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Keywords:

  • transitional cell carcinoma;
  • upper urinary tract;
  • ureter;
  • segmental ureterectomy;
  • conservative treatment

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 (outcome)

Level of Evidence 2b

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

Upper Urinary Tract (UUT) Transitional Cell Carcinoma (TCC) is an uncommon disease and represents approximately 5% of all urothelial carcinomas. We report our series on 73 patients treated with Kidney Sparing Surgery for UUT TCC. Good results have been achieved in terms of oncological outcome comparing this conservative approach to the radical nephrourectomy.

OBJECTIVES

  • • 
    To report the long-term oncological outcome in patients with transitional cell carcinoma of the ureter electively treated with kidney-sparing surgery.
  • • 
    To compare our data with the few series reported in the literature.

PATIENTS AND METHODS

  • • 
    We considered 73 patients with transitional cell carcinoma of the distal ureter treated in five Italian Departments of Urology.
  • • 
    The following surgeries were carried out: 38 reimplantations on psoas hitch bladder (52%), 21 end-to-end anastomoses (28.8%), 11 direct ureterocystoneostomies (15.1%) and three reimplantations on Boari flap bladder (4.1%).
  • • 
    The median follow-up was 87 months.

RESULTS

  • • 
    Tumours were pTa in 42.5% of patients, pT1 in 31.5%, pT2 in 17.8% and pT3 in 8.2%.
  • • 
    Recurrence of bladder urothelial carcinoma was found in 10 patients (13.7%) after a median time of 28 months.
  • • 
    The bladder recurrence-free survival at 5 years was 82.2%.
  • • 
    The overall survival at 5 years was 85.3% and the cancer-specific survival rate at 5 years was 94.1%.

CONCLUSION

  • • 
    Our data show that segmental ureterectomy procedures do not result in worse cancer control compared with data in the literature regarding nephroureterectomy.

Abbreviations
RNU

radical nephroureterectomy

UUT

upper urinary tract

KSS

kidney-sparing surgery

INTRODUCTION

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

Radical nephroureterectomy (RNU) with bladder cuff excision is considered the gold standard treatment for patients with TCC of the upper urinary tract (UUT). According to the high reported recurrence rate in the ipsilateral urothelium, tumours are frequently multifocal. Moreover, the incidence of contralateral synchronous and metachronous disease is low [1–3]. By eliminating the risk of ipsilateral recurrence, radical surgery requires less frequent follow-up examinations, thereby reducing costs [3].

Kidney-sparing surgery (KSS) has been used for UUT TCC in patients with severely impaired renal function, solitary kidneys, bilateral synchronous tumours or the necessity of platinum-based chemotherapy for future treatment [4,5]. In view of the encouraging oncological results in these patients, a kidney-sparing approach has also been proposed for patients with no imperative indications [6,7]. Whether KSS represents a valid alternative to standard RNU for elective indications remains a matter of debate, as long-term survival data from the few reported series are limited [8–15].

The aim of the present study was to evaluate the long-term oncological outcome in patients with primary TCC of the ureter electively treated with KSS, comparing our data with those in the current literature.

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

STUDY POPULATION

We considered the surgery registers of five major Italian urological centres: the Urology Clinics of the Universities of Genoa, Trieste, Florence and Modena and the Department of Urology of the ‘Luigi Sacco’ Hospital, Milan. A consecutive series of 91 patients with TCC of the distal ureter were retrospectively analysed. Patients with primary, solitary, unilateral TCC of the distal ureter and a normal-functioning contralateral kidney were included. Eighteen patients had previous or concomitant radical cystoprostatectomy for TCC, distant metastasis at diagnosis, other malignancies or incomplete follow-up data and consequently were excluded.

Therefore, our final cohort included 73 patients. A total of 21 patients (28.8%) presented a history of previous superficial bladder tumours. No patients presented with bladder tumours at the time of surgery. The preoperative evaluation included serum creatinine, cysto-urethroscopy with biopsy and/or transureteric resection of bladder tumour where present, CT of the abdomen/pelvis and chest X-ray. Routine ureteroscopy with tumour biopsy was not used in accordance with our national guidelines, to avoid putative tumour cell spillage into the UUT. Based on the CT findings, preoperative hydronephrosis was graded as absent, mild (ureter only dilated), moderate (ureter and renal pelvis dilated) or severe (ureter, renal pelvis and calyces dilated) (Table 1). Tumour size was measured by CT.

Table 1. Preoperative characteristics
Age, years (mean ±sd, range)69.2 ± 8.6 (51–86)
Sex (M/F)62/11
Side (left/right)41/32
Position (number, %) 
 Intramural part43 (58.9%)
 Pelvic ureter21 (28.8%)
 Middle third9 (12.3%)
Tumour size, mm (mean, range)18 (5–23)
Creatinine serum level, mg/dL (mean ±sd, range)1.1 ± 0.35 (0.8–1.4)
Presenting symptom (number, %) 
 Haematuria49 (67.1%)
 Flank pain14 (19.2%)
 Diagnosis during follow-up of bladder tumour10 (13.7%)
Hydronephrosis (number, %) 
 Absent4 (5.5%)
 Mild34 (46.6%)
 Moderate35 (47.9%)
 Severe0

In order to have a complete overview of the argument and carry out a significant comparison between our results and the current literature we also did a MEDLINE search using the National Library of Medicine database (http://www.ncbi.nlm.nih.gov/pubmed) with a combination of different terms such as upper urinary tract, urothelial carcinoma, transitional cell, treatment, surgery, ureterectomy, kidney-sparing surgery, conservative management; we considered papers between 1990 and 2011, excluding reviews, case reports and papers not written in English (Table 2).

Table 2. Anatomopathological characteristics
 Number (%)
Stage 
 pTa31 (42.5%)
 pTis0
 pT123 (31.5%)
 pT213 (17.8%)
 pT36 (8.2%)
Grading 
 G115 (20.5%)
 G228 (38.4%)
 G330 (41.1%)
pTis associated4 (5.5%)
Positive margin2 (2.7%)
 Lymph nodes 
 pN010
 pN11

TREATMENTS

No patients underwent conservative operation of necessity. The following surgery was carried out on a cohort of 73 patients with TCC of the distal ureter, divided as follows: reimplantation on psoas hitch bladder, 38 patients (52%); end-to-end anastomosis, 21 patients (28.8%); direct ureterocystoneostomy, 11 patients (15.1%); reimplantation on Boari flap bladder, three patients (4.1%). After resection of the ureter a ureteroscopy was intra-operatively performed in all the patients to check for the presence of cancer in the proximal part of the ureter.

ANATOMOPATHOLOGICAL FINDINGS

Tumour stage and grade were designated according to the 2002 International Union Against Cancer TNM classification [16] and the 1973 WHO grading system [17].

FOLLOW-UP

Usually cytology, blood tests for renal function and ultrasound were done every 3 months for the first 3 years and every year thereafter. A CT was performed at yearly intervals.

STATISTICAL ANALYSIS

Parametric continuous variables are reported as mean value ± standard deviation. The ranges of survival are defined by the time elapsed since surgery and the last clinical evaluation or the patient's death. The survival curves are estimated using Kaplan–Meier curves. Patients who survived or died from causes different from TCC are censored (cancer-specific survival). The log-rank test is used to compare survival curves and for different analyses.

RESULTS

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

In our series, tumours were pTa in 42.5% of patients, pT1 in 31.5%, pT2 in 17.8% and pT3 in 8.2% of patients. Ipsilateral pelvic lymph node dissection was performed in 11 patients (15.1%), five of whom were pT1, four pT2 and two pT3. Just one dissection resulted in nodal disease (9%) in a patient that turned out to be pT2 and died because of the disease 37 months after surgery. The grading was distributed as follows: 20.5% G1, 38.4% G2 and 41.1% G3. Four patients (5.5%) had associated pTis (Table 3).

Table 3. Five-year cancer-specific survival in patients with primary UUT TCC treated with segmental ureterectomy from the major series published in the literature
Authors/yearPatients (no.)Median/mean follow-up (months)Stage (no. of patients)Five-year cancer-specific survival
  1. *Value not specified for conservative approach. †Including partial nephrectomy. ‡Including patients treated with endoscopic approach. §Including patients treated with radical approach.

Maier et al. (1990) [27]5241.4Ta (15), T1 (21), T2 (11), T3 (4), T4 (1)69.2% (41.4 months)
Das et al. (1990) [28]10Long term*A (5), B (3), D (2) *
Bukurov et al. (1992) [29]1011–14 years * 73%
Bouffioux et al. (1994) [30]2041Ta (7), T1 (9), T2 (2), T3 (2)90%
Racioppi et al. (1997) [31]4775 * 25% (15 years)
Hall et al. (1998) [32]3664 * 23%
Fujimoto et al. (1999) [33]1083.5Tis (1), Ta (1), T1 (4), T2 (1), T3 (2)91.7%
Chen et al. (2005) [34]1249.3§Ta (1), T1 (11)46.4%§
van der Poel et al. (2005) [35]3681 * *
Rouprêt et al. (2007) [36]632Ta (5), T2 (1)100%
Raman et al. (2007) [37]1844.1§ * *
Giannarini et al. (2007) [26]1958Ta (13), T2 (4), T3 (2)64%
Lehman et al. (2007) [38]5196Ta (17), T1 (14), T2 (9), T3 (3), T4 (5)80% (10 years)
Dragicevic et al. (2009) [39]2167T1 (7), T2 (10), T3 (4)55%§
Eandi et al. (2010) [40]430.5Tis (1), T1 (2), T2 (1)100%
Jeldres et al. (2010) [25]56930T1 (231), T2 (192), T3 (124), T4 (22)86.6%
Colin et al. (2012) [41]5226Ta (22), T1 (12), T2 (12), T3 (5), T4 (1)87.9%
Our results7387Ta (31), T1 (23), T2 (13), T3 (26)94.1%

Adjuvant chemotherapy based on gemcitabine and cisplatin was administered to the pN+ patient. The median follow-up was 87 months. Recurrence of bladder urothelial carcinoma was found in 10 patients (13.7%) after a median time of 28 months (Fig. 1).

image

Figure 1. Bladder cancer recurrence-free survival.

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The overall survival at 5 years was 85.3%. The bladder recurrence-free survival at 5 years was 82.2%. Except for one patient, bladder cancer recurrences were all multifocal and localized in the perimeter area of previous ureteric cancers. Urothelial recurrence in the ipsilateral ureter was diagnosed in two patients (2.7%), one of whom was initially treated for a cancer pTaG2 and the other for a pT1G3. In the first patient the recurrence was endoscopically treated 56 months after the first operation with a laser resection of a pTaG2 tumour located distally to the previous TCC. In the second one the recurrence was treated after 98 months with a nephroureterectomy for a multifocal pT1G3 TCC of the ureter and a pT2G3 of the renal pelvis. Ten of the 73 patients (13.7%) died, six of them due to the disease. All the patients who underwent reimplantation on Boari flap were living and free of disease at the time of follow-up; they had undergone previous transurethral resections for bladder TCC with the following histological results: one pTaG1, one pTaG2 and one pT1G3. The cancer-specific survival at 5 years was 94.1%. Survival was also stratified by the stage of malignancy (Fig. 2) and no patient with pTa tumour died from the disease.

image

Figure 2. Cancer-specific survival stratified by stage.

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Regarding cancer stage, pTa and pT1 patients were also stratified by histological grade of malignancy. In this case, the survival curves were not significant for pTa (log-rank P= 0.29; Fig. 3) and significant for pT1 tumours (log-rank P= 0.04; Fig. 4) where the survival decreases with increasing grade of the disease. PT2 stage tumours occurred in 13 of 73 patients in whom we found a cancer-specific survival of 77.8% at 77.2 months of follow-up (range 24–120). Patients in whom the tumour occurred in stage pT3 were only six of the 73 total and we observed a cancer-specific survival of 75% at 70 months (range 24–85).

image

Figure 3. Cancer-specific survival stratified by grade for pTa tumours (log-rank P = 0.29).

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image

Figure 4. Cancer-specific survival stratified by grade for pT1 tumours (log-rank P = 0.04).

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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

In this paper we try to elucidate doubts about long-term oncological outcome in patients with UUT TCC treated with an elective open conservative approach. Analysing our series of patients we focused on the lack of data in the current literature regarding the most appropriate management; it is important to consider that the strength of the present study may probably be seen in the combination of a considerable number of patients and a quite long median follow-up. As we wanted to highlight in Table 3, these two aspects are not easy to find in the literature; in fact most studies enrolling a large number of patients usually have a shorter median follow-up and poorer information about tumour stage and bladder recurrence-free survival. There is also commonly a lack of data about the correlation between the conservative surgical approach with follow-up and tumour stage, as shown in the table.

Upper tract TCC is an uncommon disease. Primary upper tract TCC represents approximately 5% of all urothelial carcinomas and 10% of all primary renal tumours. Like TCC of the bladder, upper tract urothelial carcinoma may occur, recur and progress in any location in the urinary tract. The most common location for ureteric TCC is the distal ureter (70%), followed by the middle (25%) and proximal (5%) ureter [18]. Recurrence in the ipsilateral kidney is common and may be as high as 84%. Upper tract TCC is frequently multifocal (up to 44%).

Recurrence rates in the contralateral ureter are less common. The incidence of contralateral synchronous and metachronous recurrence ranges from 1.8% to 5% [19,20]. The risk for contralateral recurrence persists even at 5 and 10 years. Surveillance for contralateral recurrence should continue for up to 10 years [21].

The treatment of choice for TCC of the distal ureter still remains controversial. According to the updated European Association of Urology guidelines [3], it is still considered to be RNU. For distal ureteric TCC the option of KSS is mentioned, but no clear recommendations are made. The National Comprehensive Cancer Network guidelines support the use of segmental ureterectomy in properly selected patients with low grade mid-ureteric lesions and in individuals with distal ureteric tumours [22]. Nonetheless RNU remains an equally important option for these two categories of ureteric TCC.

The concept of KSS might be supported by the fact that, in patients with UUT TCC, tumour stage, grade and location within the ureter are the most important prognostic factors, irrespective of the treatment. Tumours of the distal ureter are more common than those of the mid-ureter and proximal ureter and are more frequently solitary, smaller and of lower stage and grade than their renal pelvic or upper ureteric counterparts [2,13]. Furthermore, they are less often associated with recurrent disease within the UUT. Recurrences, if any, occur almost exclusively distal to the primary tumour site and are frequently also of lower stage and grade [8,15,23].

Gathering these data, tumours of the distal ureter should be the most amenable in the UUT for elective KSS [2,23]. The benefit of segmental ureterectomy may reside in lesser morbidity and in renal preservation, which may protect patients from non-cancer-related mortality [24]. Recently Jeldres et al. [25] illustrated the lack of inferiority when segmental ureterectomy is compared with RNU, with or without bladder cuff removal, for TCC of the ureter. The present study has several limitations related to the use of a population-based tumour registry. In particular there is no information about the localization of ureteric TCC lesions and about chemotherapy or radiotherapy administered to patients. Furthermore there is no information about recurrence-free survival and bladder recurrence-free survival.

In our series the cancer-specific survival after segmental ureterectomy is comparable with other studies (Table 3) which consider KSS and RNU so it would seem that segmental ureterectomy may offer a good oncological outcome in patients with TCC of the ureter, also in a long-term follow-up. Regarding recurrence-free survival, our series illustrates that urothelial recurrence in the ipsilateral ureter was diagnosed only in 2.7% of patients. These patients were subsequently subjected to other treatments, the first undergoing endoscopic treatment and the other a nephroureterectomy. They are now alive and free from the disease. Regarding recurrence of bladder urothelial carcinoma, our data show that the bladder recurrence-free survival at 5 years is 82.2% and this value is comparable with that obtained with RNU as described in the literature [26].

The sample size of patients with locally advanced disease (pT2–3 TCC) was small. Therefore, the findings regarding patients with pT2–3 disease should be interpreted with caution. However, our data seem to show that these patients should not be excluded from consideration for segmental ureterectomy. In these individuals, KSS may allow the administration of adjuvant or salvage chemotherapy, which may not be an option when RNU is performed and the glomerular filtration rate becomes unacceptably low.

This is a retrospective non-randomized study, which is clearly a limitation. However, this feature was also shared with all other studies about UUT TCC [14,15,23,25,26]. We also did not have a central pathological review. Randomized controlled trials should be encouraged but such studies are difficult to complete due to the relative rarity of the disease.

In conclusion, segmental ureterectomy represents an interesting alternative for the treatment of UUT tumours because it allows a less invasive procedure and guarantees the preservation of renal units. Furthermore, our data seem to show that this procedure does not result in worse cancer control compared with data in the literature regarding nephroureterectomy. When technically possible, segmental ureterectomy may be a valuable option in patients with carcinoma of the ureter.

REFERENCES

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