Circulating Insulin-Like Growth Factor 1-Related Biomarkers and Risk of Lethal Prostate Cancer.

Background: Experimental and epidemiologic evidence supports the role of circulating insulin-like growth factor-1 (IGF-1) levels with the risk of prostate cancer. Most circulating IGF-1 is bound to specific binding proteins, and only about 5% circulates in a free form. We explored the relation of free IGF-1 and other components of the IGF system with lethal prostate cancer. Methods: Using prospectively collected samples, we undertook a nested case-only analysis among 434 men with lethal prostate cancer and 524 men with indolent, nonlethal prostate cancer in the Physicians' Health Study and the Health Professionals Follow-up Study. Prediagnostic plasma samples were assayed for free IGF-1 and total IGF-1, acid labile subunit, pregnancy-associated plasma protein A (PAPP-A), and intact and total IGF binding protein 4. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations between IGF-1-related biomarkers and lethal prostate cancer using unconditional logistic regression models adjusted for age, height, and body mass index. Results: Men in the highest quartile of PAPP-A levels had 42% higher odds of lethal prostate cancer (pooled adjusted OR = 1.42, 95% CI = 1.04 to 1.92) compared with men in the lowest 3 quartiles. There were no statistically significant differences in the other plasma analytes. The positive association between PAPP-A and lethal prostate cancer was present among men with intact PTEN but not among those with tumor PTEN loss (2-sided P interaction = .001). Conclusions: Our study provides suggestive evidence that among men who later develop prostate cancer, higher plasma PAPP-A levels measured prior to diagnosis are associated with increased risk of lethal compared with indolent disease.

Molecular risk classifier score and biochemical recurrence risk are associated with cribriform pattern type in Gleason 3+4=7 prostate cancer.

PURPOSE: Among Gleason pattern 4 types, cribriform pattern is associated with the worst outcomes. We hypothesized that larger cribriform patterns would be associated with increased Decipher scores and higher biochemical recurrence (BCR) risk in Gleason 3+4=7 prostatectomy patients. MATERIALS AND METHODS: The slide from patients who underwent prostatectomy from January 2016 to March 2020 on which Decipher was performed was re-reviewed for Gleason score and cribriform patterns, with large cribriform defined as cribriform acini with greater than 12 lumens and simple cribriform as 12 or fewer lumens. Differences in Decipher score were analyzed in a generalized linear model controlling for pathology stage and tumor margin status. A multivariable Cox proportional hazards model was performed for BCR-free survival. RESULTS: Of 337 cases, 118 were Gleason 3+4=7. The mean Decipher scores in 3+4=7 cases without cribriform, with simple cribriform, and with large cribriform were 0.41, 0.54, and 0.62, respectively. In a multivariable model with pathology stage, margin tumor length, and percentage pattern 4 as covariates, compared to cases without cribriform, simple cribriform was associated with 0.10 increase in Decipher (p=0.03) and 4.7-fold hazard ratio of BCR (95% confidence interval [CI], 0.4-56.5; p=0.22) and large cribriform was associated with 0.17 increase in Decipher (p<0.001) and 16.0-fold hazard ratio of BCR (95% CI, 1.4-181.2; p=0.02). CONCLUSIONS: Among Gleason 3+4=7 carcinomas, large cribriform was associated with higher Decipher scores and greater BCR risk. Our results support that large cribriform is an aggressive pattern 4 subtype and should be considered a contraindication for active surveillance.

Intraductal Adenocarcinoma of the Prostate With Cribriform or Papillary Ductal Morphology: Rare Biopsy Cases Lacking Associated Invasive High-grade Carcinoma.

Prostatic duct adenocarcinoma, characterized by pseudostratified columnar epithelium, has historically been considered invasive carcinoma, although it may commonly have an intraductal component. Usual (acinar) intraductal carcinoma of the prostate (IDC-P) is a noninvasive high-risk lesion typically associated with high-grade, high-stage prostate cancer. Whereas there have been rare biopsy studies of pure acinar IDC-P or IDC-P associated with only low-grade carcinoma, there have been no analogous series of IDC-P with cribriform or papillary ductal morphology on biopsy unassociated with invasive high-grade carcinoma. We identified 14 patients with biopsies showing IDC-P with ductal morphology, defined as prostatic duct adenocarcinoma confined to glands/ducts with immunohistochemically proven retention of basal cells. Our series includes 12 patients with pure IDC-P and 2 patients with concurrent low-volume Grade Group 1 invasive cancer in unassociated cores. Three patients underwent radical prostatectomy: 2/3 had high-grade cancer in their resection specimen (Grade Group 3, Grade Group 5), including 1 with advanced stage and nodal metastases; 1/3 had Grade Group 1 organ-confined carcinoma and spatially distinct IDC-P with ductal morphology. Five men had only follow-up biopsies: 2/5 had cancer (Grade Group 2, Grade Group 4); 1/5 had IDC-P (on 2 repeat biopsies); and 2/5 had benign transurethral resection of the prostate. In all 5 cases with invasive cancer, the invasive portion was comprised purely of acinar morphology; no invasive ductal component was identified. Five patients did not have follow-up biopsies and were treated with radiation therapy±androgen deprivation. One patient had no follow-up information. In an analogous situation to acinar IDC-P, we propose that rarely there is a precursor form of ductal adenocarcinoma that can exist without concurrent invasive high-grade carcinoma and propose the term "IDC-P with ductal morphology," consistent with the terminology for acinar prostate adenocarcinoma. Until more evidence is accumulated, we recommend reporting and treating patients with IDC-P with ductal morphology in a manner analogous to those with acinar IDC-P. As with pure IDC-P with acinar morphology, we would also recommend not grading pure IDC-P with ductal morphology. Finally, we propose a new addition to the diagnostic criteria of IDC-P to include intraductal lesions with ductal morphology consisting of papillary fronds or cribriform lesions lined by cytologically atypical pseudostratified epithelium.

Subpathologies and genomic classifier for treatment individualization of post-prostatectomy radiotherapy.

PURPOSE/OBJECTIVE: Risk-stratification for post-prostatectomy radiotherapy (PORT) using conventional clinicopathologic indexes leads to substantial over- and under-treatment. Better patient selection could spare unnecessary toxicities and improve outcomes. We investigated the prognostic utility of unfavorable subpathologies intraductal carcinoma and cribriform architecture (IDC/CA), and a 22-gene Decipher genomic classifier (GC) in prostate cancer (PCa) patients receiving PORT. MATERIAL/METHODS: A cohort of 302 men who received PORT at 2 academic institutions was pooled. PORT was predominately delivered as salvage (62% of cases); 20% received HT+PORT. Specimens were centrally reviewed for IDC/CA presence. In 104 cases, GC scores were determined. Endpoints were biochemical relapse-free (bRFR) and metastasis-free (mFR) rates. RESULTS: After a median follow-up of 6.49-years, 135 (45%) and 40 (13%) men experienced biochemical relapse and metastasis, respectively. IDC/CA were identified in 160 (53%) of cases. Men harboring IDC/CA experienced inferior bRFR (HR 2.6, 95%CI 1.8-3.2, P<0.001) and mFR (HR 3.1, 95%CI 1.5-6.4, P = 0.0014). Patients with GC scores, 22 (21%) were stratified low-, 30 (29%) intermediate-, and 52 (50%) high-risk. GC low-risk was associated with superior bRFR (HR 0.25, 95%CI 0.1-0.5, P<0.001) and mFR (HR 0.15, 95%CI 0.03-0.8, P = 0.025). On multivariable analyses, IDC/CA and GC independently predicted for bRFR, corresponding to improved discrimination (C-index = 0.737 (95%CI 0.662-0.813)). CONCLUSIONS: IDC/CA subpathologies and GC predict for biochemical relapse and metastasis beyond conventional clinicopathologic indexes in the PORT setting. Patients harboring IDC/CA are at higher risk of relapse after maximal local therapies, thus warranting consideration for treatment intensification strategies. Conversely, for men with absence of IDC/CA and low GC scores, de-intensification strategies could be explored.

How accurate is 68Gallium-prostate specific membrane antigen positron emission tomography / computed tomography (68Ga-PSMA PET/CT) on primary lymph node staging before radical prostatectomy in intermediate and high risk prostate cancer? A study of patient- and lymph node- based analyses.

BACKGROUND AND AIM: Gallium-68 (68Ga)-Prostate Membrane Specific Antigen Positron Emission Tomography/Computed Tomography (68Ga-PSMA PET/CT) is an emerging diagnostic modality which is gaining importance in individualized prostate cancer (PCa) management era. This study aimed to investigate the diagnostic accuracy of 68Ga-PSMA PET/CT on primary LN staging before radical prostatectomy (RP) in intermediate and high risk PCa. MATERIALS AND METHODS: The retrospectively documented 49 patients with intermediate and high risk non-metastatic PCa who had 68Ga-PSMA PET/CT before RP were enrolled into this study. The histopathology of dissected LNs was used as reference standard to evaluate the accuracy of 68Ga-PSMA PET/CT on primary LN staging, both in per-patient (n = 49) and in per-node (n = 454) analyses. The diagnostic accuracy was investigated using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), and by area under the curve (AUC) provided using receiver operating curve (ROC) analysis. RESULTS: Median age was 64 (48-79) years and, median and mean PSA values were 10 (1.31-138) ng/ml and 16.2 (±19.8) ng/ml, respectively. 22 (44.9%) and 27 (55.1%) of patients had intermediate and high risk PCa, respectively. A total of 5 (10.2%) patients had histopathologically proven LN metastasis and 3 (60%) of them was detected in 68Ga-PSMA PET/CT. In per patient analysis, the sensitivity, specifity, PPV and NPV of 68Ga-PSMA PET/CT on primary LN staging were 0.60, 0.96, 0.60 and 0.96, respectively. Among overall 454 LNs, 16 (3.5 %) of them were reported as metastatic in histopathology and, 13 (2.9%) of these metastatic LNs were detected in 68Ga-PSMA PET/CT. In per-node analysis, the sensitivity, specificity, PPV and NPV of 68Ga-PSMA PET/CT on primary LN staging were 0.82, 0.99, 0.87 and 0.99, respectively. The ROC analyses found AUCs for primary LN staging as 0.777 (95%CI:0.508-1.0) in per patient analysis and, as 0.904 (95%CI:0.790 - 1.0) in per node analysis, respectively. CONCLUSION: The use of 68Ga-PSMA PET/CT has promising diagnostic accuracy on primary LN staging before RP in intermediate and high risk PCa. However, the efforts should be taken to increase sensitivity of 68Ga-PSMA PET/CT in individualized treatment era.

Should Grade Group 1 (GG1) be called cancer?

INTRODUCTION: ISUP Grade Group 1 prostate cancer is the lowest histologic grade of prostate cancer with a clinically indolent course. Removal of the term 'cancer' has been proposed and has historical precedent both in urothelial and thyroid carcinoma. METHODS: Evidence-based review identifying arguments for and against Grade Group 1 being referred to as cancer. RESULTS: Grade Group 1 has histologic evidence of tissue microinvasion and 0.3-3% rate of extraprostatic extension. Genomic evaluation suggests overlap of a minority of Grade Group 1 cancers with those of Grade Group 2. Conversely, Grade Group 1 tumors appear to have distinct genetic and genomic profiles from Grade Group 3 or higher tumors. Grade Group 1 has no documented ability for regional or distant metastasis and long-term follow up after treatment or active surveillance is safe with excellent oncologic outcomes. DISCUSSION: Grade Group 1 prostate cancer, while showing evidence of neoplasia on histology has a remarkably indolent natural history more akin to non-neoplastic precursor lesions. Consideration should be given to renaming Grade Group 1 prostate cancer, which has the potential to minimize overtreatment, treatment-related side effects, patient anxiety, and financial burden on the healthcare system.

Evaluating the Outcomes of Active Surveillance in Grade Group 2 Prostate Cancer: Prospective Results from the Canary PASS Cohort.

PURPOSE: Active surveillance (AS) for grade group (GG) 2 patients is not yet well defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort. MATERIALS AND METHODS: Participants were prospectively enrolled in an AS study with protocol-directed followup at 10 centers in the U.S. and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology and recurrence were also analyzed. RESULTS: At diagnosis, 154 (9%) had GG2 and 1,574 (91%) had GG1. Five-year reclassification rates were similar between GG2 and GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p <0.001) and GG at diagnosis was associated with time to treatment (HR=1.41; p=0.01). Treatment rates were similar in patients who reclassified during AS, but in patients who did not reclassify, those diagnosed with GG2 underwent definitive treatment more often than GG1 (5-year treatment rates 52% and 12%, p <0.0001). In participants who underwent radical prostatectomy after initial surveillance, the adjusted risk of adverse pathology was similar (HR=1.26; p=0.4). Biochemical recurrence within 3 years of treatment for GG2 and GG1 patients was 6% for both groups. CONCLUSIONS: In patients on AS, the rate of definitive treatment is higher after an initial diagnosis of GG2 than GG1. Adverse pathology after radical prostatectomy and short-term biochemical recurrence after definitive treatment were similar between GG2 and GG1.

Adoption of New Risk Stratification Technologies Within US Hospital Referral Regions and Association With Prostate Cancer Management.

Importance: The clinical decisions that arise from prostate magnetic resonance imaging (MRI) and genomic testing in patients with prostate cancer are not well understood. Objective: To evaluate the association between regional uptake of prostate MRI and genomic testing and observation vs treatment for prostate cancer. Design, Setting, and Participants: This retrospective cohort study of commercial insurance claims for prostate MRI and genomic testing included 65 530 patients 40 to 89 years of age newly diagnosed with prostate cancer from July 1, 2012, through June 30, 2019. Exposures: Patient- and regional-level use of prostate MRI and genomic testing. Main Outcomes and Measures: Observation vs definitive treatment for prostate cancer. Patient-level analyses examined the association between receipt of testing or residing in a hospital referral region (HRR) that adopted testing and observation. In regional-level analyses, the dependent variable was the change in the proportion of patients observed for prostate cancer at the HRR level between 2 periods: July 1, 2012, to June 30, 2014, and July 1, 2017, to June 20, 2019. The independent study variables included HRR-level changes in the proportion of men undergoing prostate MRI and genomic testing between these periods, and the models were adjusted for contextual factors associated with prostate cancer care and socioeconomic status. Results: This study identified 65 530 patients, including 27 679 in the early period (mean [SD] age, 58.0 [5.9] years) and 37 851 in the late period (mean [SD] age, 59.0 [5.7] years). Use of prostate MRI increased significantly from 7.2% (95% CI, 6.9%-7.5%) to 16.7% (95% CI, 16.3%-17.1%) from the early to late period. Use of genomic testing increased significantly from 1.3% (95% CI, 1.1%-1.4%) to 12.7% (95% CI, 12.3%-13.0%) from the early to late period. Compared with the lowest, the highest HRR quartiles of prostate MRI and genomic testing uptake were associated with an adjusted 4.1% (SE, 1.1%; P < .001) and 2.5% (SE, 1.1%; P = .03) absolute increase in the proportion of patients receiving observation, respectively. Conclusions and Relevance: In this cohort study, uptake of prostate MRI and genomic testing was associated with increased use of initial observation vs treatment for prostate cancer. Marked geographic variation supports the need for further patient-level research to optimize the dissemination and outcome of testing.

Quality control stress test for deep learning-based diagnostic model in digital pathology.

Digital pathology provides a possibility for computational analysis of histological slides and automatization of routine pathological tasks. Histological slides are very heterogeneous concerning staining, sections' thickness, and artifacts arising during tissue processing, cutting, staining, and digitization. In this study, we digitally reproduce major types of artifacts. Using six datasets from four different institutions digitized by different scanner systems, we systematically explore artifacts' influence on the accuracy of the pre-trained, validated, deep learning-based model for prostate cancer detection in histological slides. We provide evidence that any histological artifact dependent on severity can lead to a substantial loss in model performance. Strategies for the prevention of diagnostic model accuracy losses in the context of artifacts are warranted. Stress-testing of diagnostic models using synthetically generated artifacts might be an essential step during clinical validation of deep learning-based algorithms.

Tumor subtype defines distinct pathways of molecular and clinical progression in primary prostate cancer.

BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.

Real-world Israeli single institution experience with PET-PSMA for staging of patients with clinically staged localized prostate carcinoma.

BACKGROUND: A recent prospective trial, the proPSMA study, showed superior specificity and sensitivity of Positron emission tomography (PET) - Prostate-specific membrane antigen (PSMA) imaging compared standard Computerized tomography (CT) and bone scan for staging of recently diagnosed high-risk local prostate carcinoma for curative intent treatment. AIM: To share our experience with false-positive PET PSMA scans in newly diagnosed intermediate-risk prostate cancer. METHODS AND RESULTS: Here, we report a series of eight patients who underwent systemic staging using PET-PSMA with false-positive results who were ultimately treated with definitive radiation or surgery. Of the eight patients, two patients were diagnosed with favorable intermediate disease, four with unfavorable intermediate risk, and two with high-risk disease. Seven of eight were shown to have false-positive bone uptake, one patient had uptake in lung nodules. Three patients underwent bone biopsy and proven benign. The rest of the patients were proven as non-metastatic radiologically by repeat PSMA, CT, or Magnetic resonance imaging (MRI). All subsequently preceded to definitive localized treatment and remain disease free as of this study. CONCLUSION: This study emphasizes the importance of prudent clinical judgment when utilizing this highly sensitive imaging technique.

Copy number signature analysis tool and its application in prostate cancer reveals distinct mutational processes and clinical outcomes.

Genome alteration signatures reflect recurring patterns caused by distinct endogenous or exogenous mutational events during the evolution of cancer. Signatures of single base substitution (SBS) have been extensively studied in different types of cancer. Copy number alterations are important drivers for the progression of multiple cancer. However, practical tools for studying the signatures of copy number alterations are still lacking. Here, a user-friendly open source bioinformatics tool "sigminer" has been constructed for copy number signature extraction, analysis and visualization. This tool has been applied in prostate cancer (PC), which is particularly driven by complex genome alterations. Five copy number signatures are identified from human PC genome with this tool. The underlying mutational processes for each copy number signature have been illustrated. Sample clustering based on copy number signature exposure reveals considerable heterogeneity of PC, and copy number signatures show improved PC clinical outcome association when compared with SBS signatures. This copy number signature analysis in PC provides distinct insight into the etiology of PC, and potential biomarkers for PC stratification and prognosis.

Five-alpha reductase inhibitors in men undergoing active surveillance for prostate cancer: impact on treatment and reclassification after 6 years follow-up.

OBJECTIVES: To evaluate the impact of 5-alpha reductase inhibitors (5-ARIs) on definitive treatment (DT) and pathological progression (PP) in patients on active surveillance (AS) for prostate cancer. METHODS: We identified 361 consecutive patients, from an IRB-approved database, on AS for prostate cancer with minimum 2 years follow-up. Patients were grouped into two cohorts, those using 5-ARIs (5-ARI; n = 119) or not using 5-ARIs (no 5-ARI; n = 242). Primary and secondary endpoints were treatment-free survival (TFS) and PP-free survival (PPFS), which were evaluated by Kaplan-Meier analysis. Univariate and multivariable cox regression analysis were used to identify predictors for PP and DT. A p value < 0.05 was considered statistically significant. RESULTS: Baseline characteristics and the prostate biopsy rate were similar between the two groups. Median (range) follow-up was 5.7 (2.0-17.2) years. Five-year and 10-year TFS was 92% and 59% for the 5-ARI group versus 80% and 51% for the no 5-ARI group (p = 0.005), respectively. Five-year and 10-year PPFS was 77% and 41% for the 5-ARI group versus 70% and 32% for the no 5-ARI group (p = 0.04), respectively. Independent predictors for treatment and PP were not taking 5-ARIs (p = 0.005; p = 0.02), entry PSA > 2.5 ng/mL (p = 0.03; p = 0.01) and Gleason pattern 4 on initial biopsy (p < 0.001; p < 0.001), respectively. The main limitation is the retrospective study design. CONCLUSIONS: 5-ARIs reduces reclassification and cross-over to treatment in men on active surveillance for prostate cancer. Further, taking 5-ARIs was an independent predictor for prostate cancer progression and definitive treatment.

Association of Negative Followup Biopsy and Reclassification during Active Surveillance of Prostate Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: With the growing adoption of active surveillance clinical parameters that can tailor the intensity of monitoring are increasingly needed. Therefore, we aimed to evaluate the prognostic value of negative followup biopsy for reclassification and upgrading in prostate cancer patients managed with active surveillance. MATERIALS AND METHODS: The PubMed®, Web of ScienceTM, and Scopus® databases were queried to identify relevant studies published until November 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. We performed a formal meta-analysis for the reclassification and upgrading in the full cohort and selected subgroups. RESULTS: We identified 13 and 9 studies eligible for the systematic review and meta-analysis, respectively. A total of 2,628 patients were included in the meta-analysis. Any negative followup biopsy was associated with significantly lower risk of reclassification (HR 0.46, 95% CI 0.39-0.55; p <0.01), and upgrading (HR 0.54, 95% CI 0.44-0.66; p <0.01). For the confirmatory biopsy subgroup, the results remained significant for reclassification (HR 0.44, 95% CI 0.36-0.55; p <0.01) and upgrading (HR 0.55, 95% CI 0.42-0.73; p <0.01). These patterns remained robust among patients with only Gleason Grade prognostic group 1 (reclassification HR 0.47, 95% CI 0.39-0.57; p <0.01; upgrading HR 0.54, 95% CI 0.42-0.69; p <0.01). CONCLUSIONS: A negative followup biopsy is associated with an approximately 50% decrease in the risk of future reclassification and upgrading. Incorporation of the negative followup biopsy into current protocols should allow for personalized active surveillance tailoring and more precise decision making.

Role of PSMA PET/CT imaging in the diagnosis, staging and restaging of prostate cancer.

Prostate-specific membrane antigen (PSMA) PET/CT is a novel imaging technique for the detection and staging of either primary or recurrent prostate cancer. Early studies demonstrated its improved sensitivity and specificity over and in combination with other currently employed imaging techniques, such as multiparametric MRI, bone scan, PET and CT. However, the lack of strength and confidence in these studies has meant incorporation of PSMA PET/CT into clinical guidelines and practice has been limited to date. In response, a number of high-quality prospective studies have recently emerged and reflect exciting results seen in preceding publications. Here we recount some of the key earlier publications, report results from the latest studies and look to the future discussing some of the eagerly awaited ongoing clinical trials.

Cribriform prostate cancer: Morphologic criteria enabling a diagnosis, based on survey of experts.

Among four sub-patterns of Gleason grade 4 prostate cancer, voluminous evidence supports that the cribriform pattern holds an unfavorable prognostic impact, as compared with poorly-formed, fused, or glomeruloid. The International Society of Urological Pathology (ISUP) recommends specifying whether invasive grade 4 cancer is cribriform. Recently, ISUP experts published a consensus definition of cribriform pattern highlighting criteria that distinguish it from mimickers. The current study aimed to analyze morphologic features separately to identify those that define the essence of the cribriform pattern. Thirty-two selected photomicrographs were classified by 12 urologic pathologists as: definitely cribriform cancer, probably cribriform, unsure, probably not cribriform, or definitely not cribriform. Consensus was defined as 9/12 agree or disagree, with ≤1 strongly supporting the opposite choice. Final consensus was achieved in 21 of 32 cases. Generalized estimating equation (GEE) model with logit link was fitted to estimate effect of multiple morphologic predictors. Fisher exact test was used for categorical findings. Presence of intervening stroma precluded calling cribriform cancer (p = 0.006). Mucin presence detracted (p = 0.003) from willingness to call cribriform cancer (only 3 cases had mucin). Lumen number was associated with cribriform consensus (p = 0.0006), and all consensus cases had ≥9 lumens. Predominant papillary pattern or an irregular outer boundary detracted (p = NS). Invasive cribriform carcinoma should have absence of intervening stroma, and usually neither papillary pattern, irregular outer boundary, nor very few lumens. Setting the criteria for cribriform will help prevent over- or undercalling this important finding.

A comparative study of PCS and PAM50 prostate cancer classification schemes.

BACKGROUND: Two prostate cancer (PC) classification methods based on transcriptome profiles, a de novo method referred to as the "Prostate Cancer Classification System" (PCS) and a variation of the established PAM50 breast cancer algorithm, were recently proposed. Both studies concluded that most human PC can be assigned to one of three tumor subtypes, two categorized as luminal and one as basal, suggesting the two methods reflect consistency in underlying biology. Despite the similarity, differences and commonalities between the two classification methods have not yet been reported. METHODS: Here, we describe a comparison of the PCS and PAM50 classification systems. PCS and PAM50 signatures consisting of 37 (PCS37) and 50 genes, respectively, were used to categorize 9,947 PC patients into PCS and PAM50 classes. Enrichment of hallmark gene sets and luminal and basal marker gene expression were assessed in the same datasets. Finally, survival analysis was performed to compare PCS and PAM50 subtypes in terms of clinical outcomes. RESULTS: PCS and PAM50 subtypes show clear differential expression of PCS37 and PAM50 genes. While only three genes are shared in common between the two systems, there is some consensus between three subtype pairs (PCS1 versus Luminal B, PCS2 versus Luminal A, and PCS3 versus Basal) with respect to gene expression, cellular processes, and clinical outcomes. PCS categories displayed better separation of cellular processes and luminal and basal marker gene expression compared to PAM50. Although both PCS1 and Luminal B tumors exhibited the worst clinical outcomes, outcomes between aggressive and less aggressive subtypes were better defined in the PCS system, based on larger hazard ratios observed. CONCLUSION: The PCS and PAM50 classification systems are similar in terms of molecular profiles and clinical outcomes. However, the PCS system exhibits greater separation in multiple clinical outcomes and provides better separation of prostate luminal and basal characteristics.

Multiparametric MRI Lesion Classified as Prostate Imaging-Reporting and Data System 5 but Histopathologically Described as Benign: A Case Report and Review of Literature.

INTRODUCTION: Prostate cancer (PCa) is the most common malignancy in men. The multiparametric MRI (mpMRI) significantly improved the diagnostic approach of PCa. Although PCa is highly likely to be present in prostate imaging-reporting and data system (PI-RADS) 5 lesions, there are up to 18% of PI-RADS 5 lesions with benign histopathology after targeted biopsy. CASE DESCRIPTION: We present the case of a 66-year-old man who was referred to our hospital for MRI/ultrasound fusion-based targeted biopsy due to an elevated PSA and a PI-RADS 5 lesion described in the mpMRI. After 2 consecutive biopsies, the mpMRI target showed no malignancy. The lesion was described as PI-RADS 2 two years later. CONCLUSION: This case demonstrates the risk of false-positive classified PI-RADS 5 lesions in the mpMRI and the challenge in some cases to distinguish between BPH nodules and cancer. Until today, a limited amount of studies exists concerning this issue. However, further studies are required to evaluate further characteristics associated with a higher possibility of histopathologically benign findings in PI-RADS 5 lesions.

Adjuvant vs. salvage Radiation Therapy after Radical Prostatectomy: Role of Decipher® in the Era of Personalized Medicine.

Prostate Cancer (PCa) is the most prevalent cancer in men. Radical Prostatectomy (RP) as a primary definitive treatment may be followed by adjuvant or salvage radiotherapy. However, there are some uncertainties about receiving immediate adjuvant radiation after RP in men with adverse pathological features versus early salvage radiation therapy. Decipher is a novel genomic classifier and almost all studies have confirmed Decipher as a reliable predictor of metastasis, recurrence and mortality. With the aid of Decipher, clinicians are able to determine the need for adjuvant versus salvage radiotherapy. Decipher has the potential to reduce decisional conflicts in clinical recommendations, and is cost-effective. However, further investigations are required to prove Decipher's role in clinical outcome improvement in patients receiving Decipher-based course of treatment compared with those receiving usual care.