Diagnostic and prognostic implications of a three-antibody molecular subtyping algorithm for non-muscle invasive bladder cancer.

Intrinsic molecular subtypes may explain marked variation between bladder cancer patients in prognosis and response to therapy. Complex testing algorithms and little attention to more prevalent, early-stage (non-muscle invasive) bladder cancers (NMIBCs) have hindered implementation of subtyping in clinical practice. Here, using a three-antibody immunohistochemistry (IHC) algorithm, we identify the diagnostic and prognostic associations of well-validated proteomic features of basal and luminal subtypes in NMIBC. By IHC, we divided 481 NMIBCs into basal (GATA3- /KRT5+ ) and luminal (GATA3+ /KRT5 variable) subtypes. We further divided the luminal subtype into URO (p16 low), URO-KRT5+ (KRT5+ ), and genomically unstable (GU) (p16 high) subtypes. Expression thresholds were confirmed using unsupervised hierarchical clustering. Subtypes were correlated with pathology and outcomes. All NMIBC cases clustered into the basal/squamous (basal) or one of the three luminal (URO, URO-KRT5+ , and GU) subtypes. Although uncommon in this NMIBC cohort, basal tumors (3%, n = 16) had dramatically higher grade (100%, n = 16, odds ratio [OR] = 13, relative risk = 3.25) and stage, and rapid progression to muscle invasion (median progression-free survival = 35.4 months, p = 0.0001). URO, the most common subtype (46%, n = 220), showed rapid recurrence (median recurrence-free survival [RFS] = 11.5 months, p = 0.039) compared to its GU counterpart (29%, n = 137, median RFS = 16.9 months), even in patients who received intravesical immunotherapy (p = 0.049). URO-KRT5+ tumors (22%, n = 108) were typically low grade (66%, n = 71, OR = 3.7) and recurred slowly (median RFS = 38.7 months). Therefore, a simple immunohistochemical algorithm can identify clinically relevant molecular subtypes of NMIBC. In routine clinical practice, this three-antibody algorithm may help clarify diagnostic dilemmas and optimize surveillance and treatment strategies for patients.

Attitudes and experience of urology trainees in interpreting prostate magnetic resonance imaging.

INTRODUCTION: Multiparametric magnetic resonance imaging (mpMRI) has resulted in accurate prostate cancer localization and image-guided targeted sampling for biopsy. Despite its more recent uptake, knowledge gaps in interpretation and reporting exist. Our objective was to determine the need for an educational intervention among urology residents working with mpMRIs. METHODS: We administered an anonymous, cross-sectional, self-report questionnaire to a convenience sample of urology residents in U.S. and Canadian training programs. The survey included both open- and closed-ended questions employing a five-point Likert scale. It was designed to assess familiarity, exposure, experience, and comfort with interpretation of mpMRI. RESULTS: Fifty-three surveys were completed by residents in postgraduate years (PGY) 1-5 and of these, only 12 (23%) reported any formal training in mpMRI interpretation. Most residents' responses demonstrated significant experience with prostate biopsies, as well as familiarity with reviewing mpMRI for these patients. However, mean (± standard deviation [SD]) Likert responses suggested a relatively poor understanding of the components of Prostate Imaging-Reporting and Data System (PI-RADS) v2 scoring for T2-weighted films (2.45±1.01), diffusion-weighted imaging (DWI) films (2.26±0.90), and dynamic contrast-enhanced (DCE) films (2.21±0.99). Similar disagreement scores were observed for questions around interpretation of the different functional techniques of MRI images. Residents reported strong interest (4.21±0.91) in learning opportunities to enhance their ability to interpret mpMRI. CONCLUSIONS: While mpMRI of the prostate is a tool frequently used by care teams in teaching centers to identify suspicious prostate cancer lesions, there remain knowledge gaps in the ability of trainees to interpret images and understand PI-RADS v2 scoring. Online modules were suggested to balance the needs of trainee education with the residency workflow.

Effect of centralization on complex surgical care: A population-based case study of radical cystectomy.

INTRODUCTION: We sought to determine whether non-mandated or passive centralization of radical cystectomy (RC) to higher-volume centers leads to enhanced processes of care and outcomes. METHODS: This is a population-based, retrospective, cohort study that used the Ontario Cancer Registry (OCR) to identify all incident patients who underwent RC from 1994-2013. Electronic records of treatment were linked to OCR; pathology records were obtained for all cases and reviewed by a team of trained data abstractors. The primary objective was to describe annual provider RC volumes. Secondary objectives included investigating process and outcome measures. RESULTS: For the 5574 patients identified, the mean annual surgeon volume and hospital volume of RC from 1994-2008 was 4.5 (95% confidence interval [CI] 4.4-4.7) and 12.2 (95% CI 11.8-12.5), respectively. From 2009-2013, these volumes significantly increased to 6.8 (95% CI 6.5-7. 1) and 16.4 (95% CI 15.8-16.9). Process variables improved over time, including the use of neoadjuvant chemotherapy. Over the study period, there was a substantial improvement in cancer-specific survival (CSS): hazard ratio (HR) 0.60 (95% CI 0.53-0.67) for 2009-2013. During the most recent era, there was still evidence of a provider volume effect on both process measures and CSS. CONCLUSIONS: There has been recent passive centralization of RC to higher-volume providers in the province of Ontario, with measurable improvements in processes of quality care. Although centralization was also associated with improvement in CSS, in the most recent era, there continues to be low-volume providers with a residual volume-outcome effect.

Prognostic pathological factors in radical cystectomy after neoadjuvant chemotherapy.

AIMS: We undertook a systematic evaluation of the prognostic value of numerous histological factors in 165 radical cystectomies (RCs) of patients with invasive urothelial carcinoma (UC) who underwent surgery after neoadjuvant chemotherapy (NAC). METHODS AND RESULTS: Tumour regression grade (TRG) and therapy-related stromal and epithelial changes were also recorded. Locally advanced disease (≥pT2 and/or pN+) was present in 64% of patients, 22% had no evidence of residual carcinoma (pT0 + pN0), and 28% had no evidence of residual muscle-invasive carcinoma (≤pT1 + N0). TRG1, TRG2 and TRG3 were found in 32%, 15% and 50% of patients, respectively. Histological variants of UC were reported in 25% of cases. The most common therapy-related stromal change was fibroblastic reaction (78%), and the most common epithelial change in residual UC was smudgy and poorly preserved chromatin (28%). Prominent stromal and epithelial changes were noted in 41% and 5% of RCs, respectively. Progression was found in 45% of patients, and cancer-related deaths occurred in 30%. Multivariate analysis showed that the only independent prognostic parameters for progression were T stage, N stage, lymphovascular invasion, and margin status. Similarly, only T stage, N stage and margin status correlated with cancer-related deaths. Neither TRG nor any of the stromal-related or epithelial-related variables correlated with outcome. CONCLUSIONS: We confirm that the traditional and routinely reported histological parameters in RC post-NAC remain the most powerful prognosticators of disease course. The significance of TRG in the bladder remains unconfirmed.

Erratum: Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer.

[This corrects the article DOI: 10.3233/BLC-170120.].

Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer.

BACKGROUND: Urothelial bladder cancer (UBC) is a highly prevalent disease in North America, however its optimal management remains elusive. The contribution of B cell associated responses is poorly understood in bladder cancer. Lymphoid neogenesis is a hallmark of an active immune response at tumor sites that sometimes leads to formation of tertiary lymphoid structures (TLS) that resemble germinal centers formed in secondary lymphoid organs. OBJECTIVE: This study was conducted with an aim to investigate the presence and characteristics of TLS in UBC with a focus to compare and contrast the TLS formation in treatment naive low grade non-muscle invasive (NMIBC) and muscle invasive bladder cancers (MIBC). METHODS: The study cohort consisted of transurethral bladder resection tumour (TURBT) specimens from 28 patients. Sections showing lymphoid aggregates in hematoxylin and eosin (H&E) stained TURBT specimens were further subjected to multi-color immunohistochemistry using immune cell markers specific to CD20+ B cells, CD3+ and CD8+ T cells, PNAd+ high endothelial venules, CD208+ mature dendritic cells, CD21+ follicular dendritic cells to confirm the hallmarks of classical germinal centers. RESULTS: Our pilot study investigating the presence of TLS in bladder cancer patients is the first to demonstrate that well-formed TLS are more common in aggressive high grade MIBC tumors compared to low grade NIMBC. CONCLUSIONS: These novel findings suggest B cell mediated anti-tumour humoral immune responses in bladder cancer progression.