Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: A novel prostate cancer marker

Objectives. We describe the expression of a potentially new tumor marker, human glandular kallikrein 2 (hK2), that may be useful as an adjunct to prostate-specific antigen (PSA) in the diagnosis and monitoring of prostate cancer.Methods. We evaluated 257 radical prostatectomy specimens removed at the Mayo Clinic with pathologic Stage T2 adenocarcinoma to compare the cytoplasmic expression of hK2, PSA, and prostatic acid phosphatase (PAP) in benign tissue, high-grade prostatic intraepithelial neoplasia (PIN), and adenocarcinoma. Two monoclonal antibodies, hK2-A523 and hK2-G586, specific for hK2 were used, as well as antibodies against PSA (PSM-773) and PAP (polyclonal).Results. Intense epithelial cytoplasmic immunoreactivity was observed in every case for hK2-A523, hK2-G586, PSA, and PAP (100% of cases, respectively). The intensity and extent of hK2 expression for both antibodies were greater in cancer than high-grade PIN; furthermore, high-grade PIN was greater than benign epithelium. Cases of Gleason primary grade 4 and 5 cancer showed hK2 staining in almost every cell, whereas there was greater heterogeneity of staining in lower grades of cancer. In marked contrast to hK2, PSA and PAP immunoreactivity was most intense in benign epithelium and stained to a lesser extent in PIN and carcinoma. The number of immunoreactive cells for hK2 and PSA was not predictive of cancer recurrence.Conclusions. hK2 was expressed in every cancer, and the expression incrementally increased from benign epithelium to high-grade PIN and adenocarcinoma. PSA and PAP displayed inverse immunoreactivity compared with hK2. The expression of hK2 and PSA was not predictive of cancer recurrence in patients with Stage T2 carcinoma. Expression of hK2 indicates that this kallikrein antigen is both prostate localized and tumor associated. Tissue expression of hK2 appears to be regulated independently of PSA and PAP. Further studies are needed to determine whether tissue immunoreactivity of hK2 will prove clinically useful in the diagnosis and monitoring of prostate cancer.     

Amphiregulin expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 93 cases

BACKGROUND: Amphiregulin (AMP) is a heparin-binding glycoprotein that is structurally and functionally related to epidermal growth factor. Its effects are mediated by the tyrosine kinase activity of the epidermal growth factor receptor (EGF-R), and specific nuclear targeting sequences. AMP induces cell proliferation after androgen stimulation of human prostate cancer cell lines. An autocrine proliferative loop involving AMP, androgen, and EGF-R may, therefore, play a role in prostatic carcinogenesis. The purpose of this study was to compare the expression of AMP in benign prostatic epithelium, high-grade prostatic intraepithelial neoplasia (PIN), and adenocarcinoma. METHODS: We performed an immunohistochemical study of select sections from 93 radical prostatectomies performed at the Mayo Clinic between 1987 and 1991. All patients were previously untreated and found to have pathologic stage T2N0M0 adenocarcinoma after routine handling of surgical specimens. Affinity-purified polyclonal antibody directed against AMP was applied to tissue sections using the streptavidin-biotin method. For each case, the percentage of immunoreactive cells in benign epithelium, PIN, and adenocarcinoma was estimated in 10% increments. Intensity on a scale from 0 (negative) to 3 (strongly immunoreactive) and pattern of expression (nuclear versus cytoplasmic) also were recorded. RESULTS: AMP immunoreactivity was present in benign prostatic epithelium, PIN, and prostatic adenocarcinoma in all cases. The mean percentage of AMP-immunoreactive cells was 53.8% in benign epithelium, 65.9% in PIN, and 74.3% in cancer. Intensity was moderate in all cases. The pattern of expression was usually nuclear in benign epithelium (secretory and basal cells), and usually cytoplasmic or nuclear and cytoplasmic in PIN and adenocarcinoma. There were rare scattered immunoreactive cells in the stroma, ejaculatory duct epithelium, and urethral urothelium. Endothelial cells were invariably unstained. CONCLUSIONS: AMP expression in prostate increases progressively from benign epithelium to PIN and cancer. Increased expression of AMP may contribute to the development of prostatic adenocarcinoma. Predominantly nuclear staining was observed in benign epithelium, whereas cytoplasmic or nuclear and cytoplasmic staining was observed in PIN and adenocarcinoma. The differences in nuclear and cytoplasmic localization of immunoreactivity may reflect the presence of two pathways of activation, and hence varying biological functions of AMP.     

Cost-effectiveness of Prostate Health Index for prostate cancer detection

Study Type – Diagnostic (cost effectiveness) Level of Evidence 2b What's known on the subject? and What does the study add? The Beckman Coulter prostate health index (phi) was developed as a combination of serum prostate specific antigen (PSA), free PSA and a PSA precursor form [?2]proPSA to calculate the probability of prostate cancer and was used as an aid in distinguishing prostate cancer from benign prostatic conditions for men with PSA test 2–10 ng/mL and non‐suspicious digital rectal examination. Phi has been shown to improve diagnostic accuracy in prostate cancer detection compared with total and free PSA. An earlier 1‐year budget impact analysis revealed it to be a complementary approach to current prostate cancer screening strategies. The current study evaluated the cost‐effectiveness of early prostate cancer detection with phi in combination with a PSA test compared with a PSA test alone from the US societal perspective. The model with over 25 annual screening cycles for men aged 50–75 years indicated that PSA plus phi dominated the PSA test alone in prostate cancer detection and consequent treatment. PSA plus phi may be an important strategy for prostate cancer detection.

OBJECTIVE

• ? To evaluate the cost‐effectiveness of early prostate cancer detection with the Beckman Coulter Prostate Health Index (phi) (not currently available in the USA) adding to the serum prostate‐specific antigen (PSA) test compared with the PSA test alone from the US societal perspective.

PATIENTS AND METHODS

• ? Phi was developed as a combination of PSA, free PSA, and a PSA precursor form [?2]proPSA to calculate the probability of prostate cancer and was used as an aid in distinguishing prostate cancer from benign prostatic conditions for men with a borderline PSA test (e.g. PSA 2–10 ng/mL or 4–10 ng/mL) and non‐suspicious digital rectal examination.
• ? We constructed a Markov model with probabilistic sensitivity analysis to estimate expected costs and utilities of prostate cancer detection and consequent treatment for the annual prostate cancer screening in the male population aged 50–75 years old.
• ? The transition probabilities, health state utilities and prostate cancer treatment costs were derived from the published literature. The diagnostic performance of phi was obtained from a multi‐centre study. Diagnostic related costs were obtained from the 2009 Medicare Fee Schedule.
• ? Cost‐effectiveness was compared between the strategies of PSA test alone and PSA plus phi under two PSA thresholds (≥2 ng/mL and ≥4 ng/mL) to recommend a prostate biopsy.

RESULTS

• ? Over 25 annual screening cycles, the strategy of PSA plus phi dominated the PSA‐only strategy using both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL, and was estimated to save $1199 or $443, with an expected gain of 0.08 or 0.03 quality adjusted life years, respectively.
• ? The probabilities of PSA plus phi being cost effective were approximately 77–70% or 78–71% at a range of $0–$200 000 willingness to pay using PSA thresholds ≥2 ng/mL and ≥4 ng/mL, respectively.

CONCLUSION

• ? The strategy PSA plus phi may be an important strategy for prostate cancer detection at both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL to recommend a prostate biopsy compared with using PSA alone.

     

Radical prostatectomy as initial monotherapy for patients with pathologically confirmed high‐grade prostate cancer

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To report the long‐term outcome of high‐grade prostate cancer treated with radical prostatectomy (RP) as initial monotherapy, analyse the effect of clinical and pathological variables on survival, and report cancer‐related symptoms.

PATIENTS AND METHODS

A retrospective chart review was conducted to identify patients with Gleason 8–10 prostate cancer found on pathological review in men undergoing RP as initial therapy for clinically localized disease between 1988 and 2005. Kaplan‐Meier analysis was used to calculate event‐free survival. Univariable and multivariable analyses were used to assess the effects of clinical and pathological variables on prostate‐specific antigen (PSA) recurrence.

RESULTS

After excluding 20 patients, 119 were identified with pathologically confirmed high‐grade cancers at the time of RP. The overall median (interquartile range) follow‐up was 73 (41–113) months. Twenty‐four (20%) patients had organ‐confined cancer, 60 (50%) had specimen‐confined cancer, and 14 (12%) had nodal metastasis. Kaplan‐Meier analysis showed overall survival rates at 5 and 10 years, respectively, of 90% and 75%, cancer‐specific survival of 92% and 82%, and a PSA recurrence‐free follow‐up at 5 years of 31%. Using univariable analysis, preoperative PSA level, pathological Gleason score, pathological stage, surgical margin status and tumour volume were found to significantly affect the PSA recurrence‐free follow‐up. No variables were significant on multivariable analysis. Cancer‐related symptoms were reported by only 14 patients, with a median time from surgery to first symptom of 43 months.

CONCLUSION

High‐grade prostate cancer can be treated with RP as initial monotherapy with an acceptable 10‐year cancer‐specific survival (82%). The PSA recurrence‐free follow‐up is poor (31% at 5 years). However, few patients progress to symptomatic recurrence after PSA relapse within the first 5 years.     

Expression and prognostic relevance of annexin A3 in prostate cancer

Objectives

By differential quantitative protein expression, it has previously been shown that annexin A3 (ANXA3) expression is associated with prostate cancer. However little is known about the role and biology of ANXA3 in the human prostate. The aim of this study was to thoroughly analyze ANXA3 expression patterns and its potential as a prognostic marker in a large set of benign, preneoplastic, and neoplastic prostate tissue samples.

Methods

Immunohistochemistry-based ANXA3 protein expression was analyzed for 1589 prostate cancers as well as smaller subsets of benign epithelium and high-grade prostatic intraepithelial neoplasia (PIN) in a tissue microarray format.

Results

All samples of benign prostatic epithelium and PIN showed ANXA3 protein expression, with PIN lesions showing a decreased staining intensity compared with benign epithelium (p < 0.0001). In cancer, ANXA3 protein expression was essentially reduced, resulting in a negative staining rate of 27.2%, which correlated with increasing pT stage and Gleason score (p < 0.0001). ANXA3 status in cancer was shown to be an independent adverse prognostic factor and enabled substratification of the large group of intermediate-risk patients (n = 969) into high- and low-risk subgroups.

Conclusions

ANXA3 represents a promising candidate tissue marker, and when combined with the standard prognostic parameters, is suggested to provide a more precise prediction of prognosis in the individual patient, therefore harboring the potential to contribute to future patient management.     

The utility of prostate-specific antigen velocity thresholds in clinical practice: a population-based analysis

OBJECTIVE

To investigate the ability of prostate‐specific antigen velocity (PSAV) to predict prostate cancer, and assess the test characteristics of several PSAV thresholds for identifying prostate cancer and high‐grade cancers.

PATIENTS AND METHODS

From a population‐based database of PSA results, men with an initial PSA level of <10.0 ng/mL, taken between I January 1994 and 31 December 2003, were identified. Those with three or more PSA tests before diagnosis, taken over ≥18 months, were included. Men were followed for a diagnosis of prostate cancer or histologically confirmed benign disease until 31 December 2003.

RESULTS

In all, 24 709 men were included, with 716 (2.9%) diagnosed with prostate cancer and 1488 (6.0%) with benign histology. The mean (10.38 vs 0.43 ng/mL/year) and median (1.47 vs 0.03 ng/mL/year) PSAV were considerably higher in men with prostate cancer than in those with no cancer (P < 0.001). There was no PSAV threshold that could reliably identify prostate cancer or high‐grade cancers without requiring many men to proceed to prostate biopsy.

CONCLUSION

In this population, PSAV had additional value over one PSA value in identifying men with prostate cancer. Many men with prostate cancer might have a ‘normal’ (<0.75 ng/mL/year) PSAV. As with total PSA level, there was no PSAV threshold that could reliably predict prostate cancer, but rather a continuum of risk of cancer associated with PSAV level.     

Transatlantic Consensus Group on active surveillance and focal therapy for prostate cancer

Study Type – Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? There is little data on the utility of digital rectal examination (DRE) as a diagnostic tool in the era of prostate‐specific antigen (PSA) testing. Using a population‐based database, we found that detection of prostate cancer while still localized among men with high‐grade PSA‐occult disease may result in survival benefit.

OBJECTIVE

• ? To determine whether detection of high‐grade prostate cancer while still clinically localised on digital rectal examination (DRE) can improve survival in men with a normal prostate‐specific antigen (PSA) level.

PATIENTS AND METHODS

• ? From the Surveillance, Epidemiology and End Results database, 166 104 men with prostate cancer diagnosed between 2004 and 2007 were identified.
• ? Logistic regression was used to identify factors associated with the occurrence of palpable, PSA‐occult (PSA level of <2.5 ng/mL), Gleason score 8–10 prostate cancer.
• ? Fine and Gray's and Cox multivariable regressions were used to analyse whether demographic, treatment, and clinicopathological factors were associated with the risk of prostate cancer‐specific mortality (PCSM) and all‐cause mortality (ACM), respectively.

RESULTS

• ? Both increasing age (adjusted odds ratio [aOR] 1.02, 95% confidence interval (CI) 1.01–1.03; P < 0.001) and White race (aOR 1.26, 95% CI 1.03–1.54; P= 0.027) were associated with palpable, Gleason 8–10 prostate cancer. Of 166 104 men, 685 (0.4%) had this subset of prostate cancer.
• ? Significant factors associated with risk of PCSM included PSA level (adjusted hazard ratio [aHR] 0.71, 95% CI 0.51–0.99; P= 0.04), higher Gleason score (aHR 2.20, 95% CI 1.25–3.87; P= 0.006), and T3–T4 vs T2 disease (aHR 3.11, 95% CI 1.79–5.41; P < 0.001).
• ? Significant factors associated with risk of ACM included age (aHR 1.03, 95% CI 1.01–1.06; P= 0.006), higher Gleason score (aHR 2.05, 95% CI 1.36–3.09; P < 0.001), and T3–T4 vs T2 disease (aHR 2.11, 95% CI 1.38–3.25, P < 0.001)

CONCLUSIONS

• ? Clinically localised disease on DRE among men with PSA‐occult high‐grade prostate cancer was associated with improved PCSM and ACM, suggesting that DRE in this cohort (older age and White race) may have the potential to improve survival.

     

Outcomes in patients with Gleason score 8-10 prostate cancer: relation to preoperative PSA level

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐grade prostate cancers are associated with poor disease‐specific outcomes. A proportion of these tumours produce little PSA. This study demonstrates that among Gleason 8–10 prostate cancers, some of the worst survival outcomes are associated with the lowest PSA levels.

OBJECTIVE

• ? To assess outcomes of patients with Gleason score 8–10 prostate cancer (CaP) with a low (≤2.5 ng/mL) vs higher preoperative serum PSA levels.

PATIENTS AND METHODS

• ? From 1983 to 2003, 5544 patients underwent open radical prostatectomy, of whom 354 had a Gleason 8–10 tumour in the prostatectomy specimen.
• ? Patients were stratified according to preoperative PSA level into four strata: ≤2.5 ng/mL (n= 31), 2.6–4 ng/mL (n= 31), 4.1–10 ng/mL (n= 174), and >10 ng/mL (n= 118).
• ? We compared biochemical progression‐free survival (PFS), metastasis‐free survival (MFS), and cancer‐specific survival (CSS) as a function of preoperative PSA level.

RESULTS

• ? Patients with PSA level ≤2.5 ng/mL were more likely to have seminal vesicle invasion (P= 0.003).
• ? On Kaplan–Meier survival analysis, patients with a PSA level ≤2.5 ng/mL had proportionately worse outcomes than their counterparts with higher PSA levels.
• ? The 7‐year PFS in the PSA ≤2.5 ng/mL stratum was lower than those of the PSA 2.6–4 ng/mL and 4–10 ng/mL strata (36% vs 50 and 42%, respectively); however, the lowest 7‐year PFS was found in those with a PSA level >10 ng/mL (32%, P= 0.02).
• ? Gleason score 8–10 tumours with a PSA level ≤2.5 ng/mL also tended to have the lowest 7‐year MFS (75, 93, 89 and 92% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.2) and CSS (81, 100, 94 and 90% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.3), although these differences were not statistically significant.
• ? In the subset with palpable disease, Gleason grade 8–10 disease with PSA level ≤2.5 ng/mL also was associated with a worse prognosis.

CONCLUSIONS

• ? In patients with Gleason grade 8–10 disease, a proportion of these tumours are so poorly differentiated that they produce relatively little PSA.
• ? Patients with high‐grade, low‐PSA tumours had less favourable outcomes than many of those with higher PSA levels.

     

Serial analysis of resected prostate cancer suggests up‐regulation of type 1 IGF receptor with disease progression

What’s known on the subject? and What does the study add? In a previous study of diagnostic prostate biopsies, we showed that the insulin‐like growth factor (IGF) receptor is up‐regulated in primary prostate cancers. In this study we identified prostate cancer cases in which multiple transurethral resections had been performed, and showed that IGF receptor expression increased or remained high with disease progression. Thus, the IGF receptor is an attractive therapeutic target for patients with advanced prostate cancer.

OBJECTIVE

• ? To compare immunostaining protocols using different antibodies for the type 1 insulin‐like growth factor receptor (IGF‐1R) in channel transurethal resection of the prostate (chTURP) chips, and to investigate how IGF‐1R expression varies with time in serial prostate cancer specimens from individual patients.

METHODS

• ? We studied IGF‐1R expression in 44 prostate cancer specimens from 18 patients who had undergone serial chTURP at least 3 months apart.
• ? Retrospective analysis of the hospital notes was undertaken to obtain clinical information, including age, Gleason score, prostate‐specific antigen (PSA) level, hormone treatment and metastatic disease status at the time of each operation.
• ? After an optimization process using three commercially‐available IGF‐1R antibodies, we used two antibodies for semiquantititve immunostaining of serial chTURP chips.

RESULTS

• ? Santa Cruz antibody sc713 gave positive staining in IGF‐1R null R– cells, and was not used further. Antibodies from Cell Signaling Technology (Beverly, MA, USA) (CS) and NeoMarkers Inc. (Fremont, CA, USA) (NM) did not stain R– cells and, in prostate tissue, showed staining of the glandular epithelium, with negligible stromal staining. All 44 chTURP samples contained identifiable malignant tissue and, of these, 73% and 64% scored moderately or strongly (score 3 or 4) with the CS and NM antibodies respectively.
• ? There was significant correlation of IGF‐1R scores of malignant tissue between the two antibodies (P < 0.001). By contrast, staining of benign glands showed poor correlation between antibodies: CS gave significantly weaker staining than malignant epithelium in the same sections (P < 0.001), whereas NM showed poor discrimination between malignant and benign glands. IGF‐1R staining scores generated by the CS antibody were used to analyze the clinical data.
• ? Most patients (six of seven) with falling IGF‐1R staining scores were responding to androgen deprivation therapy (confirmed by PSA response) between operations. Conversely, in seven of eight patients who had progression to androgen‐independence between procedures, IGF‐1R levels increased or remained high. Finally, seven of 11 patients who developed radiologically confirmed metastases between procedures showed stable or increasing IGF‐1R staining scores.

CONCLUSION

• ? The present study is the first to assess changes in IGF‐1R expression in serial prostate cancer samples. The results obtained indicate that IGF‐1R expression usually remains high throughout the course of histologically‐proven disease progression in serial specimens, suggesting that the IGF‐1R remains a valid treatment target for advanced prostate cancer.

     

Immediate radical prostatectomy in patients with atypical small acinar proliferation. Over treatment?

PURPOSE: The term atypical small acinar proliferation (ASAP) has been proposed by pathologists to indicate foci of small atypical acini found in prostatic biopsies that have some but not all of the features of adenocarcinoma. We determined the incidence of ASAP at our institution and evaluated the role of immediate radical prostatectomy (RP) in these patients. MATERIALS AND METHODS: From January 2001 to December 2002, 1,327 patients underwent systematic transrectal prostate biopsies because of increased prostate specific antigen (PSA). Of the 1,327 patients 71 (5.3%) had suspicious cytokeratin negative lesions diagnosed as ASAP, as confirmed by a review pathologist. Mean patient age was 62 years and mean PSA was 8.48 ng/ml (range 5.6 to 19.6). Of the 71 patients 25 underwent pelvic bilateral lymphadenectomy and RP with a nerve sparing procedure immediately after the diagnosis of ASAP. A 79-year-old patient underwent transurethral resection of the prostate. A total of 45 patients were followed with PSA determination every 3 months and with prostatic mapping every 6 months (12 to 14 biopsies). RESULTS: All 25 patients (100%) with ASAP who underwent immediate RP had a final pathological diagnosis of adenocarcinoma, as confirmed by a review pathologist. Pathological stage was pT2a in 9 patients, pT2b in 8, pT2c in 6, pT3a in 1 and pT4 in 1. The Gleason sum was 2 to 6 in 21 patients, 7 in 2 and 8 in 2. One of the 25 patients had positive nodes (pT4N1G3). The pathological diagnosis in patients with transurethral resection was benign prostatic hyperplasia. Nine of the 45 patients who were followed were seen every 3 months for PSA determination because of age (older than 78 years). Of the 45 patients 23 (51.1%) underwent a second set of biopsies, which revealed adenocarcinoma in 6 of 23 (26%), benign prostatic hyperplasia in 6 (26%), ASAP again in 5 (21.7%), atypia in 4 (17.3%) and high grade PIN in 2 (8.6%). Six of 17 patients had a third set of biopsies (a total of 14 cores), including 3 with adenocarcinoma, 1 with ASAP and 2 with high grade PIN. Two of 45 patients (4.4%) did not undergo a second biopsy because of other malignancies. Four of 45 patients (8.8%) are awaiting a third or fourth biopsy. Ten of 45 patients (22.2%) were lost to followup. CONCLUSIONS: The results of our study confirm that immediate RP could be the treatment of choice in young patients with ASAP.     

Diagnostic significance of [−2]pro-PSA and prostate dimension-adjusted PSA-related indices in men with total PSA in the 2.0–10.0 ng/mL range

Purpose

One of the most important issues to address when developing an optimal screening system for prostate cancer is investigating appropriate biopsy indications following serum prostate-specific antigen (PSA) measurements in order to maintain high sensitivity and avoid unnecessary biopsy.

Methods

Between April 2004 and December 2007, 239 consecutive men with total PSA levels of 2.0–10.0 ng/mL underwent measurements of PSA, free PSA, and [?2]pro-PSA. We assessed the significance of laboratory-based PSA-related indices including free PSA/total PSA (%f-PSA), p2PSA/free PSA (%p2PSA), p2PSA/%f-PSA, Prostate Health Index (phi, an index combining PSA, free PSA, and p2PSA), total prostate volume (TPV)-adjusted PSA-related indices, including PSA density, %p2PSA density, p2PSA/%f-PSA density, and phi density, and transition zone (TZ) prostate volume-adjusted PSA-related indices such as PSA TZ density (PSATZD), %p2PSA TZD, p2PSA/%fPSA TZD, and phi TZD.

Results

The positive biopsy rate was 22.2 %. When sensitivity was fixed at 95 %, unnecessary biopsies could be avoided in 28 % of men when phi was used as a biopsy indication. In cases where total and transition zone prostate volumes were available, the use of %p2PSA density, phi density, p2PSA/%f-PSA TZD, and phi TZD resulted in the avoidance of 48, 47, 54, and 54 % of unnecessary biopsies, respectively, while maintaining a high sensitivity of 90 %.

Conclusions

At 90 and 95 % sensitivity, laboratory-based indices containing p2PSA, particularly phi, showed significantly greater specificity for prostate cancer as compared with %f-PSA. The diagnostic accuracy of prostate volume-adjusted p2PSA-related indices could be excellent, particularly the transition zone volume-adjusted indices at fixed sensitivities of 95 and 90 %.     

Concomitant pathology in the prostate in cystoprostatectomy specimens: a prospective study and review

OBJECTIVES

To investigate possible associated pathology in the prostate removed from patients with invasive bladder cancer and determine if there is a justification for prostate‐sparing cystectomy.

PATIENTS AND METHODS

Between March 2005 and July 2007, 425 men (mean age 59 years, sd 8.23) had a cystoprostatectomy at our institute. The prostate was step sectioned at 2–3 mm intervals and any associated pathology determined; patient and tumour characteristics were correlated with prostatic pathology. The results were compared with those published previously, and the potential functional advantages of prostate sparing are reviewed and discussed.

RESULTS

Prostatic adenocarcinoma was detected in 90 of the 425 (21.2%) patients. There was no significant correlation between preoperative prostate‐specific antigen level and the presence of adenocarcinoma, Gleason score or prostatic tumour stage. There was prostatic involvement as a result of direct invasion by the primary bladder tumour (contiguous) in 39 cases (9.2%). Concomitant (non‐contiguous) transitional cell carcinoma of the prostatic urethra and/or ducts was detected in 27 specimens (6.4%). Additional findings were high‐grade prostatic intraepithelial neoplasia in 43 patients (10.1%) and benign prostatic hyperplasia in 175 (41.2%).

CONCLUSION

We think that the potential oncological risks of prostate‐sparing cystectomy outweigh any small and possible functional benefits; accordingly, the prostate should not be retained.     

Reliability of the 34βE12, keratin 5/6, p63, bcl-2, and AMACR in the diagnosis of prostate carcinoma

Objective

In this study, we aimed to investigate which basal cell marker should be used with α-methylacyl coenzyme A racemase (AMACR) to increase diagnostic accuracy in the diagnosis of prostate carcinoma.

Materials and methods

A total of 98 cases of prostate biopsy, comprising 65 cases with prostate adenocarcinoma and 33 cases without adenocarcinoma, were included in this study. Prostate-specific antigen (PSA) serum levels before biopsies were obtained. The number of cores with malignant glands and Gleason scores for each case were determined. Paraffin sections were stained immunohistochemically with 34βE12, keratin 5/6, p63, bcl-2, and AMACR.

Results

According to staining pattern, extensiveness, and intensity of basal cell markers in benign glands, 34βE12 gave the best results. As negative markers for prostate adenocarcinoma, the best markers were p63 and 34βE12. According to the AUC values in ROC curves for both extensiveness and intensity, the arrangement from the best to the worst was 34βE12, p63, bcl-2, and keratin 5/6. The 34βE12 had the best sensitivity and specificity values (95% and 98%, respectively). Staining extensiveness and intensity of keratin 5/6 in malignant glands, and those of bcl-2 in benign glands had statistically significant positive correlation with serum PSA levels. Even though AMACR is a negative marker for benignity, some of the benign glands also had positive immune reaction with AMACR. However, AMACR positivity was usually focal and weak. Nevertheless, intensively stained subjects were also present. No correlation was present between AMACR and basal cell markers.

Conclusions

As a result, we suggest that keratin 5/6 and bcl-2 should not be used to identify benign glands in prostate biopsy since they show high positivity in malignant glands and high negativity in benign glands. 34βE12 should be the first choice as a basal cell marker. p63 can be used together with 34βE12, but it may not give additional diagnostic information. When we evaluated the correlation of basal cell markers, we did not find any complementary staining results among basal cell markers. Our study showed that 34βE12 is the most appropriate negative marker to combine with AMACR as a positive marker for the diagnosis of prostate adenocarcinoma.     

Population‐based prostate‐specific antigen testing in the UK leads to a stage migration of prostate cancer

OBJECTIVE

To determine, within the UK, the stage and grade of prostate cancers that would be found through population‐based prostate specific antigen (PSA) testing and biopsy.

SUBJECTS AND METHODS

In the ‘Prostate Testing for Cancer and Treatment’ trial (ProtecT), men aged 50–69 years were recruited from nine cities in the UK and from randomly selected practices of general practitioners. Those with a PSA level of >3 ng/mL were offered a prostate biopsy. Age, PSA, stage and grade at diagnosis of ProtecT participants with cancer were compared with contemporaneous incident cases aged 50–69 years (age‐restricted Cancer Registry cases) registered with the Eastern Cancer Registration and Information Centre (ECRIC).

RESULTS

Within ProtecT, 94 427 men agreed to be tested (50% of men contacted), 8807 (≈9%) had a raised PSA level and 2022 (23%) had prostate cancer; 229 (≈12%) had locally advanced (T3 or T4) or metastatic cancers, the rest having clinically localized (T1c or T2) disease. Within ECRIC, 12 661 cancers were recorded over the same period; 3714 were men aged 50–69 years at diagnosis. Men in ProtecT had a lower age distribution and PSA level, and the cancers were of lower stage and grade (P < 0.001 for all comparisons). If population‐based PSA testing were introduced in the UK, ≈2660 men per 100 000 aged 50–69 years would be found to have prostate cancer, compared to current rates of ≈130 per 100 000. If half of men accepted PSA testing, ≈160 000 cancers would be found, compared to 30 000 diagnosed each year at present.

CONCLUSIONS

Population‐based PSA testing resulted in a significant downward stage and grade migration, and most such cancers were of low stage and grade, which could lead to risks of over‐treatment for some men.     

Expression of cystatins,high molecular weight cytokeratin,and proliferation markers in prostatic adenocarcinoma and hyperplasia

BACKGROUND: Prostatic adenocarcinoma is the most common malignancy among men in the western world but the diagnostic and prognostic criteria for it are still not clearly defined. Additional means for its diagnosis and prognosis are clearly needed. Previously it has been shown that cystatin A is expressed in the basal cells of normal prostate and the expression disappears in prostatic carcinoma. METHODS: We have now studied the expression of both cystatins A and B in benign prostatic hyperplasias (BPH), prostatic intraepithelial neoplasias (PIN) and carcinomas of the prostatic epithelium and compared it with the expression of high molecular weight (HMW) cytokeratin as well as the proliferation markers cyclin A and Ki-67. The expression of the proteins was immunohistochemically assessed using 33 total prostatectomy specimens. RESULTS: Cystatin A was expressed in the basal cells in all cases of BPH, low-grade PIN, and high-grade PIN whereas carcinomas showed no staining of cystatin A. The 34 beta E12 cytokeratin expression was similar to basal cystatin A staining and was not seen in carcinoma foci. Cystatin B showed both nuclear and cytoplasmic expression in the columnar epithelial cells. The decrease in median cytoplasmic staining of cystatin B in carcinomas compared to other lesions was significant, but there was a significant increase in expression with dedifferentiation of carcinoma. Also cyclin A and Ki-67 staining were significantly different in non-carcinomatous foci compared to carcinoma foci and had a remarkably similar negative correlations with basal cystatin A and 34 beta E12 staining. CONCLUSIONS: The results show that cystatin expression can be used as an aid in the diagnosis of prostatic adenocarcinoma and especially cystatin A in the distinction between high grade PIN and grade I carcinoma.     

Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study

Study Type – Prognostic (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Previous studies used the decrease in PSA after 6 months of dutasteride treatment as a new ‘baseline’ PSA value from which subsequent rises may serve as a warning for prostate cancer; however, PSA tends to continue to decrease as dutasteride treatment continues. By comparing positive biopsy rates in the REDUCE study using any rise from nadir in the dutasteride arm and standard PSA decision criteria (NCCN) in the placebo arm, we demonstrated that the ability to detect prostate cancer and high grade prostate cancer is maintained with dutasteride treatment.

OBJECTIVES

? To determine if dutasteride‐treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. ? To analyse whether the use of treatment‐specific criteria for repeat biopsy maintains the usefulness of prostate‐specific antigen (PSA) level for detecting high grade cancers.

PATIENTS AND METHODS

? The REDUCE study was a randomized, double‐blind, placebo‐controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy‐detectable prostate cancer in men with a previous negative biopsy. ? The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. ? The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. ? Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds.

RESULTS

? Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. ? If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8–10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8–10 cancers would have been missed in the placebo group. ? In both groups, the incidence of Gleason 7 and Gleason 8–10 cancers generally increased with greater rises in PSA. ? Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7–10 cancers in men treated with dutasteride vs placebo. ? Men with Gleason 7 and Gleason 8–10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds.

CONCLUSION

? Using treatment‐specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. ? The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8–10) or higher than (Gleason 7–10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.     

Age-associated changes in alpha-methyl CoA racemase (AMACR) expression in nonneoplastic prostatic tissues

Alpha-methyl CoA racemase (AMACR) is overexpressed in several human cancers, most notably colon and prostate. AMACR expression in the prostate has been investigated primarily in patients, in an older age group, treated for prostatic carcinoma and benign prostatic hypertrophy. No studies have assessed the age distribution of AMACR expression in normal men. Archival paraffin-embedded prostate tissue from 41 organ donor men (age range, 13-63 years) with no evidence of prostate neoplasia was stained with a monoclonal antibody for AMACR. Intensity was graded on a scale of 0 to 3. Semi-quantitative analysis of staining in acinar cells was used to generate a composite score (CS) [Sigma(% area x intensity)] for each case. Nondonor cases with foci of prostate cancer and high-grade prostatic intraepithelial neoplasia (PIN) were used as external positive controls for AMACR. These sections were also stained for Ki-67, to assess proliferative index. The 41 cases encompassed different age groups (13-20 years, N = 11; 20-45 years, N = 17; >45 years, N = 13). Acinar cells showed granular cytoplasmic staining. Focal positive staining was also seen in the prostatic urethra and the periurethral glands. There was wide variation in the level of expression within each age group. The level of expression seen in subjects younger than 45 years was higher (mean CS = 41.3; median CS = 22.5) than that seen in subjects older than 45 years (mean CS = 8.8; median CS = 9.0) with a P value of 0.01. Most cases in the control set of prostatic adenocarcinoma cases showed moderate to strong staining. A negative correlation was seen evaluating CS and age in subjects 20 years of age and older (r = -0.47). Ki-67 staining was variable. 1) AMACR expression can be seen in benign prostatic glandular epithelium, across all age groups. However, it is age-related, with significantly lower expression in subjects younger than 45 years. This could account for the negative staining reported in benign glands, due to biased sampling of the older population. 2) Focal positive staining is seen in the prostatic urethra and periurethral glands in 71% of the cases, with no age correlation. This is of concern because this epithelium could potentially be misinterpreted as foci of PIN. 3) The low expression of AMACR in benign glands in the older age group makes this marker useful in detecting malignancy. However, AMACR staining should be interpreted with caution and the diagnosis of PIN or prostate cancer should be rendered only with convincing histologic evidence. 4) Ki-67 staining was very variable and showed no correlation with age and AMACR expression levels. AMACR expression had no correlation with proliferative index.     

The role of a standardized 36 core template-assisted transperineal prostate biopsy technique in patients with previously negative transrectal ultrasonography-guided prostate biopsies

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Template assisted transperineal biopsy of the prostate has become increasingly popular over the past decade. Several studies have demonstrated that transperineal prostate biopsy (TPB) is associated with an increased rate of cancer detection, increased histological concordance with final prostatectomy samples and an increase in anterior and apical prostate cancers than standard TRUS biopsy. However, interpretation of the literature is difficult due to considerable variation between studies in terms of technique and equipment. We examined a small cohort (n= 40) of patients using a standardized 36 core template assisted TPB technique. We show that utilising this technique is associated with high cancer (68%) detection rate in patients with two previous negative TRUS biopsies. Of patients were found to have anterior gland tumours which would not have been detected by standard TRUS guided biopsy.

OBJECTIVE

? To determine the efficacy and safety of a standardized 36 core template‐assisted transperineal biopsy technique for detecting prostate cancer in patients with previously negative transrectal ultrasonography‐guided prostate biopsies and elevated prostate‐specific antigen (PSA) levels.

PATIENTS AND METHODS

? Between April 2008 to September 2010, a total of 40 patients with a mean (range) age of 63 (49–73) years, a mean (range) elevated PSA level of 21.9 (4.7–87) ng/mL and two previous sets of negative TRUS‐guided prostate biopsies underwent standardized 36 core template‐assisted transperineal prostate biopsies under general anaesthetic as a day case procedure. ? The cancer detection rate and complications for all cases were evaluated.

RESULTS

? In total, 27 of 40 (68%) patients were found to have adenocarcinoma of the prostate, two patients (5.0%) had atypical small acinar proliferation, one had high‐grade prostatic intraepithelial neoplasia (2.5%), four (10%) had chronic active inflammation and six (15%) had benign histology. ? Gleason scores were in the range 6–9, with a median Gleason score of 7. ? There were no cases of urosepsis, urinary tract infections or haematuria. A single patient experienced acute urinary retention, with a subsequent succesful trial without a catheter, and haematospermia was common, although minor.

CONCLUSIONS

? Our standardized 36 core template‐assisted transperineal prostate biopsy technique is safe and associated with a high detection rate of prostate cancer. ? This technique should be considered in patients with elevated PSA levels and previously negative TRUS‐guided prostate biopsies.     

Predicting the outcome of prostate biopsy: comparison of a novel logistic regression‐based model,the prostate cancer risk calculator,and prostate‐specific antigen level alone

OBJECTIVES

To develop a logistic regression‐based model to predict prostate cancer biopsy at, and compare its performance to the risk calculator developed by the Prostate Cancer Prevention Trial (PCPT), which was based on age, race, prostate‐specific antigen (PSA) level, a digital rectal examination (DRE), family history, and history of a previous negative biopsy, and to PSA level alone.

PATIENTS AND METHODS

We retrospectively analysed the data of 1280 men who had a biopsy while enrolled in a prospective, multicentre clinical trial. Of these, 1108 had all relevant clinical and pathological data available, and no previous diagnosis of prostate cancer. Using the PCPT risk calculator, we calculated the risks of prostate cancer and of high‐grade disease (Gleason score ≥7) for each man. Receiver operating characteristic (ROC) curves for the risk calculator, PSA level and the novel regression‐based model were compared.

RESULTS

Prostate cancer was detected in 394 (35.6%) men, and 155 (14.0%) had Gleason ≥7 disease. For cancer prediction, the area under the ROC curve (AUC) for the risk calculator was 66.7%, statistically greater than the AUC for PSA level of 61.9% (P < 0.001). For predicting high‐grade disease, the AUCs were 74.1% and 70.7% for the risk calculator and PSA level, respectively (P = 0.024). The AUCs increased to 71.2% (P < 0.001) and 78.7% (P = 0.001) for detection and high‐grade disease, respectively, with our novel regression‐based models.

CONCLUSIONS

ROC analyses show that the PCPT risk calculator modestly improves the performance of PSA level alone in predicting an individual’s risk of prostate cancer or high‐grade disease on biopsy. This predictive tool might be enhanced by including percentage free PSA and the number of biopsy cores.