4D pathology: translating dynamic epithelial tubulogenesis to prostate cancer pathology.

The Gleason score is the gold standard for grading of prostate cancer (PCa) and is assessed by assigning specific grades to different microscopical growth patterns. Aside from the Gleason grades, individual growth patterns such as cribriform architecture were recently shown to have independent prognostic value for disease outcome. PCa grading is performed on static tissue samples collected at one point in time, whereas in vivo epithelial tumour structures are dynamically invading, branching and expanding into the surrounding stroma.

Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients.

Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness.

ISUP Consensus Definition of Cribriform Pattern Prostate Cancer.

The presence of a cribriform pattern is now recognized as a clinically important, independent adverse prognostic indicator for prostate cancer. For this reason the International Society of Urological Pathology (ISUP) recently recommended its inclusion in standard reporting. In order to improve interobserver agreement as to the diagnosis of cribriform patterns, the ISUP assembled an international panel of 12 expert urogenital pathologists for the purpose of drafting a consensus definition of cribriform pattern in prostate cancer, and provide their opinions on a set of 32 images and on potential diagnostic criteria.

On cribriform prostate cancer.

The management of newly diagnosed prostate cancer is challenging because of its heterogeneity in histology, genetics and clinical outcome. The clinical outcome of patients with Gleason score 7 prostate cancer varies greatly. Improving risk assessment in this group is of particular interest, as Gleason score 7 prostate cancer on biopsy is an important clinical threshold for active treatment.

Statins Promote Cardiac Infarct Healing by Modulating Endothelial Barrier Function Revealed by Contrast-Enhanced Magnetic Resonance Imaging.

Objective: The endothelium has a crucial role in wound healing, acting as a barrier to control transit of leukocytes. Endothelial barrier function is impaired in atherosclerosis preceding myocardial infarction (MI). Besides lowering lipids, statins modulate endothelial function.

Characteristics and outcome of prostate cancer patients with overall biopsy Gleason score 3 + 4 = 7 and highest Gleason score 3 + 4 = 7 or > 3 + 4 = 7.

Aim: Prostate cancer heterogeneity and multifocality might result in different Gleason scores (GS) at individual biopsy cores. According to World Health Organisation/International Society of Urologic Pathology (WHO/ISUP) guidelines, the GS in each biopsy core should be recorded with optional reporting of overall GS for the entire case. We aimed to compare the clinicopathological characteristics and outcome of men with overall biopsy GS 3 + 4 = 7 with highest GS 3 + 4 = 7 (HI = OV) to those with highest GS > 3 + 4 = 7 (HI > OV).

Characteristics of Prostate Cancer Found at Fifth Screening in the European Randomized Study of Screening for Prostate Cancer Rotterdam: Can We Selectively Detect High-grade Prostate Cancer with Upfront Multivariable Risk Stratification and Magnetic Resonance Imaging?

Background: The harm of screening (unnecessary biopsies and overdiagnosis) generally outweighs the benefit of reducing prostate cancer (PCa) mortality in men aged ≥70 yr. Patient selection for biopsy using risk stratification and magnetic resonance imaging (MRI) may improve this benefit-to-harm ratio.

Objective: To assess the potential of a risk-based strategy including MRI to selectively identify men aged ≥70 yr with high-grade PCa.

Effect of pathologic revision and Ki67 and ERG immunohistochemistry on predicting radical prostatectomy outcome in men initially on active surveillance.

Objective: To investigate if pathologic biopsy reevaluation and implementation of immunohistochemical biomarkers could improve prediction of radical prostatectomy outcome in men initially on active surveillance.

Methods: Biopsy specimens from diagnosis until switching to radical prostatectomy in men initially on active surveillance in the Dutch part of the Prostate cancer Research International Active Surveillance (PRIAS) study were collected and revised by a single pathologist. Original and revised biopsy Gleason score were compared and correlated with radical prostatectomy Gleason score.

Presence of invasive cribriform or intraductal growth at biopsy outperforms percentage grade 4 in predicting outcome of Gleason score 3+4=7 prostate cancer.

Relative increase of grade 4 and presence of invasive cribriform and/or intraductal carcinoma have individually been associated with adverse outcome of Gleason score 7 (GS 7) prostate cancer. The objective of this study was to investigate the relation of Gleason grade 4 tumor percentage (%GG4) and invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. We reviewed 1031 prostate cancer biopsies from the European Randomized Study of Screening for Prostate Cancer.

Risk-stratification based on magnetic resonance imaging and prostate-specific antigen density may reduce unnecessary follow-up biopsy procedures in men on active surveillance for low-risk prostate cancer.

Objectives: To assess the value of risk-stratification based on magnetic resonance imaging (MRI) and prostate-specific antigen density (PSA-D) in reducing unnecessary biopsies without missing Gleason pattern 4 prostate cancer in men on active surveillance (AS).

Patients And Methods: In all, 210 men on AS with Gleason score 3 + 3 prostate cancer received a first MRI and if indicated [Prostate Imaging Reporting and Data System (PI-RADS) score ≥3] targeted biopsy (TBx) using MRI-transrectal ultrasonography (TRUS) fusion. The MRI was performed 3 months after diagnosis (group A: n = 97), at confirmatory biopsy (group B: n = 39) or at surveillance biopsy after one or more repeat TRUS-guided systematic biopsies (TRUS-Bx) (group C: n = 74).

Biopsy undergrading in men with Gleason score 6 and fatal prostate cancer in the European Randomized study of Screening for Prostate Cancer Rotterdam.

Objectives: A total of 15 men who died of prostate cancer had cT1/2 biopsy Gleason score ≤6 prostate cancer at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam. Our objective was to explain (part of) these prostate cancer deaths by undergrading with the classical Gleason score.

Methods: Biopsy specimens of 98 men with classical Gleason score ≤6 or 3 + 4 = 7 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam were retrospectively reviewed by two pathologists using the International Society of Urological Pathology 2014 modified Gleason score.

Gene-expression analysis of gleason grade 3 tumor glands embedded in low- and high-risk prostate cancer.

The Gleason score (GS) of prostate cancer on diagnostic biopsies is an important parameter for therapeutic decision-making. Biopsy GS under-estimates the actual GS at radical prostatectomy in a significant number of patients due to samplingartifact. The aim of this study was to identify markers that are differentially expressed in Gleason grade 3 (GG3) tumor glands embedded in GS 4 + 3 = 7 and GS 3 + 3 = 6 prostate cancer using laser capture microdissection and RNA sequencing.

EpCAM Expression in Lymph Node and Bone Metastases of Prostate Carcinoma: A Pilot Study.

There is an urgent need for new imaging modalities in prostate carcinoma staging. A non-invasive modality that can assess lymph node and bone metastases simultaneously is preferred. Epithelial cell adhesion molecule (EpCAM) is a membranous protein of interest as an imaging target since it is overexpressed in prostatic carcinoma compared with benign prostate epithelium and compared with stroma.

Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases.

Phosphodiesterase 4D7 was recently shown to be specifically over-expressed in localized prostate cancer, raising the question as to which regulatory mechanisms are involved and whether other isoforms of this gene family (PDE4D) are affected under the same conditions.We investigated PDE4D isoform composition in prostatic tissues using a total of seven independent expression datasets and also included data on DNA methylation, copy number and AR and ERG binding in PDE4D promoters to gain insight into their effect on PDE4D transcription.We show that expression of PDE4D isoforms is consistently altered in primary human prostate cancer compared to benign tissue, with PDE4D7 being up-regulated while PDE4D5 and PDE4D9 are down-regulated.

Prostate cancer outcomes of men with biopsy Gleason score 6 and 7 without cribriform or intraductal carcinoma.

Aim Of The Study: Gleason score (GS) 3 + 4 = 7 prostate cancer patients with presence of cribriform or intraductal carcinoma (7(+)) have a worse disease-specific survival than those without. The aim of this study was to compare the clinicopathologic characteristics and patient outcomes of men with biopsy GS 3 + 4 = 7 without cribriform or intraductal carcinoma (7(-)) to those with GS 3 + 3 = 6.

Materials And Methods: We included all patients from the first screening round of the European Randomized Study of Screening for Prostate Cancer (1993-2000) with a revised GS ≤ 3 + 4 = 7 (n = 796) following the 2014 International Society of Urological Pathology criteria.

Three-dimensional microscopic analysis of clinical prostate specimens.

Aims: Microscopic evaluation of prostate specimens for both clinical and research purposes is generally performed on 5-μm-thick tissue sections. Because cross-sections give a two-dimensional (2D) representation, little is known about the actual underlying three-dimensional (3D) architectural features of benign prostate tissue and prostate cancer (PCa). The aim of this study was to show that a combination of tissue-clearing protocols and confocal microscopy can successfully be applied to investigate the 3D architecture of human prostate tissue.

MET expression during prostate cancer progression.

Tyrosine-kinase inhibitors of the hepatocyte growth factor receptor MET are under investigation for the treatment of hormone-refractory prostate cancer (HRPC) metastasis. Analysis of MET protein expression and genetic alterations might contribute to therapeutic stratification of prostate cancer patients. Our objective was to investigate MET on protein, DNA and RNA level in clinical prostate cancer at various stages of progression.

mTOR pathway activation is a favorable prognostic factor in human prostate adenocarcinoma.

Prostate cancer patients with localized disease are treated with curative intent. However, the disease will recur in approximately 30% of patients with a high incidence of morbidity and mortality. Prognostic biomarkers are needed to identify patients with high risk of relapse.

Gleason grade 4 prostate adenocarcinoma patterns: an interobserver agreement study among genitourinary pathologists.

Aims: To assess the interobserver reproducibility of individual Gleason grade 4 growth patterns.

Methods And Results: Twenty-three genitourinary pathologists participated in the evaluation of 60 selected high-magnification photographs. The selection included 10 cases of Gleason grade 3, 40 of Gleason grade 4 (10 per growth pattern), and 10 of Gleason grade 5.

Disease-specific survival of patients with invasive cribriform and intraductal prostate cancer at diagnostic biopsy.

Invasive cribriform and intraductal carcinoma in radical prostatectomy specimens have been associated with an adverse clinical outcome. Our objective was to determine the prognostic value of invasive cribriform and intraductal carcinoma in pre-treatment biopsies on time to disease-specific death. We pathologically revised the diagnostic biopsies of 1031 patients from the first screening round of the European Randomized Study of Screening for Prostate Cancer (1993-2000).