Analyse des recoupes urétérales extemporanées lors de la cystectomie : pourquoi et pour qui ? (revue de la littérature)

16 mai 2021

Auteurs : F. Saint, A. Masson-Lecomte
Référence : Prog Urol, 2021, 6, 31, 303-315




 




Introduction


Radical cystectomy (RC) with pelvic lymph node dissection is the standard treatment option for non-metastatic, resectable muscle invasive bladder cancer (BCa) with a life expectancy rate close to 70% at 5 years [1]. However, in order to maximize oncologic outcome, the surgical procedure has to be standardized [2]. Patients with BCa are at risk of experiencing upper urinary tract recurrences (UUTR) during the follow-up period [3]. Upper urinary tract recurrence is frequently symptomatic, advanced disease, and associated with a metastatic evolution that severely affect survival expectancy [3, 4, 5].


Although patients with a positive ureteral intraoperative frozen section have been found to be at increased risk of developing UUTR during follow-up [6, 7, 8, 9], the optimal intraoperative management of patients with intraoperative positive ureteral margin is still under debate. Surgeons make the decision to evaluate margins intraoperatively on a case-by-case basis. Analysis of available literature questions both:

•
the ability of intraoperative frozen sections to properly predict final involvement of the ureters;
•
the impact of invaded intraoperative ureteral sections (with or without achieving negative ureteral margin) on upper urinary tract recurrences and oncological outcome;
•
patients most likely to benefit of intraoperative ureteral frozen section.


In that regard, the latest EAU guidelines do not provide any recommendations [2]. The aim of this review was to evaluate frequency, reliability and impact of positive distal ureteral margin after radical cystectomy for bladder cancer on upper tract recurrence, cancer specific and overall survival, and to identify best candidates for intraoperative frozen section analyses.


Material and methods


A systemic review was performed following the PRISMA guideline using PubMed/Medline and Cochrane Library databases to identify eligible studies published between the creation of the databases and April 2020. The primary search string included the following items: bladder cancer OR cystectomy AND frozen section OR ureteral margin. Filters were applied to exclude any studies not performed on humans. Additionally, a manual search of the reference lists of relevant meta-analysis was conducted to identify all available studies.


The reference lists from selected papers were also searched for relevant studies that may have been missed during the initial searches. Papers for inclusion analyzed at patient treated by radical cystectomy for urothelial carcinoma of the bladder (bladder cancer, BCa). The papers studied ureteral margin, prognostic factors associated with positive ureteral margin and their conversion to negative, and evaluated impact on upper urinary tract recurrence-free rate (UUTR), cancer specific survival, and overall survival of these positive ureteral margins. Randomized controlled trials and prospective or retrospective analyses exploring patients with BCa treated by RC and studied on the basis of ureteral margin have been included. All previous reviews were automatically excluded, as were single case reports, editorial pieces, comment, and titles that were not available in English/French. The subsequently available papers were then systematically reviewed. The ultimate goal of this review was to assess any available papers that examined ureteral margin status at time of RC (frozen [FS] and permanent sections [PS]), that identified prognostic factors associated with positive ureteral margins, and that evaluated impact on upper urinary tract recurrence-free rate (UUTR), cancer specific survival (CSS), and overall survival (OS). The search technique is summarized in Figure 1.


Figure 1
Figure 1. 

PRISMA flow diagram.





Results


In total, thirty-two relevant studies were identified. All studies published between 1989 and 2020 were retrospective, except the one published by Osman et al. [7]. Of these, seventeen studies reported specifically ureteral margin status (Table 1), and seventeen studies have recorded reliability of FS using PS as a reference (Table 2). Furthermore, twelve studies reported ureteral margin status (FS and/or PS) and upper urinary tract recurrence risk and three studies evaluated distal ureteral margin status as prognostic factor for cancer specific or overall survival after cystectomy (Table 3). Twelve studies explored prognostic factors associated with pathological positive ureteral margin at time of RC (Table 4). Potential studies bias have been reported Table 5.


Positive frozen section (FS) and permanent section (PS) rate


In contemporary series, the incidence of initial positive ureteral margin ranged between 1.1% to 25.4% for FS, and between 0.8% and 15% for PS (Table 1) [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. Sensibility ranged from 45 to 100% and specificity from 83 to 100%. Positive predictive value (PPV) ranged from 25 to 100% and negative predictive value (NPV) from 91 to 100%. Positive margin was successfully converted to negative margin during surgery for 39% to 100% patients (Table 2) [6, 7, 8, 9, 12, 13, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26].


Positive ureteral margins and upper urinary tract recurrence (UUTR), cancer specific and overall survival


After total cystectomy, upper urinary tract recurrence (UUTR) is an uncommon event and was recorded for 0.2% to 6.2% of patients (Table 3) [6, 8, 9, 10, 12, 13, 15, 19, 20, 21, 22]. Positive section was associated with higher rate of UUTR [6, 8, 9, 21, 22]. However, intraoperative positive frozen section converted to negative was associated with lower risk of UUTR compared to non-converted [8, 9, 21, 22].


In some papers, specific attention was paid to discriminate specific incidence of invasive tumor in uretero-ileal anastomosis from UUTR. Anastomotic recurrence was uncommon and its occurrence ranged between 0% and 1% (Table 3) [6, 8, 9, 10, 12, 13, 15, 16, 19, 22].


Regarding association with cancer specific mortality, results are equivocal. Cancer specific mortality attributable to concomitant carcinoma in situ on ureteral section appeared to be weak, probably hidden by bladder cancer specific mortality. Two contemporary retrospective studies (with more than 300 patients) failed to associate positive frozen section to survival [16, 20], while Moschini et al. associated positive frozen section with CSS and OS in one of the largest retrospective study published (n =1147) [21].


Prognostic factors associated with positive ureteral margins


Eleven studies reported prognostic factors associated with positive ureteral sections. All but one included a multivariate analysis. No prospective study was identified. Involvement of the prostatic urethra, history of bladder Cis, trigone involvement, hydronephrosis, clinical stage over pT2, tumor multifocality were advocated [6, 7, 9, 16, 17, 18, 19, 21, 22, 24, 27, 28] (Table 4). Bladder CIS was the most consistent factor associated with positive ureteral section (FS and/or PS) at time of radical cystectomy (odds ratio between 6.4 and 177.9 for FS and between 3.3 and 11.1 for PS [Table 4]).


Discussion


To our knowledge, this study is the first systemic extended review related to ureteral margin frequency, reliability and impact of positive distal ureteral margin on upper tract recurrence, cancer specific and overall survival. This systemic review have shown a significant degree of clinical and methodological heterogeneity across all studies (including patient groups, length of follow-up and outcome measures), preventing pooled analysis of the results and making direct comparison between the papers sometime very challenging. Furthermore quality of these reports did not meet current standards of evidence-based medecine and were most of the time based on retrospective studies (level 4).


Positive frozen section rate


Performing frozen section analysis of the distal ureteral margins at the time of cystectomy is daily routine in many urologic institutions. Positive results would lead to additional tissue resection in order to obtain a negative margin status. In old series, assiduous approaches using step-sectioning techniques have demonstrated that more than half of patients showed intraepithelial carcinoma or more advanced ureteric lesions for solid papillary bladder tumors, and more than one third showed carcinoma in situ or more advanced lesions in the ureteric stumps [29, 30].


In contemporary series, we observed a high variability in the positive ureteral section rate (1.1% to 25.4%) [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. It can be explained as much by some differences in pathologic evaluation and definition of ureteral sample (presence of carcinoma and CIS for most of the authors, associated with high grade dysplasia and atypia for others), as well as by differences in intraoperative management of ureteral length (shortening of the ureter probably minimizes the risk of positive surgical margins). Hence, when the redundant ureter segment resected above the common iliac vessels was performed, carcinoma in situ was detected in only 0.1% on permanent section, suggesting that ureteral frozen section analysis is probably unnecessary in the majority of patients undergoing RC [15].


Sensibility and specificity of ureteral frozen section (FS)


Despite the risk of distal ureteric malignancy on radical cystectomy specimen [15], the clinical value of routine FS remains questionable. Studies reported in this review showed that FS confirmed a very good specificity and a very good NPV [6, 9, 13, 16, 18, 20, 22, 24, 25]. Using “presence of carcinoma” as pathologic definition of ureteral sample increased the specificity without large compromises in sensitivity [20]. However, with its low positive predictive value, FS tends to underestimate disease at the ureteral margin [7, 13, 16].


From a surgical point of view: indeed, there is no detrimental effect of performing FS (it is not time consuming). However, in case of resection of the redundant ureter segment above the common iliac vessels, some authors reported that carcinoma in situ was not detected for 99.9% patients on permanent section, suggesting that ureteral frozen section analysis is probably unnecessary in the majority of patients undergoing RC. One may consider that resecting 5cm or 10cm (to be above the common iliac vessels) doesn’t take much more time to surgeons than performing FS. Moreover, this technical point should be useful to avoid damage inflicted on the ureter during distal surgical mobilization, and subsequent complications such as necrosis and stenosis. From a cost-effectiveness point of view, the direct and indirect costs associated with FS are substantial and should be considered given the questionable clinical value of this test. Therefore, for some authors FS should be advocated and performed for selected patients undergoing radical cystectomy [16]. From a Human Resources point of view, access conditions to FS are somewhat heterogeneous in terms of hospitalization structure and execution (e.g. cryostat, décimu), making the availability of this examination sometimes difficult.


Positive ureteral margins (PUM) and upper urinary tract recurrence (UUTR), cancer specific and overall survival


Several retrospective studies have shown that a positive ureteral margin does predict upper urinary tract recurrence [6, 8, 15, 22, 24, 31] and may be associated with malignant ureteroenteric stricture occurring in approximately 0.2% to 1% [14, 32] of the cases. For Schumacher et al. when frozen sections were negative, 3% of patients developed UUTR, versus 17% when frozen sections were positive [15]. However, frequency of UUTR was probably linked to differences in intraoperative management performed by surgeons, and when the redundant ureteral segment was resected above the common iliac vessels, UUTR was detected in only 0.3% of patients [15]. Moreover, recurrence side did not always match with the positive ureteral section side [6, 8, 14, 20].


Consequently, intraoperative analysis of ureteral margin should theoretically facilitate tumor removal, decrease upper urinary tract recurrence (UUTR) rate and improve cancer specific survival. On a practical level, in many cases, an initial positive margin on frozen section can be converted to a final negative margin by sequential sectioning of the ureter (more than 50% of cases) [7, 12, 13, 15, 16, 18, 19, 20, 22, 23, 25, 26], even if for some authors sequential ureteral resection was associated with low intraoperative conversion rates [6, 9].


So far, there is no definitive evidence that complete extirpation of malignant ureteric involvement (proven by negative frozen sections margin during RC) eliminates the risk for recurrence of UUT disease [4, 5, 6, 15, 33, 34] even if conversion from positive FS to negative FS, and/or negative PS, may improve UUTR free status in several retrospective studies [8, 9, 21, 22].


Indeed, pagetoid spread of CIS makes it is impossible to guarantee that negative frozen sections ensure that CIS is not more proximal. Some data support the theory that, in addition to local field progression of the disease, a multicentric process is involved in the etiology of UUTR (due to intraluminal seeding and intraepithelial migration). Such hypothesis is also consistent with the fact that, in patients with bladder cancer CIS, upper tract involvement is associated with high rate of prostate involvement (67.6%) and bilateral ureteral disease (32%) [35]. Because urothelial carcinoma is associated with pan epithelial field defect and skip lesions are more common in patients with bladder CIS, tumor may occur anywhere in the urinary tract after treating an initial carcinoma [25]. Hoang et al. analyzed 660 patients who underwent RC and found 4.8% of ureteric skip lesion, half of them related to CIS [25]. Then, positive ureteral surgical margin did not necessarily translate to a large impact on patient outcome, and the risk of UUTR remained difficult to be evaluated (small cohorts, short follow-ups and competing risk with dying from bladder cancer) [5, 6, 31, 36].


As for UUTR, it remains controversial if clearing the margins improves cancer survival. Given the low number of upper tract recurrences and the weak association between such recurrences and death, it is unlikely to have a significant impact on reducing recurrences on cancer specific survival and overall survival outcome. Various groups suggested that ureteral carcinoma in situ in ureteral surgical margin barely contributes to cancer specific survival and overall mortality in patients who undergo radical cystectomy [8, 12, 14, 16, 20, 22]. Only one large retrospective study, published by Moschini et al. reported the beneficial effect of sequential sectioning FS on cancer specific survival and overall survival, only for patients who were found N0, R0, and <pT3 [21].


Prognostic factors for positive ureteral margins


Targeting the high-risk subgroups for positive margins could confirm the utility, the clinical significance and the impact on UUTR, cancer specific survival and overall survival of FS at time of radical cystectomy (RC).


Based on step-sectioning, radical cystectomy specimen was associated with grade 3 carcinomas mucosal involvement (CIS and high grade dysplasia) adjacent to and remote from the visible tumor for 30 to 50% of patients [30, 37]. Trigone region and contiguous posterior wall were particularly affected, and 57.1% patients were concerned by ureteral involvement (demonstrating direct intramucosal spread of malignant epithelial cells process) [30]. Finding published by Johnson et al. and Schumacher et al. suggested that patients with CIS of the bladder could have concomitant CIS of the distal ureter, in as many as 24% of patients [10, 15].


Long ago, Johnson et al. emphasized the importance of careful examination of the ureteral margin prior to constructing ureteroenteric anastomoses in patients with multifocal carcinoma in situ involving either the bladder or prostatic ducts [10]. Two contemporary studies with low numbers of patients [7, 17] and with low frequency CIS within the bladder (20% and 27.7% respectively) [17, 22], showed no association with positive ureteral margin [7, 17, 22]. However, even if some problem for histopathological diagnosis may exist, in several retrospective recent studies, ureteral CIS involvement was significantly associated with the presence of the CIS within the bladder [6, 16, 18, 19, 21, 24, 27, 28].


Schumacher et al. reported that close to 80% of patients with CIS in the ureter have CIS in the bladder [15], and Raj et al. reported 30% of patients with bladder CIS have ureteric involvement in the RC versus only 9% of patients without [6]. Unfortunately, the presence of CIS in TURBT and RC specimens was also predictive and correlated with ureteric skip lesion (odds ratio [OR] 4.15, 95% CI 2.00–8.55, P <0.001 and [OR] 7.87, 95% CI 3.19–19.23, P <0.001), respectively [25].


Due to the retrospective nature of studies, we were unable to determine whether CIS was focal or diffuse and if the extent of CIS was associated with an altered risk of ureteral involvement, upper recurrence or survival outcomes. However, factors associated with an increasing risk ratio for UUTR, included history of CIS, history of recurrent bladder cancer, cystectomy for noninvasive bladder cancer [3, 35]. Typically, Cis is present in close to 10% of TUR specimens versus 30 to 50% after cystectomy and final examination. This can be explained by the fact that less material was analyzed during TUR and by the difficulty and dedication required to determine the presence of concomitant Cis at the morphologic level (inter-observer variability). However some qualitative concepts, associated with adherence to specific National and International guideline, must be reminded to really rely on TUR specimen [2]. Initial treatment for bladder cancer involves transurethral resection (TUR) of tumors to remove all possible tumors and obtain material for histological examination. As a result, resection patients are started on treatment pathways that reflect the nature and the potential of their disease. If TUR should include a deeper part, which has to be sent in separately, incomplete TUR should be exceptional (technical considerations) to avoid re-TUR necessity (morbidity and cost implication) and to reflect as close as possible the nature of the disease. Additional, bladder biopsy should be associated for bladder abnormal-looking urothelium and when cytology is positive and when a non-papillary appearance was found. In the 21st century (equipment shall be available), photodynamic diagnosis could be considered to identify associated carcinoma in situ (Cis), and since the presence of Cis may lead to a modified treatment plan (e.g. chemo radiation) [2].


In orphan retrospective studies, other prognostic factors were discussed like tumor location (trigone), tumor multifocality, clinical stage, number of tumor, intramural invasion, mucosal or ductal prostatic urothelial cancer, and hydronephrosis [9, 17, 19, 22, 28].


Studies limitations


Most of the results published were derived from retrospective, observational data. Due to several limitations like patient-selection factors, surgical technique, multiplicity of surgeons, frequency follow-up, neoadjuvant chemotherapy before RC, imaging modalities used – which improved during last decade, and limited number of UUTR, the statistical relevance should be questioned. In retrospective studies, potential errors introduced by incomplete data acquisition and patient-selection bias should be discussed [17]. In context, differences in survival recorded in the subgroup of patients with negative soft tissue margins and negative node metastases could be an indirect effect of uncontrolled factors [21].


Conclusion


Literature data suggest that ureteral frozen section analysis is probably unnecessary in the majority of patients undergoing RC, and even more so when the redundant ureteral segment was resected above the common iliac vessels. For patients with CIS within the bladder, frozen section (FS) at the time of RC can accurately detect ureteral involvement with reliable specificity.


Several retrospective studies have shown that conversion from positive FS to negative may improve UUTR free status. Only one retrospective study showed the beneficial effect of sequential sectioning FS on cancer specific survival and overall survival only for patients (<pT3, R0, N0).


Adequate powered randomized controlled trial, based on large structured collaborative studies, are necessary to confirm the clinical significance and utility (UUTR, cancer specific survival and overall survival) of FS at time of radical cystectomy.


Disclosure of interest


The authors declare that they have no competing interest.




Table 1 - Studies reporting ureteral margin status.
Author [Reference]  Year of publication  Type of study  Follow-up  Number of patients studied  % of patients with positive ureteral margins  % of patients with positive ureteral margin  Definition 
      Mean (median) [–] months  (n Frozen section (FS)  Permanent section (PS)  Histologic finding 
          % (n % (n  
Johnson et al. [10 1989  Retrospective  24 [8–66]  n =403  2% (8/403)  –  Ta, T1, CIS 
          7,2% (29/403)  –  Ta, T1, CIS, dysplasia 
Batista et al. [11 1994  Retrospective  24.5 [4–72]  n =242  –  5.7% (14/242)  CIS 
Schoenberg et al. [12 1996  Retrospective  67 [3–148]  n =97  8.2% (8/97)  12.3% (12/97)  All carcinoma, CIS, mild atypia to severe atypia 
Silver et al. [13 1997  Retrospective  31.8 (22.9) [2–74.2]  n =401  6.2% (25/401)  5.2% (21/401)  Carcinoma, CIS 
Lee et al. [14 2006  Retrospective  (37.1) [2–113]  n =115  –  4.3% (5/115)  CIS 
Schumacher et al. [15 2006  Retrospective  (30) [2–96]  n =805  4.8% (39/805)    All carcinoma, CIS, Severe Atypia 
          1.1% (9/805) TCC  0.8% (7/805) TCC   
          3.7% (30/805) Cis  2.7% (22/805) Cis   
          1.4% (11/805) severe atypia     
Raj et al. [6 2006  Retrospective  (38.4) [1.2–204]  n =1330  10%a (124/1217)  13% (171/1330)  All carcinoma, CIS 
          (a) ureter unit  9%a (222/2579)  High grade atypia or dysplasia 
            (a) ureter unit   
Osman et al. [7 2006  Prospective  –  n =100  14% (14/100)  24% (24/100)  All carcinoma, CIS 
          8%a (16/193)  15%a (29/193)   
          (a) ureter unit  (a) ureter unit   
Tollefson et al. [8 2010  Retrospective  (43.2) [0.1–337.2] patients dead  n =1397  12.7% (178/1378)  –  All carcinoma, CIS 
      (168) [0.4349.2] patients alive        High grade atypia or dysplasia 
Touma et al. [16 2010  Retrospective  31.3  n =301  2.8%a (10/362)  8.8%a (32/362)  All carcinoma, CIS 
          (a) ureter unit  (a) ureter unit   
Gakis et al. [9 2011  Retrospective  (24) [1–116]  n =218  6.9% (15/218)  9.2% (20/218)  All carcinoma, CIS 
          4%a (17/425)  5.2%a(23/425)   
          (a) ureter unit  (a) ureter unit   
Gondo et al. [17 2013  Retrospective  –  n =197  19.3%a (38/197)  –  All carcinoma, CIS 
          (a) positive ureteral involvement (FS and/or PS)     
Zhou et al. [18 2014  Retrospective  –  n =203  8.4% (17/203)  –  All carcinoma, CIS 
Kim et al. [19 2015  Retrospective  –  n =402  11.5% (46/402)  8.7% (35)  All carcinoma, CIS, atypia, dysplasia 
Reder et al. [20 2015  Retrospective  (26) [0–156]  n =364  6.3%a (48/768) Cis  7.2%a (55/768) Cis  All carcinoma, CIS 
          3.8%a (29/768) carcinoma  3.7%a (28/768) carcinoma   
          (a) ureter unit  (a) ureter unit   
Moschini et al. [21 2016  Retrospective  95 (102)  n =1447  25.4% (368/1447)  13.1% (190/1447)  All carcinoma, CIS, high grade atypia 
Satkunasivam et al. [22 2016  Retrospective  (12.4) [1.9–10.1]  n =2047  8.6% (178/2047)  3.2% (66/2047)  All carcinoma, CIS, Severe atypia 



[a] 
Ureter unit.


Table 2 - Reliability of frozen section using permanent section as a reference.
Authors [Reference]  Year of publication  Sensibility  Specificity  PPV  NPP  % positive FS converted to negative 
Schoenberg et al. [12 1996  50%  97.6%  75%  93.2%  50% 
Silver et al. [13 1996  75%  97.4%  60%  98.6%  50% 
Schumacher et al. [15 2006  –  –  –  –  55.6% for TCC 
            96.7% for CIS 
Raj et al. [6 2006  73.7%  98.9%  90.3%  96.3%  39% 
Osman et al. [7 2006  45%  98%  81%  91%  100% 
Tollefson et al. [8 2010  –  –  –  –  82.6% 
Touma et al. [16 2010  71.9%  96.1%  63.9%  97.2%  – 
Gakis et al. [9 2011  73.9%  99.8%  94.4%  98.5%  41.1% 
Gordetsky et al. [23 2014  –  –  –  –  52.5% 
Loeser et al. [24 2014  –  –  100%  98%  – 
Hoang et al. [25 2014  80% (without skip lesions)  95% (without skip lesion)  25% (without skip lesion)  99.5% (without skip lesion)  – 
    22% (with skip lesions)  89% (with skip lesions)  62.5% (with skip lesions)  54.5% (with skip lesions)   
Zhou et al. [18 2014  100%  100%  100%  100  – 
Kim et al. [19 2014  75%  96%  55.5%  98.3%  75.6% 
    69% (CIS and carcinoma only)  99%  96%  98.2%   
Reder et al. [20 2015  82% (severe dysplasia/CIS)  99%  88%  98%  – 
    86% (carcinoma only)  99%  89%  99%   
Moschini et al. [21 2016  69%  83%  –  –  48% 
Satkunasivam et al. [22 2016  59.1%  93%  –  –  66.4% 
Cerf et al. [26 2020  91.5%  100%  100%  98.4%  74% 



Légende :
PPV: positive predictive value; NPV: negative predictive value; FS: frozen section.



Table 3 - Studies reporting ureteral margin status and upper urinary tract recurrence (UUTR), cancer specific survival (CSS) and overall survival (OS).
Authors [Reference]  Year of publication  % (n ) of patients with FS(+)  % (n ) of patients tumor free after new section  % of patients (n ) with upper urinary tract recurrence (UUTR)  % of patients (n Upper urinary tract recurrence-free rates according to the first and final margin ureteral status 
  (n       Ureteroenteric site recurrence (UER)   
Johnson et al. [10 1989  2% (8/403)  17% (1/6)  0.2% (1/403) dysplasia on FS  0%  – 
  (n =403)           
Schoenberg et al. [12 1996  8.2% (8/97)  50%  1% (1/97) (Cis on PS)  0%  – 
  (n =97)           
Silver et al. [13 1997  6.2% (25/401)  50%  0.5% (2/401)  0.25% (1/401)  – 
  (n =401)           
Schumacher et al. [15 2006  3.5%  55,6% for TCC  3.9% (31/805)  0.25% (2/805) (1 with CIS on frozen section)  – 
  (n =805)  (29/805)  96,7% for Cis       
Raj et al. [6 2006  13% (171/1330)  39%  6.2% (82/1330)  1% (13/1330)  PS(+) was associated with UUTR 
  (n =1330)        a2/13 PS(+) at anastomosis  HR 1.8; 95% CI, 1.1–3.1 (P =0.04) 
          (1.3%. 2/156)  PS(+) was not associated with UER (P =0.2) 
          a11/13 PS(−) at anastomosis   
          (0.5%; 11/2423)   
          (a) ureter unit   
Tollefson et al. [8 2010  12.7% (178/1378)  82.6%  5% (69/1378)  0.9% (13/1378)  FS(+) was associated with UUTR 
  (n =1397)        54% (7/13) with FS(+)  HR 4.88, 95% CI 3.02–7.90, P <0.001) 
            Conversion of FS(+) to FS(−) was associated with low UUTR 
            HR 4.39, 95% CI 2.59–7.43, P <0.001) 
            No conversion of FS(+) was worse 
            HR 7.37, 95% CI 4.3–16.4, P <0.01) 
            P =0.04 
            UUTR was ipsilateral to the FS(+) in 64% (18/28) 
Touma et al. [16 2010  2.8%a (10/362)  –  2% (6/301)    FS(+) was not associated with UUTR and overall survival 
  (n =301)  (a) ureter unit  –  67% with PS(−)  0%   
Gakis et al. [9 2010  6.9% (15/218)  41.1%  2.3% (5/218)  0.9% (2/218)  Conversion from FS(+) to PS(−) was associated with no UUTR 
  (n =218)  4%a (17/425)    10% PS(+) (1/10) 1.9% PS(−) (4/208)     
    (a) ureter unit    (P =0.03)     
Kim et al. [19 2015  5.2% (CIS and carcinoma only)  75.6%  2.7% (11/402)  0.2% (1/402)  FS(+) and PS(+) were not associated with UUTR 
  (n =402)  11.5% (46/402)         
Reder et al. [20 2015  6.3%a (48/768) CIS  –  2.7%  –  FS(+) and PS(+) were not associated with CFS and OS 
  (n =364)  3.8%a (29/768) carcinoma    None have FS(+)     
    (a) ureter unit         
Moschini et al. [21 2016  25.4% (368)  48%  7.1% if FS(+)  –  FS(+) conversion to PS(−) was associated with low 
  (n =1147)      4.5% if negative conversion     
        9.5% non-negative conversion    UUTR P <0.05 
            CFS P =0.01 
            OS P <0.05 
Satkunasivam et al. [22 2016  8.6% (178/2047)  66.4%  1.4% (28/2047)  0%  FS(+) associated with UUTR 
  (n =2047)      54% FS (−)  14.2% of 21 NUT have incidental (CIS, pTa) at ureteroenteric anastomosis  HR 6.2, CI 2.9–13.5 
            PS(+) associated with UUTR 
            HR 7.2, CI 2.7–18.9 P <0.001 
            FS(+) conversion to FS(−) was not associated with UUTR 



[a] 
Ureter unit.


Table 4 - Predicting pathological positive ureteral margin at time of RC.
Authors [Reference]  Year of publication  Pronostic factors for positive PS  Analysis  Type of study  Odds ratio 
  Patients (n       OR (95% CI) 
Nakanishi et al. [27 2006  CIS within bladder  Multivariate  Retrospective  3.33, CI: 1.05–10.53 (PS) P =0.04 
  n =158         
Raj et al. [6 2006  CIS within bladder  Multivariate  Retrospective  3.99, CI: 1.87–8.51 P <0.0005 
  n =1330         
Osman et al. [7 2006  FS(+)  Univariate  Prospective  PS+: 30% (with bladder Cis) and 9% (without) 
  n =100  Male gender      P <0.01 
    CIS within bladder      P =0.01 
          12.9% (no bladder Cis) versus 26.7% (bladder Cis) NS 
Touma et al. [16 2010  CIS within bladder  Multivariate  Retrospective  P <0.02 
  n =301  CIS of prostatic urethra      P <0.02 
Gakis et al. [9 2011  FS(+)  Multivariate  Retrospective  P <0.0001 
  n =218  Tumor multifocality      P <0.04 
Gondo et al. [17 2013  Tumor trigone location  Multivariate  Retrospective  (a) for FS(+) and/or PS(+) 
  n =197  Clinical stage>or=cT3      a2.408, CI: 1.116–5.200 P =0.0252 
    Number of tumor (> or =3)      a3.190, CI: 1.432–7.105 P =0.0045 
          a3.245, CI: 1.431–7.363 P =0.0048 
Loeser et al. [24 2014  CIS within bladder  Multivariate  Retrospective  0.85% (no bladder Cis) versus 35.6% (bladder Cis) P <0.0001 
  n =243         
Zhou et al. [18 2014  CIS within bladder  Multivariate  Retrospective  0% (no bladder Cis) versus 15.5% (bladder Cis) P <0.001 
  n =203         
Kim et al. [19 2015  CIS within bladder  Multivariate  Retrospective  11.1, CI: 2.3–54.03 P =0.003 
  n =402  Intramural invasion      7.82, CI: 1.97–31.04 P =0.003 
    Lymp node status      5.01, CI: 1.19–21.03 P =0.02 
    FS(+)      177.91, CI: 36.27–872.67 P <0.001 
Moschini et al. [21 2016  CIS within bladder  Multivariate  Retrospective  3.83, CI: 1.83–8 (PS) P <0.001 
  n =1447        6.40, CI: 2.86–14.3 (FS) P <0.001 
Satkunasivam et al. [22 2016  Mucosal or ductal prostatic urothelial cancer  Multivariate  Retrospective  a1.78, CI: 1.11–2.86 
  n =2047        (a) for FS(+) 
Masson et al. [28 2017  CIS within adder  Multivariate  Retrospective  Cohort A: hydronephrosis: odds ratio [OR]=4.9, P =0.004; CIS: OR=3.9, P =0.01 
    Hydronephrosis      Cohort B: hydronephrosis: [OR]=5.9, P =0.01; CIS: OR=3.4, P =0.10 
  Cohorte A: n =441         
  Cohorte B: n =307         



Légende :
FS: frozen section; PS: permanent section.

[a] 
Ureter unit.


Table 5 - Potentially associated biases.
References  Biases 
[3, 6, 8, 10, 11, 15, 19, 21, 22, 23, 24, 25, 36 Histological bias (mild atypia and dysplasia recorded at distal ureteral margin) 
[7, 12, 14, 17, 26, 27, 37 Bias due to low number of patients (<200) 
[5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 25, 26, 27, 28, 37 Short-term follow-up (mean follow-up<5 years) 
[7, 8, 9, 10, 12, 13, 15, 17, 18, 19, 20, 25, 26, 28, 36 Follow-up (imaging modalities) 
[4, 5, 6, 11, 14, 22, 24, 31, 33, 34 Not described 
[3, 4, 5, 6, 14, 21, 22, 24, 27, 31, 32, 33, 34 IVP 
  CTS 
[4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 32, 34, 36, 37 Surgical technique: intraoperative management of ureteral length not described (made by the surgeon on a case-by-case basis) 
[3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 36 Multiplicity of surgeons 
[3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 36, 37 Retrospective study (incomplete data, patients selection bias) 
[3, 4, 5, 6, 7, 8, 9, 10, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 31, 32, 33, 36, 37 Additional treatment done before and/or after cystectomy (external beam radiation, chemotherapy) not specified 



Légende :
IVP: intravenous pyelogram; CTS: computerized tomographic scan.


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