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Purpose: The American Urological Association guideline for asymptomatic microhematuria recommends in patients with a negative initial workup, repeat workup should be considered for those with persistent/recurrent microhematuria. However, there is little data on the yield of repeat evaluation. Our hypothesis was that repeat workup yields a low detection rate of urologic malignancy., Materials and Methods: We retrospectively reviewed all patients at our institution who underwent microhematuria workup with cystoscopy and upper tract imaging from May 2010 to June 2016. Microhematuria was defined as ≥3 RBCs/HPF on a properly collected specimen in the absence of a benign cause. Demographics, age, smoking history, history of radiation, and findings on repeat cystoscopy and imaging were collected. Our primary endpoint was a new diagnosis of urologic malignancy., Results: Our initial cohort included 1,332 patients, of whom 21 were diagnosed with urothelial carcinoma and 7 with suspicious renal masses on initial workup. A total of 637 patients with negative initial workup had persistent/recurrent microhematuria. Repeat cystoscopy was performed in 161 (25%) patients at a median of 39 months, and repeat upper tract imaging was performed in 317 (50%) patients at a median of 39 months. Overall, repeat cystoscopy revealed new bladder cancer in 2 (1.2%) patients and repeat imaging revealed new suspicious renal mass in 4 (1.3%) patients., Conclusions: We observed a low number of newly diagnosed malignancies among patients with persistent/recurrent asymptomatic microhematuria who had a prior negative workup. Additional research is required to determine the utility of a repeat AMH workup., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The Paris System (TPS) for Reporting Urinary Cytology (UCyto) was published in 2016, but to date, no study addressing the unsatisfactory (UNSAT) category has been published. We aimed to identify the negative predictive value (NPV) for UNSAT UCyto after the implementation of TPS at our institution., Method: For the period from January 1, 2017, to December 31, 2019, we identified all cases with UNSAT diagnosis on UCyto specimens and available cytologic and/or surgical pathology follow-up within 6 months from the UNSAT diagnosis. Cases were deemed true negative (TN) if the follow-up was "negative for high-grade urothelial carcinoma" (NHGUC). Information regarding previous medical history, clinical indications, and specimen type were tabulated and analyzed., Results: From 6348 UCyto specimens, there were 230 (3.6%) UNSAT diagnoses made on 209 patients (112 [53.6%] men and 97 [46.4%] women) with a median age of 64 years. Of these, 116 UCyto specimens from 106 patients, which had cytologic and/or surgical pathology follow-up within 6 months, were further studied. Most UNSAT UCyto specimens were bladder washing/barbotage (BW/BB), and the most common indication for UCyto was cancer surveillance. The main cause of UNSAT UCyto was low cellularity. There were 5 false-negative (FN) results for high-grade urothelial carcinoma (HGUC), which corresponds to an overall NPV of 84.4%. NPV was highest for patients with UCyto for hematuria, and for patients with BW/BB as UCyto specimen type., Conclusions: Our results show that UNSAT diagnoses have a lower NPV than that typical of NHGUC diagnoses, and should be managed accordingly., (Published by Elsevier Inc.)

Introduction: The Paris System for Reporting Urinary Cytology (TPS) was first published in 2016 to standardize reporting and placed a specific emphasis on high-grade urothelial carcinoma (HGUC). The urinary tract is anatomically divided into the upper tract (UT) and the lower tract (LT). A major morphologic criterion in TPS for HGUC defines the nuclear-to-cytoplasmic (N/C) ratio as ≥ 0.7. In this study, we evaluated N/C ratios of HGUC arising from UT and LT urine specimens, to ascertain differences due to location., Materials and Methods: Digital annotations of whole slide scanned images were performed and enumerated., Results: The cohort consisted of 59 ThinPrep specimens from 52 patients. The majority of the tumors were located in LT (39 of 59, 66.1%). A total of 590 cells were analyzed (10 cells per case). In UT, the average N/C was 0.58 and LT the average was 0.54 (P < 0.001). The average nuclear area for UT was 126.3 and for LT was 158.2 μm 2 (P = 0.01). The average cytoplasmic area for UT was 219.1 μm 2 and for LT was 296.2 μm 2 (P < 0.001). The average cellular circumference for UT was 59.4 μm and for LT was 66.1 μm (P < 0.001)., Conclusions: We found that UT HGUCs have higher N/C ratios, smaller cell circumference, smaller nuclei, and less cytoplasm compared with LT. When UT was divided into renal pelvis and ureter, no statistical difference was identified., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Plasmacytoid and micropapillary variants of high-grade urothelial carcinoma (HGUC) exhibit unique histologic morphology and very aggressive clinical behavior. However, the morphology of these 2 variants in urinary cytology is not well studied and evaluated using The Paris System for reporting urinary cytology., Materials and Methods: A database search was performed in all patients with the diagnosis of plasmacytoid or micropapillary HGUC. A total of 5 patients with positive urinary cytology cases were identified. The cytomorphology of every urinary cytology case was correlated with the histologic features in the surgical specimens from the same patient., Results: One urine and 4 bladder washings were evaluated. Cytologically, plasmacytoid HGUCs are characterized by single, large tumor cells with hyperchromasia, irregular nuclear membranes, and vacuolated cytoplasm. The nuclear-to-cytoplasmic (N:C) ratio was less than 0.5 in many of the malignant cells due to the abundant cytoplasm. The cytology features of micropapillary HGUC include the presence of micropapillae of tumor cells with no fibrovascular core. Individual high-grade urothelial cells were also identified in all 4 cases, but 1 (25%) of these had only rare cells meeting The Paris System criteria for HGUC due to abundant cytoplasm and lack of hyperchromasia in most malignant cells., Conclusions: Plasmacytoid and micropapillary variants of HGUC have unique cytomorphologic features in urinary cytology specimens, which are reflective of the corresponding histological findings. These 2 clinically aggressive variants of HGUC may not be as readily interpreted as malignant using The Paris System for reporting urinary cytology, creating potential diagnostic pitfalls., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Urothelial carcinoma (UC) requires lifelong monitoring, commonly through urinary cytology and cystoscopy. Urine cytology has a relatively high sensitivity for detecting high-grade urothelial carcinoma (HGUC); however, its sensitivity for low-grade urothelial neoplasm (LGUN) is significantly lower with wide interobserver variability. The Paris System (TPS) was proposed to create standardized diagnostic categories with defined cytomorphologic criteria. We attempt to evaluate diagnostic efficacy of identifying UC using TPS through cytologic-histologic correlation., Materials and Methods: A retrospective search identified 170 cases of urine cytology cases with concurrent biopsies collected during a 2-year time period at University of Rochester Medical Center. Patient age, sex, smoking history, prior malignancy diagnoses, cystoscopy findings, specimen collection method, UroVysion results, and 1-year follow-up of surgical pathology cases were included., Results: Cytologic-histologic correlation was identified in 59% of cases, with 18% true positives and 41% true negatives. Discordant results were identified in 41% of cases; of these, 4% were false positives, 11% false negatives, 12% potential sampling bias, and 14% were low-grade urothelial carcinoma (LGUC). The analysis of this 2-year study finds a positive predictive value of urine cytology for HGUC to be 81%, a negative predictive value of 79%, a sensitivity of 61%, a specificity of 91%, and an accuracy of 79%., Conclusions: Our results support TPS's ability to improve the reliability and accuracy of interpretations in urine cytology for HGUC. Nevertheless, additional studies are essential to improve the diagnostic accuracy of LGUN, and urine adequacy, in order to improve patient care and early detection, while identifying potential sampling bias., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: The Paris System (TPS) for reporting urine cytology was developed for standardization of diagnosis focusing on the detection of high-grade urothelial carcinoma (HGUC). Probably the most challenging task for TPS is to provide criteria for the atypical urothelial cell (AUC) category. The TPS criteria for AUC include increased nuclear/cytoplasmic (N/C) ratio (>0.5) and 1 of the 3 minor criteria including nuclear hyperchromasia (NH), coarse chromatin (CC) and irregular nuclear membrane (INM). We evaluated TPS-AUC diagnostic value and investigated whether other morphologic parameters can improve its criteria., Materials and Methods: Urine samples with diagnoses of AUC collected during a 6-month period were re-reviewed. Data captured included N/C ratio >0.5, NH, CC, INM, and 2 additional criteria including enlarged nuclear size (ENS) and the presence of nucleolus (N). ENS was considered when the nucleus was 2 times larger than the urothelial cell or 3 times larger than lymphocyte., Results: By applying the TPS-AUC criteria, the rate of atypia diagnosis reduced in comparison to Pre-TPS (9% versus 13%, P = 0.02). Among the AUC minor criteria, NH was the best criterion with the highest interobserver agreement (IOA) and correlation with HGUC (k = 0.342, r = 0.61, P < 0.001) and strong PPV (93.6%). ENS had the highest PPV (95.8%) and, after NH, had the highest IOA and correlation with HGUC (k = 0.29, r = 0.52, P < 0.001)., Conclusion: TPS improves the diagnostic value of urine cytology, particularly in cases with atypia. ENS is a strong criterion for increasing the diagnostic value of AUC and potentially can improve TPS performance as a minor criterion., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Cytology and cystoscopy are used to detect urothelial carcinoma (UC), but together they still fail to detect some UC cases and are not suitable for screening asymptomatic individuals. Mutations are present in more than 98% of UC, mutations have therapeutic significance, and they can be detected by next generation sequencing (NGS) in urine samples. We review the role of NGS in UC detection., Materials and Methods: Comprehensive literature review on UC genetics, economics of NGS, and previous reports of UC detection by NGS., Results: The raw costs of NGS have decreased to about 14,000 base pairs per penny, making it appear economically feasible to use NGS widely. Reported NGS assays fall short of predicted sensitivity. Decreased sensitivity is attributed to a low frequency of mutant alleles in many urine samples. Attempts to increase the percentage of mutant alleles, by using cell-free urinary DNA, or by using cell sorting and microfluidics, have been unsuccessful or remain unproven. However, cytologic examination can immediately enable NGS: Urine cytologies with sufficient proportions of abnormal cells could be directly triaged to NGS with high sensitivity for UC detection. For cases with a low proportion of abnormal cells, cytologically targeted microdissection of cells for NGS should maintain sensitivity and decrease sequencing costs. Cytologically targeted urothelial cells for NGS could allow a screening test for low grade UC., Conclusions: Cytology is immediately poised to allow NGS to improve the diagnosis of UC, allowing NGS to be an ancillary test for atypical cytologies, and potentially allowing a screening test for low-grade UC., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: The Paris System for Reporting Urinary Cytology (TPS) was developed for standardization purposes and it placed an emphasis on screening for high-grade urothelial carcinoma (HGUC). Since then, it has shown to reduce atypia rates and better correlate with surgical specimens. The aim of this study was to calculate the negative predictive value (NPV) of urinary cytology for detecting HGUC using TPS and compare these data to our recently published pre-TPS cohort. As a screening test, it is imperative that TPS has a high NPV., Material and Methods: A search of our institution's pathology database for the term "negative for HGUC" from January 1, 2016, to December 31, 2017, was conducted. A true negative was defined as a patient with at least 1 subsequent negative urine cytology/surgical biopsy specimen or the patient being clinically negative for 6 months. NPV rates were calculated based on the data obtained., Results: The cohort consisted of 2960 urine cytology specimens from 1894 patients. A total of 99 false negatives were identified, generating a NPV of 96.7% (2861/2960). This NPV is identical to our previously published pre-TPS cohort (years 2012-2013; NPV: 96.7%). The clinical indication most effected NPV, with a history of urothelial carcinoma with a NPV of 93.9% followed by hematuria at 98.9%. The atypia rate in years 2012-2013 was 8.2% and in 2016-2017 it was 5.7% (P < 0.001)., Conclusions: We demonstrate that TPS did not alter the NPV for detecting HGUC compared to our pre-TPS cohort. We believe that TPS is an effective reporting system for screening HGUC in urinary cytology., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Some high-grade urothelial carcinomas (UCs) in urine cytology have hypochromatic chromatin, but the incidence and criteria for diagnosis are not well described., Materials and Methods: Urine cytology cases with biopsy follow up were reviewed., Results: Cytospin preparations from 331 cases with biopsy follow up (230 benign/low-grade UC, 101 malignant) were reviewed. There were no false-positive cases. Cases with malignant cells with hypochromatic chromatin were identified in a total of 17 cases (16.8% of all malignancies). These comprised 2 carcinoma in situ, 11 high-grade papillary UC, 3 invasive UC, and 1 adenocarcinoma. Sixteen of 93 high-grade UCs (17.2%) had cells with hypochromatic chromatin. These cells were the only type of malignant cell in 4 of 101 cases (4.0%). All cases had cells with high nuclear-to-cytoplasmic ratios and markedly indented and irregular nuclear membranes that could be identified on both cytology and subsequent histology., Conclusions: Malignant urothelial cells in urine cytology with hypochromatic chromatin can be present in 17% of cases and can be diagnosed as "positive for malignancy" based on their high nuclear-to-cytoplasmic ratio, and markedly indented and irregular nuclear membranes., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Studies have shown that expression of human telomerase reverse transcriptase (hTERT) in mature urothelial cells indicates an increased risk of urothelial carcinoma. We evaluated the utility of immunocytochemistry with a commercially available anti-hTERT antibody (SCD-A7) in 100 consecutive urine cytology specimens using ThinPrep processing., Materials and Methods: ThinPrep slides prepared from 100 consecutive urine specimens were stained using anti-hTERT antibody (SCD-A7) after staining optimization had been successfully completed. Patient demographics, cytology diagnoses, histologic follow-up data, and anti-hTERT staining results were recorded., Results: The cytology diagnoses included 7 cases of high-grade urothelial carcinoma (HGUC), 2 cases suspicious for HGUC (SHGUC), 24 cases of atypical urothelial cells (AUCs), and 67 cases negative for HGUC (NHGUC). Of 92 samples, 68 (74%) were positive and 24 (26%) were negative for anti-hTERT staining. Although 31 of 32 specimens (97%) with a diagnosis of AUCs and greater showed positive staining, 37 of 60 NHGUC cases (62%) were also positive for anti-hTERT. Although the HGUC and suspicious for HGUC cases were more likely to show strong staining (6 of 9; 67%), 7 AUC (32%) and 8 NHGUC (22%) cases also demonstrated strong staining. Eight samples (8%) were unsatisfactory for interpretation. Anti-hTERT staining of nonurothelial cells was seen in 77 of 92 samples (84%)., Conclusions: Interpretation of anti-hTERT immunocytochemical staining of ThinPrep material is challenging owing to obscuring of nonurothelial cell staining and difficulty discerning individual urothelial cell cytomorphology when the cells are stained. The significance of the large number of anti-hTERT-positive but cytology-negative cases in our study is uncertain., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Recent cytology classification systems have become more evidence-based and advocate for the use of risk of malignancy (ROM) as a measure of test performance. From the statistical viewpoint, ROM represents the post-test probability of malignancy, which changes with the test result and also with the prevalence of malignancies (or pre-test probability) in each individual practice setting and individual patient presentation. Evidence-based medicine offers likelihood ratios (LRs) as a measure of diagnostic accuracy for multilevel diagnostic tests, superior to sensitivity and specificity as data binarization and information loss are avoided. LRs are used in clinical medicine and could be successfully applied to the practice of cytopathology. Our aim was to establish LRs to compare diagnostic accuracy of The Paris System for Reporting Urinary Cytology (TPS) and of a historic urine cytology reporting system., Materials and Methods: We analyzed sequential voided urine cytology cases with histologic outcomes: 188 pre-TPS and 167 post-TPS. LRs were calculated as LR = True positive % (per category)/False positive % (per category) [95% confidence interval] and interpreted LRs = 1 nondiagnostic, LR >1 favor, LR >10 strongly favor, LRs <1 favor exclusion, and LR <0.1 strongly favor exclusion of a target condition, respectively. CATmaker open source software and Fagan nomograms were used for calculation and visualization of the corresponding post-test probability (ROM) of high-grade urothelial carcinoma (HGUC) in various scenarios., Results: Both reporting systems show near-similar performance in terms of LRs, with moderate discriminatory power of negative, suspicious, and positive for HGUC test results. The atypical urothelial cell (AUC) category establishes as indiscriminate LR = 1 in the TPS, whereas in pre-TPS it favored a benign condition. We further demonstrate the utility of LRs to determine individual post-test probability (ROM) in a variety of clinical scenarios in a personalized fashion., Conclusions: The LRs allow for a quantitative performance measure in case of urine cytology across different scenarios adding numeric information on diagnostic test accuracy and post-test probability of HGUC. The diagnostic accuracy of pre-TPS and post-TPS remained similar for all but the AUC category. With the TPS, the AUC category has become genuinely diagnostically and statistically indeterminate and requires further patient investigations., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Urothelial carcinomas of the upper urinary tract (UUT) are uncommon. Cytological examination of voided urine or washings from the UUT has been part of the standard workup for upper tract urothelial carcinoma (UTUC); however, its value remains controversial. The lack of uniform terminology and specific diagnostic criteria could also have contributed to the inferior performance of urinary cytology for detecting UTUC. The Paris System for Reporting Urinary Cytology (TPS) has provided a standardized reporting system for urinary cytology specimens with clearly defined cytomorphologic diagnostic criteria and found acceptance on an international level after its implementation in 2016. Recent studies have shown that TPS has led to improved diagnostic performance of urinary cytology; however, most of these studies had focused on the evaluation of lower urinary tract cytology specimens. Only a limited number of new research studies have analyzed the effect of TPS when applied to UUT cytology specimens. In the present report, we have summarized the current understanding and utility of UTUC, including its molecular biology, and reviewed the current literature., (Published by Elsevier Inc.)

Introduction: The Paris System for Urine Cytology (TPS) provides well-defined diagnostic criteria for the category of atypical urothelial cells (AUC). The current study compares the rate of AUC diagnoses at a large academic medical center before and after an educational intervention (EI) by a urine cytology expert., Materials and Methods: An expert in TPS delivered an educational intervention consisting of an interactive microscope session and a didactic session that focused on the AUC diagnostic category. The number of urine cytology cases, the AUC rate, and the false-negative percentage were calculated before and after the EI, using the electronic medical records and cytologic-histologic correlation records., Results: A total of 4026 urine cytology cases were signed out in the 25 months prior to the educational intervention and 1585 cases were signed out in the 10 months after the intervention. EI had a significant impact on diagnostic categorization, including a reduction in AUC (19.6% versus 12.5%) and suspicious for high-grade urothelial carcinoma (3.9% versus 3.1%) diagnoses. The cytotechnologists also placed fewer cases into the AUC category during primary screening (27.6% versus 23.0%). Although a higher percentage of cases was reported as negative for high-grade urothelial carcinoma, the false-negative rate did not significantly change after the intervention (1.8% versus 2.0% of negative cases, P = 0.65)., Conclusions: Focused educational sessions for pathologists and cytotechnologists on the diagnostic criteria for AUC as defined by TPS can significantly reduce the rate of atypical diagnoses without a significant increase in the rate of false negatives., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: The Paris System for Reporting Urinary Cytology (TPS) was first published in 2016 with clear objectives to standardize cytologic diagnostic criteria and provide uniform reporting, in order to improve patient stratification and associated clinical management. The aim of this paper is to evaluate the performance of TPS and review the literature published since TPS was introduced., Materials and Methods: Original articles focusing on the utilization and performance of TPS in urinary cytology specimens were identified using PubMed for publications from January 2016 to July 2020, using the keywords "Paris System", "urine cytology", and "urinary cytology"., Results: Twenty-three relevant articles in the literature regarding the use of TPS were included in the review from a total of 30,802 urine cytology specimens, of which 21,485 (69.8%) had available diagnoses. Distribution of cases among categories ranged from 50.5% to 95.3% for negative for high-grade urothelial carcinoma (NHGUC), 1.2% to 23% for atypical urothelial cells (AUC), 0.2% to 6.6% for suspicious for high-grade urothelial carcinomas (SHGUC), and 2.2% to 14.1% for high-grade urothelial carcinomas (HGUC). The calculated risk of high-grade malignancy (ROHM) ranged from 8.7% to 36.8% for NHGUC, 12.3% to 60.9%% for AUC, 33.3% to 100% for SHGUC, and 58.8% to 100% for HGUC. Mean ROHM weighted by sample size was calculated at 15.7% (±7.8%), 38.5% (±14.3%), 76.2% (±17.2%), and 88.8% (±12.7%) for NHGUC, AUC, SHGUC, and HGUC, respectively. Reported sensitivity of TPS ranged from 40% to 84.7%, specificity from 73% to 100%, PPV from 62.3% to 100%, and NPV from 46% to 90%., Conclusions: The application of TPS in the selected series has improved the screening and surveillance potential of urine cytology, while reducing high rates of indeterminate diagnoses, improving sensitivity and providing proper risk stratification for patients., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Polyomavirus cytopathic effect (BK-CPE) is classified as "negative for high-grade urothelial carcinoma" (NHGUC) in the Paris System for Reporting Urinary Cytology. However, polyomaviruses have been historically associated with tumor development and have been recently reported as an independent risk factor for renourinary carcinoma in transplant patients. The aim of the present study was to investigate the relationship between polyomavirus infection in the urinary tract and the subsequent risk of developing high-grade urothelial carcinoma (HGUC) in the general population., Materials and Methods: A retrospective case-control study was conducted to assess BK-CPE in all urinary cytology examinations performed from 2009 to 2011 for cases with an interpretation of NHGUC, NHGUC with BK, atypical urothelial cells (AUCs), or AUCs with BK. The endpoint of the present study was a diagnosis of HGUC on either bladder biopsy or urine cytology for those patients with subsequent follow-up data., Results: A total of 252 cases with a urinary cytology interpretation of NHGUC, 234 with NHGUC + BK, 255 with AUCs, and 64 with AUCs + BK were identified. The surgical and cytological follow-up data showed that the overall risk of the development of HGUC for those with NHGUC, NHGUC + BK, AUCs, and AUCs + BK was 6.0%, 6.8%, 23.5%, and 12.5%, respectively. No statistically significant differences were found between the patients with NHGUC and those with NHGUC + BK. A statistically significant difference was found for patients with AUCs compared with patients with NHGUC + BK and those with AUCs + BK (P < 0.001)., Conclusions: The presence of BK-CPE in urine cytology samples does not increase the overall risk of the development of HGUC. Our results support the recommendation from the Paris System for Reporting Urinary Cytology to place urine samples with BK-CPE in the NHGUC category., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the usefulness of adding diffusion-weighted MRI (DW-MRI) to CT urography (CTU) for diagnosing upper tract urothelial carcinoma (UTUC)., Materials and Methods: We retrospectively evaluated 102 high-risk patients with UTUC who underwent both CTU and DW-MRI. The diagnostic performance of CTU and DW-MRI was evaluated in all the patients. Then, the diagnostic performance of DW-MRI in the patients with positive CTU findings was assessed based on the types of CTU findings (mass formation, wall thickening, and small filling defects). The diagnostic performance of DW-MRI and selective urine cytology sampling in these patients was also compared., Results: The sensitivity of DW-MRI (92%) was less than that of CTU (98%) (P = 0.25), since DW-MRI could not detect any small papillary tumors. The specificity of DW-MRI (91%) was greater than that of CTU (78%) (P = 0.065), since DW-MRI could discriminate some benign conditions from UTUC. Among the 59 positive CTU lesions, DW-MRI correctly diagnosed all 41 mass-forming lesions and improved the accuracy from 36% using CTU alone to 79% for 14 wall-thickening lesions but could not add any additional information for 4 small filling-defect lesions. Among the 44 patients with positive CTU findings who underwent selective urine cytology sampling, the sensitivity of DW-MRI (95%) was significantly greater than that of selective urine cytology sampling (56%) (P < 0.001)., Conclusions: The addition of DW-MRI would be useful for both mass-forming and wall-thickening lesions. DW-MRI has the potential to reduce the frequency of selective urine cytology sampling for such lesions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Arsenic exposure is an environmental risk factor for urothelial carcinoma (UC). The natural history of upper tract urothelial carcinoma (UTUC) differs from that of bladder cancer (BC). However, the risk factors of BC and UTUC are not exactly the same and should be discussed separately. The aims of this study were to evaluate 1) the association between arsenic methylation capacity and UTUC and/or BC, separately, and 2) the association between polymorphisms of the arsenic metabolism-related genes AS3MT, GSTOs, and PNP against BC and/or UTUC, separately. We conducted a hospital-based study and collected 216 BC and 212 UTUC cases, and 813 healthy controls, from September 2007 to October 2011. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generator-atomic absorption spectrometry. The polymorphisms of AS3MT, GSTO, and PNP were identified using the Sequenom MassARRAY platform with iPLEX Gold chemistry. We found that inefficient arsenic methylation capacity was associated with BC in a significant dose-response relationship, but only found that high urinary total arsenic concentration was related to the risk of UTUC, also in a significant dose-response manner. Those with a total urinary arsenic level of > 30.28 μg/L compared to ≤ 9.78 μg/L, had a odds ratio (OR), and 95% confidence interval (CI) of UTUC, of 4.80 (2.22-10.39). The polymorphisms of AS3MT rs11191438, AS3MT rs10748835, and AS3MT rs1046778 were related to the risk of BC and UTUC, while the polymorphisms of AS3MT rs3740393, AS3MT rs11191453, and AS3MT rs11191454 were associated with arsenic methylation capacity. The AS3MT gene polymorphisms and arsenic methylation capacity appear to independently affect the risk of BC and UTUC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Hematuria is the most common symptom of urothelial carcinomas (UC) but is often idiopathic. Cystoscopy is expensive which involves considerable patient discomfort, and conventional urine cytology for noninvasive UC detection and disease monitoring suffers from poor sensitivity. We aim to evaluate the performance of genes selected from a previous study in detecting UC, especially among patients with gross hematuria, as well as upper tract urothelial carcinoma (UTUC) and bladder carcinoma separately, in voided urine samples., Methods: Using methylation-specific polymerase chain reaction, we examined the promoter methylation status of 10 genes in voided urine samples among 473 patients at our institution, including 217 UC patients and 256 control subjects., Results: The final combination of VIM, CDH1, SALL3, TMEFF2, RASSF1A, BRCA1, GDF15, and ABCC6 identified UC with a sensitivity of 0.83 and a specificity of 0.60. Additionally, a panel of selected genes (CDH1, HSPA2, RASSF1A, TMEFF2, VIM, and GDF15) identified UTUC with a sensitivity of 0.82 and a specificity of 0.68, while a panel of selected genes (VIM, RASSF1A, GDF15, and TMEFF2) identified bladder carcinoma with a sensitivity of 0.82 and a specificity of 0.53. Remarkably, a different panel (CDH1, SALL3, THBS1, TMEFF2, VIM, and GDF15) identified UC in patients with gross hematuria with 0.89 sensitivity and 0.74 specificity, and sensitivity (0.91) and specificity (0.92) could be achieved when cytology was included., Conclusions: The selected urine-DNA methylation biomarkers are reliable, noninvasive, and cost-effective diagnostic tools for bladder carcinoma and UTUC, especially among patients with gross hematuria., (Copyright © 2018. Published by Elsevier Inc.)

Background: To gain new insights into the origin and prevention of diagnostic delays in the evaluation of hematuria in an electronic health record (EHR)-based integrated care setting., Methods: We performed a retrospective review of 298 consecutive patients with new-onset hematuria at a Veterans Affairs facility from January 1, 2011 to December 31, 2013 excluding those where diagnostic evaluation was unnecessary (i.e., cystoscopy within 3 years prior). We collected data on presentation, such as red flags of painless gross hematuria (PGH) or asymptomatic microhematuria (AMH) and subsequent evaluation (imaging, urologic referral, and cystoscopy). Delay was defined when evaluation was not completed within 60 days. Logistic regression was performed to identify predictors of delay., Results: Of 201 patients, 149 had delays. PGH was present in 99 patients. These patients had a higher rate of urology referral within 1 year than patients with AMH (86.7% vs. 64.7%; P<0.01) and were more likely to undergo cystoscopy (75.8% vs. 52%; P<0.01). Delays occurred in 67% of PGH patients vs. 81% of AMH patients (OR 0.46; P = 0.02), and roughly a third were related to scheduling/coordination, patient-related issues, or delay in primary care referral. Bladder neoplasms were detected in 18% of patients with PGH and 2% of those with AMH., Conclusion: Delays in evaluation for hematuria occur commonly, regardless of strength of the red-flag. Many delays were preventable and could be targeted with interventions including EHR-based tracking systems or reformed scheduling practices., (Published by Elsevier Inc.)

Background: Urologic cancer has a lower prevalence in women compared with men; however, there are no differences in the recommended evaluation for women and men with microscopic hematuria., Objectives: The purpose of this study was to identify risk factors that are associated with urologic cancer in women with microscopic hematuria and to determine the applicability of a hematuria risk score for women., Study Design: We conducted a retrospective cohort study within an integrated healthcare system in Southern California. All urinalyses with microscopic hematuria (>3 red blood cells per high-power field) that were performed from 2009-2015 were identified. Women who were referred for urologic evaluation were entered into a prospective database. Clinical and demographic variables that included the presence of gross hematuria in the preceding 6 months were recorded. The cause of the hematuria, benign or malignant, was entered into the database. Cancer rates were compared with the use of chi-square and logistic regression models. Adjusted risk ratios of urologic cancer were estimated with the use of multivariate regression analysis. We also explored the applicability of a previously developed, gender nonspecific, hematuria risk score in this female cohort., Results: A total of 2,705,696 urinalyses were performed in women during the study period, of which 552,119 revealed microscopic hematuria. Of these, 14,539 women were referred for urologic evaluation; clinical data for 3573 women were entered into the database. The overall rate of urologic cancer was 1.3% (47/3573). In women <60 years old, the rate of urologic cancer was 0.6% (13/2053) compared with 2.2% (34/1520) in women ≥60 years old (P<.01). In women who reported a history of gross hematuria, the rate of urologic cancer was 5.8% (20/346) compared with a 0.8% (27/3227) in women with no history of gross hematuria (P<.01). In multivariate analysis, > 60 years old (odds ratio, 3.1; 95% confidence interval, 1.6-5.9), a history of smoking (odds ratio, 3.2; 95% confidence interval, 1.8-5.9), and a history of gross hematuria in the previous 6 months (odds ratio, 6.2; 95% confidence interval, 3.4-11.5) were associated with urologic cancers. A higher microscopic hematuria risk score was associated with an increased risk of cancer in this test cohort (P<.01). Women in the highest risk group had a urologic cancer rate of 10.8% compared with a rate of 0.5% in the lowest risk group., Conclusions: In this female population, >60 years old and a history of smoking and/or gross hematuria were the strongest predictors of urologic cancer. Absent these risk factors, the rate of urologic cancer did not exceed 0.6%. A higher hematuria risk score correlated significantly with the risk of urologic cancer in this female test cohort., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cisplatin is a widely used anticancer drug, but its nephrotoxicity is a serious problem. To examine whether the novel biomarker, urinary vanin-1, could predict reduction in renal function after dosing of cisplatin. We conducted a prospective single-center pilot study of 24 patients with urothelial carcinoma who received cisplatin-based chemotherapy between 2012 and 2015. The primary outcome was a 20% or greater decline in estimated glomerular filtration rate (eGFR) from baseline within the first 6days of cisplatin. Urine concentration of creatinine, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and NAG (N-acetyl-β-d-glucosaminidase) as well as vanin-1 were measured during the perioperative period. During 6days after cisplatin, 37.5% (9/24) of patients showed more than 20% decline in eGFR (baseline, 68.8±11.1mL/min/1.73m(2); on day 6, 51.0±2.5mL/min/1.73m(2)) and this reduction persisted until day 10. Urinary vanin-1, but not KIM-1, NGAL and NAG, significantly elevated early on day 3 after cisplatin, which preceded the elevation of serum creatinine on day 6. Sensitivity and specificity of a cutoff point of urinary vanin-1 (9.31ng/mg Cr) on day 3 were calculated to be 66.7% (95% CI: 0.30-0.93) and 83.3% (95% CI: 0.52-0.97), respectively, for predicting 20% decline in eGFR during 6days after cisplatin. These data suggest that urinary vanin-1 is an early predictive biomarker for decline in eGFR in patients with urothelial carcinoma after dosing of cisplatin., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Objective: Few studies have addressed the predictive value of positive urine cytology for prognosis in patients with upper tract urothelial carcinoma (UTUC). We investigated whether the status of preoperative urine cytology could provide additional prognostic information following radical nephroureterectomy (RNU)., Materials and Methods: The study included 474 patients with primary nonmetastatic UTUC (pTa-4N0M0) from a retrospective multi-institutional cohort. The median follow-up period was 35 months. Associations between the status of urine cytologic evaluation and outcomes were analyzed using multivariate Cox regression models. Urine cytology was evaluated preoperatively using voided samples. Disease recurrence was defined as any relapse in nonbladder lesions and was coded separately from intravesical recurrence., Results: Positive urine cytology was detected in 184 patients (38.8%) preoperatively. Disease recurrence occurred in 127 patients, while intravesical recurrence occurred in 219 patients; 83 patients died of UTUC during follow-up. Kaplan-Meier analysis revealed that only the incidence of intravesical recurrence was significantly associated with the status of urine cytologic evaluation (P = 0.024); the intravesical recurrence-free survival rates at 1 and 3 years following RNU were 61.4% and 46.2% in patients with positive urine cytology and 71.1% and 51.6% in their counterparts, respectively. Multivariate analysis showed that gender (hazard ratio [HR] = 1.74, 95% confidence interval [CI]; 1.28-2.43), tumor multifocality in RNU specimens (HR = 1.64, 95% CI; 1.09-2.47), and positive urine cytology (HR = 1.41, 95% CI; 1.08-1.85) were independent risk factors for subsequent intravesical recurrence., Conclusions: The results showed the prognostic value of positive urine cytology in patients with primary UTUC, and preoperative positive urine cytology may be associated with a significant increase in the prevalence of intravesical recurrence following RNU., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Micro-ribonucleic acids (miRNAs) are small noncoding RNAs that posttranscriptionally regulate gene expression. The ability of miRNAs to inhibit translation of oncogenes and tumor suppressors implies that they may be involved in carcinogenesis. Our review focuses on the potential of urinary miRNAs to serve as biomarkers of urologic cancers. We discuss in detail the recent knowledge about the origin of urinary miRNAs, their stability, quality control, and their utility as a potential new class of biomarkers in urologic cancer. Finally, we summarize the studies focusing on detection and characterization of urinary miRNAs as potential biomarkers in bladder, prostate, and kidney cancers., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To evaluate the performance of urine cytology (CYT), the UroVysion test [(fluorescence-in-situ-hybridization (FISH)], the uCyt+-test, and the nuclear matrix protein 22 ELISA (NMP22) at different grades of microscopic hematuria (HU) in a cohort of 2,365 patients suspicious for urothelial cell carcinoma (UCC)., Patients and Methods: A cohort of 2,365 consecutive patients suspected to have UCC underwent testing of at least 1 of the 4 noninvasive urine markers followed by cystoscopy, upper urinary tract imaging and, in case of suspicious findings, transurethral biopsy and/or resection of suspicious lesions. The grade of microscopic HU was determined by dipstick evaluation and urine microscopy and subdivided into 4 grades. The test results were compared with the HU status by contingency analysis and Cochran-Armitage test for trend separated for patients without evidence of UCC and with histologically proven UCC., Results: In case of grade 0, I, II, and III HU, rates of false positive CYT were 13.0, 17.4, 16.3, and 19.5% (P = 0.02), false negative CYT distributed 37.9, 18.5, 20.0, and 15.5% (P = 0.0003). FISH was false positive in 16.7, 19.8, 19.8, and 23.3% (P = 0.051) and false negative in 42.7, 27.5, 25.9, and 25.0% (P = 0.1). The uCyt+ was false positive in 12.5, 16.9, 24.0 and 35.1% (P < 0.0001), and false negative in 57.1, 26.4, 31.5, and 12.7% (P = 0.0003). NMP22 was false positive in 35.3, 55.3, 75.2, and 79.7% (P < 0.0001) and false negative in 50.0, 36.2, 22.6, and 8.2% (P < 0.0001)., Conclusion: The extent of microscopic HU significantly influences the performance of noninvasive urine markers for UC. False positive rates of CYT, uCyt+, and NMP22 significantly increase with the degree of HU whereas false negative results of CYT, uCyt+, and NMP22 are less frequent in patients with high grade microscopic HU. These results underline the relevance of the grade of HU for the appropriate interpretation of urine tests., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Current rapid evaluation protocols for patients with hematuria tend to exclude those with urinary tract infection since this is assumed to be evidence of a benign treatable cause. The likelihood of a urinary tract cancer in such patients is, however, uncertain, and we have therefore analyzed a prospective hematuria clinic database to determine risk., Patients and Methods: A total of 1,740 patients were enrolled prospectively in this study at our unit's one stop fast track hematuria clinic between April 2003 and March 2006. Evaluation of patients consisted of basic demographics, history and examination, urinalysis, urine culture, urine cytology, and serum creatinine. All patients then underwent a renal ultrasound, intravenous urogram, and cystoscopy., Results: A total of 1,067 males and 673 females with a mean (range) age of 60.8 (16-96) years were included in the study. One hundred sixty-one patients had a positive mid-stream urine (MSU) on a specimen collected at the hematuria clinic. Amongst this group 20% (32) patients had a urologic malignancy diagnosed, of whom 12% (4) had metastatic disease at presentation. Only 1% (3) of patients had a urologic malignancy with a previous history of a treated urinary tract infection (UTI) and negative MSU at the clinic. The risk of urologic malignancy was 24% (303) in the remaining 1,249 patients with no history of a UTI prior to presentation and a negative MSU on a specimen collected at the one stop fast track hematuria clinic., Conclusion: Despite selection bias inherent in this analysis, it appears that the presence of UTI does not decrease the likelihood of having a urologic malignancy diagnosed. Hence, there is no indication to delay prompt evaluation in patients with hematuria and a positive urine culture collected at the hematuria clinic., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Strong indications have been presented that dietary poisoning with aristolochic acids (AA) is responsible for Endemic Nephropathy (EN) and AA associated cancer of the upper urinary tract (UUTC). Our recent investigation showed drastic urinary proteome changes in AA treated mice. This study was designed to identify proteome changes associated with AA nephrotoxicity in experimental animal model. The DBA and C57BL mice, which differ in AA sensitivity, were exposed to AA for 4 days. The strategy for urinary, plasma and kidney tissue proteome study of AA exposed and control mice integrated gel-based and in-solution tryptic digestion combined with LC-ESI-MS/MS. To maximize proteome coverage, plasma fractionation scheme was developed and MS compatible sequential tissue extraction procedure was established. Proteomic analyses of urinary, plasma and kidney tissue tryptic digests resulted in identification of several cytoskeletal proteins, as well as proteins involved in kidney development and inflammatory response, that are differentially expressed in both AA exposed and control mice. These proteins are consistent with renal pathogenesis of endotoxicity and cancer. This proteomic strategy could be effectively translated for unbiased discovery of potential biomarkers for EN and associated UUTC in humans. At the same time, these results highlight the significance of AA exposure with EN. This article is part of a Special Issue entitled: Integrated omics., (Published by Elsevier B.V.)

A sensitive and specific method for the determination of diamines and polyamines by ion-pair high-performance liquid chromatography is described. The 5-dimethylaminonaphthalene-1-sulfonyl derivatives of putrescine, 1,6-diaminohexane, spermidine and spermine are separated on a muBondapak C18 reversed-phase column with 1-heptanesulfonic acid and acetonitrile as the mobile phase. All compounds are eluted within 30 min using a programmed solvent gradient system. The method has a lower detection limit of 1 pmole on column. Because of the simplicity of the method, its application provides a better means for closely monitoring patients undergoing treatment for various types of genito-urinary neoplastic diseases.