The application of cytology in urological diseases

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1 Voided urine cytology The application of cytology in urological diseases Dr Ashish Chandra FRCPath DipRCPath (Cytol) Guy s & St Thomas NHSfT London Detection of high grade urothelial carcinoma Monitoring of high grade urothelial carcinoma after TURBT & intravesical treatment (BCG/Mitomycin) Recognition of non-urothelial malignancies & metaplasias BK virus, schistosomiasis, HPV Non-neoplastic conditions: casts and dysmorphic red blood cells in renal parenchymal disease eg vasculitis No disclosures or conflicts of interest Talk will be made available on the conference website Urinary casts 1

Upper tract urothelial neoplasia in conjunction with ureteroscopic and radiological findings

2 Other specimen types Bladder washings Detection of background high grade urothelial carcinoma (CIS) at the end of TURBT or at surveillance cystoscopy Ureteric and renal pelvic urine/washings Upper tract urothelial neoplasia in conjunction with ureteroscopic and radiological findings Ileal conduit & urethral washings (post cystectomy) Detection of recurrent high grade urothelial carcinoma 2

3 Pitfalls Low grade urothelial neoplasia: papillary hyperplasia caused by reactive changes due to calculi, infection and catheter reaction. Can be equally tricky on histology as well and correlation with cystoscopic or ureteroscopic appearances is essential High grade urothelial carcinoma: BK virus reactivation, seminal vesicle epithelial cells 3

4 Diagnostic categories in the TPS The focus is on high grade urothelial carcinoma! 1. Non-diagnostic or unsatisfactory 2. Negative for high grade urothelial carcinoma 3. Atypical urothelial cells 4. Suspicious for high grade urothelial carcinoma 5. Low grade urothelial neoplasia 6. High grade urothelial carcinoma 7. Other primary and metastatic malignancies & miscellaneous lesions 4

Non-diagnostic or unsatisfactory Sample compromised by blood,

(SurePath), 25ml (ThinPrep) Cellularity: Bladder washings 20

HGUC) Uniform size Fine chromatin Round nuclei Smooth borders

Non-degenerated Non-superficial No deep hyperchromasia N:C ratio

fragments Changes 2 0 stones Viral cytopathic effect eg.

5 Non-diagnostic or unsatisfactory Sample compromised by blood, exudate and degenerative changes Adequacy: volume 30ml (SurePath), 25ml (ThinPrep) Cellularity: Bladder washings 20 cells/10hpf (ThinPrep) Reactive Urothelial Cells (Negative for HGUC) Uniform size Fine chromatin Round nuclei Smooth borders Small nucleoli Negative for HGUC Normal urothelial cells Non-degenerated Non-superficial No deep hyperchromasia N:C ratio < 0.5 but taking basal cells into account NOT ATYPIA! Report as negative. Reactive urothelial cells Degenerative changes True tissue fragments Changes 2 0 stones Viral cytopathic effect eg. Polyoma virus Post-Rx for bladder cancer esp. BCG Post-Rx for pelvic malignancies Systemic chemotherapy Enteric epithelium, conduits & neobladders Seminal vesicle cells 5

Atypia- a diagnostic tip Reporting rates of AUC: 2% to 31% Risk of HGUC: 8.3% to 37.

based criteria to refine the category has been an outstanding achievement of TPS Atypical

urothelial cells with a high N/C ratio > 0.

6 Atypia- a diagnostic tip Reporting rates of AUC: 2% to 31% Risk of HGUC: 8.3% to 37.5% Low grade lesions sometimes included here Clinicians have variable reaction to Atypia Development of subcategories eg. Atypia, favour reactive or neoplastic or uncertain significance Application of evidence based criteria to refine the category has been an outstanding achievement of TPS Atypical urothelial cells Criteria for Atypical urothelial cells Non-superficial and non-degenerated urothelial cells with a high N/C ratio > 0.5 (required) and one of the following: Hyperchromasia (compared to the umbrella cells or the intermediate squamous cell nucleus) Irregular clumped chromatin Irregular nuclear membranes Atypical urothelial cells 6

Studies on TPS (2016-17) Author Journal Key findings Miki et al Cytopathol AUC + FISH = 50% HGUC Virk et al Diagn Cytopathol Review article on FISH Torous et al JASC Reduction in atypia Atypical

40% cases of atypia downgraded to negative Granados et al Acta Cytol Reported increase in atypia in originally negative cases Malviya et al Acta Cytol Decrease in atypia rate from 11.9% to 5.

the cost of specificity of diagnosis of HGUC UroVysion FISH performed on all AUC cases On review of AUC cases over 6 years applying TPS, number of AUC further reduced Follow up of AUC: HGUC (50%,

7 Studies on TPS ( ) Author Journal Key findings Miki et al Cytopathol AUC + FISH = 50% HGUC Virk et al Diagn Cytopathol Review article on FISH Torous et al JASC Reduction in atypia Atypical urothelial cells Recent studies ( ) implementing TPS Authors Journal Main findings Hassan et al Am J Clin Pathol Atypia rate reduced by 13%; 20% increase in HGUC on biopsy Cowan et al Cancer 40% cases of atypia downgraded to negative Granados et al Acta Cytol Reported increase in atypia in originally negative cases Malviya et al Acta Cytol Decrease in atypia rate from 11.9% to 5.1% Straccia et al Cancer Cytopathol Atypia on TP was less predictive of HGUC than on cytospins Our results (Miki et al 2017) Historically, a low (5-10%) AUC rate, probably sacrificing sensitivity at the cost of specificity of diagnosis of HGUC UroVysion FISH performed on all AUC cases On review of AUC cases over 6 years applying TPS, number of AUC further reduced Follow up of AUC: HGUC (50%, FISH positive), LGUN (20%) or Negative (30%, FISH negative, surveillance cases) on follow up Pitfalls of FISH must be recognisedanticipatory false positive results Wang et al Cancer Cytopathol Decrease in atypia and increase in negatives 7

2018;00:1 7 20% of mismatch between HGUC vs LGUN on histology and cytology can be due to overcall on histology.

8 Correlation with histology Bertsch EC, Siddiqui MT, Ellis CL. The Paris system for reporting urinary cytology improves correlation with surgical pathology biopsy diagnoses of the lower urinary tract. Diagnostic Cytopathology. 2018;00:1 7 20% of mismatch between HGUC vs LGUN on histology and cytology can be due to overcall on histology. Lee et al 2016 Diagn Cytol Suspicious for HGUC Non-superficial and non-degenerated urothelial cells with a high N/C ratio > 0.7 (required) Suspicious for HGUC Hyperchromasia (compared to the umbrella cells or the intermediate squamous cell nucleus) (required) and one of the following: Irregular clumpy chromatin Suspicious for HGUC Irregular nuclear membranes 8

atypical urothelial cells is an important criterion to

diagnosis of HGUC seems valid from the clinical

grade urothelial carcinoma Low grade urothelial

the use of the term carcinoma for a non-invasive tumour

9 High grade urothelial carcinoma VI. High grade urothelial carcinoma (HGUC) The number of atypical urothelial cells is an important criterion to classify urine cytology specimens into the positive or the suspicious categories. A cut off number of >10 cells to render a definitive diagnosis of HGUC seems valid from the clinical standpoint (bladder washings) Brimo et al 2016 High grade urothelial carcinoma Low grade urothelial neoplasm (LGUN) Anomaly in histological terminology in the use of the term carcinoma for a non-invasive tumour Different disease to high grade urothelial carcinoma Recurrent but low progression rate to high grade, high stage disease 9

Low grade urothelial neoplasm (LGUN) Papillary structures with fibrovascular cores Cell blocks may be helpful Diagnosis of LGUN may be made in correlation with

of atypical cells HGUC Suspicious for HGUC Atypia >10 5-10 5-10 N:C ratio >0.7 >0.7 0.5 0.

explanatory notes for each category Any one of the three criteria VII. Other malignancies Unsatisfactory/Non-diagnostic (?

for Malignancy (0-2%) Clinical follow up as needed Atypical Urothelial Cells (8-35%). Clinical follow up as needed. Use of ancillary testing Suspicious for HGUC (50-90%).

10 Low grade urothelial neoplasm (LGUN) Papillary structures with fibrovascular cores Cell blocks may be helpful Diagnosis of LGUN may be made in correlation with cystoscopic or biopsy findings The Paris System: criteria for HGUC, Suspicious & Atypia* Category Criteria No. of atypical cells HGUC Suspicious for HGUC Atypia > N:C ratio >0.7 > Hyperchromasia + + Clumped chromatin / Irregular nuclear borders Either one of the two criteria Either one of the two criteria *In conjunction with explanatory notes for each category Any one of the three criteria VII. Other malignancies Unsatisfactory/Non-diagnostic (?<5%) Repeat cytology, cystoscopy in 3 months if high clinical suspicion ADC Clear cell ADC TPS categories: Risk of malignancy & clinical management Negative for Malignancy (0-2%) Clinical follow up as needed Atypical Urothelial Cells (8-35%). Clinical follow up as needed. Use of ancillary testing Suspicious for HGUC (50-90%). More aggressive follow up, cystoscopy, biopsy Low Grade Urothelial Neoplasm LGUN. (~10%). Need biopsy to further evaluate grade and stage High Grade UC (>90%). More aggressive follow up, cystoscopy, biopsy, staging Other malignancy (>90%). More aggressive follow up, cystoscopy, biopsy, staging Lymphoma Melanoma 10

TPS a success story Potential for high clinical impact globally due to a common specimen type Applicability across

Adaptability across conventional cytology as well as LBP Evidence based diagnostic criteria for number of cells for

TPS a success story Impact on reducing the Atypia category and improving its performance Correlates well with histology

11 TPS a success story Potential for high clinical impact globally due to a common specimen type Applicability across samples from the lower and upper urinary tract Useful advice to clinicians and patients on the volume of sample required Adaptability across conventional cytology as well as LBP Evidence based diagnostic criteria for number of cells for adequacy Have you switched to TPS yet? If yes, tell us about it If not, why not? TPS a success story Impact on reducing the Atypia category and improving its performance Correlates well with histology and ancillary tests Refers to possible low grade tumours as neoplasms PIRST results on the horizon: very high interobserver agreement in the negative, HGUC, LGUN categories 11

12 References Reynolds JP, Voss JS, Kipp BR, Karnes RJ, Nassar A, Clayton AC, Henry MR, Sebo TJ, Zhang J, Halling KC. Comparison of urine cytology and fluorescence in situ hybridization in upper urothelial tract samples. Cancer Cytopathol Jun;122(6): Dimashkieh H, Wolff DJ, Smith TM, Houser PM, Nietert PJ, Yang J. Evaluation of urovysion and cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic correlation. Cancer Cytopathol Oct;121(10): Rosenthal DL, Vandenbussche CJ, Burroughs FH, Sathiyamoorthy S, Guan H, Owens C. The Johns Hopkins Hospital template for urologic cytology samples: part I-creating the template. Cancer Cytopathol Jan;121(1): References VandenBussche CJ, Sathiyamoorthy S, Owens CL, Burroughs FH, Rosenthal DL, Guan H. The Johns Hopkins Hospital template for urologic cytology samples: parts II and III: improving the predictability of indeterminate results in urinary cytologic samples: an outcomes and cytomorphologic study. Cancer Cytopathol Jan;121(1):21-8. Owens CL, Vandenbussche CJ, Burroughs FH, Rosenthal DL. A review of reporting systems and terminology for urine cytology. Cancer Cytopathol Jan;121(1):9-14. Rezaee N, Tabatabai L and Olson M. Adequacy of voided urine specimens prepared by ThinPrep and evaluated using The Paris System for Reporting Urinary Cytology. JASC Volume 6, Issue 4, Pages

Toyonori Tsuzuki MD, PhD Professor and Chair Department of Surgical Pathology Aichi Medical University Hospital

29th European Congress of Pathology (ECP 2017) Amsterdam RAI. The Paris System for Reporting Urinary Cytology: The Concept and Management Toyonori Tsuzuki MD, PhD Professor and Chair Aichi Medical University