A new 7-point method facilitates accurate diagnosis of high-grade urothelial carcinoma in routine urinary cytology practice.

INTRODUCTION: This study was designed to identify the minimal and necessary cell morphologies to be considered for high-precision diagnosis of high-grade urothelial carcinoma (HGUC) in a routine urinary cytology practice. MATERIALS AND METHODS: We included 338 urine cytology specimens from 11 medical facilities in Japan. Six experts evaluated these Papanicolaou-stained specimens using their own diagnostic criteria to categorize them within an initial 4-tiered classification system. Of the 338 cases, 70 HGUC and 32 benign cases (with a complete consensus diagnosis of 6 experts) were included for the analysis. Two of the cytologists evaluated the specimens for 20 specific cellular features. The results were analyzed using a contingency table and by discriminant analysis. RESULTS: Of the original 338 cases, 165 were originally diagnosed as HGUC, but only 70 (42.4%) were scored as malignant by all participating cytologists; of the 101 benign cases, only 32 (31.7%) were classified as such in all examinations. These specimens were re-evaluated by 6 experts using a panel of 20 specific cellular features used to distinguish between HGUC and benign diseases; tests of significance and discriminant analyses identified 7 critical features that were most useful for cytological diagnosis. Statistical analysis revealed that a focus on these 7 features led to a diagnosis of HGUC with a probability of over 95%. CONCLUSIONS: The accuracy of our presently used method to evaluate urinary cytology is not consistently high. This novel classification system, which focuses on 7 critical features, facilitates the high accurate diagnosis of HGUC in routine cytology practice.

Urinary MicroRNAs as Potential Markers for Non-Invasive Diagnosis of Bladder Cancer.

Currently, voided urine cytology (VUC) serves as the gold standard for the detection of bladder cancer (BCa) in urine. Despite its high specificity, VUC has shortcomings in terms of sensitivity. Therefore, alternative biomarkers are being searched, which might overcome these disadvantages as a useful adjunct to VUC. The aim of this study was to evaluate the diagnostic potential of the urinary levels of selected microRNAs (miRs), which might represent such alternative biomarkers due to their BCa-specific expression. Expression levels of nine BCa-associated microRNAs (miR-21, -96, -125b, -126, -145, -183, -205, -210, -221) were assessed by quantitative PCR in urine sediments from 104 patients with primary BCa and 46 control subjects. Receiver operating characteristic (ROC) curve analyses revealed a diagnostic potential for miR-96, -125b, -126, -145, -183, and -221 with area under the curve (AUC) values between 0.605 and 0.772. The combination of the four best candidates resulted in sensitivity, specificity, positive and negative predictive values (NPV), and accuracy of 73.1%, 95.7%, 97.4%, 61.1%, and 80.0%, respectively. Combined with VUC, sensitivity and NPV could be increased by nearly 8%, each surpassing the performance of VUC alone. The present findings suggested a diagnostic potential of miR-125b, -145, -183, and -221 in combination with VUC for non-invasive detection of BCa in urine.

Educational Case: Bladder Carcinoma In Situ.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.

Significance of positive urine cytology on progression and cancer-specific mortality of non--muscle-invasive bladder cancer.

BACKGROUND: Positive results from voided urine cytology (VUC) indicate the fragility of the intercellular adhesion of bladder cancer cells, a critical biological process for invasion and metastasis, along with the presence of atypical cells. Few studies have focused on the prognostic role of VUC in non-muscle-invasive bladder cancer (NMIBC). METHODS: Between 2000 and 2010, 326 patients diagnosed pathologically with Ta or T1 bladder urothelial carcinoma underwent 597 transurethral resections of bladder tumor (TURBTs). Clinicopathological data were prospectively collected at each TURBT. Reports of cells of class IIIb or greater were considered positive VUC results. Muscle-invasive or metastatic recurrences were considered progression. Risk factors for progression and cancer-specific mortality (CSM) were determined using time-fixed and time-dependent Cox models. Variables at the study entry and at each TURBT were used for time-fixed and time-dependent models, respectively. RESULTS: The 5-year cumulative progression and CSM rates were, respectively, 7% and 5% (median follow-up, 46 months). The 5-year cumulative progression and CSM rates for patients with positive VUC were 20% and 15%, respectively, compared with 2% (P < .0001) and 2% (P = .0002), respectively, for patients with negative VUC results. A positive VUC result was a significant and independent risk factor for progression and CSM in the time-fixed and time-dependent models. In time-dependent models, 7 predictors for progression or CSM were identified (positive VUC results, T1 disease, lack of intravesical instillation, higher prior recurrence rate, higher histological grade, male gender, and advanced age), whereas 3 predictors were identified in time-fixed models (positive VUC, T1 disease, and higher prior recurrence rate). VUC results consistently outperformed histological grade as a prognostic predictor. CONCLUSION: Positive VUC results predict the progression and CSM of NMIBC, independent of and outperforming histological grade.

Intravesical seeding of upper urinary tract urothelial carcinoma cells during nephroureterectomy: an exploratory analysis from the THPMG trial.

OBJECTIVE: The Pirarubicin Monotherapy Study Group trial was a randomized Phase II study that evaluated the efficacy of intravesical instillation of pirarubicin in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma. This study conducted further analysis of the Pirarubicin Monotherapy Study Group cohort, focusing on intravesical seeding of cancer cells. METHODS: Using the data from the Pirarubicin Monotherapy Study Group trial, bladder recurrence-free survival rates and factors associated with bladder recurrence in the control group were analyzed. RESULTS: Of 36 patients in the control group, 14 with positive urine cytology had more frequent recurrence when compared with the 22 patients with negative cytology (P = 0.004). Based on the multivariate analysis in the control group, voided urine cytology was an independent predictive factor of bladder recurrence (hazard ratio, 5.54; 95% confidence interval 1.12-27.5; P = 0.036). Of 72 patients in the Pirarubicin Monotherapy Study Group trial, 31 had positive urine cytology. Among the 31 patients, 17 patients who received pirarubicin instillation had fewer recurrences when compared with 14 patients who received control treatment (P = 0.0001). On multivariate analysis, pirarubicin instillation was an independent predictor of better recurrence-free survival rates in the patients with positive urine cytology (hazard ratio, 0.02; 95% confidence interval, 0.00-0.53; P = 0.018). Of 21 patients with bladder recurrence, 17 had recurrent tumor around cystotomy or in the bladder neck compromised by the urethral catheter, supporting the notion that tumor cells seeded in the injured urothelium. CONCLUSIONS: Intravesical instillation of pirarubicin immediately after nephroureterectomy significantly reduced the bladder recurrence rate in patients with positive voided urine cytology. The results suggest that intravesical seeding of upper urinary tract urothelial carcinoma occurs during nephroureterectomy.

Multiplex protein signature for the detection of bladder cancer in voided urine samples.

PURPOSE: Accurate urine assays for bladder cancer detection would benefit patients and health care systems. Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples. In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort. MATERIALS AND METHODS: We performed a case-control, phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders. The urinary concentration of 8 biomarkers (IL-8, MMP-9 and 10, PAI-1, VEGF, ANG, CA9 and APOE) was assessed by enzyme-linked immunosorbent assay. Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values, eg sensitivity and specificity. RESULTS: Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer. The 7 biomarkers were assessed in a new model, which had an AUROC of 0.88 (95% CI 0.84-0.93), and 74% sensitivity and 90% specificity. In contrast, the sensitivity of voided urine cytology and the UroVysion® cytogenetic test in this cohort was 39% and 54%, respectively. Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls. CONCLUSIONS: The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays.

Primary large cell neuroendocrine carcinoma of the ureter.

Large cell neuroendocrine carcinoma (LCNEC) is the rarest type of urinary tract malignancy. Herein, we report a case of LCNEC that arose in the ureter of a 78-year-old Japanese man with a history of ascending colon cancer that had been excised by a right hemicolectomy. Left-sided hydronephrosis associated with the ureteral tumor was discovered during follow-up. A left nephroureterectomy combined with a partial resection of the urinary bladder was performed because atypical cells were detected using voided urine cytology. A histopathological examination revealed that the ureteral tumor contained large atypical epithelial cells of neuroendocrine morphology without a urothelial carcinomatous component. The neoplastic cells were immunohistochemically positive for synaptophysin, chromogranin A, CD56, and cytokeratins, but they were negative for uroplakin III and thyroid transcription factor-1. The Ki-67 labeling index of the neoplastic cells was 50%. Transmission electron microscopy demonstrated the presence of numerous dense granules in the cytoplasm of the neoplastic cells. The ureteral lesion was finally classified as stage III, pT3 cN0 cM0. The patient's postoperative course was uneventful without chemoradiotherapy, and LCNEC did not recur in the subsequent nine months. This case demonstrates that LCNEC can occur in the ureter, which normally does not contain neuroendocrine cells in the urothelium.