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Volume 63, issue 1, pages e1-e14, January 2013

ICUD-EAU International Consultation on Bladder Cancer

ICUD-EAU International Consultation on Bladder Cancer 2012: Urothelial Carcinoma of the Prostate

Juan Palou a lowast , David Wood b, Bernard H. Bochner c, Henk van der Poel d, Hikmat A. Al-Ahmadie e, Ofer Yossepowitch f, Mark S. Soloway g and Lawrence C. Jenkins g

Accepted 6 August 2012, Published online 15 August 2012, pages 81 - 87

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Abstract

Context

The Second International Consultation on Bladder Cancer recommendations on urothelial carcinoma (UC) of the prostate were presented at the 2011 European Association of Urology Congress in Vienna, Austria, on March 18, 2011.

Objective

Our aim is to summarize the Second International Consultation on Bladder Cancer recommendations on UC of the prostate to help clinicians assess the current evidence-based management.

Evidence acquisition

The committee performed a thorough review of new data and updated previous recommendations. Levels of evidence and grades of recommendation were assigned based on a systematic review of the literature that included a search of online databases and review articles.

Evidence synthesis

Once a non–muscle-invasive high-grade tumor or carcinoma in situ (CIS) of the bladder has been diagnosed, careful follow-up of the prostatic urethra is necessary. Noninvasive UC including CIS of the prostate should be treated with intravesical bacillus Calmette-Guérin (BCG) following endoscopic resection. A transurethral resection of the prostate may improve contact of BCG with the prostatic urethra, and it appears that response rates to BCG are increased (level of evidence: 3). Transurethral biopsy of the prostatic urethra is effective in identifying prostatic involvement but may not accurately reveal the extent of involvement, particularly with stromal invasion. Stromal invasion by UC of the prostate carries a poor prognosis. Radical cystoprostatectomy is the treatment of choice for locoregional control in patients with prostatic stromal invasion.

Conclusions

These recommendations contain updated information on the diagnosis and treatment of UC of the prostate. However, prospective trials are needed to further elucidate the best management of these patients.

Take Home Message

High-grade noninvasive urothelial carcinoma and carcinoma in situ of the prostate should be treated with transurethral resection of the prostate followed by intravesical bacillus Calmette-Guérin (grade C). Radical cystoprostatectomy is the treatment of choice for locoregional control in patients with prostatic stromal invasion (grade B).

Keywords: Diagnosis, Follow-up, Guidelines, Prostate, Recommendations, Treatment, Urothelial cancer.

Article Outline

1. Introduction

This paper summarizes the Second International Consultation on Bladder Cancer recommendations on urothelial carcinoma (UC) of the prostate as presented at the 2011 European Association of Urology Congress in Vienna, Austria, on March 18, 2011.

UC of the prostate can arise from the urothelium or by invasion from the bladder. Because the latter often occurs by extension of a muscle-invasive bladder cancer (MIBC) with invasion into the prostatic stroma, it carries a worse prognosis. Papillary Ta and carcinoma in situ (CIS) of the prostatic urethra (PU) are managed differently than stromal invasion [1].

2. Evidence acquisition

The committee performed a thorough review of new data and updated previous recommendations. The levels of evidence (LEs) and grades of recommendation were assigned based on a systematic review of the literature that included a search of online databases and review articles. The evidence available was analyzed using the Oxford method of assigning the LEs, and summary recommendations based on these LEs were graded as advised by the Oxford Centre for Evidence-based Medicine [2]. Much of the literature reviewed is of LE 3; therefore, the recommendations created are generally grade C only.

3. Evidence synthesis

3.1. Incidence of urothelial carcinoma in the prostatic urethra

Any UC in the PU was historically termed stage T4 disease, implying a poor prognosis. With further understanding gained over the past 20 yr, it was shown that substaging is possible and that each substage carries a different prognosis.

3.1.1. Carcinoma in situ incidence

In 1952 Melicow and Hollowell described Bowen's disease of the PU [3]. Ortega et al. were the first to describe CIS of the PU in 1953 (LE: 3) [4]. CIS of the PU is almost always associated with a papillary or solid bladder tumor [5]. It is often diagnosed in the context of multifocal disease of the bladder (LE: 3) [4]. Its prevalence was evaluated in 1529 patients with primary bladder tumors who had random biopsies; 19% had CIS of the bladder and 2.7% had CIS in the PU (LE: 3) [6]. CIS in the PU is common in high-risk Ta/T1 bladder cancer (9–25%) and can evolve to prostatic stromal disease (LE: 3) [7]. The presence of PU CIS increased with the duration of bladder cancer. Secondary tumor involvement of the PU and ducts may be detected in 10–15% of patients with high-risk Ta/T1 bladder cancer within 5 yr and in 20–40% within 15 yr (LE: 3) [8], [9], and [10].

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3.1.2. Papillary tumor incidence

Primary papillary tumors in the PU are uncommon (1–4% of cases) [11], [12], and [13]. In most cases, a tumor in the PU is associated with UC elsewhere in the urinary tract [14]. Mungan et al. reported multiplicity as the only risk factor of PU involvement in patients with non-MIBC (NMIBC) [15].

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3.1.3. Stromal invasion incidence

Adequate specimen processing by whole mount sectioning of the prostate is essential for determining the true incidence and pattern of stromal invasion. Using this technique, several contemporary cystoprostatectomy series indicated that prostatic stromal invasion is more common than generally appreciated. In a prospective pathologic assessment, Revelo et al. reported the results of 121 consecutive cystoprostatectomy specimens analyzed by whole mount (LE: 3) [16]. Fifty-eight cases (48%) had UC involving the PU, of which 19 (33%) had apical involvement. Stromal invasion was present in 37–64% of men with prostate involvement at cystoprostatectomy for invasive bladder cancer [1] and [17]. Shen et al. studied 214 consecutive cystoprostatectomy specimens and found invasive prostatic UC in 39 patients (18%) [18]. Esrig et al. analyzed their findings of prostatic involvement in 143 of 489 cystectomy specimens (LE: 3) [19]. Nineteen cases showed direct penetration from the bladder to the prostate and had a poor prognosis. The remaining 124 patients had different stages of indirect prostatic involvement.

The prostatic stroma might be involved not only in those with invasive bladder cancer but also in men with noninvasive bladder cancer previously managed by transurethral resection (TUR) and intravesical therapy. Herr and Donat evaluated 186 consecutive men with Ta/T1 bladder cancer and found that 14% relapsed with prostatic stromal involvement [10]. Nixon et al. reviewed 192 consecutive radical cystectomy specimens and noted PU involvement in 30 (15.6%) (LE: 3) [20]. Of patients with CIS in the bladder, 31.3% (25 of 80) had PU involvement. Similarly, 34.7% (25 of 72) with multifocal UC of the bladder had PU involvement. Multivariate analysis revealed the risk of PU involvement to be 12- to 15-fold higher if CIS or multifocal UC of the bladder was present. More recent data showed a prostatic tumor location in 38% of 248 cystoprostatectomy specimens [16]. In the majority, the tumor originated from the urothelial mucosa, whereas in 4% the tumor extended through the bladder wall into the prostate [21]. Wood et al. reported a 43% incidence of UC of the prostate in cystectomy specimens (LE: 3) [14]. In this series, 94% of those with prostatic involvement had disease present in the PU, including 67% with CIS of the prostatic ducts or acini. Risk factors included CIS of the bladder neck or trigone, prior intravesical therapy, and ureteral involvement by UC.

Stromal invasion into the prostate was shown to be associated with an increased risk of nodal metastases, and stromal invasion carries a poor prognosis [1], [22], and [23]. Survival in men with PU involvement without stromal invasion was >60% 5 yr after a cystoprostatectomy, whereas <30% of men survived when stromal invasion was present [1].

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3.2. Diagnosis

UC of the prostate is often underdiagnosed; correct staging has to be achieved to avoid progression due to undetected stromal invasion (LE: 3) [10] and [19]. Interestingly, prostatic involvement of UC was the only predictor of understaging in recurrent high-risk NMIBC: 53% understaging in men with prostate involvement versus 20% in men without. This suggests that prostatic sampling plays a role in the management of NMIBC [24]. Cystoscopy was described as a valuable tool to diagnose PU involvement if there are macroscopic lesions [20]. Stromal invasion detected in transurethral biopsies in the PU was reported to be only 56% [25]. Even at cystoprostatectomy specimen pathology, an accurate protocol is required to prevent undersampling of the PU [26].

The only way to approach 100% accuracy would be to perform an extensive transurethral resection of the prostate (TURP), an impractical approach for the routine staging of patients with bladder cancer (LE: 3) [27]. Multiple random biopsies of the bladder and PU are not recommended as a normal routine in Ta and T1 bladder cancer. There is a very low incidence of CIS in the PU, but this means that CIS of the prostate will be undetected in patients with some primary bladder tumors (LE: 3) [27] and [28]. Solsona et al. recommended a prostatic biopsy in patients with positive cytology in the absence of macroscopic tumors or CIS or in those with macroscopic lesions in the prostate (LE: 3) [27]. Herr and Donat reported a 39% rate of prostate relapse in patients with high-grade Tis/Ta/T1 bladder cancer (LE: 3) [10].

The staging of bladder carcinoma should include independent evaluation and staging of any prostatic lesion (Table 1, Table 2, and Table 3) (LE: 3) [23], [29], [30], and [31]. Involvement of the prostate by CIS is almost always associated with bladder CIS (LE: 3) [5]. UC in the prostate is commonly silent and insidious with no evidence of macroscopic disease. Once stromal invasion is detected, the management changes completely. Cystoscopy is a valuable measure of PU involvement in macroscopic lesions, with a sensitivity of 83.3% and a specificity of 95.1% (LE: 3) [20]. But it is not always a valuable tool; in patients with recurrent UC after bacillus Calmette-Guérin (BCG) treatment, when considering suspicious or visible lesions, Orihuela et al. had a 48% negative biopsy rate of the PU (LE: 3) [32]. Rikken et al. stressed the need to perform a biopsy of the PU in every patient with high-grade Ta/T1 bladder cancer, with the intention of identifying patients with tumors in that location to allow better therapeutic planning (LE: 3) [33].

Table 1 Classification of prostatic involvement according to Hardeman and Soloway [29]

Stage 1 Tumor confined to prostatic urothelium
Stage 2 Invasion of ducts and acini but confined to the basal membrane
Stage 3 Stromal invasion

Table 2 TNM (2001) classification of prostatic urothelial (transitional cell) carcinoma [30]

Tis pu CIS affecting prostatic urethra
Tis pd CIS affecting prostatic ducts
T1 Tumor invading subepithelial connective tissue
T2 Tumor invading prostatic stroma, spongiosum body, or periurethral muscle
T3 Tumor invading cavernous body prostatic capsule or bladder neck (extraprostatic extension)
T4 Tumor that invades surrounding organs

CIS = carcinoma in situ.

Table 3 TNM classification (2009) of T4 urothelial (transitional cell) carcinoma of the bladder [31]

T4 Tumor invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall
T4a Tumor invades prostate stroma, seminal vesicles, uterus, or vagina
T4b Tumor invades pelvic wall or abdominal wall

Wood et al. were the first to assess the diagnostic yield of transurethral prostate biopsies, needle biopsies of the prostate, and fine-needle aspiration of the prostate to identify prostatic involvement in 25 consecutive patients [14]. Although superficial prostate involvement was accurately identified in most of the patients, the overall diagnostic accuracy for stromal invasion was poor with only two of the five patients identified by TUR biopsies. In a more recent study from the same group, 6 of 35 cystectomy specimens (17%) harbored UC involving the prostatic stroma (either tumor extension from the bladder involving periprostatic tissue or direct extension via the urethra) [34]. In the five patients who had a TUR biopsy prior to surgery, the diagnostic yield of prostatic involvement including superficial urethral and stromal invasion was 100%. To identify stromal invasion, resectoscope loop biopsies of the PU are taken from the lateral lobes and floor beginning distal to the bladder neck and extending just proximal to the verumontanum [7], [35], and [36]. Donat et al. evaluated 246 male patients undergoing cystectomy. Biopsies were obtained at the 4 and 8 o’clock positions from the bladder neck to the verumontanum. With a sensitivity of 53%, specificity of 77%, and positive predictive value of 45%, the authors concluded that transurethral biopsy is an imperfect tool for detecting stromal invasion by UC [25].

Survival is optimized if radical cystectomy precedes stromal invasion (LE: 3) [10]. The detection of prostatic relapse, particularly early stromal invasion, is difficult. That is why frequent biopsies of the bladder neck and prostate are recommended in patients with recurrent high-grade papillary and in situ tumors of the bladder (LE: 3) [10].

3.3. Mechanisms of stromal invasion

Prostatic stromal invasion is defined by the presence of irregular invasive tumor nests or single cells within the dense fibromuscular stroma of the prostate or admixed within benign prostate glands. A distinction can be made between contiguous and noncontiguous tumor growth into the prostate. The former describes direct invasion of bladder tumor into the prostate as an extravesical tumor extension (stage ≥pT3b) penetrating into the stroma directly through the prostatic capsule, whereas the latter refers to the synchronous presence of PU tumors as a pagetoid spread of urethral tumor into the stroma via the ducts and acini. In a series of 320 cystoprostatectomy specimens, Ayyathurai et al. described contiguous tumor growth into the prostate in 9% of cases and noncontiguous in 15% [1]. Several studies showed worse prognosis for contiguous versus noncontiguous growing tumors (Table 4) [1], [19], and [37].

Table 4 Classification of Involvement of the prostate according to Pagano et al. [37]

Stage No. of patients (%) Survival, %
Contiguous 44 (61) 7
Noncontiguous 28 (39) 46
Urethral mucosa 6 100
Ductal/acinar 14 50
Stromal 8 40
Extracapsular invasion 0 –

A third pattern was described as tumors located at the bladder neck/trigone extending into the prostatic stroma through thin lamina propria of the bladder neck without histologic evidence of extravesical or intraurethral spread [25], but the prognostic significance remains unknown.

3.4. Predicting prostatic stromal invasion

Given the lack of accurate diagnostic tools, clinical factors that might help clinicians predict stromal invasion would be particularly useful. Most studies assessing predictors of prostatic involvement by UC, however, have combined superficial urethral involvement and stromal invasion into a single end point in their multivariate analyses. Wood et al. identified CIS involving the trigone, bladder neck, periurethral structures, and ureter, and a history of intravesical instillations as predictors of PU involvement [14]. Similarly, Pettus and colleagues found prostatic UC in 77 of 235 cystoprostatectomy specimens (stromal invasion was present in about half) and identified CIS at the trigone as a significant predictor of prostatic involvement (odds ratio [OR]: 6.3) [38]. In a more recent series of 96 cystoprostatectomy specimens, Richards et al. found prostatic stromal involvement in 18 patients (19%) [17]. After adjusting for clinical stage, lymphovascular invasion, and tumor multifocality, the presence of CIS (OR: 3.2) and location of tumor at or below the trigone (OR: 3.3) were the only independent clinical predictors of stromal invasion. Taken together, even in the absence of positive findings on transurethral loop biopsies, the presence of cancer, in particular CIS, at the bladder neck/trigone should be considered a strong risk factor for prostatic stromal invasion. Recently, a study by Arce et al. found in a multivariate analysis of a series of 717 cystectomy specimens that the presence of solitary T2–T3 bladder tumors at the trigone or bladder neck was predictive of invasive prostatic involvement [39].

3.5. Treatment
3.5.1. General comments

Local resection and staging of concurrent bladder tumors are essential for the management of PU UCs. Often the bladder cancer dictates treatment, in particular in cases with a muscle-invasive bladder tumor.

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3.5.2. Management of high-grade or carcinoma in situ urothelial carcinomas

The prognostic implications of detecting CIS of the PU are defined by the risk of progression (LE: 3) [7]. Some authors believe that this finding mandates the need to offer radical cystoprostatectomy as primary therapy (LE: 3) [40] and [41]. Both the PU and distal ureter have been considered extravesical locations of urothelial neoplasms that cannot be managed with intravesical therapy. Since Morales introduced BCG as intravesical therapy of Ta/T1/CIS UC of the bladder, several authors have reported its efficacy both on bladder CIS and CIS of the PU (LE: 3) [23], [42], [43], [44], and [45]. Ta and ductal tumors of the prostate can be effectively treated if they are completely resected and treated with intravesical BCG. TUR with intravesical BCG provides a significantly better prophylaxis of PU tumor recurrence in Ta and T1 bladder cancer than TUR alone (LE: 2) [46]. Palou et al. reported a bladder preservation rate of 72.7% with BCG and close follow-up [47]. Hillyard et al. and Solsona et al. advocated radical surgery in patients with ductal and stromal involvement (LE: 3) [36] and [48].

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3.5.3. Bacillus Calmette-Guérin penetration in the prostatic urethra

There is not complete agreement on the degree to which BCG penetrates or bathes the PU in bladder instillations. Some authors propose a primary resection of the bladder neck to obtain direct contact between the drug and the prostatic urothelium [43] and [49]. Several studies on the prostatic biopsy tissue of patients who received BCG without prior resection of the prostate demonstrated the presence of granulomas, indicating that BCG establishes contact with the prostate (LE: 3) [50], [51], and [52].

Patients with a previous TURP appear to have an open bladder neck and reflux to the prostatic ducts. Both could facilitate the entrance of BCG into the prostate. BCG instillations were shown to result in lower local recurrences in patients after TURP compared with men without TURP [15], [36], [46], [47], [53], and [54].

Leibovici et al. found a clinically significant elevation of prostate-specific antigen (PSA) in 41.6% of the patients receiving BCG therapy that reverted to normal in 3 mo (LE: 3) [55]. The variation of PSA levels following instillation of BCG was evaluated (LE: 3) [56]. The variation was higher in patients who had previously undergone a TUR of the prostate compared with those who had not, 1.2–10.9 and 2.1–4.5, respectively; which may be related to better penetration of BCG into the prostate. Sakamoto et al. found prostatic involvement in 31 of 134 cystoprostatectomy specimens in patients with primary bladder cancer (LE: 3) [57]. They differentiated between superficial (periurethral) and deep prostatic glands and demonstrated that there was prostatic UC involvement of glands around the verumontanum in 93% of the cases, and at 5 and 7 o’clock in 84%; only one patient had deeper gland involvement without superficial gland involvement.

Given these results, resection of the bladder neck or prostate is advisable, with separate superficial and deep sampling at 5 and 7 o’clock on both sides of the verumontanum. This allows better initial staging and gives the best chance to detect prostatic duct involvement. This maneuver also facilitates penetration of BCG in the prostate.

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3.5.4. Bacillus Calmette-Guérin treatment

Treatment of CIS of the PU associated with a Ta/T1 bladder tumor has resulted in complete response rates of 70–100% in the PU and 47–72% when both the bladder and prostate are considered [15], [36], [46], [53], [54], and [58]. In the series by Bretton et al, therapeutic failure was always evidenced as disease progression in the bladder; they believe that TURP contributed significantly to the successful control of tumor in the PU (LE: 3) [36]. Schellhammer et al. reported an update of the series of Hillyard et al. and described recurrent disease in 9 of 17 patients (LE: 3) [35]. Seven were treated with cystectomy. Four presented with recurrence or progression in the bladder, one in the prostate and two in both bladder and prostate. They obtained good results in 8 of 10 patients with mucosal carcinoma and in 4 of 7 with ductal involvement. Therefore, a more aggressive approach is warranted in cases with ductal or acinar involvement.

In selected cases, a disease-specific survival of 89% was reported at 7.5-yr follow-up for 28 patients with Ta/T1 PU involvement and Ta/T1 bladder cancers [54]. However, 28% had a cystectomy for local recurrence or progression. In a series of 33 patients, progression occurred in eight cases, three of them in the PU (LE: 3). The therapeutic response of this form of disease reaches 70%, whereas the global vesicoprostatic response is only 40%. Palou et al. showed an 82% response rate of BCG for intraprostatic duct CIS even without TURP [47]. Therefore, the results support the view that BCG is a valid option to treat CIS of the PU even without a previous TUR and that it achieves an improved response. However, with longer follow-up, disease progression occurs in 24% of the cases, and these patients have a high disease-specific mortality.

Very few cases of recurrence in the PU after BCG failure have been treated conservatively. Orihuela et al. treated five patients, and only two patients with papillary lesions sustained a complete response (LE: 3) [32]. The other three patients with CIS or high-grade tumors recurred and progressed. Patients who progress and those with UC of the bladder undergoing radical cystectomy should not be considered for prostate-sparing surgery, given the high degree of prostatic involvement (LE: 3) [14], [18], and [59].

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3.5.5. Stromal invasion treatment

Prostatic stromal invasion is associated with a higher likelihood of lymph node (LN) metastases and a poor survival. Shen and colleagues, for example, detected LN metastases in 74% of the patients with stromal invasion; the 5-yr survival in this group was 32% [59]. Similar findings were reported by Barocas et al, who found LN metastases in 74% of men with a bladder tumor extending into the stroma and estimated the 3-yr overall survival of men with stromal invasion with and without LN involvement to be 7% and 17%, respectively [20].

Although lacking support from level l evidence, one might consider an extended LN dissection in the context of stromal invasion. The more extensive the dissection and the more nodes removed, the higher the staging accuracy and therapeutic benefit to patients [60], [61], and [62]. In addition to LN status, it has been suggested that the outcome of men with stromal invasion can be stratified by the pattern and depth of stromal invasion. Based on evidence in the neoadjuvant literature with MIBC and the poor prognosis related with stromal invasion, neoadjuvant chemotherapy could be considered.

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3.6. Follow-up of the prostatic urethra

With increasing numbers of patients receiving initially longer courses of intravesical therapy for high-grade Ta/T1 bladder cancer or CIS rather than radical surgery, there will be an increased number of patients at risk of developing UC of the prostate.

In the series reported by Herr and Donat, 39% of patients with Ta/T1 bladder cancer (72% with associated CIS treated with BCG) relapsed in the prostate at a median follow-up of 28 mo (LE: 3) [10]. In 62%, the tumors were noninvasive, and in 38% there was stromal invasion. Solsona et al. strongly recommend frequent random biopsies of the PU during initial and repeated cystoscopic examinations (LE: 3) [25]. The patients were checked quarterly in the first 2 yr and then semiannually until the fifth year. For patients with positive cytology in follow-up in the absence of macroscopic bladder carcinoma, it is recommended to evaluate the bladder and the PU with multiple biopsies (LE: 3) [27]. Bladder recurrence is most likely to be the cause with a positive cytology during the first 6 mo of follow-up after conservative management of a Ta/T1 bladder carcinoma (LE: 3) [63]. The PU should be considered if there has been associated CIS, tumor near the bladder neck, or multifocal disease (LE: 3) [10], [18], and [36]. If positive cytology appears in longer term follow-up, the upper urinary tract should be evaluated (LE: 3) [64].

4. Conclusions

Primary papillary low-grade tumors of the prostate are rare and most often associated with bladder cancer. In radical cystectomy specimens, the incidence of prostatic stromal invasion by UC of the prostate is related to the extent of pathologic evaluation and is associated with a poor prognosis. Underreporting of the true incidence of prostatic involvement is common. Series of patients who underwent cystectomy for UC of the bladder report an incidence of UC of the prostate from 12% to 48% with stromal invasion in 7.6–16.6% [10], [14], [19], [20], [23], [37], [59], [65], [66], and [67]. TURP may improve response to instillation therapy such as BCG. Careful follow-up is required because recurrence in the prostate predicts poor prognosis in NMIBC.


Author contributions: Juan Palou had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Palou, Wood.

Acquisition of data: Palou, Wood, Bochner, van der Poel, Al-Ahmadie, Yossepowitch.

Analysis and interpretation of data: Palou, Wood, Bochner, van der Poel, Al-Ahmadie, Yossepowitch.

Drafting of the manuscript: Palou, Wood, Bochner, van der Poel, Al-Ahmadie, Yossepowitch.

Critical revision of the manuscript for important intellectual content: Palou, Wood, Bochner, van der Poel, Al-Ahmadie, Yossepowitch, Soloway, Jenkins.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Palou.

Other (specify): None.

Financial disclosures: Juan Palou certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

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Footnotes

a Department of Urology, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain

b Department of Urology, Beaumont Health System, Royal Oak, MI, USA

c Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

d Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands

e Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

f Institute of Urology, Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel

g Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA

lowast Corresponding author. Fundació Puigvert, Universitat Autònoma de Barcelona, Calle Cartagena 340, Barcelona 08025, Spain. Tel. +34 93 416 97 00; Fax: +34 93 416 97 30.

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