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Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations., Methods: Three separate TMA sets were built that differ by purpose and disease state., Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases., Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation., Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment., (©2022 The Authors; Published by the American Association for Cancer Research.)

Prostate development depends on balanced cell proliferation and differentiation, and acetylated KLF5 is known to alter epithelial proliferation. It remains elusive whether post-translational modifications of transcription factors can differentially determine adult stem/progenitor cell fate. Here we report that, in human and mouse prostates, Klf5 is expressed in both basal and luminal cells, with basal cells preferentially expressing acetylated Klf5. Functionally, Klf5 is indispensable for maintaining basal progenitors, their luminal differentiation, and the proliferation of their basal and luminal progenies. Acetylated Klf5 is also essential for basal progenitors' maintenance and proper luminal differentiation, as deacetylation of Klf5 causes excess basal-to-luminal differentiation; attenuates androgen-mediated organoid organization; and retards postnatal prostate development. In basal progenitor-derived luminal cells, Klf5 deacetylation increases their proliferation and attenuates their survival and regeneration following castration and subsequent androgen restoration. Mechanistically, Klf5 deacetylation activates Notch signaling. Klf5 and its acetylation thus contribute to postnatal prostate development and regeneration by controlling basal progenitor cell fate.

Purpose: To investigate the pathologic outcomes of additional random biopsies from areas with no visible MR targets in the setting of targeted in-bore MRI-guided biopsy and to assess the negative predictive value (NPV) of areas with no visible MR targets stratified according to patients' different biopsy statuses., Materials and Methods: A retrospective analysis of patients who underwent in-bore MRI-guided biopsy with additional random biopsies in areas with no visible MR targets (Prostate Imaging-Reporting and Data System, version 2 category 1 or 2) was conducted in this study. Diagnostic scans and in-bore MRI-guided biopsy were performed with a 3-T MRI scanner. Areas with no visible MR targets were biopsied in a random fashion whenever a zone or side did not have a visible focal target. Clinically significant cancers (CSCs) were defined as a Gleason score of 7 or greater. NPVs were stratified based on patient's prior biopsy status. Descriptive analysis was performed., Results: A total of 59 consecutive patients were included, with a median age of 65 years (interquartile range [IQR], 59-71 years). The median prostate-specific antigen level was 7 ng/mL (IQR, 4.9-10.8 ng/mL). Of the 59 patients, 16 (27.1%) were biopsy naive, 24 (40.7%) had prior negative transrectal US-guided biopsy findings, and 19 (32.2%) had prior positive transrectal US-guided biopsy findings. Forty-two (71.2%) biopsies revealed prostate cancer. A total of 112 areas with no visible MR targets were biopsied, of which 20 (17.9%) were cancers and 11 (9.8%) were CSCs. The NPV of areas with no visible MR targets was approximately 78% for all cancers and was 88.1% for CSCs. NPVs in biopsy-naive patients, patients with prior negative transrectal US-guided biopsy findings, and patients with prior positive transrectal US-guided biopsy findings were 62.5%, 83.3%, and 84.2%, respectively, for all cancers and 75.0%, 91.7%, and 94.7%, respectively, for CSCs., Conclusion: Areas with no visible MR targets in patients with MR-suspicious foci may still harbor CSCs that may significantly affect management plans. Additional biopsies from areas with no visible MR targets are warranted in this population. Keywords: Biopsy/Needle Aspiration, Interventional-Body, MR-Imaging, Prostate, Urinary© RSNA, 2019., Competing Interests: Disclosures of Conflicts of Interest: K.K.E. disclosed no relevant relationships. C.P.F. disclosed no relevant relationships. M.G.S. disclosed no relevant relationships. A.O.O. disclosed no relevant relationships. S.G.N. disclosed no relevant relationships., (2019 by the Radiological Society of North America, Inc.)

We evaluated 18 F-fluciclovine uptake parameters that correlate with true positivity for local recurrence in non-prostatectomy-treated patients. Methods: Twenty-one patients (prostate-specific antigen level, 7.4 ± 6.8 ng/mL) with biochemical recurrence after nonprostatectomy local therapy (radiotherapy and cryotherapy) underwent dual-time-point 18 F-fluciclovine (364.1 ± 37.7 MBq) PET/CT from pelvis to diaphragm. Prostatic uptake over background was delineated and coregistered to a prostate-biopsy-planning ultrasound. Transrectal biopsies of 18 F-fluciclovine-defined targets were completed using a 3-dimensional visualization and navigation platform. Histologic analyses of lesions were completed. Lesion characteristics including SUV max , target-to-background ratio (TBR), uptake pattern, and subjective reader's suspicion level were compared between true-positive (malignant) and false-positive (benign) lesions. Univariate analysis was used to determine the association between PET and histologic findings. Receiver-operating-characteristic curves were plotted to determine discriminatory cutoffs for TBR. Statistical significance was set at a P value of less than 0.05. Results: Fifty lesions were identified in 21 patients on PET. Seventeen of 50 (34.0%) targeted lesions in 10 of 21 patients were positive for malignancy. True-positive lesions had a significantly higher SUV max (6.62 ± 1.70 vs. 4.92 ± 1.27), marrow TBR (2.57 ± 0.81 vs. 1.69 ± 0.51), and blood-pool TBR (4.10 ± 1.17 vs. 2.99 ± 1.01) than false-positive lesions at the early time point ( P < 0.01) and remained significant at the delayed time point, except for blood-pool TBR. Focal uptake (odds ratio, 12.07; 95% confidence interval, 2.98-48.80; P < 0.01) and subjective highest suspicion level (odds ratio, 10.91; 95% confidence interval, 1.19-99.69; P = 0.03) correlated with true positivity. Using the receiver-operating-characteristic curve, optimal cutoffs for marrow TBR were 1.9 (area under the curve, 0.82) and 1.8 (area under the curve, 0.85) at early and delayed imaging, respectively. With these cutoffs, 15 of 17 malignant lesions were identified at both time points; however, fewer false-positive lesions were detected at the delayed time point (5/33) than at the early time point (11/33). Conclusion: True positivity of 18 F-fluciclovine-targeted prostate biopsy in non-prostatectomy-treated patients correlates with focal uptake, TBR (blood pool and marrow), and subjective highest suspicion level. A marrow TBR of 1.9 at the early time point and 1.8 at the delayed time point had optimal discriminating capabilities. Despite the relatively low intraprostate positive predictive value (34.0%) with 18 F-fluciclovine, application of these parameters to interpretative criteria may improve true positivity in the treated prostate., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Primary mucinous tumors and secondary tumors involving the prostate gland are relatively uncommon, however they have important diagnostic, therapeutic, and prognostic implications. The primary mucinous tumors of the prostate include mucinous (colloid) adenocarcinoma of the prostate, prostatic adenocarcinoma with mucinous features, and mucinous adenocarcinoma of the prostatic urethra (mucin-producing urothelial-type adenocarcinoma of the prostate). Mucinous adenocarcinoma of the prostate is defined as a primary prostatic acinar tumor characterized by the presence of at least 25% of the tumor composed of glands with extraluminal mucin. This diagnosis can only be made in radical prostatectomy specimens. Recent studies have shown that these tumors have a similar or in some cases better prognosis than conventional prostatic adenocarcinoma treated by radical prostatectomy. The preferred terminology for tumors that are composed of <25% extraluminal mucinous component in radical prostatectomy specimens is 'prostatic adenocarcinoma with mucinous features.' All cases of prostatic adenocarcinoma with extraluminal mucinous components in prostate needle core biopsies or transurethral resection of the prostate specimens are also referred to as 'prostatic adenocarcinoma with mucinous features.' Mucinous adenocarcinoma of the prostatic urethra (mucin-producing urothelial-type adenocarcinoma of the prostate) as the name implies, does not arise from prostatic acini or ducts, and is a distinct entity that arises from the prostatic urethra usually from urethritis glandularis or glandular metaplasia with malignant transformation, and is analogous to adenocarcinoma with mucinous differentiation arising from the urinary bladder. This tumor is aggressive and has a relatively poor prognosis. The most common secondary tumors that arise from adjacent organs and spread (direct extension or metastasis) to the prostate gland, include urothelial carcinoma of the bladder and colorectal adenocarcinoma. Other secondary tumors that may involve the prostate include metastatic epithelial tumors from several other sites, malignant melanoma and soft tissue tumors.

Small cell carcinoma of the prostate (PSCC) is a highly aggressive malignancy that often develops in patients previously treated with hormonal therapy for metastatic prostatic acinar adenocarcinoma. The TMPRSS2-ERG gene rearrangement is highly specific for prostate cancer and shared by PSCC; however, the role of androgen receptor (AR) gene alterations and interaction with TMPRSS2-ERG rearrangement are incompletely understood in PSCC. Sixty-one cases of PSCC were examined for AR gene copy number and TMPRSS2-ERG rearrangement by fluorescence in situ hybridization (FISH) and AR protein expression by immunohistochemistry. Of 61 cases of PSCC, 51% (31/61) demonstrated increased AR gene copy number (FISH+), 54% (33/61) were positive for TMPRSS2-ERG gene fusion, and 38% (23/61) showed AR protein expression. Of the 31 AR FISH+ cases, 23 also showed TMPRSS2-ERG gene fusion, and 16 expressed AR protein. Of the 33 cases with TMPRSS2-ERG fusion, 28 were AR FISH+ or expressed AR protein. Statistically significant correlations were observed between AR gene copy number or AR protein expression and TMPRSS2-ERG gene fusion (P = 0.001 and P = 0.03, respectively). In summary, high AR gene copy number emerges during the development of PSCC, often in association with TMPRSS2-ERG rearrangement. This potential mechanism warrants further study. Improvement will come from understanding the biology of the disease and integrating new therapies into the treatment of this rare and aggressive tumor., (© 2014 Wiley Periodicals, Inc.)

Basal cell carcinoma (also referred to as adenoid cystic carcinoma) is a rare tumor of the prostate. Although largely characterized as indolent, poor outcomes have been reported in a considerable fraction of cases. As yet, optimum treatment strategies for this cancer have not been developed. This study investigates protein expression of common or potential molecular therapeutic targets and reports on the clinicopathological features of 9 new cases. We evaluated the expression of ERBB2, KIT, androgen receptor, PTEN, EGFR, ERG, and p53 via immunohistochemistry. We also examined EGFR amplification and TMPRSS2-ERG gene rearrangement by fluorescence in situ hybridization. The mean clinical follow-up was 44 months. We found that basal cell carcinoma behaved aggressively with almost one-half of the cases displaying high-risk pathologic features or local recurrence (44%). One patient died as a result of metastatic disease. The most consistent abnormalities included a loss of PTEN expression (56% of cases) and EGFR overexpression (67% of cases). EGFR overexpression occurred in the absence of gene amplification. The TMPRSS2-ERG rearrangement was not detected in any of the tumors studied, nor was ERG protein positivity identified by immunostaining. In addition, ERBB2, KIT, p53, and androgen receptor expressions were either absent or showed only weak, limited reactivity. Our results suggest that there is a high morbidity associated with this tumor, and more intense follow-up and additional treatment may be indicated. Furthermore, targeted therapies directed against the EGFR and PTEN proteins or their constitutive pathways may be promising for future clinical management., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Schistosomiasis with involvement of the prostate is relatively uncommon and is rarely diagnosed in needle core biopsies., Case: A 45-year-old, African American man who had recently returned from the Middle East presented with hematospermia of unknown etiology. He also had an elevated PSA level and a positive family history of prostate cancer. Prostate needle core biopsies were obtained. On microscopy he had multiple foci of acute and chronic inflammation. In other foci, Schistosoma haematobium ova were identified in the absence of a host inflammatory response. All his biopsies were negative for carcinoma. A diagnosis of schistosomiasis of the prostate was made., Conclusion: Schistosomiasis should be considered in the differential diagnosis of parasitic diseases involving the prostate, especially in patients who live in or have recently visited endemic regions.

The histologic features seen in the prostate following cryotherapy can be highly variable. However, most previous studies were performed on specimens following salvage cryotherapy, which introduces additional confounding variables of the histologic changes after the other primary treatment modalities. We examined prostate needle core biopsies from a cohort of patients following cryotherapy as monotherapy for prostatic adenocarcinoma, to evaluate the true spectrum of morphologic changes in the prostate. Cases that had prior radiation therapy or androgen-deprivation therapy were excluded from the study. Thirty cases were identified. The average patient age was 69 years (range, 51-81 years), and the average time interval between cryotherapy and repeat biopsy was 19.2 months (range, 2-60 months). The original Gleason scores were as follows: 3 + 3 = 6 in 14 (46%) of 30 cases, 3 + 4 = 7 in 8 (27%) of 30 cases, 4 + 3 = 7 in 2 (7%) of 30 cases, 4 + 4 = 8 in 3 (10%) of 30 cases, 4 + 5 = 9 in 2 (7%) of 30 cases, and 5 + 4 = 9 in 1 (3%) of 30 cases. Postcryotherapy, 11 of 30 cases (37%) had recurrent/residual prostatic adenocarcinoma, which showed no therapy-related changes, similar to the residual benign glands. Gleason scores were higher in 5 (46%) of 11 cases, same in 4 (36%) of 11 cases, and lower in 2 (18%) of 11 cases. Multiple additional histologic findings were documented. Unlike other nonsurgical therapeutic modalities, cases with recurrent/residual prostatic adenocarcinoma and benign glands showed therapy-related changes predominantly involving the stroma. It is therefore conceivable that benign or malignant prostatic glands are either completely destroyed during cryotherapy or left unaltered if not in the direct field of cryoablation., (Published by Elsevier Inc.)

Unlabelled: What's known on the subject? and What does the study add? High grade prostatic intraepithelial neoplasia is a pre-malignant lesion to prostate cancer and is associated with 20%-25% risk of prostate cancer in subsequent repeat biopsies. ERG is a highly prostate-cancer-specific marker. Expression of ERG is rare in isolated high grade prostatic intraepithelial neoplasia diagnosed in prostate biopsy and is not associated with cancer risk in subsequent repeat biopsies., Objectives: • To evaluate how often ERG, a highly prostate-cancer-specific marker, is expressed in isolated high grade prostatic intraepithelial neoplasia (HGPIN) by immunohistochemistry. • To study whether a positive ERG immunostain in HGPIN correlates with prostate cancer (PCa) detection in subsequent repeat biopsies., Patients and Methods: • Patients with initial HGPIN in biopsies and at least one follow-up prostate biopsy were included. • Biopsies with HGPIN were immunostained for ERG. • The ERG staining results were then correlated with the PCa risk in subsequent biopsies., Results: • The mean age of 94 patients was 63 years (range 48-78). A mean of 1.8 (range 1-5) repeat biopsy sessions were carried out at a mean interval of 27.4 months (range 1.5-140). The repeat biopsies showed PCa and non-cancer lesions (benign, HGPIN, atypical glands suspicious for cancer) in 36 patients (38%) and 58 patients (62%) respectively. • ERG immunostain was positive in five (5.3%) biopsies with HGPIN, in which PCa was found in two (40%) subsequent biopsies. Of 89 biopsies with negative ERG staining, PCa was found in 34 (38%) repeat biopsies. The cancer detection rate was not different between ERG positive and negative cases (P= 0.299)., Conclusions: • This is the first study to investigate the ERG protein expression in prostate biopsy containing HGPIN only and its use to stratify the cancer risk associated with HGPIN. We found that ERG expression is distinctly uncommon in isolated HGPIN (5.3%). • Positive ERG expression is not associated with increased cancer detection in subsequent repeat biopsies. The use of ERG immunostain in the evaluation and cancer risk stratification of HGPIN is of limited value., (© 2012 BJU INTERNATIONAL.)

This update on prostate pathology is very timely, as we celebrate the 20 anniversary of our great society, the International Society of Urological Pathologists (ISUP). Most of the key advances in this field over the past two decades have been made by several distinguished members of our society, as will be demonstrated herein. I am therefore indeed honored and privileged to be given the opportunity to present this paper. I will start with a brief historical perspective prior to delving into the update on prostate pathology over the past two decades and beyond. The topics discussed in this update will be somewhat limited, but will include The Gleason grading system; handling and staging of radical prostatectomy specimens; variants of prostatic adenocarcinoma; treatment effect on the prostate; other primary and secondary tumours involving the prostate, and biomarkers of prostate cancer.

Aims: To evaluate the utility of p63 and high molecular weight cytokeratin in the distinction between urothelial carcinoma with prostatic stromal invasion and urothelial carcinoma with colonisation of prostatic ducts and acini which may be challenging on H&E, especially for general pathologists who may occasionally encounter these cases., Methods: A search of surgical pathology and consultation files was made for cystoprostatectomy specimens with confirmed urothelial carcinoma with prostatic stromal invasion. Intensity for both p63 and high molecular weight cytokeratin within the tumour cells were scored as negative/weak or strong., Results: A total of 34 cases were identified, 23 (68%) of which had associated foci of urothelial carcinoma with colonisation of prostatic ducts and acini. Mean patient age was 68.5 years (range 44-88 years). In all cases, basal cells of benign prostatic glands showed strong staining for both p63 and high molecular weight cytokeratin. Seventeen of 34 cases (50%) of urothelial carcinoma showed no or weak expression of high molecular weight cytokeratin in the tumour cells. The other 17 cases (50%) of urothelial carcinoma showed strong expression of high molecular weight cytokeratin in the tumour cells. Fourteen of 34 cases (41%) showed negative or weak expression of p63 in tumour cells. Twenty of 34 cases (59%) showed strong expression of p63 in tumour cells. In the 14 of 34 cases (41%) and 17 of 34 cases (50%) which showed negative/weak expression of p63 and high molecular weight cytokeratin, respectively, in the tumour cells, the positive staining of the basal cells by p63 and high molecular weight cytokeratin in the benign prostatic glands and acini or those colonised by urothelial carcinoma, aided in the distinction from urothelial carcinoma with prostatic stromal invasion. In the remaining 20 of 34 cases (59%) and 17 of 34 cases (50%) in which the tumour cells showed strong expression of p63 and high molecular weight cytokeratin, respectively, larger malignant tumour cells and smaller benign basal cells of the prostatic glands and acini were highlighted with these markers, and were easily distinguishable., Conclusion: Our study suggests that p63 and high molecular weight cytokeratin may be utilised in the distinction between urothelial carcinoma with prostatic stromal invasion and urothelial carcinoma with colonisation of prostatic ducts and acini., ((C) 2012 Royal College of Pathologists of Australasia.)

Urothelial carcinoma of the bladder with prostatic stromal invasion is included in stage pT4a of the new 2010 American Joint Committee on Cancer/Tumor-Node-Metastasis classification. Despite being a strong indicator of poor prognosis, there have been few large studies investigating the impact of extent of prostatic stromal invasion on patient outcome. A search of the surgical pathology and expert consultation files at our institution was made for cystoprostatectomy specimens diagnosed as urothelial carcinoma with prostatic stromal invasion from 2002 to 2009. Cases were further stratified as follows: group 1--focal prostatic stromal invasion and group 2--extensive prostatic stromal invasion. Only patients who had surgery as monotherapy and those with available follow-up information were selected for this study. Thirty-five cases of urothelial carcinoma with prostatic stromal invasion and follow-up information were identified. Mean patient age was 70 years (range, 44-88 years). Of these 35 patients, 15 (43%) had focal prostatic stromal invasion and 20 (57%) had extensive prostatic stromal invasion. Angiolymphatic invasion was identified in 93% of group 1 cases and 79% of group 2 cases. Positive margins were identified in 50% of group 1 cases and 45% of group 2 cases. Incidence of nodal metastasis was 64% for group 1 and 60% for group 2. Four (27%) of 15 cases in group 1 and 6 (30%) of 20 cases in group 2 had various histologic variants identified. In group 1, there were 2 cases of urothelial carcinoma with micropapillary features and urothelial carcinoma with focal squamous differentiation. In group 2, there were 3 cases of urothelial carcinoma with focal squamous differentiation, 2 cases of urothelial carcinoma with focal sarcomatoid differentiation, and 1 case of urothelial carcinoma with focal micropapillary features. One- and 3-year overall survival for group 1 was 53% and 27%, respectively. One- and 3-year overall survival for group 2 was 47% and 12%, respectively. Mean survival was 17.4 and 16.3 months for groups 1 and 2, respectively. Overall survival curves did not show a statistically significant difference between the 2 groups from initial diagnosis (P = .889) and radical cystoprostatectomy (P = .369). Our study suggests that extent of prostatic stromal invasion by urothelial carcinoma of the bladder as an independent factor does not impact overall patient survival. Other well-known prognostic factors including positive margin status, presence of aggressive histologic variants of urothelial carcinoma, angiolymphatic invasion, and distant metastasis likely play more critical roles in predicting outcome in male patients who have urothelial carcinoma with prostatic stromal invasion., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: To assess the interpretation of modern criteria for evaluating surgical margins (SMs), by examining the incidence of positive SMs (PSMs) and subsequent biochemical recurrence in a single-surgeon series of radical prostatectomy (RP) at two institutions, as the criteria for determining PSMs after RP are subject to individual interpretation, and this might explain some of the variability in biochemical recurrence rates with different rates of PSMs., Patients and Methods: We reviewed 301 consecutive perineal RPs by one surgeon (T.K.) at Emory University Hospital (EUH) and the Medical University of South Carolina (MUSC), with each pathology department using modern criteria to evaluate the SMs. The SM status and biochemical recurrence (BCR) were analysed, the latter defined as a prostate-specific antigen level of > or =0.2 ng/mL., Results: There were 158 perineal RPs at EUH followed by 143 at MUSC. PSMs were reported in 39 patients (24.7%) at EUH, whereas six (4.2%) were positive at MUSC. The overall BCR rates were similar between the groups, but BCR within margin-positive cases was 100% at MUSC vs 25.6% at EUH (P < 0.01). The presence of tumour at <1 mm from the margin did not increase the rate of BCR compared to those with obvious negative SMs (P = 0.731)., Conclusion: In this single-surgeon series, using the same criteria to evaluate the SMs resulted in significantly different PSM rates and margin-positive BCR rates between the institutions. Although the reason for these differences is difficult to determine, the study shows clearly that tumour within 1 mm of the margin should not be classified as margin-positive.