On cribriform prostate cancer

This general aim of the thesis is to study the clinical relevance, interobserver reproducibility, and genetics of cribriform growth in prostate cancer. More specifically, the aims and outline of this thesis are • To study the metastatic potential of modified Gleason score 3+3 prostate cancer in radical prostatectomies. (Chapter 2) • To examine the prognostic value of individual Gleason grade 4 patterns in prostate cancer in radical prostatectomy and diagnostic biopsy specimens. (Chapter 3 and 4) • To examine whether biopsy Gleason score 3+4 patients without cribriform growth could be candidates for active surveillance by comparing them with Gleason score 3+3 patients. (Chapter 5) • To study the relation between Gleason grade 4 tumor percentage and cribriform prostate cancer in Gleason score 3+4 biopsies. (Chapter 6) • To study the reproducibility of various Gleason grade 4 patterns, particularly that of cribriform growth, by undertaking an inter-observer reproducibility study among an international group of genitourinary pathologists. (Chapter 7) • To study which genetic events are associated with cribriform growth in prostate cancer by using Next Generation Sequencing technology. (Chapter 8

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 tumor's 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

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 0.0150 mm2 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.Comment: 15 pages, 6 figure

Grading of prostate cancer: a work in progress

Grading of prostate cancer has evolved substantially over time, not least because of major changes in diagnostic approach and concomitant shifts from late- to early-stage detection since the adoption of PSA testing from the late 1980s. After the conception of the architecture-based nine-tier Gleason grading system more than 50 years ago, several changes were made in order to increase its prognostic impact, to reduce interobserver variation and to improve concordance between prostate needle biopsy and radical prostatectomy grading. This eventually resulted in the current five-tier grading system, with a much more detailed description of the individual architectural patterns constituting the remaining three Gleason patterns (i.e. grades 3–5). Nevertheless, there is room for improvement. For instance, distinction of common grade 4 subpatterns such as ill-formed and fused glands from the grade 3 pattern is challenging, blurring the division between low-risk patients who could be eligible for deferred therapy a

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 &lt; 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.</p

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 stud

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

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 &lt; 0.001] and percentage of positive cores (OR = 1.18, 95% CI = 1.08–1.29; P &lt; 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.</p

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.</p