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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.)

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.)

Introduction: Flat urothelial lesions fall into one of four diagnostic categories including urothelial carcinoma in-situ (CIS). There is morphologic overlap between the categories leading to immunohistochemistry (IHC) utilization in difficult cases. The purpose of this study was to examine the frequency, variation and utility of IHC use in bladder biopsy specimens over a 17 year period., Methods: A search of "CD44", "p53", and "CK20" keywords was conducted from the pathology files (1/1/2003 to 12/31/2017) on bladder biopsy specimens at our institution. Atypical (AUS), dysplastic (UD) and CIS rates were calculated., Results: A total of 4597 cases were identified. IHC was performed on 345 specimens (7.5%, 345/4597). For cases without IHC (H&E only), the AUS rate was 4.8% (206/4252), UD rate was 9.4% (399/4252), and the CIS rate was 8.4% (359/4252). For IHC cases, the AUS rate was 5.2% (18/345), the UD rate was 8.1% (28/345), and the CIS rate was 11.3% (39/345). There was no statistical difference between the H&E only or IHC rates (p > 0.05). The absolute number IHC orders per year increased until 2011 (60 cases) but drastically declined over the last five years (5 total cases in 2017). The CIS rates have remained relatively constant., Conclusion: We found the AUS, UD and CIS rates were similar regardless of IHC use. Our institution was an early adopter of IHC and it quickly fell out of favor. We agree with the ISUP in that IHC has limited clinical utility for flat urothelial lesions and morphology remains the gold standard., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: We undertook a systematic evaluation of the prognostic value of numerous histological factors in 165 radical cystectomies (RCs) of patients with invasive urothelial carcinoma (UC) who underwent surgery after neoadjuvant chemotherapy (NAC)., Methods and Results: Tumour regression grade (TRG) and therapy-related stromal and epithelial changes were also recorded. Locally advanced disease (≥pT2 and/or pN+) was present in 64% of patients, 22% had no evidence of residual carcinoma (pT0 + pN0), and 28% had no evidence of residual muscle-invasive carcinoma (≤pT1 + N0). TRG1, TRG2 and TRG3 were found in 32%, 15% and 50% of patients, respectively. Histological variants of UC were reported in 25% of cases. The most common therapy-related stromal change was fibroblastic reaction (78%), and the most common epithelial change in residual UC was smudgy and poorly preserved chromatin (28%). Prominent stromal and epithelial changes were noted in 41% and 5% of RCs, respectively. Progression was found in 45% of patients, and cancer-related deaths occurred in 30%. Multivariate analysis showed that the only independent prognostic parameters for progression were T stage, N stage, lymphovascular invasion, and margin status. Similarly, only T stage, N stage and margin status correlated with cancer-related deaths. Neither TRG nor any of the stromal-related or epithelial-related variables correlated with outcome., Conclusions: We confirm that the traditional and routinely reported histological parameters in RC post-NAC remain the most powerful prognosticators of disease course. The significance of TRG in the bladder remains unconfirmed., (© 2018 John Wiley & Sons Ltd.)

The main purpose of urine cytology is to detect high-grade urothelial carcinoma. With this principle in mind, The Paris System (TPS) Working Group, composed of cytopathologists, surgical pathologists, and urologists, has proposed and published a standardized reporting system that includes specific diagnostic categories and cytomorphologic criteria for the reliable diagnosis of high-grade urothelial carcinoma. This paper outlines the essential elements of TPS and the process that led to the formation and rationale of the reporting system. TPS Working Group, organized at the 2013 International Congress of Cytology, conceived a standardized platform on which to base cytologic interpretation of urine samples. The widespread dissemination of this approach to cytologic examination and reporting of urologic samples and the scheme's universal acceptance by pathologists and urologists is critical for its success. For urologists, understanding the diagnostic criteria, their clinical implications, and limitations of TPS is essential if they are to utilize urine cytology and noninvasive ancillary tests in a thoughtful and practical manner. This is the first international/inclusive attempt at standardizing urinary cytology. The success of TPS will depend on the pathology and urology communities working collectively to improve this seminal paradigm shift, and optimize the impact on patient care.

Background: After radical cystectomy and urinary diversion (RC-UD), upper urinary tract and urethral recurrences of urothelial carcinoma (UCa) are reported to occur in 2% to 17% of patients. The objective of the current study was to determine the performance of urinary cytology (UCy) in the diagnosis of recurrences in the remnant urothelium (RRU) after RC-UD., Methods: The authors retrospectively identified all patients who underwent RC-UD for UCa at the study institution from January 2002 to April 2014, and collected data from all available follow-up UCy and biopsies. Cytologies were classified as unsatisfactory, negative, suspicious, positive for malignancy, or atypical urothelial cells (AUC). The authors calculated the sensitivity, specificity, positive predictive value, and negative predictive value of suspicious or positive UCy for the diagnosis of histologically confirmed RRU., Results: Of the 222 patients who underwent RC-UD for UCa of the urinary bladder during the study period, 111 had at least 1 follow-up UCy performed at the study institution, for a total of 477 UCy samples. During a mean follow-up interval of 40.8 months (range, 3-155 months), the RRU rate was 9.9% (11 of 111 patients). Positive/suspicious UCy results were noted in 12 of 111 patients, 9 of whom had RRU. A diagnosis of AUC was made in 8.6% of samples from 29 patients (41 of 477 samples). The sensitivity, specificity, positive predictive value, and negative predictive value of UCy for RRU were 82%, 97%, 75%, and 98%, respectively. Six of the 28 patients with diagnoses of AUC (21.4%) were eventually diagnosed with RRU., Conclusions: In the current series, UCy demonstrated good sensitivity and high specificity for the detection of disease recurrence of UCa after RC-UD., (© 2015 American Cancer Society.)

Objectives: 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)., Methods: 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., Results: 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., Conclusions: 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., (Copyright© by the American Society for Clinical Pathology.)

The utility of intraoperative frozen sections for determining ureteral and urethral margin status is controversial. In this study, we evaluated the sensitivity and specificity of frozen section diagnosis with the corresponding final tissue diagnosis in a series of 364 patients undergoing radical cystectomy for urothelial carcinoma of the urinary bladder. Multiple definitions of a positive diagnosis were analyzed. We then used clinical follow-up data to determine the effect of various frozen section diagnoses, frozen/permanent section discordance, and surgical margins on overall survival and disease-free survival. Increasing severity of dysplasia was associated with corresponding increases in positive likelihood ratio, with carcinoma displaying the highest positive likelihood ratio (211.43) for an accurate frozen section diagnosis. A diagnosis of carcinoma on frozen section did not affect overall or disease-free survival nor did a positive surgical margin. Frozen/permanent discordance did not show significant associations with overall survival or disease-free survival. The lone variable approaching statistical significance was an association between frozen/permanent discordance of ureteral samples and disease-free survival (hazard ratio, 3.23; P = .07; multivariate Cox proportional hazards model). The results of this study, the first to evaluate the use of different cutoffs for a positive diagnosis and the effects of frozen/permanent discordance, do not support the routine use of intraoperative frozen section during radical cystectomy for urothelial carcinoma. However, subgroups at high risk for positive ureteral margins may benefit from intraoperative frozen section evaluation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The purposes of this study are to evaluate the adequacy of pathologic lymph node (LN) staging in radical cystectomy specimens from patients with urothelial carcinoma of the bladder and to analyze the frequency of LN metastases among different anatomic regions. All radical cystectomies performed for primary urothelial bladder cancer over a 5-year period (January 2007-September 2012) at a single institution were reviewed. Particular attention was paid to the total number of LNs examined, the number and location of LNs with metastases (positive LNs), and the presence or absence of extranodal tumor extension and/or lymphovascular invasion in the cystectomy specimen. Results and data were analyzed with Origin 6.0 and Microsoft Office Excel 2007 software. A total of 248 radical cystectomies with 8,432 LNs were reviewed. A total of 60 (24 %) cases, with 274 positive LNs out of the 1,982 total (13.8 %), were identified with a male to female ratio of 6.5:1 (52 male, 8 female patients). The average number of LNs examined in each case was 33.0 ± 20.9 (range 5-112). The average number of positive LNs identified in each case was 4.5 ± 4.8 (range 1-26). Among all of the LNs, the hypogastric/obturator (internal iliac) LNs were the most commonly submitted (35.2 %) and also yielded the highest number of positive LNs (46.0 %). On average, for cases staged pN1 and pN2, there was one positive LN per 17.8 and 8.9 LNs examined from the primary drainage LNs, respectively. For pN3 cases, one out of 4.4 secondary drainage LNs was found to be positive. Similarly, one out of 4.0 distant LNs was found to be positive in cases with pM1 staging. Our study suggests that, on average, 23 LNs (including 18 primary drainage LNs and five secondary drainage LNs) should be submitted for optimal pN staging. For adequate pM1 staging, an average of four distal LNs should be evaluated. In total, an average of 27 LNs (23 for pN staging and 4 for pM staging) should be examined in radical cystectomy specimens. We also propose to stratify the number of positive LNs according to the drainage area.

Background: In urine cytology, the diagnosis of atypia is subjective and clinical management based on these results can be difficult to determine. In this study, the authors determined the percentage of atypical urine diagnoses that progressed to positive cytology or surgical pathology results over an 11-year period., Methods: In a retrospective review of the authors' institution, 1320 atypical urine cytology diagnoses were identified in specimens from 851 patients obtained from January 2000 through December 2010. All subsequent pathology reports were reviewed to determine which patients developed positive cytology/surgical pathology diagnoses. In total, 4106 cytology and surgical pathology specimen reports were reviewed., Results: At the authors' institution, 1320 of 16,299 of urine cytology specimens (8.1%) were diagnosed as atypical during the 11-year period. Overall, 271 of 1320 initial atypical urine specimens (21%) progressed to positive cytology or surgical pathology results with a mean time to progression of 155 days. Of the cases that progressed to malignancy, 118 were high-grade urothelial carcinoma and 92 were low-grade urothelial carcinoma., Conclusions: The rate of atypia in urine specimens at this institution was 8.1%. Of the specimen types, atypia was the most common in urinary diversion specimens (16%) and the least common in upper tract cytology (3.8%). When diagnosed as atypical, upper tract specimens had the highest percentage of progression to high-grade carcinoma. Therefore, the authors concluded that the diagnosis of atypia in this specimen group has higher clinical significance and should be managed more aggressively. Cancer (Cancer Cytopathol) 2013;121:387-391. © 2013 American Cancer Society., (© 2012 American Cancer Society.)

Urothelial carcinoma (UC) is the most common malignant neoplasm of the urinary tract. Metastases of UC are most common in the regional lymph nodes, lungs, liver, bone, and adrenal glands. Fine-needle aspiration cytology diagnosis of such metastases can be difficult, particularly in the setting of incomplete clinical history or when multiple primary neoplasms may be present. This review focuses on the cytologic features helpful in differentiating UC from its potential mimics, as well as ancillary studies that may be helpful in the distinction., (Copyright © 2011 Wiley Periodicals, Inc.)

Accurate recognition of urinary bladder muscularis propria (MP) invasion by urothelial carcinoma is crucial as it is the critical crossroad between conservative and aggressive management for the patient. It is now widely known that an inconsistent layer of muscularis mucosae (MM) muscle exists in the lamina propria, which can mimic the MP muscle, particularly when hyperplastic, making staging extremely challenging in some limited, unoriented, or highly cauterized specimens. Smoothelin is a novel smooth muscle-specific contractile protein expressed only by fully differentiated smooth muscle cells, and not by proliferative or noncontractile smooth muscle cells and myofibroblasts. We performed immunohistochemical staining in the bladder for smoothelin to: (a) evaluate its expression in MM and MP muscle in cystectomy specimens and by comparing the staining pattern with smooth muscle actin (SMA), (b) study MP variations in the bladder trigone and at the ureteric insertion in the bladder wall, and (c) assess the staining pattern of MM and MP in a representative group of transurethral resection of bladder tumor specimens. In contrast to SMA, which equitably stained both types of muscle fibers, smoothelin displayed striking differential immunoreactivity between MM and MP muscle. With smoothelin, the MM muscle (including hyperplastic forms) typically showed absent (19/42, 45%) or weak and focal (18/42, 43%) staining, whereas the MP muscle typically showed strong and diffuse staining (36/42, 86%). Smoothelin accentuated individual muscle fibers within groups of MP bundles only, a feature which was evident in both MM and MP stained by SMA. When only strong and diffuse immunoreactivity in muscle was set as a threshold for positivity, 100% specificity and positive predictive value of smoothelin for MP (vs. MM) was achieved in our study. Smoothelin staining confirmed the morphologic variations in MP muscle in the bladder wall of the trigone and at the ureteric insertion. In addition to the well-defined muscle layers of MM and MP, SMA staining revealed a continuous band of ill-defined haphazardly oriented compact spindle cells that were immediately subjacent to the urothelium in all cases. These spindle cells blended with the morphologically recognizable thin slender fascicles of the MM muscle. We designate this hitherto uncharacterized thin layer of SMA-positive [muscle-specific actin positive (6/6), Masson trichrome stain predominantly blue (5/6)] and smoothelin-negative cells as suburothelial band of myofibroblasts. In all 10 transurethral resection of bladder tumor sections, smoothelin staining was in agreement with the routine light microscopic presence and absence of MP muscle. In conclusion, the relatively distinct immunohistochemical staining pattern of smoothelin between MP and MM (including its hyperplastic forms) makes it a robust and attractive marker to be incorporated in the contemporary diagnostic armamentarium for the sometimes difficult area of staging bladder urothelial carcinoma.