Nodal involvement

J├╝rgen E Gschwend

Department of Urology, University of Munich, Germany

Introduction

Radical cystectomy and bilateral pelvic lymph-node dissection (PLND) has been established as standard treatment for muscle-invasive bladder cancer.1,2 As regards lymph-node involvement, it has clearly been shown that the presence of nodal metastasis is an indication for at least limited systemic tumour spread, and does translate into decreased survival compared to node-negative patients, despite radical surgery. However, recent data indicate that patients with minimal nodal disease and otherwise organ-confined primary bladder tumours do benefit from radical cystectomy and PLND, and that even a proportion of patients with grossly node-positive bladder cancer can be cured by surgery and thorough lymph-node dissection.3-7

Historical aspects of nodal involvement for invasive bladder cancer

Regional lymph-node dissection has been integrated in the management of breast, cervical, gastric and colon cancer for decades. Jewett and Strong have published an important study of autopsy cases stratified into various tumour stages.8 This study gave the rationale basis for radical cystectomy and PLND, as well as the knowledge for local extension of transitional cell carcinoma of the bladder during the course of clinical tumour development. Brunschwig et al. described the technique of radical cystectomy with resection of pelvic lymphatic tissue for carcinoma of the bladder for the management of advanced bladder cancer by exenterative pelvic surgery.9 Whitmore and Marshall were among the first to clinically analyze the relative impact of radical cystectomy and PLND on survival.10 Among a small subgroup of patients with limited nodal involvement, longterm survival was noted in less than 20%. Subsequent studies reported contradicting results regarding the prognostic impact of PLND in patients with proven nodal metastasis. In the early 1980s, Skinner et al. were the first to report data that gave a clear rationale for a meticulous pelvic lymph-node dissection for management of invasive bladder cancer.11 However, the true impact of PLND on outcome and survival depended on the stage of the primary bladder tumour, and the number, size and location of involved lymph nodes was still a matter of debate until recently, when studies addressing these questions were reported.3-7,12-14

Distribution and incidence of regional lymph node metastases

Lymphatic drainage of the urinary bladder is accomplished through a network of lymphatic vessels and nodal plexus which can be divided into distinct transmitting and collecting units. Regional lymph nodes can be divided into perivesical nodes, hypogastric nodes along the internal iliac artery, obturator nodes, external iliac nodes and presacral nodes. These regional lymphatics drain into the common iliac, inguinal, para-aortal and paracaval nodes, which are usually secondary landing zones for bladder cancer metastasis. According to Smith and Whitmore, nodes in the obturator (74%) and external iliac region (65%) are of most importance because of their frequency of involvement by bladder cancer metastasis.15 Nodes in the common iliac region (19%), the hypogastric region (17%) and perivesical nodes (16%) are less frequently involved. In a recently reported study by Mills et al., 44.5% of node-positive patients had nodal involvement confined to a single region, whereas 55.5% had positive nodes in at least two regions.14 In 7.2% of patients, nodes were positive only on the contralateral side to a lateralized bladder tumour, and in another 12% the ipsilateral as well as contralateral regions were involved. This emphasizes the importance of a thorough lymph-node dissection of the whole primary landing zone for lymph-node metastasis in the pelvis, including the region along the internal iliac vessels.

The overall incidence of nodal metastasis in patients undergoing radical cystectomy and PLND is reported to be between 13% and 28% in large series.16 The majority of these patients present with nodes that appear macroscopically to be normal at surgery. The incidence ofnodal involvement correlates directly with the stage of the primary in the bladder, ranging from less than 5% in superficial to more than 40% in deeply infiltrating, high-grade tumours. Skinner reported nodal metastasis in 6% of p1, 30% of p2, 31% of p3a and 65% of p3b tumours.11 Smith and Whitmore described positive lymph nodes in 2% of p1, 8% of p2 and 47% of p3 tumours.15 In the largest reported series of 193 node-positive cystectomy patients, 77.2% of node-positive patients presented with extension of the primary tumour beyond the bladder wall (p3b to p4b) whereas only 22.8% presented with organ-confined tumours (p0 to p3a).6 Mills et al. reported in their study a frequency of nodal involvement in 5-12% for organ-confined and 28-38% for non-organ-confined primary tumours.14

To minimize the sampling error during PLND, which influences the incidence of positive nodes, it is important to understand that neither the size of individual lymph nodes nor the location of enlarged lymph nodes within the boundaries of PLND correlates positively with the true incidence of metastasis. Therefore, selection of lymphatic tissue should not be made by the surgeon, rather the entire specimen should be sent for assessment of histology. Another factor that influences the incidence of nodal metastasis is the number of nodes in the specimens examined by the pathologist. This number does significantly impact on the local control and survival of stages pNO and pN+ disease.13 The quality of surgical resection during PLND and radical cystectomy is critical to identify patients who have positive nodes. Herr et al. provide evidence that at least nine lymph nodes are necessary to allow adequate assessment of the lymph node status and to determine patient prognosis as regards the node status.13 The more extensive the lymph node dissection, the more likely it is that an increased number of lymph nodes, including more microscopic positive lymph nodes, may be excised and examined by the pathologist. However, further prospective studies are necessary to determine the number of nodes in order to ensure a high-quality operation. On the other hand, the routine practice of lymph-node examination by the pathologist, with or without visual enhancement techniques, can vary in thoroughness. The method of step sectioning lymph nodes can account for a higher than 30% false rate of pathologic interpretation error over random pathologic evaluation when studying pelvic nodes for tumour involvement.17

Summary

1 Regional lymphatic drainage of the urinary bladder takes place through perivesical nodes, hypogastric nodes along the internal iliac artery, obturator nodes, external iliac nodes and presacral nodes.

2 The overall incidence of nodal metastasis in patients undergoing radical cystectomy and PLND is reported to be between 13% and 28%.

3 Positive nodes may be present on the ipsilateral and contralateral side to a lateralized bladder tumour.

4 The incidence of nodal metastasis is influenced by the number of nodes in the specimens examined by the pathologist.

Technical considerations and extent of pelvic lymph-node dissection along with radical cystectomy

Pelvic lymph-node dissection should be performed as a standard procedure. All connective and lymphatic tissue must be removed from the common iliac bifurcation along the external and internal iliac vessels to the inguinal ligament and from the psoas muscle fascia. The lateral limit is the genitofemoral nerve. All crossing tissue elements may be divided by use of electrocautery or by bipolar scissors. The caudal and cephaled side of the lymphatics should be ligated or clipped to avoid postoperative lymphoceles. However, haemoclips tend to become disloged from lymphatic vessels during the surgical procedure, therefore, ligations are preferable. The obturator fossa is cleared from all lymphatic tissue around the obturator nerve and vessels. If adequate, the obturator vessels are dissected and removed, together with the lymphatic tissue. Careful dissection along the ventral aspect of the internal iliac vein and from the obturator muscle is recommended. The presacral region and the internal iliac artery are freed from lymphatic tissue after dissection of the umbilical artery that crosses the ureter.

A pelvic lymph-node dissection as described above clearly eases radical cystectomy, since the vascular pedicle of the bladder is anatomically exposed. Based on pelvic anatomy on the one hand and clinical data on the other, some surgical centres promote a more extended PLND that includes dissection of all lymphatic tissue along the aortic bifurcation.12,14 There is strong evidence that microscopic nodal involvement may be present in any location within the small pelvis, independent from the location of the bladder tumour, and that even nodes above the common iliac bifurcation may be a primary landing zone for metastatic disease.

Guidelines for colorectal cancer indicate that at least 12 to 14 lymph nodes should be found and examined by the pathologist.18,19 Similar guidelines have not yet been established for bladder cancer. Poulson et al. reported a survival advantage in patients with stage pN0 and organ-confined bladder tumours after more extensive lymph-node dissection.12 Extended PLND yielded a median of 25 lymph nodes, whereas limited or conventional PLND yielded only a median of 14 nodes. Of the patients with extended dissection, 12.5% had positive nodes compared to only 8.9% with limited dissection. It is also important to point out that the number of lymph nodes may vary among institutions and surgeons, depending on patient selection, the extent of PLND, how lymph nodes are submitted for pathologic evaluation and how many lymph nodes are examined. However, there is still no data from prospective studies that prove the benefits of an extended pelvic lymph-node dissection over standard PLND.

When grossly positive nodes are found at surgery, a number of considerations influence the decision to proceed with radical cystectomy. The most important question is whether the nodes and the bladder can be resected completely without leaving gross tumour behind, and whether they can be resected safely, with low morbidity?7 The patient's age does not seem to be a major factor, as studies prove that even octogenarians tolerate radical cystectomy and extended pelvic lymph-node dissection as well as younger patients.20

Complications from standard pelvic lymph-node dissection along with radical cystectomy are rarely reported. In most series, the intra- and post-operative risk of complications is not related to PLND.3,4,21-24 Since PLND is usually performed with radical cystectomy via an intraperitoneal approach, post-operative pelvic lymphoceles are not a major problem. It appears that after this procedure, extravasated lymph is resorbed easily from the peritoneal surface, thus minimizing the risk of lymphocele formation. A rate of 3.5% lymphoceles following PLND along with radical cystectomy and orthotopic ileal neobladder has been reported.25 With regard to extended pelvic lymph-node dissection, when a nerve-sparing procedure is planned, careful attention must be made to the preservation of the autonomic plexus and nerve fibres that run along the common and internal iliac arteries and descend into the pelvis. Damage to the autonomic innervation of the corpora cavernosa at the level of the autonomic plexus, or to sympathetic fibres that contribute to the urethral smooth muscle innervation, may be a complication in concert with an extended PLND.26

Summary

1 Pelvic lymph-node dissection should be performed as a standard procedure. A thorough pelvic lymph-node dissection clearly eases radical cystectomy since the vascular pedicle of the bladder is anatomically exposed.

2 The number of dissected lymph nodes varies among institutions and surgeons, depending on patient selection, the extent of PLND, how lymph nodes are submitted for pathologic evaluation, and how many lymph nodes are examined.

3 Major complications from a standard pelvic lymph-node dissection along with radical cystectomy are rarely reported.

Impact of regional lymph node involvement on survival following PLND and radical cystectomy

Regional lymph node status has consistently been found to be one of the strongest predictors of survival. Cystectomy candidates found to have positive pelvic lymph nodes at time of PLND are generally regarded as having a poor prognosis, but considerable variation exists among the reported survival rates (Table 1).

While historical series report rather dismal outcomes, more contemporary analyses have demonstrated that radical surgery in combination with PLND may in fact provide favourable longterm survival in a substantial number of cases, and that patients most likely to benefit from radical surgery are those with favourable stage and/or with limited or microscopic lymph node involvement.3-6,15 In a detailed analysis of node-positive cystectomy candidates 1-, 3-, 5- and 10-year survival rates were reported to be 67%, 33%, 25% and 21% respectively.6 Survival appears to be especially a function of the extent of the primary tumour (Figure 1) with an actuarial five-year survival of 51% for bladder confined (pT0-pT3a), and 17% for tumours extending outside the bladder wall (pT3b-pT4b) (p < 0.001).

Survival also seems to be inversely related to the extent and bulk of the tumour in the regional pelvic nodes. Among patients with involvement of a single lymph node (pN1), 33% survived five years, whereas only 22% with

Table 1: Incidence and survival of patients with nodal metastases following radical cystectomy and pelvic lymph-node dissection

Authors

Period

No. of patients

pN+

Strata

Survival >5 years

Whitmore and Marshall (1962)10

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