Centralized prostatectomy with intraoperative NeuroSAFE margin assessment improves surgical margin control.

AIMS: To investigate the surgical margin status in patients with prostate cancer who underwent robot-assisted radical prostatectomy (RARP) with intraoperative neurovascular structure-adjacent frozen-section analysis (NeuroSAFE) and evaluate differences compared to patients who underwent radical prostatectomy without NeuroSAFE. PATIENTS AND METHODS: Between September 2018 and January 2021, 962 patients underwent centralized RARP with NeuroSAFE. A secondary resection was performed in case of a positive surgical margin (PSM) on intraoperative frozen section (IFS) analysis to convert a PSM into a negative surgical margin (NSM). A retrospective cohort consisted of 835 patients who had undergone radical prostatectomy in a tertiary centre without NeuroSAFE between January 2000 and December 2017. We performed multivariable logistic regression to evaluate differences in risk of PSM between cohorts after controlling for clinicopathological variables. RESULTS: Patients operated with NeuroSAFE in the centralized clinic had 29% PSM at a definitive pathological RP examination. The median cumulative length of definitive PSM was 1.1 mm (interquartile range: 0.4-3.8). Among 275 men with PSM, 136 (49%) had a cumulative length ≤1 mm and 198 (72%) ≤3 mm. After controlling for PSA, Grade group, cribriform pattern, pT-stage, and pN-stage, patients treated in the centralized clinic with NeuroSAFE had significantly lower odds on PSM (odds ratio [OR]: 0.70, 95% confidence interval [CI]: 0.56-0.88; P = 0.002), PSM length >1 mm (OR: 0.14, 95% CI: 0.09-0.22; P < 0.001), and >3 mm (OR: 0.21, 95% CI: 0.14-0.30; P < 0.001). CONCLUSION: This study provides a detailed overview of surgical margin status in a centralized RP NeuroSAFE cohort. Centralization with NeuroSAFE was associated with lower PSM rates and significantly shorter PSM cumulative lengths, indicating improved control of surgical margin status.

Biopsy prostate cancer perineural invasion and tumour load are associated with positive posterolateral margins at radical prostatectomy: implications for planning of nerve-sparing surgery.

AIMS: Radical prostatectomy (RP) for prostate cancer is frequently complicated by erectile dysfunction and urinary incontinence. However, sparing of the nerve bundles adjacent to the posterolateral sides of the prostate reduces the number of complications at the risk of positive surgical margins. Preoperative selection of men eligible for safe, nerve-sparing surgery is therefore needed. Our aim was to identify pathological factors associated with positive posterolateral surgical margins in men undergoing bilateral nerve-sparing RP. METHODS AND RESULTS: Prostate cancer patients undergoing RP with standardised intra-operative surgical margin assessment according to the NeuroSAFE technique were included. Preoperative biopsies were reviewed for grade group (GG), cribriform and/or intraductal carcinoma (CR/IDC), perineural invasion (PNI), cumulative tumour length and extraprostatic extension (EPE). Of 624 included patients, 573 (91.8%) received NeuroSAFE bilaterally and 51 (8.2%) unilaterally, resulting in a total of 1197 intraoperative posterolateral surgical margin assessments. Side-specific biopsy findings were correlated to ipsilateral NeuroSAFE outcome. Higher biopsy GG, CR/IDC, PNI, EPE, number of positive biopsies and cumulative tumour length were all associated with positive posterolateral margins. In multivariable bivariate logistic regression, ipsilateral PNI [odds ratio (OR) = 2.98, 95% confidence interval (CI) = 1.62-5.48; P < 0.001] and percentage of positive cores (OR = 1.18, 95% CI = 1.08-1.29; P < 0.001) were significant predictors for a positive posterolateral margin, while GG and CR/IDC were not. CONCLUSIONS: Ipsilateral PNI and percentage of positive cores were significant predictors for a positive posterolateral surgical margin at RP. Biopsy PNI and tumour volume can therefore support clinical decision-making on the level of nerve-sparing surgery in prostate cancer patients.

Large and small cribriform architecture have similar adverse clinical outcome on prostate cancer biopsies.

AIMS: Invasive cribriform and intraductal carcinoma (IDC) are associated with adverse outcome in prostate cancer patients, with the large cribriform pattern having the worst outcome in radical prostatectomies. Our objective was to determine the impact of the large and small cribriform patterns in prostate cancer biopsies. METHODS AND RESULTS: Pathological revision was carried out on biopsies of 1887 patients from the European Randomised Study of Screening for Prostate Cancer. The large cribriform pattern was defined as having at least twice the size of adjacent benign glands. The median follow-up time was 13.4 years. Hazard ratios for metastasis-free survival (MFS) and disease-specific survival (DSS) were calculated using Cox proportional hazards regression. Any cribriform pattern was found in 280 of 1887 men: 1.1% IDC in grade group (GG) 1, 18.2% in GG2, 57.1% in GG3, 55.4% in GG4 and 59.3% in GG5; the large cribriform pattern was present in 0, 0.5, 9.8, 18.1 and 17.3%, respectively. In multivariable analyses, small and large cribriform patterns were both (P < 0.005) associated with worse MFS [small: hazard ratio (HR) = 3.04, 95% confidence interval (CI) = 1.93-4.78; large: HR = 3.17, 95% CI = 1.68-5.99] and DSS (small: HR = 4.07, 95% CI = 2.51-6.62; large: HR = 4.13, 95% CI = 2.14-7.98). Patients with the large cribriform pattern did not have worse MFS (P = 0.77) or DSS (P = 0.96) than those with the small cribriform pattern. CONCLUSIONS: Both small and large cribriform patterns are associated with worse MFS and DSS in prostate cancer biopsies. Patients with the large cribriform pattern on biopsy have a similar adverse outcome as those with the small cribriform pattern.

NeuroSAFE in radical prostatectomy increases the rate of nerve-sparing surgery without affecting oncological outcome.

OBJECTIVES: To investigate the impact of intra-operative neurovascular structure-adjacent frozen-section examination (NeuroSAFE) on the rate of nerve-sparing surgery (NSS) and oncological outcome in a large radical prostatectomy (RP) cohort. PATIENTS AND METHODS: Between January 2016 and December 2020, 1756 prostate cancer patients underwent robot-assisted RP, of whom 959 (55%) underwent this with NeuroSAFE and 797 (45%) without (control cohort). In cases where NeuroSAFE showed tumour in the margin, a secondary resection was performed. The effect of NeuroSAFE on NSS and positive surgical margin (PSM) status was analysed using logistic regression. Cox regression was used to identify predictors of biochemical recurrence-free survival (BCRFS). RESULTS AND LIMITATIONS: Patients in the NeuroSAFE cohort had a higher tumour grade (P < 0.001) and clinical stage (P < 0.001) than those in the control cohort. NeuroSAFE enabled more frequent NSS for both pT2 (93% vs 76%; P < 0.001) and pT3 disease (83% vs 55%; P < 0.001). In adjusted analysis, NeuroSAFE resulted in more frequent unilateral (odds ratio [OR] 3.90, 95% confidence interval (CI) 2.90-5.30; P < 0.001) and bilateral (OR 5.22, 95% CI 3.90-6.98; P < 0.001) NSS. While the PSM rate decreased from 51% to 42% in patients with pT3 stage disease (P = 0.031), NeuroSAFE was not an independent predictor of PSM status (OR 0.85, 95% CI 0.68-1.06; P = 0.2) in the entire cohort. Patients who underwent NeuroSAFE had better BCRFS compared to the control cohort (hazard ratio 0.62, 95% CI 0.45-0.84; P = 0.002). This study is limited by its comparison with a historical cohort and lack of functional outcomes. CONCLUSIONS: NeuroSAFE enables more unilateral and bilateral NSS without negatively affecting surgical margin status and biochemical recurrence. This validation study provides a comprehensive overview of the implementation, evaluation and intra-operative decision making associated with NeuroSAFE in clinical practice.

Percentage Gleason pattern 4 and PI-RADS score predict upgrading in biopsy Grade Group 2 prostate cancer patients without cribriform pattern.

PURPOSE: To identify parameters to predict upgrading in biopsy Grade Group (GG) 2 prostate cancer patients without cribriform and intraductal carcinoma (CR/IDC) on biopsy. METHODS: Preoperative biopsies from 657 men undergoing radical prostatectomy (RP) for prostate cancer were reviewed for GG, presence of CR/IDC, percentage Gleason pattern 4, and tumor length. In men with biopsy GG2 without CR/IDC (n = 196), clinicopathologic features were compared between those with GG1 or GG2 without CR/IDC on RP (GG ≤ 2-) and those with GG2 with CR/IDC or any GG > 2 (GG ≥ 2+). Logistic regression analysis was used to predict upgrading in the biopsy cohort. RESULTS: In total 283 men had biopsy GG2 of whom 87 (30.7%) had CR/IDC and 196 (69.3%) did not. CR/IDC status in matched biopsy and RP specimens was concordant in 179 (63.3%) and discordant in 79 (27.9%) cases (sensitivity 45.1%; specificity 92.6%). Of 196 biopsy GG2 men without CR/IDC, 106 (54.1%) had GG ≥ 2+ on RP. Multivariable logistic regression analysis showed that age [odds ratio (OR): 1.85, 95% confidence interval (CI)1.09-3.20; p = 0.025], percentage Gleason pattern 4 (OR 1.54, 95% CI 1.17-2.07; p = 0.003), PI-RADS 5 lesion (OR 2.17, 95% CI 1.03-4.70; p = 0.045) and clinical stage T3 (OR 3.60; 95% CI 1.08-14.50; p = 0.049) were independent parameters to predict upgrading to GG ≥ 2+ on RP in these men. CONCLUSIONS: Age, clinical stage T3, percentage Gleason pattern 4 and presence of PI-RADS 5 lesions are independent predictors for upgrading in men with biopsy GG2 without CR/IDC. These findings allow for improved clinical decision-making on surveillance eligibility in intermediate-risk prostate cancer patients.

Intraductal carcinoma has a minimal impact on Grade Group assignment in prostate cancer biopsy and radical prostatectomy specimens.

AIMS: Intraductal carcinoma (IDC) is an adverse histopathological parameter for prostate cancer outcome, but is not incorporated in current tumour grading. To account for its dismal prognosis and to omit basal cell immunohistochemistry, it has been proposed to grade IDC on the basis of its underlying architectural pattern. The aim of this study was to determine the impact of IDC grade assignment on prostate cancer biopsy and radical prostatectomy tumour grading. METHODS AND RESULTS: A cohort of 1031 prostate cancer biopsies and 835 radical prostatectomies were assigned a Grade Group according to the 2014 International Society of Urological Pathology guidelines, without incorporation of IDC in grading. Tumour grading was compared with a Grade Group in which IDC was graded on the basis of its underlying architecture. Of 1031 biopsies, 139 (13.5%) showed IDC. Grade assignment of IDC led to a Grade Group change in 17 (1.6%) cases: four of 486 (0.8%) Grade Group 1 cases were reclassified as Grade Group 2, nine of 375 (2.4%) Grade Group 2 cases were reclassified as Grade Group 3, and four of 58 (6.9%) Grade Group 4 cases were reclassified as Grade Group 5. IDC was observed in 213 of 835 (25.5%) radical prostatectomies, and its grading led to a change in tumour grade in five of 835 (0.6%) patients, with upgrading in two of 207 (1.0%) patients with Grade Group 1 cancer, in two of 420 (0.5%) patients with Grade Group 2 cancer, and in one of 50 (2%) patients with Grade Group 4 cancer. CONCLUSION: IDC grade assignment led to a Grade Group change in 1.6% of prostate biopsy specimens and in 0.6% of radical prostatectomy specimens. Although the inclusion of IDC in or the exclusion of IDC from the Grade Group might affect decision-making in individual patients, it has a minimal impact on overall prostate cancer management.

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). METHODS AND RESULTS: Prostate cancer biopsies from the European Randomised Study of Screening for Prostate Cancer (ERSPC) were revised according to WHO/ISUP 2014 guidelines (n = 1031). In total, 370 patients had overall GS 3 + 4 = 7, 60 of whom (16%) had had at least one biopsy core with GS 4 + 3 = 7 or 4 + 4 = 8. Men with higher GS than 3 + 4 (HI > OV) in any of the cores had higher age, prostate-specific antigen (PSA) level, number of positive biopsies, percentage tumour involvement, percentage Gleason grade 4 and cribriform or intraductal growth (all P < 0.05) than those with GS 3 + 4 = 7 at highest (HI = OV). In multivariable Cox regression analysis, including PSA, percentage positive biopsies and percentage tumour involvement, biochemical recurrence-free survival after radical prostatectomy (P = 0.52) or radiotherapy (P = 0.35) was not statistically different between both groups. CONCLUSION: Among patients with overall GS 3 + 4 = 7, those with highest GS > 3 + 4 = 7 had worse clinicopathological features, but clinical outcome was not statistically significant. Therefore, the use of overall GS instead of highest GS for clinical decision-making is justified, potentially preventing overtreatment in prostate cancer patients.

Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations.

BACKGROUND: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA). METHODS: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set. RESULTS: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC. Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs. CONCLUSIONS: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement.

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. 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.

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. These 98 men included 15 men with cT1/2 classical Gleason score ≤6 who died of prostate cancer (cases) and 83 randomly selected men with classical Gleason score ≤6 or 3 + 4 = 7 (controls). The primary outcome was the reclassification rate from classical Gleason score ≤6 to modified classical Gleason score 3 + 4 = 7 (grade group 2) stratified for prostate cancer death. The secondary outcome was the rate of cribriform/intraductal carcinoma in Gleason score-reclassified men stratified for prostate cancer death. RESULTS: A total of 79 out of 98 men had classical Gleason score ≤6 prostate cancer. A total of eight out of 15 (53%) prostate cancer deaths with classical Gleason score ≤6 were reclassified to modified Gleason score 3 + 4 = 7, compared with 16 out of 64 (25%) men with non-fatal prostate cancer (P = 0.017). A total of five out of eight (63%) Gleason score-reclassified men with fatal prostate cancer had cribriform/intraductal carcinoma, compared with two out of 16 (13%) Gleason score-reclassified men with non-fatal prostate cancer (P = 0.011). CONCLUSIONS: Part of the prostate cancer deaths with Gleason score ≤6 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam could be explained by biopsy undergrading. The present study confirms that the International Society of Urological Pathology 2014 modified Gleason score is more accurate for prognostic assessment based on prostate biopsy than the classical Gleason score.

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.

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. METHODS AND RESULTS: Optical clearing of intact fresh and formalin-fixed paraffin-embedded (FFPE) clinical prostate specimens allowed us to visualize tissue structures up to a depth of 800 µm, whereas, in uncleared tissue, detection of fluorescence was only possible up to 70 µm. Fluorescent labelling with a general nuclear dye and antibodies against cytokeratin (CK) 5 and CK8-18 resulted in comprehensive 3D imaging of benign peripheral and transition prostate zones, as well as individual PCa growth patterns. After staining, clearing, and imaging, samples could still be processed for 2D (immuno)histochemical staining and DNA analysis, enabling additional molecular and diagnostic characterization of small tissue specimens. CONCLUSIONS: In conclusion, the applicability of 3D imaging to archival FFPE and fresh clinical specimens offers unlimited opportunities to study clinical and biological topics of interest in their actual 3D context.

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. Participants were asked to select a single predominant Gleason grade per case (3, 4, or 5), and to indicate the predominant Gleason grade 4 growth pattern, if present. 'Consensus' was defined as at least 80% agreement, and 'favoured' as 60-80% agreement. Consensus on Gleason grading was reached in 47 of 60 (78%) cases, 35 of which were assigned to grade 4. In the 13 non-consensus cases, ill-formed (6/13, 46%) and fused (7/13, 54%) patterns were involved in the disagreement. Among the 20 cases where at least one pathologist assigned the ill-formed growth pattern, none (0%, 0/20) reached consensus. Consensus for fused, cribriform and glomeruloid glands was reached in 2%, 23% and 38% of cases, respectively. In nine of 35 (26%) consensus Gleason grade 4 cases, participants disagreed on the growth pattern. Six of these were characterized by large epithelial proliferations with delicate intervening fibrovascular cores, which were alternatively given the designation fused or cribriform growth pattern ('complex fused'). CONCLUSIONS: Consensus on Gleason grade 4 growth pattern was predominantly reached on cribriform and glomeruloid patterns, but rarely on ill-formed and fused glands. The complex fused glands seem to constitute a borderline pattern of unknown prognostic significance on which a consensus could not be reached.

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

OBJECTIVES: To assess the metastasis-free survival (MFS) and disease-specific survival (DSS) in men with Gleason score ≤6 prostate cancer at radical prostatectomy (RP). PATIENTS AND METHODS: We included 1101 consecutive RP patients operated between March 1985 to July 2013 at a single institution. The outcome variables were MFS and DSS. The postoperative survival was estimated by the Kaplan-Meier method. RESULTS: The Gleason score distribution of the study population (1101 patients) was Gleason score ≤6 (449, 41%), Gleason score 3 + 4 = 7 (436, 40%), Gleason score 4 + 3 = 7 (99, 9%) and Gleason score 8-10 (117, 11%). The median (interquartile range) postoperative follow-up was 100 (48-150) months. During follow-up 197 men (18%) died, of whom 42 (3.8%) died from prostate cancer-related causes. In all, 19/1101 patients (1.7%) had documented lymph node metastasis at the time of RP: none with Gleason score ≤6, seven with Gleason score 3 + 4 = 7 (1.6%), six with Gleason score 4 + 3 = 7 (6.1%) and six with Gleason score 8-10 (5.1%). Distant metastasis occurred in 56/1101 patients (5.1%): none with Gleason score ≤6, 23 with Gleason score 3 + 4 = 7 (5.3%), 17 with Gleason score 4 + 3 = 7 (17%) and 16 with Gleason score 8-10 (14%). Disease-specific death, stratified per Gleason-score group was: none in ≤6, 16 (3.7%) in 3 + 4 = 7, 16 (16%) in 4 + 3 = 7 and 10 (8.5%) in 8-10 group. CONCLUSION: No metastasis or disease-specific death were seen in men with Gleason score ≤6 prostate cancer at RP, showing the negligible potential to metastasise in this large subgroup of patients with prostate cancer.

Undecussated superior cerebellar peduncles and absence of the dorsal transverse pontine fibers: a new axonal guidance disorder?

Axonal guidance disorders are a newly recognized group of diseases of the human central nervous system. These disorders are characterized by white matter tracts with abnormal course and failure to cross the midline or presence of ectopic white matter tracts. Diffusion tensor imaging (DTI) and fiber tractography are suitable neuroimaging tools to detect morphological abnormalities in the course, decussation, and location of white matter tracts. We report on a 6.5-year-old child with significant global developmental delay. Axial color-coded fractional anisotropy (FA)-maps revealed absence of (1) the midline "focal red dot" at the level of the pontomesencephalic junction representing absence of decussation of the superior cerebellar peduncles and (2) the dorsal component of the transverse pontine fibers. These findings are highly suggestive of an axonal guidance disorders. The complete neuroimaging phenotype of this child does not match well-known diseases with similar DTI findings. We show how DTI reveals important information of microstructural brain malformations that may go undetected or remains underestimated and consequently DTI may suggest the possible pathomechanism. We conclude that this child may be suffering from a not yet described subtype of an axonal guidance disorder.

Reliability of whole mount radical prostatectomy histopathology as the ground truth for artificial intelligence assisted prostate imaging.

The development of artificial intelligence-based imaging techniques for prostate cancer (PCa) detection and diagnosis requires a reliable ground truth, which is generally based on histopathology from radical prostatectomy specimens. This study proposes a comprehensive protocol for the annotation of prostatectomy pathology slides. To evaluate the reliability of the protocol, interobserver variability was assessed between five pathologists, who annotated ten radical prostatectomy specimens consisting of 74 whole mount pathology slides. Interobserver variability was assessed for both the localization and grading of PCa. The results indicate excellent overall agreement on the localization of PCa (Gleason pattern ≥ 3) and clinically significant PCa (Gleason pattern ≥ 4), with Dice similarity coefficients (DSC) of 0.91 and 0.88, respectively. On a per-slide level, agreement for primary and secondary Gleason pattern was almost perfect and substantial, with Fleiss Kappa of .819 (95% CI .659-.980) and .726 (95% CI .573-.878), respectively. Agreement on International Society of Urological Pathology Grade Group was evaluated for the index lesions and showed agreement in 70% of cases, with a mean DSC of 0.92 for all index lesions. These findings show that a standardized protocol for prostatectomy pathology annotation provides reliable data on PCa localization and grading, with relatively high levels of interobserver agreement. More complicated tissue characterization, such as the presence of cribriform growth and intraductal carcinoma, remains a source of interobserver variability and should be treated with care when used in ground truth datasets.

Urinary Incontinence and Sexual Function After the Introduction of NeuroSAFE in Radical Prostatectomy for Prostate Cancer.

BACKGROUND: Nerve-sparing (NS) radical prostatectomy (RP) results in better functional outcomes. Intraoperative neurovascular structure-adjacent frozen section examination (NeuroSAFE) significantly increases the frequency of NS surgery. The effect of NeuroSAFE on postoperative erectile function (EF) and continence is not yet clear. OBJECTIVE: To describe EF and continence outcomes for men undergoing RP with the NeuroSAFE technique. DESIGN, SETTING, AND PARTICIPANTS: Between September 2018 and February 2021, 1034 men underwent robot-assisted RP. Data for patient-reported outcomes were collected via validated questionnaires. INTERVENTION: NeuroSAFE technique for RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Continence was assessed using the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) or Expanded Prostate Cancer Index Composite short form (EPIC-26) and defined as use of 0-1 pads/d. EF was evaluated using EPIC-26 or the International Index of Erectile Function short form (IIEF-5), with data converted according to the Vertosick method and categorized. Descriptive statistics were used to asses and describe tumor characteristics and continence and EF outcomes. RESULTS AND LIMITATIONS: Of the 1034 men who underwent RP after introduction of the NeuroSAFE technique, 63% and 60% completed a preoperative and at least one postoperative questionnaire on continence and EF, respectively. Of the men who underwent unilateral or bilateral NS surgery, use of 0-1 pads/d was reported by 93% after 1 yr and 96% after 2 yr; the corresponding rates for men who underwent non-NS surgery were 86% and 78%. Overall, use of 0-1 pads/d was reported by 92% of the men at 1 yr and by 94% at 2 yr after RP. Men in the NS group had a good or intermediate Vertosick score after RP more often than the non-NS group. Overall, 44% of the men had a good or intermediate Vertosick score at 1 and 2 yr after RP. CONCLUSIONS: After introduction of the NeuroSAFE technique, the continence rate was 92% at 1 yr and 94% at 2 yr after RP. The NS group had a greater percentage of men with an intermediate or good Vertosick score and a higher continence rate after RP in comparison to the non-NS group. PATIENT SUMMARY: Our study shows that after introduction of the NeuroSAFE technique during removal of the prostate, the continence rate among patients was 92% at 1 year and 94% at 2 years after surgery. Some 44% of the men had a good or intermediate score for erectile function 1 and 2 years after surgery.

Automated detection of cribriform growth patterns in prostate histology images.

Cribriform growth patterns in prostate carcinoma are associated with poor prognosis. We aimed to introduce a deep learning method to detect such patterns automatically. To do so, convolutional neural network was trained to detect cribriform growth patterns on 128 prostate needle biopsies. Ensemble learning taking into account other tumor growth patterns during training was used to cope with heterogeneous and limited tumor tissue occurrences. ROC and FROC analyses were applied to assess network performance regarding detection of biopsies harboring cribriform growth pattern. The ROC analysis yielded a mean area under the curve up to 0.81. FROC analysis demonstrated a sensitivity of 0.9 for regions larger than [Formula: see text] with on average 7.5 false positives. To benchmark method performance for intra-observer annotation variability, false positive and negative detections were re-evaluated by the pathologists. Pathologists considered 9% of the false positive regions as cribriform, and 11% as possibly cribriform; 44% of the false negative regions were not annotated as cribriform. As a final experiment, the network was also applied on a dataset of 60 biopsy regions annotated by 23 pathologists. With the cut-off reaching highest sensitivity, all images annotated as cribriform by at least 7/23 of the pathologists, were all detected as cribriform by the network and 9/60 of the images were detected as cribriform whereas no pathologist labelled them as such. In conclusion, the proposed deep learning method has high sensitivity for detecting cribriform growth patterns at the expense of a limited number of false positives. It can detect cribriform regions that are labelled as such by at least a minority of pathologists. Therefore, it could assist clinical decision making by suggesting suspicious regions.

Comparison of Tumor Volume Parameters on Prostate Cancer Biopsies.

CONTEXT.­: Prostate biopsy reports require an indication of prostate cancer volume. No consensus exists on the methodology of tumor volume reporting. OBJECTIVE.­: To compare the prognostic value of different biopsy prostate cancer volume parameters. DESIGN.­: Prostate biopsies of the European Randomized Study of Screening for Prostate Cancer were reviewed (n = 1031). Tumor volume was quantified in 6 ways: average estimated tumor percentage, measured total tumor length, average calculated tumor percentage, greatest tumor length, greatest tumor percentage, and average tumor percentage of all biopsies. Their prognostic value was determined by using either logistic regression for extraprostatic expansion (EPE) and surgical margin status after radical prostatectomy (RP), or Cox regression for biochemical recurrence-free survival (BCRFS) and disease-specific survival (DSS) after RP (n = 406) and radiation therapy (RT) (n = 508). RESULTS.­: All tumor volume parameters were significantly mutually correlated (R2 > 0.500, P < .001). None were predictive for EPE, surgical margin, or BCRFS after RP in multivariable analysis, including age, prostate-specific antigen, number of positive biopsies, and grade group. In contrast, all tumor volume parameters were significant predictors for BCRFS (all P < .05) and DSS (all P < .05) after RT, except greatest tumor length. In multivariable analysis including only all tumor volume parameters as covariates, calculated tumor length was the only predictor for EPE after RP (P = .02) and DSS after RT (P = .02). CONCLUSIONS.­: All tumor volume parameters had comparable prognostic value and could be used in clinical practice. If tumor volume quantification is a threshold for treatment decision, calculated tumor length seems preferential, slightly outperforming the other parameters.