Charlotte F. Kweldam

Cribriform growth is highly predictive for postoperative metastasis and disease-specific death in Gleason score 7 prostate cancer.

Patients with Gleason score 7 prostate cancer on radical prostatectomy demonstrate a wide range in clinical outcome. Gleason grade 4 prostate cancer encompasses a heterogeneous group of tumor growth patterns including fused, ill-defined, cribriform, and glomeruloid glandular structures. Our objective was to determine the prognostic value of different Gleason grade 4 growth patterns. We performed a nested case–control study among 535 patients with Gleason score 7 prostate cancer at radical prostatectomy, treated between March 1985 and July 2013 at a university hospital in the Netherlands. We analyzed 52 cases (with metastasis, disease-specific mortality or both) and 109 controls, matched for age, PSA level, and pT stage. Presence of the following Gleason grade 4 patterns was recorded: fused, ill-defined, cribriform, and glomeruloid. Intraductal carcinoma of the prostate and tertiary Gleason grade 5 were additionally assessed. Outcomes were metastasis-free survival and disease-specific survival. We used Cox proportional hazards regression to determine the predictive value of Gleason grade 4 patterns for survival time. The overall prevalence of Gleason grade 4 patterns was as follows: fused 75% (n=121), ill-defined 64% (n=102), cribriform 48% (n=83), and glomeruloid 25% (n=40). Cribriform pattern was the only pattern with an unequal distribution between cases and controls. Forty-two out of 52 cases (81%) had cribriform growth pattern versus 41/109 controls (38%). In multivariate analysis, presence of cribriform growth was an adverse independent predictor for distant metastasis-free survival (HR 8.0, 95% CI 3.0–21; P<0.001) and disease-specific survival (HR 5.4, 95% CI 2.0–15, P=0.001). In conclusion, cribriform growth in Gleason grade 4 is a strong prognostic marker for distant metastasis and disease-specific death in patients with Gleason score 7 prostate cancer at radical prostatectomy.

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). Ninety percent of all patients (n=923) had received active treatment, whereas 10% (n=108) had been followed by watchful waiting. The median follow-up was 13 years. Patients who either had invasive cribriform growth pattern or intraductal carcinoma were categorized as CR/IDC+. The outcome was disease-specific survival. Relationships with outcome were analyzed using multivariable Cox regression and log-rank analysis. In total, 486 patients had Gleason score 6 (47%) and 545 had ≥7 (53%). The 15-year disease-specific-survival probabilities were 99% in Gleason score 6 (n=486), 94% in CR/IDC− Gleason score ≥7 (n=356) and 67% in CR/IDC+ Gleason score ≥7 (n=189). CR/IDC− Gleason score 3+4=7 patients did not have statistically different survival probabilities from those with Gleason score 6 (P=0.30), while CR/IDC+ Gleason score 3+4=7 patients did (P<0.001). In multivariable analysis, CR/IDC+ status was independently associated with a poorer disease-specific survival (HR 2.6, 95% CI 1.4–4.8, P=0.002). We conclude that CR/IDC+ status in prostate cancer biopsies is associated with a worse disease-specific survival. Our findings indicate that men with biopsy CR/IDC− Gleason score 3+4=7 prostate cancer could be candidates for active surveillance, as these patients have similar survival probabilities to those with Gleason score 6.

Disease-specific death and metastasis do not occur in patients with Gleason score ≤6 at radical prostatectomy

To assess the metastasis‐free survival (MFS) and disease‐specific survival (DSS) in men with Gleason score ≤6 prostate cancer at radical prostatectomy (RP).

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

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

Prognostic histopathological and molecular markers on prostate cancer needle-biopsies: a review.

Prostate cancer is diverse in clinical presentation, histopathological tumor growth patterns, and survival. Therefore, individual assessment of a tumors aggressive potential is crucial for clinical decision-making in men with prostate cancer. To date a large number of prognostic markers for prostate cancer have been described, most of them based on radical prostatectomy specimens. However, in order to affect clinical decision-making, validation of respective markers in pretreatment diagnostic needle-biopsies is essential. Here, we discuss established and promising histopathological and molecular parameters in diagnostic needle-biopsies.

Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculator for Initial Prostate Biopsy by Incorporating the 2014 International Society of Urological Pathology Gleason Grading and Cribriform growth

BACKGROUND The survival rate for men with International Society of Urological Pathology (ISUP) grade 2 prostate cancer (PCa) without invasive cribriform (CR) and intraductal carcinoma (IDC) is similar to that for ISUP grade 1. If updated into the European Randomized Study of Screening for Prostate Cancer (ERSPC Rotterdam) risk calculator number 3 (RC3), this may further improve upfront selection of men who need a biopsy. OBJECTIVE To improve the number of possible biopsies avoided, while limiting undiagnosed clinically important PCa by applying the updated RC3 for risk-based patient selection. DESIGN, SETTING, AND PARTICIPANTS The RC3 is based on the first screening round of the ERSPC Rotterdam, which involved 3616 men. In 2015, histopathologic slides for PCa cases (n=885) were re-evaluated. Low-risk (LR) PCa was defined as ISUP grade 1 or 2 without CR/IDC. High-risk (HR) PCa was defined as ISUP grade 2 with CR/IDC and PCa with ISUP grade≥3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We updated the RC3 using multinomial logistic regression analysis, including data on age, PSA, digital rectal examination, and prostate volume, for predicting LR and HR PCa. Predictive accuracy was quantified using receiver operating characteristic analysis and decision curve analysis. RESULTS AND LIMITATIONS Men without PCa could effectively be distinguished from men with LR PCa and HR PCa (area under the curve 0.70, 95% confidence interval [CI] 0.68-0.72 and 0.92, 95% CI 0.90-0.94). At a 1% risk threshold, the updated calculator would lead to a 34% reduction in unnecessary biopsies, while only 2% of HR PCa cases would be undiagnosed. CONCLUSIONS A relatively simple risk stratification tool augmented with a highly sensitive contemporary pathologic biopsy classification would result in a considerable decrease in unnecessary prostate biopsies and overdiagnosis of potentially indolent disease. PATIENT SUMMARY We improved a well-known prostate risk calculator with a new pathology classification system that better reflects disease burden. This new risk calculator allows individualized prediction of the chance of having (potentially aggressive) biopsy-detectable prostate cancer and can guide shared decision-making when considering prostate biopsy.

Presence of invasive cribriform or intraductal growth at biopsy outperforms percentage grade 4 in predicting outcome of Gleason score 3|[plus]|4|[equals]|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. In total 370 men had G3+4=7. The relation of invasive cribriform and/or intraductal carcinoma and %GG4 with biochemical recurrence-free survival (BCRFS) after radical prostatectomy (n=146) and radiation therapy (n=195) was analyzed using Cox regression. Invasive cribriform and/or intraductal carcinoma occurred in 7/121 (6%) patients with 1–10% GG4, 29/131 (22%) with 10–25%, and 52/118 (44%) with 25–50% GG4 (P<0.001). In crude analysis, both invasive cribriform and/or intraductal carcinoma (HR 2.72; 95% CI: 1.33–5.95; P=0.006) and 10–50% GG4 (HR 2.43; 95% CI: 1.10–5.37; P=0.03) were associated with BCRFS after prostatectomy. In adjusted analysis, invasive cribriform and/or intraductal carcinoma was an independent predictor for BCRFS (HR 2.40; 95% CI: 1.03–5.60; P=0.04) after prostatectomy, whereas percentage %GG4 (HR 1.00; 95% CI: 0.97–1.03; P=0.80) was not. While invasive cribriform and/or intraductal carcinoma (HR 2.58; 95% CI: 1.59–4.21; P<0.001) performed better than 10–50% GG4 (HR 1.24; 95% CI: 0.67–2.29; P=0.49) for prediction of BCRFS after radiation therapy, both parameters were insignificant in analysis adjusted for prostate-specific antigen (P=0.001), positive biopsies (P<0.001) and tumor volume (P=0.05). In conclusion, increased %GG4 is associated with invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. Invasive cribriform and/or intraductal carcinoma is an independent parameter for BCR after prostatectomy, whereas %GG4 is not. The presence of invasive cribriform and/or intraductal carcinoma has to be included in pathology reports and should act as exclusion criterion for active surveillance.

Three-dimensional microscopic analysis of clinical prostate specimens

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.

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. Architecturally, four Gleason grade 4 growth patterns are recognized: ill-formed, fused, glomeruloid and cribriform. The aim of this review is to describe the role of cribriform growth in prostate cancer with respect to diagnosis, prognosis and molecular pathology. Secondly, we will discuss clinical applications for cribriform prostate cancer and give recommendations for future research.

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

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).