Surgical factors in bladder cancer: more (nodes) + more (pathology) = less (mortality)


Radical cystectomy coupled with a pelvic lymphadenectomy is the most effective treatment for invasive bladder cancer. The curative intent of radical surgery is to remove all cancer in the bladder, pelvis and regional lymph nodes. Indeed, contemporary radical surgery cures most muscle-invasive tumours confined to the bladder (stage T2), about half that have spread into the perivesical fat (stage T3), and a significant minority of node-positive (N+) cancers [1]. Surgery also provides important pathological information to identify patients who are likely to develop recurrent disease, and well-publicised improvements in neoadjuvant and adjuvant chemotherapy regimens in high-risk patients portend better survival than with surgery alone. Largely ignored as important factors determining bladder cancer outcome have been the quality of radical cystectomy and the extent of the pelvic lymph node dissection. Detecting the influence of surgical expertise on long-term survival after cancer operations is difficult. The quality of cystectomy depends on several poorly defined factors

One is the experience of the surgeon. Experienced urological oncologists operating in high-volume centres tend to achieve better survival results than urological surgeons who perform a few cases in low-volume institutions. Another factor is that many urologists consider it futile to resect locally advanced or node-positive bladder cancers. High morbidity and uncertain surgical benefit because of the likelihood of distant metastases are often cited to justify a lack of surgical aggressiveness for extravesical tumours. A third reason is the age and health of the patient. Surgeons may perform a less radical operation in aged or infirm patients, to reduce operating time and lessen morbidity. A recent analysis of the SEER program cancer registry showed that only 40% of patients who underwent cystectomy had a lymph node dissection, and in half of all eligible patients, urologists elected not to perform a cystectomy at all! [2].

Radical cystectomy is defined as the wide resection of all perivesical fat and tissue around the bladder, prostate and urethra, to achieve a negative soft-tissue margin. A standard pelvic lymph node dissection removes all of the distal common iliac, external iliac, obturator and hypogastric nodes. Such dissection yields an average of 10–14 nodes. An extended lymph node dissection to the aortic bifurcation including the presacral nodes often yields ≥ 40 nodes. How often is radical cystectomy with at least a standard lymph node dissection done, and does it matter?

We examined surgical factors from a randomized multi-institutional cooperative group trial conducted in the USA. Half the patients received neoadjuvant MVAC chemotherapy. Of 270 patients who underwent cystectomy, 24 had no lymph node dissection, 98 had a limited dissection of only the obturator nodes, and 146 had the standard pelvic node dissection. The 5-year survival rates for each of these groups was 33%, 46% and 60%, respectively. The median number of nodes retrieved was 10; the survival rate was 44% for patients with < 10 nodes removed, compared with 61% for patients with> 10 nodes examined. A multivariate analysis showed that the extent of node dissection, number of nodes removed and number of cases performed by individual surgeons were significant factors influencing survival. Indeed, surgical factors (and not chemotherapy) were the most important predictors of outcome.

Other studies also suggest that despite the local extent of bladder tumour, patient age and comorbidity, a potentially quantifiable surrogate marker for the adequacy of surgical resection is the number of lymph nodes removed by the surgeon. In an analysis of 322 patients, we found that improved survival and fewer local recurrences were associated with a greater number of lymph nodes removed [3]. Among node-negative patients, survival was improved if ≥ 14 nodes were resected. Presumably, fewer nodes removed risked leaving microscopic positive nodes in the pelvis, contributing to later relapse, and reduced the overall survival. An update of this series in 637 patients showed that at least 11–14 nodes need to be removed to define node-negative status accurately and to optimize cure by surgery in node-positive cases [4]. The quality of lymph node dissection was also linked to the ratio of positive-to-total number of nodes removed. Of 162 patients with positive pelvic nodes, 64% who had a node density ratio of < 20% survived 5 years after cystectomy, compared with node-positive patients with a ratio> 20%[5].

The influence of the individual pathologist must not be forgotten, whose technique and diligence in searching for nodes may vary. Furthermore, validated methods used for counting nodes in cystectomy specimens have not been standardized. The surgeon may aid the pathologist by submitting nodes separately rather than en bloc with the bladder. We found that it is more difficult for the pathologist to find nodes within an en bloc specimen (average of 2.4 nodes per side) than in smaller (two or three) separate packets per side (average nine nodes) using conventional methods [6]. Fat-clearing, immunohistochemical and molecular techniques may yield higher node counts, but specialized methods are expensive, impractical, and unlikely to provide useful prognostic information over routine isolation and histological evaluation by an experienced pathologist. Recommendations for the pathological evaluation of radical cystectomy specimens have been proposed [7]. They need to be considered, revised where necessary and validated in prospective trials.

When improved survival correlates with increasing numbers of lymph nodes reported by the pathologist, three factors are potentially involved: (i) a diminished risk of local and regional recurrence may result from a complete pelvic lymphadenectomy which yields more lymph nodes in the specimen; (ii) the surgeon who performs a more complete node dissection may secure wider margins around the bladder; or (iii) a more thorough examination of the specimen by the pathologist may result in more accurate staging. It has not been possible to assign a mechanism for improved outcome from any single study reporting improved survival with increased node count, but the data emerging from collective studies shows that surgery does indeed matter, and is critical to a favourable outcome.

The need to secure and retain local and regional control of bladder cancers, even extravesical tumours, will assume increasing importance as systemic therapy improves and reduces deaths from distant metastases. Accepted standards for high-quality radical cystectomy including pelvic lymph node dissection and pathological assessment of cystectomy specimens should be established and prospectively validated. This is important not only for managing each patient but also for the design and evaluation of multimodal studies in bladder cancer. Improving the quality of surgery may even prove to be as, or more, important than anticipated improvements in chemotherapy.