==inizio objective==
Prostate cancer (PCa) is a common cancer and the second cause of cancer-related mortality in men (1, 2). Nonetheless, PCa prevalence at the histological level is higher than the clinically detected disease rates. During autopsy studies, prostatic adenocarci-noma has been histologically detected in > 30% of men older than 50 years. These tumors are usually small and clinically indolent, with the ability to exist for several years before presenting any change, such as accelerated cell proliferation, tumor metastasis and clinical detection. More importantly, accumulating evidence has shown that, in patients affected by primary bladder cancer (BC) undergoing radical cystoprostatectomy (RCP), there is a higher incidence of PCa (3, 4). RCP specimens from patients affected by diseases other than PCa can be a random sample from the prostates of asymptomatic men, offering a unique opportunity to study the incidence and morphological features of these incidental prostatic tumors. In terms of randomness, this cohort shows similarities to that of the autopsy studies, but differs in the reported higher PCa incidence in men with BC (3, 4). According to the European Association of Urology guidelines, for patients affected by muscle-invasive bladder cancer (MIBC) or any high-risk, recurrent and non-invasive BC, the RCP procedure with bilateral pelvic lymphadenectomy and various types of urinary diversion is the gold standard of therapy (5). The standard RCP in men is based on the removal of the bladder along with prostate, seminal vesicles, a part of the vasa deferentia and distal ureter, including regional lymphadenectomy (in order to provide an effective local treatment of the disease), which can have a high incidence of sexual complications and urinary incontinence. Whereas alternative techniques can be considered in highly selected cases in which it is desired to preserve potency, fertility and urinary function. In the modern era of orthotopic bladder substitution after RCP for BC, sparing the entire prostate or a portion of it has become controversial in recent years. However, these techniques, in an effort to maintain sexual and urinary functions, have raised concerns regarding the oncological outcomes due to two potential risks: urothelial cancer local invasion of the prostate and a probable association with incidental PCa (6). PCa is complex: on one hand, numerous patients with PCa receive unnecessary treatment as their disease will never become clinically significant or result in death. On the other hand, some prostatic tumors require immediate treatment, which are known as clinically detected PCa. For this reason, incidentally identified PCas are divided in two groups: clinical significant and clinical insignificant. The aim of the present single-center retrospective study was to: i) assess incidence, histopathological features and clinical significance of incidentally identified prostatic tumors in RCP specimens obtained from patients affected by bladder cancer, but with clinically normal prostates; ii) examine patients’ age, pre-operative rectal examination findings and prostate specific antigen (PSA) values, in order to evaluate whether such features can help with the prediction and treatment of significant PCas; iii) establish whether prostate sparing-cystectomy could represent a feasible option for these patients.
==fine objective==
==inizio methodsresults==
The data of 303 male patients who underwent RCP with bilateral pelvic lym-phadenectomy and different urinary diversion for BC at our Department of Urology were retrospectively reviewed. Data from the pre-operative digital rectal exam (DRE) and PSA assays were analyzed in patients diagnosed with incidental PCa, for a total of 69/303 (22.7%) patients. Treatment and prognosis of muscle invasive bladder cancer (MIBC) are determined by tumor stage and grade. So, before any curative treatment, it is essential to evaluate the presence of distant metastases. For this reason, all patients enrolled in the current study underwent CT of the chest, abdomen and pelvis, as well as MRI of the abdomen and pelvis. This staging showed that none of the patients had distant metastases or neoplastic disease of the prostate. The selection criteria were as follows: i) no previous history of PCa; ii) no previous history of chemotherapy or radiotherapy; iii) no evidence of PCa in the imaging evaluation; and iv) age ≥ 40 years old. Routine pathological examination was performed as by routine on bio-specimens. Beyond evaluation of the bladder, it was considered i) the presence of PCa; the stage of any detected prostatic adenocarcinoma following the 2002 TNM classification (7) and its Gleason score according to the World Health Organization system (8) and ii) the surgical margin status (a positive surgical margin was recorded upon detection of tumor cells at the stained margin of the specimens). Prostate involvement in bladder cancer was also assessed. The intact RCP specimens were immersed in 10% buffered formalin solution. Then, the prostate in-cluding seminal vesicles and vas deferens, was cut out from bladder, weighed and stained with Indian Ink. Sectioning was performed by cutting at 5-mm interval sections transverse to the long axis, which were then embedded in paraffin for H&E staining and exami-nation. PCa was defined as clinically significant when any of the following criteria was met: Gleason Score ≥ 4, stage > pT3, extracapsular extension (ECE), lymph node metastasis (LNM) or positive surgical margins (SM).
==fine methodsresults==
==inizio results==
In order to undergo surgery, all patients enrolled in our study underwent DRE and MRI of the abdomen and pelvis to specifically evaluate the prostate both clinically and instrumentally. Both examinations did not reveal any prostate abnormalities such as to require a prostate biopsy. Of the 303 RCP specimens, incidental PCa was detected in 69 patients (22.7%), with a median age of 71.6 years (age range, 54-89 years). We performed orthotopic bladder substitution in 29 (42%) patients, ileal conduit procedure in 14 patients (20.2%) and ureterocutaneostomy in 26 patients (37.7%). Regarding bladder cancer features, all tumors were of high grade. In 69 patients with incidental PCa, 23 of these cancers (33.33%) were regarded clinically significant. In this group of patients, only seven (for a percentage equal to 10.1%) were affected by locally advanced prostate cancer on histopathological examination. From the retrospective analysis, moreover, these patients presented a bladder tumor which invaded the trigone and the bladder neck. For this reason, the differential diagnosis between primary prostate tumor and bladder infiltration of the prostate was very difficult. Patients were subdivided into three age groups based on the 33% and 66% age quantiles (< 70, between 70-75 and > 75 years of age) and then evaluated. For both TNM stage and Gleason score no significant difference in the mean value of the respective parameter between the three age categories was identified. In total, 46 (66.66%) of 69 patients presented a “non-aggressive” PCa. None of the pre-operative factors, namely PSA level and age, were predictive factors for non-aggressive PCa. Comparisons of the mean values and rank order for age and PSA level between the patients with aggressive PCa and the patients who had non-aggressive tumor by means of unpaired t-tests and Mann-Whitney U tests did not result in any significant difference.
==fine results==
==inizio discussions==
Incidental PCas identified in RCP samples, from patients who underwent BC surgery but had no preoperative evidence of prostatic disease, show histological and morphological features similar to those of latent tumors identified in several autopsies (9-11). According to the literature, the frequency variability of incidentally discovered PCa in cystoprostatectomy specimens is extremely high, ranging from 17%-70% (12, 13), owing to various factors. The first of these is the different definition of clinically significant cancer in published studies (14). Over the past two decades, the emerging concept of “insignificant” PCa has progressed to indicate low-grade, small-volume and organ-confined prostatic tumors that are likely slowly progressing, and these, although might not need urgent therapeutic treatment, are eligible for active surveillance (15). Currently, the pathological assessment of the lesion indicates further patient management (16). Generally, PCa is diagnosed as “insignificant” when: the disease has a Gleason score < 7 (without a Gleason pattern of 4 or 5); it is confined to the organ (stage pT2); and the tumor mass has a < 0.5 cm3 volume. Here, only tumor stage and grade could be taken into account to cancer aggressiveness as tumor volume was not available on the pathological report. Our results showed that 46 (66.66%) of the incidentally diagnosed PCas were considered as “non-aggressive” as they were organ-confined or with a Gleason score of < 7 (4+3). Then, an association between BC and PCa was suggested by several previous studies (17-21). However, the association between BC and PCa can be explained as a possible detection bias, associated with more detailed clinical assessment and thorough pathological examination. For example, once a diagnosis of BC has been made, a complete investigation of the entire genitourinary system is likely to occur (22, 23). In this regard, however, it is important to note that the prognosis of patients bearing both PCa and BC is not considered to be worse than the prognosis of patients bearing only one of these two cancer types; rather, it is the stage of BC that impacts the prognosis. The different detection rate of PCa in RCP specimens may be influenced by the thickness of the prostate histological slices, because pathologists might focus more to the bladder. Indeed, Kouriefs and colleagues (24) reasoned that the lower PCa incidence observed in their study (18%) was possibly caused by thick gland sections, indicating that thinner sectioning is recommended (< 10 mm). Consistently, Abbas et al. (25) found a 45% incidence rate using 2-3-mm-thick slices and Moutzouris et al. (26) a 27% of PCa using 5-mm slices. The current study used 5-mm slices and the observed 22.7% incidence rate of PCa supported the aforementioned hypothesis, indicating that thin tissue sectioning should be used to optimize cancer detection. Finally, genetic and environmental factors may influence the variability of the findings from different countries. In the present study, the majority of prostatic tumors were well differentiated. Our data are consistent with what reported in other studies in which most of detected tumors were not clinically significant, with only few patients requiring therapeutic treatment (25, 10, 11). The preservation of continence and erectile function, as well as guaranteeing excellent oncological results, remain the primary goals of the treatment of BC with RCP. Various techniques can help to preserve postoperative continence and erectile function, such as leaving the apex or the entire tissue of the prostate; however, the potential risk of not removing the synchronous PCa can be problematic. By contrast, the probability that patients undergoing RCP and have PCa will not die from prostatic disease is high. Determining whether patients are suitable for prostate-sparing surgery can be difficult. In this regard, the RCP findings obtained in a study by Moutzouris et al. (26) raise further concerns, showing apical involvement by PCa in the 31% of cases and the presence of multifocal PCa in the 31% of patients (26). Moutzouris et al. (26) claimed that apical involvement by PCa indicates the need of a complete prostate resection. Indeed, a patient within their cohort bearing PCa in the apex had recurrent prostatic disease in the urethro-ileal anastomosis of an orthotopic bladder substitute. Similarly, Revelo et al. (27) reported a 25% of patients with apical PCa, of which about 2/3 were clinically significant. They found apical involvement of the prostate with BC in 16% of patients. Overall, they suggested that prostatic apex preservation was a feasible method to improve continence, but it was associated with the risk of incomplete cancer resection. In the attempt to overcome this risk, Revelo et al. (27) suggested to perform a pre-operative prostate biopsy and freeze intraoperative sections. However, due to possible sampling error, a negative biopsy may not completely exclude apical involvement of PCa in subjects elected for apical sparing surgery. Hautmann et al. (28) performed sextant biopsies of the prostate upon removal of RCP specimens and detected through this method PCa in only 5% of cases, showing that that biopsy detection rate was 1 out of 9 tumors. Therefore, while sextant biopsies seem not adequate to exclude clinically significant PCa, the optimal prostatic biopsy procedure still needs to be defined. So, routine biopsy has a certain degree of uncertainty regarding the ability to identify clinically significant PCa with high sensitivity when attempting to select patients for prostate-sparing cystectomy. For a successful radical cancer removal it remains crucial not to leave PCa in the apical prostatic margin or residual tissue of PCa, which might be clinically significant. According to Pettus (29), only age was a predictive factor for PCa. However, the present data suggest that patients’ age was not a preoperative factor associated with a significant status of PCa. Likewise, the preoperative PSA level seems not significantly associated with the ability to incidentally discover PCa (15). In the present study, PSA values and DRE findings were available for all patients, but their results were not indicators for cancer. This finding suggests that preoperative PSA screening and DRE in RCP candidates provide no advantages in this setting, which was consistent with results of previous studies (25).
==fine discussions==
==inizio conclusion==
The present study demonstrated that incidentally diagnosed PCa in specimens from RCP for BC was frequently found, resulting in a rate of ~23% of the current RCP spec-imens. As in other studies, also in the current report the majority of these prostatic tumors were not clinically significant, not requiring therapeutic treatment. This has increased the desire to preserve the continence and erectile function in patient undergoing RCP for bladder cancer; however, the risk of not removing the synchronous PCa shoudl be con-sidered. In effect, in our cohort, 33,3% of patients was affected by clinically significant prostate cancer. It was suggested that the differences in the incidence and behavior of prostatic disease were associated with the patient’s age. However, in this study, no preoperative predictive factors (patient’s age, PSA or DRE) were identified that were able to determine “non-aggressive” PCa status, resulting in the inabilty to adequately de-termine which patients can be safely selected for prostate-sparing surgery. So, the present results demonstrate the need for a careful and complete prostate removal during RCP. Nevertheless, since organ-sparing surgeries are widely performed in young population, due to the impossibility of predicting aggressive prostate cancer and considering the 33,3% of clinically significant prostate cancer in our cohort, these patients require close monitoring through lifelong PSA surveillance, particularly focusing on the possible re-lapse of PCa after RCP. Finally, in our study the technique for cutting the prostate at 5-mm interval sections trasverse to the long axis, allowing the detection of nearly 23% of PCA, supports the hypothesis that thin tissue sectioning should be used to optimize cancer detection (regardless of prostate volume which traditionally affects the number of biopsies to be taken).
==fine conclusion==
==inizio reference==
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==fine reference==