- Email: [email protected]
Bladder recurrence after surgery for upper urinary tract urothelial cell carcinoma: Frequency, risk factors, and surveillance
Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
Review article
Bladder recurrence after surgery for upper urinary tract urothelial cell carcinoma: Frequency, risk factors, and surveillance Marie-Dominique Azémar, M.D.a, Eva Comperat, M.D., Ph.D.b,c, François Richard, M.D., Ph.D.a, Olivier Cussenot, M.D., Ph.D.a,c, Morgan Rouprêt, M.D., Ph.D.a,c,* a b
Department of Urology, Pitié-Salpêtrière and Tenon Hospitals, GHU Est, AP-HP, Faculté de Médecine Pierre et Marie Curie, University Paris VI, Paris, France Department of Pathology, Pitié-Salpêtrière and Tenon Hospitals, GHU Est, AP-HP, Faculté de Médecine Pierre et Marie Curie, University Paris VI, Paris, France c Centre d’Etudes et de Recherche sur les Pathologies Prostatiques (CeRePP), Pierre et Marie Curie, University Paris VI, Paris, France Received 3 May 2009; received in revised form 10 June 2009; accepted 11 June 2009
Abstract Objective: To highlight the main risk factors for metachronous bladder recurrence after treatment of an upper urinary tract urothelial cell carcinomas (UUT-UCCs) based on the recent literature. Materials and methods: Data on urothelial malignancies after UUT-UCCs management in the literature were searched using MEDLINE and by matching the following key words: urinary tract cancer; bladder carcinomas, urothelial carcinomas, upper urinary tract, renal pelvis, ureter prognosis, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, cystectomy, nephroureterectomy, minimally invasive surgery, recurrence, and survival. Results: No evidence level 1 information from prospective randomized trials was available. A range of 15% to 50% of patients with a UUT-UCC will subsequently develop a metachronous bladder UCC. Intraluminal tumor seeding and pan-urothelial field change effect have both been proposed to explain intravesical recurrences. In most cases, bladder cancer arises in the first 2 years after UUT-UCC management. However the risk is lifelong and repeat episodes are common. The identification of variables that allow accurate risk stratification of UUT-UCC patients with regards to future bladder relapse is disappointing. No factors have been identified to date that can reliably predict bladder recurrences. A history of bladder cancer prior to UUT-UCC management and upper tract tumor multifocality are the only frequently reported clinical risk factors among current literature. Conclusion: Prior histories of bladder cancer and upper tract tumor multifocality are the most frequently reported risk factors for bladder tumors following UUT-UCCs. Surveillance regimen is based on cystoscopy and on urinary cytology for at least 5 years. © 2011 Elsevier Inc. All rights reserved. Keywords: Urinary tract cancer; Bladder cancer; Surveillance; Prognosis; Carcinoma; Urothelial cell; Renal pelvis; Ureter; Recurrence
1. Introduction Urothelial cell carcinomas (UCC) of the urinary tract rank fourth in incidence after prostate (or breast), lung, and colorectal cancer. Bladder cancers account for 90% to 95% of UCCs, whereas upper urinary tract (UUT) UCCs account for only 5% to 10% [1,2]. Many UCCs are multifocal; synchronous tumors are often detected in the bladder and/or UUT at diagnosis. How* Corresponding author. Tel.: ⫹33.6.60.54.41.66; fax: ⫹33.1.42.17. 84.81. E-mail address: [email protected] (M. Rouprêt). 1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2009.06.003
ever, although both bladder and UUT tumors are urothelial, differences have been reported in their mechanism of carcinogenesis and molecular pathways [3–5]. For instance, most UUT-UCCs are invasive at diagnosis, whereas most bladder UCCs are non-muscle-invasive [1,6]. In addition, genetic instability plays an important role in human carcinogenesis. In microsatellite instability, a microsatellite allele gains or loses repeat units and undergoes a somatic change in length. MSI is rarely encountered in bladder UCCs (about 3%). Since MSI occurs in more than 15% of sporadic UUT-UCCs, somatic inactivation of mismatch repair genes might be an initiating event in sporadic tumors [7,8]. This epigenetic phenomenon has primarily been noted
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
in patients with HNPCC in which an increased risk of upper tract disease has been described but not for bladder tumors [9]. All UCCs of the urinary tract nevertheless display a strong epidemiologic relationship regardless of the anatomical location of the primary tumor, as recurrence sites often “overlap”. The risk of a recurrence in the UUT after a primary bladder tumor is about 3% to 5%. Clinical practice guidelines recommend surveillance of the UUT by urinary cytology, endoscopy, and imaging after a bladder cancer [10 –12]. On the other hand, the reported recurrence rate within the bladder after treatment of a primary UUT-UCC varies considerably, from 15% to 50% [13–16]. The risk factors for a bladder recurrence are still a matter of debate [17–19]. The aim of this short review was to describe the frequency of occurrence and main risk factors for metachronous bladder recurrence after treatment of an UUT-UCC based on the recent literature.
2. Methods The literature search was done using the National Library of Medicine database (http://www.pubmed.gov). A MEDLINE search was performed with special emphasis on urothelial malignancies after UUT-UCCs management, using combinations of the following terms: urinary tract cancer; bladder carcinomas; urothelial carcinomas; upper urinary tract; renal pelvis; ureter prognosis; carcinoma; transitional cell; renal pelvis; ureter; bladder cancer; cystectomy; nephroureterectomy; minimally invasive surgery; conservative management; recurrence; risk factors and survival. Articles were considered between 1990 and 2008. No evidence level 1 information from prospective randomized trials was available. We excluded case reports and articles not published in English. Due to paucity of randomized data, articles were selected for this review with regards to the following criteria: evolution of concepts; intermediate and long-term clinical outcomes; quality of the study and relevance. Older studies were included selectively if historically relevant or in case of scanty data in more recent publications.
3. Clonal development theory UCCs are characterised by their ability to develop synchronously (multifocality) or metachronously in several anatomical locations of the urinary tract [4,5,20]. Two hypotheses have been put forward to explain this observation: (1) according to the field change hypothesis, mutagens present in the urine and therefore in contact with the entire urothelium are able to transform cells at several sites, leading to the development of several tumor clones [21,22]; (2) the intraluminal seeding and implantation hypothesis supports the clonal development of a multifocal tumor. Multiple locations and recurrences would be due either to tumor cell dissemination
131
within the lumen followed by cell grafting to the urinary tract wall, or to the intraepithelial expansion of cells from the primary tumor [21]. Several genetic studies support the clonal hypothesis [3,4]. Heterogeneity or oligoclonality could be due to clonal divergence and the selection of different subpopulations of cells originating from an initial common tumor cell. The genetic events that occur during the onset and development of the tumor have not yet all been elucidated [3,4]. Two different pathways would seem to be involved, the one leading to non-muscle-invasive tumors, the other to high-grade tumors [2,4,21].
4. Epidemiology As mentioned above, multiple anatomical locations in the urinary tract— either synchronous or metachronous— are a characteristic feature of urinary tract tumors. A third of UUT-UCCs are multifocal at diagnosis [6,16,23]. A synchronous bladder tumor is present in about 8% to 13% of cases [1,6]. The bladder is the most common recurrence site after treatment of an UUT-UCC. The recurrence rate was long considered to be in the region of 30% but reported rates actually vary considerably, from 15% to 50% [13–16]. Variability may be due to patient selection (tumor stage, initial treatment), patient numbers, and mean length of follow-up. Most studies, however, agree that 80% to 90% of metachronous bladder tumors occur within 2 years of treatment of an UUT-UCC [14 –16,18,24,25]. In addition, as emphasized by Kauffman and Raman, patient exclusion factors (e.g., exclusion of patients with metastatic disease or with less than 1 year follow-up) are heterogeneous among current literature and contribute probably to this discrepancy [26].
5. Surgery 5.1. Nephroureterectomy 5.1.1. Open surgery The bladder recurrence rate after total nephroureterectomy (NUT) by open surgery for a primary UUT-UCC varies considerably (around 30%), partly because of differences in the length of follow-up but also due to sample sizes (Table 1). In the study by Lee at al., only 19% of patients had a bladder recurrence, but some of the patients were followed up for less than 1 year [27]. Over 50% of bladder recurrences are known to occur after this time [13,17,18]. 5.1.2. Laparoscopy The laparoscopic procedure is still being assessed but does not seem to give rise to any significant difference in cancer outcomes when compared with open surgery [28,29]. The high gas pressure during the procedure might promote bladder recurrences through tumor cell dissemination within
132
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
Table 1 Bladder recurrence and survival of patients with a primary UUT-UCC treated by open or laparoscopic NUT in main contemporary series
Open surgery Lee et al., 1996 [27] Hisataki et al., 2000 [13] Salavador-Bayarri et al., 2002 [25] Kang et al., 2003 [14] Mullerad et al., 2004 [15] Hsueh et al., 2007 [30] Laparoscopy Rassweiler et al., 2004 [29] Rouprêt et al., 2007 [33] Terakawa et al., 2008 [19] Berger et al., 2008 [32]
Patients (n)
Median follow-up (month)
Bladder recurrence n (%)
5-Year disease-specific survival (%)
68 69 145 223 129 77
38.2 53 44 91 43 24
13 (19.1) 22 (31.9) 54 (37) 70 (31.2) 32 (25) 19 (24.7)
NA NA NA NA NA 69
23 20 66 100
NA 68.5 31 84
8 (34.8) 2 (10) 32 (21) 37 (37)
81 90 NA 77
NA ⫽ not available.
the urinary tract [30]. The surgical procedure per se might also be a risk factor insofar as lack of operator experience might prolong tumor exposure [17,31]. However, skilled teams whose operative times are no longer than for conventional surgery report no increase in the risk of bladder recurrence [19,24,32,33] (Table 1).
the intramural ureter exists; thus, this procedure should be avoided in patients with distal ureteral tumors [37].
6. Conservative management 6.1. Endoscopic management
5.1.3. Distal ureter The gold standard therapy for patients with a normal contralateral kidney is radical NUT with en bloc resection of a 1-cm ipsilateral bladder cuff [34]. The importance of a complete excision has been highlighted by reports of tumor recurrence in ⱕ30% of inadequately resected distal ureters [1]. As such, multiple techniques of ureter and bladder cuff resection have been described, including open excision, cystoscopic detachment and ligation, transurethral resection of the ureteral orifice (TURUO) with various modifications, laparoscopic stapling, and ureteral intussusception. Each technique has inherent advantages and disadvantages; however, thus far, no prospective, randomized trials have compared the different approaches. The reported recurrence rate within the bladder after various management of distal ureter during NUT varies considerably, from 6.7% to 50% [1,17,35–37]. Several concerns exist, however, regarding the oncologic efficacy of the original TURUO technique. This technique, also known as the “pluck” technique, was originally used during NUT and subsequently adapted for laparoscopic NUT [36]. Patients are initially placed in the lithotomy position and undergo rigid cystoscopy with aggressive resection of the ureteral orifice and intramural ureter into the perivesical fat. Once the proximal specimen is mobilized, the previous transurethral resection eases the subsequent bladder cuff excision. One disadvantage of this technique is the increase in procedure length caused by the need for repositioning. Although operative times are important, oncologic outcomes should dictate the appropriateness of the procedure. First, the potential for incomplete resection of
Advances in endourological techniques and materials have led to first-line conservative endoscopic management, with encouraging results [38,39]. Endoscopic management (ureteroscopic or percutaneous) is indicated in patients who would otherwise be on dialysis after NUT, i.e.; patients with a solitary kidney, bilateral disease, or renal insufficiency, but it is also becoming the preferred option in some patients with a normal contralateral kidney [40,41]. However, endoscopy is currently being offered to patients with a nonmuscle-invasive or low-grade UUT-UCC and a normal contralateral kidney [42,43]. Diagnostic ureteroscopy should be performed and preoperative biopsies taken, in order to identify any infiltrating or high-grade tumors with a higher likelihood of recurrence after conservative surgery [43]. Cancer outcomes after elective endoscopic management are similar to those for NUT and bladder recurrences are equivalent (17%– 47% vs. 10%– 42%). The 5-year recurrencefree survival is 50% [38,39,42,43]. These results abort the intraluminal seeding and implantation hypothesis since the residual UUT tissue would seem to favor bladder recurrence (Table 2). Lastly, Raman et al. have demonstrated that there was no correlation between surgical modality and bladder recurrence [18]. 6.2. Partial ureterectomy Endoscopic management has not yet supplanted partial ureterectomy which is still sometimes used for low-grade non-muscle-invasive UUT-UCCs. It has the advantage of providing much more tumor tissue for the pathologist.
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
133
Table 2 Bladder recurrence and survival of patients who have undergone endoscopic management for a primary UUT-UCC in contemporary series Patients (n)
Grasso et al., 1999 [40] Chen et al., 2000 [38] Goel et al., 2003 [39] Palou et al., 2004 [41] Rouprêt et al., 2007 [42] Thompson et al., 2008 [43]
Renal pelvis
Ureter
6 10 24 32 24 44
5 13 0 2 0 38
Procedure
Bladder recurrence n (%)
Median follow-up (month)
5-Year specific survival (%)
Ureteroscopy Ureteroscopy Percutaneous Percutaneous Percutaneous Ureteroscopy, percutaneous
3 (27) 7 (30) 5 (21) 15 (47) 4 (17) 37 (45)
17 35 64 51 62 55
80 82 69 71 79.5 85
There is no difference in the rate of bladder recurrences after endoscopic management and partial ureterectomy [44]. 7. Risk factors The risk factors for developing a metachronous bladder tumor after treatment of an UUT-UCC have not been elucidated. Multifocality is the only significant risk factor that has been repeatedly associated with bladder recurrence [13,14,17,19]. The risk would be multiplied 2- to 3-fold [14]. Other potential risk factors are tumor stage, site, and volume [14,16,17]. 7.1. Tumor stage The stage of the primary UUT-UCC is a highly controversial risk factor [45]. Hisataki et al. reported an increase in the risk of metachronous bladder recurrence after treatment of an invasive primary UUT-UCC [13]. Five-year diseasespecific survival after an invasive UCC is under 40%, and patients usually present invaded lymph nodes or metastases on relapse [1,6]. However, most primary UUT-UCCs are invasive at diagnosis, whereas 92.6% to 96% of bladder recurrences are superficial. Only 2 studies so far have reported an increase in the risk of bladder recurrence after treatment of superficial tumors [16,46], whereas most others have failed to address this statement [15,18,47]. 7.2. Tumor size Tumor size has been reported to be associated with bladder recurrences in one study. Theoretically, a bulkier upper tract lesion may be linked with a greater risk of intravesical recurrence due to tumor shedding and seeding. Against all the evidence, Matsui et al. [17] have demonstrated that a smaller tumor size (i.e., of less than 2 cm) was considered to increase the risk of intravesical recurrence. However, two other teams have failed to confirm this correlation [13,14]. 7.3. Tumor grade Reports on the possible influence of tumor grade on subsequent bladder cancer are still controversial [48]. Grade
was significant in some studies [49,50], whereas others found no such association [51,52]. Nevertheless, most of these data are based on the three-tiered World Health Organization (WHO) 1973 grading system (i.e., grade 1, grade 2, and grade 3). The most recent WHO/International Society of Urological Pathology grading system (i.e., low vs. high grade) seems to be better to predict bladder tumor development in this regard. Other pathologic variables for upper tract tumors, notably carcinoma in situ (CIS) and lymphovascular invasion (LVI), do not appear to correlate with bladder recurrence [13,15,50]. 7.4. Tumor site Tumors of the renal pelvis are 3 to 4 times more common than tumors of the ureter, which exhibit lower diseasespecific and recurrence-free survival [16,23,53]. According to Zigeuner et al., the location of the primary UUT-UCC would be an independent risk factor for bladder recurrence, with double the recurrence rate for ureteral compared to pyelocaliceal tumors, either because of local cell dissemination from a ureteral tumor encroaching on the bladder, or because of cell dissemination occurring during ureteral tumor excision [52]. However, most studies have found no correlation between UUT-UCC site and intravesical recurrence [17,18,31,47]. 7.5. Patient history A patient with a history of bladder cancer might be at higher risk of bladder recurrence after treatment of a primary UUTUCC [50,54]. However, an alternative explanation might be that the bladder and UUT-UCCs develop concurrently. From 20% to 30% of patients who are diagnosed with an UUT-UCC have a history of bladder cancer [1,6]. 7.6. Gender Most studies have found no relationship between gender and risk of bladder recurrence after treatment of a primary UUT-UCC. An exception is the study by Li et al. who observed an increase in risk in men (recurrence rate of 43.2% in men vs. 25.7% in women) [55]. However, this study took no account of confounding factors such as smok-
134
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
ing. Other clinical variables that fail show to correlation with intravesical recurrences include patient age, tobacco exposure, hematuria, flank pain, incidental diagnosis, renal insufficiency, and residence in the region of Taiwan, where black-foot disease is endemic [14,15,18,56]. 7.7. Histologic and molecular markers Ki-67 protein is a marker of cell proliferation. The fraction of Ki-67 positive cells (labeling index) has been shown to correlate with clinical outcomes in tumours. The labeling index can be determined by immunohistochemistry. In a study, Ki-67 was found to be an independent predictor of the development of bladder cancer in UUT tumor patients [57]. Genetic aberrations consecutively accumulate in tumor cells due to genetic instability inherent to carcinomas. 20q13.2 amplification has been implicated as a causal factor for chromosome instability in urothelial cancer cell lines. However, only one study has shown that 20q13.2 gain could predict subsequent intravesical recurrence in UUT-UCCs [58]. Main identified risk factors are summarized in Table 3.
8. Pathology and history of bladder recurrence The pathologic characteristics of recurrent bladder carcinomas in UUT-UCC patients have been studied. For instance, the pathologic features of 74 de novo bladder tumors from 36 patients have been detailed following treatment for UUT-UCCs [59]. Interestingly, there was an 80% match of pathologic grade between the upper tract and bladder specimen. Other recent series confirm this finding with concordance between primary upper tract and bladder tumor grade in up to 90% of cases [14,16,24,56]. Even though the fact that the vast majority of intravesical recurrence after UUTUCC treatment are of non-muscle-invasive pathologic stage is quite striking, no relationship has been found between the stage of the primary tumor and of the recurrence [17,49,60].
The natural history of bladder cancer recurrences following primary UUT-UCC remains unclear. Theoretically, bladder tumors that are directly seeded by UUT-UCCs should share some genetic characteristics with primary UUT-UCCs (e.g., microsatellite instability [5,61]). These concerns were addressed in a former study by detailing the pathology of repeat bladder recurrences among upper tract tumors patients [49]. Repeat recurrences showed an 80% concordance in pathologic grade with the prior bladder relapse and in no cases there was progression to invasion. In the same way, the relationship between bladder recurrences and patient survival remains a moot point. Two studies so far have reported no detectable correlation between bladder relapse and patient survival [50,56]. However, superficial UUT tumors may simply involve longer patient lifespan allowing more time for recurrence, but it has not been proven yet.
9. Bladder surveillance The most recent European clinical practice guidelines on bladder surveillance after treatment of a primary UUT-UCC were produced back in 2004 [62]. In the absence of randomized controlled trials, all recommendations were grade C. The guidelines recommend routine bladder surveillance by cystoscopy and urinary cytology for all patients treated for an UUT-UCC. Although urinary cytology is useful, it explores the cells of both the upper and lower urinary tracts. Currently, there are no urinary molecular markers for the early detection of a bladder recurrence after a primary UUT-UCC [3–5]. However, UUT-UCC tumor tissue markers, such as E-Cadherin, have been reported to predict intravesical recurrence and could be useful in daily practice in a near future [63]. The recommended surveillance schedule depends on the initial treatment, or on alleged risk factors, such as a synchronous bladder tumor at diagnosis and the stage and grade of the primary tumor. The guidelines recommend that, after
Table 3 Identified risk factors for bladder recurrence following treatment (i.e., radical or conservative) for UUT-UCCs Study
Cases (n)
Bladder recurrence N (%)
Follow-up (month, range)
Interval to recurrence
Risk factors
Analysis
Multifocality grade Multifocality; pathologic stage of primary tumor Multifocality Past history of bladder tumor Superficial primary tumor; size; multifocality Past history of bladder tumor; number of previous bladder tumors; multifocality; UUT-UCCs tumor size 20q13.2 gain Ki-67 overexpression
Univariate Multivariate
Mukamel et al., 1994 [49] Hisataki et al., 2000 [13]
69 69
33 (48) 22 (32)
77 (24–180) 35 (12–225)
94% at 2 years 95% at 5 years
Kang et al., 2003 [14] Mullerad et al., 2004 [15] Matsui et al., 2005 [17]
223 129 89
59 (31) 32 (25) 37 (41)
91 (60–168) 43 40 (12–186)
85% at 2 years — 82% at 2 years
Raman et al., 2005 [18]
103
51 (50)
39 (13–135)
82% at 2 years
Akao et al., 2006 [58] Joung et al., 2008 [57]
96 38
28 (10) 10 (26)
40 37 (13–59)
— —
Multivariate Multivariate Multivariate Multivariate
Multivariate Multivariate
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
a NUT, cystoscopy, and urinary cytology should be performed at 3 months, then each year for at least 5 years, regardless of the stage or grade of the primary UUT-UCC. After conservative treatment, an additional work-up at 12 months is recommended. For carcinomas in situ, the cytoscopy schedule after conservative surgery is increased to once every 3 months for 2 years, and then once every 6 months for the next 3 years. Some authors are in favor of closer routine surveillance especially during the first 2 years after treatment of an UUT-UCC, as this is the period during which 80% to 90% of bladder recurrences occur [14]. Raman et al. thus recommend cystoscopy and urinary cytology every 3 months for 2 years, every 6 months for a further 2 years, and then annually [59]. Bladder surveillance is thus essential although further well-designed studies are needed to be able to recommend a truly evidence-based schedule. There is obviously a need for pooling data from multiple institutions to get more reliable data regarding prognostic factors in larger sample sizes, as done recently by a collaborative group regarding oncologic outcomes after radical NUT in a population of over 1,300 patients [64]. 10. Conclusions From 15% to 50% of patients experience a bladder recurrence after a primary UUT-TCC regardless of the treatment they have received. The bladder is thus a common site for recurrence and should undergo surveillance. No reliable risk factor has yet been identified for bladder recurrence in recent literature. However, we believe that a history of bladder cancer and a multifocal primary tumor are the two factors that are most often associated with a metachronous bladder recurrence. The risk of bladder tumor progression is limited and the impact of the bladder tumors on the survival of patients with an UUT-UCC is not known. Even though most recurrences occur within 2 years of treatment of the primary tumor, we strongly advocate performing bladder surveillance by cystoscopy routinely for at least 5 years. To improve patient management would need the identification of specific molecular markers, which would detect patients at high risk of bladder recurrence. References [1] Hall MC, Womack S, Sagalowsky AI, et al. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: A 30-year experience in 252 patients. Urology 1998; 52:594 – 601. [2] Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: Epidemiology, staging and grading, and diagnosis. Urology 2005;66:4 –34. [3] Catto JW, Hartmann A, Stoehr R, et al. Multifocal urothelial cancers with the mutator phenotype are of monoclonal origin and require pan-urothelial treatment for tumor clearance. J Urol 2006; 175:2323–30.
135
[4] Catto JW, Yates DR, Rehman I, et al. Behavior of urothelial carcinoma with respect to anatomical location. J Urol 2007;177:1715–20. [5] Roupret M. Anatomical location of urothelial carcinomas of the urinary tract leads to perspectives of specific treatment. Future Oncol 2007;3:595–9. [6] Olgac S, Mazumdar M, Dalbagni G, et al. Urothelial carcinoma of the renal pelvis: A clinicopathologic study of 130 cases. Am J Surg Pathol 2004;28:1545–52. [7] de la Chapelle A. Microsatellite instability. N Engl J Med 2003;349: 209 –10. [8] Roupret M, Azzouzi AR, Cussenot O. Microsatellite instability and transitional cell carcinoma of the upper urinary tract. BJU Int 2005; 96:489 –92. [9] Roupret M, Yates DR, Comperat E, et al. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (lynch syndrome) tumor spectrum. Eur Urol 2008;54:1226 –36. [10] Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008;54:303–14. [11] Oosterlinck W, Lobel B, Jakse G, et al. Guidelines on bladder cancer. Eur Urol 2002;41:105–12. [12] Sanderson KM, Roupret M. Upper urinary tract tumor after radical cystectomy for transitional cell carcinoma of the bladder: An update on the risk factors, surveillance regimens, and treatments. BJU Int 2007;100:11– 6. [13] Hisataki T, Miyao N, Masumori N, et al. Risk factors for the development of bladder cancer after upper tract urothelial cancer. Urology 2000;55:663–7. [14] Kang CH, Yu TJ, Hsieh HH, et al. The development of bladder tumors and contralateral upper urinary tract tumors after primary transitional cell carcinoma of the upper urinary tract. Cancer 2003; 98:1620 – 6. [15] Mullerad M, Russo P, Golijanin D, et al. Bladder cancer as a prognostic factor for upper tract transitional cell carcinoma. J Urol 2004; 172:2177– 81. [16] van der Poel HG, Antonini N, van Tinteren H, et al. Upper urinary tract cancer: Location is correlated with prognosis. Eur Urol 2005; 48:438 – 44. [17] Matsui Y, Utsunomiya N, Ichioka K, et al. Risk factors for subsequent development of bladder cancer after primary transitional cell carcinoma of the upper urinary tract. Urology 2005;65:279 – 83. [18] Raman JD, Ng CK, Boorjian SA, et al. Bladder cancer after managing upper urinary tract transitional cell carcinoma: Predictive factors and pathology. BJU Int 2005;96:1031–5. [19] Terakawa T, Miyake H, Muramaki M, et al. Risk factors for intravesical recurrence after surgical management of transitional cell carcinoma of the upper urinary tract. Urology 2008;71:123–7. [20] Habuchi T. Origin of multifocal carcinomas of the bladder and upper urinary tract: Molecular analysis and clinical implications. Int J Urol 2005;12:709 –16. [21] Harris AL, Neal DE. Bladder cancer—field vs. clonal origin. N Engl J Med 1992;326:759 – 61. [22] McCarron JP Jr., Chasko SB, Gray GF Jr. Systematic mapping of nephroureterectomy specimens removed for urothelial cancer: Pathological findings and clinical correlations. J Urol 1982;128:243– 6. [23] Park S, Hong B, Kim CS, et al. The impact of tumor location on prognosis of transitional cell carcinoma of the upper urinary tract. J Urol 2004;171:621–5. [24] Bariol SV, Stewart GD, McNeill SA, et al. Oncological control following laparoscopic nephroureterectomy: 7-year outcome. J Urol 2004;172:1805– 8. [25] Salvador-Bayarri J, Rodriguez-Villamil L, Imperatore V, et al. Bladder neoplasms after nephroureterectomy: Does the surgery of the lower ureter transurethral resection or open surgery influence the evolution? Eur Urol 2002;41:30 –3.
136
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
[26] Kauffman EC, Raman JD. Bladder cancer following upper tract urothelial carcinoma. Expert Rev Anticancer Ther 2008;8:75– 85. [27] Lee SH, Lin JS, Tzai TS, et al. Prognostic factors of primary transitional cell carcinoma of the upper urinary tract. Eur Urol 1996;29: 266 –71. [28] Capitanio U, Shariat SF, Isbarn H, et al. Comparison of oncologic outcomes for open and laparoscopic nephroureterectomy: A multiinstitutional analysis of 1,249 cases. Eur Urol 2009; Epub ahead of print. [29] Rassweiler JJ, Schulze M, Marrero R, et al. Laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: Is it better than open surgery? Eur Urol 2004;46:690 –7. [30] Hsueh TY, Huang YH, Chiu AW, et al. Survival analysis in patients with upper urinary tract transitional cell carcinoma: A comparison between open and hand-assisted laparoscopic nephroureterectomy. BJU Int 2007;99:632– 6. [31] Kume H, Teramoto S, Tomita K, et al. Bladder recurrence of upper urinary tract cancer after laparoscopic surgery. J Surg Oncol 2006; 93:318 –22. [32] Berger A, Haber GP, Kamoi K, et al. Laparoscopic radical nephroureterectomy for upper tract transitional cell carcinoma: Oncological outcomes at 7 years. J Urol 2008;180:849 –54. [33] Roupret M, Hupertan V, Sanderson KM, et al. Oncologic control after open or laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: A single center experience. Urology 2007;69:656 – 61. [34] Raman JD, Scherr DS. Management of patients with upper urinary tract transitional cell carcinoma. Nat Clin Pract Urol 2007;4:432– 43. [35] Agarwal DK, Khaira HS, Clarke D, et al. Modified transurethral technique for the management of distal ureter during laparoscopic assisted nephroureterectomy. Urology 2008;71:740 –3. [36] Kawauchi A, Fujito A, Ukimura O, et al. Hand assisted retroperitoneoscopic nephroureterectomy: Comparison with the open procedure. J Urol 2003;169:890 – 4. [37] Steinberg JR, Matin SF. Laparoscopic radical nephroureterectomy: Dilemma of the distal ureter. Curr Opin Urol 2004;14:61–5. [38] Chen GL, Bagley DH. Ureteroscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidneys. J Urol 2000;164:1173– 6. [39] Goel MC, Mahendra V, Roberts JG. Percutaneous management of renal pelvic urothelial tumors: Long-term followup. J Urol 2003;169: 925–30. [40] Grasso M, Fraiman M, Levine M. Ureteropyeloscopic diagnosis and treatment of upper urinary tract urothelial malignancies. Urology 1999;54:240 – 6. [41] Palou J, Piovesan LF, Huguet J, et al. Percutaneous nephroscopic management of upper urinary tract transitional cell carcinoma: Recurrence and long-term followup. J Urol 2004;172:66 –9. [42] Roupret M, Traxer O, Tligui M, et al. Upper urinary tract transitional cell carcinoma: Recurrence rate after percutaneous endoscopic resection. Eur Urol 2007;51:709 –14. [43] Thompson RH, Krambeck AE, Lohse CM, et al. Endoscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidneys. Urology 2008;71:713–7. [44] Pohar KS, Sheinfeld J. When is partial ureterectomy acceptable for transitional-cell carcinoma of the ureter? J Endourol 2001;15:405–9. [45] Brown GA, Busby JE, Wood CG, et al. Nephroureterectomy for treating upper urinary tract transitional cell carcinoma: Time to change the treatment paradigm? BJU Int 2006;98:1176 – 80.
[46] Bloom NA, Vidone RA, Lytton B. Primary carcinoma of the ureter: A report of 102 new cases. J Urol 1970;103:590 – 8. [47] Koga F, Nagamatsu H, Ishimaru H, et al. Risk factors for the development of bladder transitional cell carcinoma following surgery for transitional cell carcinoma of the upper urinary tract. Urol Int 2001; 67:135– 41. [48] Shikanov S, Shapiro A, Baer L, et al. Vesical vs. extra-vesical patterns of recurrence after the treatment of urothelial upper tract tumors. Urol Oncol 2008;26:266 –70. [49] Mukamel E, Simon D, Edelman A, et al. Metachronous bladder tumors in patients with upper urinary tract transitional cell carcinoma. J Surg Oncol 1994;57:187–90. [50] Sakamoto N, Naito S, Kotoh S, et al. Recurrence of bladder tumors following surgery for transitional cell carcinoma of the upper urinary tract. Eur Urol 1991;20:136 –9. [51] Jarrett TW, Chan DY, Cadeddu JA, et al. Laparoscopic nephroureterectomy for the treatment of transitional cell carcinoma of the upper urinary tract. Urology 2001;57:448 –53. [52] Zigeuner RE, Hutterer G, Chromecki T, et al. Bladder tumor development after urothelial carcinoma of the upper urinary tract is related to primary tumor location. BJU Int 2006;98:1181– 6. [53] Akdogan B, Dogan HS, Eskicorapci SY, et al. Prognostic significance of bladder tumor history and tumor location in upper tract transitional cell carcinoma. J Urol 2006;176:48 –52. [54] Charbit L, Gendreau MC, Mee S, et al. Tumors of the upper urinary tract: 10 years of experience. J Urol 1991;146:1243– 6. [55] Li CC, Chang TH, Wu WJ, et al. Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients. Eur Urol 2008;54:1127–34. [56] Krogh J, Kvist E, Rye B. Transitional cell carcinoma of the upper urinary tract: Prognostic variables and postoperative recurrences. Br J Urol 1991;67:32– 6. [57] Joung JY, Yang SO, Jeong IG, et al. Identification of immunohistochemical factors that predict the synchronous or metachronous development of bladder tumors in patients with upper urinary tract tumors. Urol Int 2008;81:306 –11. [58] Akao J, Matsuyama H, Yamamoto Y, et al. Chromosome 20q13.2 gain may predict intravesical recurrence after nephroureterectomy in upper urinary tract urothelial tumors. Clin Cancer Res 2006;12: 7004 – 8. [59] Raman JD, Sosa RE, Vaughan ED Jr., et al. Pathologic features of bladder tumors after nephroureterectomy or segmental ureterectomy for upper urinary tract transitional cell carcinoma. Urology 2007;69: 251– 4. [60] Novara G, De Marco V, Dalpiaz O, et al. Independent predictors of metachronous bladder transitional cell carcinoma (TCC) after nephroureterectomy for TCC of the upper urinary tract. BJU Int 2008;101:1368 –74. [61] Roupret M, Catto J, Coulet F, et al. Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cell carcinoma. J Med Genet 2004;41:e91. [62] Oosterlinck W, Solsona E, van der Meijden AP, et al. EAU guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma. Eur Urol 2004;46:147–54. [63] Eltz S, Comperat E, Cussenot O, et al. Molecular and histological markers in urothelial carcinomas of the upper urinary tract. BJU Int 2008;102:532–5. [64] Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 2009;115:1224 –33.
Review article
Bladder recurrence after surgery for upper urinary tract urothelial cell carcinoma: Frequency, risk factors, and surveillance Marie-Dominique Azémar, M.D.a, Eva Comperat, M.D., Ph.D.b,c, François Richard, M.D., Ph.D.a, Olivier Cussenot, M.D., Ph.D.a,c, Morgan Rouprêt, M.D., Ph.D.a,c,* a b
Department of Urology, Pitié-Salpêtrière and Tenon Hospitals, GHU Est, AP-HP, Faculté de Médecine Pierre et Marie Curie, University Paris VI, Paris, France Department of Pathology, Pitié-Salpêtrière and Tenon Hospitals, GHU Est, AP-HP, Faculté de Médecine Pierre et Marie Curie, University Paris VI, Paris, France c Centre d’Etudes et de Recherche sur les Pathologies Prostatiques (CeRePP), Pierre et Marie Curie, University Paris VI, Paris, France Received 3 May 2009; received in revised form 10 June 2009; accepted 11 June 2009
Abstract Objective: To highlight the main risk factors for metachronous bladder recurrence after treatment of an upper urinary tract urothelial cell carcinomas (UUT-UCCs) based on the recent literature. Materials and methods: Data on urothelial malignancies after UUT-UCCs management in the literature were searched using MEDLINE and by matching the following key words: urinary tract cancer; bladder carcinomas, urothelial carcinomas, upper urinary tract, renal pelvis, ureter prognosis, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, cystectomy, nephroureterectomy, minimally invasive surgery, recurrence, and survival. Results: No evidence level 1 information from prospective randomized trials was available. A range of 15% to 50% of patients with a UUT-UCC will subsequently develop a metachronous bladder UCC. Intraluminal tumor seeding and pan-urothelial field change effect have both been proposed to explain intravesical recurrences. In most cases, bladder cancer arises in the first 2 years after UUT-UCC management. However the risk is lifelong and repeat episodes are common. The identification of variables that allow accurate risk stratification of UUT-UCC patients with regards to future bladder relapse is disappointing. No factors have been identified to date that can reliably predict bladder recurrences. A history of bladder cancer prior to UUT-UCC management and upper tract tumor multifocality are the only frequently reported clinical risk factors among current literature. Conclusion: Prior histories of bladder cancer and upper tract tumor multifocality are the most frequently reported risk factors for bladder tumors following UUT-UCCs. Surveillance regimen is based on cystoscopy and on urinary cytology for at least 5 years. © 2011 Elsevier Inc. All rights reserved. Keywords: Urinary tract cancer; Bladder cancer; Surveillance; Prognosis; Carcinoma; Urothelial cell; Renal pelvis; Ureter; Recurrence
1. Introduction Urothelial cell carcinomas (UCC) of the urinary tract rank fourth in incidence after prostate (or breast), lung, and colorectal cancer. Bladder cancers account for 90% to 95% of UCCs, whereas upper urinary tract (UUT) UCCs account for only 5% to 10% [1,2]. Many UCCs are multifocal; synchronous tumors are often detected in the bladder and/or UUT at diagnosis. How* Corresponding author. Tel.: ⫹33.6.60.54.41.66; fax: ⫹33.1.42.17. 84.81. E-mail address: [email protected] (M. Rouprêt). 1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2009.06.003
ever, although both bladder and UUT tumors are urothelial, differences have been reported in their mechanism of carcinogenesis and molecular pathways [3–5]. For instance, most UUT-UCCs are invasive at diagnosis, whereas most bladder UCCs are non-muscle-invasive [1,6]. In addition, genetic instability plays an important role in human carcinogenesis. In microsatellite instability, a microsatellite allele gains or loses repeat units and undergoes a somatic change in length. MSI is rarely encountered in bladder UCCs (about 3%). Since MSI occurs in more than 15% of sporadic UUT-UCCs, somatic inactivation of mismatch repair genes might be an initiating event in sporadic tumors [7,8]. This epigenetic phenomenon has primarily been noted
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
in patients with HNPCC in which an increased risk of upper tract disease has been described but not for bladder tumors [9]. All UCCs of the urinary tract nevertheless display a strong epidemiologic relationship regardless of the anatomical location of the primary tumor, as recurrence sites often “overlap”. The risk of a recurrence in the UUT after a primary bladder tumor is about 3% to 5%. Clinical practice guidelines recommend surveillance of the UUT by urinary cytology, endoscopy, and imaging after a bladder cancer [10 –12]. On the other hand, the reported recurrence rate within the bladder after treatment of a primary UUT-UCC varies considerably, from 15% to 50% [13–16]. The risk factors for a bladder recurrence are still a matter of debate [17–19]. The aim of this short review was to describe the frequency of occurrence and main risk factors for metachronous bladder recurrence after treatment of an UUT-UCC based on the recent literature.
2. Methods The literature search was done using the National Library of Medicine database (http://www.pubmed.gov). A MEDLINE search was performed with special emphasis on urothelial malignancies after UUT-UCCs management, using combinations of the following terms: urinary tract cancer; bladder carcinomas; urothelial carcinomas; upper urinary tract; renal pelvis; ureter prognosis; carcinoma; transitional cell; renal pelvis; ureter; bladder cancer; cystectomy; nephroureterectomy; minimally invasive surgery; conservative management; recurrence; risk factors and survival. Articles were considered between 1990 and 2008. No evidence level 1 information from prospective randomized trials was available. We excluded case reports and articles not published in English. Due to paucity of randomized data, articles were selected for this review with regards to the following criteria: evolution of concepts; intermediate and long-term clinical outcomes; quality of the study and relevance. Older studies were included selectively if historically relevant or in case of scanty data in more recent publications.
3. Clonal development theory UCCs are characterised by their ability to develop synchronously (multifocality) or metachronously in several anatomical locations of the urinary tract [4,5,20]. Two hypotheses have been put forward to explain this observation: (1) according to the field change hypothesis, mutagens present in the urine and therefore in contact with the entire urothelium are able to transform cells at several sites, leading to the development of several tumor clones [21,22]; (2) the intraluminal seeding and implantation hypothesis supports the clonal development of a multifocal tumor. Multiple locations and recurrences would be due either to tumor cell dissemination
131
within the lumen followed by cell grafting to the urinary tract wall, or to the intraepithelial expansion of cells from the primary tumor [21]. Several genetic studies support the clonal hypothesis [3,4]. Heterogeneity or oligoclonality could be due to clonal divergence and the selection of different subpopulations of cells originating from an initial common tumor cell. The genetic events that occur during the onset and development of the tumor have not yet all been elucidated [3,4]. Two different pathways would seem to be involved, the one leading to non-muscle-invasive tumors, the other to high-grade tumors [2,4,21].
4. Epidemiology As mentioned above, multiple anatomical locations in the urinary tract— either synchronous or metachronous— are a characteristic feature of urinary tract tumors. A third of UUT-UCCs are multifocal at diagnosis [6,16,23]. A synchronous bladder tumor is present in about 8% to 13% of cases [1,6]. The bladder is the most common recurrence site after treatment of an UUT-UCC. The recurrence rate was long considered to be in the region of 30% but reported rates actually vary considerably, from 15% to 50% [13–16]. Variability may be due to patient selection (tumor stage, initial treatment), patient numbers, and mean length of follow-up. Most studies, however, agree that 80% to 90% of metachronous bladder tumors occur within 2 years of treatment of an UUT-UCC [14 –16,18,24,25]. In addition, as emphasized by Kauffman and Raman, patient exclusion factors (e.g., exclusion of patients with metastatic disease or with less than 1 year follow-up) are heterogeneous among current literature and contribute probably to this discrepancy [26].
5. Surgery 5.1. Nephroureterectomy 5.1.1. Open surgery The bladder recurrence rate after total nephroureterectomy (NUT) by open surgery for a primary UUT-UCC varies considerably (around 30%), partly because of differences in the length of follow-up but also due to sample sizes (Table 1). In the study by Lee at al., only 19% of patients had a bladder recurrence, but some of the patients were followed up for less than 1 year [27]. Over 50% of bladder recurrences are known to occur after this time [13,17,18]. 5.1.2. Laparoscopy The laparoscopic procedure is still being assessed but does not seem to give rise to any significant difference in cancer outcomes when compared with open surgery [28,29]. The high gas pressure during the procedure might promote bladder recurrences through tumor cell dissemination within
132
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
Table 1 Bladder recurrence and survival of patients with a primary UUT-UCC treated by open or laparoscopic NUT in main contemporary series
Open surgery Lee et al., 1996 [27] Hisataki et al., 2000 [13] Salavador-Bayarri et al., 2002 [25] Kang et al., 2003 [14] Mullerad et al., 2004 [15] Hsueh et al., 2007 [30] Laparoscopy Rassweiler et al., 2004 [29] Rouprêt et al., 2007 [33] Terakawa et al., 2008 [19] Berger et al., 2008 [32]
Patients (n)
Median follow-up (month)
Bladder recurrence n (%)
5-Year disease-specific survival (%)
68 69 145 223 129 77
38.2 53 44 91 43 24
13 (19.1) 22 (31.9) 54 (37) 70 (31.2) 32 (25) 19 (24.7)
NA NA NA NA NA 69
23 20 66 100
NA 68.5 31 84
8 (34.8) 2 (10) 32 (21) 37 (37)
81 90 NA 77
NA ⫽ not available.
the urinary tract [30]. The surgical procedure per se might also be a risk factor insofar as lack of operator experience might prolong tumor exposure [17,31]. However, skilled teams whose operative times are no longer than for conventional surgery report no increase in the risk of bladder recurrence [19,24,32,33] (Table 1).
the intramural ureter exists; thus, this procedure should be avoided in patients with distal ureteral tumors [37].
6. Conservative management 6.1. Endoscopic management
5.1.3. Distal ureter The gold standard therapy for patients with a normal contralateral kidney is radical NUT with en bloc resection of a 1-cm ipsilateral bladder cuff [34]. The importance of a complete excision has been highlighted by reports of tumor recurrence in ⱕ30% of inadequately resected distal ureters [1]. As such, multiple techniques of ureter and bladder cuff resection have been described, including open excision, cystoscopic detachment and ligation, transurethral resection of the ureteral orifice (TURUO) with various modifications, laparoscopic stapling, and ureteral intussusception. Each technique has inherent advantages and disadvantages; however, thus far, no prospective, randomized trials have compared the different approaches. The reported recurrence rate within the bladder after various management of distal ureter during NUT varies considerably, from 6.7% to 50% [1,17,35–37]. Several concerns exist, however, regarding the oncologic efficacy of the original TURUO technique. This technique, also known as the “pluck” technique, was originally used during NUT and subsequently adapted for laparoscopic NUT [36]. Patients are initially placed in the lithotomy position and undergo rigid cystoscopy with aggressive resection of the ureteral orifice and intramural ureter into the perivesical fat. Once the proximal specimen is mobilized, the previous transurethral resection eases the subsequent bladder cuff excision. One disadvantage of this technique is the increase in procedure length caused by the need for repositioning. Although operative times are important, oncologic outcomes should dictate the appropriateness of the procedure. First, the potential for incomplete resection of
Advances in endourological techniques and materials have led to first-line conservative endoscopic management, with encouraging results [38,39]. Endoscopic management (ureteroscopic or percutaneous) is indicated in patients who would otherwise be on dialysis after NUT, i.e.; patients with a solitary kidney, bilateral disease, or renal insufficiency, but it is also becoming the preferred option in some patients with a normal contralateral kidney [40,41]. However, endoscopy is currently being offered to patients with a nonmuscle-invasive or low-grade UUT-UCC and a normal contralateral kidney [42,43]. Diagnostic ureteroscopy should be performed and preoperative biopsies taken, in order to identify any infiltrating or high-grade tumors with a higher likelihood of recurrence after conservative surgery [43]. Cancer outcomes after elective endoscopic management are similar to those for NUT and bladder recurrences are equivalent (17%– 47% vs. 10%– 42%). The 5-year recurrencefree survival is 50% [38,39,42,43]. These results abort the intraluminal seeding and implantation hypothesis since the residual UUT tissue would seem to favor bladder recurrence (Table 2). Lastly, Raman et al. have demonstrated that there was no correlation between surgical modality and bladder recurrence [18]. 6.2. Partial ureterectomy Endoscopic management has not yet supplanted partial ureterectomy which is still sometimes used for low-grade non-muscle-invasive UUT-UCCs. It has the advantage of providing much more tumor tissue for the pathologist.
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
133
Table 2 Bladder recurrence and survival of patients who have undergone endoscopic management for a primary UUT-UCC in contemporary series Patients (n)
Grasso et al., 1999 [40] Chen et al., 2000 [38] Goel et al., 2003 [39] Palou et al., 2004 [41] Rouprêt et al., 2007 [42] Thompson et al., 2008 [43]
Renal pelvis
Ureter
6 10 24 32 24 44
5 13 0 2 0 38
Procedure
Bladder recurrence n (%)
Median follow-up (month)
5-Year specific survival (%)
Ureteroscopy Ureteroscopy Percutaneous Percutaneous Percutaneous Ureteroscopy, percutaneous
3 (27) 7 (30) 5 (21) 15 (47) 4 (17) 37 (45)
17 35 64 51 62 55
80 82 69 71 79.5 85
There is no difference in the rate of bladder recurrences after endoscopic management and partial ureterectomy [44]. 7. Risk factors The risk factors for developing a metachronous bladder tumor after treatment of an UUT-UCC have not been elucidated. Multifocality is the only significant risk factor that has been repeatedly associated with bladder recurrence [13,14,17,19]. The risk would be multiplied 2- to 3-fold [14]. Other potential risk factors are tumor stage, site, and volume [14,16,17]. 7.1. Tumor stage The stage of the primary UUT-UCC is a highly controversial risk factor [45]. Hisataki et al. reported an increase in the risk of metachronous bladder recurrence after treatment of an invasive primary UUT-UCC [13]. Five-year diseasespecific survival after an invasive UCC is under 40%, and patients usually present invaded lymph nodes or metastases on relapse [1,6]. However, most primary UUT-UCCs are invasive at diagnosis, whereas 92.6% to 96% of bladder recurrences are superficial. Only 2 studies so far have reported an increase in the risk of bladder recurrence after treatment of superficial tumors [16,46], whereas most others have failed to address this statement [15,18,47]. 7.2. Tumor size Tumor size has been reported to be associated with bladder recurrences in one study. Theoretically, a bulkier upper tract lesion may be linked with a greater risk of intravesical recurrence due to tumor shedding and seeding. Against all the evidence, Matsui et al. [17] have demonstrated that a smaller tumor size (i.e., of less than 2 cm) was considered to increase the risk of intravesical recurrence. However, two other teams have failed to confirm this correlation [13,14]. 7.3. Tumor grade Reports on the possible influence of tumor grade on subsequent bladder cancer are still controversial [48]. Grade
was significant in some studies [49,50], whereas others found no such association [51,52]. Nevertheless, most of these data are based on the three-tiered World Health Organization (WHO) 1973 grading system (i.e., grade 1, grade 2, and grade 3). The most recent WHO/International Society of Urological Pathology grading system (i.e., low vs. high grade) seems to be better to predict bladder tumor development in this regard. Other pathologic variables for upper tract tumors, notably carcinoma in situ (CIS) and lymphovascular invasion (LVI), do not appear to correlate with bladder recurrence [13,15,50]. 7.4. Tumor site Tumors of the renal pelvis are 3 to 4 times more common than tumors of the ureter, which exhibit lower diseasespecific and recurrence-free survival [16,23,53]. According to Zigeuner et al., the location of the primary UUT-UCC would be an independent risk factor for bladder recurrence, with double the recurrence rate for ureteral compared to pyelocaliceal tumors, either because of local cell dissemination from a ureteral tumor encroaching on the bladder, or because of cell dissemination occurring during ureteral tumor excision [52]. However, most studies have found no correlation between UUT-UCC site and intravesical recurrence [17,18,31,47]. 7.5. Patient history A patient with a history of bladder cancer might be at higher risk of bladder recurrence after treatment of a primary UUTUCC [50,54]. However, an alternative explanation might be that the bladder and UUT-UCCs develop concurrently. From 20% to 30% of patients who are diagnosed with an UUT-UCC have a history of bladder cancer [1,6]. 7.6. Gender Most studies have found no relationship between gender and risk of bladder recurrence after treatment of a primary UUT-UCC. An exception is the study by Li et al. who observed an increase in risk in men (recurrence rate of 43.2% in men vs. 25.7% in women) [55]. However, this study took no account of confounding factors such as smok-
134
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
ing. Other clinical variables that fail show to correlation with intravesical recurrences include patient age, tobacco exposure, hematuria, flank pain, incidental diagnosis, renal insufficiency, and residence in the region of Taiwan, where black-foot disease is endemic [14,15,18,56]. 7.7. Histologic and molecular markers Ki-67 protein is a marker of cell proliferation. The fraction of Ki-67 positive cells (labeling index) has been shown to correlate with clinical outcomes in tumours. The labeling index can be determined by immunohistochemistry. In a study, Ki-67 was found to be an independent predictor of the development of bladder cancer in UUT tumor patients [57]. Genetic aberrations consecutively accumulate in tumor cells due to genetic instability inherent to carcinomas. 20q13.2 amplification has been implicated as a causal factor for chromosome instability in urothelial cancer cell lines. However, only one study has shown that 20q13.2 gain could predict subsequent intravesical recurrence in UUT-UCCs [58]. Main identified risk factors are summarized in Table 3.
8. Pathology and history of bladder recurrence The pathologic characteristics of recurrent bladder carcinomas in UUT-UCC patients have been studied. For instance, the pathologic features of 74 de novo bladder tumors from 36 patients have been detailed following treatment for UUT-UCCs [59]. Interestingly, there was an 80% match of pathologic grade between the upper tract and bladder specimen. Other recent series confirm this finding with concordance between primary upper tract and bladder tumor grade in up to 90% of cases [14,16,24,56]. Even though the fact that the vast majority of intravesical recurrence after UUTUCC treatment are of non-muscle-invasive pathologic stage is quite striking, no relationship has been found between the stage of the primary tumor and of the recurrence [17,49,60].
The natural history of bladder cancer recurrences following primary UUT-UCC remains unclear. Theoretically, bladder tumors that are directly seeded by UUT-UCCs should share some genetic characteristics with primary UUT-UCCs (e.g., microsatellite instability [5,61]). These concerns were addressed in a former study by detailing the pathology of repeat bladder recurrences among upper tract tumors patients [49]. Repeat recurrences showed an 80% concordance in pathologic grade with the prior bladder relapse and in no cases there was progression to invasion. In the same way, the relationship between bladder recurrences and patient survival remains a moot point. Two studies so far have reported no detectable correlation between bladder relapse and patient survival [50,56]. However, superficial UUT tumors may simply involve longer patient lifespan allowing more time for recurrence, but it has not been proven yet.
9. Bladder surveillance The most recent European clinical practice guidelines on bladder surveillance after treatment of a primary UUT-UCC were produced back in 2004 [62]. In the absence of randomized controlled trials, all recommendations were grade C. The guidelines recommend routine bladder surveillance by cystoscopy and urinary cytology for all patients treated for an UUT-UCC. Although urinary cytology is useful, it explores the cells of both the upper and lower urinary tracts. Currently, there are no urinary molecular markers for the early detection of a bladder recurrence after a primary UUT-UCC [3–5]. However, UUT-UCC tumor tissue markers, such as E-Cadherin, have been reported to predict intravesical recurrence and could be useful in daily practice in a near future [63]. The recommended surveillance schedule depends on the initial treatment, or on alleged risk factors, such as a synchronous bladder tumor at diagnosis and the stage and grade of the primary tumor. The guidelines recommend that, after
Table 3 Identified risk factors for bladder recurrence following treatment (i.e., radical or conservative) for UUT-UCCs Study
Cases (n)
Bladder recurrence N (%)
Follow-up (month, range)
Interval to recurrence
Risk factors
Analysis
Multifocality grade Multifocality; pathologic stage of primary tumor Multifocality Past history of bladder tumor Superficial primary tumor; size; multifocality Past history of bladder tumor; number of previous bladder tumors; multifocality; UUT-UCCs tumor size 20q13.2 gain Ki-67 overexpression
Univariate Multivariate
Mukamel et al., 1994 [49] Hisataki et al., 2000 [13]
69 69
33 (48) 22 (32)
77 (24–180) 35 (12–225)
94% at 2 years 95% at 5 years
Kang et al., 2003 [14] Mullerad et al., 2004 [15] Matsui et al., 2005 [17]
223 129 89
59 (31) 32 (25) 37 (41)
91 (60–168) 43 40 (12–186)
85% at 2 years — 82% at 2 years
Raman et al., 2005 [18]
103
51 (50)
39 (13–135)
82% at 2 years
Akao et al., 2006 [58] Joung et al., 2008 [57]
96 38
28 (10) 10 (26)
40 37 (13–59)
— —
Multivariate Multivariate Multivariate Multivariate
Multivariate Multivariate
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
a NUT, cystoscopy, and urinary cytology should be performed at 3 months, then each year for at least 5 years, regardless of the stage or grade of the primary UUT-UCC. After conservative treatment, an additional work-up at 12 months is recommended. For carcinomas in situ, the cytoscopy schedule after conservative surgery is increased to once every 3 months for 2 years, and then once every 6 months for the next 3 years. Some authors are in favor of closer routine surveillance especially during the first 2 years after treatment of an UUT-UCC, as this is the period during which 80% to 90% of bladder recurrences occur [14]. Raman et al. thus recommend cystoscopy and urinary cytology every 3 months for 2 years, every 6 months for a further 2 years, and then annually [59]. Bladder surveillance is thus essential although further well-designed studies are needed to be able to recommend a truly evidence-based schedule. There is obviously a need for pooling data from multiple institutions to get more reliable data regarding prognostic factors in larger sample sizes, as done recently by a collaborative group regarding oncologic outcomes after radical NUT in a population of over 1,300 patients [64]. 10. Conclusions From 15% to 50% of patients experience a bladder recurrence after a primary UUT-TCC regardless of the treatment they have received. The bladder is thus a common site for recurrence and should undergo surveillance. No reliable risk factor has yet been identified for bladder recurrence in recent literature. However, we believe that a history of bladder cancer and a multifocal primary tumor are the two factors that are most often associated with a metachronous bladder recurrence. The risk of bladder tumor progression is limited and the impact of the bladder tumors on the survival of patients with an UUT-UCC is not known. Even though most recurrences occur within 2 years of treatment of the primary tumor, we strongly advocate performing bladder surveillance by cystoscopy routinely for at least 5 years. To improve patient management would need the identification of specific molecular markers, which would detect patients at high risk of bladder recurrence. References [1] Hall MC, Womack S, Sagalowsky AI, et al. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: A 30-year experience in 252 patients. Urology 1998; 52:594 – 601. [2] Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: Epidemiology, staging and grading, and diagnosis. Urology 2005;66:4 –34. [3] Catto JW, Hartmann A, Stoehr R, et al. Multifocal urothelial cancers with the mutator phenotype are of monoclonal origin and require pan-urothelial treatment for tumor clearance. J Urol 2006; 175:2323–30.
135
[4] Catto JW, Yates DR, Rehman I, et al. Behavior of urothelial carcinoma with respect to anatomical location. J Urol 2007;177:1715–20. [5] Roupret M. Anatomical location of urothelial carcinomas of the urinary tract leads to perspectives of specific treatment. Future Oncol 2007;3:595–9. [6] Olgac S, Mazumdar M, Dalbagni G, et al. Urothelial carcinoma of the renal pelvis: A clinicopathologic study of 130 cases. Am J Surg Pathol 2004;28:1545–52. [7] de la Chapelle A. Microsatellite instability. N Engl J Med 2003;349: 209 –10. [8] Roupret M, Azzouzi AR, Cussenot O. Microsatellite instability and transitional cell carcinoma of the upper urinary tract. BJU Int 2005; 96:489 –92. [9] Roupret M, Yates DR, Comperat E, et al. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (lynch syndrome) tumor spectrum. Eur Urol 2008;54:1226 –36. [10] Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008;54:303–14. [11] Oosterlinck W, Lobel B, Jakse G, et al. Guidelines on bladder cancer. Eur Urol 2002;41:105–12. [12] Sanderson KM, Roupret M. Upper urinary tract tumor after radical cystectomy for transitional cell carcinoma of the bladder: An update on the risk factors, surveillance regimens, and treatments. BJU Int 2007;100:11– 6. [13] Hisataki T, Miyao N, Masumori N, et al. Risk factors for the development of bladder cancer after upper tract urothelial cancer. Urology 2000;55:663–7. [14] Kang CH, Yu TJ, Hsieh HH, et al. The development of bladder tumors and contralateral upper urinary tract tumors after primary transitional cell carcinoma of the upper urinary tract. Cancer 2003; 98:1620 – 6. [15] Mullerad M, Russo P, Golijanin D, et al. Bladder cancer as a prognostic factor for upper tract transitional cell carcinoma. J Urol 2004; 172:2177– 81. [16] van der Poel HG, Antonini N, van Tinteren H, et al. Upper urinary tract cancer: Location is correlated with prognosis. Eur Urol 2005; 48:438 – 44. [17] Matsui Y, Utsunomiya N, Ichioka K, et al. Risk factors for subsequent development of bladder cancer after primary transitional cell carcinoma of the upper urinary tract. Urology 2005;65:279 – 83. [18] Raman JD, Ng CK, Boorjian SA, et al. Bladder cancer after managing upper urinary tract transitional cell carcinoma: Predictive factors and pathology. BJU Int 2005;96:1031–5. [19] Terakawa T, Miyake H, Muramaki M, et al. Risk factors for intravesical recurrence after surgical management of transitional cell carcinoma of the upper urinary tract. Urology 2008;71:123–7. [20] Habuchi T. Origin of multifocal carcinomas of the bladder and upper urinary tract: Molecular analysis and clinical implications. Int J Urol 2005;12:709 –16. [21] Harris AL, Neal DE. Bladder cancer—field vs. clonal origin. N Engl J Med 1992;326:759 – 61. [22] McCarron JP Jr., Chasko SB, Gray GF Jr. Systematic mapping of nephroureterectomy specimens removed for urothelial cancer: Pathological findings and clinical correlations. J Urol 1982;128:243– 6. [23] Park S, Hong B, Kim CS, et al. The impact of tumor location on prognosis of transitional cell carcinoma of the upper urinary tract. J Urol 2004;171:621–5. [24] Bariol SV, Stewart GD, McNeill SA, et al. Oncological control following laparoscopic nephroureterectomy: 7-year outcome. J Urol 2004;172:1805– 8. [25] Salvador-Bayarri J, Rodriguez-Villamil L, Imperatore V, et al. Bladder neoplasms after nephroureterectomy: Does the surgery of the lower ureter transurethral resection or open surgery influence the evolution? Eur Urol 2002;41:30 –3.
136
M.-D. Azémar et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 130 –136
[26] Kauffman EC, Raman JD. Bladder cancer following upper tract urothelial carcinoma. Expert Rev Anticancer Ther 2008;8:75– 85. [27] Lee SH, Lin JS, Tzai TS, et al. Prognostic factors of primary transitional cell carcinoma of the upper urinary tract. Eur Urol 1996;29: 266 –71. [28] Capitanio U, Shariat SF, Isbarn H, et al. Comparison of oncologic outcomes for open and laparoscopic nephroureterectomy: A multiinstitutional analysis of 1,249 cases. Eur Urol 2009; Epub ahead of print. [29] Rassweiler JJ, Schulze M, Marrero R, et al. Laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: Is it better than open surgery? Eur Urol 2004;46:690 –7. [30] Hsueh TY, Huang YH, Chiu AW, et al. Survival analysis in patients with upper urinary tract transitional cell carcinoma: A comparison between open and hand-assisted laparoscopic nephroureterectomy. BJU Int 2007;99:632– 6. [31] Kume H, Teramoto S, Tomita K, et al. Bladder recurrence of upper urinary tract cancer after laparoscopic surgery. J Surg Oncol 2006; 93:318 –22. [32] Berger A, Haber GP, Kamoi K, et al. Laparoscopic radical nephroureterectomy for upper tract transitional cell carcinoma: Oncological outcomes at 7 years. J Urol 2008;180:849 –54. [33] Roupret M, Hupertan V, Sanderson KM, et al. Oncologic control after open or laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: A single center experience. Urology 2007;69:656 – 61. [34] Raman JD, Scherr DS. Management of patients with upper urinary tract transitional cell carcinoma. Nat Clin Pract Urol 2007;4:432– 43. [35] Agarwal DK, Khaira HS, Clarke D, et al. Modified transurethral technique for the management of distal ureter during laparoscopic assisted nephroureterectomy. Urology 2008;71:740 –3. [36] Kawauchi A, Fujito A, Ukimura O, et al. Hand assisted retroperitoneoscopic nephroureterectomy: Comparison with the open procedure. J Urol 2003;169:890 – 4. [37] Steinberg JR, Matin SF. Laparoscopic radical nephroureterectomy: Dilemma of the distal ureter. Curr Opin Urol 2004;14:61–5. [38] Chen GL, Bagley DH. Ureteroscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidneys. J Urol 2000;164:1173– 6. [39] Goel MC, Mahendra V, Roberts JG. Percutaneous management of renal pelvic urothelial tumors: Long-term followup. J Urol 2003;169: 925–30. [40] Grasso M, Fraiman M, Levine M. Ureteropyeloscopic diagnosis and treatment of upper urinary tract urothelial malignancies. Urology 1999;54:240 – 6. [41] Palou J, Piovesan LF, Huguet J, et al. Percutaneous nephroscopic management of upper urinary tract transitional cell carcinoma: Recurrence and long-term followup. J Urol 2004;172:66 –9. [42] Roupret M, Traxer O, Tligui M, et al. Upper urinary tract transitional cell carcinoma: Recurrence rate after percutaneous endoscopic resection. Eur Urol 2007;51:709 –14. [43] Thompson RH, Krambeck AE, Lohse CM, et al. Endoscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidneys. Urology 2008;71:713–7. [44] Pohar KS, Sheinfeld J. When is partial ureterectomy acceptable for transitional-cell carcinoma of the ureter? J Endourol 2001;15:405–9. [45] Brown GA, Busby JE, Wood CG, et al. Nephroureterectomy for treating upper urinary tract transitional cell carcinoma: Time to change the treatment paradigm? BJU Int 2006;98:1176 – 80.
[46] Bloom NA, Vidone RA, Lytton B. Primary carcinoma of the ureter: A report of 102 new cases. J Urol 1970;103:590 – 8. [47] Koga F, Nagamatsu H, Ishimaru H, et al. Risk factors for the development of bladder transitional cell carcinoma following surgery for transitional cell carcinoma of the upper urinary tract. Urol Int 2001; 67:135– 41. [48] Shikanov S, Shapiro A, Baer L, et al. Vesical vs. extra-vesical patterns of recurrence after the treatment of urothelial upper tract tumors. Urol Oncol 2008;26:266 –70. [49] Mukamel E, Simon D, Edelman A, et al. Metachronous bladder tumors in patients with upper urinary tract transitional cell carcinoma. J Surg Oncol 1994;57:187–90. [50] Sakamoto N, Naito S, Kotoh S, et al. Recurrence of bladder tumors following surgery for transitional cell carcinoma of the upper urinary tract. Eur Urol 1991;20:136 –9. [51] Jarrett TW, Chan DY, Cadeddu JA, et al. Laparoscopic nephroureterectomy for the treatment of transitional cell carcinoma of the upper urinary tract. Urology 2001;57:448 –53. [52] Zigeuner RE, Hutterer G, Chromecki T, et al. Bladder tumor development after urothelial carcinoma of the upper urinary tract is related to primary tumor location. BJU Int 2006;98:1181– 6. [53] Akdogan B, Dogan HS, Eskicorapci SY, et al. Prognostic significance of bladder tumor history and tumor location in upper tract transitional cell carcinoma. J Urol 2006;176:48 –52. [54] Charbit L, Gendreau MC, Mee S, et al. Tumors of the upper urinary tract: 10 years of experience. J Urol 1991;146:1243– 6. [55] Li CC, Chang TH, Wu WJ, et al. Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients. Eur Urol 2008;54:1127–34. [56] Krogh J, Kvist E, Rye B. Transitional cell carcinoma of the upper urinary tract: Prognostic variables and postoperative recurrences. Br J Urol 1991;67:32– 6. [57] Joung JY, Yang SO, Jeong IG, et al. Identification of immunohistochemical factors that predict the synchronous or metachronous development of bladder tumors in patients with upper urinary tract tumors. Urol Int 2008;81:306 –11. [58] Akao J, Matsuyama H, Yamamoto Y, et al. Chromosome 20q13.2 gain may predict intravesical recurrence after nephroureterectomy in upper urinary tract urothelial tumors. Clin Cancer Res 2006;12: 7004 – 8. [59] Raman JD, Sosa RE, Vaughan ED Jr., et al. Pathologic features of bladder tumors after nephroureterectomy or segmental ureterectomy for upper urinary tract transitional cell carcinoma. Urology 2007;69: 251– 4. [60] Novara G, De Marco V, Dalpiaz O, et al. Independent predictors of metachronous bladder transitional cell carcinoma (TCC) after nephroureterectomy for TCC of the upper urinary tract. BJU Int 2008;101:1368 –74. [61] Roupret M, Catto J, Coulet F, et al. Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cell carcinoma. J Med Genet 2004;41:e91. [62] Oosterlinck W, Solsona E, van der Meijden AP, et al. EAU guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma. Eur Urol 2004;46:147–54. [63] Eltz S, Comperat E, Cussenot O, et al. Molecular and histological markers in urothelial carcinomas of the upper urinary tract. BJU Int 2008;102:532–5. [64] Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 2009;115:1224 –33.