Low-risk prostate lesions: An evidence review to inform discussion on losing the "cancer" label.

BACKGROUND: Active surveillance (AS) mitigates harms from overtreatment of low-risk prostate lesions. Recalibration of diagnostic thresholds to redefine which prostate lesions are considered "cancer" and/or adopting alternative diagnostic labels could increase AS uptake and continuation. METHODS: We searched PubMed and EMBASE to October 2021 for evidence on: (1) clinical outcomes of AS, (2) subclinical prostate cancer at autopsy, (3) reproducibility of histopathological diagnosis, and (4) diagnostic drift. Evidence is presented via narrative synthesis. RESULTS: AS: one systematic review (13 studies) of men undergoing AS found that prostate cancer-specific mortality was 0%-6% at 15 years. There was eventual termination of AS and conversion to treatment in 45%-66% of men. Four additional cohort studies reported very low rates of metastasis (0%-2.1%) and prostate cancer-specific mortality (0%-0.1%) over follow-up to 15 years. Overall, AS was terminated without medical indication in 1%-9% of men. Subclinical reservoir: 1 systematic review (29 studies) estimated that the subclinical cancer prevalence was 5% at <30 years, and increased nonlinearly to 59% by >79 years. Four additional autopsy studies (mean age: 54-72 years) reported prevalences of 12%-43%. Reproducibility: 1 recent well-conducted study found high reproducibility for low-risk prostate cancer diagnosis, but this was more variable in 7 other studies. Diagnostic drift: 4 studies provided consistent evidence of diagnostic drift, with the most recent (published 2020) reporting that 66% of cases were upgraded and 3% were downgraded when using contemporary diagnostic criteria compared to original diagnoses (1985-1995). CONCLUSIONS: Evidence collated may inform discussion of diagnostic changes for low-risk prostate lesions.

Interobserver reproducibility of cribriform cancer in prostate needle biopsies and validation of International Society of Urological Pathology criteria.

AIMS: There is strong evidence that cribriform morphology indicates a worse prognosis of prostatic adenocarcinoma. Our aim was to investigate its interobserver reproducibility in prostate needle biopsies. METHODS AND RESULTS: A panel of nine prostate pathology experts from five continents independently reviewed 304 digitised biopsies for cribriform cancer according to recent International Society of Urological Pathology criteria. The biopsies were collected from a series of 702 biopsies that were reviewed by one of the panellists for enrichment of high-grade cancer and potentially cribriform structures. A 2/3 consensus diagnosis of cribriform and noncribriform cancer was reached in 90% (272/304) of the biopsies with a mean kappa value of 0.56 (95% confidence interval 0.52-0.61). The prevalence of consensus cribriform cancers was estimated to 4%, 12%, 21%, and 20% of Gleason scores 7 (3 + 4), 7 (4 + 3), 8, and 9-10, respectively. More than two cribriform structures per level or a largest cribriform mass with ≥9 lumina or a diameter of ≥0.5 mm predicted a consensus diagnosis of cribriform cancer in 88% (70/80), 84% (87/103), and 90% (56/62), respectively, and noncribriform cancer in 3% (2/80), 5% (5/103), and 2% (1/62), respectively (all P < 0.01). CONCLUSION: Cribriform prostate cancer was seen in a minority of needle biopsies with high-grade cancer. Stringent diagnostic criteria enabled the identification of cribriform patterns and the generation of a large set of consensus cases for standardisation.

Ductal and acinar components of mixed prostatic adenocarcinoma frequently have a common clonal origin.

BACKGROUND: Ductal adenocarcinoma (DA) is an aggressive subtype of prostate cancer. It is most commonly seen in mixed tumors together with conventional acinar adenocarcinoma (AA). The genetic profile of DA and its clonal origin is not fully characterized. OBJECTIVE: To investigate whether DA represents a distinct genetic subtype and to investigate the somatic relationship between the ductal and acinar components of mixed cancers. DESIGN, SETTING, AND PARTICIPANTS: In 17 radical prostatectomy specimens ductal and acinar tumor components from the same tumor foci were dissected. DNA was extracted and genomic sequencing performed. After exclusion of two cases with low cell yield, 15 paired samples remained for analysis. RESULTS: In 12 of 15 cases a common somatic denominator was identified, while three cases had clonally separate components. In DA, TMPRSS2-ERG gene fusions were detected in 47% (7/15), clonal FOXA1 alterations in 33% (5/15) and SPOP alterations in 27% (4/15) of cases. In one case KIAA1549-BRAF fusion was identified. Genome doubling events, resulting in an increased ploidy, were identified in the DA in 53% (8/15) of cases, but not seen in any AA. PTEN and CTNNB1 alterations were enriched in DA (6/15) but not seen in any AA. No cancers showed microsatellite instability or high tumor mutation burden. CONCLUSIONS: Ductal and acinar prostate adenocarcinoma components of mixed tumors most often share the same origin and are clonally related. DA components in mixed tumor often exhibit genome doubling events resulting in aneuploidy, consistent with the aggressive nature of high grade prostate cancer.

Primary tumour PSMA intensity is an independent prognostic biomarker for biochemical recurrence-free survival following radical prostatectomy.

PURPOSE: The prognostic value of PSMA intensity on PSMA PET/CT due to underlying biology and subsequent clinical implications is an emerging topic of interest. We sought to investigate whether primary tumour PSMA PET intensity contributes to pre- and post-operative prediction of oncological outcomes following radical prostatectomy. METHODS: We performed a retrospective cohort study of 848 men who underwent all of multiparametric MRI (mpMRI), transperineal prostate biopsy, and 68 Ga-PSMA PET/CT prior to radical prostatectomy. PSMA intensity, quantified as maximum standard uptake value (SUVmax), and other clinical variables were considered relative to post-operative biochemical recurrence-free survival (BRFS) using Cox regression and Kaplan-Meier analysis. RESULTS: After a median follow-up of 41 months, 219 events occurred; the estimated 3-year BRFS was 79% and the 5-year BRFS was 70%. Increasing PSMA intensity was associated with less favourable BRFS overall (Log rank p < 0.001), and within subgroups of Gleason score category (Log rank p < 0.03). PSMA intensity was significantly associated with shorter time to biochemical recurrence, after adjusting for pre-operative (HR per 5-unit SUVmax increase = 1.15) and post-operative (HR per 5-unit SUVmax increase = 1.10) parameters. CONCLUSION: These results in a large series of patients confirm PSMA intensity to be a novel, independent prognostic factor for BRFS.

Oncological and urinary outcomes following low-dose-rate brachytherapy with a median follow-up of 11.8 years.

OBJECTIVES: To examine the long-term oncological outcomes and urological morbidity of low-dose-rate prostate brachytherapy (LDRBT) monotherapy using live intraoperative dosimetry planning and an automated needle navigation delivery system for the treatment of men with low and intermediate-risk prostate cancer. PATIENTS AND METHODS: A prospective database of 400 consecutive patients who underwent LDRBT between July 2003 and June 2015 was retrospectively reviewed to assess urinary side-effects and biochemical progression, based on the Phoenix definition and also a definition of a prostate-specific antigen (PSA) level of ≥0.2 µg/L. RESULTS: Minimum patient follow-up was 5.5 years. The median follow-up of the entire cohort was 11.8 years. The median (range) PSA level was 6.1 (0.9-17) µg/L and the median Gleason score was 3 + 4. The biochemical relapse-free survival (RFS; freedom from biochemical recurrence) based on the Phoenix definition was 85.8% (343/400). The RFS using a 'surgical' definition of a PSA level of <0.2 µg/L was 71% (284/400). Of the 297 men followed for ≥10 years, prostate cancer-specific survival (PCSS) was 98% (291/297). Post-LDRBT urethral stricture developed in 11 men (2.8%, 11/400). For men with ≥10 years of follow-up, 22 men (7.4%, 22/297) required a pad for either stress or urge urinary incontinence (UI). UI was identified in only 2.2% (one of 46) of men who had a bladder neck incision (BNI) before LDRBT. CONCLUSION: LDRBT is associated with excellent PCSS, with a median follow-up of 11.8 years. The risk of post-implantation urethral stricture and UI is low and a pre-implantation BNI for management of bladder outflow obstruction does not increase the risk of UI or urethral stricture.

Histological comparison between predictive value of preoperative 3-T multiparametric MRI and 68 Ga-PSMA PET/CT scan for pathological outcomes at radical prostatectomy and pelvic lymph node dissection for prostate cancer.

OBJECTIVE: To evaluate the ability of preoperative multiparametric magnetic resonance imaging (mpMRI) and a gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) scan to predict pathological outcomes and also identify a group of men with a <5% risk of histological pelvic lymph node metastasis (LNM) at pelvic lymph node dissection (PLND) performed during a robot-assisted laparoscopic radical prostatectomy (RALP) for prostate cancer. We then aimed to compare these results to known risk calculators for LNM, including the Cancer of the Prostate Risk Assessment (CAPRA) score, Memorial Sloan Kettering Cancer Centre (MSKCC) and Briganti nomograms. PATIENTS AND METHODS: Between July 2014 and September 2019 only men who had both a preoperative mpMRI and staging 68 Ga-PSMA PET/CT at our institution followed by a RALP with PLND referred to a single specialist uropathology laboratory were considered for inclusion. The data were collected retrospectively prior to February 2019 and in a prospective manner thereafter. A model was built to allocate probabilities of the men with a negative 68 Ga-PSMA PET/CT scan having a <5% risk of histologically LNM at RALP based on the preoperative radiological staging. RESULTS: A total of 233 consecutive men met the inclusion criteria of which 58 men (24.9%) had a LNM identified on PLND histology. The median (range) International Society of Urological Pathology (ISUP) Grade was 5 (1-5) and the median (range) prostate-specific antigen level was 7.4 (1.5-72) ng/mL. The median (range) number of resected lymph nodes was 16 (1-53) and the median (range) number of positive nodes identified on histology was 2 (1-22). Seminal vesicle invasion on mpMRI was more common in node-positive men than in the absence of LNM (31% vs 12%). The maximum standardised uptake value of the primary tumour on 68 Ga-PSMA PET/CT was higher in men with LNM (median 9.2 vs 7.2, P = 0.02). Suspected LNM were identified in 42/233 (18.0%) men with 68 Ga-PSMA PET/CT compared with 22/233 (9.4%) men with mpMRI (P = 0.023). The positive and negative predictive value for 68 Ga-PSMA PET/CT was 66.7% and 84.3% respectively, compared to 59.1% and 78.7% for mpMRI. A predictive model showed only two men (4.2%) with a negative preoperative 68 Ga-PSMA PET/CT would be positive for a histological LNM if they are ISUP Grade < 5 and Prostate Imaging-Reporting and Data System (PI-RADS) <5; or ISUP Grade 5 with PI-RADS < 4. An inspection of three additional variables: CAPRA score, MSKCC and Briganti nomograms did not improve the predictive probability for this group. However, of the 61 men with ISUP Grade 4-5 malignancy and also a PI-RADS 5 mpMRI, 20 (32.8%) men had a microscopic LNM despite a negative preoperative 68 Ga-PSMA PET/CT. CONCLUSION: Preoperative 68 Ga-PSMA/PET CT was more sensitive in identifying histological pelvic LNM than 3-T mpMRI. Men with a negative 68 Ga-PSMA PET/CT have a lower risk of LNM than predicted with CAPRA scores or MSKCC and Briganti nomograms. We identified that the combination of a negative preoperative 68 Ga-PSMA PET/CT, ISUP biopsy Grade <5 and PI-RADS <5 prostate mpMRI, or an ISUP Grade 5 with PI-RADS <4 on mpMRI was associated with a <5% risk of a LNM. The addition of CAPRA scores, MSKCC and Briganti nomograms did not improve the predictive probability within this model. Conversely, men with ISUP Grade 4-5 malignancy associated with a PI-RADS 5 prostate mpMRI had a >30% risk of microscopic LNM despite a negative preoperative 68 Ga-PSMA PET/CT and this high-risk group would appear suitable for an extended PLND at the time of a radical prostatectomy.

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

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

Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study.

BACKGROUND: An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading. METHODS: We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50-69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa. FINDINGS: The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994-0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972-0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95-0·97) for the independent test dataset and 0·87 (0·84-0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60-0·73). INTERPRETATION: An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist. FUNDING: Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.

Perineural invasion by prostate adenocarcinoma in needle biopsies predicts bone metastasis: Ten year data from the TROG 03.04 RADAR Trial.

AIMS: Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally advanced prostate cancer treated with radiotherapy and androgen deprivation using 10 years outcome data from the TROG 03.04 RADAR trial. METHODS: Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10 years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer-specific mortality and all-cause mortality. RESULTS: PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10 years follow-up interval of the study (log-rank test P < 0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05-1.92, P = 0.021). CONCLUSIONS: The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow-up.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial.

BACKGROUND: The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial. METHODS: For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen [PSA] concentration was ≥10 µg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9-11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3-16·0) for 6AS+RT versus 9·7% (7·3-12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3-7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50-0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7-13·7) with zoledronic acid vs 11·7% (9·2-14·1) without, representing an absolute difference of -0·5% (95% CI -3·8 to 2·9; sHR 0·95 [95% CI 0·69-1·32], adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study. INTERPRETATION: 18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.

Somatic alterations detected in diagnostic prostate biopsies provide an inadequate representation of multifocal prostate cancer.

BACKGROUND: The majority of clinical prostate cancers are multifocal with morphological and molecular heterogeneity. Adequate tissue representation is crucial for the clinical utility of multigene panel sequencing of core needle biopsies. The aim of this study was to evaluate the genomic heterogeneity in multifocal prostate cancer and to analyze how representative preoperative biopsies are of spatially separated tumor foci. METHODS: We analyzed at least 2 tumor foci and 1 to 3 preoperative biopsy cores from 11 patients. Diagnostic biopsies, as well as fresh frozen and formalin-fixed paraffin-embedded samples, from major tumor foci of radical prostatectomy specimens were macrodissected for the enrichment of tumor tissue. DNA was extracted and sequenced. We analyzed structural alterations, mutations, and copy number variations and compared the genomic profiles of tumor foci with those of preoperative biopsies. RESULTS: Alterations were rarely shared between foci, indicating a high degree of genomic heterogeneity. In 8 of 11 men at least 1 tumor focus was represented by the biopsies defined as harboring at least 1 common clonal somatic event. In only one case, somatic alterations from two spatially separate tumors were identified in the biopsies. Of the mutations and structural variants detected in fresh frozen or formalin-fixed paraffin-embedded prostatectomy material, only an average of 19% (range 0-44) and 55% (range 0-100), respectively, were found in preoperative biopsies where a common somatic origin was established. CONCLUSIONS: Multifocal prostate cancer is a somatically heterogeneous disease in which systematic needle biopsies do not provide sufficient molecular representation of the somatic alterations detected in spatially distinct tumor areas. Targeted biopsies, directed at separate tumor foci, could potentially improve tissue representation of these heterogeneous foci in preoperative biopsies.

Outcomes of Primary Lymph Node Staging of Intermediate and High Risk Prostate Cancer with 68Ga-PSMA Positron Emission Tomography/Computerized Tomography Compared to Histological Correlation of Pelvic Lymph Node Pathology.

PURPOSE: The majority of men who undergo pelvic lymph node dissection at radical prostatectomy have benign lymph node histology. The aim of this study was to assess the predictive value of preoperative 68Ga-PSMA (prostate specific membrane antigen) positron emission tomography/computerized tomography to predict histological metastasis on pelvic lymph node dissection performed during radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed the sensitivity, specificity, and positive and negative predictive values of preoperative staging 68Ga-PSMA positron emission tomography/computerized tomography to identify histological lymph node metastasis in 208 consecutive men who subsequently proceeded with pelvic lymph node dissection at radical prostatectomy. RESULTS: Median prostate specific antigen was 7.6 µg/l, the lymph node count was 13 and Gleason score was 4 + 5. On a per patient basis only 21 of the 55 men with metastasis on histological examination were identified on 68Ga-PSMA positron emission tomography/computerized tomography for 38.2% sensitivity. Of the 143 men with no lymph node metastasis on 68Ga-PSMA imaging 34 had metastasis on histology for 80.8% negative predictive value. Specificity was 93.5% and positive predictive value was 67.7%. For the 172 histologically identified malignant lymph node metastases the sensitivity per node was 24.4% and specificity was 99.5%. CONCLUSIONS: If negative 68Ga-PSMA positron emission tomography/computerized tomography is used as the basis of not performing pelvic lymph node dissection, 80% of men would avoid unnecessary pelvic lymph node dissection. However, 68Ga-PSMA positron emission tomography/computerized tomography has poor sensitivity per node to detect all histologically positive lymph node metastases. Thus, pelvic lymph node dissection remains the gold standard to stage pelvic lymph nodes despite its known limitations and complications.

Grading of renal cell carcinoma.

Grading of renal cell carcinoma (RCC) has been recognised as a prognostic factor for almost 100 years. Numerous grading systems have been proposed, initially focusing upon a constellation of cytological features and more recently on nuclear morphology. It has been recommended that grading of RCC should be based upon nucleolar prominence/eosinophilia for grades 1-3, while grade 4 requires nuclear anaplasia (including tumour giant cells, sarcomatoid differentiation and/or rhabdoid morphology). The grading system was adopted formally by the International Society of Urological Pathology (ISUP) and subsequently by the World Health Organisation (WHO), being designated the WHO/ISUP grading classification in the fourth edition of the WHO classification tumours of the urinary system and male genital organs (2016). This grading system has been validated for both clear cell and papillary RCC. Validation studies for chromophobe RCC failed to demonstrate a correlation between grade and outcome for both the superseded Fuhrman grading system and the WHO/ISUP grading classification, and it has been recommended that these tumours not be graded. The WHO/ISUP system has been incorporated into the structured reports of the International Cancer Collaboration on Cancer Reporting for both clear cell and papillary RCC. It is also noted that other types of RCC may be graded, but it must be emphasised in the report that this is for descriptive and diagnostic purposes, and not outcome prediction. More recent studies have shown the incorporation of the presence of tumour necrosis into RCC grading to improve outcome prediction, and this has been validated in several studies.

Assessment of tumour-associated necrosis provides prognostic information additional to World Health Organization/International Society of Urological Pathology grading for clear cell renal cell carcinoma.

AIMS: The aims of this study were to evaluate the impact of tumour-associated necrosis (TAN) on metastasis-free survival for clear cell renal cell carcinoma (RCC), and to determine whether TAN provides survival information additional to World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading. METHODS AND RESULTS: The study consisted of 376 cases of clear cell RCC treated by nephrectomy, for which follow-up was available. WHO/ISUP grade was assigned, and sections were assessed for the presence of TAN. American Joint Committee on Cancer (AJCC) pT staging category and tumour size were also recorded. The development of metastatic disease was taken as the clinical endpoint, and survival analyses, utilising univariate and multivariate models, were performed. WHO/ISUP grades were: grade 1, 35 cases (9.3%); grade 2, 188 cases (50.0%); grade 3, 91 cases (24.2%); and grade 4, 62 cases (16.5%). Staging categories were pT1-pT2 [234 tumours (62.2%)] and pT3-pT4 [139 tumours (37.0%)]. TAN was seen in 128 cases (34.0%). Neither TAN nor metastases were seen in grade 1 tumours. Among grade 2-4 tumours, those with TAN had a significantly worse prognosis than those without TAN (P = 0.017, P = 0.04, and P = 0.006, respectively). Multivariate analysis (WHO/ISUP grade, pT staging category, and TAN) showed all three variables to be independently associated with outcome (P = 0.009, P = 0.005, and P = 0.001, respectively). For all tumour grades and pT staging categories, it was found that the presence of TAN was associated with a 2.91-fold greater risk of metastatic disease. CONCLUSION: Tumour-associated necrosis is an important prognostic factor for clear cell RCC, independently of WHO/ISUP grade. This supports the suggestion that TAN could be incorporated into tumour grading criteria.

Dataset for reporting of carcinoma of the urethra (in urethrectomy specimens): recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit organisation sponsored by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists in association with the Canadian Partnership Against Cancer, the European Society of Pathology, the American Society of Clinical Pathology and the Faculty of Pathology, Royal College of Physicians of Ireland. Its goal is to produce standardised, internationally agreed-upon, evidence-based datasets for cancer pathology reporting throughout the world. This paper describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of carcinoma of the urethra in urethrectomy specimens. The dataset is composed of 'required' (mandatory) and 'recommended' (non-mandatory) elements, which are based on a review of the most recent evidence and supported by explanatory commentary. Fourteen required elements and eight recommended elements were agreed by the international dataset authoring committee to represent the essential/required (core) and recommended (non-core) information for the reporting of carcinoma of the urethra in urethrectomy specimens. Use of an internationally agreed, structured pathology dataset for reporting carcinoma of the urethra (in urethrectomy specimens) will provide the necessary information for optimal patient management, will facilitate consistent data collection and will provide valuable data for research and international benchmarking. The dataset will be valuable for those countries and institutions that are not in a position to develop their own datasets.

Data set for the reporting of carcinoma of renal tubular origin: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: The International Collaboration on Cancer Reporting (ICCR) has provided detailed data sets based upon the published reporting protocols of the Royal College of Pathologists, the Royal College of Pathologists of Australasia and the College of American Pathologists. METHODS AND RESULTS: The data set for carcinomas of renal tubular origin treated by nephrectomy was developed to provide a minimum structured reporting template suitable for international use, and incorporated recommendations from the 2012 Vancouver Consensus Conference of the International Society of Urological Pathology (ISUP) and the fourth edition of the World Health Organisation Bluebook on tumours of the urinary and male genital systems published in 2016. Reporting elements were divided into those, which are required and recommended components of the report. Required elements are: specimen laterality, operative procedure, attached structures, tumour focality, tumour dimension, tumour type, WHO/ISUP grade, sarcomatoid/rhabdoid morphology, tumour necrosis, extent of invasion, lymph node status, surgical margin status, AJCC TNM staging and co-existing pathology. Recommended reporting elements are: pre-operative treatment, details of tissue removed for experimental purposes prior to submission, site of tumour(s) block identification key, extent of sarcomatoid and/or rhabdoid component, extent of necrosis, presence of tumour in renal vein wall, lymphovascular invasion and lymph node status (size of largest focus and extranodal extension). CONCLUSIONS: It is anticipated that the implementation of this data set in routine clinical practice will inform patient treatment as well as provide standardised information relating to outcome prediction. The harmonisation of data reporting should also facilitate international research collaborations.

Evolution, controversies and the future of prostate cancer grading.

Histological grading of prostate cancer is one of the most important tissue-based parameters for prediction of outcome and treatment response. Gleason grading remains the foundation of prostate cancer grading, but has undergone a series of changes in the past 30 years, often initiated by consensus conference decisions. This review summarizes the most important modifications that were introduced by the 2005 and 2014 International Society of Urological Pathology (ISUP) revisions of Gleason grading and discusses the impact that these have had on current grading practices. A considerable inflation in Gleason scores has been observed, especially following the ISUP 2005 revision, and the effects of this are discussed. ISUP 2014 grading recommendations are described, including the reporting of ISUP grades 1-5. Controversial issues include methods for reporting of grades on needle biopsies, reporting of percent Gleason grades 4/5 and grading of cribriform and intraductal carcinoma of the prostate. Educational programs developed recently to promote standardization of grading are described and their results assessed.

A novel technique for biobanking of large sections of radical prostatectomy specimens.

AIMS: Harvesting of unfixed tissue from radical prostatectomy specimens for research purposes is challenging. Many prostate cancers cannot be identified at gross inspection, and this tumour is notoriously multifocal and heterogeneous. We aimed to develop a technique to allow detailed topographic analysis and the sampling of a sufficient amount of tumour without jeopardising clinical reporting. METHODS AND RESULTS: A custom-made double-bladed knife was utilised for cutting a 4-mm-thick horizontal section of the prostate. The slices were split into segments that were frozen in gel, cryosections were cut, and RNA integrity numbers (RINs) were analysed. Sections were cut from all blocks of 20 cases, and the cutting time was monitored. Slides were scanned, and the slices were digitally reconstructed. Cutting frozen sections of an entire slice took 79-253 min (mean 162 min). Tumour was detected in frozen sections of 85% (17/20) of cases and in 46% (72/155) of blocks. The morphological quality was determined to be excellent, and RIN values were high (mean 8.9). CONCLUSIONS: This novel protocol for biobanking of fresh tissue from prostatectomy specimens provides sufficient tumour material for research purposes, while also enabling reporting of histopathology. The harvesting of a full tissue slice facilitates studies of tumour multifocality and heterogeneity.

Utility of Pathology Imagebase for standardisation of prostate cancer grading.

AIMS: Despite efforts to standardise grading of prostate cancer, even among experts there is still a considerable variation in grading practices. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading. METHODS AND RESULTS: The International Society of Urological Pathology (ISUP) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology reviewed independently microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval = 0.62-0.72) and consensus was reached in 50 cases. The interobserver weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score (GS) 3 + 3 = 6 (ISUP grade 1), while higher grades and particularly GS 4 + 3 = 7 (ISUP grade 3) showed considerable disagreement. Once a two-thirds majority was reached, images were moved automatically into a public database available for all ISUP members at www.isupweb.org. Non-members are able to access a limited number of cases. CONCLUSIONS: It is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease interobserver variability. It will also help to identify instances where definitions of grades need to be clarified.

Mucinous adenocarcinoma of prostate and prostatic adenocarcinoma with mucinous components: a clinicopathological analysis of 143 cases.

AIM: The clinical significance of mucinous prostatic adenocarcinoma (PCa) remains uncertain. METHODS: From 6440 cases of PCa treated by radical prostatectomy from 2009 to 2014, mucinous components of 5-100% were found in 143 (2.2%) cases. RESULTS: The mean age was 61.4 years, mean pre-operative serum prostate-specific antigen (PSA) was 7.8 ng/ml and clinical stage category was cT1 in 81% and cT2 in 19% of cases. Cases were graded using the 2014 International Society of Urological Pathology recommendation of grading underlying architecture, and Gleason scores (GS) were 3 + 4 in 13.3%, 4 + 3 in 54.5%, 4 + 4 in 2.1%, 3 + 4 or 4 + 3 with tertiary 5 in 11.9% and 9-10 in 18.2%. The mucinous component invariably had a high-grade component. Extraprostatic extension was found in 46.8% of cases. In 21.6%, tumour volume was ≥3 cm³ and 9.7% had surgical margin positivity. Seminal vesicle involvement was found in 6.9%. In 73 cases the mucinous component was >25%, and when cases were divided on the basis of the area of mucin present (≤25 versus >25%) there was no significant difference between clinical or pathological features. Similar findings were achieved when cases were compared with grade-matched non-mucinous carcinoma controls. The 5-year biochemical recurrence rates for mucinous versus non-mucinous cancer were 12.5 versus 17% (P = 0.15). CONCLUSION: PCa with mucinous components is often high grade; however, the prognosis appears to be similar to non-mucinous cancers of similar GS.