Urinary Tract Cytology Specimens Research Articles

Nuclear membrane irregularity in high-grade urothelial carcinoma cells can be measured by using circularity and solidity as morphometric shape definitions in digital image analysis of urinary tract cytology specimens.

The Paris System for Reporting Urine Cytology defines objective (elevated nuclear/cytoplasmic ratio ≥0.7) and subjective (nuclear membrane irregularity, hyperchromicity, and coarse chromatin) cytomorphologic criteria to identify conventional high-grade urothelial carcinoma (HGUC) cells. Digital image analysis allows quantitative and objective measurement of these subjective criteria. In this study, digital image analysis was used to quantitate nuclear membrane irregularity in HGUC cells. Whole-slide images of HGUC urine specimens were acquired, and HGUC nuclei were manually annotated using the open-source bioimage analysis software QuPath. Custom scripts were used to calculate nuclear morphometrics and perform downstream analysis. In total, 1395 HGUC cell nuclei were annotated across 24 HGUC specimens (48.1±6.0 nuclei per case) using both pixel-level and smooth annotation approaches. Nuclear membrane irregularity was estimated by calculating nuclear circularity and solidity. Annotating at pixel-level resolution artifactually increases nuclear membrane perimeter, thus smoothing is necessary to better approximate a pathologist's assessment of nuclear membrane irregularity. After smoothing, nuclear circularity and solidity discriminate between HGUC cell nuclei with visually apparent differences in nuclear membrane irregularity. Nuclear membrane irregularity defined by The Paris System for Reporting Urine Cytology is inherently subjective. This study identifies nuclear morphometrics that visually correlate with nuclear membrane irregularity. HGUC specimens show intercase variation in nuclear morphometrics, with some nuclei appearing remarkably regular while others show marked irregularity. A small population of irregular nuclei generates most of the intracase variation in nuclear morphometrics. These results highlight nuclear membrane irregularity as an important, but not definitive, cytomorphologic criterion in HGUC diagnosis.

The Diagnostic Dilemma of Urothelial Tissue Fragments in Urinary Tract Cytology Specimens.

Since the release of The Paris System for Reporting Urinary Cytology (TPS), the assessment of urine cytology specimens has primarily focused on the detection of high-grade urothelial carcinoma (HGUC) and carcinoma in situ (CIS). Fortunately, the malignant cells in these lesions tend to be loosely cohesive, resulting in the natural exfoliation of individual malignant cells into the urine. However, HGUC/CIS lesions occasionally exfoliate larger fragments which can be difficult to assess due to cellular overlap and fragment three-dimensionality. Furthermore, reactive benign urothelial fragments and fragments from low-grade urothelial neoplasms (LGUN) may also be seen in urine specimens and contain atypical cytomorphologic features. As a result, the significance of urothelial tissue fragments (UTFs) is often unclear. Herein, we discuss the literature on UTFs before and after the implementation of TPS, as well as strategies to help overcome this diagnostic challenge.

Clinician's commentary: Atypia in urinary tract cytology specimens.

At the 18th International Congress of Cytology in Paris in 2013, the "Paris Group" created standardized reporting system/criteria for urine cytopathology. This reporting system provided evidence-based criteria for all the urine cytopathologic diagnosis in aims to avoid atypia being used a "waste basket." The addition of standard classification system greatly helps minimizing atypia diagnosis; however, clinicians, specifically, urologist, are still left without a clear set of guidelines for how to approach atypia. Prospective collaborate work with cytopathologists and urologist can help solve the dreaded atypia cytology pathological report and provide a framework and guidelines on management, providing better care to our patients.

Abstract LB015: Clinical evaluation of The Paris System-based artificial intelligence algorithm for reporting urinary cytopathology

Abstract BACKGROUND: The Paris System (TPS) for Reporting Urinary Cytology provides standardized diagnostic criteria for urinary tract cytology specimens, focusing on the detection of high-grade urothelial carcinoma (HGUC). Since the publication in 2016, numerous studies have reported a decrease in atypical diagnosis and a significant improvement in the detection of HGUC after adopting TPS. However, the major challenges include labor-intensive screening and interobserver variations. Artificial intelligence (AI) in medical imaging analysis is an emerging tool for ancillary diagnosis. To this end, we have developed an AI algorithm and conducted a retrospective study to evaluate the AI-assisted urine cytology reporting workflow. METHODS: A total of 131 urine cytology slides from bladder cancer patients, either first diagnosis or post-treatment follow-up, were retrieved and digitized as whole slide images (WSIs). A deep learning-based computational model was used to analyze these WSIs. Candidate urothelial cells were automatically highlighted and classified into high-risk and low-risk atypia categories in each sample based on TPS criteria. Slide-wide statistical data, including a total number of high-risk and low-risk cells, nuclear-cytoplasmic ratio (N:C ratio) and nuclear area for each cell, and the distribution and mean values of these variables, were also provided. In a blind study, a cytotechnologist and a cytopathologist parallelly reviewed the AI-annotated images and quantitative data for each WSI sample. Suspicious for HUGC and HGUC were considered to be "positive" and the other diagnostic categories were considered to be "negative" according to whether trigger cystoscopy. The results were compared with the final diagnosis reviewed by a senior cytopathologist via microscopy to evaluate the performance of the AI-assisted model. RESULTS: There were 35 positive and 96 negative urine cytology samples based on the final diagnosis. The AI algorithm annotated a total of 26,502 cells and a mean of 757.2 cells at cancer risk from all positive samples and a total of 950 cells and a mean of 9.9 cells at cancer risk from all negative samples. The mean N:C ratio was 0.68 for high-risk atypical cells and 0.56 for low-risk atypical cells. The performance of the AI-assisted reports of the cytotechnologist was 88.6% sensitivity, 97.9% specificity, 93.9% positive prediction value (PPV), and 95.9% negative prediction value (NPV) and the cytopathologist was 91.4% sensitivity, 95.8% specificity, 88.9% PPV, and 96.8% NPV. CONCLUSIONS: We demonstrated an AI algorithm that can effectively assist the reporting of urine cytology by classifying urothelial cells at cancer risk and calculating quantitative data using WSI analysis. Integrating this AI model into clinical urine cytology workflow supported TPS for reporting urinary cytopathology, reduced the interobserver variations, and may potentially reduce the human labor for screening. Citation Format: Wei-Lei Yang, Jen-Fan Hang, Chi-Bin Li, Ching-Ming Lee, Yi-Sheng Lin, Tang-Yi Tsao, Ming-Chen Chang, Yen-Chuan Ou, Tien-Jen Liu. Clinical evaluation of The Paris System-based artificial intelligence algorithm for reporting urinary cytopathology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB015.

Negative predictive value and sensitivity of urine cytology prior to implementation of The Paris System for Reporting Urinary Cytology

Urinary tract cytology (UTCy) is used for screening urothelial carcinoma (UC) and it must have a high negative predictive value (NPV) to be an effective test. To the authors' knowledge, the literature regarding the NPV of UTCy provides little information regarding the risk of malignancy, especially for patients with high-grade urothelial carcinoma (HGUC). Patients with negative UTCy specimens were identified in the pathology files at the study institution for the years 2012 through 2013. Cases were deemed true-negative cases if there was at least 1 subsequent negative specimen or negative clinical follow-up within 6months of the index case. False-negative cases were defined as HGUC or carcinoma in situ by surgical biopsy and/or any UTCy with suspicious for HGUC or HGUC follow-up. A total of 2614 UTCy specimens from 2089 patients were identified. There was a disease prevalence of 6.5%. There were 87 false-negative results for HGUC, which corresponded to an overall NPV of 96.7%. When categorized by clinical indication, hematuria resulted in the highest NPV of 99.5% followed by other indications (97.7%) and a history of UC (90.1%). When categorized by the specimen type, voided urine specimens were found to have the highest NPV of 98.7% followed by other indications (96.9%) and washing specimens (96.2%). Of the 717 patients with a history of UC, the NPV was lower for washing specimens (89.8%) than for voided urine specimens (96.2%). When including either low-grade urothelial carcinoma or HGUC as a positive follow-up, the NPV dropped to 93.3% from 96.7% (HGUC only). The sensitivity of the diagnostic category of atypical urothelial cells or higher was 93.0%. Overall, UTCy appears to have a good NPV and a high sensitivity for HGUC. The clinical indication had a greater impact on NPV compared with the specimen type.

Variability among observers utilizing the CellSolutions BestCyte Cell Sorter imaging system for the assessment of urinary tract cytology specimens

Image analysis systems are not currently commonly used for evaluating urinary cytology specimens. We evaluated whether the BestCyte Cell Sorter (CellSolutions, Greensboro, NC) imaging system can reliably identify atypical cells in urinary cytology specimens. Fifty-three consecutive urine cytology specimens underwent 2 preparations: one slide using SurePath (SP; BD Diagnostics, Sparks, MD)™ for routine clinical evaluation, and a second slide using the CellSolutions F50 system for analysis by the BestCyte Cell Sorter (BCCS) scanning system. Eight observers reviewed atypical cells flagged by BCCS and assigned a BCCS diagnosis to each of the 53 specimens. The observers also blindly reviewed the SP preparation (when available) and assigned an SP diagnosis. The SP diagnoses given by one "expert" observer was considered as a reference diagnosis. There was fair-to-moderate agreement among observers for identifying any atypia and high-grade atypia (Fleiss kappa: 0.417 and 0.338, respectively) using BCCS. Review of SP preparations had slightly better agreement (Fleiss kappa: 0.558 and 0.564, respectively). Intraobserver agreement between the two methods varied greatly between individuals (Cohen's kappa range: 0.260 to 0.647). When a consensus diagnosis could be reached among the observers for cases with surgical follow-up, the consensus diagnosis was concordant in 11 of 12 instances, with one instance being a one-step discrepancy. Specimen review by BCCS resulted in slightly greater interobserver variability than review of routine SP preparations. This may have been due to variations in observer experience and comfort with the use of a digital imaging system, which is further suggested by the wide range of intraobserver agreement among individuals.

Agreement Between Cytotechnologist and Cytopathologist for the Diagnosis of Urinary Tract Cytology Specimens

Agreement Between Cytotechnologist and Cytopathologist for the Diagnosis of Urinary Tract Cytology Specimens

A Single Institutional Experience With the Paris System for Reporting Urinary Cytology: Correlation of Cytology and Histology in 194 Cases.

The Paris System for Reporting Urinary Cytology (TPS) is designed to standardize the criteria and terminology used in urinary tract cytology reporting. The aim of this study was to evaluate the impact of implementing TPS and to analyze the correlation with follow-up biopsies in order to assess its reproducibility. Urinary tract cytology specimens with follow-up biopsies over a 2-year period were reviewed and reclassified according to TPS criteria. Surgical follow-up diagnoses were correlated with the initial cytology diagnoses and TPS interpretations, and the results were compared. Applying TPS in comparison to our previous reporting system resulted in fewer cases in the atypia category (11.8% vs 24.2%) and higher specificity, accuracy, and predictive value. We observed acceptable interobserver agreement in diagnostic categories of this reporting system. TPS improves the overall performance of urinary tract cytology by standardizing the criteria and terminology.

Evaluation of Sienna Cancer Diagnostics hTERT Antibody on 500 Consecutive Urinary Tract Specimens

Objectives: Telomerase activity can be detected in up to 90% of urothelial carcinomas (UC). Telomerase activity can also be detected in urinary tract cytology (UTC) specimens and indicate an increased risk of UC. We evaluated the performance of a commercially available antibody that putatively binds the telomerase reverse transcriptase (hTERT) subunit on 500 UTC specimens. Study Design: Unstained Cytospin^TM preparations were created from residual urine specimens and were stained using the anti-hTERT antibody (SCD-A7). Two algorithms were developed for concatenating the hTERT result and cytologic diagnosis: a “no indeterminates algorithm,” in which a negative cytology and positive hTERT result are considered positive, and a “high-specificity algorithm,” in which a negative cytology and positive hTERT result are considered indeterminate (and thus negative for comparison to the gold standard). Results: The “no indeterminates algorithm” and “high-specificity algorithm” yielded a sensitivity of 60.6 and 52.1%, a specificity of 70.4 and 90.7%, a positive predictive value of 39.1 and 63.8%, and a negative predictive value of 85.0 and 85.8%, respectively. Conclusions: A positive hTERT result may identify a subset of patients with an increased risk of high-grade UC (HGUC) who may otherwise not be closely followed, while a negative hTERT immunocytochemistry result is associated with a reduction in risk for HGUC.

A 20-year and 46,000-specimen journey to Paris reveals the influence of reporting systems and passive peer feedback on pathologist practice patterns.

An important goal of The Paris System for Reporting Urinary Cytology (TPS) is to reduce unnecessary atypical diagnoses given to urinary tract cytology (UTC) specimens. Since implementation of TPS at the study institution in 2016, the institutional atypical rate has declined only slightly. The authors speculated that TPS might not have had an immediate impact because several faculty members were involved in TPS committees and because TPS contains elements that already had been integrated into institutional practice. To identify factors contributing to alterations in the institutional atypical rate, the authors examined their practice over the last 22 years. UTC specimens submitted to the study laboratory between August 11, 1995, and August 10, 2017, were identified. Specimens were linked to the responsible pathologist, specimen diagnosis and type, association with high-grade urothelial carcinoma, and relevant cytomorphologic features. An increase in the institutional atypical rate occurred between 2002 and 2005. The atypical rate among individual pathologists also peaked during this same time. The increase coincided with an increase in the use of UTC and the arrival of a pathologist with a higher rate of atypical diagnoses. A substantial decrease in the institutional atypical rate occurred between 2005 and 2010 and coincided with the creation of the Johns Hopkins Hospital Template, the authors' first standardized reporting system for UTC specimens. The use of reporting systems (Johns Hopkins Hospital Template and TPS) has coincided with decreases in the institutional atypical rate at the study institution. An individual pathologist may influence the practice patterns of his or her colleagues, resulting in fluctuations in the institutional rate of atypia over time. Cancer Cytopathol 2018;126:381-9. © 2018 American Cancer Society.

When words matter: A "suspicious" urinary tract cytology diagnosis improves patient follow-up among nonurologists.

Urinary tract cytology (UTC) specimens diagnosed using high-risk indeterminate categories such as "atypical urothelial cells, cannot exclude high-grade urothelial carcinoma" (AUC-H) or "suspicious for high-grade urothelial carcinoma" (SHGUC) have a high rate of detection of high-grade urothelial carcinoma on subsequent biopsy. Although urologists are familiar with such terminology, it is unclear whether patients receive appropriate follow-up when UTC is ordered by nonurologists. In the current study, the authors investigated whether the use of AUC-H versus SHGUC altered patient management among nonurologists. Specimens signed out as AUC-H or SHGUC were identified from the archives of the study institution, which included periods of time before the use of the standardized Johns Hopkins Hospital template, during use of the Johns Hopkins Hospital template, and after institution of The Paris System for Reporting Urinary Cytology. Approximately one-half of the specimens diagnosed as AUC-H were not investigated further when ordered by nonurologists. Patients with specimens diagnosed as AUC-H received fewer subsequent biopsies (14% vs 53%; P < .001) when the specimens were ordered by nonurologists versus urologists, despite having similar rates of high-grade urothelial carcinoma on follow-up biopsy (67% vs 66%). When specimens ordered by nonurologists were diagnosed as SHGUC, these patients received more follow-up (100%) compared with those whose specimens were diagnosed as AUC-H (44%; P < .001). Patients with specimens ordered by nonurologists also received more follow-up biopsies when these were diagnosed as suspicious (60%) compared with patients whose specimens were diagnosed as AUC-H (14%; P < .001). Use of the word "suspicious" for the high-risk indeterminate category results in greater follow-up among nonurologists ordering UTC specimens. Cancer Cytopathol 2018;126:282-8. © 2018 American Cancer Society.

Digital image analysis supports a nuclear‐to‐cytoplasmic ratio cutoff value of 0.5 for atypical urothelial cells

An elevated nuclear-to-cytoplasmic (N:C) ratio of ≥0.5 is a required criterion for the diagnosis of atypical urothelial cells (AUC) in The Paris System for Reporting Urinary Cytology. To validate the N:C ratio cutoff value and its predictive power for high-grade urothelial carcinoma (HGUC), the authors retrospectively reviewed the urinary tract cytology specimens of 15 cases of AUC with HGUC on follow-up (AUC-HGUC) and 33 cases of AUC without HGUC on follow-up (AUC-N-HGUC). The number of atypical cells in each case was recorded, and each atypical cell was photographed and digitally examined to calculate the nuclear size and N:C ratio. On average, the maximum N:C ratios of atypical cells were significantly different between the AUC-HGUC and AUC-N-HGUC cohorts (0.53 vs 0.43; P =.00009), whereas the maximum nuclear sizes of atypical cells (153.43 μM2 vs 201.47 μM2 ; P = .69) and the number of atypical cells per case (10.13 vs 7.88; P = .12) were not found to be significantly different. Receiver operating characteristic analysis demonstrated that the maximum N:C ratio alone had high discriminatory capacity (area under the curve, 79.19%; 95% confidence interval, 64.19%-94.19%). The optimal maximum N:C ratio threshold was 0.486, giving a sensitivity of 73.3% and a specificity of 84.8% for predicting HGUC on follow-up. The identification of AUC with an N:C ratio >0.486 has a high predictive power for HGUC on follow-up in AUC specimens. This justifies using the N:C ratio as a required criterion for the AUC category. Individual laboratories using different cytopreparation methods may require independent validation of the N:C ratio cutoff value. Cancer Cytopathol 2017;125:710-6. © 2017 American Cancer Society.

Improved risk stratification for patients with high-grade urothelial carcinoma following application of the Paris System for Reporting Urinary Cytology.

The Paris System for Reporting Urinary Cytology (TPS) requires 4 cytomorphologic criteria for a definitive diagnosis of high-grade urothelial carcinoma (HGUC) in urinary tract cytology (UTC) specimens: an elevated nuclear-to-cytoplasmic (N/C) ratio (at or above 0.7), markedly atypical nuclear borders, moderate to severe hyperchromasia, and coarse chromatin. However, malignant UTC specimens often contain degenerative changes, and this limits the number of malignant cells meeting all 4 TPS cytomorphologic criteria. One hundred twelve UTC specimens from patients with a subsequent diagnosis of HGUC were reviewed and reclassified according to TPS criteria. The presence of TPS cytomorphologic criteria for HGUC in each specimen was recorded, as was the proportion of atypical cells meeting all 4 criteria. The number of specimens definitively diagnosed as HGUC did not significantly change upon reclassification. However, approximately 40% of indeterminate specimens (21 of 51) were reclassified into a higher risk category. The most restrictive cytomorphologic criterion was an N/C ratio of 0.7 or higher (seen in 78% of specimens), and approximately half of specimens containing all 4 cytomorphologic criteria did not meet TPS's numerical criterion for HGUC (at least 5 malignant cells). In the majority of specimens qualifying for HGUC by TPS standards, only a small fraction of atypical cells (10%-20%) met all the criteria. When applied to malignant UTC specimens, TPS criteria improved specimen risk stratification by upgrading approximately 40% of indeterminate specimens into higher risk categories while not significantly changing the frequency of HGUC diagnoses. Cancer Cytopathol 2017;125:427-34. © 2017 American Cancer Society.

The positive predictive value of "suspicious for high-grade urothelial carcinoma" in urinary tract cytology specimens: A single-institution study of 665 cases.

"The Paris System" proposes a 7-tier classification system for urine cytology. Establishing the risk of malignancy (ROM) associated with these diagnostic categories is essential to determine the appropriate management of patients. The objective of this study was to determine the ROM associated with the "positive" and "suspicious" categories. The authors searched their electronic records for urine cytology specimens that had been diagnosed as "positive" or "suspicious" for high-grade urothelial carcinoma within an 11-year time frame. Then, the ROM was determined for these specimens within a 6-month follow-up interval. The cytologic diagnoses were correlated with surgical biopsy results, follow-up cytology results, and/or fluorescence in situ hybridization (FISH) results. In total, 662 specimens (487 "positive" and 175 "suspicious"), corresponding to 387 patients (295 men and 92 women), were included. The majority of specimens were collected by bladder washing (568 of 662 specimens; 85.4%) and for the indication of surveillance (601 of 662 specimens; 82%). On follow-up, bladder washing specimens were positive more often positive than voided urine specimens (466 of 570 [81.8%] vs 60 of 92 [65.2%]; P = .0005), and surveillance specimens were more often positive than specimens collected for other indications (82% vs 54.1%). The overall positive predictive value was higher for positive specimens than for suspicious specimens (365 of 461 [79.2%] vs 83 of 150 [55.3%]; P < .0001). Diagnoses of suspicious for high-grade urothelial carcinoma, as used at the authors' institution, have an ROM that is high but is lower than that for the "positive" category. Therefore, the authors suggest keeping the 2 categories separate, although management should be aggressive in both groups. Cancer Cytopathol 2016;124:811-9. © 2016 American Cancer Society.

Accuracy and interobserver variability of the cytologic diagnosis of low-grade urothelial carcinoma in instrumented urinary tract cytology specimens.

The aim of this study was to determine the accuracy of diagnosis and level of agreement of the cytologic diagnosis of low-grade urothelial carcinoma (LGUC) among experienced cytopathologists to help the development of the upcoming classification scheme ("The Paris System") of urinary cytology (UTCy). Forty ThinPrep (Cytyc, Boxborough, MA) UTCy specimens (19 with corresponding biopsy specimens diagnosed as LGUC and 21 with negative biopsy and/or cystoscopy specimens) were blindly reviewed by six cytopathologists from three institutions and diagnosed as negative for malignancy (NM), atypical urothelial cells (AUCs), and LGUC. Interobserver agreement was measured with the weighted κ statistic. Each observer's receiver operating characteristic (ROC) curves and the area under the ROC curve (AUROC) were calculated. Four to six reviewers diagnosed LGUC in five (26%) of 19 UTCy specimens, corresponding to a biopsy diagnosis of LGUC. Overall agreement was fair (κ = 0.30). After collapsing AUC with NM, the reviewers' ranges of sensitivity, specificity, positive predictive value, and negative predictive value for LGUC were 21% to 53%, 81% to 95%, 71% to 90%, and 57% to 67%, respectively. AUROC varied from 0.66 to 0.74. We found that UTCy has a low sensitivity but relatively high specificity, resulting in poor to fair accuracy for the diagnosis of LGUC; the level of agreement between reviewers was only fair to moderate.

Cytomorphologic features and differential diagnosis of neoplasms with small cell features in liquid-based urinary tract cytologic specimens

Urinary tract cytology (UTCy) allows the accurate diagnosis of high grade urothelial carcinoma. Rare malignancies characterized by the presence of small cells may be more difficult to recognize, however. The aim of this study was to review our experience with liquid-based (ThinPrep) UTCy specimens showing small atypical cells and characterize their cytomorphology, potential differences from previously reported morphologic features, and discuss their differential diagnostic considerations. Among 18,859 UTCy specimens reviewed during a 13-year period (2001-2012), we identified 13 cases corresponding to surgical pathology specimens diagnosed as small cell carcinoma (6), melanoma (3), lymphoma (3), and leukemic involvement of the urinary tract (1). We recorded the original diagnoses made on these cases and 10 cytomorphologic features that could aid in their diagnosis. We identified 13 cases in UTCy of 7 men and 6 women; 11 of which were diagnosed as positive or suspicious for malignancy. In 8 out of 13 cases (62%) the type of malignancy was correctly reported. Of the 10 recorded features, cellular clustering and nuclear molding were seen only in small cell carcinoma, whereas prominent nucleoli and an inflammatory background or diathesis were noted in lymphoma and melanoma cases. Intracellular pigment and multinucleation were recorded in melanoma cases. The presence of small atypical cells in liquid-based UTCy should raise the suspicion of underlying malignancy involving the urinary tract. Cell clustering, nuclear molding, and hyperchromasia are helpful hints for the diagnosis of small cell carcinoma and the presence of small atypical cells with prominent nucleoli raises the possibility of lymphoma or melanoma.

Is a consistent cytologic diagnosis of low-grade urothelial carcinoma in instrumented urinary tract cytologic specimens possible? A comparison between cytomorphologic features of low-grade urothelial carcinoma and non-neoplastic changes shows extensive overlap, making a reliable diagnosis impossible

The ability to consistently diagnose low-grade urothelial carcinoma (LGUC) in urinary tract cytology (UTCy) specimens remains controversial, as the reported sensitivity of UTCy in the detection of LGUC is as low as 10%. To determine whether a consistent cytologic diagnosis of LGUC is possible, we assessed the presence and frequency of previously described cytomorphologic features of LGUC in UTCy from patients with LGUC and a negative control group. Biopsy-proven cases of LGUC from June 1, 2010 to January 31, 2014 were identified; UTCy obtained within 3 months prior to biopsy composed the study group (n = 98). The negative control group consisted of UTCy obtained from patients with negative cystoscopy and biopsy (n = 53). All specimens were masked and reviewed in random order to evaluate 17 cytomorphologic parameters. Univariate statistical analyses demonstrated that the prevalence of paired cells, clumpy chromatin, and cytoplasmic homogeneity was higher in the study group; however, multivariate analysis did not show these features as significant predictors of LGUC. No cytomorphologic feature was statistically significant in the LGUC group versus the negative control group. The presence of 3-dimensional papillary structures with fibrovascular cores is diagnostic of LGUC, but it is only seen in a small minority (2 of 98) cases. Our results reemphasize the fact that urinary tract cytology has a low sensitivity for the diagnosis of LGUC and suggest that, instead of striving to detect LGUC in urine specimens, we should concentrate on the clinically relevant goal of urine cytology-the detection of high-grade lesions.