Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.

BACKGROUND: The most important indicator for urologic surgeons at The Johns Hopkins Hospital to have a patient undergo cystoscopy is a cytologic diagnosis of high‐grade urothelial carcinoma. The template was designed to standardize diagnostic categories so clinicians can manage their patients uniformly. The template was based in part on the Bethesda System for cervical cytology.METHODS: According to the template, reactive/inflammatory changes were included in the negative group (no urothelial atypia or malignancy identified). The category atypical urothelial cells of undetermined significance (AUC‐US) was akin to atypical squamous cells of undetermined significance (ASC‐US), as was the category of atypical urothelial cells, favor high‐grade carcinoma (AUC‐H). The categories high‐grade urothelial carcinoma (HGUC) and low‐grade urothelial carcinoma also were added.RESULTS: The Pathology Data System at the Johns Hopkins Hospital was searched for cases that met the following criteria over a period from July 1, 2007 to June 30, 2009: all cytologic specimens from the urinary tract and all surgical specimens with a diagnosis of HGUC, regardless of invasion status. All cytologic specimens were then matched with biopsies during the same period, and all surgical specimens from patients who had a cytologic diagnosis of AUC‐US or AUC‐H were retrieved for 18 months after the end of the 2‐year study period. Greater than 50% of patients who had biopsy‐confirmed HGUC had a preceding cytologic diagnosis of AUC‐H or HGUC. When patients with AUC‐US were added to the analysis, 80% of patients with HGUC had at least 1 abnormal urinary cytology result. Of those patients who had a diagnosis of AUC‐H, 38% had urothelial cancer discovered at biopsy compared with only 10% of those with an AUC‐US diagnosis.CONCLUSIONS: The authors concluded that their template is effective in targeting those patients who need to undergo cystoscopy. Cancer (Cancer Cytopathol) 2013;121:15–20 © 2012 American Cancer Society.

BACKGROUND: Urine cytology represents a major portion of testing volume in many cytopathology laboratories.METHODS: The authors previously reported a template designed to standardize urothelial diagnostic categories to enable clinicians to uniformly manage their patients. In this study, they examined the common cytomorphologic features observed in specimens diagnosed with atypical urothelial cells, cannot exclude high‐grade urothelial carcinoma (AUC‐H), which prove most predictive of high‐grade urothelial carcinoma (HGUC).RESULTS: The most common morphologic features observed in the AUC‐H specimens were hyperchromasia, irregular nuclear borders, increased nucleus‐to‐cytoplasm ratio, and anisonucleosis. Of the 58 patients who had specimens diagnosed with AUC‐H, 95% ultimately were diagnosed with HGUC on follow‐up biopsy over the study period. The small number of patients who had AUC‐H with non‐HGUC follow‐up did not allow for a statistical comparison to determine the predictive ability of the selected criteria for HGUC. Next, the authors used the same features to examine a subset of urine samples that were diagnosed with atypical urothelial cells of unknown significance (AUC‐US) in an attempt to improve the predictive value of this clinically frustrating category. A blind review was performed of 290 urine specimens from 217 patients. In contrast to the AUC‐H specimen cohort, the majority of specimens with AUC‐US did not contain atypical cells with the 4 common morphologic features. All 4 features significantly predicted HGUC in surveillance patients, but not in patients with hematuria.CONCLUSIONS: Hyperchromasia was the strongest predictor of HGUC by far in patients who were undergoing surveillance (odds ratio, 9.81). Hyperchromasia remained statistically significant in multivariate analysis, indicating its predictive strength even in the absence of other features. Cancer (Cancer Cytopathol) 2013;121:21–28 © 2012 American Cancer Society.