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

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1 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 Hospital Tuesday, September 5, 2017

2 The 29 th European Congress of Pathology Conflict of Interest (COI) Presenter: Toyonori Tsuzuki The author has no conflict of interest to disclose with respect to this presentation. Aichi Medical University Hospital

3 Outline of the presentation Why to standardize, why Paris? What is the guiding principle? What are diagnostic categories? What are the criteria? Aichi Medical University Hospital

4 Evolution of the Classification Cancer Cytopathol ;121:9-14 Aichi Medical University Hospital

5 Why standardize reporting of urinary cytology? Reproducibility Improvement of communication Atypical cells Wide intraobserver variability Nationally rates of atypical vary among institutions Range from 2% to 30% Aichi Medical University Hospital

carcinoma (HGUC) Numerous face-to-face meetings among 49

6 Where did we start? 18 th International Congress of Cytology, Paris, May, 2013 Outline of the Paris System for Reporting Urinary Cytopathology Ultimate goal detection of high grade urothelial carcinoma (HGUC) Numerous face-to-face meetings among 49 members, 28 from 10 countries including USA, Canada, France, Italy, Japan, Korea, Luxembourg, Slovenia, Switzerland, and the UK.

7 Aichi Medical University Hospital

8 Follow up schema by NCCN, Aichi Medical University Hospital

9 What is high grade urothelial carcinoma (HGUC)? Life threatened cancer Need definitive therapies Need strict follow up Including urothelial carcinoma in situ (CIS) and invasive urothelial carcinoma (with divergent differentiation) Aichi Medical University Hospital

10 Papillary Pathway 80% Normal Urothelium Non-Papillary Pathway 20% 9p-, 9qp16 Genetically Stable FGFR3 (~85%) Hyperplasia Genetically Unstable p53 (~60%) Dysplasia <10% RAS (?) Low Grade Carcinoma High Grade Carcinoma Carcinoma in situ Recurrence Recurrence The Paris System Invasive Carcinoma

Chapters in the Book I. Adequacy II. Negative for High Grade Urothelial Carcinoma III. Atypical Urothelial Cells IV. Suspicious for High Grade Urothelial Carcinoma V.

11 Chapters in the Book I. Adequacy II. Negative for High Grade Urothelial Carcinoma III. Atypical Urothelial Cells IV. Suspicious for High Grade Urothelial Carcinoma V. High Grade Urothelial Carcinoma VI. Low Grade Urothelial Neoplasm VII. Other malignancies, both primary and secondary VIII.Ancillary Studies IX. Clinical management X. Preparatory techniques relative to Urinary Tract samples Aichi Medical University Hospital

12 NEW paradigm It is all about High Grade Urothelial Carcinoma Negative for High Grade Urothelial Carcinoma AUC SHGUC HGUC Quality and Quantity Quantity LGUN Low Grade Urothelial Neoplasm Aichi Medical University Hospital

13 Adequacy Aichi Medical University Hospital

14 Adequacy Most of cytology systems require minimum cell number. Minimum requirement for voided urine is needed. What is unsatisfactory in voided urine? Which is better urine volume or cell number? Aichi Medical University Hospital

15 Evaluation of adequacy Cancer Cytopathol 2016 ;124: Aichi Medical University Hospital

16 Evaluation of adequacy (Malignant and suspicious cases) Cancer Cytopathol 2016 ;124: Aichi Medical University Hospital

17 Adequacy TPS requires 30ml, at least. Aichi Medical University Hospital

18 Negative for HGUC Negative for High Grade Urothelial Carcinoma This diagnostic category will include cases where low grade urothelial carcinoma can not be excluded If there is a cause for atypia i.e. urolithiasis, treatment related changes etc. it is negative! Aichi Medical University

19 Various conditions: Negative for HGUC Benign urothelial and squamous cells Reactive urothelial cells Polyoma Viral Cytopathic Effect: Decoy cells Benign Urothelial Tissue Fragments (BUTF) Post-therapy effect Changes associated with lithsiasis Aichi Medical University

20 What is your diagnosis?

21 What is your diagnosis?

23 Decoy cells! Aichi Medical University

24 Clinical history Patient: 50 years, Male The patient received chemotherapy for malignant lymphoma. During his chemotherapy, microhematuria was pointed out. A urine cytology test were performed Aichi Medical University

25 Are decoy cells diagnosed correctly? BK virus infection in urinary tract is well-known in immunocompromised patients. Decoy cell is BK virus infected epithelial cell. TPS recommend to diagnose decoy cell as negative, not atypical. However, decoy cells might be diagnosed as HGUC in some case. Aichi Medical University

26 Which are decoy cells? Decoy HGUC Aichi Medical University

27 Are decoy cells diagnosed correctly? Allison DB, et al. Cancer Cytopathol 2016 ;124: Aichi Medical University

28 The Item of Morphological Criteria in TPS N/C ratio Hyperchromasia Plumped chromatin Nuclear membrane contour Size DOESN T matter! Aichi Medical University

29 How to estimate N/C ratio How to estimate? Aichi Medical University

30 N/C ratio =b/a b a b a b a Do you always calculate? a b Aichi Medical University b a

31 Do we estimate correctly? Cancer Cytopathol. 2016;124: Aichi Medical University

32 Cytopathologists and cytothechnologist are aggressive! Cancer Cytopathol. 2016;124: Aichi Medical University

33 The criteria of AUC N/C ratio of Nuclear hyperchromasia, mild - moderate Irregular granular chromatin Irregular nuclear membranes: shapes and thickness Degenerated cells of uncertain atypia Aichi Medical University

34 The criteria of SHGUC N/C ratio of at least 0.7 Marked hyperchromasia Markedly clumped chromatin Deformed nuclear membranes Cells of HGUC but only 5-10 of them Size DOESN T matter! Aichi Medical University

35 The criteria of HGUC N/C ratio at least 0.7 Very hyperchromatic nuclei Grossly clumped chromatin Irregular nuclear contour Eccentric nuclei At least 10 cells Aichi Medical University

36 Hyperchromasia, Clumped chromatin, Deformed nuclear membranes

37 Size DOESN T matter! Aichi Medical University

38 Mitosis and Apoptosis are helpful, BUT do not trust! Cancer Cytopathol. 2016;124: Aichi Medical University

39 Low Grade Urothelial Neoplasm LGUN Eva M. Wojcik, Tatjana Antic, Ashish Chandra, Michael B. Cohen, Zulfia McCroskey, Jae Y. Ro, and Taizo Shiraish LGUN - combined cytologic term for low grade papillary urothelial neoplasms (LGPUN) (which include urothelial papilloma, PUNLMP and LGPUC) and flat, low grade intraurothelial neoplasia Urothelial Papilloma PUNLMP Low Grade UC Fibroblast Growth Factor Receptor 3 (FGFR3)

40 Why we avoid LGUC Almost impossible to diagnose without a mini-biopsy with fibrovascular core Cytologically normal nuclei Is it truly a carcinoma? More common than HGUC BUT, not life threatening Aichi Medical University

41 LGUN

42 LGUN

43 Negative for HGUC, NOT LGUN

44 Summary The aim of TPS is standardization of criteria and reporting. The main focus of TPS is detecting HGUC. Adequacy is important. Pitfall Decoy cell and other causes The presence of fibrovascular core is required to diagnose LGUN. Aichi Medical University

45 Question? Aichi Medical University

Rationale of The Paris System for Reporting Urinary Cytopathology: The NEW paradigm

Rationale of The Paris System for Reporting Urinary Cytopathology: The NEW paradigm Eva M. Wojcik, MD Professor and Chair of Pathology Professor of Urology Loyola University, Chicago, Il Why to standardize