SEARCH

SEARCH BY CITATION

Keywords:

  • bladder cancer;
  • lymphovascular invasion;
  • urothelial carcinoma;
  • survival

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

What's known on the subject? and What does the study add?

  • Lymphovascular invasion (LVI) is an important step in systemic cancer cell dissemination. LVI has been shown to be an independent predictor of disease recurrence and cancer-specific survival in urothelial carcinoma of the bladder (UCB) for patients with carcinoma invading bladder muscle.
  • Patients with final pathological stage T1N0 UCB who underwent radical cystectomy (RC) have not been separately analysed for influence of LVI on outcomes. Our study shows that LVI predicts disease recurrence and cancer-specific survival in patients with final stage T1 UCB after RC.

Objective

  • To determine the outcomes of patients with final pathological stage T1N0 disease after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) and to determine whether lymphovascular invasion (LVI) is an independent predictor of prognosis in these patients.

Patients and Methods

  • Records of 958 consecutive patients who underwent RC at three academic centres were reviewed.
  • A total of 101 patients with negative lymph nodes and with final stage (the higher of the pre-RC clinical/transurethral resection [TUR] and post-RC pathological stages) T1 UCB were identified.
  • The median (range) follow-up was 38 (0.4–177) months and the median (range) number of nodes examined was 19 (9–80).

Results

  • Overall, 12/101 (11.9%) patients experienced cancer recurrence and 7/101 (6.9%) died from their cancer. The 3-year recurrence-free survival probability (SD) was 0.89 (0.04) and 3-year cancer-specific survival probability (SD) was 0.96 (0.02).
  • Six of 101 (6%) patients had LVI, of whom four experienced disease recurrence and three died from bladder cancer.
  • All recurrences and deaths occurred in patients who had either LVI and/or concomitant carcinoma in situ.
  • On multivariable analysis, LVI (hazard ratio [HR] 4.9, P = 0.01) and higher pathological stage (HR 8.5, P = 0.04) predicted cancer recurrence and LVI (HR 6.7, P = 0.01) predicted cancer-specific survival.

Conclusions

  • LVI helps identify patients with final pathological T1N0 UCB who are at significantly increased risk of bladder cancer recurrence and death.
  • These patients should be considered for close monitoring after cystectomy.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

For patients with muscle-invasive urothelial carcinoma of the bladder (UCB) and those with high-risk non-muscle-invasive UCB, radical cystectomy (RC) with bilateral pelvic and iliac lymphadenectomy provides accurate staging and adequate local and regional control [1-6]. In contemporary series, the rate of pathological stage T1 (pT1) disease ranges from 14 to 25%. Up to 20% of patients with pT1 UCB at RC experience disease recurrence after surgery, despite negative lymph nodes [3]. At present, we are not able to determine accurately which pT1 patients will experience cancer progression after RC. Identification of these patients would allow selection of patients for closer monitoring after RC and also in selecting patients for earlier cystectomy and for neoadjuvant chemotherapy. We performed a multi-institutional review of patients with final T1N0 stage UCB to identify features and predictors that would help stratify these patients.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Patient Selection and Data Collection

All studies received institutional review board approval. A retrospective multi-institutional study (University of Texas Southwestern Medical Center, Baylor College of Medicine and Johns Hopkins University) was performed on 958 patients who underwent RC with bilateral lymphadenectomy for UCB between 1984 and 2003. A computerized databank was generated for data transfer. Before final analysis, the database was frozen and the final dataset was produced for the current analysis. A total of 101 patients with final pathological (the higher of the pre-RC clinical/transurethral resection (TUR) or the post-RC pathological stages) T1 UCB without nodal metastases (T1N0) were identified. None of the patients received neoadjuvant systemic chemotherapy or radiation therapy.

Pathological Evaluation

Pathological TUR, RC and lymphadenectomy specimens were processed according to institutional protocols. The 1997 TNM and WHO classifications were used for tissue staging and grading. Pelvic lymph node dissections were examined grossly, and lymphoid tissue was submitted for histological examination. Lymphovascular invasion (LVI) was defined as the presence of tumour cells within an endothelium-lined space without underlying muscular walls. Presence of a clear-cut endothelial lining was an important requirement because retraction space artifact is especially common in invasive UCB. Any equivocal foci and foci in which tumour cells merely encroached on a vascular lumen were considered negative. No attempt was made to differentiate between vascular and lymphatic vessels.

Follow-Up

Follow-up was performed according to institutional protocols. Patients generally were seen at least every 3–4 months for the first year after surgery, semi-annually for the second year, and annually thereafter. Follow-up visits consisted of a physical examination and serum chemistry evaluation, including liver function tests and alkaline phosphatase. Diagnostic imaging of the upper tracts and chest radiography were performed at least annually or when clinically indicated. Detection of cancer in the ureter and/or urethra was coded as a second (metachronous) primary and not as local or distant recurrence. When patients died, the cause of death was determined by the treating physicians, by chart review corroborated by death certificates, or by death certificates alone. Patients who were identified as having died from UCB had progressive, disseminated, and often symptomatic metastases at the time of death. Perioperative mortality (death within 30 days of surgery) was censored at time of death for bladder-cancer-specific survival analyses.

Statistical Analysis

The Kaplan–Meier method was used to calculate survival functions, and differences were assessed with the log-rank statistic. Univariable and multivariable survival analyses were performed using the Cox proportional hazard regression model. A P value ≤0.05 was considered to indicate statistical significance. All reported P values are two-sided. Analyses were performed with SAS version 9.2 (SAS Institute Inc., Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Clinical and Pathological Characteristics in Patients with T1N0 Disease

Clinical and pathological characteristics are listed in Table 2. Of the 958 patients, 101 (10.5%) had lymph-node-negative pathological (the higher of pre-cystectomy clinical or post-cystectomy pathological stage) T1 stage (Table  1). The cohort comprised 91 patients who had T1 stage on TUR before RC. Of these, 47 had pT1 stage at RC and 44 had <T1 stage (T0, n = 17; Ta, n = 6; and TIS, n = 21) at RC. An additional 10 patients had <T1 stage (Ta, n = 5; and TIS, n = 5) on TUR but were found to have T1 stage at RC. The median patient age was 64.5 (interquartile range [IQR] 57–70; range 38–87) years. Seventeen patients (17%) had no residual tumour at RC (pT0). The median number of nodes examined was 19 (IQR 16–26, range 9–80). Six (6%) patients had LVI and 63 (62%) had concomitant carcinoma in situ (CIS).

Table 1. Association between the clinical and the pathological stage among 101 patients with lymph-node-negative final stage T1 UCB at RC.
Clinical stage pre-cystectomyPost-cystectomy pathological stageTotal
T0TaCIST1
Ta55
TIS55
T1176214791
Total1762157101
Table 2. Clinical and pathological characteristics of 101 patients with lymph-node-negative final stage T1 UCB at RC.
Variablen (%)
Gender 
Male86 (85)
Female15 (15)
Clinical/TUR stage pre-RC
Ta5 (5)
TIS5 (5)
T191 (90)
Post-RC pathological stage
T017 (17)
Ta6 (6)
TIS21 (21)
T157 (56)
Grade (higher of pre-RC and post-RC grade)
210 (10)
391 (90)
Concomitant CIS on RC
No38 (38)
Yes63 (62)
Prostate involvement
No76 (88)
Yes10 (12)
LVI, N = 97 
No91 (94)
Yes6 (6)

Association of Clinical and Pathological Characteristics with Recurrence and Survival

The median follow-up duration was 38 (IQR 22–77; range 0.4–177) months for patients alive at last visit. Disease recurred in 12 patients (11.9%). Eighteen patients (17.8%) had died at the time of analysis, including seven patients (6.9%) who died from UCB.

The 3- and 5-year recurrence-free survival probabilities (SE) were 0.89 (0.04) and 0.87 (0.04), respectively (Fig. 1A). On univariable survival analyses, higher pathological stage (log-rank P = 0.05) and presence of concomitant CIS at RC (P = 0.02) and LVI (P < 0.001) predicted development of cancer recurrence (Table 3; Fig. 2A). Prostatic urethral involvement and a lower number of nodes removed during surgery showed a trend toward predicting a higher risk of disease recurrence but this did not reach significance (P = 0.07 for both). On multivariable Cox proportional hazard regression analysis, higher pathological stage (HR 8.5, P = 0.04) and LVI (HR 4.9, P = 0.01) were predictors of cancer recurrence (Table  4). Although presence of concomitant CIS at RC was not included in the final multivariable model, it showed a trend toward significance (HR 8.6, 95% CI 0.94–79, P = 0.057). Four out of six patients with LVI experienced disease recurrence (Fig. 2A) and, interestingly, all of the 12 recurrences were observed in patients who had either LVI or CIS on RC. Patients without either of these pathological features did not experience disease recurrence (Table 3).

Table 3. Univariable association of clinical and pathological characteristics with cancer recurrence and cancer-specific survival in 101 patients with lymph-node-negative final stage T1 UCB at RC.
Variable3-year recurrence-free survival (SD)Log-rank P3-year cancer-specific survival (SD)Log-rank P
Gender 0.14 0.055
Male0.91 (0.03) 0.97 (0.02) 
Female0.76 (0.12 0.92 (0.08) 
Clinical stage pre-RC 0.68 0.39
Ta0.8 (0.18 0.8 (0.18) 
TIS1 (0 1 (0) 
T10.89 (0.04) 0.97 (0.02) 
Post-RC pathological stage 0.049 0.06
T01 (0) 1 (0) 
Ta1 (0) 1 (0) 
TIS0.94 (0.06) 1 (0) 
T10.83 (0.06) 0.93 (0.04) 
Grade (higher of preoperative and postoperative grade) 0.62 0.98
Grade 20.90 (0.09) 0.90 (0.09) 
Grade 30.89 (0.04) 0.97 (0.02) 
Preoperative CIS 0.14 0.63
Yes0.87 (0.05) 1 (0) 
No0.91 (0.05) 0.91 (0.05) 
Concomitant CIS at RC 0.02 0.08
Yes0.82 (0.05) 0.93 (0.04) 
No1 (0) 1 (0) 
Prostatic involvement 0.07 0.17
Yes0.89 (0.1) 1 (0) 
No0.92 (0.04) 0.96 (0.03) 
LVI (N = 97) 0.0002 0.004
Yes0.67 (0.19) 1 (0) 
No0.90 (0.04) 0.95 (0.03) 
Pathological CIS or LVI 0.005 0.02
Yes0.83 (0.05) 0.94 (0.04) 
No1 (0) 1 (0) 
Total number of nodes removed 0.07 0.55
<190.85 (0.06) 0.95 (0.04) 
≥190.95 (0.03) 0.97 (0.03) 
Table 4. Multivariable Cox regression analysis of factors associated with cancer recurrence and cancer-specific survival in 101 patients with lymph-node-negative final stage T1 UCB at RC.
VariableRecurrenceCancer-specific mortality
HR (95% CI)PHR (95% CI)P
LVI 0.01 0.01
NoReferent Referent 
Yes4.9 (1.4–16.5) 6.7 (1.5–30.3) 
Post-RC pathological stage 0.04  
T0, Ta, TISReferent   
T18.5 (1.1–67)   
figure

Figure 1. Kaplan–Meier estimates for A, recurrence-free survival and B, cancer-specific survival in 101 patients with final stage T1 UCB, treated with RC.

Download figure to PowerPoint

figure

Figure 2. Kaplan–Meier curves of A, recurrence-free survival and B, cancer-specific survival stratified by LVI status.

Download figure to PowerPoint

The 3- and 5-year cancer-specific survival probabilities (SD) were the same, i.e. 0.96 (0.02) (Fig. 1B). On univariable survival analyses, LVI (P = 0.004) was associated with worse survival (Table 3; Fig. 2B). Higher pathological stage (P = 0.06), female gender (P = 0.055) and presence of concomitant CIS on RC (P = 0.08) showed a trend towards but did not reach statistical significance. On multivariable analysis, LVI was the only factor predictive of cancer-specific survival (HR 6.7; 95% CI 1.5–30; P = 0.01; Table 4). Of the six patients who had LVI, three died from bladder cancer. All seven cancer-specific deaths occurred in patients who had either concomitant CIS or LVI (Table 3).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Despite the large body of literature on outcomes after RC, there are only limited data on the outcomes of patients with pT1N0 UCB at RC. The present patient cohort consisted of 101 patients with final pathological (the higher of clinical or pathological stage) T1 UCB without nodal metastases (T1N0). Final pathological staging was defined as the higher of the preoperative clinical and the pathological stages. Understanding of differential outcomes of patients with pT1 UCB will lend further insight into the biology of this disease and will help establish a possible management algorithm for these patients with pT1N0 disease who are at increased risk of disease progression after RC as monotherapy.

We found that patients with pT1 disease have a durable response and good long-term survival; however, a significant proportion of patients with pT1 disease suffer from recurrence and progression. In the present study, 11.9% of patients experienced cancer recurrence and 6.9% died from UCB within a median follow-up of 38 months after RC. Overall 5-year cancer-specific survival was 96.0%. This is in accordance with data from contemporary RC series that reported 5-year survival probabilities for patients with pT1 UCB [1, 6]. Patients with pT1 disease remain at risk for disease progression and therefore require similar follow-up as patients with carcinoma invading bladder muscle.

The present study shows that LVI predicts disease recurrence and cancer-specific survival in patients with pT1 UCB at RC. Four of the six patients with LVI experienced disease recurrence and three died from bladder cancer.

Lymphovascular invasion is an important step in systemic cancer cell dissemination [7, 8]. We and other authors have shown that LVI is an independent predictor of disease recurrence and cause-specific survival and helps identify patients without lymph node involvement who are at increased risk of cancer recurrence and mortality despite RC [9-11]. The same is true in upper tract urothelial carcinoma, a disease with similar biology to UCB [12, 13]. However, none of these studies have separately analysed patients with final pathological T1 UCB who underwent RC. Although most studies have studied LVI as a prognosticator after cystectomy, it is possible that LVI found on TUR of bladder tumour (TURBT) specimens may also predict outcomes. Cho et al. [14] studied 118 patients with newly diagnosed T1 UCB and found that LVI on the TURBT specimen predicted disease progression and metastasis. Consequently, T1 UCB with LVI on TURBT should lead us to consider these patients for early cystectomy and possibly for neoadjuvant chemotherapy. These patients should also be followed up more closely. Multiple regimens of intravesical immunotherapy might be counterproductive in these patients [15].

Presence of concomitant CIS at RC was not a significant predictor of outcomes. It is possible that in larger datasets with a greater number of events, concomitant CIS may be a prognostic factor for recurrence and survival. Indeed, we and others have shown that concomitant CIS is associated with worse survival in patients with organ-confined UCB or upper tract urothelial carcinoma [16-20].

Patients with residual T1 disease at RC were at high risk for disease recurrence. We did not see a higher likelihood of cancer-specific mortality in these patients, but this may have been attributable to the small number of patients who died from bladder cancer. The presence of residual T1 disease may be a marker for higher volume and perhaps more aggressive cancer, which may predispose these patients for cancer recurrence [21]. This may be analogous to studies in which patients with residual T1 disease on repeat TUR have a higher risk of disease recurrence and mortality [22, 23].

The present study has several important limitations. First and foremost are the limitations inherent with retrospective analyses. Moreover, the population in the present study underwent surgery by multiple surgeons and had specimens evaluated by multiple pathologists. However, this can also be construed as a strength as it represents real-world practice. We did not control for repeat TUR, time from diagnosis to RC and previous intravesical therapy, which could have affected outcomes [24, 25]. Another limitation is the inherent difficulty in determining the presence of LVI at the morphological level with significant differences between local pathologists and central pathology review [26]. Pathologists should be encouraged to identify and report LVI on TURBT and cystectomy specimens more regularly. Special stains or markers may help in identification of LVI [27-29]. The present cohort was established before the 2010 TNM revision and before implementation of the revised grading system. Finally, there were few events limiting the statistical power of analysis. The present results need to be validated in larger independent datasets.

In conclusion, LVI helps identify patients with final stage T1N0 UCB who are at significantly increased risk of bladder cancer recurrence and death after RC. These patients might benefit from adjuvant therapy and should be considered for close monitoring. If LVI is found before RC, then neoadjuvant chemotherapy or early RC may be considered. Further studies with larger number of patients are necessary to corroborate these findings.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  • 1
    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 2001; 19: 666675
  • 2
    Shariat SF, Palapattu GS, Karakiewicz PI et al. Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol 2007; 51: 137151
  • 3
    Shariat SF, Karakiewicz PI, Palapattu GS et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol 2006; 176: 24142422
  • 4
    Madersbacher S, Hochreiter W, Burkhard F et al. Radical cystectomy for bladder cancer today–a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003; 21: 690696
  • 5
    Hautmann RE, Gschwend JE, de Petriconi RC, Kron M, Volkmer BG. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol 2006; 176: 486492
  • 6
    Dalbagni G, Genega E, Hashibe M et al. Cystectomy for bladder cancer: a contemporary series. J Urol 2001; 165: 11111116
  • 7
    Alitalo K, Mohla S, Ruoslahti E. Lymphangiogenesis and cancer: meeting report. Cancer Res 2004; 64: 92259229
  • 8
    Padera TP, Kadambi A, di Tomaso E et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 2002; 296: 18831886
  • 9
    Leissner J, Koeppen C, Wolf HK. Prognostic significance of vascular and perineural invasion in urothelial bladder cancer treated with radical cystectomy. J Urol 2003; 169: 955960
  • 10
    Lotan Y, Gupta A, Shariat SF et al. Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. J Clin Oncol 2005; 23: 65336539
  • 11
    Quek ML, Stein JP, Nichols PW et al. Prognostic significance of lymphovascular invasion of bladder cancer treated with radical cystectomy. J Urol 2005; 174: 103106
  • 12
    Kikuchi E, Margulis V, Karakiewicz PI et al. Lymphovascular invasion predicts clinical outcomes in patients with node-negative upper tract urothelial carcinoma. J Clin Oncol 2009; 27: 612618
  • 13
    Novara G, Matsumoto K, Kassouf W et al. Prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract: an international validation study. Eur Urol 2010; 57: 10641071
  • 14
    Cho KS, Seo HK, Joung JY et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. J Urol 2009; 182: 26252630
  • 15
    Raj GV, Herr H, Serio AM et al. Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer. J Urol 2007; 177: 12831286
  • 16
    Karam JA, Margulis V, Montorsi F et al. Carcinoma in situ of the upper urinary tract treated with radical nephroureterectomy–results from a multicenter study. Eur Urol 2008; 54: 961963
  • 17
    Otto W, Shariat SF, Fritsche HM et al. Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients. World J Urol 2011; 29: 487494
  • 18
    Wheat JC, Weizer AZ, Wolf JS Jr et al. Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ confined urothelial carcinoma following radical nephroureterectomy. Urol Oncol 2012; 30: 252258
  • 19
    Shariat SF, Palapattu GS, Karakiewicz PI et al. Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ-confined TCC at radical cystectomy. Eur Urol 2007; 51: 152160
  • 20
    Youssef RF, Shariat SF, Lotan Y et al. Prognostic effect of urinary bladder carcinoma in situ on clinical outcome of subsequent upper tract urothelial carcinoma. Urology 2011; 77: 861866
  • 21
    Tilki D, Svatek RS, Novara G et al. Stage pT0 at radical cystectomy confers improved survival: an international study of 4,430 patients. J Urol 2010; 184: 888894
  • 22
    Herr HW. The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 1999; 162: 7476
  • 23
    Herr HW, Donat SM, Dalbagni G. Can restaging transurethral resection of T1 bladder cancer select patients for immediate cystectomy? J Urol 2007; 177: 7579
  • 24
    Guzzo TJ, Magheli A, Bivalacqua TJ et al. Pathological upstaging during radical cystectomy is associated with worse recurrence-free survival in patients with bacillus Calmette-Guerin-refractory bladder cancer. Urology 2009; 74: 12761280
  • 25
    Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani PC, Fair WR. The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 1997; 158: 6267
  • 26
    Shariat SF, Svatek RS, Tilki D et al. International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy. BJU Int 2010; 105: 14021412
  • 27
    Rose AE, Christos PJ, Lackaye D et al. Clinical relevance of detection of lymphovascular invasion in primary melanoma using endothelial markers D2-40 and CD34. Am J Surg Pathol 2011; 35: 14411449
  • 28
    Mohammed RA, Martin SG, Gill MS, Green AR, Paish EC, Ellis IO. Improved methods of detection of lymphovascular invasion demonstrate that it is the predominant method of vascular invasion in breast cancer and has important clinical consequences. Am J Surg Pathol 2007; 31: 18251833
  • 29
    Mohammed RA, Martin SG, Mahmmod AM et al. Objective assessment of lymphatic and blood vascular invasion in lymph node-negative breast carcinoma: findings from a large case series with long-term follow-up. J Pathol 2011; 223: 358365
Abbreviations
UCB

urothelial carcinoma of the bladder

RC

radical cystectomy

LVI

lymphovascular invasion

CIS

carcinoma in situ

TUR

transurethral resection

HR

hazard ratio

IQR

interquartile range

TURBT

TUR of bladder tumour