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Anatomical Extent of Pelvic Lymphadenectomy in Bladder and Prostate Cancer
European Urology Supplements
European Urology Supplements 4 (2005) 15–24
Anatomical Extent of Pelvic Lymphadenectomy in Bladder and Prostate Cancer Axel Heidenreicha,*, Carsten H. Ohlmanna, Sergej Polyakovb a
Division of Oncological Urology, Department of Urology, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany Department of Urology, Research Institute of Oncology and Medical Oncology, Minsk, Belarus
b
Abstract The rationale for locoregional staging lymphadenectomy in prostate and bladder cancer lies in the accurate diagnosis of occult micrometastases in order to stratify patients who might benefit from adjuvant therapeutic measures. In prostate cancer, extended pelvic lymphadenectomy including the lymphatic tissue along the common iliac region with the ureteral crossing as cranial margin, external and internal iliac region and the obturator fossa has been shown to significantly increase the yield of both total lymph nodes and lymph node metastases. The frequency of observed positive lymph nodes in clinically localized and locally advanced prostate cancer is significantly higher than predicted by nomograms such as Partin tables and CART analysis. Although there are no prospective randomized trials demonstrating a survival benefit associated with epLA, there might be an advantage for those with minimal lymph node involvement. Various studies have documented an equal risk of cancer associated mortality in patients with no or only 1–2 positive lymph nodes. Since the surgery associated morbidity of epLA is not increased as compared to standard lymphadenectomy, epLA should be favoured for all patients undergoing radical prostatectomy. For the future, ongoing prospective trials have to demonstrate a benefit in terms of biochemical free and cancer specific survival. In bladder cancer, pelvic lymphadenectomy as a common procedure of radical cystectomy has not been standardized although evidence supports a relationship between the extent of lymph node dissection and therapeutic outcome. Recent retrospective and prospective clinical trials have carefully analysed the distribution of lymph node metastases at time of radical cystectomy thereby identifying those regions which should be included in a standard pelvic lymph node dissection. Dissecting all lymphatic tissue along the common iliac region with the aortic bifurcation as cranial margin, along the external, internal iliac region and the obturator fossa bilaterally will completely clear 80% of all positive nodes. Only if frozen section examination will demonstrate micrometastases at these regions, extending lymphadenectomy further cranially will be worthwile. Currently, epLA in bladder cancer has been shown to improve progression-free survival if >14 lymph nodes are removed. For the future, prospective trials have to demonstrate a benefit with regard to cancer specific and overall survival and in terms of regional versus distant recurrences. # 2005 Published by Elsevier B.V.
1. Pelvic lymphadenectomy in prostate cancer Currently, the rationale for an extended pelvic lymphadenectomy at time of radical prostatectomy and radical cystectomy is to achieve as much reliable
* Corresponding author. Tel. +49 221 478 86577; Fax: +49 221 478 5198. E-mail address: [email protected] (A. Heidenreich). 1569-9056/$ – see front matter # 2005 Published by Elsevier B.V. doi:10.1016/j.eursup.2005.01.006
pathohistological staging information as possible in order to trigger postoperative adjuvant management. With regard to radical prostatectomy some authors base their decision for the need for pelvic lymphadenectomy on preoperative nomograms identifying high risk patients [1–3]. Others are in favour of pelvic lymphadenectomy in all patients undergoing radical prostatectomy since positive predictive value and sensitivity of the currently used nomograms are not valid for an individualized risk adapted approach [4–6]. If
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pelvic lymphadenectomy is going to be performed, the anatomical extent of lymphadenectomy has to be defined in order to allow an adequate pathohistological staging. It will be of further clinical interest to demonstrate an oncological benefit of extended versus limited pelvic lymphadenectomy in terms of progression-free survival and cancer-specific survival. Primary intention of locoregional lymphadenectomy in surgical oncology is to obtain detailed information with regard to the local extent of a given cancer in order to accurately calculate the risk for progression and to discuss the necessity of adjuvant therapeutic measures. Furthermore, anatomically adequate lymphadenectomy respecting the primary lymphatic drainage patterns of a given organ might help to improve cancer-specific survival or progression-free survival as has been demonstrated for testicular and bladder cancer. On prostate cancer, multiple variations of lymphadenectomy are described including the minimal variant only considering the obturator fossa, the standard variant including the lymph nodes in the obturator fossa and the external iliac artery and the extended variant with a complete lymph node dissection along the obturator fossa, the external, internal and common iliac vessels up to the iliac crossing of the ureter [4–8]. The last variant is the only technique considering anatomical studies [9] where it has been shown that the prostate gland drains lymphatically into the periprostatic subcapsular network from which three groups of ducts originate: the ascending duct from the cranial gland running to the external iliac nodes; the lateral gland running to the hypogastric nodes and the posterior running to the lateral and subaortic sacral nodes of the promontory. Therefore, any pelvic lymphadenectomy performed in prostate cancer should include at least these 3 areas. 2. Anatomical extent of pelvic lymphadenectomy for staging purposes As in other malignancies the number of dissected lymph nodes and the lymph node density in case of metastatic disease have turned out to be of important prognostic significance. In an autopsy study, Weinga¨ rtner et al. [8] found that a mean of 20 dissected pelvic lymph nodes can be considered a representative sampling enabling exact locoregional staging of prostate cancer. These data are matched perfectly by the proponents of extended pelvic lymphadenectomy removing a mean of 21 to 28 lymph nodes whereas in limited pelvic lymphadenectomy only a mean of 10–11 lymph nodes are removed. The number of dissected lymph
nodes is directly associated with an increase in the detection of positive lymph nodes as has been demonstrated in a number of studies. Stone et al. compared limited with an extended pLA and found a twofold increase in the number of removed lymph nodes (9 versus 18) and a three-fold increase in the frequency of lymph node metastases (7% versus 23%). Our group has recently demonstrated that a mean of 28 and 11 lymph nodes are removed by the extended and the limited technique, respectively; the number of positive lymph nodes increased from 12% to 26% [5,6]. Finally, Bader et al. [4] came up with similar findings and identified positive lymph nodes in 24% of 365 patients undergoing extended pLA. These data, however, can only be achieved if the surgeon sticks to the concept that all lymph nodes located in the primary landing zone of the prostate are completely dissected and pathohistologically analysed. Besides the mere number of lymph nodes being removed, the regional distribution of occult metastatic disease is of utmost importance. Several studies have demonstrated that about 50% of patients with lymph node metastases harbour positive nodes along the internal iliac artery and that about twenty five percent of all micrometastases are located along the internal iliac artery only [4–6]. These lymph node would have been missed if limited or standard techniques for pelvic lymph node dissection would have been performed. In summary, there is significant advantage of extended pelvic lymphadenectomy including the nodes along the obturator fossa, the external, internal and common iliac artery in terms of diagnostic accuracy with regard to an exact lymph node staging. 2.1. When to perform pelvic lymphadenectomy? Based on preoperative nomograms, Partin tables, etc. most institutions will not perform pelvic lymphadectomy in patients with a preoperative PSA serum level <10 ng/ml, a biopsy Gleason score <7 and a clinical stage 2a since the incidence of positive lymph nodes is said be approximately only 1–5% [1–3,7]. Based on the retro- and prospective evaluation of 4690 patients with PCA having undergone radical prostatectomy and pelvic lymphadenectomy, Crawford et al. [1] identified men with a biopsy Gleason score 6, a preoperative PSA serum level 10.6 ng/ml and stage cT1c as predictors for a low risk of lymph node metastases. In a prospective validation, the false negative rate with regard to the prediction of positive lymph nodes was only 0.7%. Using logistic regression analysis, similar findings have been described by Narayan et al. [10] and Bluestein et al. [11] demonstrating that men with a preoperative serum PSA level 10 ng/ml
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and biopsy Gleason score 6 harbor a 1–2% risk for micrometastatic lymphonodular disease. In another attempt to identify with patients with a potential risk metastatic disease to the pelvic lymph nodes, Conrad et al. [12,13] published a diagnostic algorithm based on a variety of preoperative parameters of more than 600 patients undergoing radical prostatectomy. Dependend on the number of biopsy cores harbouring prostate cancer with Gleason score 7, three risk groups were identified. Risk for lymph node metastases was 45%, 19% and 2% if 4–6, 1–3, or no biopsy was involved with Gleason score 8–10 PCA, respectively. Haese et al. [14] analysed this diagnostic algorithm prospectively in a cohort of 443 consecutive patients and confirmed the validity and reproducibility of this model. In another retrospective analysis of preoperative markers including 695 patients, Naya and Babaian [15] the number of biopsies involved with Gleason grade 4/5 PCA and a preoperative PSA serum level >15 ng/ml as significant predictors for positive lymph nodes. The incidence of lymph node metastases was 20% and 9% if more than 4 biopsy cores were involved or PSA was >15 ng/ml, respectively. Contrary, <4 biopsy cores with Gleason grade 4/5 PCA and PSA <15 ng/ml were associated with a low risk of only 2.8% and 2.1%, respectively. However, all of these nomograms are based on data of a limited pelvic lymphadenectomy with a limited number of lymph nodes being dissected and pathohistologically analysed. Furthermore, pelvic lymphadenectomy only included the obturator fossa and the external iliac region with a mean number of 6–9 lymph nodes being removed thereby not reflecting the needs for an accurate staging lymphadenectomy. Therefore, all currently available nomograms with regard to the preoperative prediction of pelvic lymph node metastases have to be interpreted with caution. Partin tables, CART analysis, etc. have only been validated in the setting of limited lymphadenectomy techniques and in intra-institutional studies. In a recent study, our group has analysed the predictive accuracy of Partin tables and CART analysis in patients undergoing radical prostatectomy and extended pLA [6]. A good correlation between predicted lymph node positivity and lymph node metastases was found in the low risk group of patients with cT1c, Gleason 2–4 and PSA <20 ng/ ml with no lymph node metastases being detected. In the intermediate risk group of patients with PCA cT2a, a biopsy Gleason score of 5–7 and a preoperative PSA serum level of <10 ng/ml Partin tables and pathohistological findings at time of epLA did not differ significantly, however, with increasing preoperative PSA serum levels, significantly more patients with
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Table 1 Extended pelvic lymphadenectomy in patients with prostate cancer cT2a dependent on preoperative PSA serum level and biopsy Gleason score Gleason 2–4
Gleason 5–7
Gleason 8–10
Patients
19 (6%)
263 (82%)
39 (12%)
PSA <10 ng/ml pN+
13 (4%) 0
111 (35%) 11 (10%)
7 (2%) 4 (57%)
PSA 10–20 ng/ml pN+
3 (1%) 0
82 (26%) 24 (29%)
10 (3%) 8 (80%)
PSA >20 ng/ml pN+
3 (1%) 0
70 (22%) 27 (39%)
22 (7%) 12 (55%)
Total
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263
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positive lymph nodes were identified than predicted (Tables 1–3). Similar findings were observed in patients with Gleason score 8–10 prostate cancer: whereas the Partin tables predicted a frequency of positive lymph nodes in the range of 8% to 34%, we actually found lymph node metastases in 55% to 87% of the patients. Data from Schuhmacher et al. [16] and from Weckermann et al. [17] corroborate our findings; the authors found a 10% risk of pelvic lymph node metastases in patients with clinically localized prostate cancer in the low risk group and raise the question of a general necessity for pelvic lymphadenectomy in all patients undergoing local treatment with curative intent for prostate cancer. Table 2 Predicted and observed frequency of lymph node metastases in patients with clinical stage T1c–T2a prostate cancer using preoperative Partin tables pN+ predicted
pN+ observed
0% 2–8% 8%
0% 10% 57%
PSA 10–20 ng/ml Gleason 2–4 Gleason 5–7 Gleason 8–10
0% 12% 27%
0% 29% 80%
PSA >20 ng/ml Gleason 2–4 Gleason 5–7 Gleason 8–10
0% 27% 34%
0% 39% 55%
PSA <10 ng/ml Gleason 2–4 Gleason 5–7 Gleason 8–10
Table 3 Predicted and observed frequency of lymph node metastases in patients with clinical stage T1c–T2a prostate cancer using preoperative CART analysis
Biopsy Gleason grade 4/5 0/6 biopsies 1–3 biopsies 4–6 biopsies
pN+ predicted
pN+ observed
2.2% 19.4% 45%
17% 46% 62%
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Furthermore, we compared the reliability of the recently published CART analysis with regard to its accuracy to predict lymph node metastases [6]. We found a significant difference between the predicted frequency of positive lymph nodes in the low and intermediate risk group whereas the data in the high riskgroupwerecomparable (Tables 2 and3).Afrequency of 2.2% and 19.4% was predicted in the low and intermediate risk group, however, lymph node metastases were detected in 17% and 46%, respectively. In summary, currently available nomograms cannot accurately predict the frequency of positive lymph nodes in patients with clinically localized or locally advanced prostate cancer. Extended pelvic lymphadenectomy is recommended to be performed in at least all patients with unfavourable preoperative findings such as PSA >10 ng/ ml, >cT1c, biopsy Gleason score >6, >2 biopsy cores involved with cancer and any core containing Gleason 4 or 5 prostate cancer. In patients with low risk prostate cancer (PSA <10 ng/ml, cT1c, Gleason score <6) the risk for lymphonodular disease is between 8% and 10% and the need for pelvic lymphadenectomy especially prior to nonsurgical therapeutic alternatives has to be discussed on an individual basis. 2.2. Complications of extended pelvic lymphadenectomy in prostate cancer Surgeons are often deterred from performing an extended pelvic lymphadenectomy due to the potentially high incidence of complications. However, the high complication rate of 10% to 20% only derives from old series published in the 1970s and 1980s [18]. In recent series (Tables 4 and 5), the frequency and the severity of intra- and perioperative complications does not differ significantly between the limited and the extended variant of pelvic lymphadenectomy [5]. If performed by an experienced surgeon, the frequency of peri- and postoperative complications attributable to pelvic lymphadenectomy is around 7% [18] with symptomatic lymphoceles (2–4%) representing the most common type of complication. However, deep Table 4 Intraoperative complications in a series of consecutive patients with prostate cancer undergoing either extended pelvic lymphadenectomy (epLA) or standard pelvic lymphadenectomy (pLA)
Blood loss Blood loss <500 ml Rectal lesion Others Ureteral lesion Obturator injury
epLA
pLA
650 47 1 6 0 2
590 48 1 6 0 1
(200–1950) (52.8%) (1.1%) (7.1%) (2.2%)
(150–2100) (48%) (1%) (6%) (1%)
Table 5 Perioperative complications in a series of consecutive patients with prostate cancer undergoing either extended pelvic lymphadenectomy (epLA) or standard pelvic lymphadenectomy (pLA)
DVT Emboli Pneumonia Myocardial infarction Lymphocele Others
epLA
pLA
4 2 2 1 9 9
6 2 2 2 9 6
(4.7%) (1.2%) (1.2%) (0.6%) (10.6%) (10.6%)
(6%) (2%) (2%) (2%) (9%) (6%)
venous thrombosis, pulmonary emboli, injuries to the obturator nerve and the ureter, lymphedema of the lower extremity have also been described. Treatment associated morbidity can be reduced significantly when (1) all lymphatics lateral to the external artery are saved, (2) the distal ends of the lymphatics are either ligated or clipped with small clips exerting a higher pressure to the lymphatic vessels than large clips, (3) 2 drains are placed in each side of the pelvis, (4) drains are left in place until <50 ml/day is drained and (5) low molecular heparin is injected into the upper arm. 2.3. Therapeutic benefit of extended pelvic lymphadenectomy It has been demonstrated for a variety of malignancies such as breast, colorectal, esophageal, bladder and testicular cancer that a subgroup of patients with minimal lymph node disease will benefit from an extended variant of locoregional lymphadenectomy in terms of cancer specific and progression-free survival. With regard to prostate cancer, controversial data are discussed in the literature with regard to the potential therapeutic benefit of pelvic lymphadenectomy. Fergany et al. [19] compared biochemical relapse rates of 372 and 203 patients undergoing radical prostatectomy with and without pelvic lymphadenectomy, respectively. All patients exhibited a preoperative PSA level <10 ng/ml, a biopsy Gleason score <6 and stage cT1c and therefore were at low risk for positive lymph nodes. The 4-year progression-free survival was 91% and 97% following radical prostatectomy with or without lymphadenectomy, respectively. Similar findings are reported by El-Galley et al. and Meng et al. [20,21]. In a cohort of well selected patients undergoing radical perineal prostatectomy for clinically localised PCA, PSA relapse rates did not differ significantly between patients with or without pelvic lymphadenectomy. Although the data on the therapeutic benefit of extended pLA in PCA are sparse, some studies do already suggest a beneficial effect in a subgroup of
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patients with minimal lymph node involvement. Bader et al. [4] demonstrated the beneficial effect of extended pLA in terms of biochemical progression-free survival and cancer specific survival in a cohort of 365 patients. After a mean follow-up of 45 months, cancer specific survival was 78%, PSA progression-free survival was 24% and symptom-free survival was 47%. Performing a multivariate analysis, the group identified only the number of positive lymph nodes to be significantly associated with systemic relapse and recommend a surveillance strategy for men with only 1 lymph node involved. Our group has recently performed a casecontrol study analysing PSA progression-free survival after a minimum follow-up of 3 years in a cohort of 100 consecutive patients having undergone limited pLA as compared to a group of 100 consecutive patients having undergone extended pLA. First data indicate, that the PSA relapse rate differs significantly between both groups with 23% and 8% in the limited and extended pLA group, respectively, indicating a potential benefit of pelvic lymphadenectomy. Furthermore, dissection of al involved lymph nodes might be beneficial for adjuvant treatment purposes. In a retrospective analysis of 322 patients undergoing immediate adjuvant androgen deprivation for lymph node positive PCA following radical prostatectomy, Cheng et al. [22] observed no statistically significant difference in the cancer specific mortality between the control group of pN0 patients and men with only 1 lymph node involved. Only a more extensive involvement of positive nodes is associated with a significantly increased mortality risk despite adjuvant endocrine manipulation. In another clinical trial, Messing et al. [23] documented a therapeutic benefit in terms of progression-free and cancer-specific survival of immediate adjuvant hormonal therapy in patients with lymph node positive PCA undergoing radical prostatectomy. Therefore, any detected lymph node metastasis at time of surgery might in a survival benefit if followed by adjuvant therapy. It is, therefore, our impression that all patients should be offered the option of open or laparoscopic extended pelvic lymphadenectomy in order to achieve an optimal individual treatment. However, it might be justified to spare pelvic lymphadenectomy in a group of well selected patients with stage cT1c PCA, PSA levels <10 ng/ml and a biopsy Gleason score <6. 2.4. Alternative, noninvasive options of lymph node staging in prostate cancer A new diagnostic approach to detect lymph node metastases has recently been reported by Wawroschek et al. [24] who described a gamma probe guided
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sentinel lymph node identification in prostate cancer patients prior to radical prostatectomy. Combining preoperative lymphoscintigraphy after ultrasound guided intraprostatic injection of 99mTechnetium with intraoperative gamma probe detection of labelled nodes, the authors found positive lymph nodes in 24% of all patients. As already being described for extended pLA, 36% of the positive nodes were found outside the fields of standard lymphadenectomy and 19% were located along the hypogastric and the presacral area. Most importantly, a single sentinel node representing the primary landing zone for prostate cancer could not be identified indicating the existence of various lymphatic drainage systems from the prostate. The high diagnostic accuracy of this method with a very low rate of false negative findings, however, has not been reproduced by others so that a multiinstitutional prospective evaluation is mandatory (Fig. 1a and b). 111 Indium-Capromab immunoscintigraphy might represent another preoperative, non-invasive diagnostic option to identify lymph node metastases in patients with high-risk prostate cancer. Polasczik et al. [25] compared the data of 111Indium-Capromab immunoscintigraphy with pathohistological findings of pelvic lymphadenectomy in 198 patients with high risk prostate cancer. 39% of the patients were found to have lymph node metastases with 62% being correctly identified by scintigraphy. Although the positive predictive value is only 75%, it is higher than the correct prediction of 66–68% being achieved with clinical prediction models. Considering ROC analysis, 111 Indium-Capromab immunoscintigraphy bears a significant diagnostic advantage, however, it has to be further evaluated in prospective settings [26].
3. Summary extended pelvic lymphadenectomy in prostate cancer As has been shown in the above mentioned studies, extended pelvic lymphadenectomy harbors a significant benefit in terms of diagnostic accuracy to detect lymph node metastases in patients woth prostate cancer undergoing radical prostatectomy. Only in highly selected patients (cT1c, PSA <10 ng/ml, Gleason score <6) extended pelvic lymphadenectomy might be spared due to the very low risk of metastatic disease; however, this issue has to be discussed in detail with the patient. Complication rates of extended pLA do not differ significantly from those encountered in standard lymphadenectomy so that the procedure is safe for the patient. Although the data on a therapeutic benefit are
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Fig. 1. (a) Lymphoscintigraphy after intraprostatic injection of 99mTechnetium demonstrating isolated sentinel lymph nodes at the iliac and aortic bifurcation. (b) Intraoperatively, radioactive lymph nodes can be identified by a gamma probe enabling selective removal of single nodes.
sparse, available data suggest an advantage for a subgroup of patients with minimal involvement of only 1 or 2 nodes. It is our policy to perform extended pLA in all intermediate and high risk prostate cancer undergoing radical prostatectomy or even external bean radiation or high dose brachytherapy. If performed, lymph node dissection should include all lymphathics along the obturator fossa, the external, internal and common iliac artery up to the ureteral crossing. Based on the number of lymph nodes being removed, laparoscopic lymph node dissection is definitely inferior to the open technique.
4. Pelvic lymphadenectomy in bladder cancer Radical cystectomy with pelvic lymphadenectomy represents the standard treatment for muscle-invasive bladder cancer. Pelvic lymphadenectomy is included as part of the surgical procedure to control locoregional
disease and to potentially improve cancer-specific survival. Survival after radical cystectomy is usually predicted by the pathological tumor stage, status of surgical margins and the involvement of lymph nodes. Although earlier studies have already demonstrated a prognostic benefit of extended pelvic lymphadenectomy as compared to a limited lymphadenectomy, the anatomically adequate extent of lymph node dissection to obtain reliable staging results is still discussed controversially. In a recent prospective randomized phase III trial on the clinical efficacy of neoadjuvant chemotherapy plus cystectomy [27], it was shown that surgical factors including the extent of lymph node dissection and the individual surgeon’s experience have a major impact on the therapeutic outcome and overall survival [28]. The data of this trial also indicate that chemotherapy was more likely to be of beneficial value if patients received a high-quality surgery by an experienced surgeon. It was concluded that it is extremely important to develop universally accepted standards for radical
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cystectomy and pelvic lymph node dissection in patients with invasive bladder cancer in order to improve outcome [29].
5. Anatomical extent of pelvic lymphadenectomy Although it has been shown that long-term survival is possible in patients with lymph node positive bladder cancer, the anatomical extent of pelvic lymphadenectomy associated with radical cystectomy still has to be defined. Some others take the crossing of the ureters with the common iliac vessels as the most cranial limit for lymph node dissection [30] whereas others extend lymphadenectomy up to the aortic bifurcation. It is generally agreed that the more lymph nodes are removed the higher is the number of patients with positive lymph nodes [31]; furthermore, it has been demonstrated that survival after radical cystectomy is predicted by the pathological stage of the primary bladder tumor and pelvic nodes. Leissner et al. [32] suggested that a significant survival benefit was maintained of more than 16 lymph nodes has been removed. Stein et al. [33] reported that survival in patients with positive lymph node disease was better if more than 15 pelvic lymph nodes had been retrieved. On the other hand, Abdel-Latif an coworkers [34] and Herr [35] could not reproduce the relationship between survival and number of dissected lymph nodes by using multivariate statistical analysis. In this context, it has to be underlined that the number of retrieved lymph nodes can be influenced by many factors such as extent of lymphadenectomy [30–32], presentation of the pathological specimen [36] and pathohistological work-up and techniques of analysis [37] questioning its clinical relevance as a routine prognostic marker. Despite these suboptimal clinical factors, there are a few studies having demonstrated a significant impact of the technique of pelvic lymph node dissection with regard to therapeutic outcome. Poulsen et al. [38] were one of the first groups to compare the prognostic significance of limited versus extended pelvic lymphadectomy in a retrospective analysis of 194 patients undergoing radical cystectomy. Limited pelvic lymphadenectomy (lpLA) began at the iliac bifurcation including the lymph nodes along the external and internal iliac artery and the obturator fossa, extended pelvic lymphadectomy (epLA) began at the aortic bifurcation and included the common, external and internal iliac artery and the obturator fossa. The authors observed a substantial improvement of 5-year recurrence free survival in patients with tumors confined to
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the bladder wall (85% versus 64%, p < 0.02) and without lymph node involvement (90% versus 71%, p < 0.02). 5-year probability for locoregional (7% versus 2%) and systemic recurrences (21% versus 10%) were reduced substantially in patients with bladder cancer confined to the bladder wall in the epLA group, however, without reaching statistical significance. In another retrospective analysis of 484 patients undergoing radical cystectomy and pelvic lymphadenectomy, Leissner et al. [37] demonstrated that the total number of lymph nodes retrieved had a significant impact on recurrence-free survival (p < 0.01). The 5-year recurrence-free survival was 25% and 53% in patients with 14 and 15 lymph nodes being removed, respectively. Furthermore, the surgeon had a significant impact on the prognosis as it was shown the number of lymph nodes dissected ranged between 10.6 and 25.7 and differed significantly between the 11 different surgeons being involved in the study. These data are further corroborated by a recent paper on the standardization of radical cystectomy and pelvic lymphadectomy [29]. However, the authors did not demonstrate a significant overall and cancer-specific survival advantage for patients undergoing epLA as compared to those undergoing lpLA only. The authors further evaluated the concept of epLA in a prospective clinical trial comprising 290 patients [39]. The cranial limit of epLA was the inferior mesenteric artery, lateral border was the genitofemoral nerve and the caudal limit was the pelvic floor. A mean number of 43.1 16.1 lymph nodes were removed with 27.9% of the patients demonstrating positive lymph nodes. Although the group identified a preferred pattern of metastatic spread they were not able to identify a well-defined sentinel lymph node or lymph node area. These data are in contrast to the recently published prospective trial of Bochner et al. [40] on the evaluation of lymph node count and lymph node mapping. 144 consecutive patients were included into this monocentric evaluation with 56 and 88 patients undergoing standard and extended pLA, respectively. Standard pLA included the nodal regions of the external iliac, hypogastric and obturator fossa with the iliac bifurcation representing the cranial limit of lymph node dissection. Extended pLA included the lymph nodes at the aortic bifurcation to no more than 2 cm cranially to the bifurcation and the nodal regions of standard pLA. Although the median number of positive lymph nodes differed significantly between both groups (22.5 versus 8), there was no difference with regard to the percentage of positive nodes which was 21% in both groups. Interestingly, all patients with positive nodes above the
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aortic bifurcation also had positive nodes detected in the lower packages indicating that only extensive locoregional metastatic disease might involve the retroperitoneal areas associated with a dismal prognosis anyhow. Including the lymph nodes along the common iliac artery above the iliac bifurcation, however, appears to be of prognostic value and of clinical significance. In the study of Bochner et al. [40], 4 patients had unexpected micrometastatic lymph node disease at the common iliac region only. Reflecting the survival data of patients exhibiting micrometastatic lymph node disease at time of radical cystectomy, most of these patients are expected to have a relatively favourable outcome. Morbidity of pelvic lymphadenectomy is not increased by including the common iliac region in routine pelvic lymph node dissection, so that this area should be removed as standard part of staging lymphadenectomy. Further evidence to include the common iliac region derives from the prospective multiinstitutional study published recently by Leissner et al. [39]. 81 (27.9%) patients demonstrated lymph node involvement and 35% of all positive lymph nodes derived from above the iliac bifurcation. Furthermore, 20 patients (6.9%) were shown to harbor positive lymph nodes above the bifurcation of the common iliac artery only. Although, no data with regard to the prognostic significance in terms of cancer-specific or progression-free survival are available, these data strongly support the idea to include the lymph nodes of the common iliac region up to the aortic bifurcation in routine lymph node dissection technique for muscle invasive bladder cancer. In another study, Abol-Enein et al. [41] evaluated the locoregional distribution of positive pelvic lymph nodes in 200 consecutive patients undergoing radical cystectomy. The authors also attempted to identify the probability of lymph node clearance with increasingly wide fields of node dissection. In their investigation extended pelvic lymphadenectomy included the lymphatic tissue up to the inferior mesenteric artery, the common, external and internal iliac region. A mean number of 50.6 lymph nodes were retrieved per patient with 48 (24%) patients exhibiting positive nodes. More than one third of these patients (39.6%) demonstrated bilateral involvement, a single positive lymph node was identified in 22 (45.8%) patients. The authors demonstrated that close to 80% of all positive nodes could be cleared completely of the field of pelvic lymph node dissection included all lymphatic tissues along the common, external and internal iliac region. Metastases outside the true pelvis were only detected in multinodal disease and these metastatic deposits were always associated with metastases at the obturator fossa and/or the inter-
nal iliac region. Therefore, the authors conclude that standard lymphadectomy in bladder cancer should always include all lymphatic tissues in the true pelvis; lymph node dissection might be extended up to the inferior mesenteric artery if frozen section examination exhibits positive lymph nodes in the sentinel region of the true pelvis.
6. Summary anatomical extent of pelvic lymph node dissection in bladder cancer As has been shown by the previous studies the anatomical extent of pelvic lymph node dissection in patients undergoing radical cystectomy for muscleinvasive bladder cancer can be well defined. Standard lymphadenectomy should include all lymphatic tissues around the common iliac, intercommon iliac, internal iliac group and the obturator group bilaterally since up to one third of all positive nodes are located around the common iliac artery. This technical variant will allow to clear 80% of all positive nodes; if frozen section will demonstrate no positive lymph nodes in the true pelvis, lymph node dissection has not to be carried out further cranially. If, however, frozen section examination is not performed or if it identifies positive nodes, the inferior mesenteric artery represents the cranial border of lymph node dissection. 7. Critical issues in anatomical pelvic lymphadenectomy for bladder cancer Although the above cited studies have apparently demonstrated the clinical importance of extended pelvic lymph node dissection with regard to the most efficiant retrieval of micrometastatic lymph nodes, there are still some unresolved critical issues. Pathohistological examination of dissected lymph node specimens in these studies has been done more thoroughly and extensively than in other studies concentrating issues such as overall survival, cancer specific survival, and regional versus distant failure. Therefore, some critical facts have to be considered for the general community if extended pelvic lymphadenectomy becomes common practice in all patients undergoing radical cystectomy. Lymphatic tissues dissected from different areas should be sent separately instead of en bloc submissions for pathohistological evaluation since it has been demonstrated recently that the yield of lymph nodes increases significantly thereby increasing the frequency of micrometastatic deposits [42]. Intrainstitutional standardization of pel-
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vic lymphadenectomy appears to be of utmost importance to generate reliable and reproducible results since staging lymphadenectomy is extremely surgeon dependent as has been demonstrated by Leissner et al. [37]. Last, but not least, the various types of extended pelvic lymphadenectomies have been associated with an improved progression-free survival, none of the trials has demonstrated an advantage with regard to cancer-specific survival. Benefit in terms of progression-free survival might be just due to a stage migration associated with extensive lymph node dissection. The majority of patients found to harbour positive lymph nodes will die due distant metastatic spread in the long run and only the few patients with a single or two metastatic lymph nodes might benefit from the extended variant of lymphadenectomy. In order to solve this question, the Association of Urological Oncology of the German Cancer Society has currently
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initiated a prospective randomized clinical phase III trial to evaluate the true clinical efficacy of extended pelvic lymphadenectomy. In bladder cancer, the biological aggressiveness of a particular cancer may have already been expressed at time of diagnosis and the impact of less or more extensive surgery in terms of recurrence and survival might be completely overestimated. For the future, it will be necessary to shed light on the important clinical questions of the biological role of lymph node metastases for the likelihood of synchronous or metachronous distant metastases. It will be necessary to biologically evaluate the expression of various growth factors and mediators of systemic spread on patients with lymph node metastases and to correlate these findings with clinically important end points such as cancer specific survival, overall survival, and locoregional versus sytemic recurrence.
References [1] Crawford ED, Batuello JT, Snow P, Gamito EJ, McLeod DG, Partin AW, et al. The use of artificial intelligence technology to predict lymph node spread in men with clinically localized prostate carcinoma. Cancer 2000;88:2105–9. [2] Batuello JT, Gamito EJ, Crawford ED, Han M, Partin AW, McLeod DG, et al. Artificial neural network model for the assessment of lymph node spread in patients with clinically localized prostate cancer. Urology 2001;57:481–5. [3] Partin AW, Kattan MW, Subing ENP. Walsh PC, Wojno KJ, Oesterling JE, et al. Combination of prostate-specific antigen, clinical stage, and Gleason sum to predict pathological stage of localized prostate cancer: a multi-institutional update. JAMA 1997;277:1445–51. [4] Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a hance of cure? J Urol 2003;169:849–54. [5] Heidenreich A, von Knobloch R, Varga Z. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy in prostate cancer: high incidence of lymph node metastases. J Urol 2001; 167:1681–4. [6] Heidenreich A, von Knobloch R, Varga Z, Hofmann R. Extended pelvic lymphadenectomy in men undergoing radical retropubic prostatectomy–data on >300 cases. J Clin Oncol 2004;22(14S) [Proc ASCO, Abstract 4612]. [7] Algari M, Colton MD, Seidmon EJ, Greenberg RE, Hanno PM. The staging pelvic lymphadenectomy: implication as an adjunctive procedure for clinically localized prostate cancer. J Urol 1997;162: 243–6. [8] Weinga¨ rtner K, Ramaswamy A, Bittinger A, Gerharz EW, Vo¨ ge D, Riedmiller H. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 1996;156:1969–71. [9] Gil-Vernet JM. Prostate cancer: anatomical and surgical considerations. Br J Urol 1996;78:161–8. [10] Narayan P, Fournier G, Gajendran V, Leidich R, Lo R, Wolf JS, et al. Utility of preoperative serum prostate specific antigen concentration and biopsy Gleason score in predicting risk of pelvic lymph node metastases in prostate cancer. Urology 1994;44:519–24. [11] Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral pelvic lymphadenectomy in select patients with prostate cancer. J Urol 1994;151:1315–20.
[12] Conrad S, Graefen M, Pichlmaier U, Henke RP, Hammerer PG, Huland H. Systematic sextant biopsies improve preoperative prediction of pelvic lymph node metastasis in patients with clinically localized prostate cancer. J Urol 1998;159:2023. [13] Conrad S, Graefen M, Pichlmaer U, Henke RP, Ebersdobler A, Hammerer PG, et al. Prospective validation of an algorithm with systematic sextant biopsy to predict lymph node metastasis in patients with clinically localized prostate cancer. J Urol 2002;167:521. [14] Haese A, Epstein JI, Huland H, Partin AW. Validation of a biopsy based pathologic algorithm for predicting lymph node metastases in patients with clinically localized prostatic carcinoma. Cancer 2002;95:1016. [15] Naya Y, Babaian RJ. The predictors of pelvic lymph node metastasis at radical retropubic prostatectomy. J Urol 2003;170:2306–10. [16] Schuhmacher M, Burkhardt F, Markwalder R, Studer U. Lymph nodes metastases in patients with prostate cancer and with a PSA <10 ng/ml. Eur Urol Suppl 2004;3(2):17 [Abstract 57]. [17] Weckermann D, Wawroschek F, Harzmann R. Is there a need for pelvic lymph node dissection in low risk prostate cancer patients prior to definitive local therapy? Eur Urol 2005;47:45–51. [18] Dillioglugil JF, Leibman BD, Leibman NS, Kattan MW, Rosas AL, Scardino PT. Risk factors for complications and morbidity after radical retropubic prostatectomy. J Urol 1997;157:1760–7. [19] Fergany A, Kupelian PA, Levin HS, Zippe CD, Reddy C, Klein EA. No difference in biochemical failure reates with or without pelvic lymph node dissection during radical prostatectomy in low-risk patients. Urology 2000;56:92–5. [20] Meng MV, Carroll PR. When is pelvic lymph node dissection necessary before radical prostatectomy? A decision analysis J Urol 2000;164:1235–40. [21] El-Galley RES. Keane TE, Petros JA, Sanders WH, Clarke HS, Cotsonis GA, et al. Evaluation of staging lymphadenectomy in prostate cancer. Urology 1998;52:663–7. [22] Cheng L, Zincke H, Blute ML, Bergstralh EJ, Scherer B, Bostwick DG. Risk of prostate cancer death in patients with lymph node metastasis. Cancer 2001;91:66–71. [23] Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy versus observation after radical prostatectomy and pelvic lymphadenectomy for node positive prostate cancer: at 10 years results of EST3886. J Clin Oncol 2004;22(14S) [Proc ASCO, Abstract 4570].
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[24] Wawroschek F, Vogt H, Weckermann D, Wagner Th. Harzmann R. Radioisotope guided pelvic lymph node dissection for prostate cancer. J Urol 2001;166:1715–9. [25] Polasczik TJ, Manyak MJ, Haseman MK, Gurganus RT, Rogers B, Maguire RT, et al. Comparison of clinical staging algorithms and 111Indium-Capromab Pendetide Immunoscintigraphy in the prediction of lymph node involvement in high risk prostate carcinoma patients. Cancer 1999;85:1586–92. [26] Sodee DB, Malguria N, Faulhaber P, Resnick MI, Albert J. Bakale G, and the Prostacint Imaging Centers. Multicenter Prostacint imaging findings in 2154 patients with prostate cancer. Urology 2000;56: 988–93. [27] Grossmann HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–66. [28] Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol 2004;22:2781–9. [29] Herr H, Lee C, Chang S, Lerner S, for the Bladder Cancer Collaborative Group. Standardization of radical cystectomy and pelvic lymph node dissection for bladder cancer: a collaborative group report. J Urol 2004;171:1823–8. [30] 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. [31] Herr WH, 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 2003;167:1295–7. [32] Leissner J, Hohenfellner R, Thu¨ roff JW, Wolf HK. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder: significance for staging and prognosis. BJU Int 2000;85:817–21.
[33] Stein JP, Cai J, Groshen S, Skinner DG. Risk factors for patients with pelvic lymph node metastases following radical cystectomy with enbloc pelvic lymphadenectomy: the concept of lymph node density. J Urol 2003;170:35. [34] Abdel-Latif M, Abol-Eneim 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. [35] Herr WH. Superiority of ratio based lymph node staging for bladder cancer. J Urol 2003;169:943. [36] Bochner BH, Herr HW, Reuter VE. Impact of separate versus en bloc lymph node dissection in the number of lymph nodes retrieved in cystectomy specimens. J Urol 2001;166:2295. [37] Leissner J, Allhoff EP, Hohenfellner R, Wolf HK. Ranking of pelvic lymphadenectomy in therapy and prognosis of carcinoma of the bladder. Akt Urol 2003;34:392–7. [38] Poulsen AL, Horn T, Steven K. Radical cystectomy: extending limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 1998; 160:2015–9. [39] Leissner J, Ghoneim MA, Abol-Eneim H, et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol 2004;171:139–44. [40] Bochner BH, Cho D, Herr HW, et al. Prospectively packaged lymph node dissections with radical cystectomy: evaluation of node count variability and node mapping. J Urol 2004;172:1286–90. [41] Abol-Enein H, El-Baz M, Abd El-Hameed MA, Abdel-Latif M, Ghoneim MA. Lymph node involvement in patients with bladder cancer treated by radical cystectomy: a patho-anatomical study—a single center experience. J Urol 2004;172:1818–21. [42] Bochner BH, Herr HW, Reuter VE. Impact of separate versus en bloc pelvic lymph node dissection on the number of lymph nodes retrieved in cystectomy specimens. J Urol 2001;166:2295–6.
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Anatomical Extent of Pelvic Lymphadenectomy in Bladder and Prostate Cancer Axel Heidenreicha,*, Carsten H. Ohlmanna, Sergej Polyakovb a
Division of Oncological Urology, Department of Urology, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany Department of Urology, Research Institute of Oncology and Medical Oncology, Minsk, Belarus
b
Abstract The rationale for locoregional staging lymphadenectomy in prostate and bladder cancer lies in the accurate diagnosis of occult micrometastases in order to stratify patients who might benefit from adjuvant therapeutic measures. In prostate cancer, extended pelvic lymphadenectomy including the lymphatic tissue along the common iliac region with the ureteral crossing as cranial margin, external and internal iliac region and the obturator fossa has been shown to significantly increase the yield of both total lymph nodes and lymph node metastases. The frequency of observed positive lymph nodes in clinically localized and locally advanced prostate cancer is significantly higher than predicted by nomograms such as Partin tables and CART analysis. Although there are no prospective randomized trials demonstrating a survival benefit associated with epLA, there might be an advantage for those with minimal lymph node involvement. Various studies have documented an equal risk of cancer associated mortality in patients with no or only 1–2 positive lymph nodes. Since the surgery associated morbidity of epLA is not increased as compared to standard lymphadenectomy, epLA should be favoured for all patients undergoing radical prostatectomy. For the future, ongoing prospective trials have to demonstrate a benefit in terms of biochemical free and cancer specific survival. In bladder cancer, pelvic lymphadenectomy as a common procedure of radical cystectomy has not been standardized although evidence supports a relationship between the extent of lymph node dissection and therapeutic outcome. Recent retrospective and prospective clinical trials have carefully analysed the distribution of lymph node metastases at time of radical cystectomy thereby identifying those regions which should be included in a standard pelvic lymph node dissection. Dissecting all lymphatic tissue along the common iliac region with the aortic bifurcation as cranial margin, along the external, internal iliac region and the obturator fossa bilaterally will completely clear 80% of all positive nodes. Only if frozen section examination will demonstrate micrometastases at these regions, extending lymphadenectomy further cranially will be worthwile. Currently, epLA in bladder cancer has been shown to improve progression-free survival if >14 lymph nodes are removed. For the future, prospective trials have to demonstrate a benefit with regard to cancer specific and overall survival and in terms of regional versus distant recurrences. # 2005 Published by Elsevier B.V.
1. Pelvic lymphadenectomy in prostate cancer Currently, the rationale for an extended pelvic lymphadenectomy at time of radical prostatectomy and radical cystectomy is to achieve as much reliable
* Corresponding author. Tel. +49 221 478 86577; Fax: +49 221 478 5198. E-mail address: [email protected] (A. Heidenreich). 1569-9056/$ – see front matter # 2005 Published by Elsevier B.V. doi:10.1016/j.eursup.2005.01.006
pathohistological staging information as possible in order to trigger postoperative adjuvant management. With regard to radical prostatectomy some authors base their decision for the need for pelvic lymphadenectomy on preoperative nomograms identifying high risk patients [1–3]. Others are in favour of pelvic lymphadenectomy in all patients undergoing radical prostatectomy since positive predictive value and sensitivity of the currently used nomograms are not valid for an individualized risk adapted approach [4–6]. If
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pelvic lymphadenectomy is going to be performed, the anatomical extent of lymphadenectomy has to be defined in order to allow an adequate pathohistological staging. It will be of further clinical interest to demonstrate an oncological benefit of extended versus limited pelvic lymphadenectomy in terms of progression-free survival and cancer-specific survival. Primary intention of locoregional lymphadenectomy in surgical oncology is to obtain detailed information with regard to the local extent of a given cancer in order to accurately calculate the risk for progression and to discuss the necessity of adjuvant therapeutic measures. Furthermore, anatomically adequate lymphadenectomy respecting the primary lymphatic drainage patterns of a given organ might help to improve cancer-specific survival or progression-free survival as has been demonstrated for testicular and bladder cancer. On prostate cancer, multiple variations of lymphadenectomy are described including the minimal variant only considering the obturator fossa, the standard variant including the lymph nodes in the obturator fossa and the external iliac artery and the extended variant with a complete lymph node dissection along the obturator fossa, the external, internal and common iliac vessels up to the iliac crossing of the ureter [4–8]. The last variant is the only technique considering anatomical studies [9] where it has been shown that the prostate gland drains lymphatically into the periprostatic subcapsular network from which three groups of ducts originate: the ascending duct from the cranial gland running to the external iliac nodes; the lateral gland running to the hypogastric nodes and the posterior running to the lateral and subaortic sacral nodes of the promontory. Therefore, any pelvic lymphadenectomy performed in prostate cancer should include at least these 3 areas. 2. Anatomical extent of pelvic lymphadenectomy for staging purposes As in other malignancies the number of dissected lymph nodes and the lymph node density in case of metastatic disease have turned out to be of important prognostic significance. In an autopsy study, Weinga¨ rtner et al. [8] found that a mean of 20 dissected pelvic lymph nodes can be considered a representative sampling enabling exact locoregional staging of prostate cancer. These data are matched perfectly by the proponents of extended pelvic lymphadenectomy removing a mean of 21 to 28 lymph nodes whereas in limited pelvic lymphadenectomy only a mean of 10–11 lymph nodes are removed. The number of dissected lymph
nodes is directly associated with an increase in the detection of positive lymph nodes as has been demonstrated in a number of studies. Stone et al. compared limited with an extended pLA and found a twofold increase in the number of removed lymph nodes (9 versus 18) and a three-fold increase in the frequency of lymph node metastases (7% versus 23%). Our group has recently demonstrated that a mean of 28 and 11 lymph nodes are removed by the extended and the limited technique, respectively; the number of positive lymph nodes increased from 12% to 26% [5,6]. Finally, Bader et al. [4] came up with similar findings and identified positive lymph nodes in 24% of 365 patients undergoing extended pLA. These data, however, can only be achieved if the surgeon sticks to the concept that all lymph nodes located in the primary landing zone of the prostate are completely dissected and pathohistologically analysed. Besides the mere number of lymph nodes being removed, the regional distribution of occult metastatic disease is of utmost importance. Several studies have demonstrated that about 50% of patients with lymph node metastases harbour positive nodes along the internal iliac artery and that about twenty five percent of all micrometastases are located along the internal iliac artery only [4–6]. These lymph node would have been missed if limited or standard techniques for pelvic lymph node dissection would have been performed. In summary, there is significant advantage of extended pelvic lymphadenectomy including the nodes along the obturator fossa, the external, internal and common iliac artery in terms of diagnostic accuracy with regard to an exact lymph node staging. 2.1. When to perform pelvic lymphadenectomy? Based on preoperative nomograms, Partin tables, etc. most institutions will not perform pelvic lymphadectomy in patients with a preoperative PSA serum level <10 ng/ml, a biopsy Gleason score <7 and a clinical stage 2a since the incidence of positive lymph nodes is said be approximately only 1–5% [1–3,7]. Based on the retro- and prospective evaluation of 4690 patients with PCA having undergone radical prostatectomy and pelvic lymphadenectomy, Crawford et al. [1] identified men with a biopsy Gleason score 6, a preoperative PSA serum level 10.6 ng/ml and stage cT1c as predictors for a low risk of lymph node metastases. In a prospective validation, the false negative rate with regard to the prediction of positive lymph nodes was only 0.7%. Using logistic regression analysis, similar findings have been described by Narayan et al. [10] and Bluestein et al. [11] demonstrating that men with a preoperative serum PSA level 10 ng/ml
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and biopsy Gleason score 6 harbor a 1–2% risk for micrometastatic lymphonodular disease. In another attempt to identify with patients with a potential risk metastatic disease to the pelvic lymph nodes, Conrad et al. [12,13] published a diagnostic algorithm based on a variety of preoperative parameters of more than 600 patients undergoing radical prostatectomy. Dependend on the number of biopsy cores harbouring prostate cancer with Gleason score 7, three risk groups were identified. Risk for lymph node metastases was 45%, 19% and 2% if 4–6, 1–3, or no biopsy was involved with Gleason score 8–10 PCA, respectively. Haese et al. [14] analysed this diagnostic algorithm prospectively in a cohort of 443 consecutive patients and confirmed the validity and reproducibility of this model. In another retrospective analysis of preoperative markers including 695 patients, Naya and Babaian [15] the number of biopsies involved with Gleason grade 4/5 PCA and a preoperative PSA serum level >15 ng/ml as significant predictors for positive lymph nodes. The incidence of lymph node metastases was 20% and 9% if more than 4 biopsy cores were involved or PSA was >15 ng/ml, respectively. Contrary, <4 biopsy cores with Gleason grade 4/5 PCA and PSA <15 ng/ml were associated with a low risk of only 2.8% and 2.1%, respectively. However, all of these nomograms are based on data of a limited pelvic lymphadenectomy with a limited number of lymph nodes being dissected and pathohistologically analysed. Furthermore, pelvic lymphadenectomy only included the obturator fossa and the external iliac region with a mean number of 6–9 lymph nodes being removed thereby not reflecting the needs for an accurate staging lymphadenectomy. Therefore, all currently available nomograms with regard to the preoperative prediction of pelvic lymph node metastases have to be interpreted with caution. Partin tables, CART analysis, etc. have only been validated in the setting of limited lymphadenectomy techniques and in intra-institutional studies. In a recent study, our group has analysed the predictive accuracy of Partin tables and CART analysis in patients undergoing radical prostatectomy and extended pLA [6]. A good correlation between predicted lymph node positivity and lymph node metastases was found in the low risk group of patients with cT1c, Gleason 2–4 and PSA <20 ng/ ml with no lymph node metastases being detected. In the intermediate risk group of patients with PCA cT2a, a biopsy Gleason score of 5–7 and a preoperative PSA serum level of <10 ng/ml Partin tables and pathohistological findings at time of epLA did not differ significantly, however, with increasing preoperative PSA serum levels, significantly more patients with
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Table 1 Extended pelvic lymphadenectomy in patients with prostate cancer cT2a dependent on preoperative PSA serum level and biopsy Gleason score Gleason 2–4
Gleason 5–7
Gleason 8–10
Patients
19 (6%)
263 (82%)
39 (12%)
PSA <10 ng/ml pN+
13 (4%) 0
111 (35%) 11 (10%)
7 (2%) 4 (57%)
PSA 10–20 ng/ml pN+
3 (1%) 0
82 (26%) 24 (29%)
10 (3%) 8 (80%)
PSA >20 ng/ml pN+
3 (1%) 0
70 (22%) 27 (39%)
22 (7%) 12 (55%)
Total
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263
39
positive lymph nodes were identified than predicted (Tables 1–3). Similar findings were observed in patients with Gleason score 8–10 prostate cancer: whereas the Partin tables predicted a frequency of positive lymph nodes in the range of 8% to 34%, we actually found lymph node metastases in 55% to 87% of the patients. Data from Schuhmacher et al. [16] and from Weckermann et al. [17] corroborate our findings; the authors found a 10% risk of pelvic lymph node metastases in patients with clinically localized prostate cancer in the low risk group and raise the question of a general necessity for pelvic lymphadenectomy in all patients undergoing local treatment with curative intent for prostate cancer. Table 2 Predicted and observed frequency of lymph node metastases in patients with clinical stage T1c–T2a prostate cancer using preoperative Partin tables pN+ predicted
pN+ observed
0% 2–8% 8%
0% 10% 57%
PSA 10–20 ng/ml Gleason 2–4 Gleason 5–7 Gleason 8–10
0% 12% 27%
0% 29% 80%
PSA >20 ng/ml Gleason 2–4 Gleason 5–7 Gleason 8–10
0% 27% 34%
0% 39% 55%
PSA <10 ng/ml Gleason 2–4 Gleason 5–7 Gleason 8–10
Table 3 Predicted and observed frequency of lymph node metastases in patients with clinical stage T1c–T2a prostate cancer using preoperative CART analysis
Biopsy Gleason grade 4/5 0/6 biopsies 1–3 biopsies 4–6 biopsies
pN+ predicted
pN+ observed
2.2% 19.4% 45%
17% 46% 62%
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Furthermore, we compared the reliability of the recently published CART analysis with regard to its accuracy to predict lymph node metastases [6]. We found a significant difference between the predicted frequency of positive lymph nodes in the low and intermediate risk group whereas the data in the high riskgroupwerecomparable (Tables 2 and3).Afrequency of 2.2% and 19.4% was predicted in the low and intermediate risk group, however, lymph node metastases were detected in 17% and 46%, respectively. In summary, currently available nomograms cannot accurately predict the frequency of positive lymph nodes in patients with clinically localized or locally advanced prostate cancer. Extended pelvic lymphadenectomy is recommended to be performed in at least all patients with unfavourable preoperative findings such as PSA >10 ng/ ml, >cT1c, biopsy Gleason score >6, >2 biopsy cores involved with cancer and any core containing Gleason 4 or 5 prostate cancer. In patients with low risk prostate cancer (PSA <10 ng/ml, cT1c, Gleason score <6) the risk for lymphonodular disease is between 8% and 10% and the need for pelvic lymphadenectomy especially prior to nonsurgical therapeutic alternatives has to be discussed on an individual basis. 2.2. Complications of extended pelvic lymphadenectomy in prostate cancer Surgeons are often deterred from performing an extended pelvic lymphadenectomy due to the potentially high incidence of complications. However, the high complication rate of 10% to 20% only derives from old series published in the 1970s and 1980s [18]. In recent series (Tables 4 and 5), the frequency and the severity of intra- and perioperative complications does not differ significantly between the limited and the extended variant of pelvic lymphadenectomy [5]. If performed by an experienced surgeon, the frequency of peri- and postoperative complications attributable to pelvic lymphadenectomy is around 7% [18] with symptomatic lymphoceles (2–4%) representing the most common type of complication. However, deep Table 4 Intraoperative complications in a series of consecutive patients with prostate cancer undergoing either extended pelvic lymphadenectomy (epLA) or standard pelvic lymphadenectomy (pLA)
Blood loss Blood loss <500 ml Rectal lesion Others Ureteral lesion Obturator injury
epLA
pLA
650 47 1 6 0 2
590 48 1 6 0 1
(200–1950) (52.8%) (1.1%) (7.1%) (2.2%)
(150–2100) (48%) (1%) (6%) (1%)
Table 5 Perioperative complications in a series of consecutive patients with prostate cancer undergoing either extended pelvic lymphadenectomy (epLA) or standard pelvic lymphadenectomy (pLA)
DVT Emboli Pneumonia Myocardial infarction Lymphocele Others
epLA
pLA
4 2 2 1 9 9
6 2 2 2 9 6
(4.7%) (1.2%) (1.2%) (0.6%) (10.6%) (10.6%)
(6%) (2%) (2%) (2%) (9%) (6%)
venous thrombosis, pulmonary emboli, injuries to the obturator nerve and the ureter, lymphedema of the lower extremity have also been described. Treatment associated morbidity can be reduced significantly when (1) all lymphatics lateral to the external artery are saved, (2) the distal ends of the lymphatics are either ligated or clipped with small clips exerting a higher pressure to the lymphatic vessels than large clips, (3) 2 drains are placed in each side of the pelvis, (4) drains are left in place until <50 ml/day is drained and (5) low molecular heparin is injected into the upper arm. 2.3. Therapeutic benefit of extended pelvic lymphadenectomy It has been demonstrated for a variety of malignancies such as breast, colorectal, esophageal, bladder and testicular cancer that a subgroup of patients with minimal lymph node disease will benefit from an extended variant of locoregional lymphadenectomy in terms of cancer specific and progression-free survival. With regard to prostate cancer, controversial data are discussed in the literature with regard to the potential therapeutic benefit of pelvic lymphadenectomy. Fergany et al. [19] compared biochemical relapse rates of 372 and 203 patients undergoing radical prostatectomy with and without pelvic lymphadenectomy, respectively. All patients exhibited a preoperative PSA level <10 ng/ml, a biopsy Gleason score <6 and stage cT1c and therefore were at low risk for positive lymph nodes. The 4-year progression-free survival was 91% and 97% following radical prostatectomy with or without lymphadenectomy, respectively. Similar findings are reported by El-Galley et al. and Meng et al. [20,21]. In a cohort of well selected patients undergoing radical perineal prostatectomy for clinically localised PCA, PSA relapse rates did not differ significantly between patients with or without pelvic lymphadenectomy. Although the data on the therapeutic benefit of extended pLA in PCA are sparse, some studies do already suggest a beneficial effect in a subgroup of
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patients with minimal lymph node involvement. Bader et al. [4] demonstrated the beneficial effect of extended pLA in terms of biochemical progression-free survival and cancer specific survival in a cohort of 365 patients. After a mean follow-up of 45 months, cancer specific survival was 78%, PSA progression-free survival was 24% and symptom-free survival was 47%. Performing a multivariate analysis, the group identified only the number of positive lymph nodes to be significantly associated with systemic relapse and recommend a surveillance strategy for men with only 1 lymph node involved. Our group has recently performed a casecontrol study analysing PSA progression-free survival after a minimum follow-up of 3 years in a cohort of 100 consecutive patients having undergone limited pLA as compared to a group of 100 consecutive patients having undergone extended pLA. First data indicate, that the PSA relapse rate differs significantly between both groups with 23% and 8% in the limited and extended pLA group, respectively, indicating a potential benefit of pelvic lymphadenectomy. Furthermore, dissection of al involved lymph nodes might be beneficial for adjuvant treatment purposes. In a retrospective analysis of 322 patients undergoing immediate adjuvant androgen deprivation for lymph node positive PCA following radical prostatectomy, Cheng et al. [22] observed no statistically significant difference in the cancer specific mortality between the control group of pN0 patients and men with only 1 lymph node involved. Only a more extensive involvement of positive nodes is associated with a significantly increased mortality risk despite adjuvant endocrine manipulation. In another clinical trial, Messing et al. [23] documented a therapeutic benefit in terms of progression-free and cancer-specific survival of immediate adjuvant hormonal therapy in patients with lymph node positive PCA undergoing radical prostatectomy. Therefore, any detected lymph node metastasis at time of surgery might in a survival benefit if followed by adjuvant therapy. It is, therefore, our impression that all patients should be offered the option of open or laparoscopic extended pelvic lymphadenectomy in order to achieve an optimal individual treatment. However, it might be justified to spare pelvic lymphadenectomy in a group of well selected patients with stage cT1c PCA, PSA levels <10 ng/ml and a biopsy Gleason score <6. 2.4. Alternative, noninvasive options of lymph node staging in prostate cancer A new diagnostic approach to detect lymph node metastases has recently been reported by Wawroschek et al. [24] who described a gamma probe guided
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sentinel lymph node identification in prostate cancer patients prior to radical prostatectomy. Combining preoperative lymphoscintigraphy after ultrasound guided intraprostatic injection of 99mTechnetium with intraoperative gamma probe detection of labelled nodes, the authors found positive lymph nodes in 24% of all patients. As already being described for extended pLA, 36% of the positive nodes were found outside the fields of standard lymphadenectomy and 19% were located along the hypogastric and the presacral area. Most importantly, a single sentinel node representing the primary landing zone for prostate cancer could not be identified indicating the existence of various lymphatic drainage systems from the prostate. The high diagnostic accuracy of this method with a very low rate of false negative findings, however, has not been reproduced by others so that a multiinstitutional prospective evaluation is mandatory (Fig. 1a and b). 111 Indium-Capromab immunoscintigraphy might represent another preoperative, non-invasive diagnostic option to identify lymph node metastases in patients with high-risk prostate cancer. Polasczik et al. [25] compared the data of 111Indium-Capromab immunoscintigraphy with pathohistological findings of pelvic lymphadenectomy in 198 patients with high risk prostate cancer. 39% of the patients were found to have lymph node metastases with 62% being correctly identified by scintigraphy. Although the positive predictive value is only 75%, it is higher than the correct prediction of 66–68% being achieved with clinical prediction models. Considering ROC analysis, 111 Indium-Capromab immunoscintigraphy bears a significant diagnostic advantage, however, it has to be further evaluated in prospective settings [26].
3. Summary extended pelvic lymphadenectomy in prostate cancer As has been shown in the above mentioned studies, extended pelvic lymphadenectomy harbors a significant benefit in terms of diagnostic accuracy to detect lymph node metastases in patients woth prostate cancer undergoing radical prostatectomy. Only in highly selected patients (cT1c, PSA <10 ng/ml, Gleason score <6) extended pelvic lymphadenectomy might be spared due to the very low risk of metastatic disease; however, this issue has to be discussed in detail with the patient. Complication rates of extended pLA do not differ significantly from those encountered in standard lymphadenectomy so that the procedure is safe for the patient. Although the data on a therapeutic benefit are
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Fig. 1. (a) Lymphoscintigraphy after intraprostatic injection of 99mTechnetium demonstrating isolated sentinel lymph nodes at the iliac and aortic bifurcation. (b) Intraoperatively, radioactive lymph nodes can be identified by a gamma probe enabling selective removal of single nodes.
sparse, available data suggest an advantage for a subgroup of patients with minimal involvement of only 1 or 2 nodes. It is our policy to perform extended pLA in all intermediate and high risk prostate cancer undergoing radical prostatectomy or even external bean radiation or high dose brachytherapy. If performed, lymph node dissection should include all lymphathics along the obturator fossa, the external, internal and common iliac artery up to the ureteral crossing. Based on the number of lymph nodes being removed, laparoscopic lymph node dissection is definitely inferior to the open technique.
4. Pelvic lymphadenectomy in bladder cancer Radical cystectomy with pelvic lymphadenectomy represents the standard treatment for muscle-invasive bladder cancer. Pelvic lymphadenectomy is included as part of the surgical procedure to control locoregional
disease and to potentially improve cancer-specific survival. Survival after radical cystectomy is usually predicted by the pathological tumor stage, status of surgical margins and the involvement of lymph nodes. Although earlier studies have already demonstrated a prognostic benefit of extended pelvic lymphadenectomy as compared to a limited lymphadenectomy, the anatomically adequate extent of lymph node dissection to obtain reliable staging results is still discussed controversially. In a recent prospective randomized phase III trial on the clinical efficacy of neoadjuvant chemotherapy plus cystectomy [27], it was shown that surgical factors including the extent of lymph node dissection and the individual surgeon’s experience have a major impact on the therapeutic outcome and overall survival [28]. The data of this trial also indicate that chemotherapy was more likely to be of beneficial value if patients received a high-quality surgery by an experienced surgeon. It was concluded that it is extremely important to develop universally accepted standards for radical
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cystectomy and pelvic lymph node dissection in patients with invasive bladder cancer in order to improve outcome [29].
5. Anatomical extent of pelvic lymphadenectomy Although it has been shown that long-term survival is possible in patients with lymph node positive bladder cancer, the anatomical extent of pelvic lymphadenectomy associated with radical cystectomy still has to be defined. Some others take the crossing of the ureters with the common iliac vessels as the most cranial limit for lymph node dissection [30] whereas others extend lymphadenectomy up to the aortic bifurcation. It is generally agreed that the more lymph nodes are removed the higher is the number of patients with positive lymph nodes [31]; furthermore, it has been demonstrated that survival after radical cystectomy is predicted by the pathological stage of the primary bladder tumor and pelvic nodes. Leissner et al. [32] suggested that a significant survival benefit was maintained of more than 16 lymph nodes has been removed. Stein et al. [33] reported that survival in patients with positive lymph node disease was better if more than 15 pelvic lymph nodes had been retrieved. On the other hand, Abdel-Latif an coworkers [34] and Herr [35] could not reproduce the relationship between survival and number of dissected lymph nodes by using multivariate statistical analysis. In this context, it has to be underlined that the number of retrieved lymph nodes can be influenced by many factors such as extent of lymphadenectomy [30–32], presentation of the pathological specimen [36] and pathohistological work-up and techniques of analysis [37] questioning its clinical relevance as a routine prognostic marker. Despite these suboptimal clinical factors, there are a few studies having demonstrated a significant impact of the technique of pelvic lymph node dissection with regard to therapeutic outcome. Poulsen et al. [38] were one of the first groups to compare the prognostic significance of limited versus extended pelvic lymphadectomy in a retrospective analysis of 194 patients undergoing radical cystectomy. Limited pelvic lymphadenectomy (lpLA) began at the iliac bifurcation including the lymph nodes along the external and internal iliac artery and the obturator fossa, extended pelvic lymphadectomy (epLA) began at the aortic bifurcation and included the common, external and internal iliac artery and the obturator fossa. The authors observed a substantial improvement of 5-year recurrence free survival in patients with tumors confined to
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the bladder wall (85% versus 64%, p < 0.02) and without lymph node involvement (90% versus 71%, p < 0.02). 5-year probability for locoregional (7% versus 2%) and systemic recurrences (21% versus 10%) were reduced substantially in patients with bladder cancer confined to the bladder wall in the epLA group, however, without reaching statistical significance. In another retrospective analysis of 484 patients undergoing radical cystectomy and pelvic lymphadenectomy, Leissner et al. [37] demonstrated that the total number of lymph nodes retrieved had a significant impact on recurrence-free survival (p < 0.01). The 5-year recurrence-free survival was 25% and 53% in patients with 14 and 15 lymph nodes being removed, respectively. Furthermore, the surgeon had a significant impact on the prognosis as it was shown the number of lymph nodes dissected ranged between 10.6 and 25.7 and differed significantly between the 11 different surgeons being involved in the study. These data are further corroborated by a recent paper on the standardization of radical cystectomy and pelvic lymphadectomy [29]. However, the authors did not demonstrate a significant overall and cancer-specific survival advantage for patients undergoing epLA as compared to those undergoing lpLA only. The authors further evaluated the concept of epLA in a prospective clinical trial comprising 290 patients [39]. The cranial limit of epLA was the inferior mesenteric artery, lateral border was the genitofemoral nerve and the caudal limit was the pelvic floor. A mean number of 43.1 16.1 lymph nodes were removed with 27.9% of the patients demonstrating positive lymph nodes. Although the group identified a preferred pattern of metastatic spread they were not able to identify a well-defined sentinel lymph node or lymph node area. These data are in contrast to the recently published prospective trial of Bochner et al. [40] on the evaluation of lymph node count and lymph node mapping. 144 consecutive patients were included into this monocentric evaluation with 56 and 88 patients undergoing standard and extended pLA, respectively. Standard pLA included the nodal regions of the external iliac, hypogastric and obturator fossa with the iliac bifurcation representing the cranial limit of lymph node dissection. Extended pLA included the lymph nodes at the aortic bifurcation to no more than 2 cm cranially to the bifurcation and the nodal regions of standard pLA. Although the median number of positive lymph nodes differed significantly between both groups (22.5 versus 8), there was no difference with regard to the percentage of positive nodes which was 21% in both groups. Interestingly, all patients with positive nodes above the
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aortic bifurcation also had positive nodes detected in the lower packages indicating that only extensive locoregional metastatic disease might involve the retroperitoneal areas associated with a dismal prognosis anyhow. Including the lymph nodes along the common iliac artery above the iliac bifurcation, however, appears to be of prognostic value and of clinical significance. In the study of Bochner et al. [40], 4 patients had unexpected micrometastatic lymph node disease at the common iliac region only. Reflecting the survival data of patients exhibiting micrometastatic lymph node disease at time of radical cystectomy, most of these patients are expected to have a relatively favourable outcome. Morbidity of pelvic lymphadenectomy is not increased by including the common iliac region in routine pelvic lymph node dissection, so that this area should be removed as standard part of staging lymphadenectomy. Further evidence to include the common iliac region derives from the prospective multiinstitutional study published recently by Leissner et al. [39]. 81 (27.9%) patients demonstrated lymph node involvement and 35% of all positive lymph nodes derived from above the iliac bifurcation. Furthermore, 20 patients (6.9%) were shown to harbor positive lymph nodes above the bifurcation of the common iliac artery only. Although, no data with regard to the prognostic significance in terms of cancer-specific or progression-free survival are available, these data strongly support the idea to include the lymph nodes of the common iliac region up to the aortic bifurcation in routine lymph node dissection technique for muscle invasive bladder cancer. In another study, Abol-Enein et al. [41] evaluated the locoregional distribution of positive pelvic lymph nodes in 200 consecutive patients undergoing radical cystectomy. The authors also attempted to identify the probability of lymph node clearance with increasingly wide fields of node dissection. In their investigation extended pelvic lymphadenectomy included the lymphatic tissue up to the inferior mesenteric artery, the common, external and internal iliac region. A mean number of 50.6 lymph nodes were retrieved per patient with 48 (24%) patients exhibiting positive nodes. More than one third of these patients (39.6%) demonstrated bilateral involvement, a single positive lymph node was identified in 22 (45.8%) patients. The authors demonstrated that close to 80% of all positive nodes could be cleared completely of the field of pelvic lymph node dissection included all lymphatic tissues along the common, external and internal iliac region. Metastases outside the true pelvis were only detected in multinodal disease and these metastatic deposits were always associated with metastases at the obturator fossa and/or the inter-
nal iliac region. Therefore, the authors conclude that standard lymphadectomy in bladder cancer should always include all lymphatic tissues in the true pelvis; lymph node dissection might be extended up to the inferior mesenteric artery if frozen section examination exhibits positive lymph nodes in the sentinel region of the true pelvis.
6. Summary anatomical extent of pelvic lymph node dissection in bladder cancer As has been shown by the previous studies the anatomical extent of pelvic lymph node dissection in patients undergoing radical cystectomy for muscleinvasive bladder cancer can be well defined. Standard lymphadenectomy should include all lymphatic tissues around the common iliac, intercommon iliac, internal iliac group and the obturator group bilaterally since up to one third of all positive nodes are located around the common iliac artery. This technical variant will allow to clear 80% of all positive nodes; if frozen section will demonstrate no positive lymph nodes in the true pelvis, lymph node dissection has not to be carried out further cranially. If, however, frozen section examination is not performed or if it identifies positive nodes, the inferior mesenteric artery represents the cranial border of lymph node dissection. 7. Critical issues in anatomical pelvic lymphadenectomy for bladder cancer Although the above cited studies have apparently demonstrated the clinical importance of extended pelvic lymph node dissection with regard to the most efficiant retrieval of micrometastatic lymph nodes, there are still some unresolved critical issues. Pathohistological examination of dissected lymph node specimens in these studies has been done more thoroughly and extensively than in other studies concentrating issues such as overall survival, cancer specific survival, and regional versus distant failure. Therefore, some critical facts have to be considered for the general community if extended pelvic lymphadenectomy becomes common practice in all patients undergoing radical cystectomy. Lymphatic tissues dissected from different areas should be sent separately instead of en bloc submissions for pathohistological evaluation since it has been demonstrated recently that the yield of lymph nodes increases significantly thereby increasing the frequency of micrometastatic deposits [42]. Intrainstitutional standardization of pel-
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vic lymphadenectomy appears to be of utmost importance to generate reliable and reproducible results since staging lymphadenectomy is extremely surgeon dependent as has been demonstrated by Leissner et al. [37]. Last, but not least, the various types of extended pelvic lymphadenectomies have been associated with an improved progression-free survival, none of the trials has demonstrated an advantage with regard to cancer-specific survival. Benefit in terms of progression-free survival might be just due to a stage migration associated with extensive lymph node dissection. The majority of patients found to harbour positive lymph nodes will die due distant metastatic spread in the long run and only the few patients with a single or two metastatic lymph nodes might benefit from the extended variant of lymphadenectomy. In order to solve this question, the Association of Urological Oncology of the German Cancer Society has currently
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initiated a prospective randomized clinical phase III trial to evaluate the true clinical efficacy of extended pelvic lymphadenectomy. In bladder cancer, the biological aggressiveness of a particular cancer may have already been expressed at time of diagnosis and the impact of less or more extensive surgery in terms of recurrence and survival might be completely overestimated. For the future, it will be necessary to shed light on the important clinical questions of the biological role of lymph node metastases for the likelihood of synchronous or metachronous distant metastases. It will be necessary to biologically evaluate the expression of various growth factors and mediators of systemic spread on patients with lymph node metastases and to correlate these findings with clinically important end points such as cancer specific survival, overall survival, and locoregional versus sytemic recurrence.
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