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Keywords:

  • renal pelvis;
  • recurrence;
  • survival;
  • transitional cell carcinoma;
  • ureter

Abstract

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

Study Type – Therapy (case series)

Level of Evidence 4

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

Tumour location has been shown to be of prognostic importance in UUT-TCC, with tumours of renal pelvis having a better prognosis than ureteral tumours.

Patients from Balkan Endemic Nephropathy (BEN) areas had a higher frequency of pelvis tumours. Also, we found that belonging to a BEN area is an independent predictor of disease recurrence.

OBJECTIVE

  • • 
    To identify the impact of tumour location on the disease recurrence and survival of patients who were treated surgically for upper urinary tract transitional cell carcinoma (UUT-TCC).

PATIENTS AND METHODS

  • • 
    A single-centre series of 189 consecutive patients who were treated surgically for UUT-TCC between January 1999 and December 2009 was evaluated.
  • • 
    Patients who had previously undergone radical cystectomy, preoperative chemotherapy or contralateral UUT-TCC were excluded.
  • • 
    In all, 133 patients were available for evaluation. Tumour location was categorized as renal pelvis or ureter based on the location of the dominant tumour.
  • • 
    Recurrence-free probabilities and cancer-specific survival were estimated using the Kaplan–Meier method and Cox regression analyses.

RESULTS

  • • 
    The 5-year recurrence-free and cancer-specific survival estimates for the cohort in the present study were 66% and 62%, respectively.
  • • 
    The 5-year bladder-only recurrence-free probability was 76%. Using multivariate analysis, only pT classification (hazard ratio, HR, 2.46; P= 0.04) and demographic characteristics (HR, 2.86 for areas of Balkan endemic nephropathy, vs non-Balkan endemic nephropathy areas; 95% confidence interval, 1.37–5.98; P= 0.005) were associated with disease recurrence
  • • 
    Tumour location was not associated with disease recurrence in any of the analyses.
  • • 
    There was no difference in cancer-specific survival between renal pelvis and ureteral tumours (P= 0.476).
  • • 
    Using multivariate analysis, pT classification (HR, 8.04; P= 0.001) and lymph node status (HR, 4.73; P= 0.01) were the only independent predictors associated with a worse cancer-specific survival.

CONCLUSION

  • • 
    Tumour location is unable to predict outcomes in a single-centre series of consecutive patients who were treated with radical nephroureterectomy for UUT-TCC.

Abbreviations
BEN

Balkan endemic nephropathy

RNU

radical nephroureterectomy

UUT-TCC

upper urinary tract transitional cell carcinoma.

INTRODUCTION

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

Upper urinary tract transitional cell carcinoma (UUT-TCC) accounts for ≈10% of all renal tumours and for ≈5% of all urothelial carcinomas [1]. Of all UUT-TCCs, ≈75% are located in the collecting system of the kidney, whereas 25% occur in the ureter [2]. An unusually high incidence of UUT-TCC has been reported in Balkan countries, especially in areas of Balkan endemic nephropathy (BEN). However, the incidence of BEN and UUT-TCC in BEN regions of Serbia appears to have fallen over the last decade [3]. Patients from BEN areas have a higher frequency of ureteric tumours [3].

Pathological stage, lymph node metastasis, extent of surgery and tumour grade have been established as prognostic factors for UUT-TCC [2,4–7]. The location of the primary tumour (renal pelvis vs ureter), however, represents a controversial risk factor. Tumour location has been shown to be of prognostic importance in UUT-TCC, with tumours of renal pelvis having a better prognosis than ureteral tumours [8]. Tumours of the ureter appear to have a higher incidence of local recurrence and distant metastases compared to tumours of the renal pelvis [8]. By contrast, a large multicentre study and a population-based study both found that renal pelvis tumours present at more advanced pathological stages than ureteral UUT-TCC [5,9]. Nephroureterectomy with ipsilateral bladder cuff excision is considered the gold-standard therapy for the management of invasive, high-grade UUT-TCC [2]. Despite adequate surgical therapy, a significant percentage of patients experience either local or distant failure [2,4–9]. Identification of prognostic variables for relapse and survival is essential to provide more accurate patient counselling and guidance for operative strategies, as well as recommendations for postoperative surveillance and adjuvant therapy regimens.

The present study assessed the impact of tumour location on the disease recurrence and survival of patients who were treated surgically for UUT-TCC.

PATIENTS AND METHODS

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

The present study cohort represents 189 patients who were surgically treated for UUT-TCC with nephroureterectomy between January 1999 and December 2009. Patients who had previously undergone radical cystectomy, preoperative chemotherapy or previous contralateral UUT-TCC were excluded. In total, 133 patients were then available for evaluation. Hospital medical records from these 133 patients were reviewed retrospectively to assess the significance of tumour location on disease recurrence and survival. Tumour location was categorized as renal pelvis or ureter based on the location of the dominant tumour. The dominant lesion was defined as that with the highest pathological tumour stage (pT). For multifocal tumours at the same stage, the one with the higher grade was selected for main tumour location. The diagnosis of UUT-TCC was established by CT, excretory urography, a retrograde ureteropyelogram and/or ureteroscopy with tissue biopsies. Tumours were staged according to the TNM classification [10] and graded using the 1998 WHO classification [11]. Criteria for the areas of BEN were the same as those used in previous studies [3,12,13]. The settlements were designated as endemic when three and more cases of BEN were published or reported to the registry of BEN, and non-endemic when no autochthonous cases of BEN were previously established. Included in the analysis were patients with permanent residence in BEN or non-endemic areas from their birth to the end of follow-up.

The median follow-up for this cohort was 35 months. Routine follow-up consisted of physical examination and cystoscopy every 3 months during the first year and every 6–12 months thereafter. Chest radiography, abdominal ultrasonography, CT and excretory urography were performed annually, depending on the clinical stage of the cancer in the upper urinary tract.

Disease recurrence was defined as local failure in the tumour bed, pathologically proven failure in the bladder, regional lymph nodes or distant metastasis. Cause of death was determined by the treating physicians, and most patients who were identified as having died from UUT-TCC had progressive, widely disseminated metastases at the time of death. The initial treatment of all patients was surgical. Radical nephroureterectomy (RNU) with removal of the ipsilateral bladder cuff was the only performed procedure. When enlarged lymph nodes were encountered during nephroureterectomy, they were biopsied or resected, and the hilar and regional nodes adjacent to the ipsilateral great vessel were routinely resected.

Clinicopathological factors were analyzed using the chi-square test or an unpaired t-test. Recurrence-free probabilities and cancer-specific survival were estimated using the Kaplan–Meier method, and the log-rank test was used for the statistical differences. We defined the time of surgery as time zero. Univariate and multivariable Cox proportional hazards regression models were used to evaluate the association between tumour location and any recurrence, bladder-only recurrence and non-bladder recurrence, as well as cancer-specific mortality after RNU. In all tests, P < 0.05 (two-sided) was considered statistically significant.

RESULTS

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

Of the 133 patients included in the present study, 88 (66.2%) patients had a renal pelvis tumour and 45 (33.8%) patients had a ureteral tumour. The median (range) follow-up after surgery was 35 (2–113) months. The patients' demographic, clinical and pathological profiles stratified by tumour location are presented in Table 1. When comparing renal pelvis tumours and ureteral tumours, there were no differences in age, sex distribution, nodal status (pN+ vs pN0/pNx) or tumour side. Patients with ureteral tumours had a greater probability of having a history of carcinomas not invading bladder muscle (36% vs 15%), which was statistically significant (P= 0.006). Interestingly, for pT classification, renal pelvis tumours had a more advanced presentation than ureteral disease (P= 0.016). Specifically, 73.8% of renal pelvis vs 46.6% of ureteral tumours presented with locally advanced (T3/T4) tumours. Also, patients with renal pelvis tumours had a greater probability of having higher tumour grades (72.7% vs 51.1%), which was statistically significant (P= 0.014).

Table 1.  The characteristics of 133 patients with upper urinary tract TCC managed by radical nephroureterectomy stratified by tumour location
CharacteristicTumour location, n (%)P*
Renal pelvis 88 (66.2)Ureter 45 (33.8)
  • *

    P value for the chi-squared test.

  • P value for an unpaired t-test. BEN, Balkan endemic nephropathy.

Age (years), mean (sd)66.7 (8.9)66.6 (8.9)0.70
Sex, n (%)  0.69
 Men52 (59.1)25 (55.5)
 Women36 (40.9)20 (45.5)
Laterality, n (%)  0.054
 Right60 (68.2)23 (51.1)
 Left28 (31.8)22 (48.9)
From BEN area, n (%)  0.036
 Yes40 (45.5)12 (26.6)
 No48 (54.5)33 (73.4)
Previous carcinoma not invading bladder muscle, n (%)  0.006
 No75 (85.3)29 (64.4)
 Yes13 (14.7)16 (35.6)
Tumour focality, n (%)  0.019
 Single63 (71.6)23 (51.1)
 Multifocal25 (28.4)22 (48.9)
Tumour grade, n (%)  0.014
 G15 (5.7)9 (20.0)
 G219 (21.6)13 (28.9)
 G364 (72.7)23 (51.1)
Tumour stage, n (%)  0.016
 Ta1 (1.2)0 (0)
 T15 (5.7)3 (6.7)
 T217 (19.3)21 (46.7)
 T354 (61.3)16 (35.5)
 T411 (12.5)5 (11.1)
Lymph node metastasis, n (%)  0.50
 Negative (pNo/pNx)84 (95.5)44 (97.7)
 Positive (pN+)4 (4.5)1 (2.3)
Lymphovascular invasion, n (%)  <0.001
 Negative26 (29.5)29 (64.4)
 Positive62 (70.5)16 (35.6)

Renal pelvis tumours were present in 45.5% of patients from BEN areas, whereas ureteral tumours were present in only 26.6% of patients from BEN areas, which was also statistically significant (P= 0.036).

Cancer recurrence occurred in 45 (33.8%) patients with a 5-year recurrence-free survival estimate of 66%. No difference was noted in the probability of urothelial cancer recurrence between ureteral and renal pelvis tumours (log-rank test: P= 0.4) (Fig. 1). Using univariate analyses pT classification (hazard ratio, HR, 2.24; 95% confidence interval, CI, 1.11–4.55; P= 0.025), tumour focality (HR, 2.34; 95% CI, 1.29–4.2; P= 0.005), previous carcinoma not invading bladder muscle (HR, 2.66; 95% CI, 1.45–4.81; P= 0.002) and demographic characteristics (HR, 2.71 for areas of BEN vs non-BEN areas 95% CI, 1.34–5.47; P= 0.006) were all associated with disease recurrence (Table 2). Using multivariate analysis, only pT classification (HR, 2.46; 95% CI 1.04–5.84; P= 0.04) and demographic characteristics (HR, 2.86 for areas of BEN vs non-BEN areas 95% CI, 1.37–5.98; P= 0.005) were associated with disease recurrence (Table 2). Tumour location was not associated with disease recurrence in any of the analyses (univariate or multivariate). The most common location of disease recurrence was within the bladder, occurring in 21 (23.8%) patients with pelvis tumours and 12 (26.6%) patients with ureteral tumours. The 5-year bladder-only recurrence-free probability was 76%. Kaplan–Meier analysis showed no difference in bladder-only recurrence between renal pelvis and ureteral tumours (log-rank test: P= 0.62). There were 13 (14.7%) patients with renal pelvis tumours and seven (15.5%) patients with ureteral tumours who developed non-bladder recurrences. The 5-year non-bladder recurrence-free probability was 85.6%. There was no significant difference in non-bladder recurrence between ureteral and renal pelvis tumours (log-rank test: P= 0.748).

image

Figure 1. Kaplan–Meier estimates for recurrence-free survival (any recurrence) in 133 patients managed by nephroureterectomy, stratified by tumour location.

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Table 2.  Univariate and multivariate Cox regression models predicting disease recurrence (any recurrence) in 133 patients after radical nephroureterectomy for upper urinary tract transitional cell carcinoma
VariableUnivariateMultivariate
HR95% CIPHR95% CIP
  1. P values are for the log-rank test. BEN, Balkan endemic nephropathy; CI, confidence interval; HR, hazard ratio.

Age (years) (<60 vs >60)1.140.51–2.560.750.970.43–2.200.95
Sex (men vs women)1.200.67–2.160.541.130.61–2.110.69
From BEN area (yes vs no)2.711.34–5.470.0062.861.37–5.980.005
Previous carcinoma not invading bladder muscle (no vs yes)2.641.45–4.810.0021.750.85–3.610.12
Tumour location (renal pelvis vs ureter)1.290.71–2.360.461.040.52–2.070.90
Tumour focality (unifocal vs multifocal)2.341.29–4.200.0051.680.82–3.460.15
Tumour grade (G1 or G2 vs G3)1.150.60–2.210.660.670.29–1.560.35
Tumour stage (pT2 or less vs pT3 or greater)2.241.11–4.550.0252.461.04–5.840.04
Lymph node metastasis (pNo/pNx vs pN+)0.940.13–6.910.951.200.15–9.540.86
Lymphovascular invasion (negative vs positive)1.470.79–2.750.221.060.45–2.510.88

The 5-year cancer-specific survival estimate was 62% (Fig. 2). Using univariate analyses, pT classification (HR, 7.31; 95% CI, 2.25–23.7; P= 0.001) and lymph node status (HR, 4.64; 95% CI, 1.61–13.4; P= 0.004) were associated with cancer-specific survival (Table 3). Using multivariate analysis, pT classification (HR, 8.04; 95% CI, 2.30–28.2; P= 0.001) and lymph node status (HR, 4.73, 95% CI, 1.44–15.4; P= 0.01) were the only independent predictors associated with worse cancer-specific survival (Table 3). There was no difference in cancer-specific survival between renal pelvis and ureteral tumours (log-rank test: P= 0.476) (Fig. 2).

image

Figure 2. Kaplan–Meier estimates for cancer-specific survival in 133 patients managed by nephroureterectomy, stratified by tumour location.

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Table 3.  Univariate and multivariate Cox regression models predicting cancer-specific survival in 133 patients after radical nephroureterectomy for upper urinary tract transitional cell carcinoma
VariableUnivariateMultivariate
HR95% CIPHR95% CIP
  1. P values are for the log-rank test. BEN, Balkan endemic nephropathy; CI, confidence interval; HR, hazard ratio.

Age (years) (<60 vs >60)1.130.54–2.350.751.160.52–2.730.71
Sex (men vs women)1.070.59–1.910.830.780.39–1.550.48
From BEN area (yes vs no)1.080.60–1.950.791.550.81–2.970.18
Previous carcinoma not invading bladder muscle (no vs yes)1.800.99–3.240.0551.370.64–2.930.42
Tumour location (renal pelvis vs ureter)1.240.68–2.280.481.300.62–2.730.48
Tumour focality (unifocal vs multifocal)1.430.79–2.590.231.240.61–2.510.55
Tumour grade (G1 or G2 vs G3)1.520.72–3.190.261.010.39–2.570.98
Tumour stage (pT2 or less vs pT3 or greater)7.312.25–23.70.0018.042.30–28.20.001
Lymph node metastasis (pNo/pNx vs pN+)4.641.61–13.40.0044.731.44–15.40.010
Lymphovascular invasion (negative vs positive)1.210.64–2.260.560.740.33–1.640.45

DISCUSSION

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

In the present study, we failed to detect a difference in urothelial cancer recurrence or cancer-specific survival when stratifying patients by ureteral and renal pelvis tumour location. The literature evaluating the impact of tumour location on UUT-TCC outcomes is conflicting. For example, a study suggested that the differentially worse outcome of renal pelvis tumours could be explained by the thinner muscularis layer of the renal pelvis compared to the distal ureter [14]. Another study proposed that the differentially worse outcome of ureteral tumours was a result of the lack of a periureteral fat layer compared to the renal pelvis [15]. However, these studies were limited by their relatively small sample sizes. In the present study, we confirmed that tumour location is unable to predict outcomes in a single-centre series of consecutive patients who were treated with radical nephroureterectomy for UUT-TCC. This is in agreement with several earlier studies [5,7]. The overall 5-year recurrence-free and cancer-specific survival rates were 66% and 62%, respectively. These oncological outcomes are comparable with other contemporary series, emphasizing that RNU can achieve durable local control even for locally advanced disease [5,8,15,16]. In accordance with previous studies, we found that pathological stage and lymph node metastasis are the strongest predictors of survival in UUT-TCC cases.

We noted several interesting differences in pathological characteristics depending on tumour location. Renal pelvis tumours presented at a more advanced tumour stage than ureteral disease when considering locally advanced (T3/T4) cancers, which is in concordance with a multicentre study conducted by Raman et al. [5]. Patients with renal pelvis tumours had a greater probability of having higher tumour grades. Interestingly, we failed to show that tumour location had a differential effect on cancer recurrence and survival after adjusting for the effects of pathological stage, grade and lymph node metastasis. Thus, despite the fact that patients with renal pelvis tumours have worse pathological features, the outcomes are not different from those of patients with ureteral tumours when pathological features are considered. In the present study, patients with ureteral tumours had a greater probability of having a history of carcinomas not invading bladder muscle. On univariate analysis, it was shown that a history of bladder TCC has significant effect on disease recurrence. Akdogan et al. [17] noted that patients with previous bladder tumours had significantly lower 5-year disease-specific and recurrence-free survival rates. However, larger studies are needed to confirm that history of bladder TCC is indeed a prognostic factor for newly-diagnosed UUT-TCC. Consequently, patients on a surveillance protocol for bladder tumours should regularly undergo UUT evaluation.

In the present study, we noted that patients from BEN areas had a higher frequency of pelvis tumours, which is not in agreement with the findings reported in a recent study by Dragicevic et al. [3]. Also, we found that belonging to a BEN area is an independent predictor of disease recurrence but not of survival. Among the 80% of patients from BEN areas who developed disease recurrence, the superficial (non-invasive) type of cancer was verified histopathologically. It is possible that some unknown risk factors can cause UUT-TCC and disease recurrence. It is well documented that the incidence of UUT-TCC is significantly higher in Serbian regions of BEN [12]. Urinary bladder tumours are also more frequent (up to 12-fold) in endemic areas than in non-endemic areas [18]. BEN is a tubulointerstinal kidney disease that is usually considered as a non-inflammatory disease [19]. Some studies detected that early stages of BEN may be caused by inflammatory processes [20]. The final stage of this disease is characterized by renal failure and the shrinkage of both kidneys. The aetiology of BEN remains unknown despite numerous investigations of environmental and genetic factors [21]. A current hypothesis exists regarding the aetiological role of aristolochic acid, although the role of viruses, geochemical factors and genetic factors must not be neglected [21]. It is speculated that maternal conditions (e.g. antibodies working against kidney tissue) during pregnancy may alter the development and susceptibility of offspring kidneys [20].

In the present study, adjuvant cisplatin-based combination chemotherapy was only administered in patients with disease pT3 or pT4 and/or nodal involvement. There were no differences in the occurrence of bladder cancer recurrence between patients who received cisplatin chemotherapy (48%) and those who did not (52%) (log-rank test: P= 0.210), as reported in a previous study [22]. To date, there have been no reports confirming the efficacy of postoperative chemotherapy or radiotherapy in patients with UUT-TCC.

There are several limitations to the present study. The study comprised a retrospective analysis of a database from a single institution, and the results are subject to the inherent biases associated with high-volume tertiary care centres. The results also are potentially limited by the small patient numbers, case selection bias and a relatively short median follow-up time as a result of the small number of patients followed for 5 years. Despite these limitations, the present study has strengths such as a centralized pathological review and a standardized follow-up.

In conclusion, tumour location is unable to predict outcomes in a single-centre series of consecutive patients who were treated with radical nephroureterectomy for UUT-TCC. Pelvis and ureteral TCC are the same disease in terms of prognosis. Thus, patients with renal pelvis UUT-TCC should not be given different consideration for adjuvant therapy compared to those with ureteral UUT-TCC.

ACKNOWLEDGEMENTS

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

This work was supported by the Ministry for Science and Technology of the Republic of Serbia, through Contact No. 175042 (2011-2014).

REFERENCES

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