Urothelial and incidental prostate carcinoma in prostates from cystoprostatectomies for bladder cancer: is there a relationship between urothelial and prostate cancer?

Authors

  • Francesca Barbisan,

    1. Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy, Department of Pathology, Reina Sofia University Hospital and Faculty of Medicine, Cordoba, Spain,
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  • Roberta Mazzucchelli,

    1. Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy, Department of Pathology, Reina Sofia University Hospital and Faculty of Medicine, Cordoba, Spain,
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  • Marina Scarpelli,

    1. Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy, Department of Pathology, Reina Sofia University Hospital and Faculty of Medicine, Cordoba, Spain,
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  • Antonio Lopez-Beltran,

    1. Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy, Department of Pathology, Reina Sofia University Hospital and Faculty of Medicine, Cordoba, Spain,
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  • Liang Cheng,

    1. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA, and
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  • Ziya Kirkali,

    1. Department of Urology, School of Medicine, Dokuz Eylül University, Izmir, Turkey
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  • Rodolfo Montironi

    1. Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy, Department of Pathology, Reina Sofia University Hospital and Faculty of Medicine, Cordoba, Spain,
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Rodolfo Montironi, Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Via Conca 71, I-60126 Torrette, Ancona, Italy.
e-mail: r.montironi@univpm.it

Abstract

OBJECTIVE

To determine the incidence and features of urothelial carcinoma (UC) involving the prostate (UCP) and of prostate adenocarcinoma (PA) in radical cystoprostatectomy (RCP) for bladder cancer.

PATIENTS AND METHODS

The whole-mount prostate sections of 248 RCP consecutively examined from 1995 to 2007 were reviewed to determine the incidence and features of UCP and PA. UCP was separately evaluated for UC originating from the urethra and peri-urethral ducts (PUC) and for direct extension of bladder UC.

RESULTS

There was UCP in 94 (37.9%) of 248 patients, whereas PUC was present in 78 (31.5%). UC in situ and noninvasive papillary PUC was present in 42 (53.9%) of the 78, whereas stromal invasion was present in 36 (46.1%). Direct extension of UC from the bladder only was present in 16 (6.5%) patients. PA was present in 123 (49.6%) of 248 patients; 96 (78.1%) were in the peripheral zone. In 107 patients (87%) the Gleason score was ≤6; 96 (78.1%) were pT2a, with a lower frequency in other pT categories. The margins were negative in 96.7% of cases. All patients were pN0 for PA; in 116 (95.1%) the volume was <0.5 mL. Of the 123 patients with incidental prostate cancer, 100 cancers (81.3%) were considered clinically insignificant. UCP coexisted with PA in 43 (17.3%) of 248 patients, whereas PUC and PA occurred together in the same prostate in 32 (12.9%). Direct extension of UC from the bladder and PA occurred together in the same prostate in 11 (4.4%) patients.

CONCLUSIONS

UC involving the prostate and PA are present in most RCP specimens. UC can arise from extension of trigonal or bladder-neck tumours, proximal prostate ducts/urethra, or from cell implantation from manipulation of vesical neoplasms. The frequent high coincidence of prostate and bladder cancer can be explained by a common pathway of carcinogenesis.

Abbreviations
RCP

radical cystoprostatectomy

UC

urothelial carcinoma

UCP

UC of the prostate

PA

prostate adenocarcinoma

PUC

UC of the proximal prostate ducts/urethra

H&E

haematoxylin and eosin

CIS

carcinoma in situ

HGPIN

high-grade prostatic intraepithelial neoplasia.

INTRODUCTION

Radical cystoprostatectomy (RCP) is the standard treatment for men with invasive bladder urothelial carcinoma (UC). Following its initial description, this operation has undergone progressive refinement with the current application of nerve-sparing techniques [1,2], extended pelvic lymphadenectomy [3,4], and orthotopic bladder substitution. While technical advances have led to significant improvements in functional outcome, RCP is still associated with changes in quality of life for many patients. Involvement of the prostate with UC and prostate adenocarcinoma (PA) are both common findings in RCP specimens [5,6].

Prostate involvement by UC has been reported in 12–40% of patients undergoing RCP for bladder cancer [7–10]. UC of the prostate can arise from extension of trigonal or bladder-neck tumours, proximal prostate ducts/urethra (PUC), or from cell implantation during manipulation of the upper tract or vesical neoplasms, or the field effect.

PA is the most common visceral malignancy in the male population and one of the leading causes of death in men. However, the prevalence of PA far exceeds that of clinically detected disease, with autopsy studies showing incidental PA in ≈30% of 50-year-old men, increasing to as high as 70% in 80-year-old men [11]. Most of these incidental PAs would be considered clinically insignificant based on size, grade, organ confinement and typical life-expectancy of men of those ages. The frequency of PA incidentally discovered in RCP specimens is extremely variable, ranging from <10% to nearly 60%, most being regarded as clinically insignificant [12]. The aim of the present study was to determine the incidence and features of UCP and PA for a series of 248 patients undergoing RCP for bladder cancer.

PATIENTS AND METHODS

The study included 248 consecutive men with muscle-invasive bladder UC and no history or clinical evidence of PA before surgery, and whose RCP specimen was examined in the period 1995–2007. The mean (range) age of the patients was 68 (43–95) years; all were white men from the Marche Region, in Eastern Central Italy, where there is a relatively homogenous population. The procedure for this research project conformed to the provisions of the Declaration of Helsinki.

A routine pathological examination was used for all RCP specimens, by sectioning and totally submitting the prostate. Soon after the operation, the prostate was severed from the bladder and then covered with India ink. After fixation for 24 h in 4% neutral buffered formalin, the prostate specimens were step-sectioned at 0.3 cm intervals perpendicular to the long axis (apical-basal) of the gland (in 1995 and 1998 some of the prostate specimens were sliced at an interval of 0.5 mm) [13]. The apex, base and seminal vesicles were removed from each specimen and submitted in total for routine histological examination. The cut specimens were post-fixed for an additional 24 h and then dehydrated in graded alcohols, cleared in xylene, embedded in paraffin, and examined histologically as 5 µm-thick whole-mount haematoxylin and eosin (H&E)-stained sections [13].

All of the prostate H&E-stained slides and pathology reports were reviewed by two genitourinary pathologists (R.M., Ro.M.). The stage of prostate and urethral cancers was based on the 2002 revision of the TNM system [14]. The Gleason grading used in this study was the modified system according to the WHO [15–17]. Urethral UC was classified according to the 2004 WHO scheme [18]. Direct extension of bladder UC to the prostate was defined according to Donat et al.[19] as transmural invasion through the bladder neck or through the extravesical soft tissue into the prostatic stroma.

The volume of PA was determined using the point-counting method, as previously described [20]. Briefly, the number of grid points falling within the area with cancer were counted, multiplied by the area associated with each point (2.25 mm2), then multiplied by the thickness of the slice (3 mm) to yield the volume of cancer in the corresponding prostate tissue slice. The volume obtained in all slices was then summed and multiplied by a shrinking factor of 1.3.

For the present study, PA was considered clinically significant if any of the following criteria were present: total tumour volume ≥0.5 mL, Gleason grade ≥4, extraprostatic extension, seminal vesicle invasion, lymph node metastasis (of PA) or positive surgical margins [21].

The chi-square and Mann–Whitney tests were used to evaluate the statistical significance of differences between groups.

RESULTS

There was UCP in 94 (37.9%) of 248 patients, whereas PUC was present in 78 (31.5%). PUC coexisted with direct extension of UC from the bladder in 11 (4.4%) samples. Direct extension of UC from the bladder only was present in 16 (6.5%; Table 1). There was carcinoma in situ (CIS) and noninvasive papillary PUC in 42 (53.9%) of the 78 patients, whereas stromal invasion was present in 36 (46.1%). Involvement of the prostatic apex was found in 25 (10.1%) samples.

Table 1.  UC in the prostate
FeaturesPatients, n (%)
Allwith PAWith no PA
  • *

    pN refers to UC of both prostate and bladder.

Total with UC in the prostate (PUC + direct extension from the bladder)94/248 (37.9)43/94 (45.7)51/94 (54.3)
With PUC78/248 (31.5)32/78 (41.0)46/78 (59.0)
pT   
 Urethral CIS (pTis pu)17/78 (21.8) 7/32 (21.9)10/46 (21.7)
 CIS in periurethral ducts (pTis pd)18/78 (23.1) 7/32 (21.9) 11/46 (23.9)
 Non-invasive papillary UC (pTa) 7/78 (9) 3/32 (9.4) 4/46 (8.8)
Low grade 4/7 1/4 3/4
High grade 3/7 2/3 1/3
PUC invading:   
 Subepithelial connective tissue (pT1)20/78 (25.6)10/32 (31.3)10/46 (21.7)
 Periurethral muscle and prostatic stroma (pT2), and beyond the prostatic capsule (pT3)16/78 (20.5) 5/32 (15.5) 11/46 (23.9)
PUC coexisting with direct extension of bladder UC 11/248 (4.4)  3/11 (27.3)  8/11 (72.7)
Direct extension of UC from the bladder (no PUC)16/248 (6.5) 11/16 (69) 5/16 (31)
UC invading prostatic apex25/248 (10.1)12/25 (48)13/25 (52)
pN*   
 pNX16/94 (17) 6/43 (14) 10/51 (19.6)
 pN043/94 (45.7)21/43 (48.8)22/51 (43.1)
 pN114/94 (15) 8/43 (18.6) 6/51 (11.8)
 pN221/94 (22.3) 8/43 (18.6)13/51 (25.5)

There was PA in 123 (49.6%) of 248 patients (Table 2); all were acinar PAs, 66 (78.1%) and were in the peripheral zone. In 107 (87%) the Gleason score was ≤6; 96 (78.1%) were pT2a, whereas 11 (8.9%) and nine (7.3%) were pT2b and pT2c, respectively, with a lower frequency in other pT categories (4.1% pT3a, 1.6% pT3b and none pT4). There was involvement of the prostatic apex in two samples (1.6%). The margins were negative in 96.7% of cases, and all patients were pN0 for PA. In 116 (95.1%) the volume was <0.5 mL. Of the 123 patients with incidental PA, 100 cancers (81.3%) were considered clinically insignificant. Data from these patients were partly included in previous preliminary reports [12,13]. High-grade prostatic intraepithelial neoplasia (HGPIN) was presented in 91 (74%) of 123 incidental PAs, with isolated HGPIN in 78 (62.4%) of 125 patients without PA.

Table 2.  Incidental PA
FeaturesPatients, n (%)
Allwith PUCWith no PUC
Total with incidental PA123/248 (49.6)32/123 (26)91/123 (74)
Focality   
 Monofocal 77/123 (62.6)20/32 (62.5)57/91 (62.6)
 Multifocal 46/123 (37.4)12/32 (37.5)34/91 (37.4)
Tumour location   
 Peripheral zone 96/123 (78.1)24/32 (75)72/91 (79.1)
 Central zone 10/123 (8.1) 4/32 (12.5) 6/91 (6.6)
 Transition zone  9/123 (7.3) 3/32 (9.4) 6/91 (6.6)
 All three zones  6/123 (4.9) 1/32 (3.1) 5/91 (5.5)
 Apex  2/123 (1.6) 0/32 2/91 (2.2)
Gleason score   
 ≤6107/123 (87.0)28/32 (87.5)79/91 (86.8)
 7 (3 + 4)  9/123 (7.3) 2/32 (6.3) 7/91 (7.7)
 7 (4 + 3)  4/123 (3.3) 1/32 (3.1) 3/91 (3.3)
 8–10  3/123 (2.4) 1/32 (3.1) 2/91 (2.2)
pT   
 pT2a 96/123 (78.1)24/32 (75.0)72/91 (79.1)
 pT2b  11/123 (8.9) 2/32 (6.3) 9/91 (9.9)
 pT2c  9/123 (7.3) 2/32 (6.3) 7/91 (7.7)
 pT3a  5/123 (4.1) 3/32 (9.3) 2/91 (2.2)
 pT3b  2/123 (1.6) 1/32 (3.1) 1/91 (1.1)
 pT4  0/123 (0) 0/32 (0) 0/91 (0)
Surgical margin status   
 Negative119/123 (96.7)31/32 (96.9)88/91 (96.7)
 Positive  4/123 (3.3) 1/32 (3.1) 3/91 (3.3)
Tumour volume, mL   
 <0.5116/123 (95.1)30/32 (93.7)86/91 (94.5)
 ≥0.5  7/123 (4.9) 2/32 (6.3) 5/91 (5.5)
Clinical significance   
 Insignificant100/123 (81.3)27/32 (84.4)73/91 (80.2)
 Significant 23/123 (18.7) 5/32 (15.6)18/91 (19.8)

UCP coexisted with PA in 43 (17.3%) of 248 patients, whereas PUC and PA occurred together in the same prostate in 32 (12.9%; Table 1 and Fig. 1). In three (1.2%) patients PUC coexisted with both direct extension of UC from the bladder and PA. Direct extension of UC from the bladder and PA occurred together in the same prostate in 11 (4.4%) patients.

Figure 1.

A whole-mount section of the prostate from a RCP specimen with papillary UC (microscopically it was a noninvasive high-grade carcinoma, according the 2004 WHO classification) originating from the urethra and involving a periurethral duct (arrow). The encircled area in the anterior part of the prostate is an incidental PA (insert; microscopically it was an acinar adenocarcinoma, Gleason score 2 + 2 = 4).

Table 1 also shows the morphological data for the patients with UCP, separately for those with PA and without; there were no statistically significant differences between the latter groups. Table 2 shows the morphological data for the 123 patients with PA, separately for those with PUC and without; there were no statistically significant differences between the latter groups.

DISCUSSION

In the present study, there was involvement of the prostate by UC in 37.9%, whereas PA was present in 49.6% of patients; UCP coexisted with PA in 17.3%. Compared with previous studies, in the current study precise information on UC and PA was obtained from a relatively homogenous population in Eastern Central Italy, from a population larger than in the other series, with meticulous pathological grading and staging after review, and volume measurement with sectioning at an interval of 3 mm.

UC involvement of the prostate is a common, multifaceted clinicopathological entity [22,23], reportedly present in 12–40% of patients [7–10], whereas primary UC of the prostate is very rare, estimated at 1–4% of prostatic malignancies [24]. Schellhammer et al.[9] reported the first large series, with prostatic involvement in 12%. In studies based on whole-mount sections, a more critical analysis of the prostate yielded a higher frequency of prostatic involvement, at >40%[5,10]. In the series by Shen et al.[25] the incidence of prostatic UCP was 32%, a rate somewhat lower than previously reported series assessing whole-mounts of the entire prostate. Prostatic urethral CIS alone or together with ductal CIS occurred in 53% of the patients, whereas in almost half (47%), CIS was detected only in the prostatic ducts or acini. This result suggested that thorough sampling with a careful examination is necessary for an accurate assessment of prostatic UC involvement.

The prostate can be involved by UC by direct extension of a high-stage bladder tumour, or the prostatic urethra might be involved by CIS with or with no associated invasion. The latter could occur as a consequence of direct spread from the bladder disease, which would be expected preferentially to involve the prostate base, at least initially. Alternatively, involvement of the prostatic urethra and/or periurethral ducts by urothelial CIS could be the consequence of a field effect or cell implantation.

The frequency of PA incidentally discovered in RCP specimens is extremely variable, at <10% to nearly 60%[26]. This variability can be explained by several factors, including pathological sampling techniques. In this respect, the slice thickness of the prostate and whether the prostate is totally embedded represent two important issues. In the present study, with slices taken every 3 mm from the base to the apex of the gland, as is usually done for radical prostatectomy specimens, there was incidental PA in 49.6% of patients. Others observed similar rates of PA using the same technique [5,27–29]. Ruffion et al.[6] found a 51% rate of incidental PA, advocating the use of even finer slices (2.5 mm). The results were similar in the study by Abbas et al.[30], who examined prostatic tissue from 39 RCP specimens with serial step slices taken at 2–3-mm intervals. The frequency of autopsy-detected cancer is similar [13]. However, the incidence was lower in studies using a different pathological examination protocol. For instance, Moutzouris et al.[31] identified PA in 27% of the examined specimens when using 5-mm thick slices, while the percentage was low (4%) in a report from a Taiwanese group [32]. The latter result could be due to the influence of the study population, in addition to the pathology technique, as it is well known that the incidence of PA is higher in the West than in Asian countries [33]. Most incidental Pas are considered clinically insignificant.

A possible relationship between urothelial and prostate cancers was suggested in previous studies [34–39]. Although bladder urothelial and prostate cancers have somewhat different natural histories and causative factors, they share similarities at different levels. Epidemiologically they are predominantly diseases of men, with bladder cancer almost four times more prevalent and PA exclusively limited to men. The coincidence of prostate and bladder cancer is considered to be common. Liskow et al.[36] and Sheldon et al.[37] showed that the coincidence rate between these cancers was significantly higher than the rate of either in the general population. One factor to be considered in this setting is the likelihood of diagnostic bias, that can occur when the presence of one genitourinary cancer leads to a more detailed clinical assessment and extensive pathological examination, resulting in incidental diagnosis of another genitourinary cancer. Clinical data accounting for this bias were provided first by Chun [34], who investigated the number of patients diagnosed with prostate or bladder cancer for 6 years in the cancer registry at one medical institution. He compared the rate of clinically detectable PA in those with bladder cancer with the expected incidence rate of PA in those with bladder cancer in an age-, sex- and race-matched general population from the Surveillance, Epidemiology and End Results database. The rate of clinically detectable PA in those with bladder cancer was 19 times greater than expected [34]. Kurokawa et al.[35] investigated the prevalence rate of PA between those with a present or past history of bladder cancer and age-adjusted men within the same race and from the same region, and using the same screening regimen. The detection rate of PA was 12.3% and 1.5% in the case and control cohorts, respectively. They concluded that patients with a history of bladder cancer could be a high-risk group for PA. More recently, Singh et al.[38] evaluated the risk of a second PA in patients with a previous diagnosis of bladder UC after adjusting for possible diagnostic and treatment biases. Of 149 men initially diagnosed with bladder cancer, 18 (12.1%) had PA. The standardized incidence ratio (comparing the actual number of cases in a population at a given time to the number that would be expected based on the cancer rates in the same comparison area) of PA in patients with UC was significantly increased. The same ratio is not found to be significantly increased for other malignancies (i.e. lung, intestine, kidney).

The frequent high coincidence of prostate and urothelial cancer can be explained by a common pathway of carcinogenesis. Singh et al.[40] reported that tumour suppressor genes (p53 and Rb) are crucial in the development of both cancers. Amara et al.[41] showed, using immunohistochemical analysis, that prostate stem cell antigen is overexpressed in most human TCCs. Although these are preliminary results and the model for a common carcinogenesis remains still speculative, further investigations are necessary.

In conclusion, UC involving the prostate and PA are present in most RCP specimens. UC can arise from extension of trigonal or bladder-neck tumours, proximal prostate ducts/urethra, or from cell implantation from manipulation of vesical neoplasms, or by the field effect. The frequent high coincidence of prostate and bladder cancer can be explained by a common pathway of carcinogenesis.

ACKNOWLEDGEMENTS

The authors thanks Professor Alfredo Santinelli for the statistics.

CONFLICT OF INTEREST

None declared.

Ancillary