Grade groups (GGs) are an important parameter for therapeutic decision making in prostate cancer (Pca) patients. Invasive cribriform and/or intraductal carcinoma (CR/IDC) has an independent ...prognostic value for disease outcome, but are not included in the GG limiting their clinical use.
To perform a proof-of-principle study incorporating CR/IDC in the current GG.
All prostate biopsies of 1031 men with screen-detected Pca between 1993 and 2000 were reviewed for the current GG (ranging from 1 to 5) and CR/IDC. The cribriform grade (cGrade) was equal to the GG if CR/IDC was present and GG minus 1 if not. GG1 was cGrade1 if intraductal carcinoma was absent.
Biopsy review for GG and CR/IDC. A total of 406 patients had received radical prostatectomy (RP), 508 radiotherapy (RT), 108 surveillance, and eight hormonal therapy, and the treatment was unknown for one patient.
Outcome measurements and statistical analysis disease-specific survival (DSS), metastasis-free survival (MFS), and biochemical recurrence–free survival (BCRFS) after 15.1 yr (interquartile range 10.9–19.7 yr) follow-up were compared using Harrell’s C-statistic.
The biopsy GGs were 486 GG1, 310 GG2, 104 GG3, 64 GG4, and 67 GG5; cGrade distributions were 738 cGrade1, 102 cGrade2, 91 cGrade3, 58 cGrade4, and 42 cGrade5. The cGrade had a better discriminative value than the GG for DSS (C-index 0.79; 95% confidence interval 0.74–0.83 vs 0.76; 0.71–0.82) and MFS (0.79; 0.74–0.84 vs 0.77; 0.72–0.82). The discriminative value for BCRFS after RP and RT was similar for both models. Different diagnostic, such as use of sextant biopsies, and therapeutic strategies in the 1990s are the limitations of this study.
The cGrade is a simple Pca grade modification with better discriminative values for DSS and MFS than the GG, particularly impacting decision making in men with current GG2 Pca.
Microscopic grading is an important factor for decision making in prostate cancer (Pca) patients. We show that a simple grade modification better predicts Pca outcome and might improve treatment choices.
Pathological grading is an important parameter for decision making in prostate cancer patients. We show that a simple modification of the current International Society of Urologic Pathology/World Health Organization grade groups incorporating cribriform architecture results in a significantly better discriminative value for disease-specific and metastasis-free survival.
Molecular classification of ERG‐rearranged prostate cancer clarifies the role of TMPRSS2‐ERG in the development and progression of prostate cancer. The objective of our study was to identify direct ...ERG target genes in ERG‐rearranged prostate cancer. Two independent cohorts of primary prostate cancer (Cohort A, n=48; Cohort B, n=31), a cohort of late‐stage prostate cancer (n=51) and expression array data of a cohort of primary prostate tumors from a different institute (n=128) were analyzed for expression of genes that were coexpressed with ERG overexpression. By genome‐wide expression analysis and Q‐RT‐PCR it was shown that the gene Tudor domain containing 1 (TDRD1) was by far the strongest correlated gene with ERG overexpression in both Cohort A and B. Expression array analysis of the patient cohort from a different institute showed a large overlap in genes that were positively correlated with ERG overexpression, including TDRD1. In late‐stage prostate cancer, TDRD1 was also coexpressed with ERG overexpression, although a proportion of ERG‐negative late‐stage samples expressed TDRD1. TDRD1 expression was not associated with ETV1 overexpression. In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter. By mutation analysis we identified a functional ERG binding site in the TDRD1 promoter. Our findings show TDRD1 as the first identified upregulated direct ERG target gene that is strongly associated with ERG overexpression in primary prostate cancer.
What's new?
Fusion between ERG and the androgen‐regulated, prostate‐specific gene transmembrane protease, serine 2 (TMPRSS2) is the most frequently occurring genomic rearrangement in prostate cancer. To better understand the significance of ERG specifically, ERG‐rearranged prostate cancers were analyzed here in an attempt to identify ERG target genes. The analysis reveals a strong association between Tudor domain containing 1 (TDRD1) expression and ERG overexpression in primary prostate tumors and provides evidence that TDRD1 is a direct ERG target gene. This new knowledge sheds much‐needed light on the molecular pathways underlying ERG‐positive tumor development.
Abstract Background The European Organization for Research and Treatment of Cancer (EORTC) risk scores are not validated in an independent patient population. Molecular grade (mG) based on fibroblast ...growth factor receptor 3 ( FGFR3 ) gene mutation status and MIB-1 expression was proposed as an alternative to pathologic grade in bladder cancer (BCa) 1. Objective To validate the EORTC risk score and to determine its relation to mG in a series with long-term follow-up as well as to determine reproducibility of pathologic grade and mG. Design, setting, and participants In this multicenter study, we included 230 patients with primary non–muscle-invasive BCa (NMIBC). Measurements Four uropathologists reviewed the slides. FGFR3 mutation status was examined by two assays. MIB-1 was assessed by immunohistochemistry. The EORTC risk scores for recurrence and progression were determined. Multivariable analyses were used to find prognostic factors. Results and limitations Median follow-up was 8.62 yr (interquartile range: 6.6–11.8). FGFR3 mutations were significantly related to favorable disease parameters, whereas altered MIB-1 was frequently seen with pT1, high grade, and high EORTC risk scores. EORTC risk scores were significant in multivariable analyses for recurrence and progression. In multivariable analyses for progression and disease-specific survival, the mG had independent significance. The addition of mG to the multivariable model for progression increased the predictive accuracy from 74.9% to 81.7% ( p < 0.001; Mantel-Haenszel test). The mG (89%) was more reproducible than the pathologic grade (41–74%). Conclusions We validated the EORTC risk scores for primary NMIBC in a clinical and biomarker setting. Next to EORTC risk score, mG proved highly reproducible and predictive. Our long-term results justify an independent prospective analysis of mG and EORTC risk scores.
Objectives
To investigate the impact of intra‐operative neurovascular structure‐adjacent frozen‐section examination (NeuroSAFE) on the rate of nerve‐sparing surgery (NSS) and oncological outcome in a ...large radical prostatectomy (RP) cohort.
Patients and methods
Between January 2016 and December 2020, 1756 prostate cancer patients underwent robot‐assisted RP, of whom 959 (55%) underwent this with NeuroSAFE and 797 (45%) without (control cohort). In cases where NeuroSAFE showed tumour in the margin, a secondary resection was performed. The effect of NeuroSAFE on NSS and positive surgical margin (PSM) status was analysed using logistic regression. Cox regression was used to identify predictors of biochemical recurrence‐free survival (BCRFS).
Results and limitations
Patients in the NeuroSAFE cohort had a higher tumour grade (P < 0.001) and clinical stage (P < 0.001) than those in the control cohort. NeuroSAFE enabled more frequent NSS for both pT2 (93% vs 76%; P < 0.001) and pT3 disease (83% vs 55%; P < 0.001). In adjusted analysis, NeuroSAFE resulted in more frequent unilateral (odds ratio OR 3.90, 95% confidence interval (CI) 2.90–5.30; P < 0.001) and bilateral (OR 5.22, 95% CI 3.90–6.98; P < 0.001) NSS. While the PSM rate decreased from 51% to 42% in patients with pT3 stage disease (P = 0.031), NeuroSAFE was not an independent predictor of PSM status (OR 0.85, 95% CI 0.68–1.06; P = 0.2) in the entire cohort. Patients who underwent NeuroSAFE had better BCRFS compared to the control cohort (hazard ratio 0.62, 95% CI 0.45–0.84; P = 0.002). This study is limited by its comparison with a historical cohort and lack of functional outcomes.
Conclusions
NeuroSAFE enables more unilateral and bilateral NSS without negatively affecting surgical margin status and biochemical recurrence. This validation study provides a comprehensive overview of the implementation, evaluation and intra‐operative decision making associated with NeuroSAFE in clinical practice.
Objective
To evaluate the feasibility of confocal laser microscopy (CLM) for intraoperative margin assessment as faster alternative to neurovascular structure‐adjacent frozen‐section examination ...(NeuroSAFE) during robot‐assisted radical prostatectomy (RARP).
Patients and Methods
Surgical margins were assessed during 50 RARP procedures in patients scheduled for NeuroSAFE. Posterolateral sections were cut and imaged with CLM and further processed to conform with the NeuroSAFE protocol. Secondary resection (SR) was performed in case a positive surgical margin (PSM) was observed with NeuroSAFE. Afterwards, the CLM images were non‐blinded assessed for the presence of PSMs. The accuracy of both NeuroSAFE and CLM was compared with conventional histopathology. Agreement for detection of PSMs between NeuroSAFE and CLM was evaluated with Cohen's kappa coefficient. Procedure times were compared with a Wilcoxon signed‐ranks test.
Results
In total, 96 posterolateral sections of RP specimens were evaluated for the presence of PSMs. CLM identified 15 (16%) PSMs and NeuroSAFE identified 14 (15%) PSMs. CLM had a calculated sensitivity, specificity, positive predictive value and negative predictive value of 86%, 96%, 80% and 98% respectively for the detection of PSMs compared to definite pathology. After SR, residual tumour was found in six of 13 cases (46%), which were all identified by both techniques. There was a substantial level of agreement between CLM and NeuroSAFE (κ = 0.80). The median procedure time for CLM was significantly shorter compared to NeuroSAFE (8 vs 50 min, P < 0.001). The main limitation of this study was the non‐blinded assessment of the CLM images.
Conclusions
Compared to NeuroSAFE, CLM is a promising technique for intraoperative margin assessment and is able to reduce the time of intraoperative margin assessment.
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.
Postoperative biochemical recurrence occurs in up to 40% of prostate carcinoma patients treated with radical prostatectomy. Primary tumor grade and cribriform architecture are important parameters ...for clinical outcome; however, their relevance at positive surgical margins has not been completely elucidated yet. We reviewed 835 radical prostatectomy specimens and recorded pT-stage, surgical margin status, Grade Group, and cribriform architecture of the primary tumor and at positive surgical margins. Clinicopathologic parameters and biochemical recurrence-free survival (BCRFS) were used as endpoints. Positive surgical margins were present in 284 (34%) patients, with a median cumulative length of 5.0 mm. In 46%, the Grade Group at the margin was equal to the primary tumor grade, while being lower in 42% and higher in 12%. In multivariable analysis, Grade Group at the margin outperformed the Grade Group of the primary tumor in predicting BCRFS. Among primary Grade Group 2 patients, 56% had Grade Group 1 disease at the margin. Multivariable analysis identified cumulative length, Grade Group at the margin, and lymph node metastasis as independent predictors for BCRFS, while percentage Gleason pattern 4, tertiary Gleason pattern 5 of the primary tumor, and cribriform architecture at the margin were not. In conclusion, the Grade Group at the positive surgical margin was dissimilar to the primary tumor grade in 54% and better predicted BCRFS than the primary tumor grade. Cumulative length and tumor grade at the margin were independent predictors for BCRFS, whereas cribriform architecture at the margin was not.
Cancer invasion and metastasis are driven by epithelial-mesenchymal transition (EMT), yet the exact mechanisms that account for EMT in clinical prostate cancer are not fully understood. Expression of ...N-cadherin is considered a hallmark of EMT in clinical prostate cancer. In this study, we determined the molecular mechanisms associated with N-cadherin expression in patients with prostate cancer. We performed laser capture microdissection of matched N-cadherin-positive and -negative prostate cancer areas from patient samples (
= 8), followed by RNA sequencing. N-cadherin expression was significantly associated with an immune-regulatory signature including profound upregulation of indoleamine 2,3-dioxygenase (IDO1; log
-fold change = 5.1;
= 2.98E-04). Fluorescent immunostainings of patient samples confirmed expression of IDO1 protein and also its metabolite kynurenine in primarily N-cadherin-positive areas. N-cadherin-positive areas also exhibited a local decrease of intraepithelial cytotoxic (CD8
) T cells and an increase of immunosuppressive regulatory T cells (CD4
/FOXP3
). In conclusion, EMT in clinical prostate cancer is accompanied by upregulated expression of IDO1 and an increased number of regulatory T cells. These data indicate that EMT, which is an important step in tumor progression, can be protected from effective immune control in patients with prostate cancer.
These findings demonstrate EMT is linked to an immunosuppressive environment in clinical prostate cancer, suggesting that patients with prostate cancer can potentially benefit from combinatorial drug therapy.
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Myoid gonadal stromal tumours (MGST) represent a rare type of testicular sex cord‐stromal tumour that has recently been recognised as a distinct entity by the World Health Organization (WHO) ...classification of genitourinary tumours. MGSTs affect adult men and have been reported to behave in an indolent fashion. Histologically, MGSTs are pure spindle cell neoplasms that coexpress SMA and S100 protein. Given that the molecular features of these neoplasms remain largely undescribed, we evaluated a multi‐institutional series of MGSTs using DNA and RNA sequencing. This study included 12 tumours from 12 patients aged 28 to 57 years. Tumour sizes ranged from 0.6 to 4.3 cm. Aggressive histologic features, such as vascular invasion, necrosis, invasive growth, and atypical mitoses were invariably absent. Mitotic activity was low, with a median of less than 1 mitosis per 10 high power fields (HPF; maximum: 3 mitoses per 10 HPF). Molecular analyses did not identify recurrent mutations or gene fusions. All cases with interpretable copy number variant data (9/10 cases sequenced successfully) demonstrated a consistent pattern of chromosome arm‐level and whole‐chromosome‐level copy number gains indicative of ploidy shifts, with recurrent gains involving chromosomes 3, 6, 7, 8, 9, 11, 12, 14q, 15q, 17, 18q, 20, and 21q. Similar findings have also been recognised in pure spindle cell and spindle‐cell predominant sex cord‐stromal tumours without S100 protein expression. MGSTs are characterised by ploidy shifts and may be part of a larger spectrum of spindle cell‐predominant sex cord‐stromal tumours, including cases without S100 protein expression.
Myoid gonadal stromal tumor represents a recently recognized entity that comprises testicular sex cord stromal tumors with pure spindle cell morphology and co‐expression of SMA and S100 protein. Molecular analyses of a multi‐institutional series assessed in this study reveals that myoid gonadal stromal tumors are characterized by absence of recurrent somatic mutations and a recurrent pattern of chromosome‐level and chromosome arm‐level copy number gains.
Abstract
Objectives
To determine the potential impact of the presence of secondary variant histology on the gene expression profiles of muscle-invasive bladder cancer (MIBC) tumors.
Methods
For six ...tumors, revised samples were collected from urothelial and secondary variant components (cohort A). The commercial cohort (cohort B) consisted of the anonymized gene expression profiles of 173 patients with MIBC. Samples were obtained from the clinical use of the Decipher Bladder test that were available as part of the Decipher GRID prospective registry (NCT02609269). Secondary variant presence in cohort B was abstracted from institutional pathology reports. For the commercial cohort, only the urothelial carcinoma component was profiled.
Results
Molecular subtyping of both urothelial and variant components found micropapillary and nested cases were classified as a luminal subtype. Conversely, the sarcomatoid and small cell cases were classified as basal/squamous or neuroendocrine-like, respectively. For cohort B, 50 (29%) of 173 cases had reported secondary variant histology. Cases with squamous variant had basal profiles, small cell cases expressed neuronal markers, and micropapillary cases were classified as luminal. Sarcomatoid tumors had robust epithelial-mesenchymal transition marker expression.
Conclusions
Our data suggest that in MIBC with secondary variant, the urothelial component can demonstrate an expression profile that closely resembles the variant component.
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