Whole-mount Prostatectomy Specimens Research Articles

Prostate Cancers Invisible on Multiparametric MRI: Pathologic Features in Correlation with Whole-Mount Prostatectomy.

We investigated why some prostate cancers (PCas) are not identified on multiparametric MRI (mpMRI) by using ground truth reference from whole-mount prostatectomy specimens. A total of 61 patients with biopsy-confirmed PCa underwent 3T mpMRI followed by prostatectomy. Lesions visible on MRI prospectively or retrospectively identified after correlating with histology were considered "identified cancers" (ICs). Lesions that could not be identified on mpMRI were considered "unidentified cancers" (UCs). Pathologists marked the Gleason score, stage, size, and density of the cancer glands and performed quantitative histology to calculate the tissue composition. Out of 115 cancers, 19 were unidentified on MRI. The UCs were significantly smaller and had lower Gleason scores and clinical stage lesions compared with the ICs. The UCs had significantly (p < 0.05) higher ADC (1.34 ± 0.38 vs. 1.02 ± 0.30 μm2/ms) and T2 (117.0 ± 31.1 vs. 97.1 ± 25.1 ms) compared with the ICs. The density of the cancer glands was significantly (p = 0.04) lower in the UCs. The percentage of the Gleason 4 component in Gleason 3 + 4 lesions was nominally (p = 0.15) higher in the ICs (20 ± 12%) compared with the UCs (15 ± 8%). The UCs had a significantly lower epithelium (32.9 ± 21.5 vs. 47.6 ± 13.1%, p = 0.034) and higher lumen volume (20.4 ± 10.0 vs. 13.3 ± 4.1%, p = 0.021) compared with the ICs. Independent from size and Gleason score, the tissue composition differences, specifically, the higher lumen and lower epithelium in UCs, can explain why some of the prostate cancers cannot be identified on mpMRI.

The role of perilesional and multiparametric resonance imaging-targeted biopsies to reduce the risk of upgrading at radical prostatectomy pathology: A retrospective monocentric study.

To evaluate histopathologic upgrading between biopsy methods and whole-mount prostatectomy specimens in International Society of Urological Pathology grade group. Overall, 134 patients, including 175 magnetic resonance imaging (MRI)-suspicious lesions, diagnosed on MRI-targeted (TB) and systematic (SB) biopsies before radical prostatectomy were retrospectively analyzed from a prospectively maintained database. Perilesional (PLB) and "extended" perilesional (ePLB) biopsies were defined as those taken within a circumferential zone of 5 and 10 mm around magnetic resonance imaging (MRI)-suspicious lesion respectively. Proportion of upgrading at prostatectomy pathology were compared between TB, TB + PLB, TP + ePLB and TB + SB. Uni- and multivariable logistic regressions assessed predictors of upgrading for TB + ePLB method. Focusing on index lesion, median (interquartile range) number of cores taken was 4 (3-4) for TB, 5 (4-6) for TB + PLB, 6 (5-8) for TB + ePLB and 12 (12-15) for TB + SB. A higher upgrading proportion was detected upon comparing TB and TB + PLB methods to TB + SB (32 vs. 19%, P = 0.001, 26 vs. 19%, P = 0.04, respectively). Conversely, no significant difference was found between TB + ePLB compared to TB + SB (23 vs. 19%, P = 0.2). Proportion of downgrading was similar regardless of biopsy method (all P > 0.1). At multivariable analysis, Prostate Imaging-Reporting and Data System Steering score, total number of positive ePLB cores and International Society of Urological Pathology Grade Group were independent predictors of upgrading (all P ≤ 0.03). Similar results were found by adding data from non-index lesions. Our finding suggest that MRI-targeted biopsies associated with perilesional sampling in a circumferential zone of 10 mm reduced upgrading proportion and showed similar accuracy as the current gold standard combination. Further prospective studies comparing biopsy methods are expected to validate this diagnostic strategy.

Detection and staging of radio-recurrent prostate cancer using multiparametric MRI.

We determined the sensitivity and specificity of multiparametric magnetic resonance imaging (MP-MRI) in detection of locally recurrent prostate cancer and extra prostatic extension in the post-radical radiotherapy setting. Histopathological reference standard was whole-mount prostatectomy specimens. We also assessed for any added value of the dynamic contrast enhancement (DCE) sequence in detection and staging of local recurrence. This was a single centre retrospective study. Participants were selected from a database of males treated with salvage prostatectomy for locally recurrent prostate cancer following radiotherapy. All underwent pre-operative prostate-specific antigen assay, positron emission tomography CT, MP-MRI and transperineal template prostate mapping biopsy prior to salvage prostatectomy. MP-MRI performance was assessed using both Prostate Imaging-Reporting and Data System v. 2 and a modified scoring system for the post-treatment setting. 24 patients were enrolled. Using Prostate Imaging-Reporting and Data System v. 2, sensitivity, specificity, positive predictive value and negative predictive value was 64%, 94%, 98% and 36%. MP-MRI under staged recurrent cancer in 63%. A modified scoring system in which DCE was used as a co-dominant sequence resulted in improved diagnostic sensitivity (61%-76%) following subgroup analysis. Our results show MP-MRI has moderate sensitivity (64%) and high specificity (94%) in detecting radio-recurrent intraprostatic disease, though disease tends to be under quantified and under staged. Greater emphasis on dynamic contrast images in overall scoring can improve diagnostic sensitivity. MP-MRI tends to under quantify and under stage radio-recurrent prostate cancer. DCE has a potentially augmented role in detecting recurrent tumour compared with the de novo setting. This has relevance in the event of any future modified MP-MRI scoring system for the irradiated gland.

Abstract 3165: Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data

Abstract Introduction: Although many (~40%) of the screen-detected prostate cancers are indolent (Gleason Score &amp;lt;= 6) and pose minimal risk for progression, advanced stage prostate cancer is a lethal disease with 5-year survival rates around 29%. The challenge is to identify biomarkers for early detection of aggressive disease, when the cancer is still organ confined. Such markers would be also used to better select patients with indolent and low risk cancers for active surveillance. Material and Methods: To identify a panel of protein markers that could predict prostate cancer progression, we developed ultra-sensitive, high-pressure, high-resolution separations coupled with intelligent selection and multiplexing-selected reaction monitoring (PRISM-SRM) assays for 52 protein markers. Candidate protein markers were identified and selected from existing prostate cancer genomics data sets and validated lists of known prostate cancer drivers. The PRISM-SRM assays used heavy isotope-labeled synthetic peptides as internal standards for quantitative proteomics analysis. Study comprised of a prostate cancer patient cohort with organ confined primary tumors (N=338) presenting following post-surgery features: 53 (15.7%) metastatic progression, 124 (36.7%) biochemical recurrence (BCR), and 161 (47.6%) no progression after more than ten years of follow-up after radical prostatectomy. Index tumor region for each case was scraped from representative 10-m sections of formalin-fixed paraffin embedded (FFPE)-whole-mounted prostatectomy specimens and processed for PRISM-SRM analysis. Results: Overall, PRISM-SRM analysis of the FFPE tissue samples enabled the detection of 42 (80.8%) out of 52 biomarker candidates; in comparison regular LC-SRM without the front-end chromatographic enrichment could detect only 21 (40.4%) of these candidates at the protein level. Kruskal-Wallis testing was used for statistical evaluation of the PRISM-SRM results and comparison of relative protein levels between the “no progression”, BCR and “metastatic progression” groups. Several prostate differentiation/androgen receptor signaling related proteins (FOLH1, PSA and NCOA) and tumor progression-related proteins (TGFB1, CCND1 and SPRC) had significantly different expression levels between the three groups, and showed initial promise in predicting progression to invasive cancer, BCR and metastasis. Conclusion: Ultra-sensitive targeted proteomics can be used to select and verify performance of early prognostic markers based on the analysis of prostatectomy specimens. The top performing markers appeared able to predict progression from organ confined cancer to BCR and metastasis. Citation Format: Yuqian Gao, Yi-Ting Wang, Hui Wang, Denise Young, Jennifer Cullen, Yingjie Song, Yongmei Chen, Athena Schepmoes, Gyorgy Petrovics, Thomas Fillmore, Tujin Shi, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, Albert Dobi, Inger Rosner, Karin Rodland, Isabell Sesterhenn, Shiv Srivastava, Tao Liu. Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3165.

All over the map: An interobserver agreement study of tumor location based on the PI-RADSv2 sector map.

Prostate imaging reporting and data system version 2 (PI-RADSv2) recommends a sector map for reporting findings of prostate cancer mulitparametric MRI (mpMRI). Anecdotally, radiologists may demonstrate inconsistent reproducibility with this map. To evaluate interobserver agreement in defining prostate tumor location on mpMRI using the PI-RADSv2 sector map. Retrospective. Thirty consecutive patients who underwent mpMRI between October, 2013 and March, 2015 and who subsequently underwent prostatectomy with whole-mount processing. 3T mpMRI with T2 W, diffusion-weighted imaging (DWI) (apparent diffusion coefficient [ADC] and b-2000), dynamic contrast-enhanced (DCE). Six radiologists (two high, two intermediate, and two low experience) from six institutions participated. Readers were blinded to lesion location and detected up to four lesions as per PI-RADSv2 guidelines. Readers marked the long-axis of lesions, saved screen-shots of each lesion, and then marked the lesion location on the PI-RADSv2 sector map. Whole-mount prostatectomy specimens registered to the MRI served as ground truth. Index lesions were defined as the highest grade lesion or largest lesion if grades were equivalent. Agreement was calculated for the exact, overlap, and proportion of agreement. Readers detected an average of 1.9 lesions per patient (range 1.6-2.3). 96.3% (335/348) of all lesions for all readers were scored PI-RADS ≥3. Readers defined a median of 2 (range 1-18) sectors per lesion. Agreement for detecting index lesions by screen shots was 83.7% (76.1%-89.9%) vs. 71.0% (63.1-78.3%) overlap agreement on the PI-RADS sector map (P < 0.001). Exact agreement for defining sectors of detected index lesions was only 21.2% (95% confidence interval [CI]: 14.4-27.7%) and rose to 49.0% (42.4-55.3%) when overlap was considered. Agreement on defining the same level of disease (ie, apex, mid, base) was 61.4% (95% CI 50.2-71.8%). Readers are highly likely to detect the same index lesion on mpMRI, but exhibit poor reproducibility when attempting to define tumor location on the PI-RADSv2 sector map. The poor agreement of the PI-RADSv2 sector map raises concerns its utility in clinical practice. 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2018;48:482-490.

Assessment of prostate cancer with integrated CT-perfusion using a sector-wise approach.

The role of computed tomography perfusion (CTP) in characterizing primary prostate cancer (PCa) is not definitely known. The aim of the present study was to investigate the relationship between CTP parameters and histopathological features of PCa tissue, using a sector-wise approach. Fifty-one patients with biopsy-proven PCa underwent prospectively a CTP scan prior to radical prostatectomy. Blood flow (BF), mean blood volume (BV) and mean transit time (MTT) were calculated, with the prostate being divided into eight sectors. Corresponding sector-wise histopathological analysis of whole-mount prostatectomy specimens was performed to determine tumoral area (mm2), mean microvessel density (MVD), Gleason patterns (primary, secondary) and total Gleason score. Spearman's rank correlation coefficient was used to analyze the association between CTP and histopathological parameters. BF correlated weakly with tumoral area [ρs coefficient (p-value): 0.25 (0.00)] and MVD [ρs coefficient (p-value): 0.23 (0.00)]. No valuable correlation was found between CTP parameters and primary and secondary Gleason patterns, whereas total Gleason score was weakly correlated with BV [ρs coefficient (p-value): 0.22 (0.00)] and MTT [ρs coefficient (p-value): 0.25 (0.00)]. BF correlates weakly with size and vascularity of PCa. There is a need for further studies to elucidate the association between CTP parameters and other histopathological parameters.

History of PSA screening on prostate cancer aggressiveness.

5066 Background: In 2012, PSA screening for prostate cancer (CaP) detection was given a “Grade D” recommendation for all men by the USPSTF. Recent U.S. studies report declines in PSA screening with concomitant increases in advanced CaP at diagnosis. This study examined the association between PSA screening history and CaP aggressiveness in a racially diverse, military cohort with equal health care access. Methods: This retrospective cohort study evaluated CaP patients undergoing radical prostatectomy (RP) from 1994-2015 at Walter Reed National Military Medical Center. Whole-mounted prostatectomy specimens were classified using 2014 ISUP Gleason grading system. Excluding the diagnostic PSA, screening history was categorized as: ≥ 6 PSA’s prior to CaP diagnosis (uppermost quartile), 1-5 (lower 3 quartiles), vs. no screening history. Multivariable logistic regression (MLR) was used to examine NCCN risk stratum (intermediate-high vs. low) and Gleason upgrade (GU) from biopsy to RP. Multivariable Cox proportional hazards (Cox PH) analyses were used to model time to biochemical recurrence (BCR). Multivariable models controlled for age at RP, race, family history and obesity (BMI &gt; 30 vs. ≤ 30 kg/m2). The GU and BCR models also controlled for NCCN risk classification. Results: There were 1,772 eligible patients with a median follow-up and age at RP of 7.0 and 59.8 years, respectively. Prior to CaP diagnosis, 42% and 19% of men had 1-5 and ≥ 6 PSA’s screenings, respectively. MLR showed greater odds of intermediate or high vs. low risk disease for PSA screening history of none vs. 1-5 (OR = 1.33, CI = 1.03-1.70, p = 0.028) but not for none vs. ≥ 6 (p = 0.44). MLR showed increased odds of GU for none vs. ≥ 6 (OR = 1.81, CI = 1.23-2.7, p &lt; 0.001). Multivariable Cox PH models showed incrementally poorer BCR-free survival as screening history decreased (HRNone vs. ≥6 = 2.27, CI = 1.54-3.33, p &lt; 0.001; HRNone vs. 1-5= 1.49, CI = 1.15-1.92, p = 0.002). Conclusions: In this RP cohort, higher risk stratum, increased GU, and poorer BCR-free survival were associated with no PSA screening history. BCR-free survival was incrementally worsened by less PSA screening. A complete absence of PSA screening may lead to more aggressive disease at presentation and poorer clinical outcomes.

Does prostate HistoScanning™ play a role in detecting prostate cancer in routine clinical practice? Results from three independent studies

To evaluate the ability of prostate HistoScanning™ (PHS; Advanced Medical Diagnostics, Waterloo, Belgium) to detect, characterize and locally stage prostate cancer, by comparing it with transrectal ultrasonography (TRUS)-guided prostate biopsies, transperineal template prostate biopsies (TTBs) and whole-mount radical prostatectomy specimens. Study 1. We recruited 24 patients awaiting standard 12-core TRUS-guided biopsies of the prostate to undergo PHS immediately beforehand. We compared PHS with the TRUS-guided biopsy results in terms of their ability to detect cancer within the whole prostate and to localize it to the correct side and to the correct region of the prostate. Lesions that were suspicious on PHS were biopsied separately. Study 2. We recruited 57 patients awaiting TTB to have PHS beforehand. We compared PHS with the TTB pathology results in terms of their ability to detect prostate cancer within the whole gland and to localize it to the correct side and to the correct sextant of the prostate. Study 3. We recruited 24 patients awaiting radical prostatectomy for localized prostate cancer to undergo preoperative PHS. We compared PHS with standardized pathological analysis of the whole-mount prostatectomy specimens in terms of their measurement of total tumour volume within the prostate, tumour volume within prostate sextants and volume of index lesions identified by PHS. The PHS-targeted biopsies had an overall cancer detection rate of 38.1%, compared with 62.5% with standard TRUS-guided biopsies. The sensitivity and specificity of PHS for localizing tumour to the correct prostate sextant, compared with standard TRUS-guided biopsies, were 100 and 5.9%, respectively. The PHS-targeted biopsies had an overall cancer detection rate of 13.4% compared with 54.4% for standard TTB. PHS had a sensitivity and specificity for cancer detection in the posterior gland of 100 and 13%, respectively, and for the anterior gland, 6 and 82%, respectively. We found no correlation between total tumour volume estimates from PHS and radical prostatectomy pathology (Pearson correlation coefficient -0.096). Sensitivity and specificity of PHS for detecting tumour foci ≥0.2 mL in volume were 63 and 53%. These three independent studies in 105 patients suggest that PHS does not reliably identify and characterize prostate cancer in the routine clinical setting.

Contrast Enhanced Transrectal Ultrasound for the Detection of Prostate Cancer: A Randomized, Double-Blind Trial of Dutasteride Pretreatment

The identification of clinically significant disease is crucial for optimal treatment of prostate cancer. Selective detection of prostate cancer with increased microvessel density is possible with contrast enhanced ultrasound. Preliminary studies suggest that pretreatment with a 5α-reductase inhibitor may improve the efficiency of contrast enhanced ultrasound targeted biopsy. This study was designed to quantify prostate cancer detection with contrast enhanced ultrasound with or without short-term pretreatment with dutasteride. In this randomized, double-blind, placebo controlled trial of oral dutasteride pretreatment, contrast enhanced ultrasound findings were graded and used to direct targeted biopsy (up to 6 cores per prostate). A blinded 12-core systematic biopsy was subsequently performed on every subject based on standard medial and lateral sampling of each sextant. Of 311 subjects who underwent randomization, 272 completed participation. Positive biopsies were obtained in 276 of 3,264 (8.5%) systematic cores and 203 of 1,237 (16.4%) targeted cores (OR 2.1, 95% CI 1.7-2.6, p <0.001). ROC analysis for the detection of all prostate cancers demonstrated an increase in diagnostic accuracy from pre-contrast imaging to contrast enhanced ultrasound (A(z) 0.60 vs 0.64, p = 0.005). For the detection of high grade cancer (Gleason score 7 or greater) ROC analysis demonstrated improved accuracy for pre-contrast imaging (A(z) 0.74) and contrast enhanced ultrasound (A(z) 0.80, p = 0.0005). For the detection of high grade cancer with greater than 50% biopsy core involvement, excellent accuracy was demonstrated with pre-contrast and contrast enhanced ultrasound, A(z) 0.83 and 0.90, respectively (p = 0.001). Pretreatment with dutasteride had no significant impact on the detection of prostate cancer (p = 0.97). Contrast enhanced ultrasound targeted biopsy provides a significant benefit for the detection of high grade/high volume prostate cancer.

Differences in Frequency of ERG Oncoprotein Expression Between Index Tumors of Caucasian and African American Patients With Prostate Cancer

To systematically evaluate the ETS-related gene (ERG) alterations in the multifocal tumor context using whole-mount prostatectomy specimens from African and Caucasian American patients matched for age, pathologic grade and stage. Oncogenic activation of the ERG is the most common early genomic alteration in patients with prostate cancer (CaP) in Western countries. However, ERG alterations have not been systematically examined in African American patients with a known greater risk of CaP incidence and mortality. ERG oncoprotein expression was analyzed in 91 Caucasian and 91 African American patients with CaP, who were matched for age, Gleason score, and pathologic stage. A unique aspect of the present study was the evaluation of ERG in whole-mount prostatectomy sections, minimizing sampling bias and allowing the careful assessment of the ERG in the multifocal tumor context of CaP. The frequency of ERG-positive prostate tumors was significantly greater among Caucasian Americans than among African Americans when assessed in all tumor foci (41.9% vs 23.9%, P < .0001). A markedly greater frequency of ERG oncoprotein expression was noted between the index tumors of the Caucasian Americans (63.3%) and those of the African Americans (28.6%). Also, in the African American patients, the higher grade index tumors were predominantly ERG negative. ERG typing of CaP established a major difference between the index tumors of Caucasian and African American patients. ERG-negative index tumors might indicate a less favorable outcome for African American patients. The results of the present study underscore that typing of CaP for the ERG could enhance our understanding of the biologic differences between the examined ethnic groups.

Initial Results of 3-Dimensional 1H-Magnetic Resonance Spectroscopic Imaging in the Localization of Prostate Cancer at 3 Tesla

The purpose of this study was to compare the diagnostic performance of 3 Tesla, 3-dimensional (3D) magnetic resonance spectroscopic imaging (MRSI) in the localization of prostate cancer (PCa) with and without the use of an endorectal coil (ERC). Our prospective study was approved by the institutional review board, and written informed consent was obtained from all patients. Between October 2004 and January 2006, 18 patients with histologically proven PCa on biopsy and scheduled for radical prostatectomy were included and underwent 3D-MRSI with and without an ERC. The prostate was divided into 14 regions of interest (ROIs). Four readers independently rated (on a 5-point scale) their confidence that cancer was present in each of these ROIs. These findings were correlated with whole-mount prostatectomy specimens. Areas under the receiver-operating characteristic curve were determined. A difference with a P < 0.05 was considered significant. A total of 504 ROIs were rated for the presence and absence of PCa. Localization of PCa with MRSI with the use of an ERC had a significantly higher areas under the receiver-operating characteristic curve (0.68) than MRSI without the use of an ERC (0.63) (P = 0.015). The use of an ERC in 3D MRSI in localizing PCa at 3 Tesla slightly but significantly increased the localization performance compared with not using an ERC.

Global Expression Analysis of Prostate Cancer-associated Stroma and Epithelia

Characterization of gene expression profiles in tumor cells and the tumor microenvironment is an important step in understanding neoplastic progression. To date, there are limited data available on expression changes that occur in the tumor-associated stroma as either a cause or consequence of cancer. In the present study, we employed a 54,000 target oligonucleotide microarray to compare expression profiles in the 4 major components of the microenvironment: tumor epithelium, tumor-associated stroma, normal epithelium, and normal stroma. Cells from 5 human, whole-mount prostatectomy specimens were microdissected and the extracted and amplified mRNA was hybridized to an Affymetrix Human Genome U133 Plus 2.0 GeneChip. Using the intersection of 2 analysis methods, we identified sets of differentially expressed genes among the 4 components. Forty-four genes were found to be consistently differentially expressed in the tumor-associated stroma; 35 were found in the tumor epithelium. Interestingly, the tumor-associated stroma showed a predominant up-regulation of transcripts compared with normal stroma, in sharp contrast to the overall down-regulation seen in the tumor epithelium relative to normal epithelium. These data provide insight into the molecular changes occurring in tumor-associated stromal cells and suggest new potential targets for future diagnostic, imaging, or therapeutic intervention.

Complex patterns of ETS gene alteration arise during cancer development in the human prostate

An ERG gene 'break-apart' fluorescence in situ hybridization (FISH) assay has been used to screen whole-mount prostatectomy specimens for rearrangements at the ERG locus. In cancers containing ERG alterations the observed pattern of changes was often complex. Different categories of ERG gene alteration were found either together in a single cancerous region or within separate foci of cancer in the same prostate slice. In some cases the juxtaposition of particular patterns of ERG alterations suggested possible mechanisms of tumour progression. Prostates harbouring ERG alterations commonly also contained cancer that lacked rearrangements of the ERG gene. A single trans-urethral resection of the prostate specimen examined harboured both ERG and ETV1 gene rearrangements demonstrating that the observed complexity may, at least in part, be explained by multiple ETS gene alterations arising independently in a single prostate. In a search for possible precursor lesions clonal ERG rearrangements were found both in high grade prostatic intraepithelial neoplasia (PIN) and in atypical in situ epithelial lesions consistent with the diagnosis of low grade PIN. Our observations support the view that ERG gene alterations represent an initiating event that promotes clonal expansion initially to form regions of epithelial atypia. The complex patterns of ERG alteration found in prostatectomy specimens have important implications for the design of experiments investigating the clinical significance and mechanism of development of individual prostate cancers.

Prostatic basal cells in the peripheral and transitional zones: Zonal variation in morphology and in immunophenotype

Benign prostatic hyperplasia and prostatic adenocarcinoma exhibit prominent zonal predilections. Basal cells from the transitional zone and from the peripheral zone are postulated to have different underlying biological properties. We studied basal cells in both prostatic zones. Tissue microarrays (TMA) were prepared from 65 whole-mounted prostatectomy specimens with prostatic adenocarcinoma. The transitional zone and peripheral zone were sampled from each prostate. TMA sections were stained with a basal cell cocktail (CK 34betaE12 + p63). The immunostaining pattern and the morphology of basal cells were recorded. Triangular-shaped basal cells were highlighted by CK 34betaE12 cytoplasmic and p63 nuclear staining. These basal cells had their long axis oriented perpendicular to the basement membrane and their apex toward the lumen interdigited between secretory luminal cells. This morphology was seen in the majority of peripheral zone benign prostatic glands (92.0%) but only a minority of transitional zone benign prostatic glands (18.0%). Basal cells of the transitional zone showed weak or absent CK 34betaE12 staining in 65.9% of glands while maintaining p63. All glands with high-grade prostatic intraepithelial neoplasia (HGPIN) contained the triangular basal cells. In addition, basal cell clusters were identified in 8.7% of peripheral zone glands and 5.2% of HGPIN glands. Our results indicate that the basal cell morphology and the basal cell immunophenotype have a zonal variation. The finding of a unique morphology of basal cells and the presence of basal cell clusters in the peripheral zone suggests that the peripheral zone might be the stem/progenitor cell-rich area in the human prostates.

Gene Promoter Methylation in Prostate Tumor–Associated Stromal Cells

Gene expression can be silenced through the methylation of specific sites in the promoter region. This mechanism of gene silencing has an important role in the carcinogenesis of prostate and other cancers. Although tumor-associated stromal cells also exhibit changes in gene expression, promoter methylation has not been described in these cells. Tumor epithelia, tumor-associated stroma and normal epithelia, and stroma adjacent to tumor tissues were isolated from whole-mount prostatectomy specimens (two per patient) of patients (n = 5) with localized prostate cancer and from normal epithelia and stroma from benign prostate hyperplasia specimens (two per patient) from men (n = 5) without prostate cancer by using laser capture microdissection or expression microdissection. The methylation status of three genes important in prostate carcinogenesis, GSTP1, RARbeta2, and CD44, were evaluated using quantitative methylation-sensitive polymerase chain reaction. GSTP1 and RARbeta2 were methylated in the tumor epithelium of all five prostate cancer patients and in the tumor-associated stroma in four of the five patients. CD44 was methylated in the tumor epithelium from four of the five patients but not in the tumor stroma. GSTP1 and RARbeta2 were methylated in normal epithelium of two and four patients, respectively, and in normal stroma of one and two patients, respectively, that were isolated from regions adjacent to the tumors and may have resulted from a tumor-field effect; CD44 methylation was not observed in normal epithelium or stroma. In contrast, normal epithelia and stroma from benign prostate hyperplasia specimens showed no promoter methylation in GSTP1, RARbeta2, or CD44. The observation of promoter methylation in the non-neoplastic cells of the prostate tumor microenvironment may advance our understanding of prostate cancer development and progression and lead to new diagnostic and prognostic markers and therapeutic targets.

Prostate Cancer Volume – Can It Be Predicted Preoperatively?

Introduction: The prostate cancer volume (PCvol) is described as a significant predictor for tumor progression after radical prostatectomy, but its determination has not become a routine procedure yet due to high demands on technical standards, labor intensity, and costs. The objective of this study is to predict the PCvol by using common preoperative variables. Material and Methods: Between 1996 and 2001, 365 whole-mounted prostatectomy specimens, processed according to the Stanford protocol, were used for computerized reconstruction of the total PCvol. Widely accepted preoperative variables such as prostate-specific antigen (PSA), digital rectal examination findings, and Gleason score and grading (WHO) of the biopsy cores were correlated and analyzed for a relation to the PCvol by Spearman rho method and Mann-Whitney U test. Integrating these parameters in a multiple linear regression model, independent variables predicting the PCvol were determined, multiplied by their risk factors, and used for calculation of the estimated PCvol. In order to evaluate the precision of our results, we correlated measured and estimated tumor volumes. A nomogram was constructed, in order to visualize our results. Results: Multiple linear regression analysis revealed categorized PSA, grading (WHO), and Gleason score to be independent predictors for the PCvol. The estimated PCvol ranged from 0.5 to 9.8 cm³ and the measured PCvol from 0.02 to 53 cm³. An identical mean value of 4.1 cm³ was observed. The Spearman rho method showed a highly significant correlation (coefficient = 0.5) between estimated and measured PCvol (p < 0.001). Conclusions: The PCvol is regarded as a significant predictive parameter of tumor progression after radical prostatectomy, but due to its time-consuming determination, it has not become a routine procedure yet. Currently used preoperative parameters such as PSA and grading (WHO) and Gleason score of the biopsy cores do predict the total tumor volume. These results were reconfirmed by correlation analysis. Consequently, by use of our nomogram, the labor-intensive measurement of the PCvol becomes unnecessary.

Quantitative Computed Tomography Perfusion of Prostate Cancer: Correlation with Whole-Mount Pathology

PurposeMicrovessel density within the prostate is associated with presence of cancer, disease stage, and disease-specific survival. We evaluated multidetector computed tomography (CT) to estimate prostate perfusion and localize prostate cancer. Patients and MethodsTen subjects were evaluated with contrast enhanced CT before radical prostatectomy with the Mx8000IDT 16-slice scanner. Following baseline pelvic scan, 100 cc of Optiray® 300 was administered intravenously (4 cc per second). Repeated dynamic scans through the prostate were obtained at 20, 30, 40, 50, and 60 seconds following initiation of contrast injection. Computed tomography perfusion was compared with pathologic findings of Gleason score and tumor volume on whole-mount prostatectomy specimens. ResultsConventional adenocarcinoma (Gleason score, 6-10) was present in all subjects, including one who also demonstrated a mucinous variant of prostate cancer. Visible focal CT enhancement was noted in 1 patient with a high-volume tumor and a Gleason score of 10. A positive correlation between local estimates of CT perfusion and percent of prostate volume occupied by tumor in each sextant was found for half of the subjects (Pearson correlation coefficient, 0.3-0.95; mean, 0.48) but statistically significant correlation (P < 0.05; Pearson coefficient, 0.9- 0.95) was present in only the 2 subjects with the highest Gleason scores (8 and 10) and the highest tumor volume (≥ 50% in ≥ 1 sextant region). ConclusionVisible enhancement of prostate cancer during dynamic CT is present in a minority of subjects. Correlation between quantitative CT perfusion and tumor location is statistically significant only in subjects with localized high-volume, poorly differentiated prostate cancer.

Anatomic distribution and pathologic characterization of small-volume prostate cancer (

Some investigators consider small-volume prostate cancer (0.5 ml or less) without Gleason pattern 4/5 elements as clinically insignificant. The objective of this study was to characterize the anatomic distribution and pathologic features of small tumors (aggregate volume of 0.5 ml or less) in whole-mount prostatectomy specimens. Between 1999 and 2003, 371 consecutive patients underwent radical prostatectomy at the Indiana University Hospitals for localized prostate cancer. Patients who received hormonal or radiation therapy prior to the surgery were excluded from the study. A total of 62 specimens with total tumor volume of 0.5 ml or less were identified and included in this study. All specimens were embedded and whole-mounted. Tumor volume was measured using the grid method. The mean age at the time of surgery was 59 years (median, 61 years; range, 37–72 years). The mean preoperative prostate-specific antigen (PSA) was 6.5 ng/ml (range: 0.3–18 ng/ml). The mean prostate weight was 53 g (range: 16–132 g). The mean tumor volume was 0.29 ml (median, 0.35 ml; range, 0.02–0.48 ml). Tumor multifocality and bilaterality were present in 69 and 37% of cases, respectively. Three (5%) had positive surgical margins. The largest tumor was located in the peripheral zone, transitional zone, and central zone in 79, 16, and 5% of cases, respectively. The largest tumor was located in the anterior prostate in 10 cases (16%) and in the posterior prostate in 52 cases (84%). The distribution of Gleason scores was 5 (12 cases, 19 %), 6 (40 cases, 65 %), and 7 (10 cases, 16 %). One case had a primary Gleason pattern 4. None had extraprostatic extension, seminal vesicle invasion, or lymph node metastasis. Small-volume prostate cancers are often multifocal and bilateral, with predilection for the peripheral zone. Of these small-volume cases, 16% had Gleason pattern 4 and might, therefore, be clinically significant.

Prediction by quantitative histology of pathological stage in prostate cancer

Aims To find a predictor of extraprostatic extension in clinically localized prostate cancer (PCa), pre-operative ultrasound-guided prostate needle biopsies and clinico-pathological data were reviewed. Methods One hundred and eighty-three consecutive patients who underwent radical retropubic prostatectomy for clinical T1-T2 PCa and serum PSA <10 ng/ml were reviewed. Pre-operative biopsy was performed according to an extended protocol and whole-mount prostatectomy specimens were processed. The following biopsy variables were categorized to this analysis: Gleason score (≤6, >6), TPC (≤20%; >20%), GPC (≤50%; >50%), cancer-positive cores (≤2; >2), cancer-positive cores in both lateral portions (yes; no), PCa (monolateral; bilateral). Results Only 60/183 specimens showed an organ-confined PCa; the remaining ones showed pT3a in 57 cases, pT3b in 11 and pT3 with positive surgical margins in 55. A locally advanced PCa was found in 60.2 and 76.8% of T1c and T2 clinical stage, respectively. The positive predictive value and negative predictive value of biopsy findings to predict a locally advanced PCa was 89.9 and 75%, respectively. All biopsy variables associations were statistically significant; however, among these variables (non-categorized), in multivariate logistic regression analysis, only GPC was significantly associated with pathologic stage (odds ratio estimate was 1.075, 95% CI: 1.053–1.098). Conclusions Quantitative histology, especially GPC, seems to be helpful for pre-operative staging of PCa in patients with T1c-T2 clinical stage and PSA <10 ng/ml.

Preoperative Prediction of Pathological Stage by Quantitative Histology in 102 Patients with Prostate Cancer (PCa) and Serum PSA ≤10 ng/mL

Purpose. To find a predictor of extraprostatic extension in clinically localized prostate cancer (PCa), preoperative ultrasound-guided prostate needle biopsies and clinicopathological data were reviewed. Materials and Methods 102 consecutive patients (median age 63 years) with serum PSA ≤10 ng/mL who underwent radical retropubic prostatectomy were included. Preoperative prostate biopsies according to an extended protocol were performed and whole-mount prostatectomy specimens were processed. One or more of the following biopsy variables were considered predictive of locally andvanced PCa: more than 2/12 cancer-positive cores, total percentage of cancer (TPC) &gt;20%, greatest percentage of cancer (GPC) &gt;50%, bilateral PCa, presence of cancer in both lateral portions, Gleason score &gt;6. Results Only 32/102 (31.4%) specimens showed an organ-confined PCa; the remaining were pT3a in 30 (29.4%) cases, pT3b in 6 (5.9%) and pT2–T3 with positive surgical margins in 34 (33.3%). Quantitative histology predicted an organ-confined PCa in 41.2% of patients. In all 102 patients and in 56 with T1c clinical stage, the positive predictive value (PPV) and negative predictive value (NPV) of biopsy findings, to predict an organ confined PCa, was 81.2 vs 92% and 91.6 vs 93.4%, respectively. The PPV and NPV to predict a locally advanced PCa was 92.8 and 86.5%, respectively. Conclusions Quantitative histology seems to be helpful for locally staging of PCa in patients with T1c clinical stage and PSA ≤10 ng/mL.