The association of quantitative PSMA PET parameters with pathologic ISUP grade: an international multicenter analysis.

PURPOSE: To assess if PSMA PET quantitative parameters are associated with pathologic ISUP grade group (GG) and upgrading/downgrading. METHODS: PCa patients undergoing radical prostatectomy with or without pelvic lymph node dissection staged with preoperative PSMA PET at seven referral centres worldwide were evaluated. PSMA PET parameters which included SUVmax, PSMAvolume, and total PSMA accumulation (PSMAtotal) were collected. Multivariable logistic regression evaluated the association between PSMA PET quantified parameters and surgical ISUP GG. Decision-tree analysis was performed to identify discriminative thresholds for all three parameters related to the five ISUP GGs The ROC-derived AUC was used to determine whether the inclusion of PSMA quantified parameters improved the ability of multivariable models to predict ISUP GG ≥ 4. RESULTS: A total of 605 patients were included. Overall, 2%, 37%, 37%, 10% and 13% patients had pathologic ISUP GG1, 2, 3, 4, and 5, respectively. At multivariable analyses, all three parameters SUVmax, PSMAvolume and PSMAtotal were associated with GG ≥ 4 at surgical pathology after accounting for PSA and clinical T stage based on DRE, hospital and radioligand (all p < 0.05). Addition of all three parameters significantly improved the discrimination of clinical models in predicting GG ≥ 4 from 68% (95%CI 63 - 74) to 74% (95%CI 69 - 79) for SUVmax, 72% (95%CI 67 - 76) for PSMAvolume, 74% (70 - 79) for PSMAtotal and 75% (95%CI 71 - 80) when all parameters were included (all p < 0.05). Decision-tree analysis resulted in thresholds that discriminate between GG (SUVmax 0-6.5, 6.5-15, 15-28, > 28, PSMAvol 0-2, 2-9, 9-20 and > 20 and PSMAtotal 0-12, 12-98 and > 98). PSMAvolume was significantly associated with GG upgrading (OR 1.03 95%CI 1.01 - 1.05). In patients with biopsy GG1-3, PSMAvolume ≥ 2 was significantly associated with higher odds for upgrading to ISUP GG ≥ 4, compared to PSMAvolume < 2 (OR 6.36, 95%CI 1.47 - 27.6). CONCLUSION: Quantitative PSMA PET parameters are associated with surgical ISUP GG and upgrading. We propose clinically relevant thresholds of these parameters which can improve in PCa risk stratification in daily clinical practice.

Multi-sequence MRI-based radiomics model to preoperatively predict the WHO/ISUP grade of clear Cell Renal Cell Carcinoma: a two-center study.

OBJECTIVES: To develop radiomics models based on multi-sequence MRI from two centers for the preoperative prediction of the WHO/ISUP grade of Clear Cell Renal Cell Carcinoma (ccRCC). METHODS: This retrospective study included 334 ccRCC patients from two centers. Significant clinical factors were identified through univariate and multivariate analyses. MRI sequences included Dynamic contrast-enhanced MRI, axial fat-suppressed T2-weighted imaging, diffusion-weighted imaging, and in-phase/out-of-phase images. Feature selection methods and logistic regression (LR) were used to construct clinical and radiomics models, and a combined model was developed using the Rad-score and significant clinical factors. Additionally, seven classifiers were used to construct the combined model and different folds LR was used to construct the combined model to evaluate its performance. Models were evaluated using receiver operating characteristic (ROC) curves, area under the curve (AUC), and decision curve analysis (DCA). The Delong test compared ROC performance, with p < 0.050 considered significant. RESULTS: Multivariate analysis identified intra-tumoral vessels as an independent predictor of high-grade ccRCC. In the external validation set, the radiomics model (AUC = 0.834) outperformed the clinical model (AUC = 0.762), with the combined model achieving the highest AUC (0.855) and significantly outperforming the clinical model (p = 0.003). DCA showed that the combined model had a higher net benefit within the 0.04-0.54 risk threshold range than clinical model. Additionally, the combined model constructed using logistic regression has a higher priority compared to other classifiers. Additionally, 10-fold cross-validation with LR for the combined model showed consistent AUC values (0.849-0.856) across different folds. CONCLUSION: The radiomics models based on multi-sequence MRI might be a noninvasive and effective tool, demonstrating good efficacy in preoperatively predicting the WHO/ISUP grade of ccRCC.

International Society of Urological Pathology (ISUP) Gleason Grade Groups stratify outcomes in the CHHiP Phase 3 prostate radiotherapy trial.

OBJECTIVES: To compare the results of Gleason Grade Group (GGG) classification following central pathology review with previous local pathology assessment, and to examine the difference between using overall and worst GGG in a large patient cohort treated with radiotherapy and short-course hormone therapy. PATIENTS AND METHODS: Patients with low- to high-risk localized prostate cancer were randomized into the multicentre CHHiP fractionation trial between 2002 and 2011. Patients received short-course hormone therapy (≤6 month) and radical intensity-modulated radiotherapy (IMRT). Of 2749 consented patients, 1875 had adequate diagnostic biopsy tissue for blinded central pathology review. The median follow-up was 9.3 years. Agreement between local pathology and central pathology-derived GGG and between central pathology-derived overall and worst GGG was assessed using kappa (κ) statistics. Multivariate Cox regression and Kaplan-Meier methods were used to compare the biochemical/clinical failure (BCF) and distant metastases (DM) outcomes of patients with GGG 1-5. RESULTS: There was poor agreement between local pathology- and central pathology-derived GGG (κ = 0.19) but good agreement between overall and worst GGG on central pathology review (κ = 0.89). Central pathology-derived GGG stratified BCF and DM outcomes better than local pathology, while overall and worst GGG on central pathology review performed similarly. GGG 3 segregated with GGG 4 for BCF, with BCF-free rates of 90%, 82%, 74%, 71% and 58% for GGGs 1-5, respectively, at 8 years when assessed using overall GGG. There was a progressive decrease in DM-free rates from 98%, 96%, 92%, 88% and 83% for GGGs 1-5, respectively, at 8 years with overall GGG. Patients (n = 57) who were upgraded from GGG 2-3 using worst GS had BCF-free and DM-free rates of 74% and 92% at 8 years. CHHiP eligibility criteria limit the interpretation of these results. CONCLUSION: Contemporary review of International Society of Urological Pathology GGG successfully stratified patients treated with short-course hormone therapy and IMRT with regard to both BCF-free and DM-free outcomes. Patients upgraded from GGG 2 to GGG 3 using worst biopsy GS segregate with GGG 3 on long-term follow-up. We recommend that both overall and worst GS be used to derive GGG.

Ultrasound contrast-enhanced radiomics model for preoperative prediction of the tumor grade of clear cell renal cell carcinoma: an exploratory study.

BACKGROUND: This study aims to explore machine learning(ML) methods for non-invasive assessment of WHO/ISUP nuclear grading in clear cell renal cell carcinoma(ccRCC) using contrast-enhanced ultrasound(CEUS) radiomics. METHODS: This retrospective study included 122 patients diagnosed as ccRCC after surgical resection. They were divided into a training set (n = 86) and a testing set(n = 36). CEUS radiographic features were extracted from CEUS images, and XGBoost ML models (US, CP, and MP model) with independent features at different phases were established. Multivariate regression analysis was performed on the characteristics of different radiomics phases to determine the indicators used for developing the prediction model of the combined CEUS model and establishing the XGBoost model. The training set was used to train the above four kinds of radiomics models, which were then tested in the testing set. Radiologists evaluated tumor characteristics, established a CEUS reading model, and compared the diagnostic efficacy of CEUS reading model with independent characteristics and combined CEUS model prediction models. RESULTS: The combined CEUS radiomics model demonstrated the best performance in the training set, with an area under the curve (AUC) of 0.84, accuracy of 0.779, sensitivity of 0.717, specificity of 0.879, positive predictive value (PPV) of 0.905, and negative predictive value (NPV) of0.659. In the testing set, the AUC was 0.811, with an accuracy of 0.784, sensitivity of 0.783, specificity of 0.786, PPV of 0.857, and NPV of 0.688. CONCLUSIONS: The radiomics model based on CEUS exhibits high accuracy in non-invasive prediction of ccRCC. This model can be utilized for non-invasive detection of WHO/ISUP nuclear grading of ccRCC and can serve as an effective tool to assist clinical decision-making processes.

MRI-based PI-RADS score predicts ISUP upgrading and adverse pathology at radical prostatectomy in men with biopsy ISUP 1 prostate cancer.

INTRODUCTION: Most men diagnosed with very-low and low-risk prostate cancer are candidates for active surveillance; however, there is still a misclassification risk. We examined whether PI-RADS category 4 or 5 combined with ISUP 1 on prostate biopsy predicts upgrading and/or adverse pathology at radical prostatectomy. MATERIALS AND METHODS: A total of 127 patients had ISUP 1 cancer on biopsy after multiparametric MRI (mpMRI) and then underwent radical prostatectomy. We then evaluated them for ISUP upgrading and/or adverse pathology on radical prostatectomy. RESULTS: Eight-nine patients (70%) were diagnosed with PI-RADS 4 or 5 lesions. ISUP upgrading was significantly higher among patients with PI-RADS 4-5 lesions (84%) compared to patients with equivocal or non-suspicious mpMRI findings (26%, p < 0.001). Both PI-RADS 4-5 lesions (OR 24.3, 95% CI 7.3, 80.5, p < 0.001) and stage T2 on DRE (OR 5.9, 95% CI 1.2, 29.4, p = 0.03) were independent predictors of upgrading on multivariate logistic regression analysis. Men with PI-RADS 4-5 lesions also had significantly more extra-prostatic extension (51% vs. 3%, p < 0.001) and positive surgical margins (16% vs. 3%. p = 0.03). The only independent predictor of adverse pathology was PI-RADS 4-5 (OR 21.7, 95% CI 4.8, 99, p < 0.001). CONCLUSION: PI-RADS 4 or 5 lesions on mpMRI were strong independent predictors of upgrading and adverse pathology. Incorporating mpMRI findings when selecting patients for active surveillance must be further evaluated in future studies.

Role of [68Ga]Ga-PSMA-11 PET radiomics to predict post-surgical ISUP grade in primary prostate cancer.

PURPOSE: The aim of this study is to investigate the role of [68Ga]Ga-PSMA-11 PET radiomics for the prediction of post-surgical International Society of Urological Pathology (PSISUP) grade in primary prostate cancer (PCa). METHODS: This retrospective study included 47 PCa patients who underwent [68Ga]Ga-PSMA-11 PET at IRCCS San Raffaele Scientific Institute before radical prostatectomy. The whole prostate was manually contoured on PET images and 103 image biomarker standardization initiative (IBSI)-compliant radiomic features (RFs) were extracted. Features were then selected using the minimum redundancy maximum relevance algorithm and a combination of the 4 most relevant RFs was used to train 12 radiomics machine learning models for the prediction of PSISUP grade: ISUP ≥ 4 vs ISUP < 4. Machine learning models were validated by means of fivefold repeated cross-validation, and two control models were generated to assess that our findings were not surrogates of spurious associations. Balanced accuracy (bACC) was collected for all generated models and compared with Kruskal-Wallis and Mann-Whitney tests. Sensitivity, specificity, and positive and negative predictive values were also reported to provide a complete overview of models' performance. The predictions of the best performing model were compared against ISUP grade at biopsy. RESULTS: ISUP grade at biopsy was upgraded in 9/47 patients after prostatectomy, resulting in a bACC = 85.9%, SN = 71.9%, SP = 100%, PPV = 100%, and NPV = 62.5%, while the best-performing radiomic model yielded a bACC = 87.6%, SN = 88.6%, SP = 86.7%, PPV = 94%, and NPV = 82.5%. All radiomic models trained with at least 2 RFs (GLSZM-Zone Entropy and Shape-Least Axis Length) outperformed the control models. Conversely, no significant differences were found for radiomic models trained with 2 or more RFs (Mann-Whitney p > 0.05). CONCLUSION: These findings support the role of [68Ga]Ga-PSMA-11 PET radiomics for the accurate and non-invasive prediction of PSISUP grade.

Multiphase CT radiomics nomogram for preoperatively predicting the WHO/ISUP nuclear grade of small (< 4 cm) clear cell renal cell carcinoma.

BACKGROUND: Small (< 4 cm) clear cell renal cell carcinoma (ccRCC) is the most common type of small renal cancer and its prognosis is poor. However, conventional radiological characteristics obtained by computed tomography (CT) are not sufficient to predict the nuclear grade of small ccRCC before surgery. METHODS: A total of 113 patients with histologically confirmed ccRCC were randomly assigned to the training set (n = 67) and the testing set (n = 46). The baseline and CT imaging data of the patients were evaluated statistically to develop a clinical model. A radiomics model was created, and the radiomics score (Rad-score) was calculated by extracting radiomics features from the CT images. Then, a clinical radiomics nomogram was developed using multivariate logistic regression analysis by combining the Rad-score and critical clinical characteristics. The receiver operating characteristic (ROC) curve was used to evaluate the discrimination of small ccRCC in both the training and testing sets. RESULTS: The radiomics model was constructed using six features obtained from the CT images. The shape and relative enhancement value of the nephrographic phase (REV of the NP) were found to be independent risk factors in the clinical model. The area under the curve (AUC) values for the training and testing sets for the clinical radiomics nomogram were 0.940 and 0.902, respectively. Decision curve analysis (DCA) revealed that the radiomics nomogram model was a better predictor, with the highest degree of coincidence. CONCLUSION: The CT-based radiomics nomogram has the potential to be a noninvasive and preoperative method for predicting the WHO/ISUP grade of small ccRCC.

Risk and predictors of adverse pathology after radical prostatectomy in patients diagnosed with IUSP 1-2 prostate cancer at MRI-targeted biopsy: a multicenter analysis.

PURPOSE: Although active surveillance (AS) is recommended for low- to favorable intermediate-risk prostate cancer (PCa), risk of upgrading at radical prostatectomy (RP) is not negligible. Available studies based on systematic transrectal ultrasound biopsy might not be applicable to contemporary cohorts diagnosed with MRI-targeted biopsy (TB). The aim of the present study is to explore rates and risk factors for adverse outcomes (AO) at RP in patients with ISUP ≤ 2 PCa detected at TB with concomitant systematic biopsy (SB). METHODS: Multicenter, retrospective analysis of 475 consecutive patients with ISUP ≤ 2 PCa at MRI-TB + SB is treated with RP. AO were defined as ISUP upgrading, adverse pathology (upgrading to ISUP ≥ 3 and/or ≥ pT3 at RP, and/or pN1) (AP) or biochemical recurrence (BCR) in men with follow-up (n = 327). RESULTS: The rate of ISUP upgrading, upgrading ≥ 3, and AP were 39%, 21%, and 43%. Compared to ISUP2, men with ISUP1 PCa had a higher rate of overall upgrading (27 vs. 67%, p < 0.001), but less upgrading to ≥ 3 (27 vs. 10%, p < 0.001). AP was more common when ISUP2 was detected with a combined MRI-TB + SB approach compared to considering TB (p = 0.02) or SB (p = 0.01) alone. PSA, PSA density, PI-RADS, ISUP at TB, overall biopsy ISUP and EAU classification were predictors of upgrading to ISUP ≥ 3 and AP. The 1 year BCR-free survival was 94% with no differences in BCR rates between subgroups. CONCLUSION: Upgrading in ISUP ≤ 2 PCa remains prevalent even in men diagnosed in the MRI era. The use of MRI-TB with concomitant SB allows for the accurate identification of ISUP2 PCa and predicts the risk of AO at RP.

Transcriptome Profiling of Prostate Cancer, Considering Risk Groups and the TMPRSS2-ERG Molecular Subtype.

Molecular heterogeneity in prostate cancer (PCa) is one of the key reasons underlying the differing likelihoods of recurrence after surgical treatment in individual patients of the same clinical category. In this study, we performed RNA-Seq profiling of 58 localized PCa and 43 locally advanced PCa tissue samples obtained as a result of radical prostatectomy on a cohort of Russian patients. Based on bioinformatics analysis, we examined features of the transcriptome profiles within the high-risk group, including within the most commonly represented molecular subtype, TMPRSS2-ERG. The most significantly affected biological processes in the samples were also identified, so that they may be further studied in the search for new potential therapeutic targets for the categories of PCa under consideration. The highest predictive potential was found with the EEF1A1P5, RPLP0P6, ZNF483, CIBAR1, HECTD2, OGN, and CLIC4 genes. We also reviewed the main transcriptome changes in the groups at intermediate risk of PCa-Gleason Score 7 (groups 2 and 3 according to the ISUP classification)-on the basis of which the LPL, MYC, and TWIST1 genes were identified as promising additional prognostic markers, the statistical significance of which was confirmed using qPCR validation.

Direct comparison between Grade Group assessed on systematic and MRI/ultrasound fusion targeted biopsies correlated to the radical prostatectomy specimens in patients with prostate cancer.

OBJECTIVES: To compare the correlation of Gleason score (GS) and ISUP grade determined by prostate biopsies (PBx) and radical prostatectomy (RP) specimens according to the biopsy technique: ultrasound randomised (RBx) vs. MRI/ultrasound fusion targeted (TBx). MATERIALS AND METHODS: Between March 2013 and June 2018, we retrospectively included patients who underwent RP for prostate cancer (PCa) histopathologically proven by RBx and/or TBx. All patients had a prebiopsy MRI by a single radiologist (using PI-RADS score), then transrectal RBx (12cores, blinded to MRI lesions) and TBx (2-4 cores/target) with elastic MRI/ultrasound fusion (UroStation™, Koelis, Grenoble, France). Histological findings were compared: PBx vs. RP. RESULTS: One hundred and four patients underwent RP after RBx and/or TBx. ISUP concordance rate was better with the association RBx+TBx 49% (51/104) vs. 43.3% with TBx (P=0.07) and 43.3% with RBx (P=0.13). With RBx, 50% of the patients were downgraded (52/104) against 42.3% (44/104) with TBx (P=0.088). The association RBx+TBx significantly decreased the rate of downgrading of the ISUP score compared to the ISUP score of RP 35.6% (37/104) vs. RBx (50%, P=0.0001) and vs. TBx (42.3%, P=0.016). CONCLUSION: In half of cases, the ISUP score was underestimated in RBx compared to RP specimens. Adding TBx to RBx significantly reduced downgrading. The combination of both biopsy techniques appeared to be the best protocol to get closer to ISUP score and GS of the RP specimens. LEVEL OF EVIDENCE: C.

Concordance of biopsy and pathologic ISUP grading in salvage radical prostatectomy patients for recurrent prostate cancer.

PURPOSE: To investigate the concordance of biopsy and pathologic International Society of Urological Pathology (ISUP) grading in salvage radical prostatectomy (SRP) patients for recurrent prostate cancer. METHODS: Within a high-volume center database, we identified patients who underwent SRP for recurrent prostate cancer (PCa) between 2004 and 2020. Upgrading, downgrading, concordance, and any discordance between posttreatment biopsy ISUP and ISUP at SRP were tested. Logistic regression models were used to predict ISUP upgrading and ISUP discordance. Models were adjusted for prostatic specific antigen before SRP, age at surgery, initial prostatic specific antigen (PSA), type of primary treatment, time from primary PCa diagnosis to SRP, number of positive cores at biopsy, and original Gleason score. RESULTS: Overall, 184 patients with available biopsy and pathologic ISUP grading were identified. Of those, 17.4% (n = 32), 40.8% (n = 75), 19.6% (n = 36), and 22.2% (n = 41) harbored biopsy ISUP 1, ISUP 2, ISUP 3, and ISUP 4-5 grading, respectively. Pathologic ISUP 1, ISUP 2, ISUP 3, and ISUP 4-5 grading was recorded in 6.0% (n = 11), 40.8% (n = 75), 32.1% (n = 59), and 21.2% (n = 39), respectively. Median PSA before SRP was 5.5 ng/ml (interquartile range [IQR]: 3.1-8.1 ng/ml), median age at SRP was 65.1 years (IQR:60.7-69.4 years) and median time from original PCa diagnosis to SRP was 47 months (IQR: 27.3-85.2 months). Concordance of biopsy and pathologic ISUP was identified in 45.1% (n = 83). Conversely, any ISUP discordance, upgrading and downgrading of at least one ISUP group was identified in 54.9% (n = 101), 35.3% (n = 65), and 19.6% (n = 36). In logistic models, none of the preoperative characteristics was associated with upgrading or ISUP discordance (all p > 0.1). CONCLUSION: Discordance between biopsy and pathologic ISUP grading is common at SRP. However, in 45% of SRP cases biopsy ISUP is capable to predict pathologic ISUP. Further studies are necessary to identify characteristics for ISUP upgrading at SRP.

Correlation of the Grade Group of Prostate Cancer according to the International Society of Urological Pathology (Isup) 2014 Classification between Prostate Biopsy and Radical Prostatectomy Specimens.

ABTRACTWe aimed to assess the correlation between ISUP 2014 grades of needle biopsy (NB) and radical prostatectomy (RP) specimens and the parameters effecting this correlation. A total of 353 patients, who underwent a radical prostatectomy with diagnose of prostate cancer, were included in the study. Especially, the maximum percentage of core involved by cancer (MPCI) of upgraded group was significantly higher than those of correlated group and downgraded group. MPCI might be used as a preoperative value to determine risk classification and to help counsel patients with regard to treatment decision and prognosis of disease.

Tumour blood flow for prediction of human prostate cancer aggressiveness: a study with Rubidium-82 PET, MRI and Na+/K+-ATPase-density.

PURPOSE: Tumour blood flow (TBF) is a crucial determinant of cancer growth. Recently, we validated Rubidium-82 (82Rb) positron emission tomography (PET) for TBF measurement in prostate cancer (PCa) and found TBF and cancer aggressiveness positively correlated. The aims of the present study were to determine the ability of TBF for separating significant from insignificant PCa and to examine the relation to underlying Na+/K+-ATPase density, which is relevant as 82Rb is transported intracellularly via the Na+/K+-ATPase. METHODS: One hundred and two patients were included for pelvic 82Rb PET scan prior to magnetic resonance imaging (MRI)-guided prostate biopsy. Findings constituted 100 PCa lesions (86 patients) and 25 benign lesions (16 patients). Tumours were defined on MRI and transferred to 82Rb PET for TBF measurement. Immunohistochemical Na+/K+-ATPase staining was subsequently performed on biopsies. RESULTS: TBF was the superior predictor (rho = 0.68, p < 0.0001, inflammatory lesions excluded) of MRI-guided biopsy grade group (GG) over lowest apparent diffusion coefficient (ADC) value (rho = -0.23, p = 0.01), independent of ADC value and tumour volume (p < 0.0001). PET could separate GG-2-5 from GG-1 and benign lesions with an area under the curve (AUC), sensitivity, and specificity of 0.79, 96%, and 59%, respectively. For separating GG-3-5 from GG-1-2 and benign lesions the AUC, sensitivity, and specificity were 0.82, 95%, and 63%, respectively. Na+/K+-ATPase density per PCa cell profile was 38% lower compared with that of the benign prostate cell profiles. Neither cell density nor Na+/K+-ATPase density determined tumour 82Rb uptake. CONCLUSION: TBF is an independent predictor of PCa aggressiveness and deserves more attention, as it may be valuable in separating clinically significant from insignificant PCa.

Comprehensive evaluation of 68Ga-PSMA-11 PET/CT parameters for discriminating pathological characteristics in primary clear-cell renal cell carcinoma.

PURPOSE: To evaluate parameters derived from 68Ga-PSMA-11 PET/CT images for discriminating pathological characteristics in primary clear-cell renal cell carcinoma (ccRCC). METHODS: The study retrospectively examined data for 36 ccRCC patients with preoperative 68Ga-PSMA-11 PET/CT scan and surgical specimens. Radiological parameters including maximal tumor diameter, mean CT value, and maximal standard uptake value (SUVmax) were derived from PET/CT images. Pathological characteristics included WHO/ISUP grade and adverse pathology (tumor necrosis or sarcomatoid or rhabdoid feature). Values of radiological parameters were compared within subgroups of pathological characteristics. Receiver operating characteristic (ROC) curve analysis was used for the effectiveness of radiological parameters in differentiating pathological characteristics, estimating area under the ROC curve (AUC) and 95% confidence intervals (CIs). RESULTS: The WHO/ISUP grade distribution for 36 tumors was grade 1, 9 (25.0%); grade 2, 12 (33.3%); grade 3, 9 (25.0%); and grade 4, 6 (16.7%). Adverse pathology was positive for 15 (41.7%). Radiological tumor diameter and SUVmax significantly differed by WHO/ISUP grade, pT stage, and adverse pathology (all P < 0.05), with no difference by CT value. Tumor diameter demonstrated sensitivity 86% and specificity 88% for pT stage, with cutoff 6.70 and AUC 0.91 (95% CI, 0.79-1.00, P < 0.001). SUVmax could effectively differentiate WHO/ISUP grade (3-4 vs. 1-2) and adverse pathology (positive vs. negative), with AUC 0.89 (95% CI, 0.81-0.98, P < 0.001), cutoff 16.4, sensitivity 100%, and specificity 71% and AUC 0.92 (95% CI, 0.85-0.99, P < 0.001), cutoff 18.5, sensitivity 94%, and specificity 87%, respectively. CONCLUSION: 68Ga-PSMA-11 PET/CT could effectively identify aggressive pathological features of ccRCC.

2-[18F]FDG PET/CT parameters associated with WHO/ISUP grade in clear cell renal cell carcinoma.

PURPOSE: To explore the potential parameters from preoperative 2-[18F]FDG PET/CT that might associate with the World Health Organization/the International Society of Urological Pathology (WHO/ISUP) grade in clear cell renal cell carcinoma (ccRCC). METHODS: One hundred twenty-five patients with newly diagnosed ccRCC who underwent 2-[18F]FDG PET/CT prior to surgery or biopsy were retrospectively reviewed. The metabolic parameters and imaging features obtained from 2-[18F]FDG PET/CT examinations were analyzed in combination with clinical characteristics. Univariate and multivariate logistic regression analyses were performed to identify the predictive factors of WHO/ISUP grade. RESULTS: Metabolic parameters of primary tumor maximum standardized uptake value (SUVmax), tumor-to-liver SUV ratio (TLR), and tumor-to-kidney SUV ratio (TKR) were significantly different between any two of the four different WHO/ISUP grades, except those between the WHO/ISUP grade 3 and grade 4. The optimal cutoff values to predict high WHO/ISUP grade for SUVmax, TLR, and TKR were 4.15, 1.63, and 1.59, respectively. TLR (AUC: 0.841) was superior to TKR (AUC: 0.810) in distinguishing high and low WHO/ISUP grades (P = 0.0042). In univariate analysis, SUVmax, TLR, TKR, primary tumor size, tumor thrombus, distant metastases, and clinical symptoms could discriminate between the high and low WHO/ISUP grades (P < 0.05). In multivariate analysis, TLR (P < 0.001; OR: 1.732; 95%CI: 1.289-2.328) and tumor thrombus (P < 0.001; OR: 6.199; 95%CI: 2.499-15.375) were significant factors for differentiating WHO/ISUP grades. CONCLUSION: Elevated TLR (> 1.63) and presence of tumor thrombus from preoperative 2-[18F]FDG PET/CT can distinguish high WHO/ISUP grade ccRCC effectively. 2-[18F]FDG PET/CT may be a feasible method for noninvasive assessment of WHO/ISUP grade.

The modified International Society of Urological Pathology system improves concordance between biopsy and prostatectomy tumour grade.

OBJECTIVES: To assess the concordance between biopsy and radical prostatectomy (RP) specimens using the 2005 Gleason score (GS) and the International Society of Urological Pathology (ISUP) 2014/World Health Organization 2016 modified system, accounting for the introduction of transperineal biopsy and pre-biopsy multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: Between 2002 and 2019, we identified 2431 patients with paired biopsy and RP histopathology from a prospectively recorded and maintained prostate cancer database. Biopsy specimens were graded according to the 2005 GS or ISUP 2014 modified system, according to the year of diagnosis. Multivariable logistic regression analysis was conducted to retrospectively assess the impact of prostate-specific antigen (PSA), PSA density, age, pre-biopsy mpMRI, and biopsy method, on the rate of upgraded disease. The kappa coefficient was used to establish the degree of change in concordance between groups. RESULTS: Overall, 24% of patients had upgraded disease and 8% of patients had downgraded disease when using the modified ISUP 2014 criteria. Agreement in the updated ISUP 2014 cohort was 68%, compared with 55% in the 2005 GS group, which was validated by a kappa coefficient that was good (k = 0.5 ± 0.4) and poor (k = 0.3 ± 0.1), respectively. In multivariable models, a change in grading system independently improved overall disease concordance (P = 0.02), and there were no other co-segregated patient or pathological factors such as PSA, total number of cores, maximum cancer length, biopsy route or the use of mpMRI that impacted this finding. CONCLUSION: The 2014 ISUP modifed system improves overall concordance between biopsy and surgical specimens, and thus allows more accurate prognostication and management in high-grade disease, independent of more extensive prostate sampling and the use of mpMRI.

Circulating preoperative testosterone level predicts unfavourable disease at radical prostatectomy in men with International Society of Urological Pathology Grade Group 1 prostate cancer diagnosed with systematic biopsies.

PURPOSE: The association between circulating total testosterone (T) levels and clinically significant PCa is still a matter of debate. In this study, we evaluated whether serum testosterone levels may have a role in predicting unfavorable disease (UD) and biochemical recurrence (BCR) in patients with clinically localized (≤ cT2c) ISUP grade group 1 PCa at biopsy. METHODS: 408 patients with ISUP grade group 1 prostate cancer, undergone to radical prostatectomy and T measurement were included. The outcome of interest was the presence of unfavourable disease (UD) defined as ISUP grade group [Formula: see text] 3 and/or pT [Formula: see text] 3a. RESULTS: Statistically significant differences resulted between serum testosterone values and ISUP grade groups (P < 0.0001). Significant correlation was found analyzing testosterone values versus age (P < 0.0001), and versus PSA (P = 0.008). BCR-free survival was significantly decreased in patients with low levels of testosterone (P = 0.005). These findings were confirmed also in the ISUP 1-2 subgroups (P = 0.01). ROC curve analysis showed that T outperformed PSA in predicting UD (AUC 0.718 vs AUC 0.525; P < 0.001) and was and independent risk factor for BCR. CONCLUSION: Our findings suggested that circulating total T was a significant predictor of UD at RP in patients with preoperative low- to intermediate-risk diseases, confirming the potential role of circulating androgens in preoperative risk assessment of PCa patients.

Combining two grading systems: the clinical validity and inter-observer variability of the 1973 and 2004 WHO bladder cancer classification systems assessed in a UK cohort with 15 years of prospective follow-up.

PURPOSE: Paucity of reliable long-term data on the prognostic implications of the 2004 WHO bladder cancer classification system necessitates utilisation of both this and the 1973 grading systems. This study evaluated, in noninvasive (pTa) bladder tumours, the prognostic value of the 2004 system independently and in combination with the 1973 system while establishing concordance between tertiary centre uropathologists. METHODS: We used a cohort of non-muscle invasive bladder cancer (NMIBC) patients diagnosed between 1991 and 93 where tumour features were gathered prospectively with detailed cystoscopic follow-up data recorded over 15 years. Initial grading was by one senior expert uropathologist (UP1) using the 1973 WHO classification alone. Subsequently, two other expert uropathologists (UP2 and UP3), blinded to the previous grading, re-evaluated the pathology slides and graded the tumours using both the 1973 and 2004 systems. Association between grade and recurrence/progression was analysed and the Cohen Kappa test assessed concordance between pathologists. RESULTS: Of 370 new NMIBC, 229 were staged noninvasive (pTa). Recurrence rates were 46.2% and 50.0% for LGPUC (low-grade papillary urothelial carcinoma) and HGPUC (high-grade papillary urothelial carcinoma), respectively, while progression was seen in 3.9% and 10.0% of LGPUC and HGPUC, respectively. Concordance between uropathologists UP2 and UP3 for the 2004 and 1973 systems was good (Kappa = 0.69) and fair (Kappa = 0.25), respectively. CONCLUSIONS: With good inter-observer concordance, the 2004 WHO classification system of noninvasive bladder tumours appears to accurately predict recurrence and progression risks. The combination of both grading systems to low-grade tumours allows further refinement of the natural history.

Comparative influence of cribriform growth and percent Gleason 4 in prostatic biopsies with Gleason 3+4 cancer.

The International Society of Urological Pathology endorses specifying presence of cribriform architecture in Gleason (G)4 prostate cancer because of cribriform's aggressiveness. The relative effect of cribriform presence versus percentage G4 within grade group (GG)2 or 3 was uncertain. 194 men's biopsies with GG2 with or without cribriform (excluding glomeruloid from cribriform) and GG3 without cribriform (controls) from 4 years were reviewed. 173 cases had follow-up including 147 GG2 (15/147 or 10% had cribriform) and 26 GG3. Effects of total tumor specimen involvement, %Gleason 4, and cribriform were stratified into prostatectomy (n = 90), radiotherapy (n = 61), and watching waiting (n = 22) groups. Median follow-up duration was 3.32 years (range 1.90-6.18). Biochemical failures in the above 3 cohorts numbered 9 (9/90; 10%), 5 (5/61; 8%), and 13 (13/22; 59%) respectively. In all groups, (GG2+ GG3, n = 173), the HR for C pattern was 1.64. In GG2, cribriform presence (considering glomeruloid as non-cribriform) conferred a hazard ratio (HR) of 1.51 (p = 0.48). It was 1.38, excluding glomeruloid. In watchful waiting cohort only, presence of C conferred a HR of 2.62 (p = 0.086). All remaining comparisons including percent G4, remained not significant. Thus, only in WW group did cribriform pattern presence approach significance. Detection of differences otherwise was not feasible, probably because: 1) biochemical failure is too rare in GG2 cancer; 2) cribriform frequency was only 10% in GG2 (in current study), less than in higher-grade cancer. 3) Use of biopsy tissue is subject to sampling variation which may undersample cribriform pattern, though biopsy forms the basis of treatment decisions.

Tumor grade estimation of clear cell and papillary renal cell carcinomas using contrast-enhanced MDCT and FSE T2 weighted MR imaging: radiology-pathology correlation.

BACKGROUND: Discrimination of low grade (grade 1-2) renal tumors from high grade (grade 3-4) ones carries crucial importance in terms of the management of these patients and also in the decision-making of appropriate treatment strategies. Our aim was to investigate whether contrast-enhanced multidetector computed tomography (MDCT) and T2 weighted fast spin echo (FSE) magnetic resonance imaging (MRI) could play a specific role in the discrimination of low grade versus high grade tumors in clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) patients. METHODS: In this study, we retrospectively evaluated 66 RCC patients based on histopathologic findings who had underwent either partial or total nephrectomies. Our cohort consisted of 52 ccRCC and 14 pRCC patients, of whom 50 were male (%76) and 16 were female (%24). Among the 52 ccRCC patients, 18 had both cortico-medullary phase contrast-enhanced CT and MRI, 15 had only cortico-medullary phase CT and 19 had only MRI examination. In the pRCC group, 8 patients had both cortico-medullary phase contrast-enhanced CT and MRI, 3 had only cortico-medullary phase CT and 3 had only MRI. We both calculated mean tumor attenuation values on cortico-medullary phase MDCT images as HU (hounsfield unit) and also tumor mean signal intensity values on FSE T2 weighted MR images, using both region of interest and whole lesion measurements including normal renal cortex. The obtained values were compared with the grading results of the ccRCC and pRCC tumors according to the WHO/International Society of Urological Pathology grading system. RESULTS: A significant positive correlation was found between the mean attenuation values of both tumor subtypes on cortico-medullary phase contrast-enhanced CT and their grades (p < 0.001). High grade tumors exhibited higher mean attenuation values (74.3 ± 22.3 HU) than the low grade tumors (55.2 ± 23.7 HU) in both subtypes. However, a statistically significant correlation was not found between the mean signal intensity values of the two tumor subtypes on FSE T2 weighted MR images and their grades (p > 0.05). Low grade tumors had a mean signal intensity value of 408.9 ± 44.6, while high grade tumors showed a value of 382.1 ± 44.2. The analysis of the ccRCC group patients, yielded a statistically significant correlation between the mean signal intensity values on T2 weighted images and tumor grading (p < 0.001). Low grade (grade 1-2) ccRCC patients exhibited higher mean signal intensity values (475.7 ± 51.3), as compared to those of high grade (grade 3-4) (418.5 ± 45.7) tumors. On the other hand, analysis of the pRCC group patients revealed that there was a significant correlation between the mean attenuation values of tumors on cortico-medullary phase contrast-enhanced CT and their grades (p < 0.001). High grade papillary subtype tumors (54.2 ± 25.2) showed higher mean attenuation values than the low grade (35.5 ± 18.8) ones. CONCLUSIONS: Contrast-enhanced MDCT and T2 weighted FSE MRI can play a considerable role in the discrimination of low grade versus high grade tumors of both subtype RCC patients. Thus, these non-invasive evaluation techniques may have positive impact on the determination of the management and treatment strategies of these patients.