The Prognostic Significance of Metastatic Perivesical Lymph Nodes Identified in Radical Cystectomy Specimens for Transitional Cell Carcinoma of the Bladder

0022-5347/03/1706-2253/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 170, 2253–2257, December 2003 Printed in U.S.A.

DOI: 10.1097/01.ju.0000095804.33714.ea

THE PROGNOSTIC SIGNIFICANCE OF METASTATIC PERIVESICAL LYMPH NODES IDENTIFIED IN RADICAL CYSTECTOMY SPECIMENS FOR TRANSITIONAL CELL CARCINOMA OF THE BLADDER ANTHONY J. BELLA, LARRY W. STITT, JOSEPH L. CHIN

AND

JONATHAN I. IZAWA*,†

From the Departments of Surgery and Oncology (AJB, JLC, JII), Division of Urology and Clinical Research Unit (LWS), London Regional Cancer Centre, University of Western Ontario, London, Ontario, Canada

ABSTRACT

Purpose: We determined the prognostic significance of metastatic perivesical lymph nodes (PVLN) in transitional cell carcinoma of the bladder (TCC). Materials and Methods: A retrospective review of 198 consecutive patients who underwent radical cystectomy for clinically organ confined TCC identified 32 patients with PVLN in pathology specimens. Patient characteristics were compared. Overall survival, disease-specific survival (DSS) and disease-free survival were estimated using Kaplan-Meier actuarial methodology. The log-rank test was used to compare the differences between patients with and without metastatic TCC to PVLN. Cox multivariate regression analysis was used to determine whether the effect of metastatic PVLN on survival was independent of pathological stage. Results: Metastatic TCC was found in the PVLN of 14 patients. Median followup and age were 13.5 months and 66.5 years, respectively. Patients with and without metastatic PVLN had similar characteristics and pathological disease staging. The overall survival, DSS and diseasefree survival were significantly less for patients with metastatic TCC in PVLN (p ⫽ 0.002, p ⫽ 0.013 and p ⬍0.001, respectively), and involvement of PVLN and pelvic nodes (p ⫽ 0.001, p ⫽ 0.010 and p ⫽ 0.041, respectively). Metastatic PVLN was an independent predictor of OS and DSS (p ⫽ 0.016 and p ⫽ 0.025, respectively). Conclusions: Metastases to PVLN appear to confer a significantly worse prognosis for patients undergoing radical cystectomy. Patients with identifiable metastatic PVLN may benefit from early adjuvant therapies. KEY WORDS: bladder neoplasms, cystectomy, neoplasm metastasis, lymph nodes, survival

Prognostic factors in transitional cell carcinoma of the bladder (TCC) after radical cystectomy and pelvic lymphadenectomy include pathological stage of the primary tumor and histological status of excised regional lymph nodes.1– 4 Patients with pathologically confined primary tumors in the radical cystectomy specimen and metastases to the excised pelvic lymph nodes can obtain a survival benefit from radical surgery.1, 2, 5–10 Indeed, a select group of patients with grossly positive pelvic node metastases from TCC have survived 10 years after radical cystectomy and extended pelvic lymph node dissection.8, 10 Perivesical lymph nodes (PVLN) are located in the perivesical fat. The prognostic significance of metastatic PVLN in TCC is not definitively known. To our knowledge there are no published reports in the current literature pertaining to the impact of metastatic PVLN in the radical cystectomy specimen on disease recurrence and patient survival. Despite resection, the identification of metastases to PVLN may confer a worse prognosis for patients undergoing radical cystectomy. To test this hypothesis we retrospectively reviewed data on 198 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for TCC at our institution. Our objectives were to evaluate the frequency of

identified PVLN in radical cystectomy specimens and the prognostic importance of metastatic PVLN in patients with TCC. MATERIALS AND METHODS

Between January 1990 and March 2001 a total of 198 patients were identified who underwent radical cystectomy and pelvic lymphadenectomy for clinically organ confined TCC at the London Health Sciences Center. All patients had chest roentgenography, computerized tomography of the abdomen and pelvis, and certain patients had bone scans for disease staging purposes. There was no evidence of metastatic disease on physical examination or staging studies. All operations were performed by 2 surgeons (JLC and JII), and consisted of radical cystectomy, pelvic lymphadenectomy and various urinary diversions. A review of surgical pathology reports yielded 32 patients with PVLN identified in the pathology specimen. Of these patients 29 had TCC and 3 had squamous cell carcinoma of the bladder. These particular patients all underwent radical cystectomy, urinary diversion and pelvic lymphadenectomy whereby the obturator, internal iliac and external iliac lymph nodes were excised up to the common iliac chain. There was no attempt to incorporate the internal iliac nodes with the cystectomy specimen en bloc. Medical records, including those from the primary care physician, were reviewed to obtain complete followup information on each patient. Clinical parameters studied included age at time of surgery, sex, histopathology (primary tumor, PVLN and pelvic lymph nodes), pathological stage of disease, site and time of disease recurrence, and date and cause of death. Patients were con-

Accepted for publication June 13, 2003. Supported by Scholarship Grant R3255A01 from the Canadian Urological Association. * Requests for reprints: The London Health Sciences CentreWestminster Campus, Department of Surgery, Division of Urology, 800 Commissioners Rd. East, Suite 3250, London, Ontario, Canada N6A 4G5 (telephone: 519-685-8550; FAX: 519-685-8455; e-mail: [email protected]). † Recipient of Grant R02019 from the Northeastern Section of the American Urological Association. 2253

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sidered to have disease recurrence by physical examination, histological confirmation or radiological evidence of metastatic disease as determined by chest roentgenogram, bone scan or computerized tomography. Data were analyzed with SAS version 8.2 (SAS Institute Inc., Cary, North Carolina, 1999), a commercially available statistical software package. Patients with positive and negative PVLN were compared with respect to age at time of surgery using Student’s t-test, disease stage (pTa-pT2b vs pT3a-pT3b vs pT4) using Fisher’s exact test and gender using the chi-square test. Overall survival (OS), disease-free survival (DFS) and disease specific survival (DSS) were estimated using the Kaplan-Meier actuarial methodology. The log rank test was used to compare survival between positive and negative PVLN groups. Only patients with TCC were evaluated. We compared patients with negative vs metastatic PVLN. We also evaluated patients with concurrent positive pelvic lymph nodes and PVLN to determine if metastases to PVLN added any further prognostic information. Cox regression analysis was used to determine whether metastatic disease to PVLN was an independent predictor of disease recurrence or survival. A value of p ⬍0.05 was considered statistically significant.

TABLE 2. Statistical analysis of age and pathological stage of transitional cell carcinoma of the bladder and perivesical lymph nodes

Median age No. group 1 (pTa-pT2b) No. group 2 (pT3a-pT3b) No. group 3 (pT4)

Metastatic TCC to PVLN

Neg PVLN

p Value

69.0 2 4 4

62.0 4 8 1

0.35 1.0 0.90 0.15

TABLE 3. Pattern of recurrence Local Distant Local ⫹ distant

No. Metastatic TCC to PVLN

No. Neg PVLN

2 5 2

2 3 1

RESULTS

Patient characteristics. We identified 32 patients with PVLN. A total of 14 patients had metastatic TCC to PVLN, with 10 identified with metastatic TCC to PVLN without pelvic lymph node metastases. Patient characteristics are shown in table 1. Patients were divided into 3 groups (pTapT2b, pT3a-pT3b and pT4 as groups 1, 2 and 3, respectively). There were no statistically significant differences observed among groups (table 2). Of 23 patients 16 died, with 11 dying secondary to metastatic TCC. Distant metastatic disease was identified in 7 of 10 patients with positive PVLN (table 3). We identified 4 patients with concurrent TCC metastases to PVLN and pelvic nodes, 2 each with pT3b and pT4a disease. Two patients with metastatic TCC to pelvic lymph nodes without perivesical lymph node involvement were identified and both had pT3b disease. Cisplatin based systemic chemotherapy was administered to 16 patients. All but 1 of the 6 patients with metastatic pelvic lymph nodes, 2 patients with locally advanced TCC without metastases and 2 patients who had locally advanced TCC with metastatic PVLN received immediate adjuvant chemotherapy. Of the 16, 7 patients received chemotherapy when a metastatic recurrence was identified, and included 5 patients without metastases identified in the surgical specimen and 2 who had metastatic PVLN only identified in the surgical specimen. One patient with metastatic PVLN only in the surgical specimen received neoadjuvant chemotherapy for locally advanced TCC. Overall survival. Figure 1 shows a significant difference in

TABLE 1. Clinical characteristics of patients and pathological stage of transitional cell carcinoma of the bladder and perivesical lymph nodes No. males No. females Median age No. stage: pTa pT1 pT2a pT2b pT3a pT3b pT4

Metastatic TCC to PVLN

Neg PVLN

7 3 69.0

11 2 61.5

0 1 0 1 0 4 4

1 0 1 2 1 7 1

FIG. 1. Overall survival after radical cystectomy and pelvic lymphadenectomy comparing patients with metastatic transitional cell carcinoma of bladder to perivesical lymph nodes versus patients with negative PVLN.

OS after radical cystectomy and pelvic lymphadenectomy between patients with metastatic TCC to PVLN and patients with negative PVLN (p ⫽ 0.002). All but 1 patient with TCC in PVLN died within 14 months of followup with a median survival of 6 months (range 2 to 39). There was also a statistically significant difference in OS observed between patients with metastatic TCC to pelvic nodes stratified for the presence or absence of metastases to PVLN (p ⫽ 0.001, fig. 2). Disease-free survival. There was a significant difference in DFS between patients with metastatic TCC to PVLN vs patients with negative PVLN (p ⬍0.001, fig. 3). The presence of metastatic TCC to PVLN conferred greater risk of disease recurrence with median DFS of patients with metastatic TCC to PVLN of 5.5 months (range 1 to 39) vs median DFS of 11.5 months (range 1 to 52) for patients without PVLN metastases. All but 1 patient with metastatic TCC to PVLN had disease recurrence by 12 months. A statistically significant difference in DFS was also observed when patients with metastatic TCC to pelvic nodes were included in this group (p ⫽ 0.023, fig. 4). Disease specific survival. A significant DSS benefit in patients with negative PVLN vs patients with metastatic TCC to PVLN was also demonstrated (p ⫽ 0.013, fig. 5). Of the 11 (64%) patients 7 with metastatic TCC to PVLN died secondary to TCC. The additional patient with metastatic TCC to pelvic nodes also presented with a significant difference in DSS observed (p ⫽ 0.010, fig. 6).

PROGNOSTIC IMPACT OF METASTATIC PERIVESICAL LYMPH NODES IN BLADDER CANCER

FIG. 2. Overall survival after radical cystectomy and pelvic lymphadenectomy in patients with pelvic node metastases and presence or absence of metastases to perivesical lymph nodes.

FIG. 3. Disease-free survival after radical cystectomy and pelvic lymphadectomy comparing patients with metastatic transitional cell carcinoma of bladder to perivesical lymph nodes versus patients with negative PVLN.

Cox multivariate regression. Multivariate analysis was performed to determine whether the presence of metastatic TCC to PVLN predicted a statistically significant survival disadvantage independent of pathological stage. This relationship was observed for OS (p ⫽ 0.016) and DSS (p ⫽ 0.025). However, PVLN metastases were not shown to predict patient DFS independently (p ⫽ 0.098). DISCUSSION

We evaluated the effect of metastatic TCC to PVLN on OS, DFS and DSS after radical cystectomy, pelvic lymphadenectomy and urinary diversion for clinically organ confined TCC. Prior studies have shown that the incidence of positive pelvic lymph nodes in a similar patient population approaches 20%.4, 6, 7, 11 However, we could not identify any published data which analyzed the impact that metastatic PVLN may have on prognosis. PVLN were identified in 32 of 198 (16.1%) pathology spec-

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FIG. 4. Disease-free survival after radical cystectomy and pelvic lymphadenectomy comparing patients with metastatic transitional cell carcinoma of bladder to pelvic lymph nodes and presence or absence of metastases to perivesical lymph nodes.

FIG. 5. Disease specific survival after radical cystectomy and pelvic lymphadenectomy for patients with metastatic transitional cell carcinoma of bladder to perivesical lymph nodes versus patients with negative PVLN.

imens studied by a variety of pathologists. Although autopsy studies have shown that 25% to 33% of patients dying of bladder cancer do not have pelvic lymph node metastases,12 optimizing pathological evaluation and identifying PVLN in radical cystectomy specimens may identify patients with previously unidentified metastases. Previous studies show the most common sites of TCC metastases are the obturator and external iliac nodal groups, with PVLN metastases identified in 16% of patients with regional lymph node involvement.13 In this series 10 (5.1%) patients were identified with metastatic TCC confined solely to PVLN by conventional histology. Our data suggest that the prognosis is worse if there are metastases to PVLN. Therefore, these patients may benefit from early adjuvant therapy, and it may be beneficial to identify techniques which increase the ability to identify metastatic PVLN in gross specimens missed by palpation and sectioning.

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from 17% to 50% within the first 3 to 5 years after radical cystectomy. In the current study distant metastatic progression and death secondary to muscle invasive TCC was seen in 7 of 10 patients with clinically organ confined disease, positive PVLN and negative pelvic nodes. Given the poor prognosis for these patients systemic adjuvant chemotherapy may be beneficial. Inherent weaknesses of this retrospective study include the small sample size and the possibility of selection bias influencing outcome. The results will hopefully stimulate further study to determine the prognostic importance of metastatic PVLN in patients with bladder cancer and to stratify patients who may benefit from adjuvant therapies. CONCLUSIONS

Based on our study metastatic TCC to PVLN appears to confer a significantly worse prognosis for patients undergoing radical cystectomy. Patients with identifiable metastases to PVLN may benefit from early adjuvant therapies in an attempt to decrease the probability of disease relapse and to improve survival. FIG. 6. Disease specific survival after radical cystectomy and pelvic lymphadenectomy comparing patients with metastatic transitional cell carcinoma of bladder to pelvic lymph nodes and presence or absence of metastases to perivesical lymph nodes.

Nonpalpable PVLN in perivesical fat may be identified using molecular approaches such as reverse transcription polymerase chain reaction for markers specific for urothelial tissue such as the uroplakin II gene, identifying patients who may harbor residual disease not appreciated by conventional histology.14 A novel technique using lymph node revealing solution (95% ethanol, diethyl ether, glacial acetic acid and buffered formalin), identifies nodes as white, chalky nodules against the background of yellow fat. This technique has been shown to enhance the yield of identifying normal and metastatic lymph nodes in radical cystectomy specimens. This technique allows for the identification of smaller lymph nodes and for more accurate disease staging.15 The role of sentinel lymph nodes in bladder cancer continues to be defined. Early studies using lymphoscintigraphy and dye marker techniques have shown that sentinel lymph nodes are often located outside the obturator lymphatic field and include metastases isolated to PVLN.16 The presence of metastatic TCC to PVLN appeared to confer a significantly worse prognosis in this series with respect to OS, DFS and DSS. Multivariable analysis determined metastatic TCC to PVLN independently confers a significant disadvantage in terms of OS and DSS. Metastatic PVLN did not independently predict DFS, and this finding might have been secondary to the small sample size and short overall survival in this cohort, and to the rapid recurrence rate regardless of PVLN status. These patients had advanced pathological stage disease, and although DFS was not independently predicted by metastatic PVLN, the burden of metastatic disease was greater with positive PVLN to impact OS and DSS independently, but not the time of recurrence alone. Ratio based lymph node disease staging may provide further prognostic information.17 We were unable to analyze ratio based lymph node staging in this study due to a lack of documented numbers of pelvic lymph nodes in several pathological reports. The finding of metastatic PVLN predicting survival outcomes may also be related to ratio based lymph node staging. Prolonged progression-free survival for patients suffering from locally advanced bladder cancer through adjuvant systemic chemotherapy has been suggested by 3 randomized studies since 1991.18 –20 Patients most likely to benefit from adjuvant chemotherapy include those with limited lymph node positive disease, demonstrating a DFS benefit ranging

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