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Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience
Urological Science xxx (2017) 1e4
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Original article
Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience Yen-Hsi Lee a, Henry Y. Lin a, Chung-Hsien Chen a, Yu-Chi Chen a, Ching-Yu Huang a, Kevin Lu a, Chao-Yang Jiang a, Hua-Pin Wang a, Victor C. Lin a, b, * a b
Department of Urology, E-DA Hospital, Kaohsiung, Taiwan School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 March 2016 Received in revised form 7 December 2016 Accepted 8 December 2016 Available online xxx
Objective: Radical nephroureterectomy with bladder-cuff excision has been the traditional treatment for upper tract urothelial carcinoma because of its high rate of recurrence. However, given the morbidity of nephrectomy and the risk of developing chronic kidney disease or dialysis-dependent renal failure, the nephron-sparing approach may be preferable in selected patients. Materials and methods: A total of 118 patients who received unilateral distal ureterectomy with reimplantation at a single center in Taiwan were included, using surgical code numbers, from March 2006 to December 2014. A total of 82 patients were excluded due to nonmalignancy and 17 due to concomitant bladder cancer. Finally, 19 patients with primary, solitary, unilateral ureter lesions and confirmed to have ureter malignancy (urothelial carcinoma, n ¼ 18; squamous cell carcinoma, n ¼ 1) were included. Results: Of the 19 patients (13 males and 6 females) included, the mean age was 69.3 ± 10.7 years. Tumor pathological staging was Tis (n ¼ 1), Ta (n ¼ 3), T1 (n ¼ 2), T2 (n ¼ 6), and T3 (n ¼ 5). Histopathology grading was low grade (n ¼ 3) and high grade (n ¼ 13). No local recurrence was noted; nine patients had bladder recurrence (47.4%), three had distant metastasis (15.8%), and two had progression and finally underwent radical nephroureterectomy (10.5%). The mean time to bladder recurrence was 12.4 months (3e24 months); the mean follow-up time was 28.1 months (1e90 months). The 5-year overall survival rate was 73.7% (14/19); four patients were lost to follow-up, and one patient expired. The mean 5-year progression-free survival was 67.74%. The mean preoperative creatinine level was 1.61 mg/dL, and at 12 months after operation it was 1.56 mg/dL (p ¼ 0.95). Conclusion: In selected patients, distal ureterectomy with reimplantation, in our experience, is a feasible option for distal ureter tumor. Favorable postoperative outcomes with a low local recurrence rate, a low rate of progression to nephroureterectomy, and renal function preservation may prove the value of this modality and should be taken into consideration in suitable patients. Copyright © 2017, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: distal ureter cancer distal ureterectomy nephron-sparing management
1. Introduction Comprising only 5% of all renal and urothelial tumors, upper tract urothelial carcinoma (UTUC) is a rare genitourinary malignancy.1 For resectable tumors, radical nephroureterectomy (RNU) with bladder-cuff excision has been the gold standard treatment of choice. However, given the morbidity after nephrectomy and the risk of developing chronic kidney disease (CKD), cardiovascular * Corresponding author. Department of Urology, E-DA Hospital, Kaohsiung, Taiwan. E-mail address: [email protected] (V.C. Lin).
morbidity, or dialysis-dependent renal failure, a nephron-sparing approach may be preferable in selected patients.2,3 Nephronsparing management (NSM) has been used for UTUC in patients with severely impaired renal function, solitary kidneys, bilateral synchronous tumors, or the necessity of platinum-based chemotherapy for future treatment.4,5 According to the European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines, segmental resection of the distal ureter could be an option for distal ureteral urothelial carcinomas (UCs) even in patients with highgrade, locally invasive distal ureteral UC, particularly for individuals with imperative indications.6,7
http://dx.doi.org/10.1016/j.urols.2016.12.002 1879-5226/Copyright © 2017, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Lee Y-H, et al., Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2016.12.002
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Y.-H. Lee et al. / Urological Science xxx (2017) 1e4
To our knowledge, it remains controversial whether NSM represents a valid alternative to standard RNU in selected patients, due to limited long-term oncological results of NSM for UTUC. This study aimed to evaluate the oncological outcome in patients with distal ureteral carcinoma who were treated with NSM in a single center (Kaohsiung City, Taiwan). We retrospectively analyzed the oncological outcomes and changes in the renal function of patients with distal ureteral malignancy who underwent distal ureterectomy (DU) with reimplantation of the ureter. 2. Materials and methods 2.1. Study population A total of 118 patients who received unilateral distal ureteral resection with reimplantation at a single center in Southern Taiwan from March 2006 to December 2014 were included. The exclusion criteria were aged < 18 years, concomitant bladder cancer, and a history of bladder cancer. Eighty-two patients were excluded due to nonmalignancy and 17 due to concomitant bladder cancer. Therefore, our final cohort included 19 patients with a primary, solitary, unilateral ureteric lesion confirmed as a ureteral malignancy (UC, n ¼ 18; squamous cell carcinoma, n ¼ 1) on final pathology. The preoperative evaluation included serum creatinine, renal echo, intravenous pyelography, computed tomography of the abdomen/pelvis or magnetic resonance imaging of the abdomen, magnetic resonance imaging of urography (MRU), and chest X-ray. Cystourethroscopy or ureteroscopy with tumor biopsy was not routinely performed, to avoid tumor cell spillage into the upper urinary tract. The tumor location and length can be evaluated using image studies such as intravenous pyelogram (IVP) and abdominal computed tomography. If the image study failed to evaluate the tumor location and length, we performed ureteroscopy for intraluminal evaluation. Some patients had a biopsy report at a previous hospital before the surgery; others had strong evidence of malignancy on image studies. As for resection length, the bulging tumor can be identified during the operation grossly, and the proximal and distal margins were sent for frozen section examination for confirmation that there was no malignancy. 2.2. Surgical procedures All 19 patients received DU with reimplantation of the ureter using the Lich method, with psoas hitch bladder, direct ureteroneocystostomy, or Boari flap bladder. A frozen section of the proximal ureteral margin was examined during the operation and confirmed to be negative for malignancy. The indication for and extent of lymphadenectomy were considered by the surgeon. At a minimum, a lymphadenectomy was performed when lymphadenopathy was detected by imaging studies or during surgery. 2.3. Follow-up Urine cytology, biochemical studies, including renal function and renal echo, were routinely performed every 3 months in the first 2 years and annually thereafter. Outcome measures were recurrence or distant metastasis, renal function preservation, time to recurrence, and overall survival. 2.4. Statistical analysis Continuous parametric variables were reported as the mean value ± standard deviation. The survival range was defined by the
time elapsed since the day of surgery and the last clinical evaluation or the patient's death. Survival curves were estimated using KaplaneMeier curves. Analyses used SPSS version 18 (SPSS Statistics 18; IBM, Armonk, New York, United States). A p value < 0.05 was considered statistically significant. 3. Results A total of 19 patients (13 males and 6 females) were included, and the mean age was 69.3 ± 10.7 years. Eleven patients received ureteral reimplantation by Lich method, four received psoas hitch bladder reimplantation, and four received Boari flap bladder reconstruction. Tumor pathological staging was T0 (n ¼ 1), Ta (n ¼ 3), Tis (n ¼ 1), T1 (n ¼ 2), T2 (n ¼ 6), T3 (n ¼ 5), and T4 (n ¼ 1). The pT4 case had ureter tumor that invaded into the myometrium of the uterus. All had malignancy except one patient with pathology T0 who had endoscopic biopsy-proven malignancy before. The lesion might have been removed during the previous endoscopic biopsy procedure, and the patient had no further recurrence during the follow-up period. Histopathology grading was presented as follows: low grade, n ¼ 3; high grade, n ¼ 13. For the other three patients, the final pathology was pT0 in one patient and squamous cell carcinoma was found in another patient, which had no grading. The grading was not found in the remaining patient (Table 1). There were no local recurrences, but nine patients had bladder recurrence (47.4%), three had distant metastasis (15.8%), and two had progression and, ultimately, underwent RNU (10.5%). The mean time to bladder recurrence was 12.4 months (3e24 months) and the mean follow-up time was 28.1 months (1e90 months). The recurrence incidence was 66.7% (4/6) and distal metastasis incidence was 16.7% (1/6) for the Ta, T1, and Tis groups. The recurrence incidence was 50% (6/12) and distal metastasis incidence was 16.7% (2/12) for the T2, T3, and T4 groups. Furthermore, the recurrence incidence was 66.7% (2/3) and distal metastasis incidence was 33.3% (1/3) for the pathology low-grade group. The recurrence incidence was 61.5% (8/13) and distal metastasis incidence was 15.4% (2/13) for the pathology high-grade group. The 5-year overall survival rate was 73.7% (14/19); among them, four patients were lost to follow-up and one patient expired. The mean 5-year progression-free survival was 67.74% (Figure 1). The mean preoperative creatinine level was 1.61 mg/dL, and the postoperative creatinine level was 1.56 mg/dL at 12 months (p ¼ 0.95). The KaplaneMeier curves for bladder recurrence-free survival are displayed in Figure 2. The 5year progression-free survival rate, stratified by stage, is presented in Figure 3. Owing to the limited cases, the relationship between stage and bladder recurrence incidence was not significant in this study. Table 1 Patient characteristics (n ¼ 19). Age (y) Sex (M:F) Preop creatinine (mg/dL) Stage pT0 pTa pTis pT1 pT2 pT3 pT4 Grade Low High Other N/A
69.3 (46e82) 13:6 1.61 (1.0e2.5) 1 3 1 2 6 5 1 3 13 2 1
N/A ¼ not applicable.
Please cite this article in press as: Lee Y-H, et al., Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2016.12.002
Y.-H. Lee et al. / Urological Science xxx (2017) 1e4
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Figure 3. Progression-free survival stratified by stage (log rank p ¼ 0.67).
Figure 1. Progression-free survival.
Figure 2. Bladder recurrence-free survival.
4. Discussion UTUC is a rare disease. Primary UTUC represents approximately 5% of all UCs and 10% of all primary renal tumors. Resembling UC of the bladder, UTUC may recur and progress in any location in the urinary tract. The most common location for ureteral UC is the distal ureter (70%), followed by the middle (25%) and proximal (5%) ureter.8 However, the ratio of UTUC in Taiwan is relatively higher than in other countries. The incidence of UTUC was relatively high
(the ratio of renal pelvis:ureter:urinary bladder was 1:2.08:6.72), despite the majority of patients residing outside the endemic “blackfoot disease” area in Taiwan.9 The NSM for UTUC, other than traditional RNU, may be a valuable alternative for select patients, particularly in Taiwan. Among UTUCs, tumors of the distal ureter are more common than those of the midureter and proximal ureter, and are more frequently solitary, smaller, and of lower stage and grade than their renal pelvic or upper ureteral counterparts.10,11 Furthermore, distal ureteral UC is less often associated with recurrent disease within the upper urinary tract. Recurrences occur almost exclusively distal to the primary tumor, site and are frequently of lower stage and grade.12 Namely, tumors of the distal ureter may be the most optimal candidate among UTUCs for using NSM. Dalpiaz et al13 demonstrated that DU is an effective treatment option for distal ureteral tumors and did not appear to be inferior to RNU regarding the oncological outcome. Fukushima et al14 also concluded that the oncological outcome of DU is comparable with that of RNU in distal ureteral UC patients, and DU results showed enhanced preservation of renal function. It is well known that the patients who received RNU had notable decreases in renal function and will develop CKD in the future. Serial complications of CKD, such as cardiovascular morbidity or dialysis-dependent renal failure, may also occur among these patients. Kaag et al15 retrospectively reviewed the data of 388 patients who underwent nephroureterectomy for UTUC between 1991 and 2009, and concluded that estimated glomerular filtration rate (eGFR) is significantly diminished after nephroureterectomy, particularly in elderly patients. These changes in renal function likely affect the eligibility for adjuvant cisplatin-based therapy. The value of renal function preservation seemed to be more important in advanced UTUC patients for further adjuvant chemotherapy. In our case series, preservation of patient’s renal function could be identified from the preoperative and 1-year postoperative serum creatinine levels. The mean preoperative creatinine level was 1.61 mg/dL, and the creatinine level at 12 months after operation was 1.56 mg/dL (p ¼ 0.95). There was no significant difference between preoperative creatinine and creatinine at 12 months after operation, which appears to be an advantage for further adjuvant chemotherapy if indicated. The surgical candidates of our small case series were similar to previous studies, which mainly included patients with severely
Please cite this article in press as: Lee Y-H, et al., Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2016.12.002
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impaired renal function, solitary kidneys, bilateral synchronous tumors, or the necessity of platinum-based chemotherapy for future treatment. Furthermore, this NSM was applied only to our patients with a single lesion at the distal ureter, according to the image study or endoscopy results. The percentage of patients with locally advanced disease (pT2e3) in our case series was 57.9% (11/19), which was higher compared with previous studies (26% in Simonato et al’s12 series). This may be one of the reasons that the bladder recurrence rate was relatively higher in our series. However, there was no local recurrence in our series and two patients received RNU during the follow-up period due to disease progression. During regular follow-up, one patient had renal pelvis tumor with inferior vena cava (IVC) thrombus of ipsilateral side without other distant metastasis, and RNU with bladder-cuff excision and IVC thrombectomy were performed. For another patient, an ipsilateral renal pelvis tumor and a bladder tumor with uterus invasion were found, and RNU with bladder-cuff excision and hysterectomy with oophorectomy were performed. Meanwhile, one patient died of UTUC. According to our experience, these patients should not be excluded from the opportunity of receiving NSM. The relatively small case number due to the rarity of the disease and the short follow-up period are the limitations of our retrospective non-randomized study. It's one of our study limitations that lack of head to head outcome comparison to standard nephroureterectomy with bladder cuff resection. Owing to the rarity of the UTUC cases, the number of cases with pure single-lesion distal ureter cancer was even fewer. According to the chart review of our institute, there was one patient with single distal ureter cancer who received standard nephroureterectomy with bladder-cuff resection. A randomized controlled trial may be too difficult to complete; hence, these retrospective studies may be valuable when interpreted with caution. 5. Conclusion In the selected patients (with CKD and solitary kidney), DU with reimplantation surgery in our experience is a feasible option for distal ureteral tumors. Favorable postoperative outcomes with a low local recurrence rate, a low rate of progression to nephroureterectomy, and renal function preservation may prove the
value of this modality and should be considered in suitable patients. Conflicts of interest All authors declare no conflicts of interest. References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10e29. 2. Huang WC, Levey AS, Serio AM, Snyder M, Vickers AJ, Raj GV, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol 2006;7:735e40. 3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Eng J Med 2004;351:1296e305. 4. Gibson TE. Local excision in transitional cell tumors of the upper urinary tract. J Urol 1967;97:619e22. 5. Petkovic SD. Conservation of the kidney in operations for tumors of the renal pelvis and calyces: a report of 26 cases. Br J Urol 1972;44:1e8. 6. Clark P, Spiess P, Agarwal N, Bangs R, Boorjian S, Buyyounouski M, et al., National Comprehensive Cancer Network, Inc. National comprehensive cancer guidelines: bladder cancer including upper urinary tract tumours and urothelial carcinoma of the prostate, vol. 1; 2015. 7. Roupret M, Babjuk M, Comperat E, Zigeuner R, Sylvester R, Burger M, et al. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol 2013;63:1059e71. 8. Ho KL, Chow GK. Ureteroscopic resection of upper-tract transitional-cell carcinoma. J Endourol 2005;19:841e8. 9. Yang MH, Chen KK, Yen CC, Wang WS, Chang YH, Huang WJ, et al. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology 2002;59:681e7. 10. Tawfiek ER, Bagley DH. Upper-tract transitional cell carcinoma. Urology 1997;50:321e9. €m C, Johansson SL, Pettersson S, Wahlqvist L. Carcinoma of the ure11. Anderstro ter: a clinicopathological study of 49 cases. J Urol 1989;142:280e3. 12. Simonato A, Varca V, Gregori A, Benelli A, Ennas M, Lissiani A, et al. Elective segmental ureterectomy for transitional cell carcinoma of the ureter: longterm follow-up in a series of 73 patients. BJU Int 2012;110(11 Pt B):E744e9. 13. Dalpiaz O, Ehrlich G, Quehenberger F, Pummer K, Zigeuner R. Distal ureterectomy is a safe surgical option in patients with urothelial carcinoma of the distal ureter. Urol Oncol 2014;32. 34.e1ee8. 14. Fukushima H, Saito K, Ishioka J, Matsuoka Y, Numao N, Koga F, et al. Equivalent survival and improved preservation of renal function after distal ureterectomy compared with nephroureterectomy in patients with urothelial carcinoma of the distal ureter: a propensity score-matched multicenter study. Int J Urol 2014;21:1098e104. 15. Kaag MG, O’Malley RL, O’Malley P, Godoy G, Chen M, Smaldone MC, et al. Changes in renal function following nephroureterectomy may affect the use of perioperative chemotherapy. Eur Urol 2010;58:581e7.
Please cite this article in press as: Lee Y-H, et al., Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2016.12.002
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Original article
Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience Yen-Hsi Lee a, Henry Y. Lin a, Chung-Hsien Chen a, Yu-Chi Chen a, Ching-Yu Huang a, Kevin Lu a, Chao-Yang Jiang a, Hua-Pin Wang a, Victor C. Lin a, b, * a b
Department of Urology, E-DA Hospital, Kaohsiung, Taiwan School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 March 2016 Received in revised form 7 December 2016 Accepted 8 December 2016 Available online xxx
Objective: Radical nephroureterectomy with bladder-cuff excision has been the traditional treatment for upper tract urothelial carcinoma because of its high rate of recurrence. However, given the morbidity of nephrectomy and the risk of developing chronic kidney disease or dialysis-dependent renal failure, the nephron-sparing approach may be preferable in selected patients. Materials and methods: A total of 118 patients who received unilateral distal ureterectomy with reimplantation at a single center in Taiwan were included, using surgical code numbers, from March 2006 to December 2014. A total of 82 patients were excluded due to nonmalignancy and 17 due to concomitant bladder cancer. Finally, 19 patients with primary, solitary, unilateral ureter lesions and confirmed to have ureter malignancy (urothelial carcinoma, n ¼ 18; squamous cell carcinoma, n ¼ 1) were included. Results: Of the 19 patients (13 males and 6 females) included, the mean age was 69.3 ± 10.7 years. Tumor pathological staging was Tis (n ¼ 1), Ta (n ¼ 3), T1 (n ¼ 2), T2 (n ¼ 6), and T3 (n ¼ 5). Histopathology grading was low grade (n ¼ 3) and high grade (n ¼ 13). No local recurrence was noted; nine patients had bladder recurrence (47.4%), three had distant metastasis (15.8%), and two had progression and finally underwent radical nephroureterectomy (10.5%). The mean time to bladder recurrence was 12.4 months (3e24 months); the mean follow-up time was 28.1 months (1e90 months). The 5-year overall survival rate was 73.7% (14/19); four patients were lost to follow-up, and one patient expired. The mean 5-year progression-free survival was 67.74%. The mean preoperative creatinine level was 1.61 mg/dL, and at 12 months after operation it was 1.56 mg/dL (p ¼ 0.95). Conclusion: In selected patients, distal ureterectomy with reimplantation, in our experience, is a feasible option for distal ureter tumor. Favorable postoperative outcomes with a low local recurrence rate, a low rate of progression to nephroureterectomy, and renal function preservation may prove the value of this modality and should be taken into consideration in suitable patients. Copyright © 2017, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: distal ureter cancer distal ureterectomy nephron-sparing management
1. Introduction Comprising only 5% of all renal and urothelial tumors, upper tract urothelial carcinoma (UTUC) is a rare genitourinary malignancy.1 For resectable tumors, radical nephroureterectomy (RNU) with bladder-cuff excision has been the gold standard treatment of choice. However, given the morbidity after nephrectomy and the risk of developing chronic kidney disease (CKD), cardiovascular * Corresponding author. Department of Urology, E-DA Hospital, Kaohsiung, Taiwan. E-mail address: [email protected] (V.C. Lin).
morbidity, or dialysis-dependent renal failure, a nephron-sparing approach may be preferable in selected patients.2,3 Nephronsparing management (NSM) has been used for UTUC in patients with severely impaired renal function, solitary kidneys, bilateral synchronous tumors, or the necessity of platinum-based chemotherapy for future treatment.4,5 According to the European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines, segmental resection of the distal ureter could be an option for distal ureteral urothelial carcinomas (UCs) even in patients with highgrade, locally invasive distal ureteral UC, particularly for individuals with imperative indications.6,7
http://dx.doi.org/10.1016/j.urols.2016.12.002 1879-5226/Copyright © 2017, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Lee Y-H, et al., Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2016.12.002
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Y.-H. Lee et al. / Urological Science xxx (2017) 1e4
To our knowledge, it remains controversial whether NSM represents a valid alternative to standard RNU in selected patients, due to limited long-term oncological results of NSM for UTUC. This study aimed to evaluate the oncological outcome in patients with distal ureteral carcinoma who were treated with NSM in a single center (Kaohsiung City, Taiwan). We retrospectively analyzed the oncological outcomes and changes in the renal function of patients with distal ureteral malignancy who underwent distal ureterectomy (DU) with reimplantation of the ureter. 2. Materials and methods 2.1. Study population A total of 118 patients who received unilateral distal ureteral resection with reimplantation at a single center in Southern Taiwan from March 2006 to December 2014 were included. The exclusion criteria were aged < 18 years, concomitant bladder cancer, and a history of bladder cancer. Eighty-two patients were excluded due to nonmalignancy and 17 due to concomitant bladder cancer. Therefore, our final cohort included 19 patients with a primary, solitary, unilateral ureteric lesion confirmed as a ureteral malignancy (UC, n ¼ 18; squamous cell carcinoma, n ¼ 1) on final pathology. The preoperative evaluation included serum creatinine, renal echo, intravenous pyelography, computed tomography of the abdomen/pelvis or magnetic resonance imaging of the abdomen, magnetic resonance imaging of urography (MRU), and chest X-ray. Cystourethroscopy or ureteroscopy with tumor biopsy was not routinely performed, to avoid tumor cell spillage into the upper urinary tract. The tumor location and length can be evaluated using image studies such as intravenous pyelogram (IVP) and abdominal computed tomography. If the image study failed to evaluate the tumor location and length, we performed ureteroscopy for intraluminal evaluation. Some patients had a biopsy report at a previous hospital before the surgery; others had strong evidence of malignancy on image studies. As for resection length, the bulging tumor can be identified during the operation grossly, and the proximal and distal margins were sent for frozen section examination for confirmation that there was no malignancy. 2.2. Surgical procedures All 19 patients received DU with reimplantation of the ureter using the Lich method, with psoas hitch bladder, direct ureteroneocystostomy, or Boari flap bladder. A frozen section of the proximal ureteral margin was examined during the operation and confirmed to be negative for malignancy. The indication for and extent of lymphadenectomy were considered by the surgeon. At a minimum, a lymphadenectomy was performed when lymphadenopathy was detected by imaging studies or during surgery. 2.3. Follow-up Urine cytology, biochemical studies, including renal function and renal echo, were routinely performed every 3 months in the first 2 years and annually thereafter. Outcome measures were recurrence or distant metastasis, renal function preservation, time to recurrence, and overall survival. 2.4. Statistical analysis Continuous parametric variables were reported as the mean value ± standard deviation. The survival range was defined by the
time elapsed since the day of surgery and the last clinical evaluation or the patient's death. Survival curves were estimated using KaplaneMeier curves. Analyses used SPSS version 18 (SPSS Statistics 18; IBM, Armonk, New York, United States). A p value < 0.05 was considered statistically significant. 3. Results A total of 19 patients (13 males and 6 females) were included, and the mean age was 69.3 ± 10.7 years. Eleven patients received ureteral reimplantation by Lich method, four received psoas hitch bladder reimplantation, and four received Boari flap bladder reconstruction. Tumor pathological staging was T0 (n ¼ 1), Ta (n ¼ 3), Tis (n ¼ 1), T1 (n ¼ 2), T2 (n ¼ 6), T3 (n ¼ 5), and T4 (n ¼ 1). The pT4 case had ureter tumor that invaded into the myometrium of the uterus. All had malignancy except one patient with pathology T0 who had endoscopic biopsy-proven malignancy before. The lesion might have been removed during the previous endoscopic biopsy procedure, and the patient had no further recurrence during the follow-up period. Histopathology grading was presented as follows: low grade, n ¼ 3; high grade, n ¼ 13. For the other three patients, the final pathology was pT0 in one patient and squamous cell carcinoma was found in another patient, which had no grading. The grading was not found in the remaining patient (Table 1). There were no local recurrences, but nine patients had bladder recurrence (47.4%), three had distant metastasis (15.8%), and two had progression and, ultimately, underwent RNU (10.5%). The mean time to bladder recurrence was 12.4 months (3e24 months) and the mean follow-up time was 28.1 months (1e90 months). The recurrence incidence was 66.7% (4/6) and distal metastasis incidence was 16.7% (1/6) for the Ta, T1, and Tis groups. The recurrence incidence was 50% (6/12) and distal metastasis incidence was 16.7% (2/12) for the T2, T3, and T4 groups. Furthermore, the recurrence incidence was 66.7% (2/3) and distal metastasis incidence was 33.3% (1/3) for the pathology low-grade group. The recurrence incidence was 61.5% (8/13) and distal metastasis incidence was 15.4% (2/13) for the pathology high-grade group. The 5-year overall survival rate was 73.7% (14/19); among them, four patients were lost to follow-up and one patient expired. The mean 5-year progression-free survival was 67.74% (Figure 1). The mean preoperative creatinine level was 1.61 mg/dL, and the postoperative creatinine level was 1.56 mg/dL at 12 months (p ¼ 0.95). The KaplaneMeier curves for bladder recurrence-free survival are displayed in Figure 2. The 5year progression-free survival rate, stratified by stage, is presented in Figure 3. Owing to the limited cases, the relationship between stage and bladder recurrence incidence was not significant in this study. Table 1 Patient characteristics (n ¼ 19). Age (y) Sex (M:F) Preop creatinine (mg/dL) Stage pT0 pTa pTis pT1 pT2 pT3 pT4 Grade Low High Other N/A
69.3 (46e82) 13:6 1.61 (1.0e2.5) 1 3 1 2 6 5 1 3 13 2 1
N/A ¼ not applicable.
Please cite this article in press as: Lee Y-H, et al., Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2016.12.002
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Figure 3. Progression-free survival stratified by stage (log rank p ¼ 0.67).
Figure 1. Progression-free survival.
Figure 2. Bladder recurrence-free survival.
4. Discussion UTUC is a rare disease. Primary UTUC represents approximately 5% of all UCs and 10% of all primary renal tumors. Resembling UC of the bladder, UTUC may recur and progress in any location in the urinary tract. The most common location for ureteral UC is the distal ureter (70%), followed by the middle (25%) and proximal (5%) ureter.8 However, the ratio of UTUC in Taiwan is relatively higher than in other countries. The incidence of UTUC was relatively high
(the ratio of renal pelvis:ureter:urinary bladder was 1:2.08:6.72), despite the majority of patients residing outside the endemic “blackfoot disease” area in Taiwan.9 The NSM for UTUC, other than traditional RNU, may be a valuable alternative for select patients, particularly in Taiwan. Among UTUCs, tumors of the distal ureter are more common than those of the midureter and proximal ureter, and are more frequently solitary, smaller, and of lower stage and grade than their renal pelvic or upper ureteral counterparts.10,11 Furthermore, distal ureteral UC is less often associated with recurrent disease within the upper urinary tract. Recurrences occur almost exclusively distal to the primary tumor, site and are frequently of lower stage and grade.12 Namely, tumors of the distal ureter may be the most optimal candidate among UTUCs for using NSM. Dalpiaz et al13 demonstrated that DU is an effective treatment option for distal ureteral tumors and did not appear to be inferior to RNU regarding the oncological outcome. Fukushima et al14 also concluded that the oncological outcome of DU is comparable with that of RNU in distal ureteral UC patients, and DU results showed enhanced preservation of renal function. It is well known that the patients who received RNU had notable decreases in renal function and will develop CKD in the future. Serial complications of CKD, such as cardiovascular morbidity or dialysis-dependent renal failure, may also occur among these patients. Kaag et al15 retrospectively reviewed the data of 388 patients who underwent nephroureterectomy for UTUC between 1991 and 2009, and concluded that estimated glomerular filtration rate (eGFR) is significantly diminished after nephroureterectomy, particularly in elderly patients. These changes in renal function likely affect the eligibility for adjuvant cisplatin-based therapy. The value of renal function preservation seemed to be more important in advanced UTUC patients for further adjuvant chemotherapy. In our case series, preservation of patient’s renal function could be identified from the preoperative and 1-year postoperative serum creatinine levels. The mean preoperative creatinine level was 1.61 mg/dL, and the creatinine level at 12 months after operation was 1.56 mg/dL (p ¼ 0.95). There was no significant difference between preoperative creatinine and creatinine at 12 months after operation, which appears to be an advantage for further adjuvant chemotherapy if indicated. The surgical candidates of our small case series were similar to previous studies, which mainly included patients with severely
Please cite this article in press as: Lee Y-H, et al., Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2016.12.002
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impaired renal function, solitary kidneys, bilateral synchronous tumors, or the necessity of platinum-based chemotherapy for future treatment. Furthermore, this NSM was applied only to our patients with a single lesion at the distal ureter, according to the image study or endoscopy results. The percentage of patients with locally advanced disease (pT2e3) in our case series was 57.9% (11/19), which was higher compared with previous studies (26% in Simonato et al’s12 series). This may be one of the reasons that the bladder recurrence rate was relatively higher in our series. However, there was no local recurrence in our series and two patients received RNU during the follow-up period due to disease progression. During regular follow-up, one patient had renal pelvis tumor with inferior vena cava (IVC) thrombus of ipsilateral side without other distant metastasis, and RNU with bladder-cuff excision and IVC thrombectomy were performed. For another patient, an ipsilateral renal pelvis tumor and a bladder tumor with uterus invasion were found, and RNU with bladder-cuff excision and hysterectomy with oophorectomy were performed. Meanwhile, one patient died of UTUC. According to our experience, these patients should not be excluded from the opportunity of receiving NSM. The relatively small case number due to the rarity of the disease and the short follow-up period are the limitations of our retrospective non-randomized study. It's one of our study limitations that lack of head to head outcome comparison to standard nephroureterectomy with bladder cuff resection. Owing to the rarity of the UTUC cases, the number of cases with pure single-lesion distal ureter cancer was even fewer. According to the chart review of our institute, there was one patient with single distal ureter cancer who received standard nephroureterectomy with bladder-cuff resection. A randomized controlled trial may be too difficult to complete; hence, these retrospective studies may be valuable when interpreted with caution. 5. Conclusion In the selected patients (with CKD and solitary kidney), DU with reimplantation surgery in our experience is a feasible option for distal ureteral tumors. Favorable postoperative outcomes with a low local recurrence rate, a low rate of progression to nephroureterectomy, and renal function preservation may prove the
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Please cite this article in press as: Lee Y-H, et al., Nephron-sparing management (distal ureterectomy with reimplantation of ureter) for carcinoma of distal ureter: A single-center experience, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2016.12.002