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Keywords:

  • ureteric tumour;
  • tumour location;
  • surgical approach;
  • recurrence-free survival;
  • cancer-specific survival

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Study Type – Therapy (case series)

Level of Evidence 4

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

Pathological stage, lymph node metastasis and tumour grade have been established as prognostic factors for upper-tract urothelial carcinoma, but there are few studies to date assessing location within the ureter as a prognostic factor. There are also few studies comparing surgical approaches to radical nephroureterectomy (NU), partial ureterectomy and endoscopic resection (ENDO) with regard to oncological outcomes.

This study did not find any prognostic significance for tumour location or surgical approach with regard to outcomes in patients with ureteric tumours. Although NU is the standard treatment for invasive ureteric tumours, partial ureterectomy and ENDO can safely be performed in selected patients. Despite the risk of a shorter time to recurrence, ENDO can be recommended in low grade, non-invasive ureteric tumours but only with close, thorough surveillance practices.

OBJECTIVE

  • • 
    To assess the impact of tumour location within the ureter and the impact of surgical approach on recurrence-free survival (RFS) and cancer-specific survival (CSS) with regard to ureteric tumours.

PATIENTS AND METHODS

  • • 
    Data were retrospectively reviewed from 60 patients with isolated primary ureteric tumours, treated at a single tertiary referral centre.
  • • 
    Patients were treated with radical nephroureterectomy (NU, n= 33), partial ureterectomy (n= 17) or endoscopic resection (ENDO, n= 10).
  • • 
    Kaplan–Meier curves were used for the analysis of RFS and CSS after surgery, stratified by tumour location and surgical approach.

RESULTS

  • • 
    With a median follow-up of 29 months, tumour location was not associated with disease recurrence (P= 0.423).
  • • 
    The ENDO group had shorter time to disease recurrence.
  • • 
    There were no significant differences in the probability of CSS with regard to either tumour location or surgical approach (P= 0.523 and P= 0.904, respectively).

CONCLUSIONS

  • • 
    Tumour location or surgical approach were not significant predictors of oncological outcomes in patients with ureteric tumours.
  • • 
    Although NU is standard treatment for invasive ureteric tumours, partial ureterectomy and ENDO can safely be performed in selected patients. Despite the risk of a shorter time to recurrence, ENDO can be recommended in low grade, non-invasive ureteric tumours.
  • • 
    All urothelium-preserving approaches require thorough surveillance.

Abbreviations
RFS

recurrence-free survival

CSS

cancer-specific survival

NU

nephroureterectomy

ENDO

endoscopic resection

UTUC

upper-tract urothelial carcinoma

CIS

carcinoma in situ

IQR

interquartile range

ASA

American Society of Anesthesiologists

BMI

body mass index

NMIBC

non-muscle-invasive bladder cancer

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Upper-tract urothelial carcinoma (UTUC) is a relatively rare tumour that accounts for ≈5% of all urothelial carcinomas [1,2]. UTUC can occur in either the renal collecting system or the ureter, and occasionally in both. Because ureteric tumours are generally not reported separately, their exact incidence remains unclear. Pathological stage, lymph node metastasis and tumour grade have been established as prognostic factors for UTUC [3–6], but there have been few studies to date assessing location within the ureter as a prognostic factor [7].

For invasive, non-metastatic UTUC, radical nephroureterectomy (NU) with bladder cuff removal is the standard treatment [8]. Partial ureterectomy is usually reserved for low grade, non-invasive tumours too large for endoscopic ablative management, or for isolated high grade tumours where nephron-sparing was imperative [9,10]. Endoscopic management was originally offered only in patients with imperative indications for nephron-sparing [11–13]. With new data supporting the importance of nephron-sparing whenever possible, endoscopic management is becoming more relevant [14], but there are limited data comparing surgical approaches to radical NU, partial ureterectomy and endoscopic resection (ENDO) with regard to oncological outcomes.

The aim of the present study was to assess the impact of tumour location within the ureter and the impact of surgical approach on recurrence-free survival (RFS) and cancer-specific survival (CSS) with regard to ureteric tumours in a contemporary cohort of patients treated at a single tertiary referral centre.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

PATIENTS AND PROCEDURES

After institutional review board approval, we retrospectively reviewed the database of 70 consecutive patients with primary ureteric tumours, treated at North Shore-Long Island Jewish Health System (New York, NY, USA) between October 2000 and December 2010. We excluded patients treated with previous or concurrent radical cystectomy or systemic therapy (n= 4), and patients with metastatic disease before the procedure (n= 4). Furthermore, owing to its multifocal nature and different management strategy, patients with carcinoma in situ (CIS) alone were also excluded (n= 2). The 60 remaining patients were the subjects of the present analysis.

Open radical NU (n= 5) or laparoscopic NU (n= 28) was performed according to the standard criteria with extirpation of the kidney as well as the entire length of the ureter and adjacent segment of the bladder cuff. In selected patients with distal or mid tumours (n= 17) a partial ureterectomy was performed. In the case of superficial, low grade tumours (n= 10), ENDO was performed. For the ENDO group, if recurrence occurred, the decision to perform repeat endoscopic management vs NU was reconsidered. If invasive disease was found by histological sampling, extirpative surgery was performed.

Tumour location was stratified as follows: (i) the proximal ureter (from ureteropelvic junction down to the ureter at the upper level of the sacrum); (ii) the mid ureter (from the upper level of the sacrum down to the crossing of the common iliac artery); and (iii) the distal ureter (intrapelvic). Tumours located in the ureteric ostium, and resectable from within the bladder, were considered to be bladder tumours and excluded from the analysis [7]. As previously described [15], the dominant tumour was defined as that with the highest pathological tumour stage. For multifocal tumours with the same stage, tumour size was used to define the index lesion for location classification. Bladder tumours were considered concomitant when diagnosed within 3 months before or after the diagnosis of ureteric tumour [7]. Concomitant CIS was defined as the presence of CIS in association with another pathological stage.

PATHOLOGICAL EVALUATION

Surgical specimens were processed according to standard pathological procedures at our institution. All specimens were histologically confirmed to be urothelial carcinomas. Tumours were staged according to the 2002 American Joint Committee on Cancer/Union Internationale Contre Le Cancer TNM classification. Tumour grading was assessed according to the 1998 WHO/International Society of Urological Pathology consensus classification [16].

FOLLOW-UP REGIMEN

Patients were followed every 3 months for the first year, every 4 months for the second year, every 6 months from the third to the fifth years, and annually thereafter. Follow-up consisted of a history, physical examination, routine blood work and serum chemistry studies, urinary cytology, chest radiograph, cystoscopic evaluation of the urinary bladder, and radiographic evaluation of the upper urinary tracts. Since 2001, CT urograms have been the standard imaging method for evaluating the abdomen and pelvis for urothelial recurrence. Elective bone scan, chest CT, and MRI were performed when clinically indicated. Disease recurrence was defined as any documented recurrence – by radiograph, endoscopy or pathology – in the bladder, surgical site, contralateral upper tract, ipsilateral kidney, regional lymph nodes or distant metastases. Cause of death was determined by chart review corroborated by death certificate. Most patients who were identified as having died from a ureteric tumour had progressive widely disseminated metastases at the time of death.

STATISTICAL METHODS

The Mann–Whitney U-test, chi-squared test and Fisher's exact test were used for the statistical analysis. RFS and CSS were estimated using Kaplan–Meier methods, with differences assessed using the log-rank test. Survival time was calculated from the date of surgery. Patients without disease recurrence were censored at the date of their last follow-up. In all tests a P value of <0.05 was considered to indicate statistical significance.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

PATIENT CHARACTERISTICS

The cohort of 60 patients had a median (interquartile range [IQR]) age at diagnosis of the first ureteric tumour of 73 (64.0–82.8) years and consisted of 29 males and 31 females (Table 1). There was no significant difference in age, gender, American Society of Anesthesiologists (ASA) score, body mass index (BMI) or smoking history among the different tumour location groups. Preoperative characteristics were also similar among different groups of surgical approach (Table 2).

Table 1. Preoperative characteristics according to ureteric tumour location
VariableAll patients, N= 60Tumour location
Distal, n= 31Mid, n= 12Proximal, n= 17 P
Median (IQR) age, years73 (64–82.8)73 (63–78)76.5 (60.5–84.5)74 (67–83.5)0.537
Gender, n (%)     
 Male29 (48)15 (48)6 (50)8 (47)0.988
 Female31 (52)16 (52)6 (50)9 (53)
ASA score, n (%)     
 13 (5)1 (3)1 (8)1 (6)0.912
 231 (52)16 (52)6 (50)9 (53)
 326 (43)14 (45)5 (42)7 (41)
Median BMI (IQR)25.5 (23.1–28.9)25.2 (22.7–27.2)24.4 (23.2–31.1)27.6 (23.4–33.9)0.260
Smoking history, n (%)41 (68)21 (68)8 (67)12 (71)0.970
Table 2. Patient characteristics according to surgical approach
VariableAll patients, N= 60Surgical approach
NU, n= 33Partial ureterectomy, n= 17ENDO, n= 10 P
Median (IQR) age,years73 (64–82.8)74 (68–84)70 (62–75.5)75 (65.8–82.5)0.195
Gender, n (%)     
 Male29 (48)12 (36)11 (65)6 (60)0.119
 Female31 (52)21 (64)6 (35)4 (40)
ASA score, n (%)     
 13 (5)2 (6)1 (6)0 (–)0.983
 231 (52)16 (48)9 (53)6 (60)
 326 (43)15 (45)7 (41)4 (40)
Median BMI (IQR)25.5 (23.1–28.9)25.2 (23.0–31.3)25.9 (24.5–29.7)23.9 (18.1–26.0)0.091
pT stage, n (%)     
 pTa27 (45)12 (36)6 (35)9 (90)0.01
 pT18 (13)6 (18)2 (12)0 (–)
 pT210 (17)3 (9)6 (35)1 (10)
 pT315 (25)12 (36)3 (18)0 (–)
Tumour grade, n (%)     
 Low15 (25)3 (9)4 (24)8 (80)0.163
 High45 (75)30 (91)13 (76)2 (20)

As shown in Table 3, patients with proximal ureteric tumours were more likely to have high grade tumours (proximal vs distal vs mid: 94% vs 71% vs 58%), and they were more likely to have non-organ-confined disease (pT3%: proximal vs diatal vs mid: 35% vs 23% vs 17%); however, these differences were not significant (both P > 0.05). The location within the ureter was found not to be associated with pathological characteristics, including tumour stage, grade and focality. As expected, patients treated with ENDO had more non-muscle-invasive disease (P= 0.01).

Table 3. Pathological characteristics according to ureteric tumour location
VariableAll patients, N= 60Tumour location
Distal, n= 31Mid, n= 12Proximal, n= 17 P
  • *

    Percentage of 45 patients with ureteric tumours.

pT stage, n (%)     
 pTa27 (45)13 (42)7 (58)7 (41)0.481
 pT18 (13)4 (13)2 (17)2 (12)
 pT210 (17)7 (23)1 (8)2 (12)
 pT315 (25)7 (23)2 (17)6 (35)
pN stage, n (%)     
 Nx/N058 (97)31 (100)12 (100)15 (88)0.073
 N+2 (3)0 (–)0 (–)2 (12)
Tumour grade, n (%)     
 Low15 (25)9 (29)5 (42)1 (6)0.069
 High45 (75)22 (71)7 (58)16 (94)
Tumour focality, n (%)     
 Unifocal43 (72)25 (81)8 (67)10 (59)0.252
 Multifocal17 (28)6 (19)4 (33)7 (41)
Concomitant CIS, n (%)     
 No48 (80)27 (83)10 (83)11 (65)0.170
 Yes12 (20)4 (13)2 (17)6 (35)
Concomitant NMIBC, n (%)     
 No52 (87)26 (84)11 (92)15 (88)0.777
 Yes8 (13)5 (16)1 (8)2 (12)
Grade of ureteric tumour with concomitant bladder cancer     
 Low21.000
 High (%)*6 (13)

As shown in Table 3, eight (13%) patients had concomitant non-muscle-invasive bladder cancer (NMIBC) equally distributed between male and female patients (4/29 vs 4/31). In five patients bladder tumours were found more than 3 months before the ureteric tumour. Ureteric tumour location and grade could not predict the presence of concomitant bladder cancer (P= 0.777 and P= 1.000, respectively). Concomitant CIS was present in 12 (20%) patients, and prevalence of concomitant CIS was not associated with tumour stage (P= 0.102) but increased with higher tumour grade (P= 0.025 [Table 4]).

Table 4. Pathological characteristics according to concomitant CIS
Variable n (%)Concomitant CIS
Absent, n= 48Present, n= 12 P
pT stage    
 pTa27 (45)23 (48)4 (33)0.102
 pT18 (13)8 (17)0 (–)
 pT210 (17)7 (15)3 (25)
 pT315 (25)10 (21)5 (42)
Tumour grade    
 Low15 (25)15 (31)0 (–)0.025
 High45 (75)33 (69)12 (100)

RECURRENCE-FREE SURVIVAL

The median (IQR) follow-up of the entire cohort was 29 (11.8–44.4) months. At last follow-up, 25 (42%) patients had developed disease recurrence. The 2- and 5-year RFS rates were 66% and 37%, respectively. The most common location of disease recurrence was within the bladder, occurring in 12 (20%) patients overall. As far as bladder recurrence was concerned, there was no significant difference between the NU group (6/33) and the partial ureterectomy group (4/17; P= 0.941). All 13 (22%) non-bladder recurrences involved the ipsilateral ureter (n= 6), distant metastases (n= 5), and the ipsilateral renal pelvis (n= 2). Of the 10 patients treated with ENDO, eight had recurrence after a median time of 17 months postoperatively, including two bladder-only recurrences and six ipsilateral recurrences. Figures 1 and 2 show the RFS after first surgery, stratified by tumour location and surgical approach. Tumour location was not associated with disease recurrence (P= 0.423); however, in Fig. 2, the CI of the ENDO group overlapped neither with the NU group nor with the partial ureterectomy group. This shows that the ENDO group had shorter time to disease recurrence.

image

Figure 1. Kaplan–Meier curve of RFS after first surgery, stratified by tumour location.

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image

Figure 2. Kaplan–Meier curve of RFS after first surgery, stratified by surgical approach.

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CANCER-SPECIFIC SURVIVAL

Eight patients died from the ureteric tumour, and seven patients died from other causes. The 2- and 5-year CSS estimates were 89% and 73%, respectively. Six patients with ipsilateral recurrence, initially treated with ENDO, were re-operated with partial ureterectomy (n= 4) or NU (n= 2). The 2- and 5-year CSS estimates for these patients with non-bladder recurrence were 6/6 and 4/6 patients, respectively, and the median time to delayed surgery was 13 months. Figures 3 and 4 show the CSS estimates after surgery, stratified by tumour location and surgical approach, respectively. There were no significant differences in the probability of CSS with regard to either tumour location or surgical approach (P= 0.523 and 0.904, respectively).

image

Figure 3. Kaplan–Meier curve of CSS, after first surgery, stratified by tumour location.

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image

Figure 4. Kaplan–Meier curve of CSS after first surgery, stratified by surgical approach.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Investigators have failed to agree on the prognostic value of tumour location in UTUC. Some have reported that ureteric UTUC is associated with an adverse prognosis [17–19], while others state the opposite [7]. Recently, two large multicentre multivariate analyses identified no significant prognostic difference with respect to the location of UTUC [5,20]. To our knowledge, only one study to date examined the prognostic significance of tumour location within the ureter [7]. That study, including 127 ureteric tumour cases, reported that distal ureteric tumours have a better prognosis than more proximally located tumours [7]. In the present series, there were no significant differences in either RFS or CSS with respect to ureteric tumour location. To date, the largest population-based study on the prognostic significance of tumour location for patients with UTUC showed that, when adjusted for stage, tumour location did not affect oncological outcomes [21]. Thus, we agree that for ureteric tumours, tumour location is not an independent predictor of oncological outcome [20].

Although NU represents the treatment of choice for patients with UTUC, partial ureterectomy and ENDO may be performed in selected patients [9,10,14]. A large population-based study of 2299 patients with UTUC treated with NU or partial ureterectomy did not find that surgery type affected the cancer-specific mortality-free rates [22]. To our knowledge, the largest series ever published with exclusively ureteric tumours [10], which included145 cases, agreed with this conclusion.

A comparative study [23] including 97 patients with UTUC, with a median follow-up of 45.8 months, found that the ENDO group had more superficial tumours (81.5%), similar to the 90% in the present study. They also discovered that the ENDO group had a significantly shorter time to recurrence compared with the NU group (median time: 12 vs 19 months), which is similar to the present study with a median time to delayed NU or partial ureterectomy of 13 months. They also found that for low grade tumours, there were no differences in the 5-year CSS and disease-free survival between the NU and ENDO groups. This finding was supported not only by the present study, but also by the only other two comparative studies, each with longer follow-up in survivors (medians of 54 and 76.9 months, respectively) [24,25]. To our knowledge, while there are no large series of patients who underwent NU after failed ENDO, some authors [24,26,27] have suggested no significant impact on survival when NU is delayed. Furthermore, Pak et al.[28] convincingly described the considerable cost savings of ENDO over NU when the latter leads to end-stage or even chronic renal disease.

So although staging analysis has not been performed in the present study owing to small sample size, we agree that, when technically feasible and in select patients, ENDO is an acceptable alternative to more radical surgery for low grade, non-invasive ureteric tumours, admittedly at the cost of frequent re-treatments and close standard surveillance [25,29].

The present study has some limitations. It represents a non-randomized, retrospective analysis of a database from a single tertiary referral centre, which allows inherent selection bias to influence our results in various potential directions. Owing to relatively small sample size, it lacks staging evaluation. Given the low incidence rate of ureteric tumours, multicentre studies are needed to generalize the findings. Despite these limitations, the present study benefits from a centralized pathological review and standard, consistent follow-up practices. Moreover, clinical and pathological characteristics were similar among each study group, avoiding some selection bias.

In conclusion, the present results did not find prognostic significance of tumour location or surgical approach for outcomes in patients with ureteric tumours. Although NU is standard treatment for invasive ureteric tumours, partial ureterectomy and ENDO can safely be performed in select patients. Despite the risk of a shorter time to recurrence, ENDO can be recommended in low grade, non-invasive ureteric tumours but only with close, thorough surveillance practices.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES