably low and cannot be recommended for routine use. Accordingly, surgical excision and pathological evaluation of nodes remains the only reliable method of staging bladder cancer.
Prognostic risk factors—pT and N stage The prognosis of bladder cancer patients is primarily determined by 2 independent risk factors, pathologic stage and lymph node status. This is demonstrated in one retrospective comparison of node-negative with node-positive disease among 1,054 cystectomy patients. Both recurrencefree and overall survival of the entire cohort was significantly related to the pathologic stage and lymph node status; as both increased there was a significantly higher recurrence rate and worse overall survival [23]. In our updated experience, the 5 and 10-yr recurrence-free survival among all node-positive patients was 35% and 34%, respectively, but was significantly better in node-positive patients with OC primary tumors, 46% and 44%, respectively [32]. Organconfined, node-negative disease is associated with the lowest recurrence rate, longest survival and best prognosis as compared with EV, node-positive disease that has the worst prognosis [6,7,19,23,32,33]. Though the prognosis of node-positive patients is worse than node-negative counterparts, stratification of survival has been equivocally correlated with N category as defined by the 1997 TNM staging system [34]. Vieweg et al. [6] demonstrated strong correlation between disease-free survival rates and N-stage. They found 3-yr disease-free survival rates of 50.6%, 34.5%, and 0% among N1, N2 and N3 patients, respectively. However, a more recent investigation by Herr et al. revealed that N stage among node-positive patients was not significantly correlated with survival [35]. Though the 1997 TNM system may not be germane as a staging tool for nodal disease, it is clear that those patients with limited lymph node involvement, smaller-sized nodal
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metastases, and without lymph node capsule perforation have better outcomes [19].
Does lymphadenectomy improve patient survival? Both node-negative and node-positive patients benefit from resection of nodal tissue at the time of cystectomy [7,10, 32,36 –38]. While the presence of nodal metastases generally confers a poor prognosis, often despite pelvic lymph node dissection and radical cystectomy, a significant minority of node-positive patients treated with aggressive surgical resection will enjoy long-term survival [7,10,20,32]. Even among 84 patients with gross adenopathy (TNM stage [34] N2 or N3) treated with surgical resection alone, 24% of patients survived for 10-yrs [36]. This is a rather extraordinary number given that these patients were not given adjuvant systemic therapy and demonstrates that even with gross tumor involvement of the pelvic nodes, node dissection can be curative.
What aspects of the lymph node dissection contribute to improved prognosis? One of the most reliable parameters for predicting survival following radical cystectomy and LND is the total number of nodes retrieved. A larger number of nodes removed at cystectomy is strongly correlated with increased overall survival, and this is independent of the presence or number of metastatic nodes [6,8,11,19,33,37,40 – 43]. While widely reported, our own recent study failed to identify the total node number as a statistically significant prognostic variable [32]. This is likely attributable to the limited number of patients with fewer than 15 nodes removed available for analysis in our series, because of the extended nature of the pelvic node dissection in our entire cohort. A wide range of node retrieval per patient, averaging from 0 to 43, has been described in the literature [9,23,33,35] and reflects both surgeon-dependent and surgeon-independent factors. One of the factors over which the surgeon has no influence is the inherent anatomic diversity between individuals. This variation was nicely demonstrated by Weingartner et al. in their report of 30 postmortem standard pelvic node dissections performed on cadavers all deceased from noncancer related illness. Lymph node identification techniques and boundaries of dissection were identical in all cases. The mean number of nodes retrieved per standard dissection was 22.7 nodes but varied significantly from 8 to 56 [44]. These results clearly indicate that certain individuals have less nodal tissue than others. Another factor that directly impacts the ultimate number of nodes identified in a specimen is the diligence of the pathologist in locating nodes within the specimen. To facilitate isolation of nodes from fatty tissue within a large en bloc cystectomy specimen, submission of separate nodal packets divided intra-operatively by the surgeon is strongly
advised. This approach also assures that each packet submitted will receive an independent diagnosis, thus encouraging a more thorough search for nodal tissue. Bochner et al. demonstrated a more than threefold increase in the mean number of nodes, from 2.4 to 8.5, following conversion from submission of cystectomy and nodes en bloc to submission of separate lymph node packets [39]. These results are consistent with the USC experience in which the median number of nodes examined by the pathologist increased from 30 to 56 as a result of this protocol change adopted in May 2002 (unpublished data). While the correlation between total number of nodes removed and outcome is widely acknowledged in the literature, no consensus exists as to the minimum number of nodes necessary to achieve a survival advantage [21,33,38]. Leissner et al. reported that removal of at least 16 nodes was necessary to improve rates of local recurrence, distant metastases and 5-yr disease-free survival; 17%, 10.5%, 35% in the group with ⬎16 nodes examined as compared to 27%, 17%, 23% in those with fewer than 16 nodes, respectively [38]. The removal of only four nodes was necessary to significantly decrease the risk of death from bladder cancer in an analysis of 1,923 cystectomy patients included within the SEER cancer database [21]. Furthermore, the impact on survival, when controlled for age, gender, race, stage, histology, chemotherapy and radiation, was greatest in the group with 10 to 14 nodes removed. In fact, the only factors significantly associated with survival in this retrospective study were advanced pathologic stage and the total number of nodes removed [21].
Extent of dissection—an independent prognostic risk factor? Overall survival among bladder cancer patients is not only influenced by the total number of nodes retrieved, but also by the extent of the dissection [6 –11,19,20,23,32,35,42]. An extended dissection, as performed at our institution, includes dissection of the aorta and inferior vena cava distal to the inferior mesenteric artery, laterally to the genitofemoral nerve and distally to the circumflex iliac vein. This dissection always includes resection of the interaortocaval, right paracaval, left para-aortal, presacral, common iliac, external iliac and obturator nodes. This is in contrast to the more limited, “standard” dissection in which dissection is limited proximally to the bifurcation of the common iliacs and laterally to the medial aspect of the external iliac vein. Poulsen et al. [37] reported on their single institution, retrospective study in which survival and recurrence data were compared between consecutive patients undergoing radical cystectomy with either extended or limited pelvic LND by a single surgeon. Node-negative patients in the extended LND cohort experienced a 90% 5-yr recurrencefree survival in comparison to only 71% in the standard LND cohort. This survival benefit translated to the entire
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node-negative cohort, regardless of pT stage [37]. For example, among node-negative patients with OC disease, 5-yr recurrence-free survival was 85% as compared to 64% in the patients undergoing the lesser dissection. Rates of pelvic and distant metastases were also reduced at 5 yrs (2% vs. 7% and 10% vs. 21%, respectively) in the extended LND group. The extended lymphadenectomy correlated with increased survival among the node-positive cohort as well. The 5-yr recurrence-free survival among all stages of nodepositive disease was 24% in the extended LND group as compared to 7% in group receiving the limited dissection [37]. Importantly, because the node-positive group was skewed by a larger number of advanced stage primary tumors, these results are less significant than would be expected. One could predict that the survival advantage identified in the extended LND cohort would be even greater if not for the higher staged tumors within this cohort. Further evidence to support the superiority of the extended LND is offered by H.W. Herr [22]. In a multiinstitutional, randomized study of 270 bladder cancer patients stratified by extent of lymph node dissection (no LND vs. resection of obturator nodes only versus standard LND), the 5-yr survival rates for patients improved relative to the extent of nodal dissection, 33%, 46% and 60%, respectively [22]. However, the author also notes that the surgeon’s experience and number of nodes removed were as significant in predicting overall survival as the extent of node dissection.
Number of nodes or dissection limits—which matters more? Predictably, by extending the boundaries of dissection, the number of nodes retrieved increases. Poulsen et al. reported an increase in the average number of nodes retrieved, from 14 (5–32) in the standard dissection to 25 (9 – 67) in the extended dissection [37]. Bochner et al. also reported that the mean number of nodes yielded in an extended LND was significantly higher, 36.5, than those retrieved in a standard dissection, 8.5 [39]. In light of the fact that numerous studies have documented the survival benefit of increased node retrieval, is this survival advantage associated with the extended dissection merely a reflection of the increased number of nodes retrieved, or is it actually the result of the removal of micrometastatic lesions outside the boundaries of the standard dissection that would otherwise have been unresected and undiagnosed? Review of recently published data may provide insight into this important question. Leissner et al. [9] reported the results of a prospective lymph node mapping study in which the authors performed extended lymph node dissections (proximal boundary was the IMA) on 290 consecutive bladder cancer patients in conjunction with radical cystectomy.
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Lymph node packets were submitted separately after being marked as to location of retrieval. Tumor positive nodes were identified in 27.9% of the patients and were most often located within the boundaries of the standard lymph node dissection (25.8% of all positive nodes were located adjacent to the external iliacs and 13.2% of all positive nodes were located in the deep obturator spaces) [19]. Interestingly, a significant number of positive nodes (15.8%) were located lateral to the iliacs and bounded by the genitofemoral nerve, in contrast to previous reports in which no nodal metastases were identified in this region [13]. Surprisingly, isolated nodal involvement in the common iliac and/or presacral regions was identified in 25% (20/81) of lymph nodepositive patients, indicating the ability of bladder tumor metastases to “skip” the external iliac and obturator node chains. Among patients with nodal metastases located within the limits of the standard LND, a significant proportion also had nodal involvement at the level of the common iliacs and above the aortic bifurcation, 57% and 31%, respectively. The authors conclude that had lymphadenectomy been limited to the obturator spaces, 74.1% of all positive nodes would have been left behind, and 6.8% (20/290) of the patients in this cohort misclassified as nodenegative [9]. Confirmation of the highly variable nature of the lymphatic drainage of bladder tumors is provided by further subset analysis of unilateral, solitary bladder tumors. Among patients in which the primary tumor was localized to one hemisphere of the bladder with a solitary nodal metastasis, 30% of the positive nodes were actually located on the contralateral side, [9] contrary to previous reports [14,45]. This corroborates a previous report of crossing lymphatic drainage patterns in 41% of node-positive patients with unilateral tumor [19]. The unpredictable, often crossing, lymphatic drainage of the bladder, the presence of “skip lesions” in the pelvic lymph node chain and the significant percentage of patients with nodal metastases above the iliac bifurcation are well documented by this and other studies [30,31]. These results support our strongly held belief that the survival advantage conferred by a more comprehensive bilateral resection is the result of the removal of metastatic disease that would not otherwise have been resected.
Lymphadenectomy in practice Despite convincing data correlating a comprehensive LND with improved prognosis, large numbers of patients undergoing radical cystectomy for bladder cancer are not undergoing adequate lymph node dissection. Extrapolating from the large population-based SEER cohort, 40% of all patients undergoing cystectomies had no lymph nodes removed, and in another 12.7%, fewer than four nodes were removed in total [46]. Though factors beyond the purview of the surgeon play a role in the ultimate number of nodes
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retrieved, including anatomic variation and pathologic evaluation, surgeon preference continues to plays the major role in determining the completeness of LND. Surgical practices may reflect the surgeon’s misconception that patients with advanced stage disease, gross adenopathy or extravesical extension, derive little survival benefit from radical surgical resection of nodal tissue. This may explain why fewer than one-half of the 26,140 patients in the SEER registry undergoing cystectomy with EV and/or node-positive disease in the study had one or more nodes removed at the time of cystectomy [46]. As previously described, local tumor control, prevention of distant metastases and long-term survival can all be improved by aggressive surgical intervention [7,21,36]. At the other end of the spectrum, low-staged patients also seem to be denied the benefits of lymphadenectomy. Among the Stage I/PIS patients within the SEER database, fewer than 1% had any nodes removed at the time of cystectomy [46]. This is particularly unfortunate given that up to 5% of patients with low stage (T1 or less) disease will have occult nodal disease, and lymph node dissection for those patients would likely be curative [9,41]. Time constraints and concern over the potential increased complication rate may contribute to the reluctance of urologists to complete a comprehensive node dissection. Admittedly, an extended node dissection requires approximately 60 additional minutes to complete [9]. However, completion of the cystectomy is made easier by the dissection and identification of pelvic vessels during the lymphadenectomy, resulting in a safer procedure. Of note, the extended dissection has not been associated with an increase in blood loss, complication rate or peri-operative mortality [13,37–39].
TNM—is there a better alternative for stratification of positive nodes? In the current TNM staging system, [34] lymph node metastases are stratified by the absolute number and size of tumor-positive nodes. For this categorization strategy to be a reliable prognostic indicator, the extent and comprehensiveness of the node dissection would need to be consistent for every patient. Given the inconsistencies in the completion of the LND, direct comparison of prognosis based upon the current N staging system may be unreliable. For example, a patient in whom 3 positive nodes were identified in the lymphadenectomy specimen would be stratified into N2 category of the 1997 TNM staging system regardless of the total number of nodes analyzed. If this patient had a total of three nodes excised and all three were involved with tumor, this would clearly imply a more ominous prognosis than for the patient in which 3 of 40 nodes were involved with metastatic disease. This is not only intuitive, but also supported by the literature. In fact, in a recent retrospective study comparing various prognostic indicators with outcome, the N cat-
egory of the current TNM staging system failed to reach statistical significance [35]. Interest in identifying additional parameters that would more accurately predict survival following radical cystectomy has led to the recent description of “lymph node density.” Node density combines 2 of the most reliable predictors of outcome, number of positive nodes and total number of nodes removed, into 1 ratio. The numerator (number of positive nodes) accounts for the nodal tumor burden while the denominator (total number of nodes retrieved) acts as a surrogate for the completeness of dissection. Integration of these 2 variables, both independent predictors of survival, [11,23,33,43] may result in a more precise assessment of overall survival. Stein et al. first reported that lymph node density was strongly predictive of recurrence and survival at both 5 and 10 yrs when stratifying by node density of ⬎20% vs. less than 20% [32]. Additionally, in a large population based study, the percentage of positive nodes (i.e., LN density) proved to be the strongest predictor for survival in node-positive, EV disease [21]. Further investigation of the efficacy of lymph node density was completed by Herr et al. in a retrospective study of 162 patients following cystectomy and LND [35]. This group compared node density with the current TNM staging system as predictors of survival. Lymph node density proved to be the strongest predictor of recurrence and survival, even when stratified by P stage. Thus, lymph node density discriminates survival and local control better than conventional lymph node staging methods and may be useful in future staging systems.
Conclusion Lymph node dissection at the time of radical cystectomy is an essential part of the treatment of bladder cancer. A comprehensive dissection provides both important staging information, and possibly therapeutic benefits for patients with high grade, invasive disease. As indicated above, nearly one-quarter of patients undergoing cystectomy will be diagnosed with nodal disease at the time of cystectomy. Given the current limitations of preoperative imaging techniques, information provided by the node dissection is otherwise unattainable. Once accurately staged, patients at high risk for recurrence can be offered adjuvant treatment protocols. While the optimal limits of the lymph node dissection have yet to be defined, considerable evidence suggests that the extended dissection provides the best chance for control of local disease and long-term survival.
References [1] Whitmore WF, Marshall VF. Radical total cystectomy for cancer of the bladder: 230 consecutive cases five years later. J Urol 1962;87: 853– 68.
K.M. Sanderson et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 205–213 [2] Kerr WS, Colby FH. Pelvic lymph node dissection and total cystectomy in the treatment of carcinoma of the bladder. J Urol 1950;63: 842–51. [3] Halstead WS. The treatment of wounds. Johns Hopkins Hosp Rep 1891;2:279. [4] Colston JA, Leadbetter WF. Infiltrating carcinoma of the bladder. J Urol 1936;36:669 – 89. [5] Jewett HJ, Strong GH. Infiltrating carcinoma of the bladder: relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J Urol 1946;55:366 –72. [6] Vieweg J, Gschwend JE, Herr HW, et al. The impact of primary stage on survival in patients with lymph node positive bladder cancer. J Urol 1999;161:72– 6. [7] Vieweg J, Gschwend JE, Herr H, et al. Pelvic lymph nodes dissection can be curative in patients with lymph node positive disease. J Urol 1999;161:449 –54. [8] Stein JP, Skinner DG. Results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. BJU 2003;92:12–7. [9] Leissner J, Ghoneim H, Abol-Enein J, et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol 2004;171:139 – 44. [10] Skinner DG. Management of invasive bladder cancer: a meticulous pelvic node dissection can make a difference. J Urol 1982;128:34 – 6. [11] Lerner SP, Skinner DG, Lieskovsky G, et al. The rationale for en bloc PLND for bladder cancer patients with nodal metastases: long-term results. J Urol 1993;149:758 – 64. [12] Leadbetter WF, Cooper JF. Regional gland dissection for carcinoma of the bladder: a technique for one-stage cystectomy, gland dissection and bilateral uretero-enterostomy. J Urol 1950;63:242– 60. [13] Dretler SP, Ragsdale BD, Leadbetter WF. The value of pelvic lymphadenectomy in the surgical treatment of bladder cancer. J Urol 1973; 109:414 – 6. [14] Wishnow KI, Johnson DE, Ro J, et al. Incidence, extent and location of unsuspected pelvic lymph node metastasis in patients undergoing radical cystectomy for bladder cancer. J Urol 1987;137:408 –10. [15] Skinner DG. Current state of classification and staging of bladder cancer. Cancer Res 1977;37:2838 – 42. [16] Raghavan D, Quinn D, Skinner DG, et al. Surgery and adjunctive chemotherapy for invasive bladder cancer. Surg Oncol 2002;11:55– 63. [17] Skinner DC, Daniels JR, Russell CA, et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991;145:459 – 67. [18] Frieha FS, Reese J, Torti F. A randomized trial of radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996;155:1241–5. [19] Mills RD, Turner WH, Fleischmann R, et al. Pelvic lymph node metastasis from bladder cancer: outcome in 83 patients after radical cystectomy and pelvic lymphadenectomy. J Urol 2001;166:19 –23. [20] Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today—a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21:690 – 6. [21] Konety BR, Joslyn SA, O’Donnell MA. Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the surveillance, epidemiology and end results program data base. J Urol 2003;169:946 –50. [22] Herr HW. Surgical factors in bladder cancer: more (nodes) ⫹ more (pathology) ⫽ less (mortality). BJU 2003;92:187– 8. [23] 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;19:666 –75. [24] Paik ML, Scolieri MJ, Brown SL, et al. Limitations of CT in staging invasive bladder cancer before radical cystectomy. J Urol 2000;163: 1693.
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[25] Persad R, Kabala J, Gillatt D, et al. MRI in the staging of bladder cancer. Br J Urol 1993;71:566 –73. [26] Heicappell R, Muller-Mattheis V, Reinhardt M, et al. Staging of pelvic lymph nodes in neoplasms of the bladder and prostate by positron emission tomography with 2-[18F]-2-Deoxy-D-Glucose. Eur Urol 1999;36:582–7. [27] Bachor R, Kotzerke J, Reske SN, et al. Lymph node staging of bladder neck carcinoma with positron emission tomography in patients with bladder cancer. Eur J Num Med 1997;24:615–20. [28] Nathanson DS. Insights into the mechanisms of lymph node metastsis. Cancer 2003;98:413–22. [29] Perrott RE, Reintgen DS, Fenske NA. Reassessing the role of lymphatic mapping and sentinel lymphadenectomy in the management of cutaneous malignant melanoma. J Am Acad Derm 2003; 49:567– 88. [30] Sherif A, De La Torre M, Malmstrom PU, et al. Lymphatic mapping and detection of sentinel nodes in patients with bladder cancer. J Urol 2001;166:812–5. [31] Liedberg F, Chebil G, Davidsson T, et al. Bladder cancer and the sentinel node concept. Aktuel Urol 2003;34:115– 8. [32] Stein JP, Cai J, Groshen S, et al. Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: the concept of lymph node density. J Urol 2003;170:35– 41. [33] Herr HW, Bochner BH, Dalbagni G, et al. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 2002;167:1295–999. [34] Fleming ID, Cooper JS, Henson DE, et al. AJCC cancer staging system manuel. 5th ed. Philadelphia: JB Lippincott, 1997. [35] Herr H. Superiority of ratio based LN staging for bladder cancer. J Urol 2003;169:943–5. [36] Herr HW, Donat SM. Outcomes of patients with grossly node positive bladder cancer after pelvic lymph node dissection and cystectomy. J Urol 2001;165:62– 4. [37] Poulsen A, Horn T, Steven K. Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 1998;160: 2015–9. [38] Leissner J, Hohenfellner R, Thuroff JW, et al. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder: significance for staging and prognosis. BJU Int 2000;85:817–23. [39] Bochner BH, Herr HW, Reuter VE. Impact of separate versus en bloc pelvic lymph node dissection on the number of nodes retrieved in cystectomy specimens. J Urol 2001;166:2295– 6. [40] Vieweg J, Gschwend JE, Herr H, et al. Pelvic lymph nodes dissection can be curative in patients with lymph node positive disease. J Urol 1999;161:449 –54. [41] Stein JP, Skinner DG. Results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. BJU 2003;92:12–7. [42] Ghoneim MA, El-Mekresh MM, El-Baz MA, et al. Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol 1997;158:393–9. [43] Herr H. Extent of surgery and pathology evaluation has an impact on bladder cancer outcomes after radical cystectomy. Urology 2003;61: 105–9. [44] Weingartner K, Ramaswamy A, Bittinger A, et al. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 1996;156:1969 –71. [45] Marshall VF. The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J Urol 1952; 68:714 – 6. [46] Konety BR, Joslyn SA. Factors influencing aggressive therapy for bladder cancer: an analysis of data from the SEER program. J Urol 2003;170:1765–71.
Seminar article
The evolving role of pelvic lymphadenectomy in the treatment of bladder cancer Kristin M. Sanderson, M.D., M.P.H.*, John P. Stein, M.D., F.A.C.S., Donald G. Skinner, M.D. Department of Urology, USC Norris Cancer Center, Los Angeles, CA, USA
Abstract Regional lymphadenectomy is integral to the surgical management of high-grade invasive bladder cancer. A growing body of evidence suggests that a lymph node dissection may provide not only improved prognostic information, but also a clinically significant therapeutic benefit for both lymph node positive and negative patients undergoing radical cystectomy. While the inclusion of lymph node resection in conjunction with radical cystectomy for patients with clinically negative nodes is well accepted, the extent of the nodal dissection remains highly contentious. Similarly, the benefit of node dissection for patients with advanced disease and gross adenopathy or for those with superficial disease (Ta, T1 or TIS) remains a topic of heated debate. This review describes the historical evolution of lymphadenectomy in the surgical treatment of bladder cancer and provides a comprehensive review of the current literature addressing the role of lymph node dissection in the treatment of bladder cancer. © 2004 Elsevier Inc. All rights reserved. Keywords: Bladder neoplasm; Transitional cell carcinoma; Lymphadenectomy; Cystectomy; Lymph node dissection; Lymph node metastasis; Lymph node density; Bladder cancer
Introduction
Historic perspective
It was more than 50 yrs ago that the first reports of pelvic lymph node dissection as an adjunct to radical cystectomy surfaced in the American medical journals. Invasive bladder cancer at the time carried a dismal prognosis. The operative treatment itself, simple cystectomy, was associated with a 30% to 40% peri-operative mortality rate and exceedingly high rates of pelvic and distant recurrences [1,2]. The presence of gross pelvic adenopathy encountered at surgery was associated with 5-yr survival rate approaching zero [1]. It was at this point that the astute observations of some of the pioneers in Urology led to a paradigm shift in the treatment of bladder cancer, the addition of lymph node resection. With the advent of the pelvic lymph node dissection (LND) as an adjunct to cystectomy, surgeons were finally able to make a meaningful impact on survival outcomes. Today, lymphadenectomy is recognized as an integral part of the treatment of bladder cancer, providing both therapeutic benefit and valuable diagnostic information.
Regional lymph node dissection as an essential part of radical surgery was first introduced by Halstead in 1886. As a surgeon treating carcinoma of the breast, Halstead noted improved survival in advanced breast cancer patients following the addition of a regional lymph node dissection (LND) to the mastectomy, thus was born the Halsteadian philosophy: primary tumors metastasize through lymphatics to regional lymph nodes [3]. Several decades later, interest in the role of lymphadenectomy for the treatment of bladder cancer was growing. The prevailing belief regarding advanced bladder carcinoma with gross adenopathy was that it was uniformly fatal as a result of systemic spread and, therefore, beyond the limits of surgical intervention. In 1936, Drs. Colston and Leadbetter completed an autopsy series on 98 patients with bladder cancer, and the results would challenge the wisdom of the day. They identified a significant number of cadavers in whom limited metastatic disease was restricted to the pelvic lymph nodes and thus, potentially amenable to surgical resection [4]. These findings were confirmed and expanded by Dr. H.J. Jewett one decade later. In 1946, Dr. Jewett published his
* Corresponding author. Tel.: ⫹1-323-865-3700; fax: ⫹1-323-8650120. E-mail address: [email protected] (K.M. Sanderson). 1078-1439/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2004.04.030
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important autopsy series of 107 patients in which he identified a small percentage of patients with extravesical carcinoma who had metastatic involvement limited to the pelvic lymph nodes, “a cardinal site of metastasis” [5]. He also definitively correlated the depth of invasion of the primary tumor with the incidence and extent of lymphatic involvement. This “index of curability” [5] would form the basis of the first widely accepted staging system, the Jewett-Marshall staging system. The correlation between primary tumor stage and lymph node metastasis, first described by Jewett, is now well accepted and has been confirmed in numerous studies [6 –10]. In contemporary series, lymph node metastases increase relative to the invasiveness of the primary tumor. Nodal metastases have been identified in 6% of P1, 9% to 30% of P2, 23% to 31% of P3a, 43% to 60% of P3b and 47% of P4 patients [6,10]. In another series, patients with organ confined (OC) disease comprised only 22.8% of the total node-positive cohort, whereas EV disease accounted for the remaining 77.2% [7]. Even in low-stage disease (Pa, PIS, P0 and P1), up to 7% of patients with will have positive nodes identified by lymphadenectomy [8,11]. The first correlation of pelvic LND with improved prognosis among bladder cancer patients was described in 1950. Drs. Kerr and Colby are credited with the first report of long-term survival in two node-positive patients undergoing radical cystectomy with pelvic LND. In their original manuscript, the authors state that they were “considerably disturbed” over the high incidence of pelvic recurrence after simple cystectomy and this prompted their routine inclusion of lymphadenectomy with radical cystectomy [2]. As a result of this change, they noted a decreased pelvic recurrence rate as well as increased overall survival, prompting them to advocate the routine. These findings led them to advocate the routine completion of a pelvic node dissection during cystectomy to “increase the curability” of carcinoma of the bladder. In that same year, Leadbetter and Cooper [12] published a comprehensive work that detailed his technique of extended pelvic lymph node dissection and defined the boundaries of dissection (i.e., proximal– distal aorta; lateral– genitofemoral nerve; distal– circumflex iliac vein and lymph node of Cloquet) that remain in use today. The authors concluded “it seems possible that . . . a more radical cystectomy combined with pelvic gland dissection may be expected to extend the limits of palliative and curative treatment of infiltrating cancer of the bladder.” [12] More than a decade later, Whitmore and Marshall reported their promising early success with this new treatment modality. Of 55 stage D1 patients (lymph node involvement confined to the pelvis by the Jewett-Marshall system) undergoing radical cystectomy and pelvic node dissection, 4% survived for 5 yrs, a significant improvement over this otherwise uniformly fatal stage of disease. The observation that each of the 2 surviving patients had fewer than 3 involved nodes led them to conclude that “in patients with only limited nodal metastases, radical
cystectomy has provided some 5-yr successful results—the only such of which we are aware” [1]. Improved survival in patients with nodal metastases was replicated in later studies, particularly in OC disease and, importantly, no increased morbidity or mortality was attributed to the extended lymph node dissection [13]. In contrast to Leadbetter, Wishnow became a proponent of a more limited dissection (cephalad limit of dissection–iliac bifurcation) based upon his observation that, in the absence of gross adenopathy, metastatic nodal disease was never present above the level of the iliac bifurcation [10]. This dissection is now commonly referred to as the “standard” LND. The aggregate experience from these early leaders in Urology has formed the cornerstone of our current understanding of the treatment of bladder carcinoma. The pelvic lymphadenectomy is now an integral part of radical cystectomy for bladder cancer. When meticulously completed, the procedure offers not only curative potential, but also valuable staging information. However, ongoing controversy exists to this day regarding the optimal boundaries of lymph node dissection necessary to accurately diagnose metastases and to provide maximal therapeutic benefit without increasing peri-operative morbidities.
Why is accurate staging important for prognosis? Staging allows for the standardized comparison of patient risk factors and the evaluation of treatment results based on a universally accepted system [15]. Accurate staging of bladder cancer is essential to correctly identify those at high-risk for recurrence, particularly node-positive patients, who would potentially benefit from adjuvant therapy and/or a more aggressive surveillance regimen. Determining which patients should receive adjuvant chemotherapy is generally based upon the probability of death from the cancer. The presence of regional metastasis, therefore, plays a critical role in this analysis, as most patients will require subsequent systemic treatment. An inadequate resection of the lymphatics, risking misclassification of the nodal status, would preclude high-risk node-positive patients from receiving this potentially beneficial therapy. Evidence to support the role of adjuvant chemotherapy in the treatment of node-positive bladder cancer is mounting, though it has yet to be definitively proven in a prospective, randomized trial. Previous prospective trials have shown trends in disease-free and overall survival but failed to show statistical significance because of design errors and inadequate power [16 –18]. However, retrospective studies of lymph node-positive patients have provided evidence for the efficacy of adjuvant chemotherapy in this high-risk group. In one study, addition of adjuvant chemotherapy following the surgical treatment of 83 node-positive patients resulted in a statistically significant survival advantage that was maintained when controlled for age, pT stage, pN stage and number of nodes [19]. In another series, adjuvant chemotherapy resulted in a near doubling of disease-free survival (21.5 vs. 13.1 months) [20].
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In addition, the use of chemotherapy was significantly associated with increased survival in a retrospective review of 1,923 population based patients undergoing cystectomy, though the total number of nodes resected during cystectomy was more significant in predicting survival [21]. Though not all retrospective studies have confirmed the benefit of chemotherapy in extending overall survival of node-positive patients [7,22], evidence seems to support the role of adjuvant chemotherapy in this population.
Preoperative staging alternatives—noninvasive identification and localization of metastatic nodes Occult metastatic disease involving grossly normal-appearing nodes is a well-described phenomenon. Dr. Kerr, in 1950, reported unsuspected micrometastases in 40% of his clinically node-negative patients [2]. Despite modern imaging modalities [computed tomography (CT) scan and magnetic resonance imaging (MRI)], efforts to preoperatively diagnose occult nodal disease have been largely unsuccessful and reported rates of occult lymph node metastasis remain substantial, ranging from 14% up to 27% [9,19 –23]. CT scan and MRI fail to accurately identify pelvic nodal micrometastases in 21% and 15% of patients, respectively [24,25]. Positron emission tomography (PET) scan, the newest addition to the imaging armamentarium, has also proven to be disappointing in this capacity. In a recent study, eight patients completed both CT and PET scans prior to radical cystectomy and standard pelvic LND. No false positives were noted and the PET scan was able to correctly detect nodal metastases in 2 patients, 1 of whom was negative by CT scan. However, the false negative rate was 33% [26]. These data are consistent with the results from the largest study to date in which one-third of the patients with pathologically confirmed nodal metastases were missed [27]. An alternative attempt to better localize lymphatic spread from the primary tumor is the sentinel lymph node biopsy (SLN). Proven to be successful and accurate in predicting the lymphatic drainage in both melanoma and breast cancer, SLN has provided confirmation of the orderly anatomic progression of tumor cells from primary site to regional lymph nodes in these cancers [28]. Preoperative injection of either lymphophilic dye or radiolabeled tracer around the neoplastic lesion allows for localization of the primary nodal drainage of the tumor. During surgery, a handheld detection tube is used to localize the concentration of tracer, and nodes are visually assessed for the concentration of blue dye. Once this nodal packet is excised and examined, wider dissection of lymph nodes is then completed only if the primary packet is determined to be positive for metastatic disease. When used in the surgical treatment of melanoma, approximately 80% of patients have been spared the morbidity of an extensive lymph node dissection [29]. Because of the difficulty in accurately predicting the presence and location of lymph node metastases in bladder cancer, the utility of sentinel node biopsy has been investigated pro-
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spectively in 2 small studies [30,31]. Patients underwent preoperative endoscopic injection of tracer before cystectomy. In all cases, a standard lymphadenectomy was completed. Intraoperatively, no distinct SNL could be identified in 15% to 20% of these patients. In those in whom a SLN was localized, the node lay outside the obturator lymph node packet in 33% of the patients. Of 12 patients with metastatic tumors involving the nodes, a positive sentinel node was identified in eleven, with one false-negative (8.6%). Thus, based upon the intraoperative findings, one patient would have been denied a more extensive, possibly curative, node resection had the SLN methodology been employed. Of interest, in a majority of patients (63–75%) the sentinel node was located above the bifurcation of the common iliacs and outside the boundaries of a standard LND [30,31]. Although preliminary, these reports are promising. In the future, the use of sentinel node technology may prove to be valuable in determining the primary drainage site of bladder tumors. Currently, however, the accuracy of this technology is unacceptably low and cannot be recommended for routine use. Accordingly, surgical excision and pathological evaluation of nodes remains the only reliable method of staging bladder cancer.
Prognostic risk factors—pT and N stage The prognosis of bladder cancer patients is primarily determined by 2 independent risk factors, pathologic stage and lymph node status. This is demonstrated in one retrospective comparison of node-negative with node-positive disease among 1,054 cystectomy patients. Both recurrencefree and overall survival of the entire cohort was significantly related to the pathologic stage and lymph node status; as both increased there was a significantly higher recurrence rate and worse overall survival [23]. In our updated experience, the 5 and 10-yr recurrence-free survival among all node-positive patients was 35% and 34%, respectively, but was significantly better in node-positive patients with OC primary tumors, 46% and 44%, respectively [32]. Organconfined, node-negative disease is associated with the lowest recurrence rate, longest survival and best prognosis as compared with EV, node-positive disease that has the worst prognosis [6,7,19,23,32,33]. Though the prognosis of node-positive patients is worse than node-negative counterparts, stratification of survival has been equivocally correlated with N category as defined by the 1997 TNM staging system [34]. Vieweg et al. [6] demonstrated strong correlation between disease-free survival rates and N-stage. They found 3-yr disease-free survival rates of 50.6%, 34.5%, and 0% among N1, N2 and N3 patients, respectively. However, a more recent investigation by Herr et al. revealed that N stage among node-positive patients was not significantly correlated with survival [35]. Though the 1997 TNM system may not be germane as a staging tool for nodal disease, it is clear that those patients with limited lymph node involvement, smaller-sized nodal
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metastases, and without lymph node capsule perforation have better outcomes [19].
Does lymphadenectomy improve patient survival? Both node-negative and node-positive patients benefit from resection of nodal tissue at the time of cystectomy [7,10, 32,36 –38]. While the presence of nodal metastases generally confers a poor prognosis, often despite pelvic lymph node dissection and radical cystectomy, a significant minority of node-positive patients treated with aggressive surgical resection will enjoy long-term survival [7,10,20,32]. Even among 84 patients with gross adenopathy (TNM stage [34] N2 or N3) treated with surgical resection alone, 24% of patients survived for 10-yrs [36]. This is a rather extraordinary number given that these patients were not given adjuvant systemic therapy and demonstrates that even with gross tumor involvement of the pelvic nodes, node dissection can be curative.
What aspects of the lymph node dissection contribute to improved prognosis? One of the most reliable parameters for predicting survival following radical cystectomy and LND is the total number of nodes retrieved. A larger number of nodes removed at cystectomy is strongly correlated with increased overall survival, and this is independent of the presence or number of metastatic nodes [6,8,11,19,33,37,40 – 43]. While widely reported, our own recent study failed to identify the total node number as a statistically significant prognostic variable [32]. This is likely attributable to the limited number of patients with fewer than 15 nodes removed available for analysis in our series, because of the extended nature of the pelvic node dissection in our entire cohort. A wide range of node retrieval per patient, averaging from 0 to 43, has been described in the literature [9,23,33,35] and reflects both surgeon-dependent and surgeon-independent factors. One of the factors over which the surgeon has no influence is the inherent anatomic diversity between individuals. This variation was nicely demonstrated by Weingartner et al. in their report of 30 postmortem standard pelvic node dissections performed on cadavers all deceased from noncancer related illness. Lymph node identification techniques and boundaries of dissection were identical in all cases. The mean number of nodes retrieved per standard dissection was 22.7 nodes but varied significantly from 8 to 56 [44]. These results clearly indicate that certain individuals have less nodal tissue than others. Another factor that directly impacts the ultimate number of nodes identified in a specimen is the diligence of the pathologist in locating nodes within the specimen. To facilitate isolation of nodes from fatty tissue within a large en bloc cystectomy specimen, submission of separate nodal packets divided intra-operatively by the surgeon is strongly
advised. This approach also assures that each packet submitted will receive an independent diagnosis, thus encouraging a more thorough search for nodal tissue. Bochner et al. demonstrated a more than threefold increase in the mean number of nodes, from 2.4 to 8.5, following conversion from submission of cystectomy and nodes en bloc to submission of separate lymph node packets [39]. These results are consistent with the USC experience in which the median number of nodes examined by the pathologist increased from 30 to 56 as a result of this protocol change adopted in May 2002 (unpublished data). While the correlation between total number of nodes removed and outcome is widely acknowledged in the literature, no consensus exists as to the minimum number of nodes necessary to achieve a survival advantage [21,33,38]. Leissner et al. reported that removal of at least 16 nodes was necessary to improve rates of local recurrence, distant metastases and 5-yr disease-free survival; 17%, 10.5%, 35% in the group with ⬎16 nodes examined as compared to 27%, 17%, 23% in those with fewer than 16 nodes, respectively [38]. The removal of only four nodes was necessary to significantly decrease the risk of death from bladder cancer in an analysis of 1,923 cystectomy patients included within the SEER cancer database [21]. Furthermore, the impact on survival, when controlled for age, gender, race, stage, histology, chemotherapy and radiation, was greatest in the group with 10 to 14 nodes removed. In fact, the only factors significantly associated with survival in this retrospective study were advanced pathologic stage and the total number of nodes removed [21].
Extent of dissection—an independent prognostic risk factor? Overall survival among bladder cancer patients is not only influenced by the total number of nodes retrieved, but also by the extent of the dissection [6 –11,19,20,23,32,35,42]. An extended dissection, as performed at our institution, includes dissection of the aorta and inferior vena cava distal to the inferior mesenteric artery, laterally to the genitofemoral nerve and distally to the circumflex iliac vein. This dissection always includes resection of the interaortocaval, right paracaval, left para-aortal, presacral, common iliac, external iliac and obturator nodes. This is in contrast to the more limited, “standard” dissection in which dissection is limited proximally to the bifurcation of the common iliacs and laterally to the medial aspect of the external iliac vein. Poulsen et al. [37] reported on their single institution, retrospective study in which survival and recurrence data were compared between consecutive patients undergoing radical cystectomy with either extended or limited pelvic LND by a single surgeon. Node-negative patients in the extended LND cohort experienced a 90% 5-yr recurrencefree survival in comparison to only 71% in the standard LND cohort. This survival benefit translated to the entire
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node-negative cohort, regardless of pT stage [37]. For example, among node-negative patients with OC disease, 5-yr recurrence-free survival was 85% as compared to 64% in the patients undergoing the lesser dissection. Rates of pelvic and distant metastases were also reduced at 5 yrs (2% vs. 7% and 10% vs. 21%, respectively) in the extended LND group. The extended lymphadenectomy correlated with increased survival among the node-positive cohort as well. The 5-yr recurrence-free survival among all stages of nodepositive disease was 24% in the extended LND group as compared to 7% in group receiving the limited dissection [37]. Importantly, because the node-positive group was skewed by a larger number of advanced stage primary tumors, these results are less significant than would be expected. One could predict that the survival advantage identified in the extended LND cohort would be even greater if not for the higher staged tumors within this cohort. Further evidence to support the superiority of the extended LND is offered by H.W. Herr [22]. In a multiinstitutional, randomized study of 270 bladder cancer patients stratified by extent of lymph node dissection (no LND vs. resection of obturator nodes only versus standard LND), the 5-yr survival rates for patients improved relative to the extent of nodal dissection, 33%, 46% and 60%, respectively [22]. However, the author also notes that the surgeon’s experience and number of nodes removed were as significant in predicting overall survival as the extent of node dissection.
Number of nodes or dissection limits—which matters more? Predictably, by extending the boundaries of dissection, the number of nodes retrieved increases. Poulsen et al. reported an increase in the average number of nodes retrieved, from 14 (5–32) in the standard dissection to 25 (9 – 67) in the extended dissection [37]. Bochner et al. also reported that the mean number of nodes yielded in an extended LND was significantly higher, 36.5, than those retrieved in a standard dissection, 8.5 [39]. In light of the fact that numerous studies have documented the survival benefit of increased node retrieval, is this survival advantage associated with the extended dissection merely a reflection of the increased number of nodes retrieved, or is it actually the result of the removal of micrometastatic lesions outside the boundaries of the standard dissection that would otherwise have been unresected and undiagnosed? Review of recently published data may provide insight into this important question. Leissner et al. [9] reported the results of a prospective lymph node mapping study in which the authors performed extended lymph node dissections (proximal boundary was the IMA) on 290 consecutive bladder cancer patients in conjunction with radical cystectomy.
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Lymph node packets were submitted separately after being marked as to location of retrieval. Tumor positive nodes were identified in 27.9% of the patients and were most often located within the boundaries of the standard lymph node dissection (25.8% of all positive nodes were located adjacent to the external iliacs and 13.2% of all positive nodes were located in the deep obturator spaces) [19]. Interestingly, a significant number of positive nodes (15.8%) were located lateral to the iliacs and bounded by the genitofemoral nerve, in contrast to previous reports in which no nodal metastases were identified in this region [13]. Surprisingly, isolated nodal involvement in the common iliac and/or presacral regions was identified in 25% (20/81) of lymph nodepositive patients, indicating the ability of bladder tumor metastases to “skip” the external iliac and obturator node chains. Among patients with nodal metastases located within the limits of the standard LND, a significant proportion also had nodal involvement at the level of the common iliacs and above the aortic bifurcation, 57% and 31%, respectively. The authors conclude that had lymphadenectomy been limited to the obturator spaces, 74.1% of all positive nodes would have been left behind, and 6.8% (20/290) of the patients in this cohort misclassified as nodenegative [9]. Confirmation of the highly variable nature of the lymphatic drainage of bladder tumors is provided by further subset analysis of unilateral, solitary bladder tumors. Among patients in which the primary tumor was localized to one hemisphere of the bladder with a solitary nodal metastasis, 30% of the positive nodes were actually located on the contralateral side, [9] contrary to previous reports [14,45]. This corroborates a previous report of crossing lymphatic drainage patterns in 41% of node-positive patients with unilateral tumor [19]. The unpredictable, often crossing, lymphatic drainage of the bladder, the presence of “skip lesions” in the pelvic lymph node chain and the significant percentage of patients with nodal metastases above the iliac bifurcation are well documented by this and other studies [30,31]. These results support our strongly held belief that the survival advantage conferred by a more comprehensive bilateral resection is the result of the removal of metastatic disease that would not otherwise have been resected.
Lymphadenectomy in practice Despite convincing data correlating a comprehensive LND with improved prognosis, large numbers of patients undergoing radical cystectomy for bladder cancer are not undergoing adequate lymph node dissection. Extrapolating from the large population-based SEER cohort, 40% of all patients undergoing cystectomies had no lymph nodes removed, and in another 12.7%, fewer than four nodes were removed in total [46]. Though factors beyond the purview of the surgeon play a role in the ultimate number of nodes
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retrieved, including anatomic variation and pathologic evaluation, surgeon preference continues to plays the major role in determining the completeness of LND. Surgical practices may reflect the surgeon’s misconception that patients with advanced stage disease, gross adenopathy or extravesical extension, derive little survival benefit from radical surgical resection of nodal tissue. This may explain why fewer than one-half of the 26,140 patients in the SEER registry undergoing cystectomy with EV and/or node-positive disease in the study had one or more nodes removed at the time of cystectomy [46]. As previously described, local tumor control, prevention of distant metastases and long-term survival can all be improved by aggressive surgical intervention [7,21,36]. At the other end of the spectrum, low-staged patients also seem to be denied the benefits of lymphadenectomy. Among the Stage I/PIS patients within the SEER database, fewer than 1% had any nodes removed at the time of cystectomy [46]. This is particularly unfortunate given that up to 5% of patients with low stage (T1 or less) disease will have occult nodal disease, and lymph node dissection for those patients would likely be curative [9,41]. Time constraints and concern over the potential increased complication rate may contribute to the reluctance of urologists to complete a comprehensive node dissection. Admittedly, an extended node dissection requires approximately 60 additional minutes to complete [9]. However, completion of the cystectomy is made easier by the dissection and identification of pelvic vessels during the lymphadenectomy, resulting in a safer procedure. Of note, the extended dissection has not been associated with an increase in blood loss, complication rate or peri-operative mortality [13,37–39].
TNM—is there a better alternative for stratification of positive nodes? In the current TNM staging system, [34] lymph node metastases are stratified by the absolute number and size of tumor-positive nodes. For this categorization strategy to be a reliable prognostic indicator, the extent and comprehensiveness of the node dissection would need to be consistent for every patient. Given the inconsistencies in the completion of the LND, direct comparison of prognosis based upon the current N staging system may be unreliable. For example, a patient in whom 3 positive nodes were identified in the lymphadenectomy specimen would be stratified into N2 category of the 1997 TNM staging system regardless of the total number of nodes analyzed. If this patient had a total of three nodes excised and all three were involved with tumor, this would clearly imply a more ominous prognosis than for the patient in which 3 of 40 nodes were involved with metastatic disease. This is not only intuitive, but also supported by the literature. In fact, in a recent retrospective study comparing various prognostic indicators with outcome, the N cat-
egory of the current TNM staging system failed to reach statistical significance [35]. Interest in identifying additional parameters that would more accurately predict survival following radical cystectomy has led to the recent description of “lymph node density.” Node density combines 2 of the most reliable predictors of outcome, number of positive nodes and total number of nodes removed, into 1 ratio. The numerator (number of positive nodes) accounts for the nodal tumor burden while the denominator (total number of nodes retrieved) acts as a surrogate for the completeness of dissection. Integration of these 2 variables, both independent predictors of survival, [11,23,33,43] may result in a more precise assessment of overall survival. Stein et al. first reported that lymph node density was strongly predictive of recurrence and survival at both 5 and 10 yrs when stratifying by node density of ⬎20% vs. less than 20% [32]. Additionally, in a large population based study, the percentage of positive nodes (i.e., LN density) proved to be the strongest predictor for survival in node-positive, EV disease [21]. Further investigation of the efficacy of lymph node density was completed by Herr et al. in a retrospective study of 162 patients following cystectomy and LND [35]. This group compared node density with the current TNM staging system as predictors of survival. Lymph node density proved to be the strongest predictor of recurrence and survival, even when stratified by P stage. Thus, lymph node density discriminates survival and local control better than conventional lymph node staging methods and may be useful in future staging systems.
Conclusion Lymph node dissection at the time of radical cystectomy is an essential part of the treatment of bladder cancer. A comprehensive dissection provides both important staging information, and possibly therapeutic benefits for patients with high grade, invasive disease. As indicated above, nearly one-quarter of patients undergoing cystectomy will be diagnosed with nodal disease at the time of cystectomy. Given the current limitations of preoperative imaging techniques, information provided by the node dissection is otherwise unattainable. Once accurately staged, patients at high risk for recurrence can be offered adjuvant treatment protocols. While the optimal limits of the lymph node dissection have yet to be defined, considerable evidence suggests that the extended dissection provides the best chance for control of local disease and long-term survival.
References [1] Whitmore WF, Marshall VF. Radical total cystectomy for cancer of the bladder: 230 consecutive cases five years later. J Urol 1962;87: 853– 68.
K.M. Sanderson et al. / Urologic Oncology: Seminars and Original Investigations 22 (2004) 205–213 [2] Kerr WS, Colby FH. Pelvic lymph node dissection and total cystectomy in the treatment of carcinoma of the bladder. J Urol 1950;63: 842–51. [3] Halstead WS. The treatment of wounds. Johns Hopkins Hosp Rep 1891;2:279. [4] Colston JA, Leadbetter WF. Infiltrating carcinoma of the bladder. J Urol 1936;36:669 – 89. [5] Jewett HJ, Strong GH. Infiltrating carcinoma of the bladder: relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J Urol 1946;55:366 –72. [6] Vieweg J, Gschwend JE, Herr HW, et al. The impact of primary stage on survival in patients with lymph node positive bladder cancer. J Urol 1999;161:72– 6. [7] Vieweg J, Gschwend JE, Herr H, et al. Pelvic lymph nodes dissection can be curative in patients with lymph node positive disease. J Urol 1999;161:449 –54. [8] Stein JP, Skinner DG. Results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. BJU 2003;92:12–7. [9] Leissner J, Ghoneim H, Abol-Enein J, et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol 2004;171:139 – 44. [10] Skinner DG. Management of invasive bladder cancer: a meticulous pelvic node dissection can make a difference. J Urol 1982;128:34 – 6. [11] Lerner SP, Skinner DG, Lieskovsky G, et al. The rationale for en bloc PLND for bladder cancer patients with nodal metastases: long-term results. J Urol 1993;149:758 – 64. [12] Leadbetter WF, Cooper JF. Regional gland dissection for carcinoma of the bladder: a technique for one-stage cystectomy, gland dissection and bilateral uretero-enterostomy. J Urol 1950;63:242– 60. [13] Dretler SP, Ragsdale BD, Leadbetter WF. The value of pelvic lymphadenectomy in the surgical treatment of bladder cancer. J Urol 1973; 109:414 – 6. [14] Wishnow KI, Johnson DE, Ro J, et al. Incidence, extent and location of unsuspected pelvic lymph node metastasis in patients undergoing radical cystectomy for bladder cancer. J Urol 1987;137:408 –10. [15] Skinner DG. Current state of classification and staging of bladder cancer. Cancer Res 1977;37:2838 – 42. [16] Raghavan D, Quinn D, Skinner DG, et al. Surgery and adjunctive chemotherapy for invasive bladder cancer. Surg Oncol 2002;11:55– 63. [17] Skinner DC, Daniels JR, Russell CA, et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991;145:459 – 67. [18] Frieha FS, Reese J, Torti F. A randomized trial of radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996;155:1241–5. [19] Mills RD, Turner WH, Fleischmann R, et al. Pelvic lymph node metastasis from bladder cancer: outcome in 83 patients after radical cystectomy and pelvic lymphadenectomy. J Urol 2001;166:19 –23. [20] Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today—a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21:690 – 6. [21] Konety BR, Joslyn SA, O’Donnell MA. Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the surveillance, epidemiology and end results program data base. J Urol 2003;169:946 –50. [22] Herr HW. Surgical factors in bladder cancer: more (nodes) ⫹ more (pathology) ⫽ less (mortality). BJU 2003;92:187– 8. [23] 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;19:666 –75. [24] Paik ML, Scolieri MJ, Brown SL, et al. Limitations of CT in staging invasive bladder cancer before radical cystectomy. J Urol 2000;163: 1693.
211
[25] Persad R, Kabala J, Gillatt D, et al. MRI in the staging of bladder cancer. Br J Urol 1993;71:566 –73. [26] Heicappell R, Muller-Mattheis V, Reinhardt M, et al. Staging of pelvic lymph nodes in neoplasms of the bladder and prostate by positron emission tomography with 2-[18F]-2-Deoxy-D-Glucose. Eur Urol 1999;36:582–7. [27] Bachor R, Kotzerke J, Reske SN, et al. Lymph node staging of bladder neck carcinoma with positron emission tomography in patients with bladder cancer. Eur J Num Med 1997;24:615–20. [28] Nathanson DS. Insights into the mechanisms of lymph node metastsis. Cancer 2003;98:413–22. [29] Perrott RE, Reintgen DS, Fenske NA. Reassessing the role of lymphatic mapping and sentinel lymphadenectomy in the management of cutaneous malignant melanoma. J Am Acad Derm 2003; 49:567– 88. [30] Sherif A, De La Torre M, Malmstrom PU, et al. Lymphatic mapping and detection of sentinel nodes in patients with bladder cancer. J Urol 2001;166:812–5. [31] Liedberg F, Chebil G, Davidsson T, et al. Bladder cancer and the sentinel node concept. Aktuel Urol 2003;34:115– 8. [32] Stein JP, Cai J, Groshen S, et al. Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: the concept of lymph node density. J Urol 2003;170:35– 41. [33] Herr HW, Bochner BH, Dalbagni G, et al. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 2002;167:1295–999. [34] Fleming ID, Cooper JS, Henson DE, et al. AJCC cancer staging system manuel. 5th ed. Philadelphia: JB Lippincott, 1997. [35] Herr H. Superiority of ratio based LN staging for bladder cancer. J Urol 2003;169:943–5. [36] Herr HW, Donat SM. Outcomes of patients with grossly node positive bladder cancer after pelvic lymph node dissection and cystectomy. J Urol 2001;165:62– 4. [37] Poulsen A, Horn T, Steven K. Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 1998;160: 2015–9. [38] Leissner J, Hohenfellner R, Thuroff JW, et al. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder: significance for staging and prognosis. BJU Int 2000;85:817–23. [39] Bochner BH, Herr HW, Reuter VE. Impact of separate versus en bloc pelvic lymph node dissection on the number of nodes retrieved in cystectomy specimens. J Urol 2001;166:2295– 6. [40] Vieweg J, Gschwend JE, Herr H, et al. Pelvic lymph nodes dissection can be curative in patients with lymph node positive disease. J Urol 1999;161:449 –54. [41] Stein JP, Skinner DG. Results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. BJU 2003;92:12–7. [42] Ghoneim MA, El-Mekresh MM, El-Baz MA, et al. Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol 1997;158:393–9. [43] Herr H. Extent of surgery and pathology evaluation has an impact on bladder cancer outcomes after radical cystectomy. Urology 2003;61: 105–9. [44] Weingartner K, Ramaswamy A, Bittinger A, et al. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 1996;156:1969 –71. [45] Marshall VF. The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J Urol 1952; 68:714 – 6. [46] Konety BR, Joslyn SA. Factors influencing aggressive therapy for bladder cancer: an analysis of data from the SEER program. J Urol 2003;170:1765–71.