Surgical Aspects
Since its first definition as a prognostic factor in the beginning of the last century, the pelvic lymphadenectomy was rarely performed due to increased risks and poor outcomes of patients with positive lymph node. It was not until 1982, when a publication from Skinner reported long-term survival in patients with metastatic nodes submitted to pelvic lymphadenectomy, that this procedure started to be considered standard. Recently, it has been demonstrated that radical cystectomy alone provides suboptimal results. The boundaries of the dissection are still a matter of discussion. Basically, there are three types of pelvic lymphadenectomy: limited, standard and extended (Table 2).
Limited Pelvic Lymphadenectomy
This type of node dissection includes only the nodes from the obturator fossa (between the obturator nerve and the external iliac vein) and is associated with small lymph node counts and inadequate staging information. Jensen et al. in a retrospective comparison of 204 patients who underwent radical cystectomy with limited pelvic lymphadenectomy versus 265 who underwent extended pelvic lymphadenectomy, confirmed these findings by showing poor lymph nodes counts (6; range: 2–17), and decreased recurrence-free survival, disease-specific survival and overall survival in the limited group. In spite of the lack of supporting data, this type of pelvic lymphadenectomy is still largely performed, as shown by Herr et al. in a multi-institutional review of 268 patients who underwent radical cystectomy in different hospital settings including academic centers, military and community hospitals . The authors verified that 37% of these patients underwent limit pelvic lymphadenectomy, and moreover 9% did not have any lymph node dissection. This phenomenon is partially explained by the fact that older and high comorbidity patients tend to have a more limited lymphadenectomy, although it has been reported that even patients with 80 years or more experience survival benefit from a more complete lymphadenectomy, with resection of more than 10 lymph nodes (cancer-specific survival, 54.5 vs 47.6%; p < 0.001).
Standard Pelvic Lymphadenectomy
Standard pelvic lymphadenectomy corresponds to the resection of the lymphatic tissue present in level I of the Leissner classification (Figure 1). The boundaries of this dissection are: the common iliac bifurcation (proximal), the circumflex iliac vein and Cloquet lymph node (distal), the genitofemoral nerve (lateral) and the internal iliac vessels (medial), which includes the obturator fossa. Although this is the most common terminology, this type of pelvic lymph node dissection is also referred to in the literature as limited. Additionally, the term 'modified standard pelvic lymphadenectomy' can be encountered when the presacral region is included in the dissection.
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Figure 1.
Leissner levels of lymph node dissection and the tumor node metastasis 2010 lymph nodes staging (pN) corresponding anatomic definition.
This type of pelvic dissection is the most commonly utilized. The majority of metastatic lymph nodes are located in this anatomical region, leading some groups to consider this region as a primary station for metastatic bladder cancer lymphatic spread. This concept was based on the failure of some previous series to show metastases above the bifurcation of the common iliac artery when the pelvic lymph nodes were negative. However, recent reports have revealed a considerable number of skip lymph node metastasis, especially to the common iliac area and the presacral area. Dangle et al. evaluated 120 patients that underwent radical cystectomy with a 30% positive lymph node incidence, and found that 11% of these patients presented with isolated lymph nodes to the common iliac or presacral regions. In a similar report, Miocinovic et al. looked at 143 patients, of which 52 had lymph node-positive disease, and found that 13% had isolated metastatic nodes at levels II and III .
Extended Pelvic Lymphadenectomy
The extended template comprises the standard package with the addition of presacral area, the proximal common iliac and aortic bifurcation. The inclusion of retroperitoneal nodes from the aortic bifurcation to the inferior mesenteric artery, is called superextended, and includes Leissner levels I, II and III. This extended procedure addresses the whole lymphatic drainage from the bladder, providing complete nodal staging information.
Irrespective of the strict boundaries definition, the extended pelvic lymphadenectomy has been associated with increased nodal counts and survival benefit. Poulsen et al., in the pioneer study, retrospectively compared 68 patient undergoing standard pelvic lymphadenectomy versus 126 undergoing extended pelvic lymphadenectomy, and found a significant improvement in the 5-year recurrence-free survival for patients with bladder-confined tumors (85 and 64%; p < 0.02) submitted to the extended modality. More recently, these data were corroborated by a prospective nonrandomized study, where Abol-enein et al. compared extended pelvic lymphadenectomy, utilizing the origin of the inferior mesenteric artery as proximal limit, to standard pelvic lymphadenectomy, where the proximal limit was the distal inch of common iliac artery. Two hundred patients were included on each arm, and the authors found a 5-year recurrence-free survival of 66.6 versus 54.7% (p = 0.043), in favor of the extended group.
While there appears to be a benefit of having a more complete lymph node sample, the extended lymph node package does not seem to increase the morbidity of radical cystectomy. In fact, a large series has demonstrated that the incidence of lymphoceles and lymphoedema was inversely related to the number of lymph nodes retrieved, being 2% with <16 nodes and 1.1% ≥16 nodes. Brossner et al. compared 46 extended pelvic lymphadenectomy patients to 46 limited pelvic lymphadenectomy patients . They reported no significant difference in complications requiring surgical intervention (11 vs 9%; p = 0.28) or postoperative deaths (2 vs 1; p = 0.57). The only disadvantage for extended pelvic lymphadenectomy in the previous publication was an increase in median operative time of 63 min.
There are currently two active randomized controlled trials comparing the oncologic outcomes of different types of pelvic lymph node dissection in the muscle invasive bladder cancer setting. The first study, from University of Ulm (AB25/05), was designed to compare the standard technique to super extended dissection. It is closed for accrual and is expected to include 450 patients. Initial results are expected in 2013. The second study (SWOG S1011) is comparing standard versus extended lymphadenectomy and is still actively recruiting patients. This study was designed to enroll 620 patients and the initial results are expected for 2022.
Type of Lymph Node Submission
Some surgeons have reported resecting the lymph nodes en bloc with the bladder, while others performed the lymph node dissection separate from the bladder specimen. There is evidence in the literature indicating that the separated methodology of resection and submission of the lymphatic tissue for pathologic analysis are associated with higher lymph node accruals. In a prospective analysis, Bochner et al. evaluated 32 patients who had undergone radical cystectomy with pelvic lymphadenectomy; 20 patients who underwent standard pelvic lymphadenectomy with an unilateral separated resection and contralateral en bloc specimens, and 12 patients who underwent extended pelvic lymphadenectomy, of which 6 had their lymph nodes submitted separately while 6 had en bloc submission with the bladder tumor. These authors found significant differences in the median node counts between separated and en bloc submission in both groups. In the standard pelvic lymphadenectomy group, the difference was 8 versus 2 (p = 0.003) and in the extended group it was 40 versus 21 (p = 0.02), respectively.
Previous studies by Stein et al. and Ather et al. confirmed that en bloc resection resulted in lower nodal yields for extended (31 vs 68; p < 0.001) and standard pelvic lymphadenectomy (7 vs 15.5; p < 0.001), respectively; however, no difference in the incidence of metastatic lymph node disease was encountered (23 vs 25%; p = 0.47 and 20.9 vs 29.4%; p = 0.43) in either of these reports. The absence of an increase in positive lymph nodes despite the increased nodal yield suggests that this effect is due to an improvement in pathologic assessment, and not to variation in the completeness of the lymphatic resection. Thus, it is important to consider the implications of this change in variables like lymph node density and minimal number of resected lymph nodes, when the same surgical boundaries for dissection are used.
Frozen Section/Sentinel Lymph Node
The principle behind the utilization of frozen section and sentinel lymph node technique is based on belief that lymphatic tumor spread follows an anatomic ordered pattern where primary drainage areas would be affected first, followed by secondary areas and so forth. This way, the extended lymphadenectomy could be restricted to patients with positive lymph node at the primary area. However, mapping studies by Roth et al. have demonstrated that the lymphatic drainage from the bladder follows a complex pattern with multiple lymph nodes (median, 4; range: 1–14) from different zones being identified after injection of radiotracer in one single area of the bladder . In a retrospective study, Ugurlu et al. looked at 284 lymph node specimens from 142 radical cystectomy patients and were only able to identify 29 of 36 positive lymph nodes using frozen sections. Liedberg et al. conducted a large analysis of 75 cystectomy patients, using a radioisotope (70 MBq 99m Tc-nanocolloid) and patent blue technique, but again the accuracy of the method was inadequate, identifying only 81% of the metastatic patients. Given the reduced morbidity associated with pelvic lymphadenectomy and the lack of accuracy of these methods to predict metastatic lesions in the intraoperative setting, these techniques are not routinely recommended.