Impact of Implementing the Paris System for Reporting Urine Cytology in the Performance of Urine Cytology A Correlative Study of 124 Cases

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1 Impact of Implementing the Paris System for Reporting Urine Cytology in the Performance of Urine Cytology A Correlative Study of 124 Cases Muhannad Hassan, MD, 1 Sharaddha Solanki, MSc, 2 Wassim Kassouf, MD, 2 Yonca Kanber, MD, 1 Derin Caglar, MD, 1 Manon Auger, 1 and Fadi Brimo, MD 1 From the Departments of 1 Pathology and 2 Urology, McGill University and McGill University Health Center, Montreal, Canada. Key Words: Paris System for Reporting Urine Cytology; Urine; Cytology; Performance; Atypical; High grade; Correlation Am J Clin Pathol September 2016;146: DOI: /AJCP/AQW127 ABSTRACT Objectives: We assessed the performance of urine cytology using the Paris System for Reporting Urine Cytology (PSRUC) in comparison to our current system. Methods: In total, 124 specimens with histologic correlation were reviewed and assigned to the PSRUC categories: benign, atypical urothelial cells (AUCs), suspicious for high-grade urothelial carcinoma (SHGUC), and high-grade urothelial carcinoma (HGUC). Original cytological diagnoses were recorded. Results: Fewer cases were given an AUC diagnosis using the PSRUC in comparison to the original diagnoses (26% vs 39%), while the association of AUCs with subsequent HGUC increased from 33% to 53% with the PSRUC. Using the PSRUC resulted in a higher number of low-grade carcinomas assigned to the benign (40%) rather than the AUC (22%) category. The performance of SHGUC/HGUC diagnoses was similar in both systems (predictive value ¼ 94%). Conclusions: The PSRUC seems to improve the performance of urine cytology by limiting the AUC category to cases that are more strongly associated with HGUC. Despite the development of new liquid- and tissuebased ancillary tests, urine cytology remains, along with cystoscopy, an essential diagnostic tool in the screening and surveillance of urothelial carcinoma. Urine cytology, which carries the advantages of being a simple, cost-effective, and noninvasive test that samples the entire urinary tract, has been shown to display a wide range of sensitivity depending on the specimen type, clinical setting, and the grade of urothelial tumors, with higher sensitivity reported for highgrade urothelial carcinoma (HGUC). 1 Urine cytology has also been proven to be a very specific detection tool for HGUC; this high specificity for HGCA represents its most attractive aspect in clinical practice. In that regard, since HGUC cells can shed in the urine, even in carcinomas that are not seen by cystoscopy (ie, occult carcinomas), a positive urine cytology diagnosis is a clinically meaningful result even in the absence of tissue confirmation. 2,3 Consequently, patients with positive cytology and negative cystoscopy or biopsy results are usually investigated further and closely monitored because a significant percentage is eventually proven to harbor HGUC. 4-6 The reporting system for urine cytology has evolved into different stages over time. Initially, Dr Papanicolaou 7 suggested having 5 different cytologic classes based on the level of diagnostic confidence and the nature of the atypical cells. Although this system was reported to be useful in diagnosing HGUC, the diagnostic criteria for each group were unclear. Following the changes in the histopathologic classification of urothelial carcinoma by the World Health Organization/International Society of Urological Pathology in 1998, and in an attempt to standardize the diagnostic 384 Am J Clin Pathol 2016;146: American Society for Clinical Pathology, All rights reserved. For permissions, please journals.permissions@oup.com

2 categories for urine cytology, the Papanicolaou Society of Cytopathology recommended a classification scheme that included an atypical urothelial cell (AUC) category similar to the Bethesda System for reporting cervical cytology. 8,9 This system recommended subclassifying the atypical group into reactive or neoplastic. Although the classification itself was appealing, it suffered from the lack of well-defined criteria for the suggested atypical subcategories. In the recent years, new classification systems with clear criteria have emerged from various institutions from where many institutional well-conducted studies were performed; the results of those studies were, however, difficult to compare due to several factors First, the institutional diagnostic categories differed in their variable inclusion of the suspicious for HGUC diagnosis as well as in their variable subdivision of the AUC category into either AUCs of undetermined significance vs AUCs cannot rule out high-grade carcinoma, AUCs favor a reactive process vs AUCs unclear whether reactive or neoplastic, or AUCs favor a reactive process vs AUCs favor neoplastic. Most important, the criteria used to define the AUC group and subgroups also differed in many aspects, resulting in a wide variation in the rates of AUCs (range, 2%-31%), as well as their association with a subsequent diagnosis of HGUC (range, 8.3%-37.5%). 10,14-18 This significant variation contributed significantly to the desensitization of many urologists to an AUC diagnosis, leading them to frequently consider and treat such AUC cases similarly to negative cases. In this context, the emergence of the newly proposed Paris System for Reporting Urine Cytology (PSRUC) is regarded as a major step toward standardization in both the cytology and urology fields. 19 This international and multiinstitutional achievement is the reflection of a major shift in the understanding of and the approach to urothelial lesions and represents a repositioning of urine cytology in the clinical landscape by focusing on its most clinically relevant aspect, which is the detection of HGUC. Consequently, the four major categories of the PSRUC are negative for HGUC (NHGUC), AUCs, suspicious for SGHUC (SHGUC), and positive for HGUC (HGUC). One important goal of this new system is to transform the AUC category into a reproducible and clinically meaningful category by including mostly cases with cells exhibiting nuclear atypia that is likely to be associated with HGUC; atypia related to low-grade urothelial neoplasms and to various reactive conditions such as polyomavirus infection and urolithiasis are excluded from the AUC category and are rather included in the NHGUC category. In our institution, we have traditionally divided urine cytology results into five categories: negative, atypical cells for which a reactive process is favored (AR), atypical cells that are unclear whether they are reactive or neoplastic (AU), suspicious for SHGUC, and positive for HGUC. 10 While we have recently adopted the PSRUC in our laboratory and we intend to report its performance prospectively, we herein aimed to test the impact of implementing this system by performing a retrospective morphologic analysis using the categories and criteria of the PSRUC in comparison to our previously used system. Materials and Methods In total, 124 consecutive cytologic specimens from the lower urinary tract that had a histologic follow-up within 1 year between 2008 and 2010 were included. The slides were reviewed by one cytopathologist (F.B.) blinded to the outcome and were assigned according to the proposed criteria to one of the four PSRUC categories: NHGUC, AUCs, SHGUC, and HGUC. As suggested by the PSRUC, the NHGUC group included cases that either had benign cytologic features or displayed a mild degree of atypia in a clinical context that is known to induce cytologic changes, such as polyomavirus infection, urolithiasis, irradiation, chemotherapy, and instrumentation Image 1A. Cases with tissue fragments in the absence of cytologic atypia were considered NHGUC, even if they were present in voided specimens. 19,20 Similarly, cells with a nuclear to cytoplasmic (N/C) ratio of more than 0.5 were considered negative if no other abnormal cytologic features were present. The PSRUC AUC diagnosis was reserved for nonsuperficial and nondegenerated urothelial cells with an increased N/C ratio (>0.5) and only one of the following features: nuclear hyperchromasia, irregular nuclear membranes, and irregular coarse clumped chromatin. Atypical degenerated cells were also assigned an AUC diagnosis even if they displayed more than one of the previously mentioned criteria. The PSRUC SHGUC and HGUC cells show similar cytologic characteristics but are differentiated by the number of malignantlooking cells (in general, <10 cells for SHGUC and 10 cells for HGUC). The cells in both categories are nonsuperficial and nondegenerated urothelial cells showing an N/C ratio of more than 0.7, moderate to severe hyperchromasia, and at least one of the two following features: irregular clumpy chromatin or marked irregular nuclear membranes. The initial institution s cytologic diagnoses were also recorded. The original classification and criteria differed with the PSRUC in many aspects. In our original classification, an N/C ratio of more than 0.5 was the defining feature of nuclear atypia, and cells showing this feature were generally assigned to the AUC category, except if the specimen was instrumented and the changes compatible with instrumentation changes or basal cells. The AR category was reserved for atypical cell clusters that showed bubbly American Society for Clinical Pathology Am J Clin Pathol 2016;146: Downloaded 385 from

3 Hassan et al /THE PSRUC AND PERFORMANCE OF CYTOLOGY A B C D Image 1 A, One urothelial cell showing homogeneous, amorphous, ground glass like intranuclear inclusion occupying most of the enlarged nuclear area and a condensed rim of chromatin in keeping with polyomavirus-related changes. The nuclear enlargement is associated with smooth and regular nuclear membranes compared with the irregular nuclear membranes in highgrade malignant cells. This will be categorized under the negative for high-grade urothelial carcinoma category in the new Paris System for Reporting Urine Cytology (PSRUC) (voided specimen, ThinPrep, Papanicolaou, 600). B, A cluster of cells with an increased nuclear to cytoplasmic (N/C) ratio, mild hyperchromasia, fine chromatin, visible nucleoli, and regular nuclear membranes. This case was originally categorized as atypical urothelial cells, favor a reactive process. According to the PSRUC criteria, such cases should be diagnosed as negative for high-grade urothelial carcinoma (voided specimen, ThinPrep, Papanicolaou, 600). C, One degenerated cell displaying a high N/C ratio, nuclear hyperchromasia, intact but irregular nuclear membranes, clumpy chromatin, and a dark India ink chromatin pattern. This case was originally labeled as atypical urothelial cells, unclear if reactive or neoplastic and was classified as atypical urothelial cells according to the PSRUC (voided specimen, ThinPrep, Papanicolaou, 600). D, One single nonsuperficial and nondegenerated urothelial cell showing a high N/C ratio, severe hyperchromasia, and irregular clumpy chromatin pattern. This case was diagnosed as suspicious for high-grade urothelial carcinoma using the PSRUC as well as the original classification (voided specimen, ThinPrep, Papanicolaou, 600). cytoplasm with intact and smooth nuclear membranes, often with conspicuous nucleoli Image 1B. On the other hand, the AU category was used when the urothelial cells, even if single or few in number, appeared to be degenerated but displayed an N/C ratio of more than 0.5 and a dark India ink chromatin pattern with or without irregular nuclear membranes Image 1C. Most cells diagnosed as AU were morphologically similar to the cells that have been termed 386 Am J Clin Pathol 2016;146: American Society for Clinical Pathology 386

4 pseudodegenerated cells by Renshaw. 13 The cytologic features of our original SHGUC and HGUC categories were close to those adopted in the PSRUC, with 10 cells being the differentiating quantitative cutoff Image 1D. The only difference is that cellular degeneration was not an exclusion criterion from the original SHGUC group, and a portion of cases in this category included degenerated cells. The original and revised categories were both correlated with the histologic outcome, which was divided into benign, low-grade neoplasms (LGNs) including papilloma, papillary neoplasm of low-malignant potential and low-grade urothelial carcinoma, and HGUC including noninvasive high-grade papillary urothelial carcinoma, invasive urothelial carcinoma, and urothelial carcinoma in situ. When more than one cytologic specimen existed in a cytohistologic follow-up and correlation, the worst was used as representative of the group for the cytologic-histologic correlation as long as it was rendered within 1 year preceding the follow-up biopsy. The chosen interval of 1 year between cytology and biopsy was considered the most valid by urologists in our institution. Longer intervals may contaminate the study results as they theoretically allow new unrelated tumors to develop during the follow-up (ie, tumors potentially absent when the index cytologic specimen was taken). 1 Results The median age was 73.8 years, and the male to female ratio was 4:1.66 patients (53.2%) who were under surveillance following a diagnosis of urothelial neoplasia, while 58 (46.8%) patients were evaluated for new urologic symptoms, including hematuria. Ninety-eight (79%) specimens were voided, and 21% were instrumented. Voided specimens were ThinPrep (Hologic, Marlborough, MA) samples and consisted of one slide each, while instrumented specimens were prepared using conventional techniques (smears or cytospins) and consisted of one to two slides each. The cytologic results and histologic correlations are shown in Table 1 and Table 2. The follow-up biopsy results were as follows: benign in 30 (24%), LGNs in 25 (20%), and HGUC in 69 (56%) patients. In comparison to the original system, using the PSRUC resulted in significantly fewer cases being assigned to the AUC cytologic category (39% vs 26%). Inversely, more cases were diagnosed as negative on cytology (36% of cases) using the PSRUC in comparison to the original system, in which only 22% were considered negative. In comparison, no significant change was noted in the rate of SHGUC/HGUC using the original system and the PSRUC (40% vs 38%, respectively). There was an important difference in the performance of the AUC category between the two systems; while 33% of AUC cases were associated with a subsequent histologic diagnosis of HGUC using the original system, this rate increased to 53% using the PSRUC. Also, using the PSRUC, 72% of cases that were subsequently diagnosed as LGUC fell in the NHGUC category, while the rate was only 28% using the original system, in which most (72%) of histologically proven LGUCs were initially diagnosed as atypical on cytology. Moreover, there was no change in the performance of an SHGUC/HGUC diagnoses using the two systems, and the predictive value for subsequent HGUC was 94%. Importantly, applying the PSRUC resulted in a sharper demarcation in the predictive values of different cytologic categories in comparison to the original system; indeed, while the rates of subsequent HGUC using the original system were 26%, 33%, 91%, and 96%, respectively, following a cytologic diagnosis of benign, AUCs, SHGUC, and HGUC, the rates were 15%, 53%, 83%, and 100%, respectively, using the PSRUC criteria. Discussion The current study demonstrates that implementing the PSRUC improved overall performance of urine cytology in several aspects. Most important was the fact that using this system not only resulted in fewer cases being assigned to the AUC category but that the association of an AUC diagnosis with subsequent HGUC increased significantly from Table 1 Correlation Between Cytology and Histology Results Within 1 Year Using the Paris System for Reporting Urine Cytology a Cytology Histology NGHUC (n ¼ 45, 36%) AUCs (n ¼ 32, 26%) SHGUC (n ¼ 18, 15%) HGUC (n ¼ 29, 23%) Benign LGN HGUC PPV for HGUC, % AUCs, atypical urothelial cells; HGUC, high-grade urothelial carcinoma; LGN, low-grade neoplasia; NHGUC, negative for high-grade urothelial carcinoma; PPV, positive predictive value; SHGUC, suspicious for high-grade urothelial carcinoma. a Values are presented as numbers unless otherwise indicated. American Society for Clinical Pathology Am J Clin Pathol 2016;146: Downloaded 387 from

5 Hassan et al /THE PSRUC AND PERFORMANCE OF CYTOLOGY Table 2 Correlation Between Cytology and Histology Results Within 1 Year Using the Original System a Cytology Histology NGHUC (n ¼ 27, 22%) AUCs (AR þ AU) (n ¼ 48, 39%) SHGUC (n ¼ 23, 19%) HGUC (n ¼ 26, 21%) Benign LGN HGUC PPV for HGUC, % AR, atypical cells for which a reactive process is favored; AU, atypical cells that are unclear whether they are reactive or neoplastic; AUCs, atypical urothelial cells; HGUC, high-grade urothelial carcinoma; LGN, low-grade urothelial neoplasia; NHGUC, negative for high-grade urothelial carcinoma; PPV, positive predictive value; SHGUC, suspicious for high-grade urothelial carcinoma. a Values are presented as numbers unless otherwise indicated. 33% to 53%. Those promising results may be explained by the following facts: while our previous definition of atypia was simply a cell with an N/C ratio of more than 0.5 after excluding instrumentation artifact and basal cells, the PSRUC requires additional cytologic features to define the cell as atypical, such as hyperchromasia, irregular nuclear membranes, or clumpy chromatin pattern. 19 As such, cases falling in our previous definition of atypical, favor reactive can be essentially diagnosed as NHGUC using the new classification system. Also, while the PSRUC considers all cases with cells showing changes typical of polyomavirus infection as NHGUC regardless of the clinical context, we have traditionally included such cases under the atypical, unclear category in the absence of a history of immunosuppression and/or transplantation. To limit the diagnosis of AUCs to the strict minimum, the PSRUC has also recommended diagnosing cell clusters or tissue fragments as NHGUC provided cytologic atypia is lacking, an approach that we have already been practicing in the past and that is therefore unrelated to the observed change in the rate of atypia in our cohort. 20 The second impact was the higher frequency of cases with subsequent LGNs assigned to the NHGUC category. In that regard, older studies have attempted to characterize the cytologic features of low-grade urothelial carcinoma, and criteria such as an N/C ratio of more than 0.5, mild hyperchromasia, nuclear grooves, and mildly irregular nuclear membranes were proposed However, the presence of cytologic overlap between low-grade urothelial carcinoma and reactive changes, the reported low sensitivity, and low interobserver agreement for diagnosing low-grade urothelial carcinoma, in addition to the fact that the detection of HGUC became the only significant clinical role for urinary cytology, have shifted the cytologic criteria toward detecting HGUC in more contemporary cytology classifications, particularly in the PSRUC. 13,24,25 In fact, following the new criteria, the only instance in which a definitive diagnosis of low-grade urothelial carcinoma can be rendered is in the presence of cellular fragments with fibrovascular cores, with cells displaying a mild degree of atypia falling short of an HGUC diagnosis, a scenario of extreme rarity in routine clinical practice. Of note, the recommended term for such cases in the PSRUC is low-grade urothelial neoplasia, a term that encompasses low-grade urothelial carcinoma, papillary urothelial neoplasm of low malignant potential, and papilloma. 19 Our results also suggest that the quantitative criteria adopted by the PSRUC to differentiate the SHGUC and HGUC categories are valid, as reflected in their distinct predictive values for subsequent detection of HGUC. Of note is that this quantitative approach was based on five studies preceding the publication of the PSRUC, in which the number of atypical urothelial cells was used and indirectly validated as being prognostically significant. In the first study, Piaton et al 11,17 recommended dividing the AUC categories into two groups: AUC of undetermined significance, or AUC-US and AUC, cannot exclude high-grade carcinoma, or AUC-H, in a division that echoes the Bethesda System for reporting gynecologic cytology. 26 In the classification by Piaton et al, the criteria used to define AUC-H correspond to a large extent to those used in the SHGUC category of the PSRUC. Quantitative criteria were also required, and the diagnosis was restricted to cases with severely abnormal urothelial cells that were few in number, generally less than Similarly, our group has been using the SHGUC category by applying morphologic and quantitative criteria comparable to the AUC-H category used by Piaton et al and by using the 10-cell cutoff to distinguish a SHGUC from an HGUC diagnosis. Using those criteria in a retrospective study in which the original diagnoses were retrieved, we have previously reported different associations of the SHGUC and HGUC categories with subsequent HGUC (80% vs 90%). 27 In a subsequent study of 112 cases in which the slides were systematically reexamined and the number of atypical cells counted, we were also able to demonstrate that cases with one to five atypical cells were equally associated with subsequent HGUC compared with those having five to 10 atypical cells (predictive value of 58%), but the association with subsequent HGUC rose to 77% in the presence of more than 10 atypical cells. 28 In a 388 Am J Clin Pathol 2016;146: American Society for Clinical Pathology 388

6 similar study in which the AUC category was explored, McCroskey et al 29 reported that the average number of atypical cells differed depending on the follow-up results, with the group of patients having a negative follow-up harboring a smaller average number of atypical cells per slide than those with a subsequent diagnosis of HGUC (nine vs 16 cells, respectively). Incorporating the findings of the current study with those of the literature not only indicate that the quantitative criteria proposed in the PSRUC are valid but also point to the fact that the suspicious and positive categories are distinct and should probably not be lumped together at the cytologic and clinical levels. This quantitative approach is not unprecedented and has also been validated in other systems, especially in the Bethesda System of gynecologic cytology, in which the main difference between ASC- H and high-grade squamous intraepithelial lesion is the number of atypical cells. 26 The study is limited by its retrospective nature and the fact that we only included cases with a histologic follow-up. Therefore, the reported percentages of different PSRUC categories are not representative of all urine cytology specimens seen in our laboratory, since most patients do not undergo a follow-up biopsy. Another limiting factor that needs to be taken into account when interpreting the results of the current study is that the original diagnoses were made by several cytopathologists, while the PSRUC criteria were applied by one author who was a member of the working groups of the PSRUC and consequently was familiar with the proposed criteria. Therefore, whether interobserver diagnostic variability between the department s cytopathologists could have also played a role in the weaker performance of the original system cannot totally be excluded. As is the case following the introduction of any newly proposed system, it is anticipated that an adaptation period preferably with reference image banks and reproducibility studies will be needed before different groups (and even different cytopathologists within the same group) reach comparable diagnostic thresholds, especially in the AUC and SHGUC categories, and before the validity of the new system can be accurately tested in clinical practice. As such, the results of the current study are considered preliminary and need to be prospectively validated. In summary, the PSRUC seems to improve the performance of urine cytology by decreasing the number of cases assigned to the AUC category and by improving its predictive accuracy for a subsequent histologic diagnosis of HGUC. 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