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Keywords:

  • bladder cancer;
  • extracapsular extension;
  • lymph node metastasis;
  • cystectomy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Previous reports have suggested that extracapsular extension (ECE) is a prognostic factor in patients with urothelial carcinoma who have positive lymph nodes at the time of radical cystectomy. In the current study, the relevance of ECE in patients treated in the contemporary era was evaluated.

METHODS.

A database search from 1993 to 2003 revealed 150 patients with pN+M0 disease detected after radical cystectomy; of these, 108 patients did not receive neoadjuvant chemotherapy and form the basis of the current report. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) data were analyzed by the Kaplan-Meier method, with log-rank tests used to evaluate associations between survival and variables studied.

RESULTS.

Five-year OS, DSS, and RFS rates were 30.9%, 45.5%, and 29.7%, respectively. Adjuvant chemotherapy was administered to 70% of patients. On multivariate analysis, adjuvant chemotherapy was significantly associated with prolonged OS, DSS, and RFS (P ≤ .01). For patients overall and when stratified by pN status, the presence of ECE of lymph node metastasis was not found to be significantly associated with OS (P = .52), DSS (P = .43), or RFS (P = .83).

CONCLUSIONS.

The current study suggests that ECE is not an independent prognostic factor in a contemporary series of patients with positive lymph nodes at radical cystectomy. This might be reflective of a paradigm shift that encompasses the adoption of multimodal therapy. Cancer 2006. © 2006 American Cancer Society.

Radical cystectomy and pelvic lymph node dissection (PLND) remains the mainstay therapy for muscle-invasive urothelial carcinoma (UC) of the bladder. Patients with lymph node involvement have a significantly worse prognosis.1–3 Whether lymph node metastasis in patients with UC of the bladder reflects systemic versus locally advanced disease is somewhat controversial. It is interesting to note that 3 recent reports from a single center (the University of Bern, Switzerland) have suggested that extracapsular extension (ECE) is an independent prognostic factor in patients with lymph node disease at time of cystectomy.4–6 Because this has a potentially significant impact on patient care, we sought to evaluate its relevance in a contemporary series of patients treated with radical cystectomy at our institution.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

We performed a search of our bladder cancer database after approval from the Institutional Review Board. The recent period of 1993–2003 was chosen to provide a contemporary series with regard to chemotherapy regimens and surgical techniques as well as providing adequate follow-up. During that period, 150 of 857 patients who underwent radical cystectomy for UC of the bladder at the M. D. Anderson Cancer Center were found to have lymph node metastasis in the surgical specimen. Metastatic work-up consisted of routine blood tests, chest X-ray, computerized tomography (CT) of the abdomen and pelvis, and bone scan. All patients were classified as having clinical N0M0 disease and underwent a radical cystectomy with PLND and urinary diversion. Of 150 patients with lymph node metastasis at cystectomy, 108 did not receive preoperative chemotherapy and form the basis of this report. The majority of patients (76 of 108 patients; 70%) received adjuvant chemotherapy; the majority of these (71 of 76 patients; 93%) were platinum-based regimens. At intervals of 3 to 6 months, the follow-up included blood tests, chest X-rays, CT of the abdomen and pelvis, and bone scans (if indicated) to assess the status of disease. Retrieved data points from the medical charts and pathology reports included age, sex, clinical stage, histology, lymphovascular invasion, type of urinary diversion, pathologic stage, lymph node density (ratio of lymph nodes involved to lymph nodes removed), presence of ECE, presence of carcinoma in situ, surgical margin status, and adjuvant chemotherapy. ECE was defined as tumor that extends beyond the capsule of the lymph node and into perinodal adipose tissue. The presence of ECE is routinely searched for and reported by our team of dedicated genitourinary pathologists.

Survival data were analyzed using the Kaplan-Meier method, with log-rank tests used to evaluate associations between survival and the variables studied. Cox proportional hazards regression was used to model survival outcomes as a function of potential prognostic factors in a univariate fashion, and hazard ratios (HRs) were estimated with 95% confidence intervals. All potential prognostic factors with a P-value <.25 from the univariate analysis were then included in a saturated multivariate model and backward elimination was used to remove factors from the model based on the likelihood ratio test in the multiple regression analysis. A P-value <.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Overall

Of the 108 patients, 92 were male and 16 were female. The median age of patients was 69 years (range, 45–85 years) with a median follow-up duration of 41.7 months for survivors. The clinical stage distribution was cT1 in 10 patients, cT2 in 78 patients, cT3b in 12 patients, and cT4a in 8 patients. Concomitant carcinoma in situ (CIS) was present in 37 patients (34%) and lymphovascular invasion was found in 58 patients (54%). Kaplan-Meier estimates of the 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) rates were 30.9%, 45.5%, and 29.7%, respectively. The median OS, DSS, and RFS survival durations were 32.8 months, 56.4 months, and 21.1 months, respectively (Fig. 1). Clinical parameters including age, clinical stage, the presence of lymphovascular invasion, and concomitant CIS were not found to be significantly associated with OS, DSS, or RFS.

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Figure 1. Kaplan-Meier estimate of overall survival (OS), recurrence-free survival (RFS), and disease-specific survival (DSS) for all patients with positive lymph nodes in the cystectomy specimen.

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Stratification by Pathological Characteristics

The pathologic T-stage distribution at cystectomy was pT0 in 3 patients, pTa in 1 patient, pT1 in 3 patients, pT2 in 14 patients, pT3 in 53 patients, and pT4 in 34 patients (Table 1). Forty-five patients (41.6%) had recurrence of disease at the time of last follow-up (10 had pelvic recurrence, 22 had distant disease, and 13 had both). The results of tests for associations of variables with survival in multivariate analysis are shown in Table 2. The median numbers of positive lymph nodes and total lymph nodes excised were 2 (range, 1–10 lymph nodes) and 12 (range, 1–58 lymph nodes), respectively. The number of positive lymph nodes was found to be significantly associated with RFS on univariate analysis (P = .04) and trended toward significance on multivariate analysis (P = .06), whereas the total number of lymph nodes was not found to be significantly associated with OS or RFS. In concert with previous reports, lymph node density was found to be significantly associated with RFS (P = .047) on multivariate analysis and trended toward significance as a prognostic variable for OS (P = .06); similarly, primary organ-confined disease (≤pT2) was found to be significantly associated with prolonged DSS compared with primary nonorgan-confined disease (>pT2) (HR 4.9, P = .01).

Table 1. Characteristics of Patients with Lymph Node Metastasis at Cystectomy
 No. of patients (%)
  • *

    Unable to determine pN status due to missing information.

No. of patients108
Median age, y69 (range, 45-85)
Sex
Male92 (85)
Female16 (15)
Pathologic stage
≤T17 (6)
T214 (13)
T353 (50)
T434 (31)
Pathologic lymph node status
pN125 (23)
pN238 (35)
pN323 (22)
Unknown*22 (20)
Extracapsular extension44 (41)
Positive surgical margins11 (10)
Adjuvant chemotherapy76 (70)
Table 2. Multivariate Analysis of Variables That Predict Overall Survival, Disease-Specific Survival, and Recurrence-Free Survival
 OSDSSRFS
  1. OS indicates overall survival; DSS, disease-specific survival; RFS, recurrence-free survival; NS, not significant (P > .05).

AgeNSNSNS
Clinical stageNSNSNS
Pathologic stageNS.01NS
Extracapsular extensionNSNSNS
No. of positive lymph nodesNSNS.06
Lymph node densityNSNS.047
Surgical margin statusNSNSNS
Adjuvant chemotherapy<.01.01<.01

ECE of the involved lymph nodes was present in 41% of the patients. ECE of involved lymph nodes was not found to be significantly associated with OS (P = .52), DSS (P = .43), or RFS (P = .82) (Fig. 2A-C). Kaplan-Meier curves for those patients who had ECE of lymph node metastasis showed 5-year OS, DSS, and RFS rates of 33.8%, 45.0%, and 34.4% respectively, compared with 28.3%, 44.6%, and 26.9%, respectively for those patients without ECE. ECE failed to have a significant impact on survival even when patients were substratified by pN status or whether they received adjuvant chemotherapy (n = 76) or not (n = 32). Adjuvant chemotherapy was significantly associated with prolonged OS, DSS, and RFS on multivariate analysis (P ≤ .01). Even in patients with ECE, adjuvant chemotherapy remained significantly associated with prolonged OS (P = .02) and RFS (P < .01).

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Figure 2. Kaplan-Meier estimate of (A) overall survival (OS), (B) disease-specific survival (DSS), and (C) recurrence-free survival (RFS) stratified by the presence of extracapsular extension (ECE) in all patients.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In our study, the presence of ECE of lymph node metastasis in patients with bladder cancer was not found to be significantly associated with OS, DSS, or RFS.

In our contemporary series, 17.5% of patients had lymph node metastasis at the time of radical cystectomy, a finding that is consistent with other series in the literature that range from 14% to 32%.2, 6–10 Contemporary 5-year survival in patients with positive lymph nodes is in the range of 30% to 35%.2 We and others have shown that primary pathologic stage, tumor burden (number of positive lymph nodes), the extent of PLND (total number of lymph nodes excised), and lymph node density (number of positive lymph nodes/total number of lymph nodes removed) at cystectomy are independent prognostic variables in patients with UC of the bladder.11–15 The 5-year OS, DSS, and RFS rates of our series were 30.9%, 45.5%, and 29.7% respectively, which are similar to those of other published series.4, 12

ECE of lymph node metastasis has been shown to be prognostic in patients with malignancies of breast, gastrointestinal tract, prostate, and penis.16–19 To our knowledge, the only published reports on the significance of ECE in bladder cancer are from the University of Bern, Switzerland.4–6 They found that ECE was an independent prognostic factor for RFS in a retrospective analysis from 1985–2000 that included 101 patients with lymph node metastasis at time of radical cystectomy.4, 5 It is interesting to note that the use of adjuvant chemotherapy did not appear to have a significant influence on RFS in their patient population. In these reports, primary pathologic stage and lymph node density had a significant influence on OS and RFS in the univariate analysis but failed to be significant factors in the multivariate analysis.4 In contrast, in our series multivariate analysis showed that adjuvant chemotherapy in patients with pN+ disease significantly improved survival, and that lymph node density ≤25% and primary pathologic T classification were significant prognostic factors.

One possible explanation for the contradictory results is that the vast majority of our patients (70%) received adjuvant chemotherapy, compared with a minority (40%) in the Swiss series. Adjuvant chemotherapy may equate all patients with lymph node metastasis toward similar survival and dilute the prognostic significance of ECE, because even in the Swiss series patients who received adjuvant therapy had longer OS. However, in our series even those patients who did not receive adjuvant chemotherapy (n = 32) had no worse outcome with the presence of ECE. Another explanation might be the number of lymph nodes removed. Although the number of lymph nodes removed in the current study was comparable to other contemporary series,14 the previous report on ECE might have been affected by the fact that more lymph nodes were examined in that series. Lastly, the median OS in our series of patients with pN+ was longer than in the Swiss series (32.8 months vs. 21 months), which may also affect the results.

One of the strengths of our study is that we focused on a contemporary series to restrict variations due to surgical techniques and chemotherapy regimens. Furthermore, our patient population excluded all nonurothelial carcinoma to limit heterogeneity with regard to tumor biology. We do, however, acknowledge the limitations of reviewing a single-center experience and that it is impossible to definitively identify an optimal therapeutic strategy from a retrospective study. However, in our series even patients who did not receive adjuvant chemotherapy (n = 32) were not adversely affected by the presence of ECE. Any negative association study runs some risk that it is underpowered to detect a difference that may exist. However, our Kaplan and Meier curves consistently demonstrated a modest but appreciable difference favoring patients with ECE. Although this is not statistically significant, it offers some further assurance that ECE is not an adverse prognostic factor.

Conclusions

ECE was not found to be an independent prognostic factor in a contemporary series of patients treated with radical cystectomy and adjuvant chemotherapy.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES