Lymphadenectomy provides important information on tumour stage and prognosis and is routinely combined with cystectomy. However, the extent of pelvic lymphadenectomy and its therapeutic effect has been a matter of controversy for many years. In various other malignancies such as gastric, breast, colorectal and cervical cancers the impact of lymphadenectomy on outcome has been well documented [1-4]. Results in these tumors have led various investigators to determine whether pelvic lymph node dissection, at the time of radical cystectomy, may not only be an important staging tool but also improve outcome in patients with bladder cancer.
Pelvic lymphadenectomy as a staging procedure
Radiologic imaging modalities such as computerized tomography, magnetic resonance imaging and lymphangiography cannot be considered reliable predictors of lymph node metastases in the pelvis and therefore cannot influence operative procedures [5,6].
Extent of pelvic lymph node dissection
Over the years there has been considerable controversy over the extent of lymph node dissection in bladder cancer. Dissection should include all primary drainage areas from the diseased organ. In bladder cancer this implies the following boundaries: laterally, the genitofemoral nerve; distally, the femoral canal; proximally, the crossing of the ureters with the common iliac artery; Inferiorly, the obturator muscle and floor of the obturator fossa down to the internal iliac vessels; medially, the side wall of the bladder. The lymphatic tissue medial to the internal iliac vessels should also be removed, which some would deem the presacral area. With these templates a median of 22 nodes (range 3-48) were removed in 507 patients with bladder cancer in our series at the University of Bern [7,8]. Positive lymph nodes were found in 24%. The number of removed nodes corresponds well with the results of an anatomical study by Weingaertner et al., who determined that approximately 20 removed lymph nodes can be considered a representative pelvic lymphadenectomy .
However certain controversy does remain. In bladder cancer some propagate inclusion of the tissue along the common iliac vessels, leading to removal of between 14 and 43 nodes. [10-13] Patients with positive nodes at this second level do not do well and most probably have other first level nodes that are affected. In addition, sympathetic nerve fibres responsible for urethral smooth muscle innervation run between the aortic and common iliac bifurcation and could be damaged, potentially having a negative impact on continence in patients with an orthotopic bladder substitute.
Results of pelvic lymph node dissection
Early studies (1973-1991) on patients with node positive bladder cancer showed poor survival in large series. [14,15] A few reported better results in smaller series. [14-18] Large contemporary series show 5 and 10 year survival rates ranging from 23-31% and 21-23%, respectively. [7,8,19-22] A substantial number of patients do have long term survival, suggesting that bilateral pelvic lymphadenectomy may have a therapeutic impact in some of these patients.
The incidence of positive nodes increases with increasing tumour stage [8,19-21]. In bladder cancer 6% of patients with superficial disease were reported to have lymph node metastases. This further stressing the need for meticulous lymph node dissection in all patients undergoing cystectomy for bladder cancer.
Furthermore, evidence is increasing that the total number of nodes removed and the number of positive nodes influences outcome and adjuvant therapeutic strategies.
Pelvic lymph node dissection and prediction of outcome:
Prognosis depends on the number of affected lymph nodes, nodal cancer volume, number of nodes removed, ratio of positive nodes to the number of nodes removed and extranodal growth, probably the strongest predictor of all.
Number of positive nodes: In bladder cancer there is substantial evidence that patients with less than 5-6 positive nodes fare better [7,18,20]. In a retrospective study minimal lymph node involvement was even an independent prognostic factor . Especially patients with localized primary tumours and minimal metastatic disease profit from lymphadenectomy .
Volume of nodal metastasis: Mills and colleagues were the first to show that the tumor volume in the lymph nodes has a significant effect on survival in patients with bladder cancer [7. The cut off was under 0.5 cm and patients with this minimal tumor burden had a survival benefit of approx. 4 years. But there are also some survivors, even with gross nodal disease, after cystectomy and lymphadenectomy, as reported by Herr and Donat . It seems quite clear that the tumour burden is the main factor influencing survival.
Number of nodes and Ratio of positive to negative nodes: In bladder cancer it has been reported that the more nodes removed the better the prognosis, even if the pathology report does not show lymph node metastases, [10,25,26] suggesting that micrometastases may have been missed by the pathologist. In addition if tumor cells are removed and not left behind, this may translate to a survival benefit, especially in patients with minimal metastatic disease.
The ratio of positive nodes reflects two important factors namely the number of positive nodes and the total number of nodes removed or the quality of lymph node dissection . Mills et al showed that in bladder cancer patients with less than 20% positive lymph nodes have a significantly better prognosis than those with more than 20% positive nodes . Herr et al. confirmed the predictive value of the ratio of the number of positive nodes to the total number of lymph nodes removed .
Extranodal growth: Histopathological characteristics reflect biological aggressiveness and can be used to classify tumors. Penetration of nodal capsule and the localisation of the penetration is considered a prognostic factor in some tumors, for example penile cancer. This has only been reported by Mills et al who determined a survival benefit in patients with no capsular penetration in bladder cancer . In fact, extranodal growth seemed to be the strongest negative predictor in a multivariate analysis.
In summary, metastatic nodal tumor burden appears to play an important prognostic role in bladder cancer. Patients with minimal nodular metastasis (eg. micrometastases) may also have a chance of cure.
Complications of pelvic lymph node dissection
Complications associated with lymph node dissection are lymphoceles, lymphedema, venous thrombosis and pulmonary embolism. However, morbidity can be significantly reduced by meticulous surgical technique and if: the lymphatic vessels are ligated at their distal end, where lymphatics from the leg are severed; 2 instead of 1 drain are placed, one on each side of the pelvis where lymphadenectomy was performed and not removed until the total amount drained is less than 50 ml/24 h; low molecular heparin is injected into the upper arm instead of the thigh. In our institution, where meticulous extended lymphadenectomy is routinely performed, 2.4% and 1.9% of patients with bladder cancer, respectively, required a prolonged hospital stay or rehospitalisation as a consequence of extended meticulous lymph node dissection .
There is growing evidence supporting meticulous extended lymph node dissection in patients with bladder cancer. Extended meticulous lymph node dissection with removal off all diseased nodes, particularly along the internal iliac vessels, has a survival benefit, allows exact staging and may even signify a chance of cure in patients with minimal metastatic disease. With a meticulous surgical technique the risk of complications as a result of extended lymphadenectomy is low.
Fiona C. Burkhard
University of Bern
Department of Urology
Inselspital, Anna Seiler-Haus
CH-3010 Berne Switzerland