Original Article

Should the BK Polyomavirus Cytopathic Effect Be Best Classified as Atypical or Benign in Urine Cytology Specimens? Derek B. Allison, MD; Matthew T. Olson, MD; Mohammed Lilo, MD; Mingjuan L. Zhang, BS; Dorothy L. Rosenthal, MD; and Christopher J. VandenBussche, MD, PhD

BACKGROUND: According to The Paris System for Reporting Urinary Cytology (TPS), the category of atypical urothelial cells (AUC) should not be applied to specimens in which cellular changes can be entirely attributed to the polyoma (BK) virus cytopathic effect (CPE). Until recently, cases with BK CPE at The Johns Hopkins Hospital were categorized as atypical urothelial cells of uncertain significance (AUC-US), which is equivalent to the TPS AUC category. This study was performed to determine how significantly the rate of AUC-US specimens would decrease if specimens with only BK CPE were classified as benign. METHODS: Two reviewers and 1 adjudicator re-evaluated urinary tract specimens to determine whether sufficient cytological atypia justified an AUC-US diagnosis independent of the presence of BK CPE. For patients with surgical follow-up, the rate of high-grade urothelial carcinoma (HGUC) on tissue biopsy was tracked over a 5-year period. RESULTS: The reclassification rate of AUC-US cases with BK CPE as benign was 62.6%. The rate of subsequent HGUC was 6.0% for cases reclassified as benign and 10.0% for cases still classified as AUC-US. These rates were not significantly elevated in comparison with control cohorts among all-comers. However, for patients without a history of HGUC, the rate of HGUC on follow-up was significantly elevated in comparison with the rate for a benign control cohort and was similar to the rate for the AUC-US control cohort. CONCLUSIONS: Reclassification as benign would have decreased the rate of AUC-US from 24.8% to 20.7% during the study year. However, the high rate of subsequent HGUC among nonsurveillance patients suggests that the reclassification of specimens with BK CPE in these patients may be inappropriate. C 2016 American Cancer Society. Cancer Cytopathol 2016;124:436-42. V

KEY WORDS: bladder cancer; BK; polyoma virus; The Paris System for Reporting Urinary Cytology; urinary tract; urine; urothelial cancer.

INTRODUCTION Urinary tract (UT) cytology is used as a cancer screening tool to evaluate high-risk patients with persistent hematuria of unknown etiology or a history of urothelial neoplasia. The primary goal of UT cytology is to exclude the presence of high-grade urothelial carcinoma (HGUC), which is the fourth leading cancer in men in the United States.1 Risk factors include smoking, exposure to certain medications and chemicals, older age, white race, and male sex.2–8 Approximately 75% of patients present with non–muscle-invasive disease (stages Ta, T1, and Tis) and thus have minimal symptoms upon presentation, the most common being hematuria.8,9 Up to 70% of all treated tumors recur; therefore, lifelong surveillance for the recurrence of disease is indicated and accomplished for these patients by urinary cytopathology and cystoscopy.10–12 Such long-term monitoring makes bladder cancer the most expensive cancer per patient in the United States.13 Corresponding author: Christopher J. VandenBussche, MD, PhD, Department of Pathology, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287; Fax: (410) 614-9556; [email protected] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Received: January 9, 2016; Revised: January 28, 2016; Accepted: February 1, 2016 Published online February 29, 2016 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/cncy.21705, wileyonlinelibrary.com

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UT cytopathology is an inexpensive and effective screening and surveillance tool for the evaluation of urothelial carcinoma. In particular, UT cytopathology has a high specificity for HGUC.14 At our institution, the Johns Hopkins Hospital template (JHHT) for urologic cytology samples was used in an attempt to standardize terminology on the basis of cytopathological findings and clinical outcomes to accurately risk-stratify patients.15–17 Subsequently, The Paris System for Reporting Urinary Cytology (TPS) has proposed similar categories. The second largest category in TPS, atypical urothelial cells (AUC), accounts for up to 26% of diagnoses according to the institution.16,18–26 In contrast to TPS recommendations, the JHHT classifies all specimens with the polyoma (BK) virus cytopathic effect (CPE) within an AUC category equivalent (atypical urothelial cells of uncertain significance [AUC-US]) because of the cytomorphologic similarity between BK CPE and degenerated HGUC cells. TPS guidelines, however, recommend that BK CPE and related changes be classified as benign unless other atypical features are present. To determine how our institution’s relatively high rate of AUC specimens (approximately 26%16) would be reduced with TPS guidelines for classifying BK CPE, we conducted a slide review of UT specimens classified as AUC-US with BK CPE over a 1-year period. Cases with atypical features in addition to BK CPE and cases in which BK CPE could not be comfortably distinguished from HGUC remained classified as AUC-US, whereas the remaining specimens were reclassified into the benign category.

Figure 1. Summary of the agreement and adjudication of the study cohort, which consisted of 107 cases with urinary tract specimens diagnosed as AUC-US with BK CPE. Cases were reclassified as benign only if they had BK CPE and no background urothelial atypia. AUC-US indicates atypical urothelial cells of uncertain significance; CPE, cytopathic effect.

MATERIALS AND METHODS

or whether other factors were present to justify a diagnosis of AUC-US. Two blinded reviewers (D.B.A. and C.J.V.) reviewed available specimens to determine whether sufficient cytological atypia was present for an AUC-US diagnosis independent of classic BK CPE. For cases in disagreement, a third blinded reviewer (D.L.R.) served as an adjudicator. In addition, it was noted whether an individual specimen contained degenerative changes (Fig. 1). When 2 of 3 reviewers agreed that a specimen contained only BK CPE in a background of otherwise benign changes, the specimen was reclassified as benign.

Case Identification

Data Analysis

The study received approval by the Johns Hopkins institution review board. The electronic pathology archives of the Johns Hopkins Hospital were searched for UT cytopathology specimens classified as AUC-US that also had BK CPE over a 1-year period (January 1, 2009 to December 31, 2009).

Statistical comparisons were performed with Fisher’s exact test. P values < .05 were considered statistically significant.

Slide Review and Reclassification of Cases

To determine the contribution of BK CPE to our institutional rate of AUC-US diagnoses, we reviewed urinary cytology slides with BK CPE to determine whether the cases were classified as AUC-US because of BK CPE alone Cancer Cytopathology

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RESULTS Patient Demographics

During the study period, 2109 urine cases were identified, 524 (24.8%) of which were classified as AUC-US. Of these 524 cases, 140 (26.7%) had BK CPE. Slides from 107 of these cases were available for immediate microscopic review. Of 107 patients, average age was 67 years, and 85 (79.4%) were male; 79 (73.8%) were white (Table 1). 437

Original Article TABLE 1. Demographics of Patients With Urinary Tract Specimens Demonstrating the BK Cytopathic Effect

Total Maintained as AUC-US Reclassified as Benign

No. (%)

Age, Mean (Range), y

Male, No. (%)

White, No. (%)

History of HGUC, No. (%)

107 (100) 40 (37.4) 67 (62.6)

67 (40–89) 69 (43–83) 66 (40–89)

85 (79.4) 32 (80.0) 53 (79.1)

79 (73.8) 31 (77.5) 48 (71.6)

18 (16.8) 8 (20.0) 10 (14.9)

Abbreviations: AUC-US, atypical urothelial cells of undetermined significance; HGUC, high-grade urothelial carcinoma. The patients were separated into 2 groups: their specimens were reclassified as benign or the diagnosis of AUC-US was kept after a glass-slide review.

Figure 2. Subsequent tissue biopsy (surgical pathology specimen) follow-up of the study cohort. AUC-US indicates atypical urothelial cells of uncertain significance; CPE, cytopathic effect; HGUC, high-grade urothelial carcinoma; LGUC, lowgrade urothelial carcinoma.

Figure 3. Subsequent tissue biopsy (surgical pathology specimen) follow-up of the hematuria cohort (nonsurveillance patients). AUC-US indicates atypical urothelial cells of uncertain significance; CPE, cytopathic effect; HGUC, high-grade urothelial carcinoma; LGUC, low-grade urothelial carcinoma.

Reclassification After Slide Review

65.9%) than those that did not require adjudication (31 of 66 or 47.0%), although this difference did not reach statistical significance (P 5 .07).

After the initial review by the 2 reviewers, 37 of the 107 cases (34.6%) were reclassified as benign, 29 (27.1%) kept an atypical diagnosis, and 41 (38.3%) required adjudication. After adjudication, 30 of the adjudicated cases (73.2%) were reclassified as benign, and 11 (26.8%) kept an atypical diagnosis. The overall number of cases reclassified to benign from AUC-US was 67 (62.6%); 40 cases (37.4%) remained classified as AUC-US. There was no statistically significant difference for reclassification as benign versus AUC-US based on age, sex, or race. In comparison with the total number of AUC-US cases during the study period, this would have resulted in 88 cases being reclassified as benign from the 524 total cases classified as AUC-US. This reclassification would have decreased the rate of AUC-US diagnosis during the study period from 24.8% to 20.7%. Overall, there was initial agreement by 2 reviewers in 66 cases (61.7%), with 41 (38.3%) requiring adjudication. Because the presence of degeneration can affect specimen interpretation, specimens with marked degenerative changes were flagged. Cases requiring adjudication were more likely to contain degenerative changes (27 of 41 or 438

Rate of Malignancy Associated With BK CPE

The reclassification of specimens with BK CPE to the benign category is valid only if the rate of malignancy among reclassified cases is more similar to that for the benign category versus the AUC-US category. Patient follow-up was examined over a 5-year period (Figs. 2 and 3). The overall rate of HGUC among all specimens was 7.5% (8 of 107), and the overall rate of low-grade urothelial carcinoma (LGUC) was 9.3% (10 of 107). When they were combined, the overall rate of cancer was 17% (18 of 107). Seventeen of the 67 patients (25.4%) with specimens reclassified as benign had subsequent tissue biopsies. Eight of these had benign biopsies, 5 had LGUC, and 4 had HGUC. Seventeen of 40 patients (42.5%) with AUC-US specimens had subsequent tissue biopsies. Eight of these had benign biopsies, 5 had LGUC, and 4 had HGUC. The overall rate of HGUC for specimens reclassified as benign was 6.0% (4 of 67), and it was 10.0% (4 of 40) for specimens kept as AUC-US (Table 2). This difference was Cancer Cytopathology

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TABLE 2. Rates of Biopsy-Confirmed HGUC for the Study Cohorts Versus the Control Cohorts Cohort

No.

Rate of HGUC, %

P (vs. BK CPE cohort)

Remained AUC-US with BK CPE (any indication) AUC-US control cohort (any indication) Benign control cohort (any indication)

40 100 100

10.0 19.0 6.0

— .30 .47

Reclassified as benign with BK CPE (any indication) AUC-US control cohort (any indication) Benign control cohort (any indication)

67 100 100

6.0 19.0 6.0

— .02 1.00

Remained AUC-US with BK CPE (nonsurveillance) AUC-US control cohort (nonsurveillance) Benign control cohort (nonsurveillance)

32 150 150

3.1 7.3 0.7

— .70 .32

Reclassified as benign with BK CPE (nonsurveillance) AUC-US control cohort (nonsurveillance) Benign control cohort (nonsurveillance)

57 150 150

7.0 7.3 0.7

— 1.00 .02

Abbreviations: AUC-US, atypical urothelial cells of undetermined significance; CPE, cytopathic effect; HGUC, high-grade urothelial carcinoma. Statistically significant P values are bolded.

statistically nonsignificant (P 5 .47). In addition, the rate of malignancy gradually increased with each year of followup (data not shown). Our institutional rate of HGUC has previously been reported to be 0.7% for the benign category and 7.9% for the AUC-US category16 over a follow-up period that varied from 18 to 36 months for each specimen. To more accurately compare the results of our study cohort with the performance of these 2 categories, we also determined the 5-year follow-up for a cohort of 100 consecutive specimens diagnosed as benign and for a cohort of 100 consecutive specimens diagnosed as AUC-US during the same study period. Over a 5-year follow-up period, the AUC-US control cohort had a 19.0% rate (19 of 100) of subsequent HGUC diagnosed by tissue biopsy, and the benign control cohort had a 6.0% rate (6 of 100) of subsequent HGUC diagnosed by tissue biopsy (P 5 .009). In comparison with the control cohorts, the rate of HGUC among study cases reclassified as benign was similar to that for the benign control cohort (6.0% for both cohorts). The rate of HGUC in specimens reclassified as AUC-US, while slightly elevated in comparison with the benign cohort (10.0% vs. 6.0%), did not approach the AUC-US control cohort (10.0% vs 19.0%), and it was not significantly different from either the benign or AUC-US control cohort (P 5 .47 and P 5 .30, respectively; Table 2).

the data were analyzed for patients presenting only with hematuria and without a history of HGUC (Fig. 3). The pretest probability for HGUC was much lower in these patients versus the patients with a history of HGUC. Among the 89 patients presenting with hematuria, 57 (64.0%) were reclassified as benign, and 32 (36.0%) remained classified as AUC-US. Interestingly, the overall rate of HGUC on follow-up for specimens reclassified as benign (7.0% or 4 of 57) was greater than that for specimens remaining classified as AUC-US (3.1% or 1 of 32); the statistical comparison was nonsignificant (P 5 .65). To allow a more accurate direct comparison of nonsurveillance patients, we catalogued the 5-year follow-up results for a control cohort of 150 consecutive patients diagnosed with AUC-US during the same study period as well as a control cohort of 150 consecutive patients with benign UT specimens. Over the 5-year follow-up period, the benign control cohort had a 0.7% rate of HGUC (1 of 150), and the AUC-US cohort had a 7.3% rate of HGUC (11 of 150; P 5 .005). In comparison with the control cohorts, the rate of HGUC was significantly higher among cases reclassified as benign versus the benign control cohort (7.0% vs. 0.7%; P 5 .02). The rate of HGUC in specimens remaining classified as AUC-US was slightly lower than the rate for the AUC-US control cohort, but the difference was not significant (3.1% vs. 7.3%; P 5 .70; Table 2).

Rate of Malignancy Associated With BK CPE Among Nonsurveillance Patients

DISCUSSION

Because the occurrence of HGUC several years after an atypical urinary cytopathology specimen may be due to a new focus of disease in patients with a history of HGUC,

Polyoma (BK) virus is a ubiquitous pathogen that is frequently encountered in UT specimens of immunocompromised patients. After viral reactivation in these patients,

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Original Article

Figure 4. Examples of the BK cytopathic effect identified in cases from the study cohort. (A-C) The BK cytopathic effect was flagged in specimens from patients who ultimately had high-grade urothelial carcinoma on follow-up tissue biopsy. (B) The 2 background cells have hyperchromatic nuclei with irregular borders; this finding is sometimes seen in indeterminate urinary tract specimens with malignant follow-up. (D-F) The BK cytopathic effect was flagged in specimens that were benign during the follow-up period (5 y).

BK virus infects the superficial urothelial cells, which shed into the urine. BK virus CPE is, therefore, a wellrecognized entity in urinary cytology specimens; however, because of the cytological similarity to degenerated HGUC, infected cells have been called decoy cells.27 BK CPE can be occasionally found in the UT specimens of patients who are not immunocompromised, and this suggests that normal individuals may have asymptomatic activation of polyoma (BK) virus throughout life, although this has not been well established. In a recent study published by the Interlaboratory Comparison Program in Nongynecologic Cytopathology (College of American Pathologists), the overinterpretation of BK CPE as HGUC occurred in 6.2% of cases.28 When UT cytology was used to monitor renal transplant patients for BK infection, BK CPE may have been more commonly seen in UT specimens. However, in the modern era of molecular testing for BK virus, most urinary specimens are submitted to the cytopathology laboratory to exclude the presence of urothelial neoplasms. With the loss of a cohort of patients at high risk for active BK infection, it is possible that BK CPE found in UT specimens may have decreased over time. If so, the likelihood that BK CPE and similar morphological changes represent true BK infections may also have decreased. 440

Given the morphological overlap of decoy cells with HGUC, our institution previously classified all specimens with presumptive BK CPE as at least indeterminate (AUCUS) rather than benign (Fig. 4). Although this increased our AUC-US rate in comparison with other institutions, it was done with the intention of improving our ability to identify patients at risk for HGUC. However, until now, we have not examined how TPS guidelines for classifying BK CPE as Negative for High Grade Urothelial Carcinoma would affect our indeterminate rate or our sensitivity for the detection of HGUC. We have now found that this reclassification would have decreased the rate of AUC-US diagnosis from 24.8% to 20.7% during the study interval, and the latter rate is more consistent with the rates of other institutions.16,18–26 The presence of degenerative changes in our study was associated with a statistically significantly higher rate of disagreement among reviewers. Possibly this finding underscores the difficulty in distinguishing BK CPE from degenerated HGUC, although it is difficult to prove this in a retrospective study. The high disagreement rate (38.3%) for the reclassification of specimens before adjudication, even in the absence of degeneration, calls into question our ability to effectively categorize BK CPE from what may be degenerated HGUC cells that mimic BK CPE. Indeed, the concern about distinguishing cells with BK CPE from Cancer Cytopathology

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degenerated HGUC cells was a primary reason for classifying all cases with BK CPE into the AUC-US category when the JHHT was first established. Most importantly, in the setting of hematuria (patients without a history of HGUC), the cases reclassified from AUC-US to benign had a 5-year rate of HGUC of 7.0%, which is very similar to the rate found for a cohort of specimens classified as AUC-US over the same study period (7.3%) and is significantly elevated over the rate found for a cohort of specimens classified as benign (0.7%). If the diagnostic categories for UT cytology are meant to provide meaningful risk stratification, this would suggest that specimens containing BK-like changes from patients with new-onset hematuria should remain in the AUC-US category because they confer a similar risk of HGUC as specimens classified as AUC-US. Otherwise, the threshold for diagnosing BK-like changes as benign should be high so that cases dismissed as being due to benign BK CPE should have a risk that approximates the risk of the benign category. Although the majority of cases containing BK-like changes had benign follow-up, a significant number were associated with HGUC on follow-up, and thus the classification of such specimens is not a trivial decision. A similar phenomenon was not identified among patients with a history of HGUC; this cohort of patients is difficult to study because of the high frequency with which HGUC recurs and the higher pretest probability for HGUC among these patients. Thus, it is possible that our study was not adequately powered to identify a significant difference between these patients and the benign control cohort. However, there may be other explanations. For instance, cancer patients with a history of recent cancer treatment may be at higher risk for reactivation of BK virus; if this is true, then the pretest probability that BK CPE and related changes represent true BK infections would be increased in comparison with the nonsurveillance (hematuria) cohort. However, very little is known about the role of BK infection in the setting of HGUC. A case has been reported of BK virus–associated urothelial carcinoma in a ureter graft,29 and there is another reported case of HGUC in a kidney transplant patient with polyomavirus nephropathy.30 As with all cytopathology specimens, the patient history is an important consideration for specimen classification and diagnosis and provides the clinical team with the most appropriate risk stratification. Much of the published literature has focused on the misinterpretation of BK CPE Cancer Cytopathology

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as AUC and/or urothelial carcinoma. However, many of these studies took place during a period in which urine cytology specimens were typically submitted from transplant patients, and the presence of BK CPE was a relevant and actionable finding.31,32 In the modern era, more sensitive and specific laboratory tests are used to exclude the presence of BK virus in this population, so many laboratories (including our own) no longer examine urine specimens to predict and prevent organ rejection.33 This trend has resulted in a decreased incidence of true BK CPE in our specimens and has likely led to a decreased pretest probability for BK CPE. Because most of our specimens are submitted to exclude HGUC, this likely has increased the pretest probability that such cellular changes represent degenerated HGUC cells rather than BK infection. This assumption is supported by the relatively high rate of HGUC on follow-up among patients who had no history of HGUC. Conversely, a clinical history of renal transplantation or an immunocompromised state in a patient makes it more likely that BK-like changes represent true BK CPE in a given specimen. In summary, our results indicate that a small group of patients can be spared an indeterminate (AUC-US) diagnosis by the classification of BK CPE as benign. A benign diagnosis would spare these patients from unnecessary concern and potentially invasive follow-up. However, an increased risk for HGUC in our cohort of study patients with no history of HGUC calls into question whether BK CPE in these patients might be better classified as indeterminate (AUC-US). At the very least, it suggests that a high threshold should be set when one is determining whether certain morphological changes truly represent benign BK CPE. Furthermore, because our data are from a relatively small cohort of patients diagnosed at only 1 institution, they require further corroboration before any change to current recommendations can be suggested. Therefore, we strongly encourage other laboratories to evaluate their data to see whether they find similar results. FUNDING SUPPORT No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.

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Should the BK polyomavirus cytopathic effect be best classified as atypical or benign in urine cytology specimens?

According to The Paris System for Reporting Urinary Cytology (TPS), the category of atypical urothelial cells (AUC) should not be applied to specimens...
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