p53 and Vimentin Double Immunostaining to Differentiate between High-Grade Urothelial Carcinoma Cells and Benign Atypical Cells.

INTRODUCTION: Urine cytology is an indispensable test for detecting high-grade urothelial carcinoma (HGUC); however, the distinction between HGUC cells and morphologically similar benign atypical cells poses clinical challenges. In this study, we performed double immunostaining for p53 and vimentin to establish a diagnostic method to accurately distinguish HGUC cells from benign atypical cells. METHODS: This study included 41 cases of HGUC, 11 of urolithiasis, and 22 of glomerular disease diagnosed histopathologically or clinically. After preparing urine cytology specimens from voided urine samples, p53 immunostaining was performed, and the p53-positive intensity and p53 positivity rate were calculated. Subsequently, vimentin immunostaining was performed on the same specimens to calculate the rate of vimentin positivity. RESULTS: The HGUC cell group had a mean p53-positive intensity of 2.40, a mean p53 positivity rate of 73.2%, and a mean vimentin positivity rate of 5.1%. In contrast, the mean p53-positive intensity, p53 positivity rate, and vimentin positivity rate were 1.63, 36.7%, and 66.2%, respectively, in the benign atypical cell group. There were significant differences between the two groups for each parameter. Moreover, two multiple logistic regression models combining the results of these three parameters exhibited higher sensitivity and specificity than solely assessing the p53-positive intensity, positivity rate, and vimentin positivity rate. CONCLUSION: Since double immunostaining with p53 and vimentin distinguishes HGUC cells from benign atypical cells, it could be to improve the diagnostic accuracy of urine cytology.

A Case of Metastatic Urothelial Carcinoma-Associated Acute Esophageal Necrosis.

Acute esophageal necrosis is a rare syndrome with endoscopic findings of a diffuse circumferential pattern of black mucosa. Although underlying pathogenesis is unclear, it is known to have associations with malignancy. We present a rare case of a patient with a history of metastatic urothelial carcinoma who was found to have acute esophageal necrosis.

Nuclear long diameter as a new criterion to distinguish high-grade urothelial carcinoma cells from benign reactive cells.

OBJECTIVE: Recently, the nuclear area has attracted attention as a morphological parameter to differentiate high-grade urothelial carcinoma (HGUC) cells from benign reactive cells. The nuclear long diameter (NLD) strongly correlates with the nuclear area and is easy to subjectively estimate. Therefore, this study examined the usefulness of the NLD-to-neutrophil diameter ratio for detecting HGUC cells in urine cytology. METHODS: This study included 29, 26 and 18 patients with HGUC, glomerular disease and urolithiasis respectively. An image analysis system was used to measure the NLD of HGUC and benign reactive cells (reactive renal tubular cells and reactive urothelial cells) and the neutrophil diameter that appeared in the voided urine in these cases. The NLD index was calculated using the NLD-to-neutrophil diameter ratio. We subsequently compared HGUC and benign reactive cells with respect to NLD and NLD indices. In addition, the HGUC cell group and benign reactive cell group were compared by selecting the five cells with the largest NLD and NLD index on each slide. RESULTS: The NLD and NLD indices of HGUC cells were significantly higher than those of benign reactive cells in all cells and in the five cells with the largest NLD and NLD indices. The cut-off value of the NLD index for detecting HGUC cells was 1.25 in all cells and 1.80 in the five cells with the largest NLD index. CONCLUSIONS: The NLD index is a useful parameter that can be introduced into routine microscopic examinations to differentiate HGUC cells from benign reactive cells.

Comparison of tissue biomarkers between non-schistosoma and schistosoma-associated urothelial carcinoma.

BACKGROUND: High-grade urothelial carcinoma either non-Schistosoma (NS-UBC) or Schistosoma (S-UBC)-associated is the tenth cause of death worldwide and represents a serious therapeutic problem. AIM: Evaluation of the immmunohistochemical expression of tumor necrosis factor-alpha (TNFα), epidermal growth factor receptor (EGFR), programmed cell death protein-1 (PDL1), estrogen receptor-alpha (ERα) and UroplakinIII, in the high-grade in NS-UBC and S-UBC as potential prognostic and therapeutic targets analyzed through estimation of area percentage, optical density and international pathological scoring system for each marker. MATERIAL AND METHODS: Sixty high grade urothelial carcinoma cases were enrolled in the study (30 cases of NS-UBC and 30 cases of S-UBC). The cases were immunohistochemically-assessed for TNFα, EGFR, PDL1, ERα and Uroplakin III expression. In S-UBC, parasite load was also evaluated for correlation with the immunohistochemical markers' expression in S-UBC. RESULTS: The area percentage of immune-expression of TNFα and EGFR was higher in S-UBC compared to NS-UBC. On the other hand, the NS-UBC displayed statistically-higher expression of PDL1 and uroplakinIII (p-value <0.001). ERα revealed higher, yet, non-significant expressions in S-UBC compared to NS-UBC (p-value =0.459). PDL1 expression showed the most superior record regarding area percentage (64.6± 34.5). Regarding optical density, TNF-α showed the highest transmittance expression (2.4 ± 0.9). EGFR positively correlated with PDL1 in S-UBC (r= 0.578, p-value =0.001) whereas in NS-UBC, TNFα and PDL1 (r=0.382, p-value=0.037) had positive correlation. Schistosoma eggs in tissues oppose uroplakin III expression and trigger immunomodulation via PDL1. CONCLUSION: Due to lower UroplakinIII expression, S-UBC is supposed to have a poorer prognosis. Hormonal therapy is not hypothesized due to a very minimal ERα expression in both NS-UBC and S-UBC. Regarding immunotherapy, anti-TNF-α is suggested for S-UBC whilst in NS-UBC, blockading PDL1 might be useful. Targeted EGFR therapy seems to carry emphasized outcomes in S-UBC. Correlations encourage combined immune therapy in NS-UBC; nevertheless, in S-UBC, combined anti-EGFR and PDL1 seem to be of benefit.

Utility of the Paris System in Urine Cytology for Improved Screening of High-Grade Urothelial Carcinoma in Bahrain.

BACKGROUND: Urothelial carcinoma, a prevalent and aggressive urological malignancy, necessitates early detection for improved prognosis. Urine cytology serves as a cost-effective screening tool, but inconsistencies in reporting due to the lack of standardized criteria limit its efficacy. The Paris System for reporting urinary cytology (TPS) was introduced to address this issue, aiming to improve diagnostic accuracy. This retrospective study investigates the effectiveness of urine cytology in detecting high-grade urothelial carcinoma (HGUC) using TPS classification, specifically focusing on atypical urothelial cells (AUC) categorized as TPS-III and suspicious for high-grade urothelial carcinoma (SHGUC) categorized as TPS-IV. METHODS: We reviewed 470 urine cytology samples collected over two years at a tertiary healthcare center in Bahrain. All samples were re-evaluated using TPS classification by two independent consultant cytopathologists blinded to the original cytology report. The analysis included only samples categorized as TPS-III or TPS-IV with corresponding histopathology reports from confirmatory biopsies performed within four months of urine collection. Biopsy results were categorized as either benign/low-grade urothelial carcinoma (non-HGUC) or malignant (HGUC). The positive predictive value (PPV) of urine cytology for HGUC detection was calculated for both TPS-III and TPS-IV categories. Statistical significance was assessed using Fisher's exact test. RESULTS: Among the 470 urine cytology samples, 40 (8.5%) were classified as TPS-III or TPS-IV. Within this subset, 16 patients underwent confirmatory biopsies. Histopathological analysis revealed HGUC in 12 (75%) patients and non-HGUC (benign or low-grade) in 4 (25%) patients. The PPV of TPS-III for HGUC was 50%, while TPS-IV demonstrated a higher PPV of 90%. However, the difference between these values was not statistically significant (p = 0.25). This study explored the utility of TPS classification in urine cytology for HGUC detection. While SHGUC (TPS-IV) exhibited a numerically higher PPV compared to AUC (TPS-III), the lack of statistical significance necessitates further investigation. Our findings highlight the potential of TPS to improve the accuracy of urine cytology. TPS implementation has been shown to reduce the number of inconclusive "atypical" diagnoses, leading to more targeted investigations. CONCLUSION: Our study suggests that SHGUC (TPS-IV) within TPS classification framework might hold promise as a more specific indicator for HGUC compared to AUC (TPS-III). However, further research with larger cohorts is necessary to definitively establish the clinical significance of this observation. This investigation paves the way for future studies exploring the potential of TPS, particularly the SHGUC category, as a reliable screening tool for HGUC, potentially leading to earlier diagnoses and improved patient outcomes.

A comparison between conventional and the Paris systems of reporting urinary cytopathology with a literature update.

INTRODUCTION: Owing to certain inherent limitations of earlier reporting systems, "The Paris System for Reporting Urinary Cytology (TPS)" was implemented in 2015 to standardize reporting urine cytology with more stringent cytomorphologic criteria. We share our post-TPS experience, comparing it with the conventional system (CS). AIM: To assess and compare the cyto-histopathologic/cystoscopic agreement between the conventional and the Paris systems (CS and TPS) for reporting urine cytology. MATERIALS AND METHODS: It is a cross-sectional study involving urine samples from 170 patients divided into two groups (CS and TPS). Of the 170 cases, 85 were reported according to the CS, and 85 were reported according to TPS with all the relevant clinical, radiologic, and cystoscopic findings. Using the kappa statistics, both groups were statistically analyzed for sensitivity, specificity, predictive values, and agreement. RESULTS: The sensitivity and specificity for high-grade urothelial carcinoma (HGUC) as per TPS were 83.33% and 94.59%, respectively, while they were 73.47% and 80.56% for the conventional system. The agreement for HGUC with TPS was 87.06% with a kappa value of 0.7416, while it was 76.5% with a kappa value of 0.53 for the CS. Implementing the TPS minimized usage of the atypical urothelial cells (AUC) category, increasing the clarity in detecting HGUC. CONCLUSION: TPS provides better agreement with histopathology than the CS for diagnosing HGUC, which is attributable to stringent TPS criteria that prompt cytopathologists to look more diligently for morphologic and numeric criteria.

Implementation of The Paris System for Reporting Urine Cytology improves diagnostic accuracy of selective upper urinary tract cytology.

BACKGROUND: The Paris System for Reporting Urine Cytology (TPS) recommends diagnostic criteria for urinary tract cytology, focusing primarily on the detection of high-grade urothelial carcinoma (HGUC) in the lower urinary tract. The second edition of TPS (TPS 2.0), published in 2022, extends these recommendations to the upper urinary tract (UUT); however, there is a lack of comprehensive data on this subject. METHODS: In total, 223 consecutive UUT cytology specimens from 137 patients were retrieved and reclassified according to TPS 2.0 criteria and were compared with the original diagnosis based on the conventional system (CS). Histologic follow-up within a 3-month period was conducted for 43 patients. RESULTS: Histologic follow-up revealed 30 HGUCs, five low-grade urothelial carcinomas (LGUCs), and eight nonneoplastic fibrotic tissues. The risk of high-grade malignancy for each TPS diagnostic category was 16.7% for nondiagnostic/unsatisfactory, 2.3% for negative for HGUC (NHGUC), 42.1% for atypical urothelial cells, 50.0% for suspicious for HGUC (SHGUC), and 81.8% for HGUC. In all five cases of histologically diagnosed LGUC, the cytologic diagnosis was NHGUC. When SHGUC/HGUC was considered positive, the diagnostic accuracy of TPS had 63% sensitivity, 95% specificity, a 90% negative predictive value, and a 79% positive predictive value, which were better than those of CS. In addition, the TPS indices did not differ significantly between the specimens obtained before and after the application of contrast reagents. CONCLUSIONS: TPS implementation improved the accuracy of UUT cytology in predicting histologic HGUC, which was unaffected by the application of contrast reagents. These data indicate the usefulness of TPS for UUT cytology in routine clinical settings.

Sensitivity of urine cytology in detecting high-grade urothelial carcinoma in patients with neoplastic urinary bladder diverticula: A major cancer center experience.

BACKGROUND: Bladder diverticula are herniations of bladder urothelium and mucosa through the muscularis propria. The reported incidence of neoplasia arising in bladder diverticula is widely variable. The authors' objective was to study the characteristics and sensitivity of urine cytology in these patients with emphasis on primary intradiverticular bladder cancer (IDBC). METHODS: A 17-year, retrospective review of all resected bladder diverticula associated with bladder carcinoma was performed. Cases that had complete diverticular resections and preresection urine samples were included in this study. The cases were divided into either primary IDBC or primary extradiverticular bladder cancer (EDBC). Demographic data and urine cytology characteristics were recorded, and sensitivity was calculated. For IDBC, a comparison between voided and cystoscopic urines was done for cases that had both collection methods performed. RESULTS: Of 70 patients with IDBC, 47 patients had urine cytology results that were either positive for high grade-urothelial carcinoma (HG-UC) or suspicious for HG-UC. The sensitivity for HG-UC in IDBC samples was 80%, compared with 82% in EDBC samples (p > .05). Also, 28 patients in the IDBC group had both voided and cystoscopic urine samples for comparisons; in seven patients, the voided urine sample yielded a more definitive diagnosis; in 10 patients, the cystoscopic urine sample yielded a more definitive diagnosis; and, in 11 patients, both samples were equally diagnostic (p > .05). CONCLUSIONS: The characteristics and sensitivity of urine cytology in bladder diverticula were investigated in association with neoplasia, with an emphasis on primary intradiverticular bladder cancer. The results indicated that urine cytology remains a reliable screening and diagnostic test for detecting IDBC, with sensitivity similar to that for detecting EDBC, and no significant difference was noted between voided and cystoscopic samples.

Cytologic evaluation of upper urinary tract specimens: An institutional retrospective study using The Paris System for Reporting Urine Cytology second edition with histopathologic follow-up.

OBJECTIVE: Cytologic evaluation of the upper urinary tract (UUT) can be challenging due to instrumentation artefacts. This study retrospectively reviewed UUT specimens using The Paris System for Reporting Urinary Cytopathology, second edition (TPS 2.0), compared it with the original reporting system (ORS) and correlated it with histopathologic follow-up. METHODS: An institutional database was reviewed for the UUT biopsy/resection histopathologic specimens, and we included 52 UUT cytology specimens pertinent to these cases in the study. These specimens were blindly reviewed and reclassified using TPS 2.0. The correlation between TPS 2.0, ORS and histopathologic follow-up was assessed. RESULTS: The UUT cytology specimens corresponded to 21 (40.4%) high-grade urothelial carcinoma (HGUC), 27 (51.9%) low-grade urothelial carcinoma (LGUC) and 4 (7.7%) benign cases on follow-up. For HGGC cases, the associated TPS categories included unsatisfactory (n = 1, 4.8%), negative for HGUC (NHGUC; n = 3, 14.3%), atypical urothelial cells (AUC; n = 6, 28.6%), suspicious for HGUC (SHGUC; n = 3, 14.3%) and HGUC (n = 8, 38.1%), while ORS categorised the specimens as unsatisfactory (n = 1, 4.8%), negative for malignant cells (NFMC; n = 3, 14.3%), AUC (n = 5, 23.8%), low-grade urothelial carcinoma (LGUC; n = 0, 0%), SHGUC (n = 5, 23.8%) and HGUC (n = 7, 33.3%). The risks of high-grade malignancy among cytologic categories were similar between ORS and TPS (p > 0.05). The majority of LGUC were classified as AUC similarly by ORS and TPS (55.6% vs. 59.3%). CONCLUSIONS: Our study demonstrated comparable performance between TPS 2.0 and ORS for UUT cytology specimens. Cytological diagnosis of UUT specimens remains challenging, especially for LGUC.

Are we on track for diagnosing high-grade urothelial carcinoma with a minimum quantity of five malignant cells in lower tract specimens? Critical analysis of The Paris System Quantitation Criteria.

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.

Diagnosis of Low-Grade Urothelial Neoplasm in the Era of the Second Edition of the Paris System for Reporting Urinary Cytology.

BACKGROUND: The Paris System for Reporting Urinary Cytology (TPS) is considered the gold standard when it comes to diagnostic classifications of urine specimens. Its second edition brought some important changes, including the abolition of the diagnostic category of "low-grade urothelial neoplasm (LGUN)", acknowledging the inability of cytology to reliably discern low-grade urothelial lesions. METHODS: In this retrospective study, we assessed the validity of this change, studying the cytological diagnoses of histologically diagnosed low-grade urothelial carcinomas during a three-year period. Moreover, we correlated the sum of the urinary cytology diagnoses of this period with the histological diagnoses, whenever available. RESULTS: Although all the cytological diagnoses of LGUN were concordant with the histological diagnoses, most low-grade urothelial carcinomas were misdiagnosed cytologically. Subsequently, the positive predictive value (PPV) of urinary cytology for the diagnosis of LGUN was 100%, while the sensitivity was only 21.7%. Following the cyto-histopathological correlation of the sum of the urinary cytology cases, the sensitivity of urinary cytology for the diagnosis of high-grade urothelial carcinoma (HGUC) was demonstrated to be 90.1%, the specificity 70.8%, the positive predictive value (PPV) 60.3%, the negative predictive value (NPV) 93.6% and the overall accuracy 77.2%, while for LGUN, the values were 21.7%, 97.2%, 87.5%, 58.6% and 61.9%, respectively. Risk of high-grade malignancy was 0% for the non-diagnostic (ND), 4.8% for the non-high-grade urothelial carcinoma (NHGUC), 33.3% for the atypical urothelial cells (AUCs), 65% for the suspicious for high-grade urothelial carcinoma (SHGUC), 100% for the HGUC and 12.5% for the LGUN diagnostic categories. CONCLUSIONS: This study validates the incorporation of the LGUN in the NHGUC diagnostic category in the second edition of TPS. Moreover, it proves the ability of urinary cytology to safely diagnose HGUC and stresses the pivotal role of its diagnosis.

The usefulness of nuclear area in the diagnosis of high-grade urothelial carcinoma cells in voided urine cytology.

OBJECTIVE: The Paris System for Reporting Urinary Cytology considered the nuclear-to-cytoplasmic (N:C) ratio as the most important cytomorphological feature for detecting high-grade urothelial carcinoma (HGUC) cells. Few quantitative studies have been conducted on other features although quantitative studies on the N:C ratio have been reported. Therefore, this study quantitatively analysed important cytomorphological features in distinguishing benign reactive cells from HGUC cells. METHODS: We analysed 2866 cells from the urine of 52 patients. A digital image analyser was used to quantitatively measure the nuclear area, cell area, N:C ratio, and nuclear roundness for HGUC cells and benign reactive cells. Additionally, the diagnostic value of quantitative cytomorphological criteria in HGUC cells was evaluated by the receiver operating characteristic curve. RESULTS: The area under the curve for the prediction of HGUC cells for all cells and the top five cells was in the following order: nuclear area (0.920 and 0.992, respectively), N:C ratio (0.849 and 0.977), cell area (0.781 and 0.920), and nuclear roundness (0.624 and 0.605). The best cutoff value of the N:C ratio to differentiate HGUC cells from benign reactive cells was 0.438, and using the N:C ratio of 0.702, the positive predictive value obtained was 100%. CONCLUSIONS: Our study indicated that nuclear area is a more important cytomorphological criterion than the N:C ratio for HGUC cell detection. Moreover, extracted data of the top five cells were more valuable than the data of all cells, which can be helpful in the routine practice and future criteria definition in urine cytology.

Prospective Validation of the ROL System in Substaging pT1 High-Grade Urothelial Carcinoma: Results from a Mono-Institutional Confirmatory Analysis in BCG Treated Patients.

Patients with pT1 high-grade (HG) urothelial carcinoma (UC) and a very high risk of progression might benefit from immediate radical cystectomy (RC), but this option remains controversial. Validation of a standardized method to evaluate the extent of lamina propria (LP) invasion (with recognized prognostic value) in transurethral resection (TURBT) specimens is still needed. The Rete Oncologica Lombarda (ROL) system showed a high predictive value for progression after TURBT in recent retrospective studies. The ROL system was supposed to be validated on a large prospective series of primary urothelial carcinomas from a single institution. From 2016 to 2020, we adopted ROL for all patients with pT1 HG UC on TURBT. We employed a 1.0-mm threshold to stratify tumors in ROL1 and ROL2. A total of 222 pT1 HG UC were analyzed. The median age was 74 years, with a predominance of men (73.8%). ROL was feasible in all cases: 91 cases were ROL1 (41%), and 131 were ROL2 (59%). At a median follow-up of 26.9 months (IQR 13.8-40.6), we registered 81 recurrences and 40 progressions. ROL was a significant predictor of tumor progression in both univariable (HR 3.53; CI 95% 1.56-7.99; p < 0.01) and multivariable (HR 2.88; CI 95% 1.24-6.66; p = 0.01) Cox regression analyses. At Kaplan-Meier estimates, ROL showed a correlation with both PFS (p = 0.0012) and RFS (p = 0.0167). Our results confirmed the strong predictive value of ROL for progression in a large prospective series. We encourage the application of ROL for reporting the extent of LP invasion, substaging T1 HG UC, and improving risk tables for urological decision-making.

Prognostic significance of minor high grade component in non-invasive papillary urothelial carcinoma of urinary bladder: (A study of 273 consecutive cases over a period of 3 years).

PURPOSE: Our study aimed to determine the prognostic significance of minor high-grade components (HGC) in non-invasive papillary urothelial carcinomas compared with pure low-grade and high-grade tumors. MATERIAL AND METHODS: We retrospectively retrieved 273 in-house cases of non-invasive papillary urothelial carcinomas (pTa) from 2016 to 2018 for which follow up data was available in hospital archives. We stratified our data into four main groups (G). G1, pure low-grade (n = 164); G2, HGC ≤5 % (n = 17); G3, HGC >5 % to ≤25 % (n = 14); and G4, pure high-grade (n = 78). Prognosis was assessed in terms of recurrence, grade and stage of progression, metastasis, and death. The mean follow up duration was 34.72 ± 20 months (range 20-60 months). RESULTS: All four groups showed no difference in tumor recurrence (G1 81.7 %, G2 88.2 %, G3 92.9 %, G4 92.3 % p-value 0.183). In terms of grade progression, there was no significant difference in G2 35.3 % and G3 35.7 % and both groups showed worst prognosis compared to G1 16.5 % p-value 0.04. Regarding stage progression (G1 6.7 %, G2 23.5 %, G3 28.6 %, G4 41% p-value 0.001), metastasis (G1 5.5 %, G2 5.9 %, G3 7.1 %, G4 17.9 % p-value 0.01) and death (G1 4.3 %, G2 5.9 %, G3 7.1 %, G4 15.4 % p-value 0.02) there was no significant difference in G2 and G3 and both groups showed worst prognosis than G1 and better than G4. CONCLUSION: Urothelial carcinomas with minor high-grade component ≤25 % behaved worst than pure low grade and better than pure high grade and should be treated as distinct grade entity.

DNA methylation analysis in urinary samples: A useful method to predict the risk of neoplastic recurrence in patients with urothelial carcinoma of the bladder in the high-risk group.

BACKGROUND: Recently, it was reported that the Bladder EpiCheck test is likely to represent a valid tool in the diagnostic process of patients who have suspected bladder carcinoma, with some controversial management decisions because of the technical limitations of cytology. METHODS: Two hundred ninety patients with a diagnosis of nonmuscle-invasive bladder carcinoma who were admitted at the authors' department from March 2019 to December 2019 were treated and followed for 1 year. During follow-up, all patients were evaluated by voided urine cytology, white-light cystoscopy (according to European Association of Urology guidelines), and the Bladder EpiCheck test. RESULTS: The cytologic diagnoses of high-grade urothelial carcinoma (HGUC) and suspicious for HGUC were histologically confirmed in 5 of 20 patients (25%) who had quantitative Bladder EpiCheck scores (EpiScores) from 60 to 69, in 23 of 36 patients (64%) who had EpiScores from 70 to 79, and in 42 of 56 patients (75%) and 57 of 63 patients (90%) who had EpiScores between 80 and 89 and EpiScores >90, respectively. Of 48 patients who had a cytologic diagnosis of HGUC or suspicious for HGUC with EpiScores ≥60 and negative histology, 20 (42%) had a recurrence of HGUC, which was cytologically and histologically confirmed, at 6-12 months during follow-up. CONCLUSIONS: To the best of the authors' knowledge, this is the first study in which patients at high risk for HGUC were stratified using the Bladder EpiCheck EpiScore. The results validate this methylation analysis tool as a useful method for predicting recurrent HGUC during the follow-up of patients with nonmuscle-invasive bladder carcinoma.

ThinPrep® imaging system-assisted vs manual screening of urinary cytology slides in the detection of the "suspicious for high-grade urothelial carcinoma" category.

BACKGROUND: The ThinPrep® Imaging System (TIS) is a Food and Drug Administration-approved review system for cervical cytopathology, where it has been shown to increase performance over manually reviewed slides. Application of the TIS to urinary cytology has only been reported in a single study, in 2013. METHODS: We aimed to compare the agreement of two cytotechnologists' and a pathologist's manual screening (dots) with the fields of view (FOVs) selected by the TIS. We also aimed to track cases in which the TIS could identify missed abnormals and reduce the false-negative fraction. Electronically marked TIS fields (EMTFs) suspicious for high-grade urothelial carcinoma (SHGUC) were controlled by follow-up cystoscopy and histology, where available. RESULTS: A total of 826 consecutive specimens were studied. Of those, 94 (11.4%) were unreadable by the TIS. There were 710 possible comparisons, of which 380 (53.5%) received no dot after manual screening. Of the 330 remaining slides, 149 (45.1%) had at least one dot matching with the TIS FOVs. After TIS reading, EMTFs were noted in 13 of 636 (2.0%) negative cytology cases. Surveillance showed that 3/13 (23.1%, 0.4% of the 710 possible comparisons) of those cases matched with high grade urothelial carcinoma (HGUC), whereas 6/13 (46.1%, 0.8% of the 710 possible comparisons) had negative follow-up at 24 months, and 4/13 (30.8%) were lost for follow-up. CONCLUSION: The TIS increases the detection rate of SHGUC cells, potentially leading to a slight decrease in the false-negative fraction, but at the expense of a slight but larger increase in the number of false-positive cases. These findings stress the importance of a careful approach to the evaluation of the FOVs.

[How has the Paris System contributed to urine cytology? Evaluating the contribution of the Paris System to urine cytology. A comparative study of the Paris System and the Papanicolaou method in a tertiary centre]. / ¿Qué ha aportado el sistema de París al diagnóstico en citología de orina? Estudio comparativo del sistema de París con el sistema clásico en un centro terciario.

INTRODUCTION AND OBJECTIVES: The Paris System (PS) has replaced the classical Papanicolaou System (PapS) in reporting urine cytology, due to its improved sensitivity and negative predictive value (NPV) without loss of specificity. Furthermore, it has enabled the risk of malignancy to be established in each cytological category. The aim of this study is to compare the Paris System with previous results and determine the changes in sensitivity, specificity, positive predictive value, NPV and risk of malignancy in our centre, MATERIALS AND METHODS: Evaluation of the diagnostic power of urine cytology by means of a retrospective cohort study, comparing two series of 400 cytological studies, one using the Papanicolaou System and the other the Paris System. RESULTS: In the detection of high-grade urothelial carcinoma, Paris System has better specificity (93.82% PapS vs 98.64% PS; P=.001) and PPV (39.5% PapS vs 70.6% PS; P=.044) than Papanicolaou System, without changes in sensitivity (53.5% PapS vs 37.5% PS; P=.299) or NPV (96.4% PapS vs 94.8% PS; P=.183). The risk of malignancy for the atypical category increases from low to high levels (1.6% PapS vs 40.0% PS; P=.001); the other categories showed no significant statistical changes. CONCLUSION: The Paris System improves specificity and positive predictive value and establishes a better indication of risk of malignancy for each category, enabling specific clinical management in each case.

The Paris System for reporting urinary cytology improves the negative predictive value of high-grade urothelial carcinoma.

BACKGROUND: The Paris System (TPS) for reporting urinary cytology differs from conventional systems (CS) in that it focuses on the diagnosis of high-grade urothelial carcinoma (HGUC). This study investigated the impact of TPS implementation on the diagnostic accuracy of HGUC by comparing it with our institutional CS. METHODS: A total of 649 patients who underwent transurethral resection of bladder tumor (TURBT) between January 2009 and December 2020 were included in this study. Our institution adopted TPS to report urinary cytology in February 2020. The diagnostic accuracy of HGUC in preoperative urinary cytology was compared with the presence or absence of HGUC in resected specimens of TURBT before and after TPS implementation. RESULTS: After implementing TPS in urinary cytology, 89 patients were reviewed and compared with 560 patients whose urinary cytology was diagnosed by CS. TPS and CS for detecting HGUC had 56.0% and 58.2% sensitivity, 97.8% and 91.2% specificity, and 93.3% and 87.9% positive predictive values, respectively. There were no significant differences between TPS and CS in terms of sensitivity, specificity, and positive predictive value for HGUC (P = 0.83, 0.21, 1.00). On the other hand, the negative predictive value for HGUC using TPS was 80.0%, which was significantly higher than that of CS (66.4%, P = 0.04) The multivariate logistic regression analysis indicated that not using TPS was one of the independent predictive factors associated with false-negative results for HGUC (odds ratio, 2.26; 95% confidence interval, 1.08-4.77; P = 0.03). CONCLUSION: In instances where urinary cytology is reported as negative for HGUC by TPS, there is a low probability of HGUC, indicating that TPS has a potential diagnostic benefit.

¿Qué ha aportado el sistema de París al diagnóstico en citología de orina? Estudio comparativo del sistema de París con el sistema clásico en un centro terciario / How has the Paris System contributed to urine cytology? Evaluating the contribution of the Paris System to urine cytology. A comparative study of the Paris System and the Papanicolaou method in a tertiary centre

Introducción y objetivos: El sistema de París (SP) ha sustituido al sistema de Papanicolaou (SPap) como sistema de citodiagnóstico de orina. La evidencia indica que el SP ha logrado aumentar la sensibilidad y el valor predictivo negativo (VPN) sin perder especificidad, y establecer un riesgo de malignidad para cada categoría diagnóstica. El objetivo de este estudio es conocer los cambios que han experimentado la sensibilidad, especificidad, valor predictivo positivo (VPP), VPN y el riesgo de malignidad en la transición en nuestro centro. Materiales y métodos: Evaluación de prueba diagnóstica a través de una cohorte retrospectiva en la que se comparan dos series de 400 citologías de orina, una diagnosticada mediante el SPap y otra con SP. Resultados: Para la detección de carcinoma urotelial de alto grado describimos con el SP mejor especificidad (93,82 SPap vs. 98,64% SP; p=0,001) y VPP (39,5 SPap vs. 70,6% SP; p=0,044), sin observar cambios significativos en la sensibilidad (53,5 SPap vs. 37,5% SP; p=0,299) y VPN (96,4 SPap vs. 94,8% SP; p=0,183), respecto al SPap. El riesgo de malignidad en el SP experimenta un cambio estadísticamente significativo para la categoría atipia con respecto a la atipia en el SPap (1,6 SPap vs. 40,0% SP; p=0.001), manteniéndose el resto de las categorías sin cambios estadísticamente significativos. Conclusiones: El SP ha conseguido mejorar la especificidad y el VPP de la citología de orina y establece un riesgo de malignidad propio para la categoría de atipia, permitiendo establecer un manejo específico para cada resultado.(AU)

Introduction and objectives: The Paris System (PS) has replaced the classical Papanicolaou System (PapS) in reporting urine cytology, due to its improved sensitivity and negative predictive value (NPV) without loss of specificity. Furthermore, it has enabled the risk of malignancy to be established in each cytological category. The aim of this study is to compare the Paris System with previous results and determine the changes in sensitivity, specificity, positive predictive value, NPV and risk of malignancy in our centre. Materials and methods: Evaluation of the diagnostic power of urine cytology by means of a retrospective cohort study, comparing two series of 400 cytological studies, one using the Papanicolaou System and the other the Paris System. Results: In the detection of high-grade urothelial carcinoma, Paris System has better specificity (93.82% PapS vs 98.64% PS; P=.001) and PPV (39.5% PapS vs 70.6% PS; P=.044) than Papanicolaou System, without changes in sensitivity (53.5% PapS vs 37.5% PS; P=.299) or NPV (96.4% PapS vs 94.8% PS; P=.183). The risk of malignancy for the atypical category increases from low to high levels (1.6% PapS vs 40.0% PS; P=.001); the other categories showed no significant statistical changes. Conclusion: The Paris System improves specificity and positive predictive value and establishes a better indication of risk of malignancy for each category, enabling specific clinical management in each case.(AU)

Digital image analysis of high-grade urothelial carcinoma in urine cytology confirms chromasia heterogeneity and reveals a subset with hypochromatic nuclei and another with extremely dark or "India ink" nuclei.

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.