| Abstract|| |
Background: Urine cytology remains to be the test of choice in the detection of high-grade urothelial carcinomas (HGUC) due to its favorable sensitivity. However, a significant rate of cases is reported under atypical/indeterminate categories, which result in a decrease in its specificity. Providing standardized cytologic criteria, one of the aims of The Paris System (TPS) is to reduce the use of indeterminate diagnoses and provide a higher predictive value in these categories. Aims: We compared the diagnostic performances of TPS and our original reporting system, and also investigated the interobserver reproducibility of the cytologic criteria used. Materials and Methods: A total of 386 urine samples were reviewed retrospectively. Original cytologic diagnoses have been made using similar cytologic features proposed by TPS. All slides were recategorized after the use of the cytologic criteria as described by TPS guideline. Results: After TPS, specificity of the test increased from 39.6% to 63.5, sensitivity decreased from 92.5% to 88.8%, and diagnostic accuracy increased from 63.6% to 75%. The use of negative category increased threefold. Frequencies of indeterminate categories of atypical urothelial cells (AUC) and suspicious for HGUC (SHGUC) decreased by 36% and 56.5%, respectively. A subsequent detection of HGUC after AUC and SHGUC categories increased by 38% and 64%, respectively. Interobserver agreement for TPS categorization was 39%. Conclusions: TPS improved diagnostic accuracy of urine cytology by reducing the use of indeterminate categories, and resulted in increase in their predictive value for subsequent diagnosis of HGUC. However, reproducibility of diagnostic categories seemed to be imperfect.
Keywords: Interobserver reproducibility, specificity, the Paris system, urine cytology
|How to cite this article:|
Onder S, Kurtulan O, Kavuncuoglu A, Akdogan B. Comparison of diagnostic performances of urine cytology before and after the use of the paris system criteria: An institutional experience from Turkey. J Cytol 2021;38:133-9
|How to cite this URL:|
Onder S, Kurtulan O, Kavuncuoglu A, Akdogan B. Comparison of diagnostic performances of urine cytology before and after the use of the paris system criteria: An institutional experience from Turkey. J Cytol [serial online] 2021 [cited 2022 Dec 5];38:133-9. Available from: https://www.jcytol.org/text.asp?2021/38/3/133/324476
| Introduction|| |
Although urine cytology has been fraught with its lower diagnostic accuracy in the diagnosis of low-grade urothelial neoplasms, it continued to be the test of choice in many institutions, including ours, in the detection of high-grade urothelial carcinomas (HGUC) due to its acceptable sensitivity. However, a significant rate of cases has been given equivocal diagnosis and reported under atypical or indeterminate categories.,,,, There have been several individual or institutional attempts to subclassify atypical cases as to convey a clinical value, however, the criteria used to define these categories were not standardized until the introduction of TPS.,,
The Paris System introduces a standardized terminology for reporting urine cytology and proposes several diagnostic categories oriented to detect or rule out principally HGUC. For this purpose, besides a HGUC category, TPS also proposes two indeterminate categories of atypical urothelial cells (AUC) and suspicious for HGUC (SHGUC) which lump equivocal cases together by their increasing risk of associated malignancy, respectively. One of the aims of TPS, besides a high sensitivity, is to limit the use of these indeterminate categories to the cases associated with a true probability of HGUC, and, thus, keep the high predictive value of the test.
In this study, we evaluated the impact of TPS criteria on the performance of urine cytology by comparing with that of our original reporting system. We also assessed the interobserver reproducibility of cytologic criteria and agreement in TPS categorization.
| Materials and Methods|| |
A total of 386 urine cytology samples from 308 patients that were reported over the last five years were selected form the cytology archives of Hacettepe University, Faculty of Medicine, Department of Pathology. The samples were composed of cytospin or liquid-base (BD SurePath™, New Jersey, USA) slides and consisted of one slide stained with Papanicolaou stain. Data of specimen type (e.g., voided urine or bladder/urinary tract washing) was not available. All cases have been previously diagnosed by the first author based on criteria similar to that of the Johns Hopkins Hospital (JHH) template for urine cytology. Our original reporting system (ORS) classified these cases under the following diagnostic categories: 1) Inadequate; 2) Negative; 3) Atypical urothelial cells of uncertain significance (AUC-US); 4) Atypical urothelial cells, cannot exclude high-grade urothelial carcinoma (AUC-H); 5) High-grade urothelial carcinoma (HGUC); 6) Low-grade urothelial carcinoma (LGUC), and 7) Other (any malignancy other than HGUC). No standardized threshold for N/C ratios or minimum required atypical cell number were applied in categorizing atypical and malignant cases. Presence of any degree of cellular atypia including hyperchromasia, nuclear membrane irregularity, nuclear pleomorphism or coarse chromatin was accepted as a diagnostic criterion. For the diagnosis of low-grade urothelial carcinomas (LGUC), presence of cell clusters with cellular atypia, with or without fibrovascular cores, was accepted as adequate.
Blinded to the cytologic diagnoses, 386 urine samples were reevaluated according to TPS criteria and reclassified under 7 diagnostic categories as previously described by Barkan et al. Following cytologic criteria were used: N/C ratio (<0.5, 0.5-0.7 range, or > 0.7) as the major criterion, and three minor criteria including hyperchromasia (present or absent), nuclear irregularity (present or absent) and chromatin pattern (fine or coarse). Diagnostic categories of TPS included 1) Nondiagnostic or Unsatisfactory, 2) Negative for high-grade urothelial carcinoma (NHGUC), 3) Atypical urothelial cells (AUC), 4) Suspicious for high-grade urothelial carcinoma (SHGUC), 5) High-grade urothelial carcinoma (HGUC), 6) Low-grade urothelial neoplasm (LGUN), and 7) Other (primary and secondary malignancies and miscellaneous lesions). A sample was reclassified as AUC when non-superficial and non-degenerated urothelial cells presented a N/C ratio >0.5 and met at least one of the minor criteria. For HGUC diagnosis one major (e.g., N/C ratio >0.7) and at least one minor criteria including hyperchromasia were provided. Cases with cytomorphologic criteria of HGUC, which fell short for required number (e.g., <10 abnormal cells) were categorized as SHGUC. Cases with crowded urothelial cell groups only presenting a fibrovascular core were accounted as LGUN.
A fourth-year training pathology resident was also asked to recategorize study samples according to TPS. However, the revision was performed on 344 cases due to the availability of the stored slides and the issues of in-department workflow at the time of his contribution. The experience of pathology resident in general cytology practice was limited by annual in-department cytology rotations, each of one month duration. Pathology resident was exposed to TPS criteria first time for the present study.
A total of 176 cases had tissue biopsies obtained concurrently (n = 166) or subsequently (within 3 months, n = 8). Diagnostic accuracy of cytologic diagnoses from ORS and TPS classifications were calculated based on the power of the test to detect a high-grade carcinoma, including HGUC or other high-grade malignancies, such as metastatic carcinomas or prostatic adonocarcinomas. Positive test group included AUC, SHGUC, HGUC and Other categories. NHGUC and LGUN categories constituted the negative test group.
For the calculations of sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and diagnostic accuracy of the reporting systems, 2 × 2 tables were used. Fisher exact probability test was used to assess the association between variables. A P value < 0.05 was considered statistically significant. Overall interobserver agreement analysis between the two observers was performed using the Cohen's Kappa (K). Statistical analysis was performed using SPSS 13.0™.
| Results|| |
After the revised criteria, a total of 242/386 (63%) cases were reclassified in categories other than their original categories. The number of ORS cases redistributed into another category was lowest among Negative cases (4/53, 8%), followed by, in increasing order, HGUC (22/60, 37%), AUC-US (115/152, 76%), AUC-H (74/87, 85%), Other (8/9, 89%) and LGUC (19/21, 90%) categories [Table 1]. After recategorization, frequency of Negative and HGUC categories increased, whereas atypical categories of AUC and SHGUC, as well as LGUN and Other categories decreased, as shown in [Table 2]. With TPS criteria, specificity and PPV of the test significantly increased from 39.6% to 63.5% and from 56.1% to 67%, respectively. NPV also slightly increased from 86.4% to 87.1% whereas sensitivity decreased from 92.5% to 88.8%, which was not significant. Overall diagnostic accuracy of the test increased from 63.5% to 75% (P < 0.0001) [Table 3].
|Table 1: Redistribution of original diagnoses after implementation of TPS|
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|Table 2: Cytological diagnoses of urine samples before and after implementation of TPS|
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Of 176 tissue biopsies in the study group, 78 were nonneoplastic conditions, 18 were low-grade papillary lesions (3 papillomas, 4 papillary urothelial neoplasm of low malignant potential, and 8 were non-invasive low-grade papillary urothelial carcinomas), 77 were HGUC, and 3 were high-grade carcinomas other than HGUC (2 high-grade prostatic adenocarcinomas and 1 high-grade metastatic adenocarcinoma). Of 77 HGUC biopsies, 72 (94%) and 69 (90%) were categorized in one of the positive test categories of ORS and TPS, respectively. With TPS, 7 out of 8 HGUC biopsies were reassigned as negative and 1 as LGUN. Among 7 negative cases, malignant cells were overlooked because of low cellularity or obscuring inflammation and blood in 4 cases, of which two were previously diagnosed as negative and two were as HGUC [Figure 1]. Among two negative cases, which were also previously diagnosed as HGUC, neoplastic cells presented highly dark and smudgy nuclei with a low N/C ratio, giving the impression of degenerative changes [Figure 2]. In one negative case, malignant cells, which were very few in number, were characterized by round and hypochromatic nuclei, and misinterpreted as BK polyoma virus cytopathic effect [Figure 3]. Original diagnosis of this case was AUC-US.
|Figure 1: Two HGUC cases which were misinterpreted as negative due to limiting factors such as low cellularity, inflammation and obscuring massive blood. (a) The slide presented few cells mostly consisted of inflammatory cells (Papanicolaou, x100). (b) High power view demonstrated few HGUC cells which were overlooked during evaluation (Papanicolaou, x400). (c) This HGUC case was obscurred with massive blood (Papanicolaou, x200). (d) Few malignant cells were barely visible among blood elements in high power (Papanicolaou, x400).|
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|Figure 2: Two carcinoma in situ cases which were misinterpreted as negative. (a and b) Severe degeneration characterized by dark and small or pyknotic nuclei was noted (Papanicolaou, x100). Although the presence of some worrisome features for malignancy, this case was reclassified as negative because of degeneration. (Papanicolaou, x400). (c and d) This case showed few degenerated cells scattered among perfectly benign urothelial cells. An atypical looking cell, which was presumably misinterpreted as a degenerated cell was seen in high power (Papanicolaou, x400)|
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|Figure 3: (a) Urine cytology from a HGUC. The malignant cell presents an increased N/C ratio <0.7 with a hypochromatic nucleus. This case, originally diagnosed as AUC-US, was reclassifed as negative with TPS, assuming a possible BK polyomavirus effect. (b) a BK polyoma virus infected urothelial cell is seen in the urine of an AML patient. Viral effect is characterized by its typical groundglass appearance in the nucleus, the diagnosis, however, may be evident only if both cells are compared. Viral infection might be highlighted with specific immunocytochemistry (anti-SV40, inset) (Papanicolaou, x400)|
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Among 30 HGUC cases that were diagnosed as HGUC both histologically and cytologically with ORS, 9 were downgraded to SHGUC (n = 5) or AUC (n = 4). SHGUC cases had cells with obvious malignant features, but <10 in number. Four AUC cases were interpreted as not to meet the criteria of N/C ratio >0.7 in two cases, and hyperchromasia in two cases [Figure 4]. With the use of TPS criteria, rate of detecting a subsequent HGUC was increased from 37% to 51% for AUC and from 53% to 87% for SHGUC, whereas it showed a mild decrease from 75% to 73% for HGUC categories [Table 4].
|Table 4: Histologic correlation of cytologic diagnoses with ORS and TPS classifications|
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|Figure 4: (a and b) A urine specimen with original cytologic diagnosis of HGUC but reclassified as AUC after TPS. Urothelial cells are significantly enlarged and show membrane irregularity. Some nuclei show hyperchromasia with a N/C ratio around 0.5 (a), whereas other nuclei are even hypochromatic (b). Concurrent biopsy revealed HGUC (a and b; Papanicolaou, x400)|
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Interobserver agreements of diagnostic categories and the N/C ratio between the senior pathologist and pathology resident are shown in [Table 5] and [Table 6], respectively. An absolute interobserver agreement between two raters among 348 cytologic diagnoses is observed in 132 (37.9%) cases (kappa = 0.19; 95% CI: 0.13-0.25). An absolute agreement for N/C ratio estimates was seen in 189 (54.3%) cases (kappa = 0.30; 95% CI: 0.23-0.38). The agreement rate was higher in HGUC categories and increased N/C ratios, and lowest in equivocal cases with N/C ratios between 0.5 and 0.7 [Figure 5].
|Table 5: Interobserver agreement for TPS categorization between the trained pathologist and pathology resident|
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|Table 6: Interobserver agreement for N/C estimation between the trained pathologist and pathology resident|
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|Figure 5: (a-c) Examples of disagreement between experienced pathologist (EP) and pathology resident (PR) in the estimation of N/C ratios between 0.5 and 0.7. EP called this atypical cell (arrow) as negative, whereas PR called as AUC. Biopsy revealed reactive epithelium (a). This urothelial group is recategorized as AUC and HGUC by EP and PR, respectively. Biopsy was normal (b). EP and PR called this case as HGUC and AUC, respectively. Biopsy was normal (c). Perfect agreement was noted in most HGUC cases when N/C ratios are >0.7 (d)|
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| Discussion|| |
In the current study, we observed that implementation of TPS criteria improved the diagnostic accuracy of urine cytology in the detection of HGUC by increasing the specificity of the test after lowering the use of atypical categories of our original reporting system (ORS), which was modified from JHH template. ORS subdivided atypical cases that were suggestive of HGUC into two categories of AUC-US and AUC-H, which correspond to AUC and SHGUC categories of TPS, respectively. However, in the previous categorization of atypical cases, no standardized cut-off values for N/C were applied, nor the additional cytologic features including hyperchromasia, irregular nuclear membrane or coarse chromatin were conjugated to N/C ratio as defined by TPS. When AUC-US cases were accounted as a positive test result for urine cytology, ORS has rendered a sensitivity of 92.5% and a specificity of 39.6% for HGUC
Increased N/C ratio is one of the most critical criteria in the prediction of HGUC, and the utility of a cut-off value of 0.5 and above in the discrimination of benign from atypical or malignant urothelial cells has been shown in several studies.,10], TPS adopted N/C ratios >0.5 and >0.7 as required (major) criteria for AUC and SHGUC/HGUC diagnoses, respectively. In addition, for AUC diagnosis, at least one of the minor criteria including hyperchromasia, nuclear membrane irregularity or coarse chromatin should be met. For SHGUC/HGUC diagnosis, in addition to N/C ratio >0.7, hyperchromasia is a necessary criterion. Most studies reported that implementation of TPS criteria resulted in a decrease in the frequency of overall indeterminate reports by up to 73%.,,, Our study showed that application of TPS rendered a decrease by 56% and 25% in the frequency of our previous AUC-US and AUC-H cytology diagnoses, respectively, and resulted in reclassification of 36% more true negative cases under NHGUC category. We also believe that the novel terminology of NHGUC for negative cases, which emphasizes its eliminating role in the high-grade urothelial carcinomas only, encouraged us to use this category more confidently. Our findings were in agreement with the scope of TPS and the observations of others in that TPS allows a decrease in the use of atypical categories and increase in the specificity of the test, while keeping a favorable NPV.,,,
Sensitivity of the test after use of TPS showed an insignificant decrease from 93% to 89% after a total of 8 cases were recategorized as negative (n = 7) or LGUN (n = 1). Among these cases, 4 were previously diagnosed as HGUC. Neoplastic cells were overlooked due to limiting factors including low cellularity or obscuring inflammation and blood in two cases, and malignant cells which were characterized by relatively small nuclei with smudgy chromatin were misinterpreted as degenerative changes. The aim for not making a diagnosis on degenerated cells, as recommended by TPS, seemed to avoid us making an even atypical, if not malignant, diagnosis. We had also one case which was previously diagnosed as atypical (e.g., AUC-US), in which nuclear changes were misinterpreted as BK polyoma virus effect, and recategorized as negative with TPS criteria. Although cytopathic changes of BK polyoma virus infection may mimic a high-grade malignancy, nuclei of HGUC cells, when degenerated, may also resemble those of a viral infection and result in a false negative diagnosis. Under TPS, degenerated cells are dismissed from evaluation, whereas viral cytopathic effects are not categorized as atypical. However, the distinction between two may be extremely difficult. Our study showed that some HGUC cases might be underdiagnosed by such an effort to disqualify degenerative changes or a possible BK polyoma virus infection. On the other hand, BK polyoma virus infection and HGUC may co-exist or the latter may follow the former. Allison et al. showed a relatively high rate of subsequent HGUC among patients with BK polyoma virus infection and questioned the appropriate classification of these cases. Correlation with patient history or application of immunocytochemistry for BK polyoma virus may be helpful in such a context, and the use of one of the indeterminate categories of TPS may be warranted in equivocal cases.
One of the aims of TPS, besides minimizing the reporting rate of indeterminate cases, is to limit the use of these categories to the cases associated with a true probability of HGUC, thus, keep the high predictive value of the test, since low specificity in urine cytology may lead to unnecessary cystoscopies. Most studies demonstrated that there is a gradual increase in the rate of HGUC in the indeterminate categories of AUC and SHGUC/HGUC after application of TPS criteria. A subsequent diagnosis of HGUC has been reported up to 53% for AUC and 100% for SHGUC/HGUC in previous studies., In agreement with these reports, we observed that the rate of detection of HGUC under TPS increased to 51% in AUC and 87% in SHGUC categories. The predictive value of HGUC category, however, showed a slight decrease from 75% to 73%, which was even lower than that of SHGUC category. In the current study, a total of 9 HGUC cases were downgraded to AUC or SHGUC diagnoses. Of those, 4 cases were assigned to AUC category as they did not meet the criteria of either N/C ratio > 0.7 or hyperchromasia, whereas 5 cases, although fulfill the these cytologic criteria, were reclassified as SHGUC due to the limited number of atypical cells (e.g., <10). Our study showed that application of strict criteria of N/C ratio, hyperchromasia and minimum number of atypical cells might be responsible from the relatively low predictive value of HGUC category. It has been reported that nuclei of HGUC cells may be even hypochromatic, and they may resemble umbrella cells and do not demonstrate an increased N/C ratio., In their study with digital image analysis, McIntire et al. showed that N/C ratio cut-off values for SHGUC and HGUC were lower than 0.7 and they advocated reducing the N/C ratio below the current threshold suggested in TPS. Various other morphologic appearances of HGUC cells which did not meet TPS criteria, as well as the errors in the mental calculation of N/C ratio might be other sources of underestimation of HGUC in our study. Difficulty of precise calculation of N/C ratios and interobserver reproducibility of N/C estimates have been addressed in several reports. Layfield et al. reported that the accuracy of assessment of N/C ratios in the critical range of 0.5-0.7 was fair. Vaickus et al. showed that N/C ratio estimates became more accurate and interobserver variability decreased as N/C ratios increased. Several other studies demonstrated that level of agreement among TPS diagnostic categories were also imperfect. Long et al. reported an average absolute agreement of 65%, which was acceptable for NHGUC but not adequate for other categories. Bakkar et al. reported an overall agreement rate of 31% for TPS diagnostic categories, and disagreements with high clinical impact were 27% in their study. Kurtycz et al. and others demonstrated that the level of agreement was highest in HGUC and NHGUC, and poorest in the equivocal AUC and SHGUC categories.
In the current study, we correlated interobserver reproducibility of N/C ratios and diagnostic performance of the test between an experienced pathologist and a pathology resident. Consistent with the previous reports, perfect agreement for N/C ratio estimates was observed only in 54% of cases (kappa = 0.30), which was highest for N/C ratios >0.7, followed by <0.5 and 0.5-0.7 range. Level of absolute interobserver agreement among diagnostic categories of TPS was also poor (39%). We observed the highest level of disagreement in cases with N/C ratios close to two critical cut-off values of 0.5 and 0.7, and cases with mild to moderate hyperchromasia. In such cases, resulting in an increased specificity, experienced pathologist seemed to adhere more strictly to TPS criteria after recategorization, which might be due to a bias related with a suspense of the value a new classification system in his personal cytology practice. Training pathology resident, however, showed higher index of suspicion and scored very high sensitivity (99%) but a low specificity (24%) at the expense, which might be in part due to a bias towards atypical/malignant diagnoses, arising from the concern of showing a poor performance in detecting malignant cases, or simply inaccurate estimation due to intrinsic nature of cytologic criteria, which might be improved with experience. Vaickus et al. reported that morphologists showed tendency to overestimate N/C ratios, and estimations were more accurate at increased N/C ratios. Although Kurtycz et al. did not did not show an association between experience and the performance level of respondents at making TPS classification in their large survey, Strittmatter et al. demonstrated the impact of learning curve on the diagnostic accuracy of urine cytology with the steady increase in the specificity over the years, and underlined the necessity of long learning period for the inexperienced.
Finally, diagnosis of low-grade urothelial neoplasms remained a diagnostic problem in the current study. In their reports, Cowan et al. showed that the performance of TPS in the detection of LGUN ranged between 77% to 100%. In our study group, there was 18 biopsy-proven LGUNs, which only one was detected with ORS but none with TPS. The only required criterion of presence of fibrovascular core has utility in selecting these cases from HGUCs, but we believe that both sensitivity and interobserver reproducibility of this criterion is still poor.
In summary, although limited by its retrospective nature, sample size and number of raters, our study showed that application of TPS criteria increased specificity and diagnostic accuracy of urine cytology. The frequency of indeterminate categories of AUC and SHGUC were decreased and associated with a higher rate of subsequent HGUC. The higher rate of HGUC after AUC diagnosis might have an impact on clinical decision-making in these patients. The poor performance of urine cytology in the diagnosis of LGUN seemed remained. Diagnostic criteria of TPS were prone to interobserver disagreement, however test performance might be improved with experience.
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Dr. Sevgen Onder
Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]