Differential classification of prostate cancer (CaP) grade group (GG) 2 and 3 tumors remains challenging, likely due to the subjective quantification of percentage of Gleason pattern 4 (%GP4). Artificial intelligence assessment of %GP4 may improve its accuracy and reproducibility and provide information for prognosis prediction. To investigate this potential, a convolutional neural network (CNN) model was trained to objectively identify and quantify Gleason pattern (GP) 3 and 4 areas, estimate %GP4, and assess whether CNN-assessed %GP4 is associated with biochemical recurrence (BCR) risk in intermediate risk GG 2 and 3 tumors. The study was conducted in a radical prostatectomy cohort (1999–2012) of African American men from the Henry Ford Health System (Detroit, Michigan). A CNN model that could discriminate four tissue types (stroma, benign glands, GP3 glands, and GP4 glands) was developed using histopathologic images containing GG 1 (n = 45) and 4 (n = 20) tumor foci. The CNN model was applied to GG 2 (n = 153) and 3 (n = 62) for %GP4 estimation, and Cox proportional hazard modeling was used to assess the association of %GP4 and BCR, accounting for other clinicopathologic features including GG. The CNN model achieved an overall accuracy of 86% in distinguishing the four tissue types. Further, CNN-assessed %GP4 was significantly higher in GG 3 compared with GG 2 tumors (p = 7.2*10− 11). %GP4 was associated with an increased risk of BCR (adjusted HR = 1.09 per 10% increase in %GP4, p = 0.010) in GG 2 and 3 tumors. Within GG 2 tumors specifically, %GP4 was more strongly associated with BCR (adjusted HR = 1.12, p = 0.006). Our findings demonstrate the feasibility of CNN-assessed %GP4 estimation, which is associated with BCR risk. This objective approach could be added to the standard pathological assessment for patients with GG 2 and 3 tumors and act as a surrogate for specialist genitourinary pathologist evaluation when such consultation is not available.
Context.— Pseudocarcinomatous urothelial hyperplasia (PCUH) architecturally and cytologically mimics cancer. The urine cytology features of PCUH have not been described. Objective.— To describe PCUH features in urine cytology. Design.— We reviewed urine cytology cases with concurrent PCUH tissue specimens from 5 academic institutions and classified them by using The Paris System criteria. Results.— Thirty-nine patients included 31 men and 8 women with a mean age of 67 years (range, 39–87 years). All patients had prior pelvic irradiation, and most presented with hematuria (n = 27). The specimens included voided urine (n = 16); bladder washing (n = 11); and urine, not otherwise specified (n = 12). The specimen preparation included cytospin (n = 29) and ThinPrep (n = 10). Original interpretations were negative for high-grade urothelial carcinoma (n = 28), atypical urothelial cells (AUCs; n = 10), and high-grade urothelial carcinoma (HGUC; n = 1). Twenty-five urine specimens (64%) had findings of PCUH. These specimens were moderately cellular and composed of sheets, cohesive groups, or isolated urothelial cells. Nucleoli were present in 23 cases. The nuclear membrane was smooth to irregular (n = 9), smooth (n = 8), and irregular (n = 8). The chromatin was glassy (n = 8), vesicular (n = 7), hyperchromatic (n = 7), and vesicular to finely granular (n = 3). The cytoplasm varied from dense squamoid, to finely vacuolated, to vacuolated. Nucleomegaly was observed in all 25 specimens, and nuclear-cytoplasmic ratio greater than 0.5 was seen in 11 of 25 cases (44%). The background contained acute inflammation (n = 14), was clean (n = 9), and contained red blood cells (n = 2). All cases originally interpreted as AUCs and HGUC had PCUH features. Conclusions.— PCUH urine features can overlap with AUCs, HGUC, and other nonurothelial malignancies. In our cohort, 44% (11 of 25) of urine specimens with PCUH changes were initially misclassified. Recognition of cytologic features of PCUH is important to avoid overcalling reactive changes.
Introduction: Prostate cancer is a heterogenous multifocal disease. We hypothesize that different tumor foci may harbor distinct driver molecular aberrations, making it a more complex disease and difficult to manage. To avoid overlooking smaller tumor foci with clinical and biological significance, we used an innovative approach to understand the genetic underpinnings of each tumor foci based on the molecular analysis of whole-mount radical prostatectomy specimens rather than a systematic sampling of dominant nodules alone. Our study aimed to identify distinct molecular subsets of prostate cancer, if any, and correlate them with clinical outcomes in Caucasians (CA) and African Americans (AA). Method: We randomly selected 834 whole-mount radical prostatectomy tissues including 463 (56%) CA and 371 (44%) AA. We used combined dual immunohistochemistry (IHC) for ERG and SPINK1 and dual RNA in-situ hybridization (ISH) for ETV1 and ETV4. The racial disparity in aberrant oncogene expression was analyzed by the Chi-squared test. The recurrence-free survival (RFS) of patients with distinct molecular subsets of prostate cancer was examined by the Kaplan-Meier method and cox-ph models. The Gleason’s grades of prostate biopsies were summarized by spaghetti plot and compared by linear mixed models. Results: Patients with localized prostate cancer expressing none, one, two, and three of four oncogenes were 16.4%, 58.4%, 21.7%, and 3.5%, respectively. The expression of ERG and SPINK1 was negatively correlated (odds ratio (OR)=0.38, 95% CI 0.29-0.51, p<.001). Compared with CA, AA had a lower incidence of ERG (38.8% vs 60.3%), a higher incidence of SPINK1 (63.3% vs 35.6%), and similar incidences of ETV1 (9.4% vs 9.3%) and ETV4 (4.6% vs 3.9%). Importantly, ETV1 expression was associated with a worse RFS in CAs (hazard ratio (HR)=2.49, 95% CI 1.15-5.38, p=.02). ETV4 expression was associated with a worse RFS in AA (HR=3.11, 95% CI 1.32-8.04, p=.01). In addition, ETV4 expression was associated with lymph node metastasis in AA (OR=4.0, 95% CI 1.06-12.44, p=.02) but not in CA (OR=0.56, 95% CI 0.03-2.85, p=.57). For those who had multiple biopsies before radical prostatectomy, Gleason’s grade increased with time in AA (0.23 per year, p<.001) but was unchanged in CA. ERG expression was associated with a lower Gleason grade (-0.20, p=.03). ETV4 was associated with a higher Gleason grade (0.50, p=.02). Conclusion: Our findings showed the molecular heterogeneity between CA and AA who had localized prostate cancer, and supported ETV1 and ETV4 as prognostic markers that can be incorporated into clinical practice to better predict prostate cancer recurrence after radical prostatectomy in CA and AA, respectively. Citation Format: Wei Zhao, Pin Li, Shannon Carskadon, Craig Rogers, James Peabody, Mani Menon, Dhananjay Chitale, Sean Williamson, Nilesh Gupta, Nallasivam Palanisamy. New perspective on racial disparities in prostate cancer: identification of new molecular subsets using whole-mount radical prostatectomy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5762.
Nearly half of the prostate cancer (PCa) cases show elevated levels of ERG oncoprotein due to TMPRSS2-ERG gene fusion. Here, we demonstrate ERG mediated upregulation of Distal-less homeobox-1 (DLX1), an established PCa biomarker. Using series of functional assays, we show DLX1 elicits oncogenic properties in prostate epithelial cells, and abrogating its function leads to reduced tumor burden in mouse xenografts. Clinically, ~60% of the PCa patients exhibit high DLX1 levels, while ~50% of these cases also harbor elevated ERG associated with aggressive disease and poor survival probability. Mechanistically, we show that ERG gets recruited onto DLX1 promoter and interacts with its enhancer-bound androgen receptor (AR) and FOXA1 to regulate DLX1 expression in TMPRSS2-ERG positive cases. Alternatively, in ERG-negative cases, DLX1 is regulated by AR/AR-V7 and FOXA1. Importantly, BET bromodomain inhibitors disrupt the transcriptional regulators of DLX1 and its associated oncogenic properties, signifying their efficacy in treatment of DLX1-positive PCa patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.