Japanese Journal of Clinical Oncology Advance Access published February 12, 2015 Japanese Journal of Clinical Oncology, 2015, 1–6 doi: 10.1093/jjco/hyv019 Original Article
Original Article
Downloaded from http://jjco.oxfordjournals.org/ at University of Massachusetts Medical School on April 8, 2015
Tumour multifocality and grade predict intravesical recurrence after nephroureterectomy in patients with upper urinary tract urothelial carcinoma without a history of bladder cancer Tsukasa Narukawa1, Tomohiko Hara1,*, Eri Arai2, Motokiyo Komiyama1, Takashi Kawahara1, Yae Kanai2, and Hiroyuki Fujimoto1 1
Urology Division, National Cancer Center Hospital, Tokyo, and 2Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
*For reprints and all correspondence: Tomohiko Hara, Urology Division, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. E-mail: [email protected] Received 9 November 2014; Accepted 21 January 2015
Abstract Objective: Patients with upper urinary tract urothelial carcinoma (UUT-UC) without a history of bladder cancer have a different natural history of intravesical recurrence after nephroureterectomy compared with those with a history of bladder cancer. The aim of this study was to identify predictive factors for post-operative intravesical recurrence in patients with non-metastatic upper urinary tract-localized urothelial carcinoma without a history of bladder cancer and who were not taking medication during the perioperative period. Methods: This retrospective study included 133 patients who were treated between 1995 and 2012. Univariate and multivariate analyses were used to evaluate the clinical and pathological factors associated with the cumulative incidence of bladder cancer. Results: Of the 133 patients, 51 (38.3%) developed intravesical recurrence during a median follow-up of 71 months (range, 0.8–210.8). In the multivariate analysis, multifocality (P = 0.03) and high tumour grade (P = 0.007) were significantly associated with the cumulative incidence of bladder cancer. We constructed a prediction classification model on the basis of the total number of risk factors. The 2-year cumulative incidence rates were 5.6, 34.8 and 50.0% in individuals with no, one and two risk factors, respectively. There was a significant difference between patients with no risk factors and those with two risk factors (P = 0.01). Conclusions: Although this retrospective study had several limitations, tumour multifocality and tumour grade were found to be potential risk factors for intravesical recurrence in our cases. Key words: urology, urologic-med, upper urinary tract urothelial carcinoma, ureteral cancer, renal pelvic cancer, intravesical recurrence
Introduction Radical nephroureterectomy (RNU) with excision of the bladder cuff is the gold standard treatment for localized upper urinary tract urothelial carcinoma (UUT-UC) (1). Intravesical recurrence after RNU is a
common event that occurs in 20–50% of cases (2,3). Several studies have tried to identify predictors of intravesical recurrence (2–17); however, these studies included heterogeneous clinical characteristics such as previous/concomitant bladder cancer, perioperative therapy and
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
1
2
Intravesical recurrence after RNU RNU for UUT-UC at our institution. Preoperative diagnosis was performed using urine cytology, cystoscopy and radiological imaging. Diagnostic ureteroscopy was not performed in any patient. Patients with continuously positive voided urine cytology just after RNU and intravesical recurrence within 2 months of RNU were regarded as concomitant bladder cancer cases. A total of 109 patients were excluded because of a history of previous/concomitant bladder cancer, neoadjuvant/adjuvant systemic chemotherapy, perioperative intravesical instillation therapy, radiotherapy for pelvic cavities, lymph node metastasis or clinical distant metastasis. The remaining 133 patients were enrolled in the study.
Surgical procedure All patients underwent RNU with excision of the bladder cuff. Twelve different surgeons performed the operation in the study period. The surgical approach was via open intra-abdominal access, open retroperitoneal access or laparoscopic intra-abdominal access. The timing of ureteral ligation was decided by the physician (Table 1).
Patients and methods Patient population
Cytological and pathological analyses
This study was approved by the Ethics Committee at our institute. Between April 1995 and December 2012, 242 patients underwent
The highest preoperative cytological grade obtained when voiding urine was regarded as the voided urine cytology. Cytological examinations were performed using standard Papanicolaou staining and were
Table 1. Clinical characteristics of 133 patients treated with radical nephroureterectomy for upper urinary tract urothelial carcinoma and the incidence of intravesical recurrence Variables
No. of patients (%)
Intravesical recurrence
Variables Yes (n = 51)
Preoperative factors Age Over 66 years 69 (51.9) Less than 65 years 64 (48.1) Gender Male 101 (75.9) Female 32 (24.1) Smoking status Current/former smoker 85 (63.9) Never smoker 35 (26.3) Unknown 13 (9.8) Hydronephrosis Positive 57 (42.9) Negative 72 (54.1) Unknown 4 (3.0) Voided urine cytology Positive 59 (44.4) Suspicious 37 (27.8) Negative 36 (27.1) Unknown 1 (0.8) Operative factors Timing of ureteral ligation Before renal vascular 19 (14.3) ligation After renal vascular 109 (82.0) ligation Unknown 5 (3.8) Surgical access Open intra-abdominal 116 (87.2) Open retroperitoneal 2 (1.5) Laparoscopic 15 (11.3) intra-abdominal
Table 2. Pathological characteristics of 133 patients treated with radical nephroureterectomy for upper urinary tract urothelial carcinoma and the incidence of intravesical recurrence No. of patients (%)
No (n = 82)
26 25
43 39
41 10
60 22
34 13 4
51 22 9
23 27 1
34 45 3
23 15 13 0
36 22 23 1
6
13
44
65
1
4
46 0 5
70 2 10
Post-operative factor Primary tumour location Renal pelvis 81 (60.9) Ureter 50 (37.6) Unknown 2 (1.5) Multifocality Monostotic 102 (76.7) Multifocal 31 (24.1) Ureteral surgical margin Positive 2 (1.5) Negative 128 (96.2) Unknown 3 (2.3) pT stage pTis 7 (5.3) pTa 19 (14.3) pT1 46 (34.6) pT2 13 (9.8) pT3 46 (34.6) pT4 2 (1.5) Tumour grade Low 28 (21.1) High 105 (78.9) Concomitant UUT-CIS Positive 60 (45.1) Negative 72 (54.1) Unknown 1 (0.8) Lymphovascular invasion Positive 32 (24.1) Negative 100 (75.2) Unknown 1 (0.8)
Intravesical recurrence Yes (n = 51)
No (n = 82)
28 22 1
53 28 1
35 16
67 15
2 47 2
0 81 1
2 6 17 5 20 1
5 13 29 8 26 1
5 46
23 59
19 32 0
41 40 1
15 36 0
17 64 1
UUT-CIS, upper urinary tract carcinoma in situ.
Downloaded from http://jjco.oxfordjournals.org/ at University of Massachusetts Medical School on April 8, 2015
metastasis. Because intravesical recurrence of patients with UUT-UC with a history of bladder cancer included that of a tumour that had originated in the bladder, the natural history of intravesical recurrence was different between the patients with and without a history of bladder cancer. Most of the previous studies did not report the natural bladder implantation history of patients who underwent RNU for UUT-UC alone. Moreover, these previous studies included many patients with a poor clinical course. Some high-risk patients with high stage and grade carcinoma died of metastatic disease before intravesical recurrence was identified. Therefore, careful patient selection and appropriate statistical analysis are mandatory to avoid bias and to precisely identify the risk factors for intravesical recurrence after RNU. In the present study, the objective was to validate previously reported predictors and to further explore predictive factors for intravesical recurrence in appropriately selected patients with post-operative non-metastatic localized UUT-UC without a history of bladder cancer and who were not taking medication during the perioperative period.
Jpn J Clin Oncol, 2015 classified as negative, suspicious or positive (18). All surgical specimens were processed according to standard pathological procedures. Histopathological extensions were re-classified according to the 2009 TNM classification of the Union for International Cancer Control (19). Two pathologists at our institution (E.A. and Y.K.) performed histopathological grading according to the 2004 World Health Organization/International Society of Urological Pathology classification (20). The primary tumour location was defined as either the renal pelvis or ureter. Tumour multifocality was defined as the synchronous presence of two or more pathologically confirmed tumours in discontinuous locations. Lymphovascular invasion (LVI) was defined as the presence of tumour cells within a lymph or vein duct. The ureteral surgical margins were defined as the presence of tumour cells at the edge of ureteral specimens.
Post-operative voided urine cytology, cystoscopy and radiological imaging were performed every 3–4 months for 2 years after RNU, every 6 months after the third year and annually after the fifth year. Intravesical recurrence was defined as bladder cancer that was clinically diagnosed according to the cystoscopic appearance, positive cytology or biopsy. The period between the date of RNU and bladder cancer incidence was defined as the period of bladder cancer-free survival.
Statistical analysis The clinical factors age, gender, smoking status, hydronephrosis, voided urine cytology, timing of ureteral ligation and surgical approach were included in the risk analysis for intravesical recurrence (Table 1). In addition, the pathological factors of primary tumour location, tumour multifocality, ureteral surgical margin, pathological
tumour stage, tumour grade, concomitant upper urinary tract carcinoma in situ (UUT-CIS) and LVI were assessed (Table 2). Patient mortality was the competing risk of cumulative bladder cancer incidence. During the analysis of competing-risk data, methods of standard survival analysis, such as the Kaplan–Meier method for the estimation of cumulative incidence, the log-rank test and the standard Cox model, usually lead to incorrect and biassed results (21). Therefore, Gray’s method (22) was used to compare the cumulative bladder cancer incidence according to each factor in the univariate analysis. The level of significance for the univariate screening regressions was set at P = 0.2, because more stringent significance levels can lead to the exclusion of potentially useful predictor variables. The candidate factors with a P value of
Original Article
Downloaded from http://jjco.oxfordjournals.org/ at University of Massachusetts Medical School on April 8, 2015
Tumour multifocality and grade predict intravesical recurrence after nephroureterectomy in patients with upper urinary tract urothelial carcinoma without a history of bladder cancer Tsukasa Narukawa1, Tomohiko Hara1,*, Eri Arai2, Motokiyo Komiyama1, Takashi Kawahara1, Yae Kanai2, and Hiroyuki Fujimoto1 1
Urology Division, National Cancer Center Hospital, Tokyo, and 2Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
*For reprints and all correspondence: Tomohiko Hara, Urology Division, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. E-mail: [email protected] Received 9 November 2014; Accepted 21 January 2015
Abstract Objective: Patients with upper urinary tract urothelial carcinoma (UUT-UC) without a history of bladder cancer have a different natural history of intravesical recurrence after nephroureterectomy compared with those with a history of bladder cancer. The aim of this study was to identify predictive factors for post-operative intravesical recurrence in patients with non-metastatic upper urinary tract-localized urothelial carcinoma without a history of bladder cancer and who were not taking medication during the perioperative period. Methods: This retrospective study included 133 patients who were treated between 1995 and 2012. Univariate and multivariate analyses were used to evaluate the clinical and pathological factors associated with the cumulative incidence of bladder cancer. Results: Of the 133 patients, 51 (38.3%) developed intravesical recurrence during a median follow-up of 71 months (range, 0.8–210.8). In the multivariate analysis, multifocality (P = 0.03) and high tumour grade (P = 0.007) were significantly associated with the cumulative incidence of bladder cancer. We constructed a prediction classification model on the basis of the total number of risk factors. The 2-year cumulative incidence rates were 5.6, 34.8 and 50.0% in individuals with no, one and two risk factors, respectively. There was a significant difference between patients with no risk factors and those with two risk factors (P = 0.01). Conclusions: Although this retrospective study had several limitations, tumour multifocality and tumour grade were found to be potential risk factors for intravesical recurrence in our cases. Key words: urology, urologic-med, upper urinary tract urothelial carcinoma, ureteral cancer, renal pelvic cancer, intravesical recurrence
Introduction Radical nephroureterectomy (RNU) with excision of the bladder cuff is the gold standard treatment for localized upper urinary tract urothelial carcinoma (UUT-UC) (1). Intravesical recurrence after RNU is a
common event that occurs in 20–50% of cases (2,3). Several studies have tried to identify predictors of intravesical recurrence (2–17); however, these studies included heterogeneous clinical characteristics such as previous/concomitant bladder cancer, perioperative therapy and
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
1
2
Intravesical recurrence after RNU RNU for UUT-UC at our institution. Preoperative diagnosis was performed using urine cytology, cystoscopy and radiological imaging. Diagnostic ureteroscopy was not performed in any patient. Patients with continuously positive voided urine cytology just after RNU and intravesical recurrence within 2 months of RNU were regarded as concomitant bladder cancer cases. A total of 109 patients were excluded because of a history of previous/concomitant bladder cancer, neoadjuvant/adjuvant systemic chemotherapy, perioperative intravesical instillation therapy, radiotherapy for pelvic cavities, lymph node metastasis or clinical distant metastasis. The remaining 133 patients were enrolled in the study.
Surgical procedure All patients underwent RNU with excision of the bladder cuff. Twelve different surgeons performed the operation in the study period. The surgical approach was via open intra-abdominal access, open retroperitoneal access or laparoscopic intra-abdominal access. The timing of ureteral ligation was decided by the physician (Table 1).
Patients and methods Patient population
Cytological and pathological analyses
This study was approved by the Ethics Committee at our institute. Between April 1995 and December 2012, 242 patients underwent
The highest preoperative cytological grade obtained when voiding urine was regarded as the voided urine cytology. Cytological examinations were performed using standard Papanicolaou staining and were
Table 1. Clinical characteristics of 133 patients treated with radical nephroureterectomy for upper urinary tract urothelial carcinoma and the incidence of intravesical recurrence Variables
No. of patients (%)
Intravesical recurrence
Variables Yes (n = 51)
Preoperative factors Age Over 66 years 69 (51.9) Less than 65 years 64 (48.1) Gender Male 101 (75.9) Female 32 (24.1) Smoking status Current/former smoker 85 (63.9) Never smoker 35 (26.3) Unknown 13 (9.8) Hydronephrosis Positive 57 (42.9) Negative 72 (54.1) Unknown 4 (3.0) Voided urine cytology Positive 59 (44.4) Suspicious 37 (27.8) Negative 36 (27.1) Unknown 1 (0.8) Operative factors Timing of ureteral ligation Before renal vascular 19 (14.3) ligation After renal vascular 109 (82.0) ligation Unknown 5 (3.8) Surgical access Open intra-abdominal 116 (87.2) Open retroperitoneal 2 (1.5) Laparoscopic 15 (11.3) intra-abdominal
Table 2. Pathological characteristics of 133 patients treated with radical nephroureterectomy for upper urinary tract urothelial carcinoma and the incidence of intravesical recurrence No. of patients (%)
No (n = 82)
26 25
43 39
41 10
60 22
34 13 4
51 22 9
23 27 1
34 45 3
23 15 13 0
36 22 23 1
6
13
44
65
1
4
46 0 5
70 2 10
Post-operative factor Primary tumour location Renal pelvis 81 (60.9) Ureter 50 (37.6) Unknown 2 (1.5) Multifocality Monostotic 102 (76.7) Multifocal 31 (24.1) Ureteral surgical margin Positive 2 (1.5) Negative 128 (96.2) Unknown 3 (2.3) pT stage pTis 7 (5.3) pTa 19 (14.3) pT1 46 (34.6) pT2 13 (9.8) pT3 46 (34.6) pT4 2 (1.5) Tumour grade Low 28 (21.1) High 105 (78.9) Concomitant UUT-CIS Positive 60 (45.1) Negative 72 (54.1) Unknown 1 (0.8) Lymphovascular invasion Positive 32 (24.1) Negative 100 (75.2) Unknown 1 (0.8)
Intravesical recurrence Yes (n = 51)
No (n = 82)
28 22 1
53 28 1
35 16
67 15
2 47 2
0 81 1
2 6 17 5 20 1
5 13 29 8 26 1
5 46
23 59
19 32 0
41 40 1
15 36 0
17 64 1
UUT-CIS, upper urinary tract carcinoma in situ.
Downloaded from http://jjco.oxfordjournals.org/ at University of Massachusetts Medical School on April 8, 2015
metastasis. Because intravesical recurrence of patients with UUT-UC with a history of bladder cancer included that of a tumour that had originated in the bladder, the natural history of intravesical recurrence was different between the patients with and without a history of bladder cancer. Most of the previous studies did not report the natural bladder implantation history of patients who underwent RNU for UUT-UC alone. Moreover, these previous studies included many patients with a poor clinical course. Some high-risk patients with high stage and grade carcinoma died of metastatic disease before intravesical recurrence was identified. Therefore, careful patient selection and appropriate statistical analysis are mandatory to avoid bias and to precisely identify the risk factors for intravesical recurrence after RNU. In the present study, the objective was to validate previously reported predictors and to further explore predictive factors for intravesical recurrence in appropriately selected patients with post-operative non-metastatic localized UUT-UC without a history of bladder cancer and who were not taking medication during the perioperative period.
Jpn J Clin Oncol, 2015 classified as negative, suspicious or positive (18). All surgical specimens were processed according to standard pathological procedures. Histopathological extensions were re-classified according to the 2009 TNM classification of the Union for International Cancer Control (19). Two pathologists at our institution (E.A. and Y.K.) performed histopathological grading according to the 2004 World Health Organization/International Society of Urological Pathology classification (20). The primary tumour location was defined as either the renal pelvis or ureter. Tumour multifocality was defined as the synchronous presence of two or more pathologically confirmed tumours in discontinuous locations. Lymphovascular invasion (LVI) was defined as the presence of tumour cells within a lymph or vein duct. The ureteral surgical margins were defined as the presence of tumour cells at the edge of ureteral specimens.
Post-operative voided urine cytology, cystoscopy and radiological imaging were performed every 3–4 months for 2 years after RNU, every 6 months after the third year and annually after the fifth year. Intravesical recurrence was defined as bladder cancer that was clinically diagnosed according to the cystoscopic appearance, positive cytology or biopsy. The period between the date of RNU and bladder cancer incidence was defined as the period of bladder cancer-free survival.
Statistical analysis The clinical factors age, gender, smoking status, hydronephrosis, voided urine cytology, timing of ureteral ligation and surgical approach were included in the risk analysis for intravesical recurrence (Table 1). In addition, the pathological factors of primary tumour location, tumour multifocality, ureteral surgical margin, pathological
tumour stage, tumour grade, concomitant upper urinary tract carcinoma in situ (UUT-CIS) and LVI were assessed (Table 2). Patient mortality was the competing risk of cumulative bladder cancer incidence. During the analysis of competing-risk data, methods of standard survival analysis, such as the Kaplan–Meier method for the estimation of cumulative incidence, the log-rank test and the standard Cox model, usually lead to incorrect and biassed results (21). Therefore, Gray’s method (22) was used to compare the cumulative bladder cancer incidence according to each factor in the univariate analysis. The level of significance for the univariate screening regressions was set at P = 0.2, because more stringent significance levels can lead to the exclusion of potentially useful predictor variables. The candidate factors with a P value of
