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Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2358-2365 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.084 Extracapsular Extension of Pelvic Lymph Node Metastases From Urothelial Carcinoma of the Bladder Is an Independent Prognostic FactorFrom the Departments of Pathology and Urology, University of Bern, Bern, Switzerland Address reprint requests to Urs E. Studer, MD, Department of Urology, University of Bern, Inselspital, CH-3010 Bern, Switzerland; e-mail: urs.studer{at}insel.ch
PURPOSE: To analyze the prognostic impact of risk factors for urothelial carcinoma of the bladder (UCB) with pelvic lymph node (LN) metastases. PATIENTS AND METHODS: We analyzed a consecutive series of 507 patients with UCB who were preoperatively staged N0M0. One hundred one of 124 eligible patients who were treated with radical cystectomy and standardized extended bilateral pelvic lymphadenectomy with curative intent and had postoperatively confirmed LN metastases were evaluated in regard to recurrence-free and overall survival.
RESULTS: A median of 22 nodes per patient (range, 10 to 43 nodes) were removed and examined. Median recurrence-free and overall survival durations were 17 months and 21 months (range for both, 1 to 191 months), respectively. In the multivariate analysis for recurrence-free survival, extracapsular extension of LN metastases was the strongest prognostic factor (P = .019). Other variables such as tumor stage (pT1/2 v pT3 and pT4), the number (< five v CONCLUSION: The results of this study indicate that radical cystectomy with bilateral lymphadenectomy can have a curative effect in a subset of patients with pelvic LN positive UCB. Provided that a representative number of LNs are removed by meticulous lymphadenectomy and that a thorough histologic examination is performed, prognosis for such patients can be determined quite reliably. In the multivariate analysis, extracapsular extension of LN metastases was the strongest factor predicting prognosis.
Whether the presence of regional lymph node metastases in patients with urothelial carcinoma of the bladder indicates systemic disease or may only be a manifestation of locally advanced disease is controversial. For these patients, the role of pelvic lymphadenectomy as a staging procedure is generally accepted, but its therapeutic value is still debated. At present, there is evidence that this node-positive cohort comprises several poorly defined subgroups with significantly different outcomes and that some patients can be cured by radical cystectomy with extended pelvic lymphadenectomy alone. We have recently shown that extracapsular extension of lymph node metastases defines a subgroup with a very poor prognosis. The aim of this study was to further evaluate the relevance of this finding in relation to other potential risk factors in terms of survival in patients with urothelial carcinoma of the bladder and metastases in the pelvic lymph nodes.
Patients and Follow-Up We analyzed a selected group of 507 consecutive patients with urothelial carcinoma of the bladder who were preoperatively staged N0M0 as determined by the noninvasive diagnostic procedures available at the time and who did not receive neoadjuvant therapies. Clinical staging included chest x-ray, ultrasonography of the liver, bone scan, intravenous urography, and computed tomography scan of the pelvis when it became available for routine use. All patients underwent cystectomy with standardized extended pelvic lymphadenectomy for invasive bladder cancer at the Department of Urology, University of Bern, Bern, Switzerland, between January 1985 and November 2000 and were followed according to a prospective standard protocol. They were seen postoperatively at 3 and 6 months and then at 6-month intervals until 5 years after cystectomy. Further follow-up was conducted yearly at the Department of Urology or by urologists in private practice as stipulated in this protocol. One hundred twenty four (24%) of these 507 patients had lymph node metastases on histologic examination. Patients without residual tumor tissue in the bladder who had the initial histologic diagnosis based on transurethral resection material made elsewhere, those without complete lymphadenectomy, and patients with pN3 disease were excluded (23 patients total), leaving 101 patients eligible for this study. There is a partial overlap of 66 patients in this population and the one reported by Mills et al.1 In contrast to the homogeneous group described here, the cohort of Mills et al comprised a heterogeneous population of patients with urothelial carcinoma, adenocarcinoma, squamous cell carcinoma, and small-cell carcinoma.
Surgical Technique
Pathology All specimens were processed and evaluated at the Institute of Pathology, University of Bern. Pathologists experienced in genitourinary pathology examined the cystectomy specimens and nodal tissues. A single pathologist (A.F.) reviewed all slides from the lymph node–positive patients. The bladder was filled with formalin and fixed at least overnight. Gross description included bladder size, the presence of the ureters, and other tissues. Tumor characteristics noted were location, size, extent of invasion, and multifocality. Sections for histology were taken from the tumor(s), including the site of deepest macroscopic invasion, the anterior and posterior wall of the bladder, the bladder neck with trigone, the dome of the bladder, and any macroscopically abnormal area of the mucosa. At least one sample was taken from each location. In cases with preoperatively diagnosed carcinoma-in-situ, the sampling was intensified. Any residual ulcer after transurethral resection was sectioned in toto. Additionally, the resection margins of ureters and urethra, tissue samples of other organs present, and any perivesical lymph nodes were taken. Histologically, the tumor type, tumor grade, tumor stage, the presence of vascular invasion, and carcinoma-in-situ were assessed. The nodal tissues from each anatomic location were examined separately by palpation, inspection, and sectioning. All macroscopically detected nodes larger than 5 mm were cut into 2- to 4-mm thick sections and completely embedded in paraffin. If no nodes could be identified, the entire tissue was embedded for histologic examination. One section per paraffin block was taken. The tumors were reclassified according to the sixth International Union Against Cancer classification of 2002.3 In this classification, tumor invasion of the lamina propria corresponds to stage pT1, invasion of the muscularis propria to pT2, invasion of perivesical tissue to pT3, and invasion of the prostate, uterus, vagina, and pelvic or abdominal wall to pT4. A metastasis in a single regional lymph node, 2 cm or less in greatest dimension, is staged as pN1. A single regional lymph node metastasis 2 cm to 5 cm in size or multiple metastases no more than 5 cm in its greatest dimension are classed as pN2. Metastases more than 5 cm in their greatest dimension are staged as pN3. The total number of histologically confirmed lymph nodes and the proportion of nodes with metastases were recorded for each region. Features of special interest were the largest diameter of each nodal metastasis measured macroscopically or microscopically on the slide and the presence of extracapsular extension of lymph node metastases, defined as perforation of the capsule by tumor tissue with extranodal growth (Fig 2). Histopathologically, extranodal extension must be differentiated from tumor deposits in the pericapsular lymphatics. In a few cases it was difficult to determine whether the metastasis was within the lymph node or had already invaded the perinodal adipose tissue. These difficult cases were very fatty metastatic lymph nodes and metastases with a strong desmoplastic stromal reaction involving the lymph node capsule. If extranodal growth was not obvious or impossible to determine, then these metastases were considered to be lymph node confined.
Statistical Analyses Kaplan-Meier plots were used to estimate the recurrence-free (data only available for 96 patients) and overall survival from surgery to the date of relapse and death, respectively, for the individual potential prognostic variables. Patients who were recurrence-free at the time of death and those still living were censored at the date of the last follow-up. Differences among the subgroups were assessed using the log-rank test. To identify independent prognostic factors in a multivariate analysis for recurrence-free survival, we used the Cox proportional hazards model. P values less than .05 were considered significant for all tests and taken as inclusion criteria for the multivariate model. The final analysis included the variables tumor stage (pT1/2 v pT3/4), percentage of positive nodes (< 20% v  20%), extracapsular extension of lymph node metastases or not, and fewer than five positive nodes or five. The selected cut points for dichotomization of number1,4 and percentage5,6 of positive nodes have been used in other studies. Statistical analyses were performed with the SPSS11 (SPSS Inc, Chicago, IL) software package.
Patient Characteristics and Outcome for the Entire Study Group The cohort comprised 14 women and 87 men (pT1/2, 18 patients; pT3, 53 patients; pT4, 30 patients). Thirty-two patients, including four with micrometastases (two with intrasinusoidal and two with parenchymal tumor deposits), had stage pN1 disease, and 69 patients had stage pN2 disease. The median age at surgery was 67 years (range, 35 to 89 years; mean, 66 years). Median follow-up was 21 months (range, 1 to 191 months). A median of 22 lymph nodes (range, 10 to 43 nodes; mean, 23 nodes; Fig 3) were found in each patient.
Median recurrence-free and overall survival durations for the entire cohort were 17 months and 21 months (range for both, 1 to 191 months), respectively (Fig 4). Seventy-three patients died. Sixty deaths were due to disseminated recurrent disease occurring at a median time of 8 months after operation (range, 1 to 59 months) and a median time to death of 14 months (range, 1 to 122 months). The remaining 13 patients died without a known recurrence and a median time to death of 12 months (range, 2 to 191 months). Twenty-eight patients survived, 24 without evidence of recurrent disease after a median follow-up of 76 months (range, 24 to 179 months); the other four patients presented with local or distant failure between 9 and 63 months after surgery.
Univariate Analysis of Recurrence-Free and Overall Survival Univariate analyses were performed for the following potential risk factors: tumor stage, pN stage (pN1 v pN2), number of positive nodes (< five v five), percentage of positive nodes (< 20% v 20%), the involved side (unilateral v bilateral positive nodes), with or without extracapsular extension of lymph node metastases, with or without adjuvant chemotherapy (results listed in Table 1), and number of examined nodes analyzed in quartiles (Figs 5 through 12).
The impact of the number of nodes found on survival was estimated by grouping the patients in quartiles: quartile 1, 24 patients with 10 to 17 nodes; quartile 2, 21 patients with 18 to 21 nodes; quartile 3, 27 patients with 22 to 28 nodes; and quartile 4, 29 patients with 29 to 43 nodes. There were no significant differences in recurrence-free (P = .81) and overall survival (P = .66) between the four groups (Fig 10). Patients with or without local recurrence showed no significant differences in the number of lymph nodes examined (P = .207).
Extracapsular extension of lymph node metastases was observed in 59 patients (58%). It defined a subgroup of patients with a significantly decreased recurrence-free (P = .0003) and overall survival (P < .0001) compared with those without such extension (Fig 11). The relevance of this feature in the nodal categories pN1 and pN2 is shown in Fig 12. The outcome was better for patients without extracapsular extension in both categories. There were no significant differences between the pN1 and pN2 categories without extracapsular extension (recurrence-free survival, P = .47; overall survival, P = .34) and between these two categories with extracapsular extension (recurrence-free survival, P = .70; overall survival, P = .65).
Adjuvant chemotherapy was given to 41 patients (median age, 61 years). No significant difference was found in recurrence-free survival (P = .092) between these and the 60 patients (median age, 70 years) without such therapy. There was, however, a significant advantage for these younger patients with chemotherapy in overall survival (P = .0012).
Multivariate Analysis
The clinical outcome in patients with node-positive bladder cancer treated with radical cystectomy and extended bilateral lymphadenectomy varies considerably. During the last years, several risk factors such as tumor and lymph node stages, number and density of positive nodes, and number of examined nodes have been evaluated as a means of stratifying these patients in terms of survival. Our analysis tested known and new prognostic variables in a homogenous population of patients with pelvic lymph node–positive urothelial carcinoma of the bladder treated according to a standard surgical protocol. Many of the results in our study are compatible with those of other series. We found significantly different survival probabilities in the univariate analysis for the stages pT1/2, pT3, and pT4. Previous studies in node-positive bladder cancer only analyzed the two subgroups of organ-confined and non–organ-confined primary tumors4,5,7 and found significant differences in outcome. Our results confirm the usefulness of the contemporary tumor stages also for patients with positive pelvic lymph nodes and the need to divide the group of patients with non–organ-confined primary tumors into those with pT3 and those with pT4 disease for prognostic analysis. The data in the literature concerning the prognostic relevance of pN stages are conflicting and difficult to compare, because the definition of the pN stages has changed over time, and different landmark times were often used for the Kaplan-Meier plots. We could not detect significant differences in recurrence-free and overall survival between the subgroups pN1 and pN2 in our cohort. This was also true for long-term survival in the studies of Vieweg et al7 and Roehrborn et al.8 Herr et al6 found no independent influence of stage pN1 versus pN2 versus pN3 in multivariate analyses for survival and local recurrences. However, in a larger series by Vieweg et al,9 significant differences existed for disease-specific survival between patients with pN1, pN2, and pN3 disease. Whether this also held for pN1 and pN2 alone was not evaluated in this series. Several studies have shown that the absolute number of positive nodes as an expression of tumor burden affects survival. The cutoff levels were set at five, six, and eight positive nodes, respectively. All studies showed a significantly better outcome for patients in the subgroups with fewer involved lymph nodes.4,5,10 Our result in the univariate analysis confirmed these findings. In contrast to the findings of Stein et al,5 the number of positive nodes was not an independent prognostic factor in the multivariate analysis of our cohort.
The density of lymph node metastases has been proposed to be an important prognosticator of survival and local tumor control.5,6 It is defined as the ratio of positive nodes to total nodes examined in percentage. This concept was created to reflect tumor burden (absolute number of positive nodes) in relation to the extent and quality of lymph node dissection (total number of lymph nodes). However, there are physiological differences in the total number of pelvic lymph nodes among individuals.11 Therefore the density of lymph node metastases is not only a function of tumor burden and extent or quality of lymph node dissection but also of the natural variation in the total number of pelvic nodes present. Furthermore, there is no evidence that this variation impacts on outcome. For these reasons the current concept of lymph node density or its utility may be questioned. However, in our series, density of lymph node metastases (< 20% v The number of lymph nodes examined is a result of the surgical approach, physiological variation, and the pathologist's performance and has been shown to have an important impact on survival, even in lymph node-negative tumors of different anatomic sites. The more nodes examined the better the outcome.12–14 This can be explained by providing a more accurate staging or a more complete lymph node dissection with removal of histologically undetected micrometastases. For patients with histologically confirmed lymph node metastases, the data are conflicting. Although Leissner et al15 and Herr et al14 found an effect of the number of nodes examined on survival, Stein et al5 could not confirm these findings. With a mean of 23 pelvic lymph nodes found per patient, we are in the range of pelvic nodes retrieved in an autopsy study with the same boundaries of lymphadenectomy. Weingartner et al11 recovered an average of 22.7 nodes per patient and recommend 20 nodes found as a normal value. By grouping the patients in quartiles by the number of nodes examined, we could not demonstrate any significant differences in recurrence-free and overall survival. This suggests that a consistent radical dissection of pelvic lymphatic tissues with equal accuracy and extent of dissection in each group leads to equal outcomes irrespective of the number of nodes removed. The absence of interquartile differences might even serve as a parameter for quality assessment in pelvic lymphadenectomy. The range in the number of lymph nodes found is primarily explained by the physiological variation in lymph node quantity.11 That the number of lymph nodes examined had a significant impact on local tumor control and survival in Herr's14 series might be due to the fact that not all patients underwent the same extent of dissection. Leissner et al15 detected a survival benefit for the subgroup of patients with a minimum of 16 nodes examined compared with those with fewer than 16 nodes in the cohort of patients with five or fewer positive nodes. This phenomenon may well be explained by a heterogeneous population with differences in the extent of lymphadenectomy. In sum, these results support the notion that lymphadenectomy is not only a staging procedure but is also of potential therapeutic value. The most important finding in this present study was the identification of extracapsular extension of lymph node metastases as an independent prognostic factor for recurrence-free survival in node-positive urothelial carcinoma of the bladder. Although extracapsular extension of nodal metastases is already an established prognostic factor for carcinomas in many different anatomic sites,16–22 including the prostate23 and the penis,24 the prognostic significance of this feature for bladder cancer has only been reported in an earlier study from our institution.1 Extracapsular extension of nodal metastases was detected in 58% of our patients and more than doubled the risk of recurrence as compared with patients without extracapsular extension. In this cohort, it defined a nodal category with a significantly worse outcome and was more discriminatory than the current nodal staging system. These findings might even make modifications of the current bladder cancer staging system necessary. They might provide for a better prediction of patient outcome and therefore should be consistently reported together with additional nodal prognostic parameters, such as localization in case of micrometastasis. In conclusion, the results of this and other studies5,9 indicate that radical cystectomy with bilateral lymphadenectomy can have a curative effect in a subset of patients with lymph node-positive carcinoma of the bladder. Multivariate analysis for recurrence-free survival of different prognostic factors revealed extracapsular extension of lymph node metastases as an independent risk factor. In this cohort, this feature made an important prognostic stratification possible that could not be achieved with the contemporary pN staging system or other prognostic factors regarding lymph node status. The number of nodes examined per patient has probably no influence on survival in node-positive disease, provided that a meticulous lymphadenectomy is performed.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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4. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666-675, 2001 5. Stein JP, Cai J, Groshen S, et al: Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: Concept of lymph node density. J Urol 170:35-41, 2003[CrossRef][Medline] 6. Herr HW: Superiority of ratio based lymph node staging for bladder cancer. J Urol 169:943-945, 2003[CrossRef][Medline] 7. Vieweg J, Whitmore WF Jr, Herr HW, et al: The role of pelvic lymphadenectomy and radical cystectomy for lymph node positive bladder cancer: The Memorial Sloan-Kettering Cancer Center experience. Cancer 73:3020-3028, 1994[CrossRef][Medline] 8. Roehrborn CG, Sagalowsky AI, Peters PC: Long-term patient survival after cystectomy for regional metastatic transitional cell carcinoma of the bladder. J Urol 146:36-39, 1991[Medline] 9. Vieweg J, Gschwend JE, Herr HW, et al: Pelvic lymph node dissection can be curative in patients with node positive bladder cancer. J Urol 161:449-454, 1999[CrossRef][Medline] 10. Lerner SP, Skinner DG, Lieskovsky G, et al: The rationale for en bloc pelvic lymph node dissection for bladder cancer patients with nodal metastases: Long-term results. J Urol 149:758-764, 1993[Medline] 11. Weingartner K, Ramaswamy A, Bittinger A, et al: Anatomical basis for pelvic lymphadenectomy in prostate cancer: Results of an autopsy study and implications for the clinic. J Urol 156:1969-1971, 1996[CrossRef][Medline] 12. Sosa JA, Diener-West M, Gusev Y, et al: Association between extent of axillary lymph node dissection and survival in patients with stage I breast cancer. Ann Surg Oncol 5:140-149, 1998[CrossRef][Medline]
13. Tepper JE, O'Connell MJ, Niedzwiecki D, et al: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19:157-163, 2001 14. Herr HW, 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 167:1295-1298, 2002[CrossRef][Medline] 15. Leissner J, Hohenfellner R, Thuroff JW, et al: Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder: Significance for staging and prognosis. BJU Int 85:817-823, 2000[CrossRef][Medline] 16. Cascinelli N, Greco M, Bufalino R, et al: Prognosis of breast cancer with axillary node metastases after surgical treatment only. Eur J Cancer Clin Oncol 23:795-799, 1987[Medline] 17. Di Giorgio A, Botti C, Sammartino P, et al: Extracapsular lymphnode metastases in the staging and prognosis of gastric cancer. Int Surg 76:218-221, 1991[Medline] 18. Alvi A, Johnson JT: Extracapsular spread in the clinically negative neck (N0): implications and outcome. Otolaryngol Head Neck Surg 114:65-70, 1996[CrossRef][Medline] 19. Yamashita H, Noguchi S, Murakami N, et al: Extracapsular invasion of lymph node metastasis is an indicator of distant metastasis and poor prognosis in patients with thyroid papillary carcinoma. Cancer 80:2268-2272, 1997[CrossRef][Medline] 20. Woolgar JA, Rogers S, West CR, et al: Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol 35:257-265, 1999[CrossRef][Medline] 21. Komuta K, Okudaira S, Haraguchi M, et al: Identification of extracapsular invasion of the metastatic lymph nodes as a useful prognostic sign in patients with resectable colorectal cancer. Dis Colon Rectum 44:1838-1844, 2001[Medline] 22. Myers JN, Greenberg JS, Mo V, et al: Extracapsular spread: A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer 92:3030-3036, 2001[CrossRef][Medline] 23. Griebling TL, Ozkutlu D, See WA, et al: Prognostic implications of extracapsular extension of lymph node metastases in prostate cancer. Mod Pathol 10:804-809, 1997[Medline] 24. Srinivas V, Morse MJ, Herr HW, et al: Penile cancer: Relation of extent of nodal metastasis to survival. J Urol 137:880-882, 1987[Medline] Submitted March 11, 2004; accepted December 30, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
