Whole-mount Prostate Sections Research Articles

Can PSMA PET detect intratumour heterogeneity in histological PSMA expression of primary prostate cancer? Analysis of [68Ga]Ga-PSMA-11 and [18F]PSMA-1007.

Prostate-specific membrane-antigen positron emission tomography (PSMA PET) is a promising candidate for non-invasive characterization of prostate cancer (PCa). This study evaluated whether PET with tracers [68Ga]Ga-PSMA-11 or [18F]PSMA-1007 is capable to depict intratumour heterogeneity of histological PSMA expression. Thirty-five patients with biopsy-proven primary PCa without evidence of metastatic disease nor prior interventions were prospectively enrolled. All patients underwent PSMA PET combined with computer tomography (CT) with either [68Ga]Ga-PSMA-11 (cohort I, 20 patients) or [18F]PSMA-1007 (cohort II, 15 patients) followed by radical prostatectomy. Specimens were scanned by ex-vivo CT and histologically prepared. On digitized whole-mount prostate sections, PCa areas with different morphologies were manually defined and H-Score of immunohistochemical PSMA expression was calculated with assistance by artificial intelligence (AI). PCa areas with similar H-Score were unified in segmentation on ex-vivo CT. After co-registration on PSMA PET-CT, Spearman's coefficients of PSMA expression to mean and maximum standardized uptake value (SUVmean and SUVmax) were calculated. Furthermore, the agreement of the co-registered tumour areas to gross tumour volume (GTV) in PSMA PET was analysed. Thirty-two patients were included in the final analysis. For histological PCa areas, immunohistochemical PSMA expression correlated significantly to SUVmean and SUVmax (p < 0.001, p = 0.001). An approximate linear correlation between H-Score and SUVmean / SUVmax was found for tumour areas larger than 400μm² in histology (p < 0.001). Tumour areas with strong PSMA expression showed a significantly larger overlap to GTV in PSMA PET after co-registration than tumour areas with very low PSMA expression (p < 0.01). No significant differences were found between the two tracer cohorts (p = 0.72). PSMA PET with both [68Ga]Ga-PSMA-11 or [18F]PSMA-1007 is able to detect changes in histological PSMA expression within PCa lesions allowing biologically targeted radiotherapy.

ERG protein expression in prostate and vascular tumors: A potential for ERG-based stratification.

e15171 Background: Frequent overexpression of ERG in prostate tumors is a result of prevalent gene fusions involving upstream sequences of androgen regulated genes (predominantly TMPRSS2) and downstream coding sequences of nuclear transcription factors within the ETS gene family (primarily ERG). Despite numerous reports of ERG alterations at the transcript and genome levels, the ERG oncoprotein remains to be defined. Using a highly specific ERG monoclonal antibody, we have recently developed a comprehensive insight into ERG expression in various cell types of benign and malignant prostate glands. Further, we have analyzed ERG protein expression in human tumors of diverse origins. Methods: Using whole-mount prostate sections from 150 prostatectomy specimens, ERG protein expression was analyzed in PIN, tumor foci, benign glands and other cell types in prostate. In randomly selected cases ERG protein expression was correlated with ERG fusion status. A broad range of vascular endothelial (n=250), other mesenchymal (n=973), and epithelial tumors (n=657) were examined. Results: CPDR ERG-MAb showed striking specificity for detecting prostate tumor cells (>99.9%). Specimens from 65% patients had one or more ERG positive tumor focus. Examination of ERG positive PINs and ERG positive tumors within the same whole-mount sections revealed a 97% concordance. In normal adult tissues, including human and mouse prostate, ERG was restricted to endothelial cells and a subset of bone marrow precursors. ERG was expressed in virtually all vascular tumors and absent in all epithelial tumors except prostate tumors. Conclusions: Taken together, the homogeneous and strong ERG expression in individual tumors and the remarkable correlation between ERG positive PIN lesions and tumors suggests a role for ERG in the pre-invasive to invasive transition of prostate cancer cells. The demonstrated high specificity of CPDR ERG-MAb has potential to provide new opportunities in prostate cancer diagnosis and stratification. Further, ERG is a highly specific new marker for benign and malignant vascular tumors.

Prediction of Prostatic Involvement by Urothelial Carcinoma in Radical Cystoprostatectomy for Bladder Cancer

To ascertain which variables of bladder urothelial carcinoma (UC) might be useful in predicting either UC involving the prostate (UCP) or incidental prostate adenocarcinoma in radical cystoprostatectomy specimens. The bladder and whole-mount prostate sections of 248 radical cystoprostatectomy specimens were reviewed. Stepwise discriminant analysis was used to predict UCP or incidental prostate adenocarcinoma. UCP was present in 94 patients (37.9%). UC originated from the prostatic urethra and periurethral ducts in 78 (31.45%), and isolated direct extension of UC from the bladder was present in 16 patients (6.45%). The periurethral ducts coexisted with direct extension of bladder UC in 11 patients (4.4%). Prostate adenocarcinoma was identified in 123 patients (49.6%). Carcinoma in situ and high-grade urothelial papillary carcinoma were seen in 8 (3.2%) and 5 (2.0%) patients, respectively. In 57 (23%), 64 (25.8%), and 87 (35.1%) patients, UC had invaded the subepithelial connective tissue, muscularis propria, and perivesical tissue, respectively. UC was multifocal in 53 patients (21.4%). The tumor was in the trigone and bladder neck in 160 patients (64.5%). Of the 248 patients, 98 (39.5%) had a history of recurrence. Stepwise discriminant analysis selected 3 variables of bladder UC (previous recurrence and location and number of foci) and correctly predicted the group in 72.2% of patients without and with UCP. Discriminant analysis selected 2 variables of bladder UC (focality and previous recurrence) and correctly predicted the group in 57.7% of patients without and with prostate adenocarcinoma. Our approach can identify bladder UC variables that could guide urologists in the selection of the most appropriate surgical procedure.

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

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. 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. 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 <or=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. 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.

Is Incidentally Detected Prostate Cancer in Patients Undergoing Radical Cystoprostatectomy Clinically Significant?

Cystoprostatectomy specimens obtained from patients with bladder cancer provide a unique opportunity to assess the features of silent prostate adenocarcinoma (PCa). The whole-mount prostate sections of 248 totally embedded and consecutively examined radical cystoprostatectomy (RCP) specimens were reviewed to determine the incidence and features of incidentally detected PCa. PCa was considered clinically significant if any of the following criteria were present: total tumor volume, 0.5 cc or more; Gleason grade, 4 or more; extraprostatic extension; seminal vesicle invasion; lymph node metastasis (of PCa); or positive surgical margins. PCa was present in 123 (49.6%) of 248 specimens. Features were as follows: acinar adenocarcinoma, 123 (100.0%); peripheral zone location, 98 (79.7%); pT2a, 96 (78.0%); pT2b, 11 (8.9%); pT2c, 9 (7.3%); pT3a, 5 (4.1%); pT3b, 2 (1.6%); pT4, 0 (0.0%); Gleason score 6 or less, 107 (87.0%); negative margins, 119 (96.7%); pN0 for PCa, 123 (100.0%); and tumor volume less than 0.5 cc, 116 (94.3%). Of the 123 incidentally detected cases of PCa, 100 (81.3%) were considered clinically insignificant. Incidentally detected PCa is frequently observed in RCP. The majority are clinically insignificant.

Calcifications in prostate and ejaculatory system: a study on 298 consecutive whole mount sections of prostate from radical prostatectomy or cystoprostatectomy specimens

Although calcifications in the prostate are a common manifestation, the relationship between calcifications and prostate cancer is not clearly documented as in breast cancer. In addition, anatomical distribution of calcifications by zones of the prostate and ejaculatory system has not been systematically studied. To study the frequency and patterns of calcifications within the prostate and ejaculatory system, we reviewed the whole mount sections of 298 consecutive prostatectomy or cystoprostatectomy specimens. Calcifications were evaluated in the prostate (central, peripheral and transition zones, and verumontanum), ejaculatory ducts, and seminal vesicles. We graded the degree of calcifications as mild, moderate, or severe. Calcifications in the prostate and ejaculatory system were common, and their frequency in our series is as follows: 88.6% (264/298) of prostates, 58.1% (173/298) of seminal vesicles, and 17.1% (51/298) of ejaculatory ducts. The prostatic calcifications occurred mostly in benign glands and/or stroma of all zones and the verumontanum. Calcifications were more common in the transition zone than other zones. There were 4 cases of prostatic calcifications in the areas of prostatic adenocarcinoma: 3 cases with calcifications in the tumor glands and 1 case with calcifications in tumor stroma but not in the accompanying tumor glands. In conclusion, calcifications are a very common finding in prostatectomy specimens and seem mostly to be associated with benign prostatic hyperplasia. However, calcifications can occur in direct association with prostatic adenocarcinoma, although the incidence of this association is not as high as in breast carcinoma. Also, ejaculatory system calcifications are not an infrequent finding.

Risk Assessment of Prostatic Pathology in Patients Undergoing Radical Cystoprostatectomy

ObjectivesTo determine the incidence and location of prostate adenocarcinoma (PCa) and prostatic urothelial carcinoma (PUC) for patients undergoing radical cystoprostatectomy (RCP) for bladder cancer and to ascertain what preoperative information may be useful in predicting PUC or PCa in patients who may be candidates for prostate-sparing cystectomy. MethodsBetween 2001 and 2004, 235 consecutive patients underwent RCP and had whole-mount sections of the prostate. We reviewed our prospective radical cystectomy database for preoperative clinicopathological information associated with each patient. The bladder and whole-mount prostate sections were re-reviewed to determine the location and depth of the bladder tumor as well as the presence of any associated PCa and PUC. ResultsWe identified 113 of 235 (48%) and 77 of 235 (33%) men with PCa and PUC, respectively. Among patients with PCa, 33 (29%) had Gleason score of ≥ 7, 25 (22%) had PCa tumor volume > 0.5 cc, and 15 (13%) had extracapsular extension. On multivariable analysis, only increasing age was significantly associated with PCa (odds ratio=1.3, p=0.046). Of the 77 with PUC, 28 (36%) had in situ disease only, while 49 (64%) had prostatic stromal invasion. Bladder tumor location in the trigone/bladder neck (p<0.001) and bladder carcinoma in situ (p<0.001) was strongly associated with PUC in the final specimen. Overall, 158 (67%) had either PCa or PUC in the prostate. ConclusionsPCa and/or PUC is present in a majority of RCP specimens. Current preoperative staging and tumor characteristics are not adequate for determining who can safely be selected for prostate-sparing cystectomy.

Whole-mount prostate sections reveal differential endoglin expression in stromal, epithelial, and endothelial cells with the development of prostate cancer.

Endoglin is a nonsignaling receptor for transforming growth factor that contributes to the action of this growth factor in diverse cell types. It may also exhibit a function of its own. Endoglin levels vary with disease states and is a marker of new blood vessels. We studied endoglin expression in whole-mount prostate sections from 64 patients with localized prostate cancer, assessing reactivity in the epithelium, the stroma, and blood vessels. Cells in normal/benign acini were negative but significantly immunoreactive (P<0.001) in both prostatic intraepithelial neoplasia (PIN; 52% of cases) and malignant areas (77% of cases). In tumors, this involved less than 25% of malignant cells in 59% of specimens. The endoglin-stained stroma was detected mainly in areas surrounding PIN acini and tumors. Endoglin antibodies detected more microvessels than von Willebrand Factor antibodies in all prostatic areas (P<0.01). In addition, the number of microvessels increased with the development of cancer and correlated with Gleason score (P<0.01). Changes in endoglin expression in PIN and malignant cells, the surrounding stroma, and related blood vessels, suggest that endoglin function may be altered in prostate cancer.

P53 Immunostaining guided laser capture microdissection (p53-LCM) defines the presence of p53 gene mutations in focal regions of primary prostate cancer positive for p53 protein.

A wide range of p53 mutations (5-65%), detected by various methods, has been reported in primary prostate cancers (CaP). IHC staining of radical prostatectomy specimens shows marked heterogeneity of focally distributed p53-positive cells. However, a significant relationship between the focal staining of p53 and cancer recurrence after radical prostatectomy has been noted. Increased frequency of p53 mutations has been generally observed in advanced stage CaP and metastatic prostate cancer cell lines. The significance of focal p53 immunostaining in primary CaP remains uncertain with respect to the p53 gene mutation or tumor progression. The goal of this study was to evaluate p53 gene mutations in focal regions of primary prostate cancers positive by p53 immunostaining. Whole-mount prostates from men with clinically organ-confined prostate cancer were immunostained for p53 protein. Laser capture microdissection (LCM) was used to harvest p53 positive cells from areas of tumor and prostatic intraepithelial neoplasia and benign gland. DNA from microdissected cells were amplified for p53 exons 5-8 by polymerase chain reaction (PCR) and analyzed for mutations by single strand conformation polymorphism and DNA sequencing. Mutation analysis of the p53 gene exons 5-8 was performed in the p53 immunostaining positive focal regions (1+ to 4+) of whole-mount prostate sections from 16 patients. Of 16 patients with p53 IHC positive tumors, 11 (69%) had p53 gene mutations as determined by DNA sequence analysis. However, randomly microdissected tumor cells from 4 of 18 patients (22%) negative for p53 IHC also demonstrated mutations in the p53 gene. A significant fraction of prostate tumors with focally positive immunostaining for p53 have been confirmed to contain mutations in the p53 gene. p53 immunostaining guided LCM combined with DNA-based analyses emphasizes the presence of focal p53 mutations in primary prostate cancers and underscores the significance of previous observations showing a correlation between focal p53 immunostaining in primary CaP and cancer recurrence after radical prostatectomy.

Predicting tumor volume in radical prostatectomy specimens from patients with prostate cancer.

Tumor volume has prognostic value in numerous malignant neoplasms; however, the determination of tumor volume in prostatic adenocarcinoma remains problematic. We tested the hypothesis that the diameter of the largest focus of carcinoma in whole-mount prostate sections predicts the volume of adenocarcinoma in the entire prostate. We evaluated 184 radical prostatectomy specimens by whole-mount processing of the entire prostate. The maximum diameter of the largest focus of carcinoma was measured directly on glass slides. Tumor volume in the entire prostate was calculated by the grid method. The maximum tumor diameter ranged from 0.1 to 4.1 cm (median, 1.6 cm). The total tumor volume ranged from 0.1 to 12.5 cm3 (median, 1.6 cm3). There were significant correlations between maximum tumor diameter and tumor volume (Spearman correlation coefficient = 0.84; P < .0001), surgical margin status (P < .001), perineural invasion (P < .001), serum prostate-specific antigen level at diagnosis (P = .004), Gleason score (P = .004), and pathologic stage (P < .0001). Maximum tumor diameter is a predictor of tumor volume and might be useful for the assessment of tumor volume in routinely processed prostatectomy specimens.

Predicting Tumor Volume in Radical Prostatectomy Specimens From Patients With Prostate Cancer

Tumor volume has prognostic value in numerous malignant neoplasms; however, the determination of tumor volume in prostatic adenocarcinoma remains problematic. We tested the hypothesis that the diameter of the largest focus of carcinoma in whole-mount prostate sections predicts the volume of adenocarcinoma in the entire prostate. We evaluated 184 radical prostatectomy specimens by whole-mount processing of the entire prostate. The maximum diameter of the largest focus of carcinoma was measured directly on glass slides. Tumor volume in the entire prostate was calculated by the grid method. The maximum tumor diameter ranged from 0.1 to 4.1 cm (median, 1.6 cm). The total tumor volume ranged from 0.1 to 12.5 cm 3 (median, 1.6 cm 3 ). There were significant correlations between maximum tumor diameter and tumor volume (Spearman correlation coefficient = 0.84; P < .0001), surgical margin status (P < .001), perineural invasion (P < .001), serum prostate-specific antigen level at diagnosis (P = .004), Gleason score (P = .004), and pathologic stage (P < .0001). Maximum tumor diameter is a predictor of tumor volume and might be useful for the assessment of tumor volume in routinely processed prostatectomy specimens. During recent decades, our understanding of the natural