The prognostic value of lymph node staging with prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and extended pelvic lymph node dissection in node-positive patients with prostate cancer.

OBJECTIVES: To investigate whether patients with suspected pelvic lymph node metastases (molecular imaging [mi] N1) on staging prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) had a different oncological outcome compared to those in whom the PSMA PET/CT did not reveal any pelvic lymph node metastases (miN0). PATIENTS AND METHODS: All patients with pelvic lymph node metastatic (pN1) disease after robot-assisted radical prostatectomy (RARP) and extended pelvic lymph node dissection (ePLND) between January 2017 and December 2020 were included. To assess predictors of biochemical progression of disease after RARP, a multivariable Cox regression analysis was performed, including number of tumour-positive lymph nodes, diameter of the largest nodal metastasis, and extranodal extension. RESULTS: In total, 145 patients were diagnosed with pN1 disease after ePLND. The median biochemical progression-free survival in patients with miN0 on PSMA PET/CT was 13.7 months, compared to 7.9 months in patients with miN1 disease (P = 0.006). On multivariable Cox regression analysis, both number of tumour-positive lymph nodes (>2 vs 1-2: hazard ratio [HR] 1.97; P = 0.005) and diameter of the largest nodal metastasis (HR 1.12; P < 0.001) were significant independent predictors of biochemical progression of disease. CONCLUSION: Patients in whom pelvic lymph node metastases were suspected on preoperative PSMA imaging (miN1), patients diagnosed with >2 tumour-positive lymph nodes, and patients with a larger diameter of the largest nodal metastasis had a significantly increased risk of biochemical disease progression after surgery.

Prognostic impact of variant histologies in urothelial bladder cancer treated with radical cystectomy.

OBJECTIVES: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). MATERIALS AND METHODS: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox' regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as 'organ-confined' (≤pT2N0), 'locally advanced' (pT3-4N0) and 'node-positive' (pTanyN1-3). RESULTS: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively. CONCLUSIONS: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management.

WHO Classification of Tumours fifth edition: evolving issues in the classification, diagnosis, and prognostication of prostate cancer.

The fifth edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of prostatic carcinoma as well as incorporating advancements in the assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: (1) recognition that prostatic intraepithelial neoplasia (PIN)-like carcinoma is not synonymous with a pattern of ductal carcinoma, but better classified as a subtype of acinar adenocarcinoma; (2) a specific section on treatment-related neuroendocrine prostatic carcinoma in view of the tight correlation between androgen deprivation therapy and the development of prostatic carcinoma with neuroendocrine morphology, and the emerging data on lineage plasticity; (3) a terminology change of basal cell carcinoma to "adenoid cystic (basal cell) cell carcinoma" given the presence of an underlying MYB::NFIB gene fusion in many cases; (4) discussion of the current issues in the grading of acinar adenocarcinoma and the prognostic significance of cribriform growth patterns; and (5) more detailed coverage of intraductal carcinoma of prostate (IDC-P) reflecting our increased knowledge of this entity, while recommending the descriptive term atypical intraductal proliferation (AIP) for lesions falling short of IDC-P but containing more atypia than typically seen in high-grade prostatic intraepithelial neoplasia (HGPIN). Lesions previously regarded as cribriform patterns of HGPIN are now included in the AIP category. This review discusses these developments, summarising the existing literature, as well as the emerging morphological and molecular data that underpins the classification and prognostication of prostatic carcinoma.

Risk factors associated with positive surgical margins' location at radical cystectomy and their impact on bladder cancer survival.

PURPOSE: To evaluate the risk factors associated with positive surgical margins' (PSMs) location and their impact on disease-specific survival (DSS) in patients with bladder cancer (BCa) undergoing radical cystectomy (RC). METHODS: We analyzed a large multi-institutional cohort of patients treated with upfront RC for non-metastatic (cT1-4aN0M0) BCa. Multivariable binomial logistic regression analyses were used to assess the risk of PSMs at RC for each location after adjusting for clinicopathological covariates. The Kaplan-Meier method was used to estimate DSS stratified by margins' status and location. Log-rank statistics and Cox' regression models were used to determine significance. RESULTS: A total of 1058 patients were included and 108 (10.2%) patients had PSMs. PSMs were located at soft-tissue, ureter(s), and urethra in 57 (5.4%), 30 (2.8%) and 21 (2.0%) patients, respectively. At multivariable analysis, soft-tissue PSMs were independently associated with pathological stage T4 (pT4) (Odds ratio (OR) 6.20, p < 0.001) and lymph-node metastases (OR 1.86, p = 0.04). Concomitant carcinoma-in-situ (CIS) was an independent risk factor for ureteric PSMs (OR 6.31, p = 0.003). Finally, urethral PSMs were independently correlated with pT4-stage (OR 5.10, p = 0.01). The estimated 3-years DSS rates were 58.2%, 32.4%, 50.1%, and 40.3% for negative SMs, soft-tissue-, ureteric- and urethral PSMs, respectively (log-rank; p < 0.001). CONCLUSIONS: PSMs' location represents distinct risk factors' patterns. Concomitant CIS was associated with ureteric PSMs. Urethral and soft-tissue PSM showed worse DSS rates. Our results suggest that clinical decision-making paradigms on adjuvant treatment and surveillance might be adapted based on PSM and their location.

Gleason grade patterns in nodal metastasis and corresponding prostatectomy specimens: impact on patient outcome.

AIMS: Lymph node metastases at the time of prostatectomy are an infrequent finding. The correlation of the pattern of nodal metastases with patient outcome has yet to be explored. METHODS AND RESULTS: Lymph node-positive prostatectomies were retrospectively reviewed. The presence of cribriform carcinoma (CC), intraductal carcinoma (IDC) and ISUP grade (G) were documented. The largest nodal metastasis was assessed for the morphological patterns present. G was assigned to the metastasis based on percentage morphological patterns present. Statistical analysis used spss to assess disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS). One hundred and ten cases were identified: G5 (n = 52), G4 (n = 8), G3 (n = 34), G2 (n = 10) and no G (n = 6; treatment effect). IDC or CC was present in 103 (94%) specimens. More than one positive node correlated with worse DFS [P = 0.012, hazard ratio (HR) = 1.951, 95% confidence interval (CI) = 1.142-3.331] and DMFS (P = 0.009, HR = 2.647, 95% CI = 1.239-5.651). G in the prostate and nodal metastasis were poorly correlated (kappa = 0.073, P = 0.195). The presence of pattern 5 was seen in 33 nodes (30%) and correlated with DFS (P = 0.020, HR = 1.903, 95% CI = 1.091-3.320), DSS (P = 0.021, HR = 5.937, 95% CI = 1.084-32.533) and DMFS (P = 0.007, HR = 2.695, 95% CI = 1.269-5.726). Nodal cribriform pattern showed no prognostic correlation and pattern 3 metastasis showed a significant trend towards better outcome (DMFS P = 0.033, HR = 0.431, 95% CI = 0.194-0.958). CONCLUSIONS: IDC or CC is identified in 94% of node-positive prostate cancers. Although G in the largest nodal metastasis has prognostic significance, its G does not reflect that of the primary prostatic adenocarcinoma.

The World Health Organization 1973 classification system for grade is an important prognosticator in T1 non-muscle-invasive bladder cancer.

OBJECTIVES: To compare the prognostic value of the World Health Organization (WHO) 1973 and 2004 classification systems for grade in T1 bladder cancer (T1-BC), as both are currently recommended in international guidelines. PATIENTS AND METHODS: Three uro-pathologists re-revised slides of 601 primary (first diagnosis) T1-BCs, initially managed conservatively (bacille Calmette-Guérin) in four hospitals. Grade was defined according to WHO1973 (Grade 1-3) and WHO2004 (low-grade [LG] and high-grade [HG]). This resulted in a lack of Grade 1 tumours, 188 (31%) Grade 2, and 413 (69%) Grade 3 tumours. There were 47 LG (8%) vs 554 (92%) HG tumours. We determined the prognostic value for progression-free survival (PFS) and cancer-specific survival (CSS) in Cox-regression models and corrected for age, sex, multiplicity, size and concomitant carcinoma in situ. RESULTS: At a median follow-up of 5.9 years, 148 patients showed progression and 94 died from BC. The WHO1973 Grade 3 was negatively associated with PFS (hazard ratio [HR] 2.1) and CSS (HR 3.4), whilst WHO2004 grade was not prognostic. On multivariable analysis, WHO1973 grade was the only prognostic factor for progression (HR 2.0). Grade 3 tumours (HR 3.0), older age (HR 1.03) and tumour size >3 cm (HR 1.8) were all independently associated with worse CSS. CONCLUSION: The WHO1973 classification system for grade has strong prognostic value in T1-BC, compared to the WHO2004 system. Our present results suggest that WHO1973 grade cannot be replaced by the WHO2004 classification in non-muscle-invasive BC guidelines.

Biopsy undergrading in men with Gleason score 6 and fatal prostate cancer in the European Randomized study of Screening for Prostate Cancer Rotterdam.

OBJECTIVES: A total of 15 men who died of prostate cancer had cT1/2 biopsy Gleason score ≤6 prostate cancer at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam. Our objective was to explain (part of) these prostate cancer deaths by undergrading with the classical Gleason score. METHODS: Biopsy specimens of 98 men with classical Gleason score ≤6 or 3 + 4 = 7 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam were retrospectively reviewed by two pathologists using the International Society of Urological Pathology 2014 modified Gleason score. These 98 men included 15 men with cT1/2 classical Gleason score ≤6 who died of prostate cancer (cases) and 83 randomly selected men with classical Gleason score ≤6 or 3 + 4 = 7 (controls). The primary outcome was the reclassification rate from classical Gleason score ≤6 to modified classical Gleason score 3 + 4 = 7 (grade group 2) stratified for prostate cancer death. The secondary outcome was the rate of cribriform/intraductal carcinoma in Gleason score-reclassified men stratified for prostate cancer death. RESULTS: A total of 79 out of 98 men had classical Gleason score ≤6 prostate cancer. A total of eight out of 15 (53%) prostate cancer deaths with classical Gleason score ≤6 were reclassified to modified Gleason score 3 + 4 = 7, compared with 16 out of 64 (25%) men with non-fatal prostate cancer (P = 0.017). A total of five out of eight (63%) Gleason score-reclassified men with fatal prostate cancer had cribriform/intraductal carcinoma, compared with two out of 16 (13%) Gleason score-reclassified men with non-fatal prostate cancer (P = 0.011). CONCLUSIONS: Part of the prostate cancer deaths with Gleason score ≤6 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam could be explained by biopsy undergrading. The present study confirms that the International Society of Urological Pathology 2014 modified Gleason score is more accurate for prognostic assessment based on prostate biopsy than the classical Gleason score.

Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

BACKGROUND: The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. METHODS: ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55-69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50-74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years' follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. FINDINGS: With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83-1·99) after 9 years (1·64 [1·58-1·69] including France), 1·66 (1·60-1·73) after 11 years, and 1·57 (1·51-1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70-1·03) after 9 years, 0·78 (0·66-0·91) after 11 years, and 0·79 (0·69-0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490-1929) men invited for screening or one per 27 (17-66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61-0·88). INTERPRETATION: In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. FUNDING: Each centre had its own funding responsibility.

Molecular and clinical support for a four-tiered grading system for bladder cancer based on the WHO 1973 and 2004 classifications.

Currently, the use of two classification systems for bladder cancer grade is advocated in clinical guidelines because the WHO2004 classification has not been sufficiently validated with biological markers and follow-up. The slides of 325 primary non-muscle invasive bladder cancers from three hospitals were reviewed by one uro-pathologist in two separate sessions for the WHO1973 (G1, G2 and G3) and 2004 (papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) and high-grade (HG)) classifications. FGFR3 status was examined with PCR-SNaPshot analysis. Expression of Ki-67, P53 and P27 was analyzed by immuno-histochemistry. Clinical recurrence and progression were determined. We performed validation and cross-validation of the two systems for grade with molecular markers and clinical outcome. Multivariable analyses were done to predict prognosis and pT1 bladder cancer. Grade review resulted in 88 G1, 149 G2 and 88 G3 lesions (WHO1973) and 79 LMP, 101 LG and 145 HG lesions (WHO2004). Molecular validation of both grading systems showed that FGFR3 mutations were associated with lower grades whereas altered expression (Ki-67, P53 and P27) was found in higher grades. Clinical validation showed that the two classification systems were both significant predictors for progression but not for recurrence. Cross-validation of both WHO systems showed a significant stepwise increase in biological (molecular markers) and clinical (progression) potential along the line: G1-LG-G2-HG-G3. The LMP and G1 categories had a similar clinical and molecular profile. On the basis of molecular biology and multivariable clinical data, our results support a four-tiered grading system using the 1973 and 2004 WHO classifications with one low-grade (LMP/LG/G1) category that includes LMP, two intermediate grade (LG/G2 and HG/G2) categories and one high-grade (HG/G3) category.

Prognostic significance of substage and WHO classification systems in T1 urothelial carcinoma of the bladder.

PURPOSE OF REVIEW: Treatment of T1 urothelial bladder cancer (T1-BC) is challenging as risk assessment criteria for progression are lacking. Histological grade and T1 substage have been identified as important prognostic factors. Currently, no consensus exists regarding the optimal sub-staging and grading systems for T1-BC. We reviewed recent advances in the various grading and sub-staging systems and their clinical applicability. RECENT FINDINGS: Stratification by muscularis mucosae invasion is the most explored sub-staging system. Its prognostic value was established by 12/23 (52%) available studies. Importantly, muscularis mucosae identification varied substantially among pathologists. Sub-staging based on diameter of invasive carcinoma [T1 microinvasive and T1 extensive-invasive (T1m/e)] proved a more reproducible system with at least equal prognostic value. However, more study is needed to investigate interobserver variation. For nonmuscle-invasive bladder cancer grading, the 1973 and 2004 WHO classifications both provide independent prognostic information. However, remarkably few studies have investigated their applicability in T1-BC only. The available reports suggest that the 1973 WHO classification is superior to WHO 2004. SUMMARY: If multicenter studies confirm the promising results of T1m/e sub-staging, it may be incorporated in the Internation Union Against Cancer TNM classification system for urinary bladder cancer. More studies are warranted to define the optimal classification system for grade in T1-BC.

Validation of stem cell markers in clinical prostate cancer: α6-integrin is predictive for non-aggressive disease.

BACKGROUND: Stem cells are postulated to mediate prostate cancer progression, and represent a small fraction of the entire tumor. Various proteins (α2-integrin, α6-integrin, CD117, CD133, EZH2, OCT3/4) are associated with a prostate cancer stem cell phenotype in cell lines and xenografts. Our objective was to investigate expression of stem cell markers in clinical prostate cancer in relation to outcome. METHODS: We validated immunohistochemical expression of stem cell markers in 481 prostate cancer patients and correlated expression with clinicopathologic parameters. RESULTS: Sporadic expression of α2-integrin was present in a fraction of tumor cells (<5%) in 94.7% of tumors and associated with PSA > 10 ng/ml (P = 0.04). α6-Integrin expression (<5%) occurred in 28.4% patients, while ≥5% α6-integrin expression was associated with PSA≤10 ng/ml (P = 0.01), Gleason score <7 (P < 0.01) and pT2-disease (P = 0.02). α6-integrin was predictive for biochemical recurrence (P < 0.01), local recurrence (P = 0.03) and disease specific death (P = 0.03). EZH2 expression was generally low with 2.6% of tumors showing ≥1% positive cells. EZH2 was associated with Gleason score ≥7 (P = 0.01) and biochemical recurrence (P = 0.01). We did not identify expression of CD117, CD133, and OCT3/4 in prostate cancer samples. CONCLUSIONS: Expression of α2-integrin and EZH2 in a small fraction of prostate cancer cells is supportive for their role as stem cell marker. Although α6-integrin was not a unique stem cell marker, it was predictive for prostate cancer biochemical and local recurrence, and disease specific death. The validity of CD117, CD133, and OCT3/4 as prostate cancer stem cell marker is questionable since these proteins were not expressed in clinical prostate cancer.

An interobserver reproducibility study on invasiveness of bladder cancer using virtual microscopy and heatmaps.

AIMS: The distinction between non-invasive (pTa) and invasive (pT1) non-muscle invasive bladder cancer (NMIBC) is subject to considerable interobserver variation. We aimed to generate a teaching set of images based on the diagnostic opinions of a panel of expert genitourinary pathologists. METHODS AND RESULTS: Twenty-five transurethral resection specimens initially reported as pT1 NMIBC from two university hospitals were selected on the basis of potential uncertainty of stromal invasion. Digitized slides were reviewed independently by a panel of eight genitourinary pathologists, who annotated any invasive area if present. Annotations were reviewed by the lead panel, and heatmaps of annotated areas were constructed. Reasons for discrepancies were analysed, and kappa scores were calculated to determine agreement among the eight panellists. Full agreement by the eight panellists was obtained in 11 of 25 cases (44%), with a multi-rater (Fleiss) kappa of 0.47 (P < 0.0001). After joint review of the seven discordant (agreement <75% of panellists) cases, consensus was obtained for six cases, and a teaching set of images was generated. CONCLUSIONS: Interobserver agreement among the panellists in the selected cases was moderate, but consensus could be reached in almost all cases. Heatmaps proved to be instrumental in generating a teaching set of images for standardization of histological criteria for NMIBC invasion.

The predictive value of immunohistochemical markers in untreated Wilms' tumour: are they useful?

PURPOSE: This study reevaluates the potential role of different tumour markers as prognostic indicators in untreated nephroblastoma. METHODS: Expression of a broad panel of tumour markers was investigated by means of immunohistochemical analysis in 43 WT patients. Patients were treated by radical nephrectomy and had a mean follow-up of 11.9 years. RESULTS: Generally, all the tumour markers studied were expressed in normal kidney tissue and at variable levels in the three cell types of WT (blastema, epithelium and stroma). Immunoreactive blastemal (Bcl-X, Bcl-2 and CD44s) and epithelial (Bcl-X, Bcl-2 and MIB-1) cells were present in the majority of tumours. No correlation was found between their expression and pathological stages. Univariate analysis showed that blastemal WT-1, TGF-α, VEGF, MIB-1 and p27 Kip1 were indicative for clinical progression. In a multivariate analysis, WT-1 protein expression by blastemal cells was an independent prognostic marker for clinical progression. CONCLUSIONS: The blastemal WT-1, TGF-α, VEGF, MIB-1 and p27Kip1 expression correlate with clinical progression in untreated nephroblastoma. Therefore, their expression may be of value in identifying patients with a high propensity to develop distant metastases.

The Search for the Optimal cut-off Value of p53-Immunohistochemistry to Predict Prognosis of Invasive Bladder Cancer: A Multi-Center, Multi-Laboratory Analysis.

Introduction: Mutations in the TP53 gene are indicative of worse outcome in bladder cancer and are usually assessed by immunohistochemistry. To define p53-overexpression, a threshold of >10% is most commonly used (cut-off1). Recently, a novel cut-off (aberrant = 0% or ≥50%) (cut-off2) showed better correlation to clinical outcome. In this study, we evaluate the association between p53-immunohistochemistry cut-offs, clinico-pathological variables and disease-specific survival (DSS). Methods: Seven-hundred-fifty chemotherapy-naïve patients who underwent radical cystectomy were included (92% muscle-invasive bladder cancer. In addition to cut-off1 and cut-off2, a third cut-off (cut-off3) was determined based on the highest Youden-index value. Cut-off values were associated with clinico-pathological variables and FGFR3 mutation status. The Kaplan-Meier method was used to estimate DSS. Results: Aberrant p53-expression was found in 489 (65%) (cut-off1) and 466 (62%) (cut-off2) tumors. Cut-off3 was determined at 25% and aberrant p53-expression in 410 cases (55%) (cutoff3). p53-expression levels were significantly associated with higher pT-stage (cut-off1/2/3: P = 0.047, P = 0.006 and P = 0.0002, respectively), higher grade (all, P < 0.0001), and FGFR3 wild-type (cut-off1: P = 0.02, cut-offs2&3: P = 0.001). Median follow-up was 5.3 years (interquartile range, 4.0-6.0 years). p53-expression was not associated with DSS for any of the three cut-offs (cut-off1/2/3: P-log-rank = 0.566, 0.77 and 0.50, respectively). If we only considered locally advanced bladder cancer, results on DSS remained non-significant. Conclusion: This multi-center, multi-laboratory study showed that, regardless of the cut-off used, p53-immunohistochemistry did not enable selection of patients with worse outcome. Our results suggest that p53-immunohistochemistry alone is not suitable to guide clinical decision making after radical cystectomy.

International Opinions on Grading of Urothelial Carcinoma: A Survey Among European Association of Urology and International Society of Urological Pathology Members.

Background: Grade of non-muscle-invasive bladder cancer (NMIBC) is an important prognostic factor for progression. Currently, two World Health Organization (WHO) classification systems (WHO1973, categories: grade 1-3, and WHO2004 categories: papillary urothelial neoplasm of low malignant potential [PUNLMP], low-grade [LG], high-grade [HG] carcinoma) are used. Objective: To ask the European Association of Urology (EAU) and International Society of Urological Pathology (ISUP) members regarding their current practice and preferences of grading systems. Design setting and participants: A web-based, anonymous questionnaire with ten questions on grading of NMIBC was created. The members of EAU and ISUP were invited to complete an online survey by the end of 2021. Thirteen experts had previously answered the same questions. Outcome measurements and statistical analysis: The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed. Results and limitations: Currently, 53% use only the WHO2004 system and 40% use both systems. According to most respondents, PUNLMP is a rare diagnosis with management similar to Ta-LG carcinoma. The majority (72%) would consider reverting back to WHO1973 if grading criteria were more detailed. Separate reporting of WHO1973-G3 within WHO2004-HG would influence clinical decisions for Ta and/or T1 tumors according the majority (55%). Most respondents preferred a two-tier (41%) or a three-tier (41%) grading system. The current WHO2004 grading system is supported by a minority (20%), whereas nearly half (48%) supported a hybrid three- or four-tier grading system composed of both WHO1973 and WHO2004. The survey results of the experts were comparable with ISUP and EAU respondents. Conclusions: Both the WHO1973 and the WHO2004 grading system are still widely used. Even though opinions on the future of bladder cancer grading were strongly divided, there was limited support for WHO1973 and WHO2004 in their current formats, while the hybrid (three-tier) grading system with LG, HG-G2, and HG-G3 as categories could be considered the most promising alternative. Patient summary: Grading of non-muscle-invasive bladder cancer (NMIBC) is a matter of ongoing debate and lacks international consensus. We surveyed urologists and pathologists of European Association of Urology and International Society of Urological Pathology on their preferences regarding NMIBC grading to generate a multidisciplinary dialogue. Both the "old" World Health Organization (WHO) 1973 and the "new" WHO2004 grading schemes are still used widely. However, continuation of both the WHO1973 and the WHO2004 system showed limited support, while a hybrid grading system composed of both the WHO1973 and the WHO2004 classification system may be considered a promising alternative.

The FGFR3 mutation is related to favorable pT1 bladder cancer.

PURPOSE: Stage pT1 bladder cancer comprises a heterogeneous group of tumors for which different management options are advocated. FGFR3 mutations are linked to favorable (low grade/stage) pTa bladder cancer while altered P53 is common in cases of high grade, muscle invasive (pT2 or greater) bladder cancer. We determined the frequency of FGFR3 mutations and P53 alterations in patients with pT1 bladder cancer and correlated these data to histopathological variables and clinical outcomes. MATERIALS AND METHODS: We included 132 patients with primary pT1 bladder cancer from a total of 2 academic centers. A uropathologist reviewed the slides for grade and confirmed the pT1 diagnosis. FGFR3 mutation status was examined by SNaPshot® analysis and P53 expression was determined by standard immunohistochemistry. Kaplan-Meier and multivariate analyses were used to assess progression. RESULTS: FGFR3 mutations were detected in 37 of 132 pT1 bladder cancer cases (28%) and altered P53 was seen in 71 (54%). Only 8% of patients had the 2 molecular alterations (p = 0.001). FGFR3 mutation correlated with lower grade and altered P53 correlated with high grade pT1 bladder cancer. Median followup was 6.5 years. FGFR3 mutation status and carcinoma in situ were significant for predicting progression on univariate and multivariate analyses but P53 status was not. CONCLUSIONS: FGFR3 mutations selectively identify patients with pT1 bladder cancer who have favorable disease characteristics. Further study may confirm that FGFR3 identifies those who would benefit from a conservative approach to the disease.

Prognostic value of molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer risk scores in primary T1 bladder cancer.

UNLABELLED: What's known on the subject? and What does the study add? The stakes are high when making treatment decisions in T1 bladder cancer (BC). Conservative management may lead to progression and possibly death from BC. Conversely, radical cystectomy could be over-treatment of non-progressive disease. The problem for clinicians is that reliable prognostic indices are lacking. We performed a head-to-head comparison of two substaging systems, European Organisation for the Research and Treatment of Cancer (EORTC) risk scores and four molecular markers in T1 carcinomas of the bladder treated conservatively with BCG. T1 sub-stage according to a new system (micro-invasive [T1m] and extensive-invasive [T1e]) was the most important clinical variable for predicting progression to carcinoma invading bladder muscle. The performance of the EORTC risk scores was disappointing for this T1 sub-group. Molecular markers were not significant in multivariable analysis for predicting progression. Future studies may lead to the incorporation of sub-stage (T1m/T1e) in the TNM classification system for urinary BC to guide clinical decision-making in T1 BC. OBJECTIVE: To evaluate the prognostic significance of four molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer (EORTC) risk scores in primary T1 bladder cancer (BC) treated with adjuvant bacille Calmette-Guérin. PATIENTS AND METHODS: The slides of 129 carcinomas of the bladder from two university hospitals were reviewed and the T1 diagnosis was confirmed. T1 sub-staging was done in two separate rounds, using a new system that identifies micro-invasive (T1m) and extensive-invasive (T1e) T1BC, and then according to invasion of the muscularis mucosae (T1a/T1b/T1c). The EORTC risk scores for recurrence and progression were calculated. Uni- and multivariable analyses for recurrence and progression were performed using clinicopathological variables, T1 sub-stage, EORTC risk scores and molecular markers (fibroblast growth factor receptor 3 gene mutation and Ki-67, P53, P27 expression). RESULTS: The median follow-up was 6.5 years. Forty-two patients remained recurrence-free (33%). Progression to T2 or metastasis was observed in 38 (30%) patients. In multivariable analysis for recurrence, multiplicity was significant. In multivariable analysis for progression, female gender, sub-stage (T1m/T1e) and carcinoma in situ (CIS) were significant. Molecular markers were significant in univariable and in multivariable analyses for recurrence. EORTC risk scores were not significant. CONCLUSIONS: CIS, female gender and sub-stage (T1m/T1e) were the most important variables for progression. The additional value of molecular markers was modest. Sub-stage (T1m/T1e) could potentially be incorporated in future tumour-node-metastasis classifications.

Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients.

OBJECTIVES: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort. PATIENTS AND METHODS: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS). RESULTS: pT-stage was

International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 2: T2 substaging and prostate cancer volume.

The 2009 International Society of Urological Pathology consensus conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the substaging of pT2 prostate cancers according to the TNM 2002/2010 system, reporting of tumor size/volume and zonal location of prostate cancers were coordinated by working group 2. A survey circulated before the consensus conference demonstrated that 74% of the 157 participants considered pT2 substaging of prostate cancer to be of clinical and/or academic relevance. The survey also revealed a considerable variation in the frequency of reporting of pT2b substage prostate cancer, which was likely a consequence of the variable methodologies used to distinguish pT2a from pT2b tumors. Overview of the literature indicates that current pT2 substaging criteria lack clinical relevance and the majority (65.5%) of conference attendees wished to discontinue pT2 substaging. Therefore, the consensus was that reporting of pT2 substages should, at present, be optional. Several studies have shown that prostate cancer volume is significantly correlated with other clinicopathological features, including Gleason score and extraprostatic extension of tumor; however, most studies fail to demonstrate this to have prognostic significance on multivariate analysis. Consensus was reached with regard to the reporting of some quantitative measure of the volume of tumor in a prostatectomy specimen, without prescribing a specific methodology. Incorporation of the zonal and/or anterior location of the dominant/index tumor in the pathology report was accepted by most participants, but a formal definition of the identifying features of the dominant/index tumor remained undecided.

International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 3: extraprostatic extension, lymphovascular invasion and locally advanced disease.

The International Society of Urological Pathology Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to extraprostatic extension (pT3a disease), bladder neck invasion, lymphovascular invasion and the definition of pT4 were coordinated by working group 3. It was agreed that prostate cancer can be categorized as pT3a in the absence of adipose tissue involvement when cancer bulges beyond the contour of the gland or beyond the condensed smooth muscle of the prostate at posterior and posterolateral sites. Extraprostatic extension can also be identified anteriorly. It was agreed that the location of extraprostatic extension should be reported. Although there was consensus that the amount of extraprostatic extension should be quantitated, there was no agreement as to which method of quantitation should be employed. There was overwhelming consensus that microscopic urinary bladder neck invasion by carcinoma should be reported as stage pT3a and that lymphovascular invasion by carcinoma should be reported. It is recommended that these elements are considered in the development of practice guidelines and in the daily practice of urological surgical pathology.