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Objectives: We studied the diagnostic accuracy and discordance of upper tract urothelial carcinoma (UTUC) by comparing biopsy and urinary cytology with matched nephroureterectomy specimens., Methods: Sixty-nine patients with UTUC without neoadjuvant treatment were retrospectively identified who had matched biopsy and nephroureterectomy specimens. Twenty patients had concurrent upper tract cytology. H&E and cytology slides were re-reviewed. Statistical analysis was performed., Results: Patients included 48 men and 21 women with a mean age of 69 years. A concordant grade between biopsy and surgical specimen was present in 49 (71%) patients. The mean size of biopsy specimens in the discordant group was significantly smaller than that in the concordant group. Invasion was evaluated in 48 biopsy cases that had adequate subepithelial tissue, and 33 of them were diagnosed with concordant invasion status. Mean tumor size in both tumor grade and invasion discordant groups was significantly larger than that in the concordant group. High-grade urothelial carcinoma was detected in 84% of cases using urinary cytology., Conclusions: Our study demonstrates the diagnostic challenges of UTUC on small biopsy specimens. Biopsy specimen size and tumor size are significantly associated with the diagnostic discordance. Upper tract cytology showed high diagnostic accuracy and should be complementary to the biopsy., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Given its frequent recurrence and the potential for high-grade transformation, accurate diagnosis of low-grade papillary urothelial carcinoma (LGPUC) in urine cytology is clinically important. We attempted to identify cytomorphologic features in urine samples, which could be helpful for the identification of LGPUC., Methods: We conducted a retrospective review of voided urine specimens collected from patients with histopathologic diagnoses of LGPUC. Their cytomorphological features were compared with those from patients with benign conditions and high-grade papillary urothelial carcinoma (HGPUC)., Results: A total of 115 voided urine specimens were evaluated, including 30 benign, 41 LGPUC, and 44 HGPUC cases. In LGPUC, 18 cases (44%) were diagnosed as atypical, a proportion significantly higher than that observed in benign cases (4 cases, 13%), while the remaining 23 cases (56%) were diagnosed as negative. LGPUC urine samples tended to have higher cellularity than benign cases, but the difference was not statistically significant. Three cytological features, namely nuclear enlargement, higher nuclear-to-cytoplasmic (N/C) ratio, and presence of small cell clusters, were statistically more prevalent in LGPUC compared to benign cases, although the changes were relatively subtle. In contrast, cytomorphological distinction between LGPUC and HGPUC was evident, as high cellularity, nuclear enlargement, hyperchromasia, high N/C ratio, irregular nuclear membrane, and apoptosis were significantly more prevalent in HGPUC cases., Conclusions: Several cytomorphologic features in voided urine samples were more prevalent in cases with LGPUC, albeit not observed in all instances. Since these alterations were relatively subtle, meticulous attention to these cytomorphologic details is crucial to suggest the possibility of LGPUC., (© 2024 John Wiley & Sons Ltd.)

As an internationally accepted diagnostic system, the Paris classification has achieved a global breakthrough in the standardization of diagnoses in urine cytology. Based on experience over the past few years since its first publication, the new edition of the Paris classification refines the diagnostic criteria and discusses diagnostic pitfalls. While the detection of high-grade urothelial carcinoma remains the main focus, other aspects of urine cytology, including cytology of the upper urinary tract and the associated challenges, have also been addressed. Low-grade urothelial neoplasia is no longer listed as a separate category but is now included in the category "negative for high-grade urothelial carcinoma" (NGHUC). Essentially, the Paris classification provides an important basis for estimating the risk of malignancy and further clinical management., (© 2024. The Author(s).)

Introduction: Compared to urothelial carcinomas (UCs), the cytomorphology of renal cell carcinomas (RCCs) is underdescribed. This study aims to investigate whether UCs and RCCS of the upper urinary tract can be differentiated cytologically, and to identify distinguishing cytomorphological features., Methodology: Consecutive urine cytology specimens with atypical/C3, suspicious/C4 or malignant/C5 diagnoses matched with a nephrectomy or ureterectomy specimen with UC or RCC over a 15-year period were reviewed for cellularity, architecture, background composition and cytomorphologic features., Results: Totally 132 specimens were retrieved, comprising 24 RCCs and 108 UCs. Clear cell RCC (CCRCC) (n = 18) was the most common RCC. Urine cytology specimens from UC showed a trend of higher cellularity (p = 0.071) against RCC and was significant in subgroup analysis with CCRCC (p < .001). Epithelial structures in sheets, tubules, and papillae were exclusive in specimens of UC (p < .05). For background features, squamous cells were more common for RCC (p = .006) including CCRCC (p = .003), whereas polymorphs (p = .011) and necrotic material (p = .010) were associated with UC. Average nuclear size was larger and nuclear size variation (p < .001) and nuclear-cytoplasmic ratio (p = .001) were greater in UC (p = .001) than RCC. Comparing RCC to high-grade UCs only, nuclear-cytoplasmic ratio maintained statistical significance (p = .006) while average nuclear size showed a trend (p = .063)., Conclusion: A clean background free of tumor necrosis and polymorphs, and the lack of complex tumor fragments favors RCC. UCs also display larger nuclear size, higher nuclear size variation and nuclear-cytoplasmic ratio. These cytomorphological features with corroboration of clinical/radiological findings, can aid in raising a diagnosis of RCC., (© 2024 The Author(s). Diagnostic Cytopathology published by Wiley Periodicals LLC.)

Background: For early detection and postoperative monitoring of upper tract urothelial carcinoma (UTUC), the traditional detection method was limited to its invasiveness and insufficient sensitivity. We aim to use urine tumour DNA (utDNA) for detecting minimal residual disease (MRD), early diagnosis and perioperative monitoring in UTUC., Method: We previously established a utDNA multidimensional bioinformatic valuation model, named utLIFE, using low-coverage whole-genome sequencing and targeted deep sequencing. This prospective cohort enrolled 93 patients diagnosed with UTUC without metastasis. We collected morning urine samples on the day of surgery and the discharge day after the operation for utLIFE testing. In addition, we also enrolled 80 healthy controls to further validate the specificity of the utLIFE model in the study., Results: The utLIFE of preoperative samples could discriminate UTUC with high specificity (96.25%, 77/80), and high sensitivity (96.77%, 90/93) regardless of stage and grade. The sensitivity of utLIFE was significantly higher than urine cytology (p < 0.001) and fluorescence in situ hybridisation (FISH) (p < 0.001) (N = 19), especially in early-stage and low-grade UTUC. Postoperative utLIFE scores were significantly decreased compared with those of preoperative samples (79 vs. 36, p < 0.001), indicating its association with tumour burden. For special pathology types, utLIFE performed less well in sensitivity and perioperative alteration., Conclusion: In conclusion, we established a bioinformatic utDNA valuation model, utLIFE, which was validated to be a rapid and noninvasive approach with high sensitivity for early detection and MRD monitoring for UTUC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The aim of this study was to develop and validate a risk stratification model for the screening of patients with suspected urothelial carcinoma (UC)., Methods: We enrolled 671 consecutive patients with suspected UC and generated a risk stratification model based on urinary parameters by using an automated urinalysis analyzer (Sysmex UN-9000). All patients received urine cytology examination from January 1, 2019, to October 31, 2022., Results: Out of the 671 patients, 191 (28.5%) were ultimately diagnosed with UC. The four features associated with the presence of malignancy on multivariable analysis can be summarized by using the mnemonic UC-PAAS: UC, protein vs. creatinine ratio (P/C), age, atypical cells (Atyp.C), and small round epithelial cell (SRC). Major criteria include Atyp.C ≥ 0.1/μL (2 points) and age ≥ 65 years (2 points); minor criteria include SRC ≥ 2.7/μL (1 point) and abnormal P/C results (1 point). The model evidenced good discrimination (area under the curve = 0.802, 95% confidence interval [0.756, 0.848]) in the training group. A UC-PAAS cutoff of more than 4 points identified a high-risk population, of whom 37 of 59 (62.7%) had UC; the negative predictive value was 0.867. The validation group yielded similar findings., Conclusions: We present a urinalysis-based screening model, the UC-PAAS, that may serve as an accessory clinical tool for the evaluation of patients with suspected UC, because the model identifies patients at higher risk who require closer follow-up than others or additional examinations.

Background: To establish the pathological diagnosis of UTUC before treatment is profitable. At present, the conventional pathological diagnostic methods have certain problems. Besides, the urine-based DNA methylation test have been already utilized to detect bladder cancer., Objective: To evaluate the sensitivity and specificity of DNA methylation plus 17 genes mutation test and compare the combined test with cytology., Materials and Methods: We included 45 patients from April 2019 to May 2022, all of whom underwent radical nephroureterectomy (RNU), nephrectomy, diagnostic ureteroscopy or tissue biopsy. Before surgery, the urine samples were collected for DNA methylation plus 17 genes mutation test and cytology. The test performance was calculated, and comparative ROC curves were drawn., Results: The median age of the patients was 67 years. The Kappa value of the DNA methylation plus 17 genes mutation test and tissue pathology was 0.59 (p<0.001). The sensitivity/specificity/PPV/NPV of DNA methylation plus 17 genes mutation test was 86/80/94/62% compared with 29/100/100/29% for cytology. The AUC of DNA methylation plus 17 genes mutation test was 0.829 (p<0.001).The mutated gene proportion of UTUC patients was 51.43% for TERT and 25.71% for TP53., Conclusion: The test performance of DNA methylation plus 17 genes mutation test was satisfactory, which may replace cytology in the future. Further multicenter studies with larger samples are needed to confirm the clinical value of this promising method., Novelty & Impact Statements: We evaluated the diagnostic efficacy of a urine-based liquid biopsy for the detection of UTUC and compared the combined test with cytology. We found satisfactory results and concluded that the test could partly replace cytology. Further studies are needed., (© 2024. The Author(s).)

Recent advancements in computer-assisted diagnosis (CAD) have catalysed significant progress in pathology, particularly in the realm of urine cytopathology. This review synthesizes the latest developments and challenges in CAD for diagnosing urothelial carcinomas, addressing the limitations of traditional urinary cytology. Through a literature review, we identify and analyse CAD models and algorithms developed for urine cytopathology, highlighting their methodologies and performance metrics. We discuss the potential of CAD to improve diagnostic accuracy, efficiency and patient outcomes, emphasizing its role in streamlining workflow and reducing errors. Furthermore, CAD tools have shown potential in exploring pathological conditions, uncovering novel biomarkers and prognostic/predictive features previously unknown or unseen. Finally, we examine the practical issues surrounding the integration of CAD into clinical practice, including regulatory approval, validation and training for pathologists. Despite the promising results, challenges remain, necessitating further research and validation efforts. Overall, CAD presents a transformative opportunity to revolutionize diagnostic practices in urine cytopathology, paving the way for enhanced patient care and outcomes., (© 2024 John Wiley & Sons Ltd.)

Objectives: To evaluate the clinical value of the Paris system for reporting urinary cytology (TPS) in the diagnosis of urothelial carcinoma (UC). Methods: A total of 1 744 cytological diagnostic records (from 751 cases) were collected retrospectively. All specimens were voided urines and histopathology as the gold standard. The sensitivity and specificity of urinary cytological diagnosis of UC and risk of high grade malignant (ROHM) in each diagnostic category were compared. Results: There were 360 cases with histopathology. The percentage of negative for high-grade urothelial carcinoma (NHGUC) was 30.1% (226/751), atypical urothelial cells (AUC) was 29.8% (224/751), suspicious for high-grade urothelial carcinoma (SHGUC) was 16.8% (126/751), high grade urothelial carcinoma (HGUC) was 21.2% (159/751), and non-urothelial malignancy (NUM) was 2.1% (16/751). The histpathologic ROHM corresponding to each cytological diagnosis category were 27.3% for NHGUC, 32.7% for AUC, 74.7% for SHGUC, 96.6% for HGUC and 100.0% for NUM, respectively. ROHM of SHGUC was significantly higher than that of AUC group, and the difference between the two groups was statistically significant ( P ＜0.001). ROHM of HGUC group was significantly higher than that of SHGUC group, and the difference was statistically significant ( P ＜0.001). With SHGUC as the cut-off value, the sensitivity and specificity of cytological diagnosis of HGUC were 76.7% (165/215) and 85.7% (18/21), and with HGUC as the cut-off value, the sensitivity and specificity of cytological diagnosis of HGUC were 53.0% (114/215) and 100.0% (21/21), respectively. Conclusions: Urine cytology has high sensitivity and specificity in the diagnosis of HGUC. The malignant risk of TPS varies with different diagnosis category. The high malignant risk population in cancer hospital leads to the relatively high malignant proportion and ROHM in each diagnosis category. Urinary cytology TPS reporting system is helpful to clinical management and has good clinical application value.

Background: Urothelial carcinoma (UC) is the second most common urological malignancy. Despite numerous molecular markers have been evaluated during the past decades, no urothelial markers for diagnosis and recurrence monitoring have shown consistent clinical utility., Methods: The methylation level of tissue samples from public database and clinical collected were analyzed. Patients with UC and benign diseases of the urinary system (BUD) were enrolled to establish TAGMe (TAG of Methylation) assessment in a training cohort (n = 567) using restriction enzyme-based bisulfite-free qPCR. The performance of TAGMe assessment was further verified in the validation cohort (n = 198). Urine samples from 57 UC patients undergoing postoperative surveillance were collected monthly for six months after surgery to assess the TAGMe methylation., Results: We identified TAGMe as a potentially novel Universal-Cancer-Only Methylation (UCOM) marker was hypermethylated in multi-type cancers and investigated its application in UC. Restriction enzyme-based bisulfite-free qPCR was used for detection, and the results of which were consistent with gold standard pyrosequencing. Importantly, hypermethylated TAGMe showed excellent sensitivity of 88.9% (95% CI: 81.4-94.1%) and specificity of 90.0% (95% CI: 81.9-95.3%) in efficiently distinguishing UC from BUD patients in urine and also performed well in different clinical scenarios of UC. Moreover, the abnormality of TAGMe as an indicator of recurrence might precede clinical recurrence by three months to one year, which provided an invaluable time window for timely and effective intervention to prevent UC upstaging., Conclusion: TAGMe assessment based on a novel single target in urine is effective and easy to perform in UC diagnosis and recurrence monitoring, which may reduce the burden of cystoscopy. Trial registration ChiCTR2100052507. Registered on 30 October 2021., (© 2024. The Author(s).)

Urine cytology is a long-used technique for the detection of high grade neoplastic urothelial lesions. Since 2016, «The Paris System» classification has revolutionized this field by introducing a standardized terminology widely adopted by cytopathologists and urologists. In this article, we explain this classification and discuss its impact on the clinical management of patients with urothelial lesions, as well as its role in the secondary prevention of these lesions.

Anti-programmed death-ligand 1 (PD-L1) Ab-based therapies have demonstrated potential for treating metastatic urothelial cancer with high PD-L1 expression. Urinary exosomes are promising biomarkers for liquid biopsy, but urine's high variability requires normalization for accurate analysis. This study proposes using the PD-L1/Alix ratio to normalize exosomal PD-L1 signal intensity with Alix, an internal exosomal protein less susceptible to heterogeneity concerns than surface protein markers. Extracellular vesicles were isolated using ExoDisc and characterized using various methods, including ExoView to analyze tetraspanins, PD-L1, and Alix on individual exosomes. On-disc ELISA was used to evaluate PD-L1 and Alix-normalized PD-L1 in 15 urothelial cancer patients during the initial treatment cycle with Tecentriq. Results showed that Alix signal range was relatively uniform, whereas tetraspanin marker intensity varied for individual exosome particles. On-disc ELISA was more reliable for detecting exosomal PD-L1 expression than standard plate ELISA-based measurement. Using exosomal Alix expression for normalization is a more reliable approach than conventional methods for monitoring patient status. Overall, the study provides a practical and reliable method for detecting exosomal PD-L1 in urine samples from patients with urothelial cancer., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Urinary cytology using the Paris system is still the method of choice for screening high-grade urothelial carcinomas. However, the use of the objective criteria described in this terminology shows a lack of inter- and intra-observer reproducibility. Moreover, if its sensitivity is excellent on instrumented urine, it remains insufficient on voided urine samples. Urinary cytology appears to be an excellent model for the application of artificial intelligence to improve performance, since the objective criteria of the Paris system are defined at cellular level, and the resulting diagnostic approach is presented in a highly "algorithmic" way. Nevertheless, there is no commercially available morphological diagnostic aid, and very few predictive devices are still undergoing clinical validation. The analysis of different systems using artificial intelligence in urinary cytology rises clear prospects for mutual contributions., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: Standardized basic morphology and the algorithmic approach make the Paris System (TPS) for Reporting Urinary Cytology understandable and applicable. This study examined how well the TPS categories are understood by pathology residents and how well these criteria are enabling them reaching accurate diagnosis., Materials/methods: A hundred consecutive cases representing all categories were selected. Authors reevaluated slides using TPS regardless of their original diagnosis. In the next step, the TPS was explained to four residents and trained them by five optimal urine cytology samples from each category. Then they were asked to diagnose the selected slides according to the TPS. The diagnoses were compared to authors. The agreement was assessed using kappa. Discordant diagnoses were classified as high and low impact based on potential on clinical practice., Results: The sensitivity of authors was 62.8%, and residents' were 24-31.8%. The specificity of authors was 98.8%, and residents' were 82.3-92.8%. Reproducibility of TPS was 40-46%. Kappa values were below 0.40 except for one resident. The highest rate of concordance was for negative for high-grade urothelial carcinoma (NHGUC): authors assigned 38 NHGUC (35 biopsy-proven benign cases). Twenty to twenty-six of them were assigned as NHGUC by residents. While authors assigned 42 cases as suspicious for high-grade urothelial carcinoma (SHGUC) or high-grade urothelial carcinoma (HGUC) (35 biopsy-proven malignant cases), residents assigned 22-29 of them. Discordant diagnosis with high clinical implication was 56-63%., Conclusion: Diagnostic accuracy rates of junior pathology residents using the TPS were unsatisfactory. The best agreement was observed in NHGUC and HGUC categories. Combining HGUC and SHGUC doubled the sensitivity of residents., (© 2024 S. Karger AG, Basel.)

Introduction: The atypical urothelial cell (AUC) category in The Paris System (TPS) in urine cytology (UrCy) is a challenging area. This study aimed to evaluate the UroVysion fluorescence in situ hybridization (U-FISH) assay in predicting the outcome of AUC. Additionally, we explored the association of abnormal U-FISH results in high-grade urothelial carcinoma (HGUC) concerning muscularis propria invasion (MPI)., Methods: This is a retrospective study, and U-FISH was done on archived Papanicolaou-stained smears. Four cohorts were included: non-neoplastic AUC (AUC-NN), neoplastic AUC (AUC-N), muscle-invasive HGUC (HGUC-MI), and muscle-free HGUC (HGUC-MF) outcome on histopathology (HPE) and with clinical follow-up of 12-29 months. U-FISH was evaluated for diagnostic purposes, and MPI and tumor stage prediction by urine FISH score (UFS; high vs. low) based on copy number gain of chromosomes (Chr)., Results: U-FISH was performed on 70 cases (20 AUC-NN, 20 AUC-N, 15 HGUC-MI, and 15 HGUC-MF) and was successful in 58/70 (82.85%) cases. All UC cases showed polysomy of ≥2Chr, and all the AUC-NN cases reported non-neoplastic on HPE were negative for U-FISH. U-FISH picked up all carcinoma cases in the AUC-N cohort. Chr 3 polysomy was statistically significant in differentiating HGUC-MI from HGUC-MF and low-grade urothelial carcinoma cases. Chr 3 signals with a cut-off of 6 signals could identify MPI with a sensitivity of 80.95% and specificity of 41.94%. The UFS of the HGUC-MI group was significantly higher than HGUC-MF., Conclusions: U-FISH successfully identified all cases of AUC with neoplastic outcomes. In the HGUC group, there was a difference in cases with and without MPI, which requires further confirmation in a larger prospective cohort., (© 2024 S. Karger AG, Basel.)

Objective: To explore the application of manual screening collaborated with the Artificial Intelligence TPS-Assisted Cytologic Screening System in urinary exfoliative cytology and its clinical values. Methods: A total of 3 033 urine exfoliated cytology samples were collected at the Henan People's Hospital, Capital Medical University, Beijing, China. Liquid-based thin-layer cytology was prepared. The slides were manually read under the microscope and digitally presented using a scanner. The intelligent identification and analysis were carried out using an artificial intelligence TPS assisted screening system. The Paris Report Classification System of Urinary Exfoliated Cytology 2022 was used as the evaluation standard. Atypical urothelial cells and even higher grade lesions were considered as positive when evaluating the recognition sensitivity, specificity, and diagnostic accuracy of artificial intelligence-assisted screening systems and human-machine collaborative cytologic screening methods in urine exfoliative cytology. Among the collected cases, there were also 1 100 pathological tissue controls. Results: The accuracy, sensitivity and specificity of the AI-assisted cytologic screening system were 77.18%, 90.79% and 69.49%; those of human-machine coordination method were 92.89%, 99.63% and 89.09%, respectively. Compared with the histopathological results, the accuracy, sensitivity and specificity of manual reading were 79.82%, 74.20% and 95.80%, respectively, while those of AI-assisted cytologic screening system were 93.45%, 93.73% and 92.66%, respectively. The accuracy, sensitivity and specificity of human-machine coordination method were 95.36%, 95.21% and 95.80%, respectively. Both cytological and histological controls showed that human-machine coordination review method had higher diagnostic accuracy and sensitivity, and lower false negative rates. Conclusions: The artificial intelligence TPS assisted cytologic screening system has achieved acceptable accuracy in urine exfoliation cytologic screening. The combination of manual screening and artificial intelligence TPS assisted screening system can effectively improve the sensitivity and accuracy of cytologic screening and reduce the risk of misdiagnosis.

Background: The Paris System for Reporting Urinary Cytology (TPS) has gained universal acceptance as the standard for reporting urine cytology requiring at least 5-10 malignant cells to diagnose high-grade urothelial carcinoma (HGUC) in lower and upper urinary tract specimens, respectively. These quantitation criteria are still subject to discussion, and this study specifically aims to validate the quantitation criterion of HGUC in lower urinary tract., Design: The authors reviewed two cohorts of lower urinary tract cases. The first cohort consisted of 100 liquid-based ThinPrep slides with the diagnosis of HGUC having positive histology on concurrent or follow-up biopsies within 3 months. The second cohort was 36 HGUC cases with negative histology on concurrent biopsies and within 3 months. The number of high-grade cells (HGCs) meeting the TPS qualitative criteria were counted under the light microscope driven in a grid-like manner., Results: The first 100 urine samples showed five cases (5.0%) with three HGCs, three cases (3.0%) had four HGCs, five cases (5.0%) showed five HGCs, and 25 cases (25.0%) had between 6-10 HGCs. The risk of high-grade malignancy (ROHM) in cases with five or more HGCs was 100%, whereas those with three HGCs was 60.0%. The second cohort of HGUC was considered "positive" despite a negative histology., Conclusion: This study confirms that quantitation is an essential key to diagnose HGUC. The current TPS criterion of a minimum of five malignant cells in lower tract is robust with a ROHM of 100%. Diagnosing HGUC with less than five HGCs runs the risk of lowering the ROHM., (© 2023 American Cancer Society.)

Background: The Paris System for Reporting Urinary Cytology (TPS) was issued to shift the focus of urine cytology to high-grade lesions to increase the diagnostic accuracy of urine cytology. The aim of this study was to evaluate the power of TPS in the atypical urothelial cells (AUC) category with histological correlation and follow-up., Methods: The data cohort consisted of 3741 voided urine samples collected during a 2-year period between January 2017 and December 2018. All samples were prospectively classified using TPS. This study focuses on the subset of 205 samples (5.5%) classified as AUC. All cytological and histological follow-up data were analyzed until 2019, and the time between each sampling was documented., Results: Of the 205 AUC cases, cytohistological correlation was possible in 97 (47.3%) cases. Of these, 36 (12.7%) were benign in histology, 27 (13.2%) were low-grade urothelial carcinomas, and 34 (16.6%) were high-grade urothelial carcinomas. Overall, the risk of malignancy was 29.8% for all cases in the AUC category, and 62.9% in the histologically confirmed cases. The risk of high-grade malignancy was 16.6% in all the AUC category samples and 35.1% in the histological follow-up group., Conclusions: The performance of 5.5% AUC cases is considered good and within the limits proposed by TPS. TPS is widely accepted by cytotechnologists, cytopathologists, and clinicians; it improves communication and patient management., (© 2023 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Introduction: The Paris classification highlights the need to focus on accurately identifying high-grade urothelial carcinoma (HGUC). Herein, we aimed to assess the overall implementation and diagnostic performance of the Paris classification for reporting urinary cytology in a cancer center., Methods: All urinary cytology reports from July 2018 to December 2019 were collected (n = 1,240). Only voided urine samples were included (n = 1,180). Risk of high-grade malignancy (ROHM) was calculated for each Paris category. The diagnostic performance of urinary cytology was assessed, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy., Results: The distribution of categories was: 0.3% unsatisfactory, 90.5% negative for HGUC, 5.6% atypical urothelial cells (AUC), 1.6% suspicious for HGUC, 1.9% HGUC, and 0.1% other malignancies. No diagnosis of low-grade urothelial neoplasia was given. The ROHM was 21.4% for negative for HGUC, 66.7% for AUC, 91.7% for suspicious for HGUC, and 100% for HGUC. When using suspicious for HGUC as a cutoff, the diagnostic performance of urinary cytology in identifying HGUC histology was 46% sensitivity, 98% specificity, 96% PPV, 68% NPV, and 74% accuracy., Conclusion: Specificity of urinary cytology was very high (with only 1 false-positive result), which is important since this will trigger a clinical intervention. The ROHM for each category was in accordance with literature, except for AUC where ROHM was slightly higher (66.7%). This may be explained by the study population characteristics (cancer center; many patients treated with intravesical therapies; lack of clinical annotation for patients referred from outside institutions)., (© 2022 S. Karger AG, Basel.)

Background: The Paris System for Reporting Urinary Cytology (TPS) uses hyperchromasia as major diagnostic criterion for high-grade urothelial carcinoma (HGUC). The purpose of the study was to evaluate cases that were diagnosed as HGUC by TPS and determine whether there are different chromatin distribution patterns (ie, subsets)., Methods: Digital image annotations were performed on microscopic images of HGUC urine specimens with surgical biopsy/resection follow-up. Median gray values were generated for each cell. Neutrophils (polymorphonuclear leukocyte [PMN]) were also enumerated in each case to serve as an internal control. A HGUC/PMN ratio was generated for each case, and the cases were distributed., Results: Sixty-nine HGUC cases yielded 2660 cells, including 2078 HGUC (30.1 cells/case) and 582 PMNs (8.4 cells/case). The average median gray value of an HGUC was 50.6 and of a PMN was 36.8 (P < .0001). Eight of 69 cases (11.6%) contained nuclei that, on average, were darker than or as dark as a PMN (extremely dark, ie, "India ink"). Fifty-one of 69 cases (74.0%) contained nuclei that, on average, were slightly brighter than a PMN (hyperchromatic). Ten of 69 cases (14.5%) contained nuclei that, on average, were much brighter than a PMN (hypochromatic). Within a single case, all cases showed heterogeneity with the hypochromatic cases showing the most dramatic effect., Conclusions: Digital image analysis reveals that there are large variations in chromasia between cases including a subset of cases with hypochromasia and another with extremely dark or "India ink" nuclei. There was much heterogeneity of chromasia seen within a single sample., (© 2022 American Cancer Society.)

Numerous studies showed that bladder urothelial carcinoma and upper urothelial tract carcinoma (UTUC) display clinical and genomic similarities. In order to analyze that the same panel of biomarkers used in the diagnosis of bladder urothelial carcinoma could be suitable for early detection of UTUC, we performed a retrospective study in which we analyzed Bladder EpiCheck scores in the urinary samples obtained by selective ureteral catheterization in a high-grade UTUC cohort, correlating the results with urinary cytology and diagnostic urethral biopsies. The present study represents a retrospective analysis of 82 patients with clinically localized high-grade UTUC (60 renal pelvis UTUC, 22 ureter UTUC) who had undergone a radical nephroureterectomy (RNU) at our Urology department from June 2018 to November 2020. Before any surgical procedure, one sample of urine, obtained by selective ureteral catheterization, was collected for each patient for cytological examination, and the remaining material was stored for the Bladder EpiCheck test. Our results showed that the sensitivity of the methylation test for high-grade UTUC was about 97.4%, significantly higher than the sensitivity of urinary cytology either considering the HGUC cytological diagnosis or including in the positive cases the SHGUC cytological diagnosis (97.4% versus 59% or 70.5%). The methylation analysis of urinary samples may represent a valid tool in the diagnostic process of patients with suspected UTUC. In cases with a difficult clinical decision after upper urinary tract biopsy and cytology, the methylation test could assist in the clinical management of UTUC patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.)

The pathogenesis of cancer involves multiple molecular alterations at the level of genome, epigenome, and stromal environment, resulting in several deregulated signal transduction pathways. Metabolites are not only end products of gene and protein expression but also a consequence of the mutual relationship between the genome and the internal environment. Considering that metabolites serve as a comprehensive chemical fingerprint of cell metabolism, metabolomics is emerging as the method able to discover metabolite biomarkers that can be developed for early cancer detection, prognosis, and response to treatment. Urine represents a noninvasive source, available and rich in metabolites, useful for cancer diagnosis, prognosis, and treatment monitoring. In this chapter, we reported the main published evidences on urinary metabolic biomarkers in the studied cancers related to hepatopancreatic and urinary tract with the aim at discussing their promising role in clinical practice.

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: Urine cytology plays an important role in diagnosing urothelial carcinoma (UC). However, urine cytology interpretation is subjective and difficult. Morphogo (ALAB, Boston, MA, USA), equipped with automatic acquisition and scanning, optical focusing, and automatic classification with convolutional neural network has been developed for bone marrow aspirate smear analysis of hematopoietic diseases. The goal of this preliminary study was to determine the feasibility of developing a machine learning algorithm on Morphogo for identifying abnormal urothelial cells in urine cytology slides., Methods: Thirty-seven achieved abnormal urine cytology slides from cases with the diagnosis of atypical urothelial cells and above (suspicions or positive for UC) were obtained from 1 hospital. A pathologist (J.R.) reviewed the slides and manually selected and annotated representative cells to feed into Morphogo with following categories: benign (urothelial cells, squamous cells, degenerated cells, and inflammatory cells), atypical cells, and suspicious cells. Initial validation of the algorithm was performed on a subset of the original 37 cases. Urine samples from additional 12 unknown cases with various histological diagnoses (6 cases of high-grade urothelial carcinoma (HGUC), 1 case of low-grade urothelial carcinoma (LGUC), 1 case of prostate adenocarcinoma, 1 case of renal cell carcinoma, and 4 cases of non-neoplastic conditions) were collected from another hospital for initial blind testing., Results: A total of 1,910 benign and 1,978 abnormal (atypical and suspicious) cells from 37 slides were annotated for developing and training of the algorithm. This algorithm was validated on 27 slides that resulted in identification of at least 1 abnormal cell per slide, with a total of 200 abnormal cells, and an average of 7.4 cells per slide. Of the 12 unknown cases tested, the original cytology was positive for tumor cells in 2 HGUC samples. Morphogo was abnormal (atypical or suspicious) for 6 samples from patients with UC, including one with LGUC and one with prostate adenocarcinoma., Conclusion: Morphogo machine learning algorithm is capable of identifying abnormal urothelial cells. Further validation studies with a larger number of urine samples will be needed to determine if it can be used to assist the cytological diagnosis of UC., (© 2020 S. Karger AG, Basel.)

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.)

Background: Performance of urinary cytology is recommended as the part of a standard diagnostic workup and base surveillance regimens in upper tract urothelial carcinoma (UTUC). However, the effect of positive voided urine cytology (VUC) on UTUC prognosis, compared with negative VUC, has not been fully demonstrated. This study aimed to evaluate the impact of preoperative VUC on predicting intravesical recurrence, disease recurrence, and mortality in patients with UTUC who underwent nephroureterectomy (RNU)., Methods: Clinicopathological information was collected from 315 UTUC patients treated with RNU. The association between VUC and oncological outcomes was analyzed using the Kaplan-Meier method with log-rank test and Cox proportional hazards regression models. Multiple logistic regression analysis was performed to identify the influence of VUC on tumor grade., Results: Preoperative positive VUC, presenting in 101 patients (32%), was significantly associated with tumor multifocality (P = 0.017) and higher tumor grade (P = 0.010). On multivariable Cox regression analyses, preoperative positive VUC was an independent prognostic factor of intravesical recurrence-free survival (RFS) (hazard ratio [HR] = 2.21, 95% confidence interval [CI] 1.06-4.64; P = 0.035), RFS (HR = 1.80, 95% CI 1.08-2.99; P = 0.023), and cancer-specific survival (CSS) (HR = 1.87, 95% CI 1.10-3.18; P = 0.020), but not overall survival (HR = 1.32, 95% CI 0.80-2.18; P = 0.28). Logistic regression analysis revealed that VUC was related to high tumor grade in UTUC (odds ratio = 2.23, 95%CI 1.15-4.52)., Conclusion: Preoperative positive VUC significantly increases the risk of intravesical recurrence in UTUC patients undergoing RNU. In addition, positive VUC is an adverse predictor of RFS and CSS, which might be due to the association between positive VUC and high tumor grade.

Objective: In 2013, The Paris System for Reporting Urinary Cytology (TPS) was developed as a uniform practical urine cytology system that could be applied worldwide. Here, we investigated the effectiveness of TPS diagnostic approach compared with that of the traditional urine cytological diagnosis method used in China., Methods: Based on the diagnostic criteria of TPS, 412 urine samples from 143 patients with histological follow-up data were retrospectively analysed, and the diagnoses were compared with the original cytological diagnoses., Results: In total, 110 patients were histologically diagnosed with high-grade urothelial carcinoma (HGUC), and 33 patients were diagnosed with low-grade urothelial neoplasia. Based on the traditional urine cytological analysis method, 50 patients (34.9%) were diagnosed as negative, 48 patients (33.6%) were diagnosed as having atypical urothelial cells, and 45 patients (31.5%) were diagnosed as positive. After reclassification using TPS, urine samples from 11 cases (7.7%) were categorised as unsatisfactory, 34 cases (23.8%) were negative, 21 cases (14.7%) were categorised as having atypical urothelial cells, 12 cases (8.4%) were diagnosed as suspicious for HGUC, 59 cases (41.2%) were diagnosed with HGUC, and six cases (4.2%) were reclassified as having low-grade urothelial neoplasia. Thus, after implementing TPS criteria, the sensitivity for positive malignancy diagnoses (HGUC alone) increased from 38.2% to 50.9%, while the specificity of the diagnosis was barely changed., Conclusions: The Paris System for Reporting Urinary Cytology greatly contributes to the standardisation of urine cytology reports and significantly improves the diagnostic sensitivity for HGUC., (© 2020 John Wiley & Sons Ltd.)

Background/aim: The Paris System (TPS) has recently been proposed as a method to standardize urinary cytology reporting. In this study, we evaluated the impact of implementing TPS compared to the traditional reporting system., Patients and Methods: In total, 299 urine samples were reclassified according to TPS. We examined correlations between cytological and histological diagnoses, and calculated probabilities for detecting high-grade urothelial carcinoma (HGUC)., Results: TPS resulted in a decrease in the proportion of cases diagnosed as atypical urothelial cell (AUC) (43% to 31%). Among the AUC cases, the proportion of histologically confirmed HGUC cases rose (75% to 80%), as did the proportion of low-grade urothelial neoplasms (57% to 71%). All probabilities for detecting HGUC significantly increased using TPS., Conclusion: TPS improved the diagnostic yield of urinary cytology. The implementation of TPS is expected to be a major step towards standardizing urinary cytology reporting and providing clear information to clinicians., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), 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.)

Background: The Paris System for Reporting Urinary Cytology (TPS) defines clear morphologic criteria to classify urinary specimens into 7 diagnostic categories. According to TPS, a nuclear-to-cytoplasmic ratio (N:C ratio) >0.7 and hyperchromasia must be observed to render a diagnosis of high-grade urothelial carcinoma (HGUC). TPS was established using only liquid-based preparation techniques, and to the authors' knowledge it is unknown whether TPS can be applied using other preparation methods., Methods: In the current prospective study, voided urine samples from patients with HGUC and negative for HGUC (NHGUC) were prepared using both ThinPrep and cytospin methods. ImageJ image processing software was used to measure the N:C ratio and hyperchromasia. For each patient, the N:C ratio and degree of hyperchromasia of urothelial cells present in both cytopreparations were compared., Results: A total of 10 HGUC cases and 9 NHGUC cases, represented by a total of 688 cells (mean, 36.7 cells in HGUC cases; and mean, 35.8 cells in NHGUC cases), were evaluated in the current study. An overall comparison of HGUC cells with NHGUC cells demonstrated that HGUC cells had a higher average N:C ratio (0.5465 vs 0.2846) and greater hyperchromasia as measured by the average nuclear pixel gray value (100.8 vs 120.7). The N:C ratio was statistically different in 4 NHGUC cases, demonstrating higher N:C ratios in the ThinPrep preparations. Hyperchromasia was found to be statistically different in 6 cases, 5 of which demonstrated increased hyperchromasia in the ThinPrep specimens., Conclusions: The morphologic features of HGUC cells appear to be similar in samples prepared using the ThinPrep and cytospin methods, and therefore TPS criteria may be applied successfully in laboratories that use these methods., (© 2019 American Cancer Society.)

Aims: The Paris System (TPS) was introduced in the diagnostic routine with the goal to simplify and standardise diagnostic reporting of urinary cytology. The diagnostic categories of TPS are based on defined cytological criteria, with a focus on high-grade urothelial carcinoma (HGUC). While the categories 'negative for HGUC (NHGUC)' and 'HGUC' are straightforward, the categories 'atypical urothelial cells (AUC)' and 'suspicious of HGUC (SHGUC)' remain inconclusive. In this study, we evaluated the feasibility of TPS in daily practice with special emphasis on ancillary fluorescence in situ hybridisation (FISH) testing in the setting of TPS categories., Methods: In a 19-month period, TPS was prospectively applied in the routine diagnostic setting on 3900 urinary cytology cases comprising bladder and upper urinary tract washings and voided urine specimens. Additionally, we analysed the results of the FISH assay UroVysion prospectively performed on a cohort of 128 cases enriched for AUC and SHGUC categories., Results: The most frequently reported category was NHGUC (n=3496, 89.7%), followed by AUC (n=178, 4.6%), HGUC (n=155, 4%), SHGUC (n=61, 1.6%), low-grade urothelial neoplasia (n=6, 0.1%) and other malignancies (n=4, 0.1%). In the FISH cohort, 40/90 (44%) cases within the AUC category were FISH positive, consistent with urothelial neoplasia. In the SHGUC category, 16/21 (76%) cases were FISH positive., Conclusions: When prospectively applying TPS in urinary cytology, inconclusive atypia accounts only for a small subset of cases. FISH additionally improves the stratification between reactive and malignant cells in the indeterminate AUC and SHGUC categories., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess willingness of adults to undergo home screening for urologic cancers via urine dipstick and determine the effect of an educational pamphlet on hematuria on screening willingness and knowledge of hematuria., Materials and Methods: We performed an online survey of adult volunteers throughout the United States from September 25, 2018 to October 15, 2018. The primary outcome was pretest willingness to undergo home screening for hematuria with urine dipstick (4 or 5 out of 5-point Likert). Secondary outcomes included changes in willingness to screen and knowledge on hematuria after exposure to an educational pamphlet., Results: Of 1442 participants, 54% were male and 87% were White. Median age was 48. Pretest willingness to home screen was high (90%). Older age was associated with an increased willingness to screen (per 10-year increase: odds ratio 1.47, 95% confidence interval 1.28-1.68, P <.001). Participants who had not previously discussed hematuria with a health care provider were less willing to screen (odds ratio 0.50, 95% confidence interval 0.27-0.94, P = .033). Patients with risk factors for urologic cancers (ie, smoking and occupational exposures) were equally willing to screen. After pamphlet exposure hematuria knowledge increased (P <.001) while willingness to screen did not change (P = .15)., Conclusion: Willingness to perform home-based screening for urologic cancers by assessing for hematuria is high in an adult population, including those with risk factors. Knowledge of hematuria improves significantly after exposure to an educational pamphlet., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate if preoperative sterile pyuria can be a prognostic factor for intravesical recurrence (IVR) and overall survival (OS)in patients with upper tract urothelial carcinoma (UTUC) undergoing surgery., Materials and Methods: We retrospectively reviewed the medical records of patients who were diagnosed with UTUC from October 2003 to December 2016 at Korea University Medical Center. Sterile pyuria was defined as urine containing five or more white blood cells per high-power field in the absence of bacteria in urine culture. We used a stepwise multivariable Cox proportional hazards model to assess the independent effects of the prognostic factors for IVR and OS., Results: We investigated a total of 176 patients who were diagnosed with UTUC. Among them, 91 (51.7%) patients had preoperative sterile pyuria. There were no significant differences in the baseline characteristics between the pyuria and non-pyuria groups concerning tumor grade, T stage, tumor multiplicity, and recurrence history. However, there was a significant difference in the IVR between the two groups. In the multivariable analysis, preoperative sterile pyuria, diabetes mellitus, high-grade tumor, and lymphovascular invasion were revealed as independent risk factors for IVR, and only lymphovascular invasion was identified as an independent risk factor for OS., Conclusions: Preoperative sterile pyuria is significantly associated with IVR in patients with UTUC undergoing surgery, but it is not associated with OS. Furthermore, diabetes mellitus, high-grade tumor, and lymphovascular invasion are also independent prognostic factors for these patients., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose., (© The Korean Urological Association, 2020.)

Objective: The development of the Paris System (TPS) has provided a standard and reproducible system for reporting urine cytopathology. Our goal was to study the impact of TPS on the diagnostic accuracy of urine cytology since we began using it in 2016., Methods: We performed a retrospective study of all urine cytology specimens received at our institution from January 2015 through July 2017. Cases were included in the study if they had corresponding surgical pathology follow up. In total, 3829 cases were identified over this time period, with 381 cases meeting inclusion criteria, comprising 87 cases from 2015, 166 from 2016 and 128 from 2017. Using the histopathology diagnosis as the gold standard, sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and diagnostic accuracy (DA) for the detection of carcinoma were calculated., Results: Before TPS, urine cytology had a sensitivity of 100.0%, specificity of 12.5%, PPV of 83.5%, NPV of 100.0% and DA of 83.9%. After TPS, for 2016, urine cytology had sensitivity of 87.1%, specificity of 95.9%, PPV of 96.4%, NPV of 85.4% and DA of 91.0%. For 2017 after TPS, the sensitivity was 81.7%, specificity was 100.0%, PPV was 100.0%, NPV was 81.4% and DA was 89.8%., Conclusion: For the detection of urinary tract malignancy, after switching to TPS, we observed a marked increase in urine cytology specificity and PPV, both of which continued to gradually increase from 2016 to 2017. The DA also improved with TPS., (© 2019 John Wiley & Sons Ltd.)

Introduction: The Paris system for reporting urinary cytology (TPS) was published in order to provide clear cytomorphological criteria for urine cytology specimens, focusing on high-grade urothelial lesions. The aim of this study was to evaluate the impact of implementing TPS and to correlate with available concomitant histological samples, accessing overall sensitivity and specificity., Methods: A retrospective analysis of urine cytology reports from 2017 to 2018 using TPS was carried out, with histological correlation to concomitant samples (up to 3 months). Statistical analysis was performed with calculation of sensitivity and specificity, positive and negative predictive values and risk of malignancy (ROM) for all TPS categories., Results: A total of 1660 specimens were evaluated. Histological specimens were available for 611 (36.8%) cases. Urine cytology categorised by TPS had 2.4% non-diagnostic cases, 87.1% negative for high-grade urothelial carcinoma (HGUC), 4.6% atypical urothelial cells, 2.7% suspicious for HGUC, 2.7% HGUC and 0.5% cases of other malignancies. Sensitivity, specificity, negative predictive value and positive predictive value were 40.0%, 99.3%, 88.2% and 92.3%, respectively. ROM of each category was 0% for non-diagnostic, 11.1% for negative for HGUC, 32.4% for atypical, 64.9% for suspicious for HGUC and 87.9% for HGUC and other malignancies., Conclusion: Our findings indicated that implementation of TPS provided a high specificity and predictive positive value for the detection of high-grade urothelial lesions, with proportionally increasing ROMs as categories progress from negative to positive., (© 2019 John Wiley & Sons Ltd.)

Background: Early detection of urothelial carcinoma (UC) by noninvasive diagnostic methods with high accuracy is still underscored. This study aimed to develop a noninvasive assay incorporating both enrichment of urine exfoliated cells and immunoassays for UC detection., Methods: Polystyrene dishes were exposed to oxygen plasma and modified with 3-aminopropyltriethoxysilane to prepare amine-functionalized nanostructured substrates (NS). Performance characterization of NS was evaluated by atomic force microscope and X-ray photoelectron spectroscopy. Urine exfoliated cells were captured by NS and then immunostained to detect urinary tumor cells (UTCs), which was called UTC assay. The receiver operating characteristic (ROC) curve, area under ROC curve (AUC), and Youden index were used to find the cutoff value of UTC assay. ROC analysis and McNemar test were used to compare the diagnostic accuracy of UTC assay with cytology. Kappa test was used to analyze the agreement of UTC assay and cytology with pathological diagnosis., Results: Nanostructured substrates had good cell binding yields of nucleated cells and tumor cells. CK20 + CD45 - CD11b - cells were considered as UTCs. UTC number ≥ 1 per sample could be considered as a positive result. By AUC and Kappa analysis, UTC assay showed good performance in UC detection. McNemar test demonstrated that UTC assay had a superior sensitivity even in low-grade subgroup and a similar specificity compared to cytology in UC diagnosis., Conclusions: Nanostructured substrates could be used to enrich the exfoliated cells from urine samples. UTC assay with NS has the potential to play a role in UC detection. The value of this assay still needs additional validation by large, multi-center studies., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)