High-grade Prostatic Adenocarcinoma Research Articles

An orthotopic prostate cancer model for new treatment development using syngeneic or patient-derived tumors.

There are limited preclinical orthotopic prostate cancer models due to the technical complexity of surgical engraftment and tracking the tumor growth in the mouse prostate gland. Orthotopic xenografts recapitulate the tumor microenvironment, tumor stromal interactions, and clinical behavior to a greater extent than xenografts grown at subcutaneous or intramuscular sites. This study describes a novel micro-surgical technique for orthotopically implanting intact tumors pieces from cell line derived (transgenic adenocarcinoma mouse prostate [TRAMP]-C2)or patient derived (neuroendocrine prostate cancer [NEPC])tumors in the mouse prostate gland and monitoring tumor growth using magnetic resonance (MR) imaging. The TRAMP-C2 tumors grew rapidly to a predetermined endpoint size of 10 mm within 3 weeks, whereas the NEPC tumors grew at a slower rate over 7 weeks. The tumors were readily detected by MRand confidently identified when they were approximately 2-3 mm in size. The tumors were less well-defined on CT. The TRAMP-C2 tumors were characterized by amorphous sheets of poorly differentiated cells similar to a high-grade prostatic adenocarcinoma and frequent macroscopic peritoneal and lymph node metastases. In contrast, the NEPC's displayed a neuroendocrine morphology with polygonal cells arranged in nests and solid sheets and high count. There was a local invasion of the bladder and other adjacent tissues but no identifiable metastases. The TRAMP-C2 tumors were more hypoxic than the NEPC tumors. This novel preclinical orthotopic prostate cancer mouse model is suitable for either syngeneic or patient derived tumors and will be effective in developing and advancing the current selection of treatments for patients with prostate cancer.

A Rare Case of Incidental Primary Follicular Lymphoma Co-Existing With Grade Group 5 Prostatic Adenocarcinoma

Abstract Introduction/Objective Primary lymphoma of the prostate is an exceedingly rare entity comprising less than 0.1% of all prostatic cancers with follicular lymphoma making up only 12% of primary prostatic lymphomas. There is very limited literature owing to their rarity and underdiagnosis. To the best of our knowledge, prostatic adenocarcinoma with an incidental follicular lymphoma presenting as a prostate imaging reporting and data system 4 (PI-RADS 4) lesion on multiparametric magnetic resonance imaging (mpMRI) with mildly elevated serum prostate specific antigen (PSA) has not been previously described. Methods/Case Report A 73 year old male presented to Danbury Hospital for follow up on benign prostatic hyperplasia (BPH) diagnosed in 2020. The patient was experiencing nocturia and had a serum PSA of 4.8. Multiparametric MRI revealed an enlarged, 5.5 x 4.1 x 3.3 cm, prostate gland (estimate weight of 45.5 grams) with a 1.2 cm PI-RADS 4 lesion in the right anterior mid gland. There was no evidence of metastatic disease on his most recent body imaging. He was subsequently scheduled for prostate needle biopsy. Histopathology showed a high grade prostatic adenocarcinoma, with a Gleason score 4 + 5=9, along with a focally prominent dense lymphoid infiltrate in four of four cores from the same area of abnormality that was detected on mpMRI. The latter comprised of ill defined follicles and sheets of small cleaved atypical lymphoid cells consistent with centrocytes and very few centroblasts. By immunohistochemical staining, the atypical cells in lymphoid follicles and interfollicular areas were positive for CD20, CD10 and BCL2 and negative for cyclin D1. CD21 stain highlighted the follicular dendritic cell meshwork in the germinal centers with a low Ki67 proliferation index. A final diagnosis of low grade follicular lymphoma (grade1-2) coexisting with the prostatic adenocarcinoma was rendered. The patient is currently undergoing lymphoma staging as the treatment for adenocarcinoma is planned. Results (if a Case Study enter NA) NA Conclusion Primary lymphoma of the prostate usually presents with non specific obstructive voiding symptoms and normal or near normal PSA levels which makes it challenging for physicians to suspect lymphomas. The lymphocytic infiltrate, originally thought to be prostatitis, underwent further evaluation with immunohistochemistry due to its monotonous appearance, which clinched the final diagnosis. Careful evaluation of prostate core needle biopsies is necessary even after spotting carcinoma in order to rule out low grade lymphomas.

Appl1, Sortilin and Syndecan-1 immunohistochemistry on intraductal carcinoma of the prostate provides evidence of retrograde spread

The presence of intraductal carcinoma of the prostate (IDCP) correlates with late-stage disease and poor outcomes for patients with prostatic adenocarcinoma, but the accurate and reliable staging of disease severity remains challenging. Immunohistochemistry (IHC) has been utilised to overcome problems in assessing IDCP morphology, but the current markers have only demonstrated limited utility in characterising the complex biology of this lesion. In a retrospective study of a cohort of patients who had been diagnosed with IDCP, we utilised IHC on radical prostatectomy sections with a biomarker panel of Appl1, Sortilin and Syndecan-1, to interpret different architectural patterns and to explore the theory that IDCP occurs from retrograde spread of high-grade invasive prostatic adenocarcinoma. Cribriform IDCP displayed strong Appl1, Sortilin and Syndecan-1 labelling patterns, while solid IDCP architecture had high intensity Appl1 and Syndecan-1 labelling, but minimal Sortilin labelling. Notably, the expression pattern of the biomarker panel in regions of IDCP was similar to that of adjacent invasive prostatic adenocarcinoma, and also comparable to prostate cancer showing perineural and vascular invasion. The Appl1, Sortilin, and Syndecan-1 biomarker panel in IDCP provides evidence for the model of retrograde spread of invasive prostatic carcinoma into ducts/acini, and supports the inclusion of IDCP into the five-tier Gleason grading system.

Utilization of NKX3.1, P501S, Prostate-Specific Antigen, and Steroidogenic Factor 1 to Distinguish Malignant Leydig Cell Tumor From Metastatic Prostatic Adenocarcinoma to the Testis.

A recent study demonstrated that NKX3.1-positive staining can uncommonly be seen in testicular Sertoli cell tumors (1 of 4 cases). Also, it was reported that 2 of 3 Leydig cell tumors of the testis showed diffuse cytoplasmic staining for P501S, although it was unclear whether it was specific granular staining that defines true positivity. However, Sertoli cell tumors do not typically pose a diagnostic dilemma with metastatic prostate carcinoma to the testis. In contrast, malignant Leydig cell tumors, which are exceedingly rare, can closely resemble Gleason score 5 + 5 = 10 prostatic adenocarcinoma metastatic to the testis. To evaluate the expression of prostate markers in malignant Leydig cell tumors and steroidogenic factor 1 (SF-1) in high-grade prostate adenocarcinoma, as no data are currently published on these topics. Fifteen cases of malignant Leydig cell tumor were collected from 2 large genitourinary pathology consult services in the United States from 1991 to 2019. All 15 cases were negative immunohistochemically for NKX3.1, and all 9 with available additional material were negative for prostate-specific antigen and P501S and positive for SF-1. SF-1 was negative immunohistochemically in a tissue microarray with cases of high-grade prostatic adenocarcinoma. The diagnosis of malignant Leydig cell tumor and its distinction from metastatic adenocarcinoma to the testis can be made immunohistochemically on the basis of SF-1 positivity and negativity for NKX3.1.

The Molecular Profile of the Urothelial Carcinoma of the Prostate

A 59-year-old-man presented with haematuria and dysuria. Concerning the pathological diagnostic a common problem was in this case to differentiate between high-grade urothelial carcinoma and high-grade prostate adenocarcinoma. The following immunohistochemical profile was found: keratin 7+, keratin 8/18 +; keratin 20+; AE1/AE3+; Ki 67+; p53+; S100-; chromogranin A-; vimentin -; PSA-. The molecular profile was a key element for establishing a correct therapeutic approach.

High-Grade Desmoplastic Foamy Gland Prostatic Adenocarcinoma.

It is important to recognize high-grade foamy gland prostatic adenocarcinoma with desmoplastic stroma given its aggressive clinical course with frequent metastases and death. To review the morphology, immunohistochemistry, and prognosis for this rare subtype of prostate adenocarcinoma. Twenty-four cases received for consultation from 2010 to 2021 were analyzed including needle biopsy (n = 21), transurethral resection (n = 2), and a cystoprostatectomy (n = 1). Patients ranged in age from 40 to 89 years (mean, 67 years). On average, 8 cores per case were involved (mean 67% core involvement). Extraprostatic extension and seminal vesicle invasion were observed in 6 of 21 (29%) and 3 of 21 (14%) needle biopsy cases, respectively. Twenty of the 24 cases (83%) were Grade Group (GG) 5 with 4 of 24 (17%) being GG4. Tumor necrosis as a component of Gleason pattern 5 was observed in 21 of 24 cases (88%). Associated intraductal adenocarcinoma (IDC) was observed in 22 of 24 cases (92%), with 4 of 24 cases (17%) demonstrating extensive IDC. Diagnostic challenges were as follows: (1) sparse isolated cancer glands embedded in the dense desmoplastic stroma; (2) fragmented glands; and (3) aberrant staining for high-molecular-weight cytokeratin in a nonbasal cell pattern in all cases. PTEN loss was observed in 9 cases, and p53 nuclear accumulation was observed in 8 cases. Three patients were lost to follow-up. Overall, of the 16 patients with meaningful follow-up, 12 (75%) either had metastases or died from prostate cancer. High-grade desmoplastic foamy gland adenocarcinoma is difficult to diagnose and grade and has a poor prognosis.

Diagnostic challenges for the distinction of high-grade prostatic adenocarcinoma and high-grade urothelial carcinoma of simultaneous occurrences - A literature review

Abstract: Two of the most prevalent types of cancer in men are prostate adenocarcinoma and urothelial carcinoma. Both can appear separately in the prostate and bladder, simultaneously as separate tumors affecting either organ or sporadically as a collision tumor. Distinguishing these tumors by the pathologist can be challenging, especially when the high-grade, poorly differentiated forms infiltrate the surrounding organs. The correct approach by the pathologist is important due to the different treatment modalities for these two entities. This review of the literature gives a comprehensive overview, our succinct understanding of the significance of correctly differentiating between these two tumors, the challenges involved in doing so, and the best collection of crucial and useful immunohistochemical markers for better diagnostic performance.The scientific papers used in this review were retrieved from the PubMed and Google Scholar databases. All the studies in this review have recently been peer-reviewed and published in academic journals. The literature was sifted through to find the most relevant and up-to-date information for medical professionals, specifically pathologists. The review concluded that: 1) Prostatic and urothelial markers such as NKX3.1, p63, thrombomodulin, and GATA3 are very useful for distinguishing prostatic adenocarcinoma from urothelial carcinoma. 2) Prostate Specific Antigen (PSA) is a good (clinical) screening tool, but because of its inverse relationship with tumor grade (the higher the grade, the lower the sensitivity of PSA staining), it is not recommended for high-grade tumor differentiation. 3) HMWCK (34βe12) and p63 are said to be more effective than thrombomodulin and S100p in detecting urothelial cancer. 4) Thrombomodulin is only moderately sensitive to urothelial carcinoma. 5) Cytokeratins 7 and 20 can be positive in both urothelial carcinoma and prostatic adenocarcinoma, therefore their use is restricted. The optimal combination of these markers may improve the ability to distinguish these tumors.

Abstract 1728: Single cell RNA-seq analysis reveals a role of pro-inflammatory tumor-associated macrophages in driving prostate cancer progression

Abstract Genomic amplification and increased expression of C-MYC are found in high-grade intraepithelial neoplasm (HGPIN) and primary prostate adenocarcinoma. What role C-MYC plays in the initiation and progression of prostate cancer remains unclear. A genetically engineered mouse model with a high level of human C-MYC protein expression under a probasin promoter (Hi-Myc model) was developed that captures prostate cancer progression from hyperplasia at 6-week-old, to HGPIN at 3-6 month-old, and ultimately to invasive adenocarcinoma at 8-month-old. Applying single-cell RNA sequencing (scRNA-seq) technology, we have carefully studied the temporal transcriptional change in MYC-expressing tumor-initiating cells and the tumor-infiltrating immune cells to understand the cell-intrinsic and -extrinsic mechanisms by which C-MYC promotes the transition from HGPIN to invasive prostate cancer. We have identified a particular type of luminal cells, Prom1+ L1 cells, as the likely tumor initiating cells in the Hi-Myc model. The MYC-expressing L1 tumor initiating cells were more abundant and cycling more often in the invasive cancer at 8-month-old, compared to the pre-invasive stage. Interestingly, significant infiltration of novel M1-like tumor-associated macrophages (TAMs) correlated with the histologic tumor progression from HGPIN to invasive cancer. Targeting TAMs with anti-CSF1R antibody delayed prostate cancer progression and invasion, which appears to be independent of CD8 T-cells. Mechanistically, TAMs expressed a high level of IL-1b, which stimulated Hi-Myc prostate cell proliferation in an organoid co-culture system. More importantly, depleting IL-1b with a neutralizing antibody slowed prostate cancer progression in Hi-Myc mice. Lastly, we found that increased macrophage gene expression was associated with higher Gleason scores and worse disease-free survival in a TCGA clinical patient cohort. In summary, we have identified a molecular mechanism involving pro-inflammatory TAMs and IL-1b in driving early prostate cancer progression in a MYC-driven prostate cancer model, opening a potential therapeutic avenue to target TAMs and pro-inflammatory cytokine in preventing early prostate cancer progression. Citation Format: Jimmy L. Zhao, Joseph Chan, Max Land, Perianne Smith, Anuradha Gopalan, Michael Haffner, Dana Pe'er, Charles Sawyers. Single cell RNA-seq analysis reveals a role of pro-inflammatory tumor-associated macrophages in driving prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1728.

Abstract 2297: Profound anti-tumor efficacy of dual CDK7 and PD1 blockade in novel syngeneic prostate cancer models

Abstract Background: Anti-PD1 immune checkpoint blockade (ICB) has largely failed as a monotherapy for metastatic prostate cancer likely due to inadequate tumor neoantigen load and inadequate T cell filtration (TILs). Strategies to increase TILs that can be tested in novel syngeneic mouse models are needed in order to fulfill this critical medical need. CDK7 is a major regulator of the cell cycle that is under investigation as a novel therapeutic target. CDK7 inhibition can trigger robust anti-tumor immunity by causing genomic instability and DNA damage in lung cancer mouse models. Herein, we characterize our novel syngeneic mouse models and report on the anti-tumor activity of CDK7 alone and in combination with anti-PD1 ICB as an immunotherapeutic strategy. Methods: We generated two models of prostate cancer organoids and syngeneic mouse models. APC and PTEN are tumor suppressor genes commonly lost in metastatic prostate cancer and are emerging as a putative mechanism of resistance to immunotherapy. The MPA and MPP models were established by ex-vivo Lenti-Cas9-sgRNA knock-out of APC or PTEN from the prostate organoids grown in 3D cultures established from the prostate of a MYCT/TP53-/- GEMM. Results: Organoids from the MPA and MPP models form orthotopic high grade prostate adenocarcinoma from 2 to 3 weeks post-implantation and spontaneously develop lung metastases 10-12 weeks after orthotopic implantation. In addition, the MPA model developed immediate castration resistance and neuroendocrine transformation following hormone deprivation in vivo. By contrast, the MPP tumors significantly regressed after in vivo androgen deprivation. Baseline immunoprofiling of the MPA and MPP orthotopic tumors showed increased infiltration from monocytic MDSCs and expression of T cell exhaustion markers. Treatment of the MPA and MPP orthotopic models with YKL-5-124, a CDK7 inhibitor, led to substantial in vivo tumor growth inhibition, which was further augmented by the addition of anti-PD-1 ICB. Immunoprofiling of tumors treated with combined YKL-5-124 and PD-1 blockade showed activation of CD4+ and CD8+ T cells, and a decrease in the Treg, B cell and NK cell population. Conclusions: The MPA and MPP orthotopic models recapitulate the biology and immune suppressive microenvironment of advanced prostate cancer and provide useful tools for immunotherapy drug development. Combination of CDK7 inhibition with anti-PD-1 blockade profoundly inhibited in vivo orthotopic tumor growth in both MPA and MPP model, providing a rationale for exploring CDK7 in combination with PD-1 checkpoint immunotherapy as a novel therapeutical strategy for advanced prostate cancer. Funding Acknowledgements: DRW is funded through 2018YI2295 Prostate Cancer Foundation Young Investigator Award and PC160944 Department of Defense Physician Research Career Development Award. Citation Format: David Wise, Luiza Doro Pereira, Jiansheng Wu, Victor R. Adorno Febles, Jonathan Melamed, Fang-Ming Deng, Hua Zhang, Kwok-Kin Wong. Profound anti-tumor efficacy of dual CDK7 and PD1 blockade in novel syngeneic prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2297.

Prognostic significance of percentage Gleason grade 5 prostatic adenocarcinoma in needle biopsies from patients treated by radical prostatectomy

Previous studies have shown that the percentage of high grade prostatic adenocarcinoma (Gleason patterns 4 and 5) in a biopsy correlates with outcome parameters. It has also been shown that the percentage Gleason pattern 4/5 tumour correlates with biochemical failure and overall survival. There are little data relating to the prognostic significance of quantifying the percentage of Gleason pattern 5 in isolation. We investigated the prognostic predictive value of quantifying the percentage of Gleason pattern 5 tumour in needle biopsies from a series of 196 cases of Gleason score 4+5=9 prostate adenocarcinoma from patients who had also undergone radical prostatectomy. Division of cases according to the percentage of Gleason pattern 5 present (based upon the core with the highest grade) and analysing these with tumour grouped as Gleason score 4+5 with <5% pattern 5 (GS 4+5 <5%), Gleason score 4+5 with 5-20% pattern 5 (GS 4+5 5-20%) and Gleason score 4+5 with 21-49% pattern 5 (GS 4+5 21-49%) showed no difference in outcome determined as time interval to prostate specific antigen biochemical failure. The results showed that each of the subgroups of GS 4+5 tumours had a significantly shorter biochemical recurrence-free survival than for a control group of 179 patients with Gleason score 4+3=7 (GS 4+3) cancer. Similar results were obtained when grading was based upon percentage of Gleason pattern 5 present in all the cores taken from the same patient (case-based grade). Adverse findings at radical prostatectomy showed each of the subgroups of GS 4+5 tumours to have a higher incidence of extraprostatic extension and seminal vesicle invasion than the GS 4+3 group of controls. Further, the differences in incidence between each of the subgroups were not significant for either extraprostatic extension or seminal vesicle invasion. These observations applied to both the highest core-based grade and the case-based grade. Our study has shown that any proportion of Gleason pattern 5 tumour in a needle biopsy is associated with a worse prognosis when compared to GS4+3 tumours and that these results are similar for grading that is core- or case-based.

Histopathological and genetic features of mismatch repair-deficient high-grade prostate cancer.

Mismatch repair (MMR) deficiency is commonly caused by functional inactivation of MLH1, PMS2, MSH2 or MSH6. The morphological and molecular correlates of MMR deficiency have been extensively characterized in certain tumour types such as colorectal and endometrial adenocarcinoma. In contrast, the histological and molecular features of MMR-deficient prostate cancer remain incompletely described. In this study, we evaluated 19 MMR-deficient prostate cancers, including 11 cases without prior systemic treatment. All treatment-naive cases (11 of 11, 100%) were grade group 4-5 and had predominant cribriform and/or solid growth patterns. Solid components (any amount) and tumour infiltrating lymphocytes were 7 cases each (7 of 11, 64%). In 68 MMR-proficient grade group 5 prostate cancers, predominant cribriform or solid growth patterns, solid components (any amount) and tumour infiltrating lymphocytes were seen at significantly lower frequencies (31 of 68, 46%; 9 of 68, 13% and 6 of 62, 9%, respectively; P < 0.001 for all comparisons). Molecular evaluation of 19 cases demonstrated that MMR-deficiency was secondary to functional loss of MSH2/MSH6 and MLH1/PMS2 in 15 (79%) and 4 cases (21%), respectively. Definite or probable germline mutations were present in 4 cases (4 of 19, 21%). TMPRSS2::ERG rearrangements were identified in 2 cases (2 of 19, 11%). Recurrent cancer-relevant somatic mutations included (but were not limited to) ATM, TP53, FOXA1, RB1, BRCA2 and PTEN. MMR deficiency was most commonly secondary to inactivation of MSH2/MSH6 in this study. Importantly, MMR-deficient high-grade prostatic adenocarcinomas had morphological features that might be useful to identify selected cases for MMR immunohistochemistry.

Diagnosis and Management of Primary Prostatic Signet Ring Cell Carcinoma: Single-Center Experience.

The purpose of the study was to retrospectively summarize the diagnosis and management of 10 primary prostatic signet ring cell carcinoma (PPSRCC) cases in our center. Ten PPSRCC patients diagnosed at the First Affiliated Hospital of Nanjing Medical University from November 2014 to December 2020 were included. Clinical characteristics, image features, therapeutic procedures, histological diagnosis, and outcomes were retrospectively analyzed. All patients received prostate-specific antigen (PSA) examination preoperatively. Nine of them accepted multiparametric magnetic resonance imaging (mpMRI) due to elevated PSA value, and further biopsied. Among them, five patients were diagnosed as prostatic adenocarcinoma and the other four cases were found a mixture of signet ring cell carcinoma (SRCC) and adenocarcinoma. Furthermore, gastrointestinal endoscope and abdominal computed tomography (CT) did not find SRCC originating in gastrointestinal tract. Therefore, these cases were considered to be PPSRCC. Nine patients accepted laparoscopic or robot-assisted RP. Only one patient with normal PSA adopted transurethral resection of the prostate. Postoperative pathological results confirmed SRCC mixed with prostatic adenocarcinoma in nine cases, and only one patient with pure SRCC. After surgery, nine patients received adjuvant hormone therapy, one of which accepted radiotherapy simultaneously. The patient with pure SRCC did not accept any adjuvant therapy postoperatively. During a mean follow-up of 31.9 months, only four patients were alive without disease progression. In summary, PPSRCC is a rare malignant tumor with few specific symptoms, rapid disease progression, and poor prognosis and is frequently accompanied by high-grade prostate adenocarcinoma patterns. There is still no clear and effective strategy to improve the prognosis.

LIM domain kinase 1

Background Despite recent advancement, prostate cancer (PC) remains to represent a leading cause of cancer mortality and morbidity in men. Diagnosis of PC faces many challenges, especially on core biopsies. Multiple signaling pathways have been involved in PC progression. However, castration resistance eventually develops, especially in metastatic PC. Identifying a marker that helps in distinguishing invasive tumor from benign and precursor lesions, as well as predicts its metastatic and prognostic potentials, is needed. LIM-domain kinase 1 (LIMK1) is a newly identified marker that affects the cytoskeleton of cancer cells. Its role in PC is still not well understood. This study aimed at evaluating LIMK1 expression in benign prostatic hyperplasia (30 cases), high-grade prostatic intraepithelial neoplasia (27 cases), and PC prostatic adenocarcinoma (60 cases) and its association with the prognostic clinicopathological parameters in PC. Results No strong expression was detected in benign prostatic hyperplasia expression compared with 25.9% and 48.3% in high-grade prostatic intraepithelial neoplasia and prostatic adenocarcinoma (Pca) groups. The expression was statistically higher in the Pca group than the other groups. There was significant association with poor prognostic parameters in Pca groups, including higher prostate-specific antigen levels, tumor percentage, Gleason scores, grade groups, T stage, positive lymph-node metastases, extracapsular extension, seminal vesicle invasion, distant metastasis, and prognostic-stage group. Conclusion LIMK1 is considered a promising diagnostic and prognostic marker in Pca.

Comment on: The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

Comment on: The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

Intraductal Carcinoma of the Prostate: Extreme Nuclear Size Is Not a Diagnostic Parameter.

High-grade prostatic adenocarcinoma involving duct/acinar structures is labeled intraductal carcinoma of the prostate (IDCP). As numerous studies have shown that IDCP is associated with high stage disease with a significant negative impact on cancer-specific survival, accurate diagnosis is crucial to ensure appropriate patient management. The definition of IDCP recommended by 2016 World Health Organization (WHO) classification suggests that cases of IDCP with micropapillary or loose cribriform architecture without comedonecrosis should have cells with ≥6× nuclear enlargement. It is unclear how this size criterion was derived and which of the parameters of nuclear size (nuclear diameter, nuclear surface area, or nuclear perimeter) it relates to. To evaluate the extent of nuclear enlargement in IDCP, we performed morphometric analyses relating to each of these parameters in 100 radical prostatectomy specimens. One hundred nuclei from foci of IDCP and 50 nuclei from foci of normal luminal epithelium were examined for each patient. Diagnosis of IDCP was based on cells with definite features of carcinoma present within duct/acinar structures. Comparing the means of each of the parameters between IDCP cells and benign luminal cells, there was a statistically significant enlargement in nuclear perimeter (P<0.0005), nuclear area (P<0.0005), and nuclear diameter (P<0.0005); however, the difference in mean nuclear size was limited to factors of 1.3×, 1.6×, and 1.3×, respectively. Three patients each had rare large nuclei (largest perimeter 45, 45, and 44 μm; maximum nuclear area 135, 136, and 136 μm2; and the largest diameter 18 µm in each). For these rare cells, the nuclear size difference, when compared with benign nuclei was; nuclear perimeter 2.0×, 2.1×, and 2.1×; nuclear area 3.6×, 3.8×, and 3.8×; and nuclear maximum diameter 3.0×, 2.5×, and 2.5×. The definition of nuclear enlargement of ≥6× was not reached in any of our cases, all of which clearly showed features of duct invasive carcinoma. In these cases, reliance on nuclear size criteria would have resulted in underdiagnosis of IDCP. This is of concern as failure to recognize IDCP, particularly in needle biopsies, could lead to delays in the timely treatment of aggressive high-grade prostate cancer, resulting in cancer progression and suboptimal patient oncological outcomes.

Extent of High-Grade Prostatic Adenocarcinoma in Multiparametric Magnetic Resonance Imaging-Targeted Biopsy Enhances Prediction of Pathologic Stage.

Multiparametric magnetic resonance imaging (mpMRI) of prostate with targeted biopsy has enhanced detection of high-grade prostatic adenocarcinoma (HG PCa). However, utility of amount of HG PCa (Gleason pattern 4/5) in mpMRI-targeted biopsies versus standard 12-core biopsies in predicting adverse outcomes on radical prostatectomy (RP) is unknown. To examine the utility of amount of HG PCa in mpMRI-targeted biopsies versus standard 12-core biopsies in predicting adverse RP outcomes. We performed a retrospective review of prostate biopsies that had corresponding RP, 1 or more mpMRI-targeted biopsy, and Grade Group 2 disease or higher. For the 169 cases identified, total millimeters of carcinoma and HG PCa and longest length HG PCa in a single core were recorded for 12-core biopsies and each set of mpMRI-targeted biopsies. For RP specimens, Gleason grade, extraprostatic extension, seminal vesicle involvement, and lymph node metastasis were recorded. The main outcome studied was prostate-confined disease at RP. A logistic regression model was used to test which pre-RP variables related to this outcome. Univariate analysis showed significant associations with adverse RP outcomes in 5 of 8 quantifiable variables; longest millimeter HG PCa in a single 12-core biopsy, highest Grade Group in any core, and total millimeter HG in mpMRI-targeted biopsies showed no statistical association (P = .54, P = .13, and P = .55, respectively). In multivariate analysis, total millimeter carcinoma in all cores, highest Grade Group in any core, and longest millimeter HG PCa in a single mpMRI-targeted core provided additional predictive value (P < .001, P = .004, and P = .03, respectively). Quantitation of HG PCa in mpMRI-targeted biopsies provides additional value over 12-core biopsies alone in predicting nonorgan confined prostate cancer at RP. Linear millimeters of HG PCa in mpMRI-targeted biopsies is a significant parameter associated with higher pathologic stage and could be of value in risk models.

Comparison of Immunohistochemistry Expression of CK7, HMWK and PSA in High-Grade Prostatic Adenocarcinoma and Bladder Transitional Cell Carcinoma.

Background & Objective:Prostate adenocarcinoma is the most common malignancy in males, and the urothelial bladder carcinoma is also prevalent. The histological characteristic of these two tumors is very similar in high-grade cases, and their differentiation is difficult. This study was performed to compare the immunohistochemistry panel of high-grade prostate adenocarcinomas and high-grade urothelial bladder carcinomas.Methods:In this cross-sectional study, 36 cases of prostate adenocarcinoma and 36 urothelial bladder carcinoma samples were collected from the pathology department of Shahid Beheshti Hospital in Hamedan. For each sample, expression of Cytokeratin 7, high-molecular-weight cytokeratin and Prostate-specific antigen markers was evaluated by immunohistochemistry. Comparison of expression of these markers in high-grade bladder tumors and prostate tumors was made by SPSS 25 using Chi-square test.Results:In this study, the Cytokeratin 7 positivity was seen in 88.9% of bladder cancer versus 27.8% of prostate cancer samples. High-molecular-weight cytokeratin positive immunoreactivity was noted in 55.6% of bladder cancer and 5.6% of prostate cancer samples. Prostate-specific antigen marker showed positive results in 94.4% of prostate cancer samples, but no positivity was evident in those of bladder cancer.Conclusion:A panel of immunohistochemical stains can be used to differentiate high-grade prostate adenocarcinoma from urothelial bladder carcinoma in those cases which are challenging to diagnose.

Kava root extracts hinder prostate cancer development and tumorigenesis by involvement of dual inhibition of MAO-A and LSD1.

Aim:Here, we aim to evaluate the chemopreventive efficacy of kava root extracts (KRE) in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and investigate potential molecular targets of kavalactones, the main components of kava.Methods:TRAMP mice were administrated with KRE formulated food for different periods of time, and then the incidences of high-grade prostatic intraepithelial neoplasia (HG-PIN) and adenocarcinomas and tumor burdens were compared between vehicle control and KRE food fed groups. In addition, the inhibitory effect of the KRE and kavalactones on monoamine oxidase A (MAO-A) and lysine-specific demethylase 1 (LSD1) enzyme activities were examined by commercially available inhibitor screening kits. Histone H3 lysine 9 dimethylation was also evaluated in prostate cancer cells and tumor tissues using Western blotting analysis.Results:Dietary feeding of 0.3% and 0.6% KRE to TRAMP mice from ages of 6 weeks to 12 weeks inhibited HG-PIN by 43.5% and 59.7%, respectively, and prostate adenocarcinoma by 53.5% and 66.4%, respectively. In addition, 0.6% KRE fed TRAMP mice from ages of 6 weeks to 24 weeks exhibited a significant reduction of genitourinary weight (a surrogate of tumor burden) by 54.5% and reduced body weight gain. Furthermore, the KRE and kavalactones showed a significant inhibition of LSD1 and MAO-A enzyme activities.Conclusion:Our results suggest that consumption of kava products through diet can delay prostate cancer development and progression and that kavalactones may be a new structure model for developing a potent dual inhibitor of LSD1 and MAO-A.

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies

Ductal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC). To assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC. A single-center retrospective review of all patients with cT1-4/N0-1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients. Metastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models. A total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation. Men undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed. This study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.

Clinicopathologic Study of Gleason Pattern 5 Prostatic Adenocarcinoma With "Single-cell" Growth Reveals 2 Distinct Types, One With "Plasmacytoid" Features.

Each Gleason score category of prostatic adenocarcinoma (or Grade Group) may encompass a diverse group of architectural patterns such as well-formed glands, poorly formed glands, cribriform structures, single cells, and/or solid sheets. We have noted heterogeneity within the single-cell subtype of Gleason pattern 5 prostatic adenocarcinoma that has not been fully addressed. Therefore, we retrospectively reviewed a series of radical prostatectomies with high-grade prostatic adenocarcinoma (Grade Group 4 or 5), identifying tumors with a component of single-cell infiltration. Additional cases identified prospectively were also included. TNM status, association with other histologic patterns, and clinical follow-up status were determined. Immunohistochemistry for NKX3.1, E-cadherin, p120 catenin, and prostate-specific antigen (PSA) were performed in each case. Eighteen cases with a component of well-developed Gleason pattern 5 characterized by single infiltrative cells that comprised ≥5% of the tumor were identified (15/202 retrospective radical prostatectomies with the high-grade disease [7.5%]). The single-cell pattern ranged from 5% to 50% of the tumor volume, with 5 cases containing ≥40%, and variable secondary architecture included diffuse infiltrating single cells with targetoid growth pattern around benign glands, solid expansive nests of noncohesive cells, and corded/single file growth pattern. Further morphologic analysis demonstrated 2 distinct histologic subtypes: (1) (subtype 1; n=9) monomorphic "plasmacytoid" tumor cells with eccentrically placed nuclei and variable intracytoplasmic vacuoles with bland cytology and discohesion and (2) (subtype 2; n=9) more cohesive tumor cells with greater cytologic atypia characterized by prominent nucleoli, greater variability in nuclear size/shape, occasional mitotic figures, and more irregular infiltration. By immunohistochemistry, NKX3.1 nuclear expression and PSA cytoplasmic expression was retained in all cases. Concomitant membranous E-cadherin loss and strong cytoplasmic p120 catenin expression were present in 5 of the 18 (28%) cases, all in subtype 1 (5/9, 56%). Overall, 56% (10/18) of patients had advanced-stage disease (≥pT3b), and 70% (7/10) of these patients had associated lymphovascular invasion. All patients had concomitant cribriform patterns of carcinoma. The outcome was available for 14 patients: 4 died of unknown cause; 6 had biochemical recurrence with distant bone metastasis in 5 of the 6; and 4 patients with <3 years of follow-up currently have undetectable serum PSA levels (2 patients received salvage radiotherapy with androgen deprivation and 2 remain on routine follow-up). In summary, the single-cell pattern of Gleason pattern 5 prostatic adenocarcinoma is uniformly associated with other high-risk histologic patterns (eg, cribriform growth), and high-stage disease with distant metastasis is not uncommon. Our data suggest that the "single-cell" Gleason pattern 5 prostatic adenocarcinoma contains 2 distinct subtypes. Somatic CDH1 alterations may play a role in the development of the "plasmacytoid" pattern characterized by monomorphic cytology with concomitant E-cadherin loss and aberrant p120 catenin expression.