3-year recurrence-free survival probability (SD) was 0.89 ... LVI helps identify patients with final pathological T1N0 ..... 14 Cho KS, Seo HK, Joung JY et al.
Lymphovascular invasion is independently associated with bladder cancer recurrence and survival in patients with final stage T1 disease and negative lymph nodes after radical cystectomy Derya Tilki1, Shahrokh F. Shariat2,3, Yair Lotan4, Michael Rink2,5, Pierre I. Karakiewicz6, Mark P. Schoenberg7, Seth P. Lerner8, Guru Sonpavde9, Arthur I. Sagalowsky4 and Amit Gupta10 1
Department of Urology, Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Munich, Germany, Department of Urology, Weill Medical College of Cornell University, 3Division of Medical Oncology, New York Presbyterian Hospital, New York, NY, 4Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 5Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 6 University of Montréal, Cancer Prognostics and Health Outcomes Unit, Montréal, QC, Canada, 7Department of Urology, Johns Hopkins University, Brady Urologic Institute, Baltimore, MD, 8Baylor College of Medicine, Department of Urology, Houston, TX, 9UAB Comprehensive Cancer Center, Birmingham, AL, and 10University of Iowa Department of Urology, Iowa City, IA, USA 2
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.
© 2012 BJU International | 111, 1215–1221 | doi:10.1111/j.1464-410X.2012.11455.x
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Keywords bladder cancer, lymphovascular invasion, urothelial carcinoma, survival
Introduction 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 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
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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-cancerspecific 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 ⱕ0.05 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 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
LVI in patients with pT1 bladder cancer
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-cystectomy T0
Ta
CIS
T1
– – 17 17
– – 6 6
– – 21 21
5 5 47 57
Table 2 Clinical and pathological characteristics of 101 patients with lymph-node-negative final stage T1 UCB at RC. Variable Gender Male Female Clinical/TUR stage pre-RC Ta TIS T1 Post-RC pathological stage T0 Ta TIS T1 Grade (higher of pre-RC and post-RC grade) 2 3 Concomitant CIS on RC No Yes Prostate involvement No Yes LVI, N = 97 No Yes
Total
n (%)
5 5 91 101
Fig. 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.
A 1.0
86 (85) 15 (15)
0.9 5 (5) 5 (5) 91 (90) 17 (17) 6 (6) 21 (21) 57 (56) 10 (10) 91 (90) 38 (38) 63 (62)
0.8 0.7
Recurrence Free Survival
Ta TIS T1 Total
Post-cystectomy pathological stage
0.6 0.5
0.4 0.3 0.2
76 (88) 10 (12)
0.1 0.0
91 (94) 6 (6)
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 Time to recurrence, months
B 1.0 0.9 0.8 0.7 0.6
Recurrence Free Survival
stage at RC and 44 had
