Prostate cancer incidence on cystoprostatectomy specimens is directly linked to age: results from a multicentre study

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1 Prostate cancer incidence on cystoprostatectomy specimens is directly linked to age: results from a multicentre study Géraldine Pignot*, Laurent Salomon, Cédric Lebacle*, Yann Neuzillet, Pierre Lunardi, Pascal Rischmann, Marc Zerbib**, Cecile Champy, Morgan Roupret,, Benoit Peyronnet, Gregory Verhoest, Thibault Murez, Herve Quintens, Stéphane Larré, Nadine Houédé, Eva Compérat, Michel Soulié and Christian Pfister, *** *Department of Urology, Bicetre Academic Hospital, Assistance Publique Hôpitaux de Paris, Paris XI University, Oncologic Committee of the French Association of Urology (CCAFU), Department of Urology, Henri Mondor Academic Hospital, Assistance Publique Hôpitaux de Paris, Paris XII University, **Department of Urology, Cochin Academic Hospital, Paris V University, Academic Department of Urology, Pitié Salpétrière Hospital, Assistance Publique Hôpitaux de Paris, University Paris 6, Paris, Department of Urology, Foch Hospital, Université Versailles-St-Quentin-en-Yvelines, Suresnes, Department of Urology, Rangueil Hospital, Toulouse University, Toulouse, Department of Urology, Pontchaillou Hospital, Rennes University, Rennes, Department of Urology, Lapeyronie Hospital, Montpellier University, Montpellier, Department of Urology, Institut Arnault Tzanck, Saint-Laurent du Var, and ***Department of Urology, Rouen Academic Hospital, Rouen, France Objective To assess the incidence and age-related histopathological characteristics of incidentally diagnosed prostate cancer from specimens obtained via radical cystoprostatectomy (RCP) for muscle-invasive bladder cancer. Patients and Methods A retrospective review of the histopathological features of 2424 male patients who underwent a RCP for bladder cancer was done at eight centres between January 1996 and June No patient had preoperative suspicion of prostate cancer. Statistical analyses were performed in different age-related groups. Results Overall, prostate cancer was diagnosed in 518 men (21.4%). Incidences varied significantly according to age (5.2% in those aged <50 to 30.5% in those aged >75, P < 0.001). Most of the prostate cancers were considered as non-aggressive, that is to say organ-confined ( pt2) and well-differentiated (Gleason score <7). Tumour-Node- Metastasis (TNM) stage and proportion with a Gleason score of 7 were significantly greater in older patients (P < 0.001). Apart from age, there were no preoperative predictive factors for non-aggressive prostate-cancer status. At the end of the follow-up, only nine patients (1.7%) had biochemical recurrence of prostate cancer, and no preoperative predictive factors were identified. Conclusion The rate of incidentally diagnosed prostate cancer from RCP specimens is 2, most of them being organ-confined and well-differentiated. The probability of having a non-aggressive prostate cancer decreases in older men. Keywords prostatic neoplasms, urinary bladder neoplasms, prognosis, incidentally detected, cystoprostatectomy Introduction One man out of six will be diagnosed with prostate cancer during his lifetime and the probability of dying from prostate cancer is 3%. The prevalence of prostate cancer far exceeds that of clinically detected disease. The sensitivity of detecting prostate cancer has been enhanced by lowering the threshold of the serum PSA concentration that is used to recommend a biopsy. However, needle biopsies detect prostate cancers in only 53% of cases [1]. Autopsy series have found unsuspected carcinomas in the prostate glands of men who have deceased from unrelated causes. The prevalence of malignant prostate disease varies according to age: from 3 of men aged <50 to 7 of men aged 80 [2 4]. Most incidental tumours are considered clinically insignificant. Prostate specimens, obtained from patients during radical cystoprostatectomy (RCP), provide an opportunity to BJU International 2014 BJU International doi: /bju BJU Int 2015; 115: Published by John Wiley & Sons Ltd. wileyonlinelibrary.com

2 Pignot et al. investigate the prevalence of incidentally detected prostate cancers. Another issue is the clinical significance of these prostate cancers. Indeed, most incidental prostate cancers detected in RCP specimens are potentially insignificant and are clinically silent diseases that are not apparent before surgery. These unsuspected prostate cancers found in RCP specimens could be considered similar to autopsy detected cancers. With the current changes in prostate cancer management and earlier screen detection of this disease, controversies of over-diagnosis and over-treatment of a subset of potentially indolent prostate cancers is being investigated, especially for certain age groups. The purpose of our multicentre study was to analyse the incidence and clinicopathological features of incidental prostate cancers in RCP specimens according to the patient s age. Patients and Methods We performed a retrospective review of RCP specimens from 2424 male patients who underwent a procedure for bladder cancer between January 1996 and June 2012 in eight French centres. Preoperative evaluations included a systematic clinical examination and a thoraco-abdominal CT in all patients. Patients with a previous history of prostate cancer or patients diagnosed after DRE or laboratory testing before surgery were excluded. A standard RCP with bilateral pelvic lymphadenectomy was performed. Medical notes and surgical pathology reports were reviewed to identify those with concomitant prostate cancer. The following clinical criteria were retrieved: age, preoperative PSA concentration, TNM stage of bladder cancer, presence and histological characteristics of prostate cancer, and survival data. Serum PSA concentration was measured postoperatively in all patients, at 1 month and then every 6 months. Biochemical recurrence of prostate cancer was defined as a postoperative increase in PSA concentration of >0.2 ng/ml. Histopathological processing and examination of bladder and prostate tissues were assessed in each centre s pathology laboratory. Prostate cancer Gleason score, stage, extracapsular invasion, surgical margin status, and pelvic lymph-node involvement were examined in all specimens. Bladder tumour TNM stage and prostatic urethral involvement by bladder cancer cells were also determined. Tumour stage was determined according to the 2002 Union Internationale Contre le Cancer (UICC) TNM classification [5]. Tumour grade was determined according to the WHO 2004 grading scheme for bladder tumours [6] and according to the Gleason score for prostate cancer [7]. Prostate cancer was defined as non-aggressive if it had a pt2 stage (organ-confined) and a Gleason score of 6 (no grade 4). The incidence of prostate cancer and its characteristics were stratified according to the patients age. For these analyses, the whole population was divided into five groups: those aged <50, 50 59, 60 69, 70 75, and those aged >75. Values and frequencies are given with statistical comparisons carried out using the Student s t-test, Pearson s chi-squared test, and Fisher s exact test. Analyses were performed using SEM software. A P < 0.05 was considered to indicate statistical significance. Results Incidence Prostate cancer was detected in 518 of the 2424 patients who underwent RCP (21.4%). The proportion of prostate cancers in RCP specimens varied from 10.9% to 32.5% between centres. This inter-centre variability was independent of the volume and surgical experience of the centres (Fig. 1A,B). Age of the Cohort The median (range) age for the whole population was 66.2 (25 96). The median (range) age of patients with an Fig. 1 (A) Number of patients who underwent a RCP in each centre. (B) Proportion of prostate cancer on RCP in each centre. A B Percentage Patients with prostate cancer on RCP Patients without prostate cancer on RCP BJU International 2014 BJU International

3 Prostate cancer incidence on cystoprostatectomy specimens incidental prostate cancer was 69.8 (41 96). The age at the time of surgery was significantly higher in patients with prostate cancer compared with those without (P < 0.001). Characteristics of Prostate Cancer The median (range) preoperative PSA concentration was 2.1 ( ) ng/ml (values available in 48.1% of cases). The pathological characteristics of prostate cancer are summarised in Table 1. Most patients had organ-confined disease (458, 88.4%). In all, 60 patients (11.6%) had extracapsular invasion, seminal-vesicle involvement, or had invasion of a nearby structure (TNM stage pt3), and 23 (4.4%) had metastatic lymph-node disease from prostate cancer. A Gleason score of 6 was found in 389 patients (75.1%), whereas 129 patients (24.9%) had a Gleason score of 7. In all, 28 patients (5.4%) had positive surgical margins on prostate specimens. In 8.9% of cases (46/518), associated high-grade prostatic intraepithelial neoplasia (HGPIN) was described in the histological report. Prostatic urethral involvement with urothelial carcinoma was present in 8.1% of cases (42/518) and was not significantly associated with the aggressiveness of prostate cancer (TNM stage and Gleason score). Characteristics of Bladder Cancer Urothelial carcinoma was the principal histological subtype (460, 88.8%). All tumours were high grade. Tumours were organ-confined (<pt3) in 50.6% of cases, were locally advanced ( pt3) in 49.4% of cases, and 30.5% had lymph-node involvement. Four patients (0.8%) had metastatic disease at the time of surgery (palliative cystectomy). In 7.5% Table 1 Clinicopathological characteristics of patients with prostate carcinoma on RCP specimens. Variable Value of cases, the surgical margins were positive. Neoadjuvant chemotherapy was administered in 25 cases (4.8%) and adjuvant chemotherapy in 113 cases (21.8%), essentially during the last decade of life. Indications were left to the protocol of each centre. Incidence and Characteristics of Prostate Cancer Stratified according to Age The incidence of prostate cancer on RCP specimens varied significantly according to age (from 5.2% in those aged <50 to 30.5% in those aged >75, P < 0.001). The age distributions are presented in Figure 2A. TNM stages were significantly higher in older patients (P < 0.001; Table 2), with locally advanced tumours in 19.1% of those aged >75 compared with 12.4% in those aged 70 75, 10.1% in those aged 60 69, 1.3% in those aged 50 59, and none in those aged <50 (Fig. 2B). Fig. 2 (A) Frequency of prostate cancer in RCP specimens according to the age of patients. (B) T-stage partitioning between age-related groups. (C) Gleason score partitioning between age-related groups. A 35% 3 25% 2 15% 1 5% B % Less than % % 23.84% 89.94% 87.61% 30.52% More than % Number of patients 518 Median (range) age (): 69.8 ( ) N (%): pt stage T2 458 (88.4) T3a 37 (7.1) T3b 12 (2.3) T4 11 (2.1) N status N0 495 (95.6) N+ 23 (4.4) Gleason score (75.1) 7(3 + 4) 80 (15.4) 7(4+ 3) 25 (4.8) 8 24 (4.6) Surgical margin R0 490 (94.6) R+ 28 (5.4) HGPIN associated Yes 46 (8.9) No 472 (91.1) 5 C Less than Less than % 93.51% % 12.39% 21.23% T3a-T % T % % Gleason 7 Gleason % More than % 63.12% More than 75 BJU International 2014 BJU International 89

4 Pignot et al. Table 2 Characteristics of prostate cancer according to age-related groups. Variable, n/n (%) Age, P < >75 Frequency 8/155 (5.2) 77/509 (15.1) 179/824 (21.7) 113/473 (23.8) 141/462 (30.5) <0.001* pt stage: <0.001 T2 8/8 76 (98.7) 161 (89.9) 99 (87.6) 114/141 (80.8) T3a T4 0 1 (1.3) 18 (10.1) 14 (12.4) 27 (19.2) Gleason score: < /8 72 (93.5) 141 (78.8) 79 (69.9) 89 (63.1) (6.5) 38 (21.2) 34 (30.1) 52 (36.9) HGPIN: 0.38 No 8/8 72 (93.5) 163 (91.1) 106 (93.8) 123 (87.2) Yes 0 5 (6.5) 16 (8.9) 7 (6.2) 18 (12.8) Surgical margin: 0.57 No 8/8 74 (91.6) 172 (96.1) 104 (92.0) 132 (93.6) Yes 0 3 (3.9) 7 (3.9) 9 (8.0) 9 (6.4) Urothelial prostate infiltration 0.88 No 7/8 70 (90.9) 164 (91.6) 104 (92.0) 131 (92.9) Yes 1/8 7 (9.1) 15 (8.4) 9 (8.0) 10 (7.1) *Pearson s chi-squared test; Fisher s exact test. The proportion with a Gleason score of 7 was significantly higher in older patients (P < 0.001; Table 2), with 36.9% in those aged >75 compared with 30.1% in those aged 70 75, 21.2% in those aged 60 69, 6.5% in those aged 50 59, and none in those aged <50 (Fig. 2C). The presence of associated HGPIN, prostatic urethral involvement with urothelial carcinoma, and positive surgical margins did not differ significantly according to age (Table 2). Aggressiveness of Prostate Cancer Among the 518 patients, 375 (72.4%) had a non-aggressive prostate cancer. Apart from age, which was significantly less in patients with a cancer that was considered nonaggressive, there were no preoperative predictive factors for non-aggressive prostate cancer status (Table 3). Discussion To our knowledge, this is the largest series to report prostate cancer found in RCP specimens. We have already confirmed in a previous study that incidentally diagnosed prostate cancer in RCP specimens was very frequent [8] and these data were in accordance with the literature [9 14]. The aim of the present study was to assess precisely the age-related histopathological characteristics of prostate cancer in RCP specimens. In the present cohort, the median age of patients with prostate cancer in a RCP specimen was From 2005 to 2009, the median age at diagnosis of prostate cancer was 67 [15]. It is noteworthy that cancers detected in RCP specimens are usually from patients who are 5 10 older than patients with cancers detected in at radical prostatectomy. The age difference in these two patient populations probably reflects the lead-time bias of more frequent PSA screening for cancers in clinical practice. It is noteworthy that the incidence of prostate cancer is low in those aged <50 (5.2%) and is elevated in those aged >75 (30.5%) in the present series. Autopsy series are interesting because they provide an insight into the true prevalence of prostate cancer. The rate of incidental cancers found in autopsies is close to the documented rates of incidental cancers found in RCPs (i.e. from 10 34%) [3,16 20]. In the autopsy series reported by Delongchamps et al. [21], one-third of diagnosed prostate cancers found in prostate biopsies would have been pathologically described as insignificant prostate cancers in living patients. This rate of insignificant prostate cancer seems to be lower than in other autopsy series, which vary from 59% to 71% of cases [3,22]. This discrepancy may be caused by the wide variation in pathology sampling methods used on prostate specimens: i.e. extended prostate biopsies [23], partial sampling, or slice thickness and complete embedding [24]. Recent studies have highlighted the importance of complete embedding and processing of RCP specimens to yield more significantly and clinically relevant identification of prostate cancers, particularly in younger men [25,26]. The notion of insignificant prostate cancer has progressively emerged in the past two decades. The clinical relevance of such a definition has been based on the fact that low-grade, small-volume, and organ-confined prostate cancers may be slowly progressing cancers, which may not require immediate curative treatment and may be eligible for active surveillance [27]. The term insignificant prostate cancer should be strictly used in living patients because any cancer found in an autopsy is clinically insignificant by definition. This is the same 90 BJU International 2014 BJU International

5 Prostate cancer incidence on cystoprostatectomy specimens Table 3 Differences between diagnoses of non-aggressive (T2 and Gleason 6) vs other prostate cancers found on RCP specimens. Variable Non-aggressive Other P N Median (range) age, 67.6 ( ) 73.7 ( ) <0.001 N (%) Histology: 0.85* Urothelial 337 (89.9) 127 (88.8) No urothelial 38 (10.1) 16 (11.2) T stage 0.34* T0 T2 195 (52.0) 67 (46.9) T3 T4 180 (48.0) 76 (53.1 pn stage 0.38* N0 256 (68.3) 104 (72.7) N (31.7) 39 (27.3) M stage 0.66* M0 373 (99.5) 141 (98.6) M1 2 (0.5) 2 (1.4) CIS associated 0.57* No 264 (70.4) 105 (73.4) Yes 111 (29.6) 38 (26.6) Urothelial prostate infiltration 0.97* No 344 (91.7) 132 (92.3) Yes 31 (8.3) 11 (7.7) HGPIN 0.44* No 339 (90.4) 133 (93.0) Yes 36 (9.6) 10 (7.0) *Pearson s chi-squared with Yates correction; CIS, carcinoma in situ. Student s t-test. concept used for prostate cancer when it is incidentally diagnosed in RCP specimens. Indeed, as the prostate is removed during the surgical procedure, the risk of progressive microfocal cancer no longer exists. However, there is no universally accepted definition of insignificant prostate cancer. To date, the most commonly used criterion is based on the pathology of the specimen [25]. Prostate cancer is usually considered insignificant if all of the following are observed: a Gleason score <7 (without a Gleason pattern of 4 or 5), organ-confined disease (stage pt2), and a tumour volume of <0.5 ml. In addition to these determinants, it is also important to account for the clinical context of the disease, as well as the patient s age and health status, in regard to treatment choice. Few studies have investigated the frequency of low-grade and low-volume prostate cancers that could be described as insignificant prostate cancer in living patients. On the other hand, the histological grade seems to be the most important predictive factor of prostate cancer aggressiveness. Indeed, recent studies have highlighted the similarity of outcomes for men with Gleason score 6 tumours if treated or not. These data suggest that well-differentiated prostate cancers may be considered as indolent, as they did not significantly impact on survival [28,29]. In our present series, which included living patients who had surgery for RCP, tumour volume was not available on pathological report and only stage and grade were used to define cancer aggressiveness. Two-thirds of the incidentally diagnosed prostate cancers in the present study were considered non-aggressive, that is to say organ-confined and a Gleason score of <7. The analyses of prostate-cancer characteristics according to the patients age in our present series allowed us to highlight that the aggressiveness of prostate disease, based on pt stage and Gleason score, increased with age. In those aged >75, locally advanced tumours (>pt2) and a high Gleason score ( 7) occurred in 19.1% and 36.9% of cases, respectively. However, the clinical significance of this is not straight forward as the outcome of these patients depends almost exclusively on the prognoses of their bladder tumours. Despite the existence of several proposed nomograms and prognostication tools [26], the ability to preoperatively predict insignificant prostate cancer in RCP specimens is still far from perfect. For Pettus et al. [23], only age was a predictive factor for prostate cancer (odds ratio 1.3, P = 0.046). This result is concordant with our present data, as the patient s age was the only preoperative factor associated with a significant status of prostate cancer in our series. Preoperative PSA concentration does not seem to be significantly associated with the likelihood of incidentally discovering prostate cancer [27,30]. For Gakis et al. [31], no preoperative clinical value could formally exclude prostate cancer in a RCP specimen. These findings confirm that we cannot adequately determine who can safely be selected for prostate-sparing cystectomy and that the treatment of choice, in cases of muscle-invasive bladder cancer, remains RCP. However, a conservative option could be considered for younger patients because the rate of BJU International 2014 BJU International 91

6 Pignot et al. aggressive prostate cancer in those aged <50 is very low (none with a T3a and none with a Gleason score >6 inthose aged <50, in our present series). From the literature, 4% to 2 of prostate cancers are potentially likely to biochemically or clinically recur during the follow-up period after a RCP. The prognostic factors associated with postoperative recurrence are a tumour volume of 0.5 ml, a Gleason score 4, extracapsular invasion or invasion of the seminal vesicles, N+ status, and/or the presence of positive surgical margins [32]. In the present series, after a mean follow-up of 30.8 months, only nine patients (1.7%) had a biochemical recurrence of prostate cancer, and these few events did not allow for the identification of potential predictive factors. One of the major limitations of the present study is that data on preoperative PSA concentration, prostate size, and tumour volume were not always available. Indeed, studies on RCP specimens generally do not provide precise analyses of the prostate. This is particularly important as the insignificant definition of prostate cancer usually takes into account tumour volume. Moreover, we did not have whole-mount prostate sections or the opportunity for centralised re-review to standardise practices. This factor could partly explain the discrepancies between our present results and those from other series. Finally, one of the weaknesses of the present study is the absence of a multivariable model comparing other potential predictors of prostate cancer, however not identified as significant in univariate analysis in our series. In conclusion, incidentally diagnosed prostate cancer was found in 2 of RCP specimens after surgery for bladder cancer. There were differences in the incidence and behaviour of this disease according to the ages of the patients. About three-quarters of patients had non-aggressive cancer (organ-confined and well-differentiated). Apart from age, there were no other preoperative predictive factors that determined non-aggressive prostate cancer status. Conflicts of Interest None declared. Sources of funding for research and publication: None. References 1 Haas GP, Delongchamps NB, Jones RF et al. Needle biopsies on autopsy prostates: sensitivity of cancer detection based on true prevalence. JNatl Cancer Inst 2007; 99: Soos G, Tsakiris I, Szanto J, Turzo C, Haas PG, Dezso B. The prevalence of prostate carcinoma and its precursor in Hungary: an autopsy study. Eur Urol 2005; 48: Stamatiou K, Alevizos A, Perimeni D, Sofras F, Agapitos E. Frequency of impalpable prostate adenocarcinoma and precancerous conditions in Greek male population: an autopsy study. Prostate Cancer Prostatic Dis 2006; 9: Sánchez-Chapado M, Olmedilla G, Cabeza M, Donat E, Ruiz A. Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study. Prostate 2003; 54: Edge S, Byrd D, Compton C eds. AJCC Cancer Staging Manual, TNM Classification of Malignant Tumors, 7th edn. New York: Springer, Eble JN, Sauter G, Epstein JI, Sesterhenn IA eds. World Health Organisation classification of tumors. In Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs, Lyon: IARC Press, 2004: Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL, ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005; 29: Pignot G, Salomon L, Neuzillet Y et al. Clinicopathological characteristics of incidental prostate cancer discovered from radical cystoprostatectomy specimen: a multicenter French study. Ann Surg Oncol 2014; 21: Bruins HM, Djaladat H, Ahmadi H et al. Incidental prostate cancer in patients with bladder urothelial carcinoma: comprehensive analysis of 1,476 radical cystoprostatectomy specimens. J Urol 2013; 190: Abdelhady M, Abusamra A, Pautler SE, Chin JL, Izawa JI. Clinically significant prostate cancer found incidentally in radical cystoprostatectomy specimens. BJU Int 2007; 99: Hosseini SY, Danesh AK, Parvin M et al. Incidental prostatic adenocarcinoma in patients with PSA less than 4 ng/ml undergoing radical cystoprostatectomy for bladder cancer in Iranian men. Int Braz J Urol 2007; 33: Mazzucchelli R, Barbisan F, Scarpelli M et al. Is incidentally detected prostate cancer in patients undergoing radical cystoprostatectomy clinically significant? Am J Clin Pathol 2009; 131: Montie JE, Wood DP Jr, Pontes JE, Boyett JM, Levin HS. Adenocarcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. Cancer 1989; 63: Saad M, Abdel-Rahim M, Abol-Enein H, Ghoneim MA. Concomitant pathology in the prostate in cystoprostatectomy specimens: a prospective study and review. BJU Int 2008; 102: Surveillance, Epidemiology, and End Results Program (SEER). 9 Incidence & U.S. Mortality Topic lifetime risk diagnosis; topic lifetime risk death; statfacts incidence-mortality. Available at: Accessed June Delongchamps NB, de la Roza G, Chandan V et al. Diagnostic accuracy of extended biopsies for the staging of microfocal prostate cancers in autopsy specimen. Prostate Cancer Prostatic Dis 2009; 12: Sakr WA, Grignon DJ, Crissman JD et al. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20 69: an autopsy study of 249 cases. In Vivo 1994; 8: Gatling RR. Prostate carcinoma: an autopsy evaluation of the influence of age, tumor grade, and therapy on tumor biology. South Med J 1990; 83: Tiszlavicz L, Szalay I. [Multiple urologic tumors in autopsy material]. Orv Hetil 1993; 134: Harbitz TB, Haugen OA. Histology of the prostate in elderly men. A study in an autopsy series. Acta Pathol Microbiol Scand A 1972; 80: Delongchamps NB, de la Roza G, Jones R, Jumbelic M, Haas GP. Saturation biopsies on autopsied prostates for detecting and characterizing prostate cancer. BJU Int 2009; 103: Erbersdobler A, Bardenhagen P, Henke RP. Numerical chromosomal anomalies in latent adenocarcinomas of the prostate. Prostate 1999; 38: Pettus JA, Al-Ahmadie H, Barocas DA et al. Risk assessment of prostatic pathology in patients undergoing radical cystoprostatectomy. Eur Urol 2008; 53: BJU International 2014 BJU International

7 Prostate cancer incidence on cystoprostatectomy specimens 24 Fritsche HM, Aziz A, Eder F et al. Potentially clinically relevant prostate cancer is found more frequently after complete than after partial histopathological processing of radical cystoprostatectomy specimens. Virchows Arch 2012; 461: Ploussard G, Epstein JI, Montironi R et al. The contemporary concept of significant versus insignificant prostate cancer. Eur Urol 2011; 60: Dong F, Kattan MW, Steyerberg EW et al. Validation of pretreatment nomograms for predicting indolent prostate cancer: efficacy in contemporary urological practice. J Urol 2008; 180: Winkler MH, Livni N, Mannion EM, Hrouda D, Christmas T. Characteristics of incidental prostatic adenocarcinoma in contemporary radical cystoprostatectomy specimens. BJU Int 2007; 99: Eggener SE, Scardino PT, Walsh PC et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 2011; 185: Nickel JC, Speakman M. Should we really consider Gleason 6 prostate cancer? BJU Int 2012; 109: Rocco B, de Cobelli O, Leon ME et al. Sensitivity and detection rate of a 12-core trans-perineal prostate biopsy: preliminary report. Eur Urol 2006; 49: Gakis G, Schilling D, Bedke J, Sievert KD, Stenzl A. Incidental prostate cancer at radical cystoprostatectomy: implications for apex-sparing surgery. BJU Int 2010; 105: Amara N, Palapattu GS, Schrage M et al. Prostate stem cell antigen is overexpressed in human transitional cell carcinoma. Cancer Res 2001; 61: Correspondence: Géraldine Pignot, Department of Urology, Bicêtre Hospital, Paris XI University, 78 rue du General Leclerc, Le Kremlin Bicêtre cedex, Paris, France. gg_pignot@yahoo.fr; geraldine.pignot@bct.aphp.fr Abbreviations: HGPIN, high-grade prostatic intraepithelial neoplasia; RCP, radical cystoprostatectomy. BJU International 2014 BJU International 93